WO2019044773A1 - Functional skin preparation for external use, antimicrobial agent and method for producing aromatic polyhydroxycarboxylic acid or derivative thereof - Google Patents

Functional skin preparation for external use, antimicrobial agent and method for producing aromatic polyhydroxycarboxylic acid or derivative thereof Download PDF

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Publication number
WO2019044773A1
WO2019044773A1 PCT/JP2018/031594 JP2018031594W WO2019044773A1 WO 2019044773 A1 WO2019044773 A1 WO 2019044773A1 JP 2018031594 W JP2018031594 W JP 2018031594W WO 2019044773 A1 WO2019044773 A1 WO 2019044773A1
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Prior art keywords
acid
derivative
carboxylic acid
derived
functional
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PCT/JP2018/031594
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French (fr)
Japanese (ja)
Inventor
中島　健一郎
藤原　大輔
賢也 橘
啓行 宮内
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住友ベークライト株式会社
公益財団法人地球環境産業技術研究機構
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Publication of WO2019044773A1 publication Critical patent/WO2019044773A1/en

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    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9706—Algae
    • 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
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9728—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/42—Hydroxy-carboxylic acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a functional external skin preparation and an antibacterial agent, and a method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof.
  • Patent Document 1 describes that aromatic hydroxycarboxylic acids are important as raw materials or intermediates for cosmetics and pharmaceuticals.
  • carbocyclic compounds other than an aromatic compound are also used as one of the components of a skin external preparation.
  • Patent Document 2 describes that shikimic acid is an active ingredient of a melanin formation inhibitor, a whitening agent, and a skin external preparation.
  • aromatic compounds are also used as one of the components of various antibacterial agents.
  • Antibacterial agents are used, for example, in the field of external preparations for skin, food and the like to prevent contamination of products with microorganisms and to obtain storage stability of the products.
  • cosmetics, pharmaceuticals and the like it is also used to prevent and ameliorate skin diseases caused by microorganisms.
  • p-hydroxybenzoic acid esters which are derivatives of aromatic hydroxycarboxylic acids, are widely used for the purpose of imparting antimicrobial properties to compositions such as pharmaceuticals, cosmetics, and foods.
  • aromatic compounds as described above are usually obtained from petroleum.
  • petroleum-derived aromatic compounds (chemicals) that can be recovered by fractional purification of petroleum are so-called basic compounds having a simple chemical structure.
  • high value-added compounds having a more complicated chemical structure can not but be derived from this basic compound through a synthesis process.
  • various isomers derived from raw materials and synthesis processes, trace components derived from catalysts, ionic components, mineral components, etc. become chemicals derived from petroleum unless the petroleum is highly fractionated and refined by neglecting the production cost. May survive.
  • These impurities contained in petroleum-derived chemicals are not preferable from the viewpoint of human safety.
  • An object of the present invention is to provide a safer functional external skin preparation and an antimicrobial agent which contains at least one of polyhydroxy aromatic carboxylic acid and its derivative as an active ingredient and does not contain petroleum-derived impurities.
  • Another object of the present invention is to provide a method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof which can be used as an active ingredient of a functional external skin preparation or an antibacterial agent.
  • a functional external skin preparation comprising, as an active ingredient, at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof.
  • X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
  • X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH.
  • R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group.
  • the polyhydroxy aromatic carboxylic acid and its derivative are 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2
  • the function according to the above (2) which is at least one selected from the group consisting of 3,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid Skin external preparation.
  • the polyhydroxyaromatic carboxylic acid and its derivative are 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid, And the functional skin external preparation as described in the above (3), which is at least one selected from the group consisting of 3- (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid.
  • the microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, coryneform bacteria, actinomycetes, cyanobacteria, methanogens, halophilic bacteria, thermophilic acid-acid bacteria, heat-resistant acid-acid bacteria, acid-fast bacteria, molds And the functional skin external preparation as described in said (1) which is yeast or those transformants.
  • An antimicrobial agent comprising, as an active ingredient, at least one of a plant-derived saccharide and a polyhydroxyaromatic carboxylic acid derived from a microorganism and a derivative thereof.
  • X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
  • X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH.
  • R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group.
  • the polyhydroxy aromatic carboxylic acids and derivatives thereof are 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2
  • the antimicrobial agent according to the above (10) which is at least one selected from the group consisting of 5, 5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid Agent.
  • the polyhydroxy aromatic carboxylic acid and the derivative thereof are 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid, And the antimicrobial agent according to the above (11), which is at least one selected from the group consisting of 3- (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid.
  • the microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, coryneform bacteria, actinomycetes, cyanobacteria, methanogens, halophilic bacteria, thermophilic acid-acid bacteria, thermophilic acid-acid bacteria, molds, yeasts or the like
  • the antimicrobial agent as described in said (9) which is a transformant.
  • a method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof, which is used as an active ingredient of a functional external skin preparation or an antibacterial agent Preparing a culture solution containing a plant-derived saccharide and a microorganism to produce at least one of the polyhydroxy aromatic carboxylic acid and a derivative thereof; Concentrating the culture to obtain a concentrate; Recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative from the concentrate by a crystallization method, a precipitation method, an extraction method, a sublimation purification method or a distillation method;
  • a process for producing a polyhydroxyaromatic carboxylic acid or derivative thereof comprising
  • a functional external skin preparation which contains at least one of polyhydroxyaromatic carboxylic acid and its derivative as an active ingredient and does not contain petroleum-derived impurities. For this reason, it is possible to provide a safer functional external skin preparation as compared to a functional external skin preparation containing impurities derived from petroleum.
  • an antibacterial agent which contains at least one of a polyhydroxyaromatic carboxylic acid and a derivative thereof as an active ingredient and does not contain impurities derived from petroleum. Therefore, a safer antibacterial agent can be provided as compared to the antibacterial agent containing impurities derived from petroleum. Furthermore, according to the present invention, polyhydroxyaromatic carboxylic acids or derivatives thereof can be efficiently produced.
  • an antimicrobial agent free of petroleum-derived impurities can be provided by using at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof as an active ingredient.
  • plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof as an active ingredient.
  • the functional skin external preparation and the antibacterial agent of the present invention each contain at least one of a plant-derived saccharide and a polyhydroxyaromatic carboxylic acid derived from a microorganism and a derivative thereof as an active ingredient.
  • the functional skin external preparation and the antibacterial agent of the present invention each comprise at least one of polyhydroxy aromatic carboxylic acid and its derivative produced by the reaction (bioprocess) of plant-derived saccharides with microorganisms (bioprocess). Contain as.
  • a functional external skin preparation which has an antioxidative effect and a whitening effect derived from at least one of polyhydroxy aromatic carboxylic acid and its derivative and does not contain petroleum-derived impurities.
  • an antibacterial agent having an antioxidant effect derived from at least one of polyhydroxy aromatic carboxylic acid and its derivative and containing no petroleum-derived impurities.
  • Such functional skin external preparations and antibacterial agents are more safe than functional skin external preparations and antibacterial agents containing impurities derived from petroleum.
  • polyhydroxy aromatic carboxylic acid and its derivative (s) are not specifically limited, It is preferable that it is a compound represented by following General formula (1).
  • X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
  • Examples of the compound represented by the above general formula (1) include 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid and 2,4-dihydroxybenzoic acid At least one selected from the group consisting of 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid is preferably used.
  • the polyhydroxy aromatic carboxylic acid and the derivative thereof may be a compound represented by the following general formula (2).
  • X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH.
  • R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group, and may have a branched or cyclic structure.
  • Examples of the compound represented by the above general formula (2) include 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid And at least one selected from the group consisting of 3- (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid is preferably used.
  • At least one of the polyhydroxy aromatic carboxylic acid and the derivative thereof produced from plant-derived saccharides is, for example, a health aid composition, a food additive, a flavor, an anticancer agent, an antiulcer agent, an antidiabetic agent, an anti Fibrosis agent, anti-aging agent, antiviral agent, anti-inflammatory agent, analgesic agent, arteriosclerotic agent, anti-lipid agent, cardiotonic agent, liver protective agent, neuroprotective agent, renal protective agent, anti-reproductive toxic agent, anti-asthmatic agent, It is also suitably used as an active ingredient such as an anticonvulsant.
  • safer health aid composition food additive, flavor, anti-cancer agent, anti-ulcer agent, anti-diabetic agent, anti-fibrotic agent, anti-aging agent, anti-viral agent, anti-inflammatory agent, analgesic agent, Arteriosclerotic agents, anti-lipid agents, cardiotonic agents, liver protective agents, neuroprotective agents, renal protective agents, anti-reproductive toxic agents, anti-asthmatic agents, anti-convulsive agents, etc. can be realized.
