Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/121—Ketones acyclic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/42—Phosphorus; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/35—Ketones, e.g. benzophenone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/39—Derivatives containing from 2 to 10 oxyalkylene groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
  • A61K8/89—Polysiloxanes
  • A61K8/891—Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q3/00—Manicure or pedicure preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

• the present invention relates to a bacterial flora improving agent.
• bacterial flora Various bacteria coexist in the human body [mucous membranes (in the oral cavity, etc.), skin, nails, etc.], forming bacterial populations called bacterial flora.
• This bacterial flora contains a mixture of so-called non-pathogenic resident bacteria and pathogenic bacteria. Normally, the bacterial flora is in a balanced state, which is a so-called healthy state, and diseases caused by pathogenic bacteria are suppressed.
• the objective of the present invention is to create a bacterial flora in the mucous membranes, skin, and/or nails that can maintain a high level of pathogenic bacteria suppression effect and continuously improve the bacterial flora balance while maintaining non-pathogenic resident bacteria.
• the object of the present invention is to provide an agent for improving bacterial flora.
• the present invention provides a compound (X1) having two or more hydroxy groups contained in the oxoacid group and a salt thereof, A compound (X2) having one hydroxy group contained in the oxoacid group and a salt thereof, A heterocyclic compound (X3) having no oxoacid group and a salt thereof, and A substance (X) that is at least one member selected from the group consisting of ketones (X4) that do not have an oxoacid group; A bacterial flora improving agent containing a base (Y) containing a non-volatile component, The oxo acid group that the compound (X1) has, the hydroxy group not included in the oxo acid group, the carbonyl group not included in the oxo acid group, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the imidazole ske
• the proportion of the total mass of nitrogen atoms contained is 45% by mass or more based on the molecular weight of compound (X1),
• the compound (X2) contains an atom having a lone pair of electrons (excluding atoms contained in an oxoacid group, and atoms contained in an amino group that does not constitute an imidazole skeleton and an amino group that does not constitute a pyridine skeleton).
• the proportion of the total mass of nitrogen atoms contained is 55% by 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 ketone (X4) has a linear ⁇ -diketone structure,
• the molecular weight of the substance (X) is 550 or less,
• the HLB value of the nonvolatile component is 7 or more, This is a bacterial flora improving agent for improving the bacterial flora of mucous membranes, skin and/or nails that satisfies the following conditions (i) to (ii).
• the worked penetration of the bacterial flora improving agent measured according to JIS K 2220 is 100 to 400.
• the bacterial flora improving agent has a viscosity of 1 to 4,000 Pa ⁇ s at 37°C as measured with a cone-plate rotational viscometer.
• the bacterial flora of mucous membranes, skin, and/or nails can be improved by exhibiting a high pathogenic bacteria suppressing effect and sustainably improving the bacterial flora balance while maintaining non-pathogenic resident bacteria. It is possible to provide an agent for improving bacterial flora.
• the bacterial flora improving agent of the present invention for improving the bacterial flora of mucous membranes, skin, and/or nails has two hydroxy groups contained in the oxoacid group.
• the bacterial flora improving agent of the present invention exhibits a high effect of suppressing pathogenic bacteria while maintaining non-pathogenic resident bacteria, and has the effect of improving the bacterial flora balance.
• high pathogenic bacteria suppression effect refers to killing harmful bacteria, inactivating harmful bacteria to suppress their growth, and suppressing the production of toxic substances (pathogenic factors) of harmful bacteria. It means at least one of the following.
• pathogenic bacteria refers to bacteria, molds, etc. that are highly pathogenic and cause various infectious diseases by multiplying, and specifically include Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa. , Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, Trichophyton rubrum, Trichophyton mentagrophytes, C Examples include Andida albicans, Candida glabrata, and the like.
• non-pathogenic resident bacteria refers to resident bacteria that inhibit the growth of the above-mentioned pathogenic bacteria and maintain health; specific examples include Staphylococcus epidermidis, Streptococcus salivarius, etc. It will be done.
• Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia are known as pathogenic bacteria that can occur in the oral cavity.
• Trichophyton rubrum, Trichophyton mentagrophytes, Staphylococcus aureus, Candida albicans, and Candida glabrata can occur on the skin and nails.
• a pathogenic bacterium can occur among the above-mentioned non-pathogenic bacteria.
• Streptococcus salivarius is known as a resident bacteria that exists in the oral cavity.
• Staphylococcus epidermidis is known as a resident bacteria that exists on the skin and nails.
• the bacterial flora improving agent of the present invention can selectively inhibit the quorum sensing mechanism (i.e., the mechanism that produces autoinducers) of pathogenic bacteria, while maintaining non-pathogenic resident bacteria. It has a high effect of suppressing pathogenic bacteria.
• the quorum sensing mechanism i.e., the mechanism that produces autoinducers
• the bacterial flora improving agent of the present invention contains substance (X).
• Substance (X) is 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, an oxo acid group and a ketone (X4) that does not have an oxo acid group.
• substance (X) two or more of each of compound (X1), compound (X2), heterocyclic compound (X3), and ketone (X4) may be used. Two or more salts of compound (X1), salts of compound (X2), and salts of compound (X3) may each be used.
• Compound (X1) has two or more hydroxy groups contained in the oxoacid group.
• Compound (X1) may have two or more oxoacid groups.
• the oxoacid group that compound (X1) has, the hydroxyl group not included in the oxoacid group, the carbonyl group (C O) not included in the oxoacid group, the carbon atom included in the imidazole skeleton and the pyridine skeleton, and the imidazole skeleton
• the proportion of the total mass of nitrogen atoms contained in the pyridine skeleton is 45% by mass or more, preferably 55% by mass or more, based on the molecular weight of compound (X1). .
• the bacterial flora improving agent contains a plurality of compounds as compound (X1), each compound satisfies this condition.
• the mass of the oxo acid group is the total mass of the central atom, the oxo group, and the hydroxy group.
• malic acid with a molecular weight of 134.1
• 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 oxoacid groups, so it is based on the molecular weight of malic acid.
• Compound (X1) has an oxo acid group as an essential group, but a hydroxy group not included in the oxo acid group, a carbonyl group not included in the oxo acid group, an imidazole skeleton, and a pyridine skeleton are not essential but optional. has.
• imidazole skeleton means (R is a hydrogen atom or a group capable of bonding to imidazole).
• pyridine skeleton is means the structure represented by These structures may be included in a fused ring.
• the ratio of the total mass of the oxo acid group, the hydroxy group not included in the oxo acid group, and the carbonyl group not included in the oxo acid group that the compound (X1) has is determined from the viewpoint of further improving the effect of the bacterial flora improving agent. Therefore, it is preferably 45% by mass or more based on the molecular weight of compound (X1).
• Examples of the compound (X1) include 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. .
• tungstic acid is considered to be a compound having two hydroxy groups contained in an oxoacid group, as shown in the following chemical formula (1), and is included in compound (X1).
• Compound (X1) preferably does not have a "--NH 2 " group from the viewpoint of the effect of the bacterial flora improving agent.
• compound (X1) is a hydroxycarboxylic acid
• the ratio between the number of moles of hydroxy groups and the number of moles of carboxy group (-COOH) possessed by the hydroxycarboxylic acid is: From the viewpoint of the effect of the bacterial flora improving agent, it is preferably 1/3 or more, and more preferably 1/2 or more.
• the salt of compound (X1) is not particularly limited, and includes, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate; acetate, citrate, maleate, malate, and oxalate.
• Organic acid salts such as salts, lactates, succinates, fumarates, propionates; Alkali metal salts such as sodium salts and potassium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; Ammonium salts; Triethylamine Salts with organic bases such as , triethanolamine, and pyridine; amino acid salts with basic amino acids or acidic amino acids such as arginine and glutamic acid, and the like. Among these, sodium salts and potassium salts are preferred.
• Compound (X2) has an atom having a lone pair of electrons (excluding atoms contained in an oxoacid group, and atoms contained in an amino group that does not constitute an imidazole skeleton and an amino group that does not constitute a pyridine skeleton).
• Preferred atoms having lone pairs include oxygen atoms contained in carbonyl groups, oxygen atoms contained in hydroxy groups (excluding oxygen atoms contained in oxoacid groups), and nitrogen atoms contained in imidazole skeletons. , a nitrogen atom contained in a pyridine skeleton, and the like.
• the oxo acid group of compound (X2), the hydroxy group not included in the oxo acid group, the carbonyl group not included in the oxo acid group, the carbon atoms contained in the imidazole skeleton and pyridine skeleton, and the imidazole skeleton and pyridine skeleton The proportion of the total mass of nitrogen atoms contained in is 55% by mass or more based on the molecular weight of compound (X2) from the viewpoint of the effect of the bacterial flora improving agent.
• the bacterial flora improving agent contains a plurality of compounds as compound (X2), each compound satisfies this condition.
• the compound (X2) has an oxo acid group as an essential group, and optionally has a hydroxy group not included in the oxo acid group, a carbonyl group not included in the oxo acid group, an imidazole skeleton, and a pyridine skeleton.
• Examples of the compound (X2) include a compound (X21) that does not have an amino group and a compound (X22) that has an amino group.
• Examples of the compound (X21) without an amino group include hydroxycarboxylic acids (gluconic acid, glucuronic acid, etc.), keto acids (levulinic acid, etc.), and the like.
• Examples of the compound (X22) having an amino group include glycylglycine, histidine, and the like.
• Examples of the salt of compound (X2) include the same salts as those explained as the salt of compound (X1), and preferred ones are also the same.
• 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.
• heterocyclic compound (X3) examples include 8-quinolinol (a compound having one pyridine skeleton and a hydroxy group), phenanthroline (a compound having two pyridine skeletons), and the like.
• the proportion of the total mass 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 that the heterocyclic compound (X3) has is the proportion of the total mass of the bacterial flora improving agent. From the viewpoint of effectiveness, it is preferably 50% by mass or more based on the molecular weight of the heterocyclic compound (X3).
• the bacterial flora improving agent contains a plurality of compounds as the heterocyclic compound (X3), each compound preferably satisfies this condition.