  • the polyhydroxy aromatic carboxylic acid or its derivative mentioned above is manufactured by the bioprocess using microorganisms, using plant origin saccharide
  • the plant-derived saccharides are not particularly limited, and include monosaccharides, polysaccharides and mixtures thereof.
  • the monosaccharide is not particularly limited, and examples thereof include saccharides that can be treated with a transformant of a microorganism described later.
  • sugars for example, tetrose (C4 sugar), pentose (C5 sugar), hexose (C6 sugar), heptose (C7 sugar) from the viewpoint of improving the phenol productivity of the transformant It can be mentioned.
  • C4 sugar tetrose
  • pentose C5 sugar
  • hexose C6 sugar
  • heptose C7 sugar
  • at least one selected from the group consisting of arabinose, xylose, glucose, mannitol, fructose, mannose, galactose, and sucrose is particularly preferable as the monosaccharide.
  • saccharides may be used alone or in combination of two or more thereof as mixed sugars.
  • the polysaccharide is a polymer of the monosaccharide.
  • the average degree of polymerization of the polysaccharide is not particularly limited, but is preferably 2 or more and 100 or less, more preferably 2 or more and 50 or less, from the viewpoint of improving the productivity in bioprocesses using microorganisms.
  • polysaccharides may be used alone or in combination of two or more. Examples of the polysaccharide include maltose, lactose, cellobiose, xylobiose, trehalose, acarbose, stachyose, fructooligosaccharide, galactooligosaccharide, mannan oligosaccharide and the like.
  • the plant-derived saccharide is preferably produced from non-edible biomass resources.
  • the raw material of the plant-derived saccharide is a non-edible biomass resource.
  • biomass resources can be used as long as they contain at least a monosaccharide or a polysaccharide.
  • the biomass resources include waste cellulose and waste starch which are recovered as process residues or waste of general food industry, in addition to grass resources represented by weeds generated from urban areas or cultivated land and thinning materials in forest production areas. Examples thereof include waste molasses, sugar cane pomace in the sugar industry, and sake lees and shochu in the sake-making industry, and these can be used alone or in combination.
  • a processed product can also be used as said biomass resource.
  • the plant-derived saccharides By saccharifying such biomass resources, the plant-derived saccharides can be obtained.
  • plant-derived saccharides cellulose-derived saccharides obtained by saccharifying waste cellulose are preferable, and cellulose-derived mixed sugars are more preferable.
  • the process using microorganisms derived from plant-derived saccharides will be described in detail.
  • the process using a microorganism using the plant-derived saccharide as the raw material is the polyhydroxy aromatic carboxylic acid produced by the microorganism using the plant-derived saccharide as the raw material (produced from the conversion of the plant-derived saccharide by the microorganism) And a step of obtaining a culture solution containing at least one of its derivatives, a step of concentrating the culture solution to obtain a concentrate, and a crystallization method, a precipitation method, an extraction method, a sublimation purification method or a distillation method from the concentrate. Recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative. Through such a process, at least one of the polyhydroxyaromatic carboxylic acid and its derivative can be efficiently obtained.
  • an active ingredient is produced (produced) as a result of the reaction between the raw material and the microorganism.
  • an active ingredient polyhydroxy aromatic carboxylic acid or the like is limited by limiting the types of raw materials and microorganisms (for example, limiting the raw materials to plant-derived saccharides and limiting the types of microorganisms to bacteria).
  • the derivative can be obtained efficiently.
  • Such an effect can be remarkably exhibited by further limiting the types of raw materials and microorganisms (eg, limiting the raw materials to cellulose-derived mixed sugar and limiting the types of microorganisms to coryneform bacteria).
  • plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof can be referred to as polyhydroxyaromatic carboxylic acids and derivatives thereof (excluding those derived from plant extracts) .
  • the recovery rate of the polyhydroxyaromatic carboxylic acid and its derivative can be improved by appropriately selecting the microorganism, the culture medium, the culture equipment and the culture conditions.
  • a culture solution containing a raw material, a microorganism, a culture medium and the like is prepared.
  • this culture solution at least one of the polyhydroxyaromatic carboxylic acid and its derivative is produced by culturing the microorganism and reacting the raw material or the like with the microorganism (by bioprocess).
  • the microorganism is not particularly limited as long as it can efficiently produce the polyhydroxyaromatic carboxylic acid and its derivative.
  • bacteria such as Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Corynebacterium glutamicum, etc., Actinomycetes such as Streptomyces griseus, microsis Cyanobacteria such as Microcystis aeruginosa, methanogens (Methanobacterium thermoautotrophicum), halobacteria (Halobacterium salinarum), thermophilic eosinophilic bacteria (Sulfolobus acidocaldarius), heat-resistant eosinophilic bacteria (Alycobacterium acidoterrestris), antifungal (Acid-fast bacteria) Archaebacteria such as (acid-fast bacteria), molds such as Aspergillus oryzae, yeasts such as Saccharomyces cerevisiae, etc. are selected
  • the culture medium a culture medium usually used for culture of microorganisms may be applied.
  • the medium contains medium components to prepare the environment necessary for the growth of the microorganism. It is preferable that the medium component contains an appropriate amount of carbon source, nitrogen source, inorganic salts or other nutrients according to the type of microorganism to be used. Therefore, it is preferable that the culture solution before the bioprocess consists of the raw material, the microorganism and the medium component.
  • Examples of the carbon source include glucose, fructose, sucrose, mannose, maltose, mannitol, xylose, arabinose, galactose, starch, molasses, carbohydrates such as molasses, sorbitol, glycerin or sugar alcohols; acetic acid, citric acid, lactic acid, fumaric acid And organic acids such as maleic acid or gluconic acid; alcohols such as ethanol and propanol.
  • a carbon source one of these may be used alone, or two or more may be mixed and used.
  • the nitrogen source examples include inorganic or organic ammonium compounds such as ammonium chloride, ammonium sulfate, ammonium nitrate and ammonium acetate, urea, aqueous ammonia, sodium nitrate, potassium nitrate and the like.
  • nitrogen-containing organic compounds such as corn steep liquor, meat extract, peptone, NZ-amine, protein hydrolysate, amino acid and the like can also be used.
  • nitrogen source one of these may be used alone, or two or more may be mixed and used.
  • the inorganic salts include potassium monophosphate, potassium monobasic, magnesium sulfate, sodium chloride, ferrous nitrate, manganese sulfate, zinc sulfate, cobalt sulfate, calcium carbonate and the like. As the inorganic salts, one of these may be used alone, or two or more may be mixed and used.
  • Examples of the nutrient include meat extract, peptone, polypeptone, yeast extract, dried yeast, corn steep liquor, skimmed milk powder, defatted soybean hydrochloric acid hydrolyzate, or extracts of animal or plant or microbial cells or their degraded products, etc.
  • vitamins can be added to the culture medium, if necessary.
  • Examples of vitamins include biotin, thiamine (vitamin B1), pyridoxine (vitamin B6), pantothenic acid, inositol, nicotinic acid and the like.
  • the culture equipment may be any of a batch system, a fed-batch system, and a continuous system, but a batch system is preferable when multi-variety production is assumed.
  • a seed culture system is generally adopted in which expansion culture is performed stepwise from flask-scale culture, and incubator groups differing in size in several stages according to production scale are used as a set.
  • the medium temperature is preferably about 15 to 45 ° C.
  • the pH of the medium is preferably about 6 to 8.
  • Other parameters such as aeration method and aeration amount to the culture tank, agitation method and rotation speed, stirring blade shape, culture time, etc. are appropriately set according to the scale and specifications of the culture equipment, and the type and concentration of microorganisms used.
  • the culture process is properly adjusted by real-time monitoring.
  • the culture solution obtained by the bioprocess can be prepared in a state in which the polyhydroxyaromatic carboxylic acid and its derivative are contained at a suitable concentration if the microorganism growth environment is appropriately selected.
  • a recovery process including a culture solution concentration step and an isolation and purification step is applied. Ru. According to such a method, polyhydroxy aromatic carboxylic acid or a derivative thereof can be efficiently produced.
  • the concentration step improves the concentration of at least one of the polyhydroxy aromatic carboxylic acid and its derivative in the culture solution obtained after the bioprocess, and the target compound is obtained in high yield and high purity in the subsequent isolation and purification step.
  • the concentration step is described below.
  • the culture solution after the bioprocess contains, in addition to at least one of the polyhydroxy aromatic carboxylic acid and its derivative produced by the bioprocess, a carbon source as a medium component, a nitrogen source, inorganic salts, nutrients, etc. And organic acids and amino acids and salts thereof.
  • a carbon source as a medium component
  • a nitrogen source as a nitrogen source
  • inorganic salts nutrients, etc.
  • organic acids and amino acids and salts thereof 70 to 99% of the total weight of the culture solution after the bioprocess is usually water. Accordingly, in the concentration step, it is desirable that the water can be efficiently removed without deteriorating or depleting the polyhydroxyaromatic carboxylic acid and the derivative thereof and without further increasing the amount of by-products with concentration.
  • Vacuum concentration is particularly preferably used in order to avoid deterioration and loss due to heat and oxidation, and to reduce the heat energy input accompanying water removal.
  • the isolation and purification step is performed for the purpose of selectively recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative from the concentrate obtained by the concentration step.
  • various chemical engineering techniques such as steam distillation, precision fractionation, temperature crystallization, acid crystallization, salting out, reprecipitation, sublimation, column purification, extraction, membrane separation and the like are applicable.
  • a suitable method is selected in consideration of the nature of the target compound and the nature of impurities and by-products to be removed.
  • Polyhydroxyaromatic carboxylic acids have different properties depending on the type and number of substituents, but when the polyhydroxyaromatic carboxylic acids and their derivatives are solid at room temperature and the water solubility of impurities and by-products is relatively high.
  • the crystallization method temperature crystallization or acid crystallization is preferably used.
  • Preferred examples of functional skin external preparations include skin care cosmetics. Specifically, lotion, milky lotion, cream, foundation, eye shadow, lipstick, blush, hair cosmetic, emollient cream, emollient lotion, cream, cream rinse, cold cream, vanishing cream, lotion, pack agent, gel, face Packs, soaps, body soaps, shampoos, conditioners, rinses, bath agents, bath agents, face wash, face creams, shaving creams, hair creams, hair lotions, hair treatments, hair packs, gloss, lip balms and the like.
  • the present invention is particularly effective for skin care cosmetics which are used while being in contact with the skin for a long time, but is not limited thereto.
  • the functional skin external preparation may be a drug or quasi drug.
  • a functional skin external preparation although it is arbitrary, for example, a lotion, a cream, an ointment, a milk, a foundation, an oil, a pack, a soap (including medicated soap), a body soap, a lipstick, a nail cosmetics Cosmetics, perfumes, facial cleansers, oral cavity (toothpaste, mouthwash, etc.), deodorant (stardust, foot odor etc.), bath agent, shampoo, rinse, hair tonic, hair spray, hair dye etc. It can be mentioned.
  • the polyhydroxy aromatic carboxylic acid and the derivative thereof in the present invention is used as an active ingredient of, for example, skin care cosmetics, preservatives, antibacterial agents, emulsifiers, in addition to water and oil as a substrate.
  • skin care cosmetics preservatives, antibacterial agents, emulsifiers
  • component adjustment agents such as surfactant and a pH adjuster, a spice component, a coloring agent, etc. according to the objective and use of skin care cosmetics.
  • the antimicrobial agent of the present invention exhibits an antimicrobial effect by being blended in various compositions.
  • the antimicrobial agent of the present invention may be blended into any composition within the range not impairing the effects of the present invention, but it is blended, for example, in food, cosmetics, daily necessities, cleaning agents, medicines, quasi-drugs, etc. .
  • ingredients include, for example, sugar, condensed milk, flour, shortening, salt, glucose, chicken egg, butter, margarine, starch syrup, calcium, iron, seasonings, spices and oils (animal and vegetable oils, mineral oils, ester oils, wax oils , Silicone oils, higher alcohols, phospholipids, fatty acids, etc.), surfactants (anionic, cationic, amphoteric or nonionic surfactants), vitamins (vitamin group A, vitamin group B, folates, etc.) Nicotinic acids, pantothenic acids, biotins, vitamin C group, vitamin D group, vitamin E group, other ferulic acid, ⁇ -oryzanol, etc., UV absorber (p-aminobenzoic acid, anthranilic acid, salicylic acid, coumarin, benzo) Triazole, tetrazole, imidazoline, pyrimidine, dioxane, furan, pyrone,
  • blending the antibacterial agent of this invention to another composition it is arbitrary.
  • fishery products such as fishery products, sausages, ham-like livestock products, western-style confectionery, Japanese-style confectionery, Chinese-style confectionery, Chinese noodles, udon, buckwheat noodles, sauces, soy sauce, seasonings such as sauce, sugar beet, juice, soup and so on It can be made into the dosage form of such as general food and drink.
  • compositions containing the antibacterial agent of the present invention is arbitrary, but for example, forms such as solution, cream, paste, gel, gel, foam, solid, powder and the like It is assumed.
  • the antimicrobial agent of the present invention may be sprayed or evaporated together with other components contained in the liquid composition, and remains in the liquid composition without being sprayed or evaporated. It does not matter.
  • the culture broth obtained by the bioprocess was concentrated under reduced pressure to a total solid concentration of 15 to 30% by mass.
  • the pressure reduction degree was 100 to 5000 Pa
  • the liquid temperature was 30 to 80 ° C.
  • concentration processing was performed using a vacuum distillation apparatus.
  • the degree of concentration depends on the treatment time, but a concentration of 15 to 30% by mass of a total solid concentration was recovered by concentration for 6 to 8 hours.
  • Hydrochloric acid was added to the concentrate to adjust the pH to 4 or less, and the mixture was further cooled to 0 ° C. to room temperature.
  • the crystallized material was recovered by filtration, appropriately washed and then dried under reduced pressure to recover high purity 3,4-dihydroxybenzoic acid having a purity of 99% or more.
  • a lotion containing the 3,4-dihydroxybenzoic acid was prepared. Specifically, 3,4-dihydroxybenzoic acid 0.1%, glycerin 5.0%, propylene glycol 4.0%, ethanol 8.0%, citric acid 0.01%, sodium citrate 0.1% A lotion containing 2.0% sodium hyaluronate, 5.0% potassium phosphate potassium, and an appropriate amount of a fragrance and a preservative was prepared. This lotion did not contain petroleum-derived impurities.
  • the antibacterial agent used for this evaluation was a lotion containing the 3,4-dihydroxybenzoic acid.
  • the antibacterial agent is 3,4-dihydroxybenzoic acid 0.1%, glycerin 5.0%, propylene glycol 4.0%, ethanol 8.0%, citric acid 0.01%, sodium citrate It was a lotion containing 0.1%, sodium hyaluronate 2.0%, phosphated potassium phosphate 5.0%, and an appropriate amount of perfume.
  • This lotion did not contain petroleum-derived impurities and contained only 3,4-dihydroxybenzoic acid (polyhydroxy aromatic carboxylic acid) as an active ingredient. For this reason, the safer antibacterial agent was able to be provided compared with the antibacterial agent containing the impurity derived from petroleum.
  • the present invention relates to the use of at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof in functional skin external preparations for antibacterial.
  • the present invention it is possible to provide a functional external preparation for skin and an antimicrobial agent which contains at least one of polyhydroxyaromatic carboxylic acid and its derivative as an active ingredient and does not contain petroleum-derived impurities. Moreover, the manufacturing method of polyhydroxy aromatic carboxylic acid or its derivative (s) which can be used as an active ingredient of these functional skin external preparations or an antimicrobial agent can be provided. Thus, the present invention has industrial applicability.

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Abstract

The functional skin preparation for external use according to the present invention comprises, as active ingredient(s), an aromatic polyhydroxycarboxylic acid derived from a plant-origin saccharide and a microorganism and/or a derivative thereof. Preferably, the aromatic polyhydroxycarboxylic acid or a derivative thereof is a compound represented by general formula (1).

Description

機能性皮膚外用剤および抗菌剤ならびにポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法Functional skin external preparation and antibacterial agent and method for producing polyhydroxy aromatic carboxylic acid or derivative thereof
　本発明は、機能性皮膚外用剤および抗菌剤ならびにポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法に関する。 The present invention relates to a functional external skin preparation and an antibacterial agent, and a method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof.
　特定の構造を有する芳香族化合物は、皮膚外用剤の成分の１つとして用いられることが知られている。例えば特許文献１には、芳香族ヒドロキシカルボン酸が、化粧品や医薬品の原料あるいは中間体として重要であることが記載されている。なお、芳香族化合物以外の炭素環式化合物も皮膚外用剤の成分の１つとして用いられることが知られている。例えば特許文献２には、シキミ酸が、メラニン生成抑制剤や、美白剤、皮膚外用剤の有効成分であることが記載されている。 An aromatic compound having a specific structure is known to be used as one of the components of a skin external preparation. For example, Patent Document 1 describes that aromatic hydroxycarboxylic acids are important as raw materials or intermediates for cosmetics and pharmaceuticals. In addition, it is known that carbocyclic compounds other than an aromatic compound are also used as one of the components of a skin external preparation. For example, Patent Document 2 describes that shikimic acid is an active ingredient of a melanin formation inhibitor, a whitening agent, and a skin external preparation.