• Examples of the salt of the heterocyclic compound (X3) include the same salts as those explained as the salt of the compound (X1).
• the ketone (X4) has a linear ⁇ -diketone structure.
• the ketone (X4) may be a salt having a counter ion.
• Examples of the ketone (X4) include benzoylacetone and acetylacetone.
• the proportion of the total mass of the carbonyl groups that the ketone (X4) has is determined by the molecular weight of the ketone (X4) [However, if the ketone (X4) is a salt having a counter ion, It is preferably 30% by mass or more based on the mass of only ions having a linear ⁇ -diketone structure excluding counter ions.
• the bacterial flora improving agent contains a plurality of compounds as ketones (X4), each compound preferably satisfies this condition.
• 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, Polyphosphoric acid (the number of repeating phosphoric acid units is preferably 2 to 5, more preferably 3 to 5) and salts thereof are more preferred, and pentasodium triphosphate is particularly preferred.
• the molecular weight of substance (X) is 550 or less from the viewpoint of the effect of the bacterial flora improving agent.
• the bacterial flora improving agent contains a plurality of compounds as the substance (X)
• the molecular weight of each molecule is 550 or less.
• the amount of magnesium captured per 100 g of substance (X) is 1 g or more when measured by an ion electrode method.
• substance (X) when substance (X) is a hydrate, it means per 100g of weight excluding hydration water.
• the above measurement by the ion electrode method is carried out using 2mM of substance (X) in a 1mM MgCl 2 aqueous solution at 20°C and pH 7.
• the bacterial flora improving agent of the present invention contains not only the above-mentioned substance (X) but also a base (Y) containing nonvolatile components. Note that the substance (X) does not correspond to the components contained in the base (Y).
• the HLB value of the nonvolatile component in the base (Y) is 7 or more. When the HLB value of the nonvolatile component is less than 7, the spreadability of the bacterial flora improving agent when applied to the affected area deteriorates.
• the HLB value of the nonvolatile component is preferably 7 to 60 from the viewpoint of spreadability. Components contained in the bacterial flora improving agent and having an HLB value of 7 or more are considered to be nonvolatile components in the base (Y).
• the HLB value is an index that indicates the balance between hydrophilicity and lipophilicity, and is calculated using the Oda method described in, for example, "Introduction to Surfactants” [published by Sanyo Chemical Industries, Ltd., 2007, written by Takehiko Fujimoto], page 212. This is a known value and is not a calculated value using Griffin's method.
• the HLB value of a compound that is a nonvolatile component can be calculated according to the following formula based on the ratio of the organic value and inorganic value of the compound.
• HLB 10 x inorganic value / organic value
• the organic value is set as 20 per carbon atom
• the inorganic value is determined as the above-mentioned "surfactant”.
• non-volatile component in the present invention is the residue after heating and drying the sample in a glass Petri dish without a lid in a circulating air dryer at 130° C. for 45 minutes.
• the content (weight ratio) of non-volatile components is preferably 0.1 to 80% by weight, based on the weight of the bacterial flora improving agent, and 1 to 70% by weight. It is more preferable that there be.
• the content (weight ratio) of non-volatile components is preferably 30 to 6,000% by weight, based on the weight of substance (X), and 50 to 5,000% by weight. 000% by weight is more preferable.
• the nonvolatile component in the base (Y) is preferably a polymer having a weight average molecular weight of 10,000 to 3,000,000. Further, as a compound contained in a polymer having a weight average molecular weight of 10,000 to 3,000,000, it is preferable that the molecular weight is 500 or more. Polymers contained in the bacterial flora improving agent that have a weight average molecular weight of 10,000 to 3,000,000 and an HLB value of 7 or more are considered to be nonvolatile components in the base (Y). Note that the weight average molecular weight in this specification can be measured using gel permeation chromatography (GPC) under the following conditions.
• GPC gel permeation chromatography
• Monomers in the above polymer include monosaccharides [ ⁇ -glucose, ⁇ -glucose, uronic acids (mannuronic acid, guluronic acid, etc.), etc.], (meth)acrylic monomers [(meth)acrylic monomers having 3 to 10 carbon atoms. acrylic acid, etc.], (alkyl)alkoxysilane [dialkyldialkoxysilane having 4 to 40 carbon atoms. For example, diethoxydimethylsilane, dimethoxydimethylsilane, etc.], alkylene oxide [alkylene oxide having 2 to 4 carbon atoms]. ethylene oxide, propylene oxide, butylene oxide, etc.].
• (meth)acrylic means acrylic and/or methacryl.
• (alkyl)alkoxysilane means alkoxysilane and/or alkylalkoxysilane.
• the above polymers include carboxyalkylcellulose and its salts (carboxymethylethylcellulose, sodium carboxymethylcellulose, etc.), alkylcellulose and its salts (methylcellulose 4000, etc.), sodium alginate, xanthan gum, starch/sodium acrylate graft copolymer. Examples include coalescence, polyalkylene glycol (polyethylene glycol such as PEG20000, etc.), polydimethylsiloxane (A), alkylene oxide adduct of aliphatic alcohol (B), and the like.