　一方、芳香族化合物は、種々の抗菌剤の成分の１つとしても用いられる。抗菌剤は、例えば皮膚外用剤、食品等の分野において、微生物による製品の汚染を防止し、製品の保存安定性を得るために用いられている。また、例えば化粧品、医薬品等の分野において、微生物によって引き起こされる皮膚疾患を予防、改善するためにも用いられている。 On the other hand, aromatic compounds are also used as one of the components of various antibacterial agents. Antibacterial agents are used, for example, in the field of external preparations for skin, food and the like to prevent contamination of products with microorganisms and to obtain storage stability of the products. In addition, for example, in the field of cosmetics, pharmaceuticals and the like, it is also used to prevent and ameliorate skin diseases caused by microorganisms.
　例えば、芳香族ヒドロキシカルボン酸の誘導体であるパラオキシ安息香酸エステルは、医薬品、化粧品、食品等の組成物に抗菌性を付与することを目的として広く使用されている。 For example, p-hydroxybenzoic acid esters, which are derivatives of aromatic hydroxycarboxylic acids, are widely used for the purpose of imparting antimicrobial properties to compositions such as pharmaceuticals, cosmetics, and foods.
特開２００７－２３８４６９号公報JP 2007-238469 A 特開２００９－２１５２６６号公報JP, 2009-215266, A
　しかし、上記のような芳香族化合物は、石油から得られるのが通常である。このような場合、石油を分留精製することにより回収され得る石油由来の芳香族化合物（化学品）は、化学構造の単純な、いわゆる基幹化合物である。一方、化学構造がより複雑な高付加価値化合物は、この基幹化合物から合成プロセスを経て誘導せざるを得ない。この場合、製造コストを度外視して石油を高度に分留精製しない限り、原料や合成工程に由来する各種異性体や触媒由来の微量成分、イオン成分、鉱物成分等が、石油由来の化学品に残存し得る。石油由来の化学品に含まれるこれらの不純物は、人体に対する安全性の観点で好ましいとは言えない。 However, such aromatic compounds as described above are usually obtained from petroleum. In such a case, petroleum-derived aromatic compounds (chemicals) that can be recovered by fractional purification of petroleum are so-called basic compounds having a simple chemical structure. On the other hand, high value-added compounds having a more complicated chemical structure can not but be derived from this basic compound through a synthesis process. In this case, various isomers derived from raw materials and synthesis processes, trace components derived from catalysts, ionic components, mineral components, etc. become chemicals derived from petroleum unless the petroleum is highly fractionated and refined by neglecting the production cost. May survive. These impurities contained in petroleum-derived chemicals are not preferable from the viewpoint of human safety.
　本発明の目的は、ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有し、石油由来の不純物を含まない、より安全な機能性皮膚外用剤および抗菌剤を提供することにある。また、機能性皮膚外用剤または抗菌剤の有効成分として用いることが可能な、ポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法を提供することにある。 An object of the present invention is to provide a safer functional external skin preparation and an antimicrobial agent which contains at least one of polyhydroxy aromatic carboxylic acid and its derivative as an active ingredient and does not contain petroleum-derived impurities. . Another object of the present invention is to provide a method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof which can be used as an active ingredient of a functional external skin preparation or an antibacterial agent.
　このような目的は、下記（１）～（１７）に記載の本発明により達成される。
（１）植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有することを特徴とする機能性皮膚外用剤。 Such an object is achieved by the present invention described in the following (1) to (17).
(1) A functional external skin preparation comprising, as an active ingredient, at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof.
（２）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、下記一般式（１）で表される化合物である上記（１）に記載の機能性皮膚外用剤。 (2) The functional skin external preparation as described in said (1) whose said polyhydroxy aromatic carboxylic acid and its derivative (s) are a compound represented by following General formula (1).
Figure JPOXMLDOC01-appb-C000003
 ［前記一般式（１）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかを表し、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。］
Figure JPOXMLDOC01-appb-C000003
 [In the above general formula (1), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
（３）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、下記一般式（２）で表される化合物である上記（１）に記載の機能性皮膚外用剤。 (3) The functional skin external preparation as described in said (1) whose said polyhydroxy aromatic carboxylic acid and its derivative (s) are a compound represented by following General formula (2).
Figure JPOXMLDOC01-appb-C000004
 ［前記一般式（２）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかであり、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。また、一般式（２）のＲ１は炭素数１～６の脂肪族アルキル基またはアルキレン基である。］
Figure JPOXMLDOC01-appb-C000004
 [In the above general formula (2), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. Further, R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group. ]
（４）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、２－ヒドロキシ安息香酸、３－ヒドロキシ安息香酸、４－ヒドロキシ安息香酸、２，３－ジヒドロキシ安息香酸、２，４－ジヒドロキシ安息香酸、２，５－ジヒドロキシ安息香酸、２，６－ジヒドロキシ安息香酸、３，４－ジヒドロキシ安息香酸および３，５－ジヒドロキシ安息香酸からなる群から選択される少なくとも１種である上記（２）に記載の機能性皮膚外用剤。 (4) The polyhydroxy aromatic carboxylic acid and its derivative are 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2 The function according to the above (2), which is at least one selected from the group consisting of 3,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid Skin external preparation.
（５）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、３－（２，３－ジヒドロキシ）プロパン－２－エノール酸、３－（２－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸、および３－（４－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸からなる群から選択される少なくとも１種である上記（３）に記載の機能性皮膚外用剤。 (5) The polyhydroxyaromatic carboxylic acid and its derivative are 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid, And the functional skin external preparation as described in the above (3), which is at least one selected from the group consisting of 3- (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid.
（６）前記一般式（２）のＲ１は、分岐または環状構造を含む上記（３）に記載の機能性皮膚外用剤。 (6) The functional skin external preparation as described in (3) above, wherein R 1 in the general formula (2) contains a branched or cyclic structure.
（７）前記微生物が、大腸菌、枯草菌、黄色ブドウ球菌、コリネ菌、放線菌、ラン藻菌、メタン生成菌、好塩菌、高温好酸菌、耐熱性好酸菌、抗酸菌、カビ、酵母またはそれらの形質転換体である上記（１）に記載の機能性皮膚外用剤。 (7) The microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, coryneform bacteria, actinomycetes, cyanobacteria, methanogens, halophilic bacteria, thermophilic acid-acid bacteria, heat-resistant acid-acid bacteria, acid-fast bacteria, molds And the functional skin external preparation as described in said (1) which is yeast or those transformants.
（８）前記植物由来糖類の原料が、非可食のバイオマス資源である上記（１）ないし（７）のいずれかに記載の機能性皮膚外用剤。 (8) The functional skin external preparation as described in any one of (1) to (7) above, wherein the plant-derived saccharide raw material is a non-edible biomass resource.
（９）植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有することを特徴とする抗菌剤。 (9) An antimicrobial agent comprising, as an active ingredient, at least one of a plant-derived saccharide and a polyhydroxyaromatic carboxylic acid derived from a microorganism and a derivative thereof.
（１０）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、下記一般式（１）で表される化合物である上記（９）に記載の抗菌剤。 (10) The antibacterial agent according to the above (9), wherein the polyhydroxyaromatic carboxylic acid and the derivative thereof are a compound represented by the following general formula (1).
Figure JPOXMLDOC01-appb-C000005
 ［前記一般式（１）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかを表し、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。］
Figure JPOXMLDOC01-appb-C000005
 [In the above general formula (1), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
（１１）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、下記一般式（２）で表される化合物である上記（９）に記載の抗菌剤。 (11) The antibacterial agent according to the above (9), wherein the polyhydroxyaromatic carboxylic acid and the derivative thereof are a compound represented by the following general formula (2).
Figure JPOXMLDOC01-appb-C000006
 ［前記一般式（２）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかであり、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。また、一般式（２）のＲ１は炭素数１～６の脂肪族アルキル基またはアルキレン基である。］
Figure JPOXMLDOC01-appb-C000006
 [In the above general formula (2), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. Further, R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group. ]
（１２）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、２－ヒドロキシ安息香酸、３－ヒドロキシ安息香酸、４－ヒドロキシ安息香酸、２，３－ジヒドロキシ安息香酸、２，４－ジヒドロキシ安息香酸、２，５－ジヒドロキシ安息香酸、２，６－ジヒドロキシ安息香酸、３，４－ジヒドロキシ安息香酸および３，５－ジヒドロキシ安息香酸からなる群から選択される少なくとも１種である上記（１０）に記載の抗菌剤。 (12) The polyhydroxy aromatic carboxylic acids and derivatives thereof are 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2 The antimicrobial agent according to the above (10), which is at least one selected from the group consisting of 5, 5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid Agent.
（１３）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、３－（２，３－ジヒドロキシ）プロパン－２－エノール酸、３－（２－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸、および３－（４－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸からなる群から選択される少なくとも１種である上記（１１）に記載の抗菌剤。 (13) The polyhydroxy aromatic carboxylic acid and the derivative thereof are 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid, And the antimicrobial agent according to the above (11), which is at least one selected from the group consisting of 3- (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid.
（１４）前記一般式（２）のＲ１は、分岐または環状構造を含む上記（１１）に記載の抗菌剤。 (14) The antibacterial agent according to the above (11), wherein R 1 in the general formula (2) contains a branched or cyclic structure.
（１５）前記微生物が、大腸菌、枯草菌、黄色ブドウ球菌、コリネ菌、放線菌、ラン藻菌、メタン生成菌、好塩菌、高温好酸菌、高温好酸菌、カビ、酵母またはそれらの形質転換体である上記（９）に記載の抗菌剤。 (15) The microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, coryneform bacteria, actinomycetes, cyanobacteria, methanogens, halophilic bacteria, thermophilic acid-acid bacteria, thermophilic acid-acid bacteria, molds, yeasts or the like The antimicrobial agent as described in said (9) which is a transformant.
（１６）前記植物由来糖類の原料が、非可食のバイオマス資源である上記（９）ないし（１５）のいずれかに記載の抗菌剤。 (16) The antibacterial agent according to any one of the above (9) to (15), wherein the plant-derived saccharide raw material is a non-edible biomass resource.
（１７）機能性皮膚外用剤または抗菌剤の有効成分として用いられる、ポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法であって、
　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を生成するように、植物由来糖類と、微生物とを含む培養液を調製する工程と、
　前記培養液を濃縮して濃縮液を得る工程と、
　前記濃縮液から晶析法、沈殿法、抽出法、昇華精製法または蒸留法により前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を回収する工程と、
を含むポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法。 (17) A method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof, which is used as an active ingredient of a functional external skin preparation or an antibacterial agent,
Preparing a culture solution containing a plant-derived saccharide and a microorganism to produce at least one of the polyhydroxy aromatic carboxylic acid and a derivative thereof;
Concentrating the culture to obtain a concentrate;
Recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative from the concentrate by a crystallization method, a precipitation method, an extraction method, a sublimation purification method or a distillation method;
A process for producing a polyhydroxyaromatic carboxylic acid or derivative thereof comprising
　本発明によれば、ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有し、石油由来の不純物を含まない機能性皮膚外用剤を提供することができる。このため、石油由来の不純物を含む機能性皮膚外用剤に比べて、より安全な機能性皮膚外用剤を提供することができる。 According to the present invention, it is possible to provide a functional external skin preparation which contains at least one of polyhydroxyaromatic carboxylic acid and its derivative as an active ingredient and does not contain petroleum-derived impurities. For this reason, it is possible to provide a safer functional external skin preparation as compared to a functional external skin preparation containing impurities derived from petroleum.
　また、本発明によれば、ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有し、石油由来の不純物を含まない抗菌剤を提供することができる。このため、石油由来の不純物を含む抗菌剤に比べて、より安全な抗菌剤を提供することができる。さらに、本発明によれば、ポリヒドロキシ芳香族カルボン酸またはその誘導体を効率よく製造することができる。 Further, according to the present invention, it is possible to provide an antibacterial agent which contains at least one of a polyhydroxyaromatic carboxylic acid and a derivative thereof as an active ingredient and does not contain impurities derived from petroleum. Therefore, a safer antibacterial agent can be provided as compared to the antibacterial agent containing impurities derived from petroleum. Furthermore, according to the present invention, polyhydroxyaromatic carboxylic acids or derivatives thereof can be efficiently produced.
　以下、本発明の機能性皮膚外用剤および抗菌剤ならびにポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法について、好適実施形態に基づいて詳細に説明する。 Hereinafter, the functional skin external preparation and the antibacterial agent of the present invention and the method for producing polyhydroxy aromatic carboxylic acid or a derivative thereof will be described in detail based on preferred embodiments.
≪機能性皮膚外用剤および抗菌剤≫
　本発明者らが鋭意検討した結果、植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分とすることで、石油由来の不純物を含まない機能性皮膚外用剤を提供し得ることを見出した。この際、植物由来糖類（原料）と微生物とを用いたバイオプロセスにより、ポリヒドロキシ芳香族カルボン酸またはその誘導体を製造することが好ましいことを見出した。さらに、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を、機能性皮膚外用剤における、抗酸化効果および美白効果を目的とした有効成分とすることが好ましいことを見出した。また、併せて、植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分とすることで、石油由来の不純物を含まない抗菌剤を提供し得ることを見出した。この際、植物由来糖類（原料）と微生物とを用いたバイオプロセスにより、ポリヒドロキシ芳香族カルボン酸またはその誘導体を製造することが好ましいことを見出した。さらに、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を、抗菌剤における、抗酸化効果を目的とした有効成分とすることが好ましいことを見出した。 «Functional skin external preparation and antibacterial agent»
As a result of intensive investigations by the present inventors, functional skin external use containing no petroleum-derived impurities can be obtained by using at least one of plant-derived saccharides and polyhydroxy aromatic carboxylic acids derived from microorganisms and derivatives thereof as an active ingredient. It has been found that an agent can be provided. Under the present circumstances, it discovered that it was preferable to manufacture polyhydroxy aromatic carboxylic acid or its derivative (s) by the bioprocess using plant origin saccharides (raw material) and microorganisms. Furthermore, it has been found that it is preferable to use at least one of the polyhydroxy aromatic carboxylic acid and the derivative thereof as an active ingredient for the antioxidative effect and the whitening effect in a functional external skin preparation. In addition, it is also found that an antimicrobial agent free of petroleum-derived impurities can be provided by using at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof as an active ingredient. The Under the present circumstances, it discovered that it was preferable to manufacture polyhydroxy aromatic carboxylic acid or its derivative (s) by the bioprocess using plant origin saccharides (raw material) and microorganisms. Furthermore, it has been found that it is preferable to use at least one of the polyhydroxy aromatic carboxylic acid and the derivative thereof as an active ingredient for an anti-oxidant effect in an antibacterial agent.
　すなわち、本発明の機能性皮膚外用剤および抗菌剤は、それぞれ、植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有する。換言すれば、本発明の機能性皮膚外用剤および抗菌剤は、それぞれ、植物由来糖類と微生物との反応（バイオプロセス）によって製造されたポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有する。 That is, the functional skin external preparation and the antibacterial agent of the present invention each contain at least one of a plant-derived saccharide and a polyhydroxyaromatic carboxylic acid derived from a microorganism and a derivative thereof as an active ingredient. In other words, the functional skin external preparation and the antibacterial agent of the present invention each comprise at least one of polyhydroxy aromatic carboxylic acid and its derivative produced by the reaction (bioprocess) of plant-derived saccharides with microorganisms (bioprocess). Contain as.
　これにより、ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方に由来する抗酸化効果および美白効果を有し、かつ石油由来の不純物を含まない、機能性皮膚外用剤を提供することができる。また、ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方に由来する抗酸化効果を有し、かつ石油由来の不純物を含まない、抗菌剤を提供することができる。このような機能性皮膚外用剤および抗菌剤は、石油由来の不純物を含む機能性皮膚外用剤および抗菌剤に比べて、安全性が高い。 As a result, it is possible to provide a functional external skin preparation which has an antioxidative effect and a whitening effect derived from at least one of polyhydroxy aromatic carboxylic acid and its derivative and does not contain petroleum-derived impurities. In addition, it is possible to provide an antibacterial agent having an antioxidant effect derived from at least one of polyhydroxy aromatic carboxylic acid and its derivative and containing no petroleum-derived impurities. Such functional skin external preparations and antibacterial agents are more safe than functional skin external preparations and antibacterial agents containing impurities derived from petroleum.
　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体は、特に限定されないが、下記一般式（１）で表される化合物であることが好ましい。 Although the said polyhydroxy aromatic carboxylic acid and its derivative (s) are not specifically limited, It is preferable that it is a compound represented by following General formula (1).