• one type of the above polymers may be used alone, or two or more types may be used in combination.
• polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) may be used in combination.
• the weighted average value of HLB values of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) [weight ratio of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) [weighted average value based on] is 7 or more.
• the base (Y) may contain only nonvolatile components, or may contain volatile components in addition to nonvolatile components.
• the base (Y) contains polydimethylsiloxane (A) which is a non-volatile component, an alkylene oxide adduct (B) of an aliphatic alcohol, and water (an additive to be described later) which is a volatile component.
• A polydimethylsiloxane
• B alkylene oxide adduct
• water an additive to be described later
• Polydimethylsiloxane (A) includes those having a structure in which the dimethylsiloxane unit ⁇ -(CH 3 ) 2 SiO- ⁇ is a repeating unit, and specifically, it is represented by the following general formula (1) Examples include things. CH 3 -[(CH 3 ) 2 SiO] n -Si-(CH 3 ) 3 (1) In the general formula (1), n is the number average number of dimethylsiloxane units, represents a number from 60 to 500, and is not necessarily an integer.
• n is preferably a number from 100 to 450, more preferably from 150 to 400, from the viewpoint of spreadability.
• polydimethylsiloxane (A) polydimethylsiloxane represented by the above general formula (1) is preferable from the viewpoint of sustainability of the effect of the bacterial flora improving agent.
• the alkylene oxide adduct (B) of aliphatic alcohol is preferably one represented by the following general formula (2) from the viewpoint of spreadability.
• R 1 is an alkyl group having 8 to 18 carbon atoms or an alkenyl group having 8 to 18 carbon atoms
• OA is an oxyalkylene group having 2 to 4 carbon atoms
• m is the number average added mole of the oxyalkylene group. It represents a number, from 1 to 50, and is not necessarily an integer.
• 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 straight chain alkyl group having 8 to 18 carbon atoms and a branched alkyl group having 8 to 18 carbon atoms.
• straight chain alkyl groups having 8 to 18 carbon atoms examples include n-octyl group, n-decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n- Examples include hexadecyl group, n-heptadecyl group and n-octadecyl group.
• Examples of branched alkyl groups having 8 to 18 carbon atoms include 2-ethylhexyl group, isodecyl group, isoundecyl group, isododecyl group, isotridecyl group, isotetradecyl group, isopentadecyl group, isohexadecyl group, isoheptadecyl group, and isooctadecyl group. etc.
• the alkenyl group having 8 to 18 carbon atoms includes a straight chain alkenyl group having 8 to 18 carbon atoms and a branched alkenyl group having 8 to 18 carbon atoms.
• Examples of the straight chain alkenyl group having 8 to 18 carbon atoms include n-octenyl group, n-dodecenyl group, n-hexadecenyl group and n-octadecenyl group.
• Examples of the branched alkenyl group having 8 to 18 carbon atoms include isodecenyl group, isododecenyl group and isooctadecenyl group.
• R 1 is preferably a straight-chain alkyl group having 8 to 18 carbon atoms, more preferably a straight-chain alkyl group having 10 to 18 carbon atoms.
• examples of OA include oxyethylene group, oxypropylene group, and oxybutylene group.
• OA an oxyethylene group is preferable from the viewpoint of spreadability.
• m is preferably a number from 3 to 40 from the viewpoint of spreadability.
• the HLB value is preferably 8.5 to 11.0, more preferably 9.0 to 10.5, from the viewpoint of spreadability.
• the weight ratio ⁇ (A)/(B) ⁇ of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) is 85/15 to 40 from the viewpoint of spreadability and duration of effect. /60 is preferred, and more preferably 80/20 to 35/65.
• the total content of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) is 0.1 to 85% by weight based on the weight of the bacterial flora improving agent, from the viewpoint of sustainability of the effect. It is preferably 1 to 85% by weight, more preferably 5 to 85% by weight, particularly preferably 40 to 85% by weight, and most preferably 50 to 80% by weight.
• the total content of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) should be determined based on the substance (X) and the nonvolatile components in the base (Y), from the viewpoint of sustainability of the effect. Based on the total weight, it is preferably from 30 to 99% by weight, more preferably from 50 to 99%, particularly preferably from 80 to 99% and most preferably from 90 to 99%.
• the bacterial flora improving agent contains only four components: substance (X), polydimethylsiloxane (A), alkylene oxide adduct of aliphatic alcohol (B), and water, and is based on three components other than substance (X).
• substance (X) polydimethylsiloxane
• alkylene oxide adduct of aliphatic alcohol (B) is determined based on the weight of the base (Y) from the viewpoint of sustainability of the effect. , preferably 1 to 85% by weight, more preferably 5 to 85% by weight, particularly preferably 40 to 85% by weight, most preferably 50 to 80% by weight.
• a method for producing a base (Y) containing polydimethylsiloxane (A), an alkylene oxide adduct of an aliphatic alcohol (B), and water for example, an alkylene oxide adduct of polydimethylsiloxane (A) and an aliphatic alcohol.
• examples include those including the step (I) of mixing (B) and water.
• the polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B) are preferably mixed in advance, and the polydimethylsiloxane (A) and the alkylene oxide adduct of an aliphatic alcohol (B) are mixed together.
• the temperature during mixing is preferably 20°C to 70°C, more preferably 25°C to 65°C, from the viewpoint of emulsifying properties.
• step (I) the weight ratio ⁇ (A)/(B) ⁇ of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) is determined from the viewpoint of spreadability and sustainability of effect. , 85/15 to 40/60, more preferably 80/20 to 35/65.
• the temperature of the water is preferably 20°C to 70°C, more preferably 25 to 65°C, from the viewpoint of emulsifying properties.
• the amount of water is 15 to 99% by weight based on the total weight of polydimethylsiloxane (A), alkylene oxide adduct of aliphatic alcohol (B), and water, from the viewpoint of sustainability of the effect. %, more preferably 20 to 99% by weight.
• step (I) from the viewpoint of gelation, it is preferable to stir with a planetary mixer.
• the rotational speed of the planetary mixer is preferably 10 to 70 rpm for rotation and 5 to 40 rpm for revolution, more preferably 15 to 60 rpm for rotation and 10 to 35 rpm for revolution.
• stirring blades include screw blades, gate-type stirring blades, and the like, and gate-type stirring blades are preferred from the viewpoint of uniformity.
• step (I) when mixing the mixture of polydimethylsiloxane (A) and alkylene oxide adduct of aliphatic alcohol (B) with water, the water is divided into 5 to 50 parts from the viewpoint of gelation. It is preferable to add in 10 to 40 parts, and more preferably in 10 to 40 parts.
• step (I) when mixing water in step (I), from the viewpoint of gelation, there is a method in which one portion of water is added, and after confirming that the appearance is sufficiently uniform, the next portion of water is added. is preferred.
• the bacterial flora improving agent of the present invention When the bacterial flora improving agent of the present invention is used to improve the oral bacterial flora balance, it contains the following (Y-A) and/or (Y-B) as non-volatile components from the viewpoint of sustainability of the effect. It is preferable, and it is more preferable to use (YA) and (YB) together.
• Y-A A polymer (sodium carboxymethyl cellulose, xanthan gum, sodium alginate, etc.) having an anionic group (carboxy group, carboxylate group, etc.) and a weight average molecular weight of 50,000 to 3,000,000 (preferably 100,000 to 3,000,000). 000 to 2,000,000), and may be a mixture of two or more types of polymers.
• ⁇ (Y-B)> (YB) is a component obtained by removing the above (YA) from components having an HLB value of 7 or more, and satisfies the following conditions (1) and/or (2).
• Viscosity of a solution diluted with water so that the concentration of (Y-B) is 1% by weight (same method as the viscosity at 37°C measured with a cone-plate rotational viscometer for bacterial flora improvers described below) ) is 1 mPa ⁇ s or more and less than 500 mPa ⁇ s (preferably 5 mPa ⁇ s or more and 450 mPa ⁇ s or less).
• 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.
• the ratio of the weight of (YA) and the weight of (YB) [(YA)/(YB)] is 0. It is preferably from 0.001 to 0.2, more preferably from 0.001 to 0.1.
• the bacterial flora improving agent of the present invention may contain components (additives) other than the above-mentioned substance (X) and nonvolatile components.
• the additive may be added separately from the base (Y) or may be included in the base (Y) as appropriate.
• additives examples include lubricants such as wax, antioxidants, ultraviolet absorbers, antifoaming agents, preservatives, fragrances, solvents [water and organic solvents (ethanol, etc.), etc.].
• the total weight of the bactericidal components should be 2% by weight or less based on the total weight of substance (X) from the viewpoint of the effect of the bacterial flora improving agent. preferable.
• the above-mentioned bactericidal ingredients are glycyrrhizic acid (salt), ⁇ -glycyrrhetinic acid, isopropylmethylphenol, cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, alkyldiaminoethylglycine chloride solution, chlorhexidine hydrochloride, chlorhexidine hydrochloride, triclosan, chloride One or more types selected from the group consisting of lysozyme, hinokitiol, lauroylsarcocinsodium, and sodium lauryl sulfate.
• the content of the above-mentioned solvent in the bacterial flora improving agent is not particularly limited as long as it can be within the range of the viscosity and worked penetration of the bacterial flora improving agent described below.
• the content is preferably 5 to 99% by weight.
• the water content in the bacterial flora improving agent is preferably 5 to 99% by weight based on the total weight of the bacterial flora improving agent, from the viewpoint of spreading properties and improving bacterial flora balance. More preferably, it is 30 to 99% by weight.
• the bacterial flora improving agent contains water, after producing the bacterial flora improving agent using the method described below, the appearance after standing at 25°C for 10 minutes is visually uniform (not separated into two or more phases). It is preferable that the
• the upper limit of the content of additives other than the above solvent in the bacterial flora improving agent is preferably 10% by weight or less, and 8% by weight or less, based on the weight of the nonvolatile components in the bacterial flora improving agent. It is more preferable that the amount is 1% by weight or less, and particularly preferably 1% by weight or less.