Figure JPOXMLDOC01-appb-C000007
 ［前記一般式（１）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかを表し、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。］
Figure JPOXMLDOC01-appb-C000007
 [In the above general formula (1), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
　上記一般式（１）で表される化合物としては、例えば、２－ヒドロキシ安息香酸、３－ヒドロキシ安息香酸、４－ヒドロキシ安息香酸、２，３－ジヒドロキシ安息香酸、２，４－ジヒドロキシ安息香酸、２，５－ジヒドロキシ安息香酸、２，６－ジヒドロキシ安息香酸、３，４－ジヒドロキシ安息香酸および３，５－ジヒドロキシ安息香酸からなる群から選択される少なくとも１種が好ましく用いられる。 Examples of the compound represented by the above general formula (1) include 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid and 2,4-dihydroxybenzoic acid At least one selected from the group consisting of 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid is preferably used.
　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体は、下記一般式（２）で表される化合物であってもよい。 The polyhydroxy aromatic carboxylic acid and the derivative thereof may be a compound represented by the following general formula (2).
Figure JPOXMLDOC01-appb-C000008
 ［前記一般式（２）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかであり、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。また、一般式（２）のＲ１は炭素数１～６の脂肪族アルキル基またはアルキレン基であり、分岐または環状構造を含んでいても構わない。］
Figure JPOXMLDOC01-appb-C000008
 [In the above general formula (2), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. Further, R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group, and may have a branched or cyclic structure. ]
　上記一般式（２）で表される化合物としては、例えば、３－（２，３－ジヒドロキシ）プロパン－２－エノール酸、３－（２－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸、および３－（４－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸からなる群から選択される少なくとも１種が好ましく用いられる。 Examples of the compound represented by the above general formula (2) include 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid And at least one selected from the group consisting of 3- (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid is preferably used.
　なお、植物由来糖類から製造されたポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方は、例えば、健康補助組成物、食品添加剤、香料、抗がん剤、抗潰瘍剤、抗糖尿病剤、抗線維化剤、抗老化剤、抗ウイルス剤、抗炎症剤、鎮痛剤、動脈硬化剤、抗脂質剤、強心剤、肝臓保護剤、神経保護剤、腎臓保護剤、抗生殖毒性剤、抗喘息剤、抗痙攣剤等の有効成分としても好適に用いられる。これにより、より安全な健康補助組成物、食品添加剤、香料、抗がん剤、抗潰瘍剤、抗糖尿病剤、抗線維化剤、抗老化剤、抗ウイルス剤、抗炎症剤、鎮痛剤、動脈硬化剤、抗脂質剤、強心剤、肝臓保護剤、神経保護剤、腎臓保護剤、抗生殖毒性剤、抗喘息剤、抗痙攣剤等を実現することができる。 In addition, at least one of the polyhydroxy aromatic carboxylic acid and the derivative thereof produced from plant-derived saccharides is, for example, a health aid composition, a food additive, a flavor, an anticancer agent, an antiulcer agent, an antidiabetic agent, an anti Fibrosis agent, anti-aging agent, antiviral agent, anti-inflammatory agent, analgesic agent, arteriosclerotic agent, anti-lipid agent, cardiotonic agent, liver protective agent, neuroprotective agent, renal protective agent, anti-reproductive toxic agent, anti-asthmatic agent, It is also suitably used as an active ingredient such as an anticonvulsant. Thereby, safer health aid composition, food additive, flavor, anti-cancer agent, anti-ulcer agent, anti-diabetic agent, anti-fibrotic agent, anti-aging agent, anti-viral agent, anti-inflammatory agent, analgesic agent, Arteriosclerotic agents, anti-lipid agents, cardiotonic agents, liver protective agents, neuroprotective agents, renal protective agents, anti-reproductive toxic agents, anti-asthmatic agents, anti-convulsive agents, etc. can be realized.
≪ポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法≫
　上述したポリヒドロキシ芳香族カルボン酸またはその誘導体は、植物由来糖類を原料として、微生物を用いたバイオプロセスにより製造されたものである。すなわち、上述したポリヒドロキシ芳香族カルボン酸またはその誘導体は、植物由来糖類および微生物を由来とするものである。 << Method for producing polyhydroxy aromatic carboxylic acid or derivative thereof >>
The polyhydroxy aromatic carboxylic acid or its derivative mentioned above is manufactured by the bioprocess using microorganisms, using plant origin saccharide | sugar as a raw material. That is, the polyhydroxy aromatic carboxylic acid or derivative thereof described above is derived from plant-derived saccharides and microorganisms.
　前記植物由来糖類としては、特に限定されず、単糖や多糖およびこれらの混合物が挙げられる。 The plant-derived saccharides are not particularly limited, and include monosaccharides, polysaccharides and mixtures thereof.
　前記単糖は、特に限定されず、後述する微生物の形質転換体で処理できる糖類が挙げられる。このような糖類（単糖）としては、形質転換体のフェノール生産性を向上させる観点から、例えば、テトロース（Ｃ４糖）、ペントース（Ｃ５糖）、ヘキソース（Ｃ６糖）、ヘプトース（Ｃ７糖）が挙げられる。これらの中でも、単糖としては、特にアラビノース、キシロース、グルコース、マンニトール、フルクトース、マンノース、ガラクトース、およびスクロースからなる群から選択される少なくとも１種が好ましい。また、このような糖類は、１種で用いてもよく、または複数を組み合わせて混合糖として用いてもよい。 The monosaccharide is not particularly limited, and examples thereof include saccharides that can be treated with a transformant of a microorganism described later. As such sugars (monosaccharides), for example, tetrose (C4 sugar), pentose (C5 sugar), hexose (C6 sugar), heptose (C7 sugar) from the viewpoint of improving the phenol productivity of the transformant It can be mentioned. Among these, at least one selected from the group consisting of arabinose, xylose, glucose, mannitol, fructose, mannose, galactose, and sucrose is particularly preferable as the monosaccharide. Moreover, such saccharides may be used alone or in combination of two or more thereof as mixed sugars.
　前記多糖は、前記単糖の重合体である。多糖の平均重合度は、特に限定されないが、微生物を用いたバイオプロセスにおける生産性を向上させる観点から、２以上１００以下が好ましく、２以上５０以下がさらに好ましい。また、多糖は、１種で用いてもよくまたは複数を組み合わせて用いてもよい。多糖としては、例えば、マルトース、ラクトース、セロビオース、キシロビオース、トレハロース、アカルボース、スタキオース、フラクトオリゴ糖、ガラクトオリゴ糖、マンナンオリゴ糖等が挙げられる。 The polysaccharide is a polymer of the monosaccharide. The average degree of polymerization of the polysaccharide is not particularly limited, but is preferably 2 or more and 100 or less, more preferably 2 or more and 50 or less, from the viewpoint of improving the productivity in bioprocesses using microorganisms. Moreover, polysaccharides may be used alone or in combination of two or more. Examples of the polysaccharide include maltose, lactose, cellobiose, xylobiose, trehalose, acarbose, stachyose, fructooligosaccharide, galactooligosaccharide, mannan oligosaccharide and the like.
　前記植物由来糖類は、非可食のバイオマス資源から製造されたものであることが好ましい。換言すれば、前記植物由来糖類の原料が、非可食のバイオマス資源であることが好ましい。 The plant-derived saccharide is preferably produced from non-edible biomass resources. In other words, it is preferable that the raw material of the plant-derived saccharide is a non-edible biomass resource.
　前記バイオマス資源としては、上述したような糖類を得る観点から、単糖または多糖を少なくとも含むものであれば種々のものを用いることができる。前記バイオマス資源は、都市部もしくは耕作地から発生する雑草類や林産地における間伐材等に代表される草木資源の他、一般食品工業の工程残滓もしくは廃棄物として回収される廃セルロースや廃デンプン、廃糖蜜、または製糖工業におけるサトウキビ絞りかすや酒造業における酒粕や焼酎粕等が挙げられ、これらは１種または複数を組み合わせて用いることができる。また、前記バイオマス資源としては、加工品を用いることもできる。 From the viewpoint of obtaining saccharides as described above, various biomass resources can be used as long as they contain at least a monosaccharide or a polysaccharide. The biomass resources include waste cellulose and waste starch which are recovered as process residues or waste of general food industry, in addition to grass resources represented by weeds generated from urban areas or cultivated land and thinning materials in forest production areas. Examples thereof include waste molasses, sugar cane pomace in the sugar industry, and sake lees and shochu in the sake-making industry, and these can be used alone or in combination. Moreover, a processed product can also be used as said biomass resource.
　このようなバイオマス資源を糖化することにより、前記植物由来糖類を得ることができる。このような植物由来糖類としては、廃セルロースを糖化したセルロース由来糖類が好ましく、セルロース由来混合糖がより好ましい。以下、植物由来糖類を原料とする微生物を用いたプロセスについて詳細に説明する。 By saccharifying such biomass resources, the plant-derived saccharides can be obtained. As such plant-derived saccharides, cellulose-derived saccharides obtained by saccharifying waste cellulose are preferable, and cellulose-derived mixed sugars are more preferable. Hereinafter, the process using microorganisms derived from plant-derived saccharides will be described in detail.
　前記植物由来糖類を原料とする微生物を用いたプロセスとは、前記植物由来糖類を原料として微生物によって生産された（植物由来糖類を微生物が変換することから生成された）前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を含む培養液を得る工程と、前記培養液を濃縮して濃縮液を得る工程と、前記濃縮液から晶析法、沈殿法、抽出法、昇華精製法または蒸留法により前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を回収する工程と、を有するプロセスである。このようなプロセスを経ることで、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を効率よく得ることができる。また、このような微生物を用いたプロセスによれば、原料と微生物との反応の結果、有効成分が生産（生成）される。このため、原料および微生物の種類を限定（例えば、原料を植物由来糖類と限定し、かつ、微生物の種類を細菌類に限定）することで、１つの有効成分のみ（ポリヒドロキシ芳香族カルボン酸またはその誘導体）を効率よく得ることができる。このような効果は、原料および微生物の種類をさらに限定（例えば、原料をセルロース由来混合糖と限定し、かつ、微生物の種類をコリネ菌に限定）することにより、顕著に発揮され得る。この点で、微生物を用いないプロセス（例えば植物からの抽出液を用いるプロセス）とは異なる。このような観点から、植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体とは、ポリヒドロキシ芳香族カルボン酸およびその誘導体（植物抽出液由来のものを除く）ということができる。 The process using a microorganism using the plant-derived saccharide as the raw material is the polyhydroxy aromatic carboxylic acid produced by the microorganism using the plant-derived saccharide as the raw material (produced from the conversion of the plant-derived saccharide by the microorganism) And a step of obtaining a culture solution containing at least one of its derivatives, a step of concentrating the culture solution to obtain a concentrate, and a crystallization method, a precipitation method, an extraction method, a sublimation purification method or a distillation method from the concentrate. Recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative. Through such a process, at least one of the polyhydroxyaromatic carboxylic acid and its derivative can be efficiently obtained. Moreover, according to a process using such a microorganism, an active ingredient is produced (produced) as a result of the reaction between the raw material and the microorganism. For this reason, only one active ingredient (polyhydroxy aromatic carboxylic acid or the like is limited by limiting the types of raw materials and microorganisms (for example, limiting the raw materials to plant-derived saccharides and limiting the types of microorganisms to bacteria). The derivative) can be obtained efficiently. Such an effect can be remarkably exhibited by further limiting the types of raw materials and microorganisms (eg, limiting the raw materials to cellulose-derived mixed sugar and limiting the types of microorganisms to coryneform bacteria). In this respect, it differs from a process which does not use a microorganism (for example, a process which uses an extract from a plant). From such a point of view, plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof can be referred to as polyhydroxyaromatic carboxylic acids and derivatives thereof (excluding those derived from plant extracts) .
　前記バイオプロセスにおいては、微生物、培地、培養設備および培養条件を適切に選定することで、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の回収率を向上させることができる。 In the bioprocess, the recovery rate of the polyhydroxyaromatic carboxylic acid and its derivative can be improved by appropriately selecting the microorganism, the culture medium, the culture equipment and the culture conditions.
　＜培養液を調製する工程＞
　まず、原料、微生物、培地等を含む培養液を調製する。この培養液において、微生物を培養するとともに、原料等と微生物とを反応させることにより（バイオプロセスにより）、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方が生産される。 <Step of Preparing Culture Solution>
First, a culture solution containing a raw material, a microorganism, a culture medium and the like is prepared. In this culture solution, at least one of the polyhydroxyaromatic carboxylic acid and its derivative is produced by culturing the microorganism and reacting the raw material or the like with the microorganism (by bioprocess).
　前記微生物としては、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体を高効率に生成し得るものであればその種類は特に問わない。一般的には大腸菌（Escherichia coli）、枯草菌（Bacillus subtilis）、黄色ブドウ球菌（Staphylococcus aureus）、コリネ菌（Corynebacterium glutamicum）等の細菌類、ストレプトミセス属（Streptomyces griseus）等の放線菌、ミクロシスティス属（Microcystis aeruginosa）等のラン藻菌、メタン生成菌（Methanobacterium thermoautotrophicum）、好塩菌（Halobacterium salinarum）、高温好酸菌（Sulfolobus acidocaldarius）、耐熱性好酸菌（Alicyclobacillus acidoterrestris）、抗酸菌（acid-fast bacterium）等の古細菌、コウジカビ（Aspergillus oryzae）等のカビ、出芽酵母（Saccharomyces cerevisiae）等の酵母から、目的に応じたものが選定され、必要に応じ既知の方法により得られるこれらの形質転換体が利用され、特に野生型コリネ菌またはその形質転換体が好ましい。 The microorganism is not particularly limited as long as it can efficiently produce the polyhydroxyaromatic carboxylic acid and its derivative. Generally, bacteria such as Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Corynebacterium glutamicum, etc., Actinomycetes such as Streptomyces griseus, microsis Cyanobacteria such as Microcystis aeruginosa, methanogens (Methanobacterium thermoautotrophicum), halobacteria (Halobacterium salinarum), thermophilic eosinophilic bacteria (Sulfolobus acidocaldarius), heat-resistant eosinophilic bacteria (Alycobacterium acidoterrestris), antifungal (Acid-fast bacteria) Archaebacteria such as (acid-fast bacteria), molds such as Aspergillus oryzae, yeasts such as Saccharomyces cerevisiae, etc. are selected according to the purpose, and these can be obtained by known methods as necessary. The transformant of is preferably used, and in particular, wild type Corynebacterium coryneform bacteria or a transformant thereof.
　前記培地としては、微生物の培養に通常使用される培地を適用すればよい。培地は、微生物の生育に必要な環境を整えるべく、培地成分を含む。培地成分は、炭素源、窒素源、無機塩類またはその他の栄養分等を使用する微生物の種類に応じて適切量含有することが好ましい。したがって、バイオプロセス前における培養液は、原料、微生物および培地成分からなることが好ましい。 As the culture medium, a culture medium usually used for culture of microorganisms may be applied. The medium contains medium components to prepare the environment necessary for the growth of the microorganism. It is preferable that the medium component contains an appropriate amount of carbon source, nitrogen source, inorganic salts or other nutrients according to the type of microorganism to be used. Therefore, it is preferable that the culture solution before the bioprocess consists of the raw material, the microorganism and the medium component.
　前記炭素源としては、例えば、グルコース、フルクトース、スクロース、マンノース、マルトース、マンニトール、キシロース、アラビノース、ガラクトース、でんぷん、糖蜜、ソルビトール、グリセリン等の糖質または糖アルコール；酢酸、クエン酸、乳酸、フマル酸、マレイン酸またはグルコン酸等の有機酸；エタノール、プロパノール等のアルコールが挙げられる。炭素源としては、これらのうちの１種を単独で使用してもよく、２種以上を混合して使用してもよい。 Examples of the carbon source include glucose, fructose, sucrose, mannose, maltose, mannitol, xylose, arabinose, galactose, starch, molasses, carbohydrates such as molasses, sorbitol, glycerin or sugar alcohols; acetic acid, citric acid, lactic acid, fumaric acid And organic acids such as maleic acid or gluconic acid; alcohols such as ethanol and propanol. As a carbon source, one of these may be used alone, or two or more may be mixed and used.
　前記窒素源としては、例えば、塩化アンモニウム、硫酸アンモニウム、硝酸アンモニウム、酢酸アンモニウム等の無機または有機アンモニウム化合物、尿素、アンモニア水、硝酸ナトリウム、硝酸カリウム等が挙げられる。また、コーンスティープリカー、肉エキス、ペプトン、ＮＺ－アミン、タンパク質加水分解物、アミノ酸等の含窒素有機化合物等も利用できる。窒素源としては、これらのうちの１種を単独で使用してもよく、２種以上を混合して使用してもよい。 Examples of the nitrogen source include inorganic or organic ammonium compounds such as ammonium chloride, ammonium sulfate, ammonium nitrate and ammonium acetate, urea, aqueous ammonia, sodium nitrate, potassium nitrate and the like. In addition, nitrogen-containing organic compounds such as corn steep liquor, meat extract, peptone, NZ-amine, protein hydrolysate, amino acid and the like can also be used. As the nitrogen source, one of these may be used alone, or two or more may be mixed and used.