• the lower limit of the content of additives other than the above solvent in the bacterial flora improving agent is not particularly limited, but may be 0.1% by weight or more based on the weight of the nonvolatile components in the bacterial flora improving agent. It will be done.
• the content (weight ratio) of substance (X) is preferably 0.01 to 5% by weight, more preferably 0.05 to 3% by weight, based on the weight of the bacterial flora improving agent.
• the lower limit of the content (weight ratio) of substance (X) is 0.01% by weight based on the weight of the bacterial flora improving agent of the present invention, from the viewpoint of suitably imparting a high pathogenic bacteria suppressing effect. is preferable, and it is more preferable that the lower limit is 0.05% by weight.
• the upper limit of the content of substance (X) is preferably 5% by weight based on the weight of the bacterial flora improving agent of the present invention, More preferably, the upper limit is 3% by weight.
• the weight ratio of the hydroxycarboxylic acid that is the compound (X2) depends on the effect of the bacterial flora improving agent. From this point of view, it is preferably 1% by weight or more based on the weight of the bacterial flora improving agent.
• the lower limit of the content of substance (X) is preferably 1% by weight, more preferably 2% by weight, based on the weight of the nonvolatile components in the bacterial flora improving agent.
• the upper limit of the content of substance (X) is preferably 200% by weight, more preferably 150% by weight, based on the weight of the nonvolatile components in the bacterial flora improving agent.
• the content of substance (X) is preferably 1 to 200% by weight, more preferably 2 to 150% by weight, based on the weight of the nonvolatile components in the bacterial flora improving agent.
• the ratio of the total weight of zinc atoms and magnesium atoms is preferably 0.5% by weight or less based on the total weight of substance (X) from the viewpoint of the effect of the bacterial flora improving agent.
• the bacterial flora improving agent of the present invention contains zinc atoms and/or magnesium atoms (including cases where it contains compounds containing these atoms)
• the proportion of the total weight of zinc atoms and magnesium atoms is From the viewpoint of the effect of the bacterial flora improving agent, it is preferably 0.005% by weight or less based on the weight of the bacterial flora improving agent.
• the worked penetration of the bacterial flora improving agent of the present invention measured according to JIS K 2220 is 100 to 400. If it is less than 100, the effect of suppressing pathogenic bacteria will deteriorate. When the number exceeds 400, it becomes difficult to maintain non-pathogenic resident bacteria.
• the worked penetration of the bacterial flora improving agent of the present invention measured according to JIS K 2220 is preferably 100 to 300 from the viewpoint of sustainability of the effect.
• the viscosity of the bacterial flora improving agent of the present invention at 37°C measured with a cone-plate rotational viscometer is 1 to 4,000 Pa ⁇ s. Specifically, it is a viscosity measured by the following measurement method.
• the above-mentioned viscosity of the bacterial flora improving agent is preferably 10 to 4,000 Pa ⁇ s, more preferably 1,000 to 4,000 Pa ⁇ s from the viewpoint of sustainability of the effect. Further, the above-mentioned viscosity of the bacterial flora improving agent is preferably 2,000 to 3,700 Pa ⁇ s from the viewpoint of spreadability.
• the pH of a solution diluted with water (ion-exchanged water, etc.) so that the concentration of the bacterial flora improving agent of the present invention is 1% by weight is preferably 6 to 8 from the viewpoint of improving bacterial flora balance. pH can be measured using a pH meter at 25°C.
• the bacterial flora improving agent of the present invention can be produced by blending each component and uniformly mixing the mixture at room temperature or, if necessary, by heating (for example, 30 to 70°C).
• the order and method of blending each component are not particularly limited.
• the bacterial flora improving agent of the present invention is a bacterial flora improving agent for improving the bacterial flora of mucous membranes, skin, and/or nails, and can be used to improve bacterial flora in affected areas [mucous membranes ⁇ oral cavity (tongue, gums, gums, etc.), intestines, eyes, etc.] , skin, nails (nail plates, etc.)] or around the affected area with a finger or the like, and the bacterial flora improving agent can be used by leaving it in the affected area, and it is particularly preferable to apply it to mucous membranes.
• the bacterial flora improving agent of the present invention when applied to the mucous membranes of the oral cavity (tongue, gums, gums, etc.), it can be expected to be effective in preventing periodontal disease that progresses through the stages of gingivitis and periodontitis.
• the bacterial flora improving agent of the present invention can be used as pharmaceuticals, medical devices (medical adhesives, wound healing materials, etc.), quasi-drugs, cosmetics, foods, etc. by using non-volatile ingredients according to the purpose. In both of the above applications, it is possible to improve the bacterial flora balance at the application site.
• Specific examples of the above-mentioned uses include toothpastes, oral gels, oral care foods, supplements, pet care products, and nail care products.
• the present disclosure (1) provides a compound (X1) having two or more hydroxy groups contained in an oxoacid group and a salt thereof, A compound (X2) having one hydroxy group contained in the oxoacid group and a salt thereof, A heterocyclic compound (X3) having no oxoacid group and a salt thereof, and A substance (X) that is at least one member selected from the group consisting of ketones (X4) that do not have an oxoacid group; A bacterial flora improving agent containing a base (Y) containing a non-volatile component, The oxo acid group that the compound (X1) has, the hydroxy group not included in the oxo acid group, the carbonyl group not included in the oxo acid group, the carbon atoms contained in the imidazole skeleton and the pyridine skeleton, and the imidazole skeleton and the pyridine skeleton.
• the proportion of the total mass of nitrogen atoms contained is 45% by mass or more based on the molecular weight of compound (X1),
• the compound (X2) contains an atom having a lone pair of electrons (excluding atoms contained in an oxoacid group, and atoms contained in an amino group that does not constitute an imidazole skeleton and an amino group that does not constitute a pyridine skeleton).
• the proportion of the total mass of nitrogen atoms contained is 55% by 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 ketone (X4) has a linear ⁇ -diketone structure,
• the molecular weight of the substance (X) is 550 or less,
• the HLB value of the nonvolatile component is 7 or more, This is a bacterial flora improving agent for improving the bacterial flora of mucous membranes, skin and/or nails that satisfies the following conditions (i) to (ii).
• the worked penetration of the bacterial flora improving agent measured according to JIS K 2220 is 100 to 400.
• the bacterial flora improving agent has a viscosity of 1 to 4,000 Pa ⁇ s at 37°C as measured with a cone-plate rotational viscometer.
• the present disclosure (2) is the bacterial flora improving agent according to the present disclosure (1), wherein the pH of a solution diluted with water so that the concentration of the bacterial flora improving agent is 1% by weight is 6 to 8.
• the present disclosure (3) provides the bacterial flora according to the present disclosure (1) or (2), wherein the weight ratio of the substance (X) is 0.01 to 5% by weight based on the weight of the bacterial flora improving agent. It is an improving agent.
• Examples 1 to 44 and Comparative Examples 1 to 16 Production of bacterial flora improving agent> Substance (X) [or (X')], base (Y) [or (Y')], and ion-exchanged water so that the concentrations (wt%) listed in Tables 1-1 to 1-6 are obtained. were mixed at 25°C. In addition, the viscosity and worked penetration of each bacterial flora improving agent were measured by the method described in the specification, and the results are listed in Tables 1-1 to 1-6. In addition, the pH of the solution diluted with ion-exchanged water so that the concentration of each bacterial flora improving agent was 1% by weight is also listed in Tables 1-1 to 1-6.
• the worked penetration of the bacterial flora improving agent of Comparative Example 14 was over 400 and could not be measured.
• the viscosity of the solution diluted with ion-exchanged water was measured by the method described in the specification so that the concentration of the nonvolatile component in each base (Y) was 1% by weight, and the HLB value of the nonvolatile component was measured by the method described in the specification. and weight average molecular weight are listed in Table 2.
• the amount (g) of magnesium captured per 100 g of substance (X) was measured by the following method when measured by the ion electrode method.
• Regarding (X-5) the amount of magnesium captured per 100 g of Na 2 WO 4 contained in (X-5) was measured.
• the above measurement by the ion electrode method was carried out using 2 mM of substance (X) in a 1 mM MgCl 2 aqueous solution at 20° C. and pH 7. The results are listed in Table 3.
• the test includes Porphyromonas Gingivalis, FUSOBACTERIUUM NUCLEATUM, PREVOTELLA INTERMEDIA, TRICHOPHYTON RUBRUM, TRICHOPHYTON MEN Tagrophytes, Staphylococcus aureus, Candida Albicans, Candida Glabrata, non -disease bacteria, STREPTOCOCCUS SALIVARIUS, STAPHYLOCUCUS E I used PiderMidis.
• modified GAM broth "Nissui” manufactured by Nissui Pharmaceutical Co., Ltd.
• menadione containing 1 ⁇ g/mL menadione was used for Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, and Strep.
• the cells were statically cultured at 37° C. under anaerobic conditions using Aneropack Kenki 10% (manufactured by Mitsubishi Gas Chemical Co., Ltd.). In addition, each strain cultured with shaking overnight at 37°C under aerobic conditions using the above medium was diluted with each culture medium so that the absorbance at 600 nm was 0.2, and bacterial flora was improved. After dispensing 500 ⁇ L of each into a 24-well plate containing the agent, the cells were cultured stationary at 37°C. The plates were collected after 48 hours, and the growth potential of each bacteria was evaluated by measuring the absorbance at 600 nm. The growth inhibitory effect was expressed as a relative value based on the turbidity of 1 when the same weight of ion-exchanged water was used instead of each bacterial flora improving agent. The results are shown in Tables 1-1 to 1-6.
• the bacterial flora improving agent of the present invention When the bacterial flora improving agent of the present invention is applied to the oral cavity, the growth of Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia is suppressed compared to when the bacterial flora improving agent is not added, and Streptococcus s multiplication of alivarius If there is no change in the properties compared to when no bacterial flora improving agent is added, it means that the growth of bacteria is selectively suppressed.
• the above-mentioned relative value may be in the following range.
• test results for Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia are 0.01 to 0.30 (preferably 0.01 to 0.15), and Streptococcus saliv
• the test result on Arius is 0.8 to 1.2 A mode of being.
• the bacterial flora improving agent of the present invention when the bacterial flora improving agent of the present invention is applied to the skin and nail plate, Trichophyton rubrum, Trichophyton mentagrophytes, Staphylococcus aureus, Candida albicans, Candida glabrata Growth rate compared to when no bacterial flora improving agent was added. If the growth of Staphylococcus epidermidis is suppressed and there is no change in the growth of Staphylococcus epidermidis compared to when the bacterial flora improving agent is not added, it means that the growth of Staphylococcus epidermidis is selectively suppressed.
• the above-mentioned relative value may be in the following range.
• test results for Trichophyton rubrum, Trichophyton mentagrophytes, and Staphylococcus aureus are 0.01 to 0.30 (preferably 0.01 to 0.15), and Staphylococcus epide Rmidis test result is 0.8 to 1.2 A mode of being.
• Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella intermedia were used as pathogenic bacteria in the test.
• modified GAM broth "Nissui” manufactured by Nissui Pharmaceutical Co., Ltd.
• menadione was used for Porphyromonas gingivalis
• modified GAM broth was used for Fusobacterium nucleatum and Prevotella intermedia.
• Bouillon "Nissui”"It was used.
• each bacterial flora improving agent prepared with the compositions listed in Tables 1-1 to 1-6 was dispensed onto each well of a 24-well plate.
• Each strain was cultured overnight at 37°C under anaerobic conditions using the above medium and diluted with each culture medium so that the absorbance at 600 nm was 0.2.
• the cells were statically cultured at 37° C. under anaerobic conditions using Aneropack Kenki 10% (manufactured by Mitsubishi Gas Chemical Co., Ltd.). After 48 hours, the plates were collected, and each culture supernatant was collected by centrifugation at 4°C and 10,000 rpm for 5 minutes.
• protease activity contained in the culture supernatant was evaluated using the Amplite protease activity measurement kit (manufactured by AAT Bioquest).
• protease production was shown as a relative value when the protease activity value when the same weight of ion-exchanged water was used instead of each bacterial flora improving agent was set to 1.
• Tables 1-1 to 1-6 The results are shown in Tables 1-1 to 1-6.
• protease is known to be one of the toxin components produced by pathogenic bacteria, and the lower the protease activity value, the more suppressed protease production is.
• the test includes Porphyromonas Gingivalis, FUSOBACTERIUUM NUCLEATUM, PREVOTELLA INTERMEDIA, TRICHOPHYTON RUBRUM, TRICHOPHYTON MEN Tagrophytes, Staphylococcus aureus, Candida Albicans, Candida Glabrata, non -disease bacteria, STREPTOCOCCUS SALIVARIUS, STAPHYLOCUCUS E I used PiderMidis.
• modified GAM broth "Nissui” manufactured by Nissui Pharmaceutical Co., Ltd.
• menadione containing 1 ⁇ g/mL menadione was used for Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia, and Strep.
• the halo was determined by measuring the length from the end of the test sample application area to the end of the halo, and if it was larger than 0 mm, it was determined that a halo was confirmed, and if it was 0 mm, it was determined that no halo was confirmed. .
• a halo it means that there is a growth-inhibiting effect, and if no halo is observed, it means that there is no growth-inhibiting effect.
• ⁇ A halo was observed in the evaluations after 24 hours and 1 week of culture, but no halo was observed in the evaluation after 2 weeks. Not confirmed (disappeared)
• ⁇ A halo was confirmed in the evaluation after 24 hours of culture, but the halo had disappeared in the evaluation after 1 week
• No halo was observed in the evaluation after 24 hours of culture
• ⁇ No halo was observed after 24 hours of culture, 1 week, and 2 weeks.
• ⁇ Halo was observed after 24 hours of culture, but no halo was observed after 1 week and 2 weeks.
• the growth of non-pathogenic bacteria was not suppressed, and the ideal bacterial flora balance was achieved, confirming the effect of improving bacterial flora.
• Comparative Examples 15 and 16 which used general antibacterial agents benzalkonium chloride or cetylpyridinium chloride
• not only pathogenic bacteria but also non-pathogenic bacteria were inhibited from growing.
• the growth of non-pathogenic bacteria could be maintained, suggesting that the inhibitory effect was selectively exerted on pathogenic bacteria.
• Examples 1 to 44 it was confirmed that they had the effect of suppressing toxin (protease) production by pathogenic bacteria. Furthermore, in comparison with Comparative Examples 11 to 12 and 14, which also showed the effect of inhibiting protease production, the long-term sustainability of the bacterial flora improvement effect was confirmed. Therefore, it can be seen that the bacterial flora improving agent of the present invention has the effect of selectively suppressing the proliferation and toxin production of pathogenic bacteria without affecting non-pathogenic bacteria, and can maintain this effect for a long period of time.
• the bacterial flora improving agent of the present invention is applied to the affected area, the effect of improving bacterial flora balance can be exerted for a long period of time, and therefore it is found to be particularly useful as a bacterial flora improving agent.

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