　前記無機塩類としては、例えば、リン酸第一カリウム、リン酸第二カリウム、硫酸マグネシウム、塩化ナトリウム、硝酸第一鉄、硫酸マンガン、硫酸亜鉛、硫酸コバルト、炭酸カルシウム等が挙げられる。無機塩類としては、これらのうちの１種を単独で使用してもよく、２種以上を混合して使用してもよい。 Examples of the inorganic salts include potassium monophosphate, potassium monobasic, magnesium sulfate, sodium chloride, ferrous nitrate, manganese sulfate, zinc sulfate, cobalt sulfate, calcium carbonate and the like. As the inorganic salts, one of these may be used alone, or two or more may be mixed and used.
　前記栄養分としては、例えば、肉エキス、ペプトン、ポリペプトン、酵母エキス、乾燥酵母、コーンスティープリカー、脱脂粉乳、脱脂大豆塩酸加水分解物、または動植物もしくは微生物菌体のエキスやそれらの分解物等が挙げられる。さらに、必要に応じて、ビタミン類を培地に添加することもできる。ビタミン類としては、例えば、ビオチン、チアミン（ビタミンＢ１）、ピリドキシン（ビタミンＢ６）、パントテン酸、イノシトール、ニコチン酸等が挙げられる。 Examples of the nutrient include meat extract, peptone, polypeptone, yeast extract, dried yeast, corn steep liquor, skimmed milk powder, defatted soybean hydrochloric acid hydrolyzate, or extracts of animal or plant or microbial cells or their degraded products, etc. Be Furthermore, vitamins can be added to the culture medium, if necessary. Examples of vitamins include biotin, thiamine (vitamin B1), pyridoxine (vitamin B6), pantothenic acid, inositol, nicotinic acid and the like.
　前記培養設備としては、バッチ式、流加式、連続式のいずれでもよいが、多品種生産を想定する場合にはバッチ式が好ましい。また、一般的にはフラスコスケールの培養から段階的に拡大培養を行うシード培養方式を採用することが多く、生産規模に応じて大きさが数段階に異なる培養器群をひと組として使用する。また、前記培養条件としては、培地温度は約１５～４５℃が好ましく、培地のｐＨは約６～８が好ましい。その他、培養槽への通気方式および通気量、撹拌方式および回転数、撹拌翼形状、培養時間等のパラメータについては、培養設備の規模および仕様、使用する微生物の種類および濃度に応じて適切に設定され、培養過程はリアルタイム監視により適切に調整される。 The culture equipment may be any of a batch system, a fed-batch system, and a continuous system, but a batch system is preferable when multi-variety production is assumed. In general, a seed culture system is generally adopted in which expansion culture is performed stepwise from flask-scale culture, and incubator groups differing in size in several stages according to production scale are used as a set. In addition, as the culture conditions, the medium temperature is preferably about 15 to 45 ° C., and the pH of the medium is preferably about 6 to 8. Other parameters such as aeration method and aeration amount to the culture tank, agitation method and rotation speed, stirring blade shape, culture time, etc. are appropriately set according to the scale and specifications of the culture equipment, and the type and concentration of microorganisms used. The culture process is properly adjusted by real-time monitoring.
　＜濃縮工程および単離精製工程＞
　バイオプロセスにより得られる培養液は、微生物生育環境が適切に選択されていれば前記ポリヒドロキシ芳香族カルボン酸およびその誘導体を好適な濃度で含有した状態で調製され得る。このように調製された培養液から前記ポリヒドロキシ芳香族カルボン酸およびその誘導体を選択的に効率よく回収する目的で、培養液の濃縮工程と、単離精製工程と、を含む回収プロセスが適用される。このような方法によれば、ポリヒドロキシ芳香族カルボン酸またはその誘導体を効率よく製造することができる。 <Concentration step and isolation and purification step>
The culture solution obtained by the bioprocess can be prepared in a state in which the polyhydroxyaromatic carboxylic acid and its derivative are contained at a suitable concentration if the microorganism growth environment is appropriately selected. In order to selectively and efficiently recover the polyhydroxyaromatic carboxylic acid and its derivative from the thus prepared culture solution, a recovery process including a culture solution concentration step and an isolation and purification step is applied. Ru. According to such a method, polyhydroxy aromatic carboxylic acid or a derivative thereof can be efficiently produced.
　前記濃縮工程は、バイオプロセス後に得られる培養液の前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方の含有濃度を向上させ、これに続く単離精製工程において目的化合物を高収率かつ高純度で回収する目的で行われる。以下、濃縮工程について、説明する。 The concentration step improves the concentration of at least one of the polyhydroxy aromatic carboxylic acid and its derivative in the culture solution obtained after the bioprocess, and the target compound is obtained in high yield and high purity in the subsequent isolation and purification step. In order to collect The concentration step is described below.
　バイオプロセス後における培養液は、バイオプロセスにより生成した前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方に加え、培地成分としての炭素源、窒素源、無機塩類、栄養分等を含むほか、バイオプロセスの際に副生する有機酸やアミノ酸およびそれらの塩類を含有する。なお、バイオプロセス後における培養液の全重量のうち７０～９９％は通常は水分である。従って前記濃縮工程においては、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体を変質または減耗させることなく、かつ濃縮に伴いさらに副生物量を増加させることなく、水分を効率的に除去出来るものが望ましい。この目的を達する為に、加熱濃縮、減圧蒸留、溶剤抽出、固体抽出、膜分離等の化学工学的手法を適用することができるが、濃縮工程中の前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の熱や酸化による変質および減耗を避けるべく、また、水分除去に伴う熱エネルギー投入量を低減すべく、減圧濃縮が特に好適に用いられる。 The culture solution after the bioprocess contains, in addition to at least one of the polyhydroxy aromatic carboxylic acid and its derivative produced by the bioprocess, a carbon source as a medium component, a nitrogen source, inorganic salts, nutrients, etc. And organic acids and amino acids and salts thereof. In addition, 70 to 99% of the total weight of the culture solution after the bioprocess is usually water. Accordingly, in the concentration step, it is desirable that the water can be efficiently removed without deteriorating or depleting the polyhydroxyaromatic carboxylic acid and the derivative thereof and without further increasing the amount of by-products with concentration. In order to achieve this purpose, chemical engineering techniques such as heat concentration, vacuum distillation, solvent extraction, solid extraction, membrane separation and the like can be applied, but the polyhydroxy aromatic carboxylic acid and its derivatives in the concentration step may be used. Vacuum concentration is particularly preferably used in order to avoid deterioration and loss due to heat and oxidation, and to reduce the heat energy input accompanying water removal.
　前記単離精製工程は、前記濃縮工程により得られる濃縮液から前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を選択的に回収する目的で行われる。 The isolation and purification step is performed for the purpose of selectively recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative from the concentrate obtained by the concentration step.
　単離精製工程では、水蒸気蒸留、精密分留、温度晶析、酸晶析、塩析、再沈殿、昇華、カラム精製、抽出、膜分離等、様々な化学工学的手法が適用可能である。目的化合物の性質、および除去されるべき不純物や副生物の性質を考慮して好適な手法が選択される。ポリヒドロキシ芳香族カルボン酸は置換基の種類や数によって性質が異なるが、前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が常温で固体であり、かつ不純物や副生物の水溶性が比較的高い場合には、晶析法（温度晶析または酸晶析）が好適に用いられる。 In the isolation and purification step, various chemical engineering techniques such as steam distillation, precision fractionation, temperature crystallization, acid crystallization, salting out, reprecipitation, sublimation, column purification, extraction, membrane separation and the like are applicable. A suitable method is selected in consideration of the nature of the target compound and the nature of impurities and by-products to be removed. Polyhydroxyaromatic carboxylic acids have different properties depending on the type and number of substituents, but when the polyhydroxyaromatic carboxylic acids and their derivatives are solid at room temperature and the water solubility of impurities and by-products is relatively high. The crystallization method (temperature crystallization or acid crystallization) is preferably used.
　＜機能性皮膚外用剤等への加工＞
　機能性皮膚外用剤の好適な例としては、スキンケア化粧品が挙げられる。具体的には、化粧水、乳液、クリーム、ファンデーション、アイシャドウ、口紅、頬紅、頭髪化粧料、エモリエントクリーム、エモリエントローション、クリーム、クリームリンス、コールドクリーム、バニッシングクリーム、ローション、パック剤、ジェル、フェイスパック、石鹸、ボディーソープ、シャンプー、コンディショナー、リンス、入浴剤、浴用剤、洗顔料、シェービングクリーム、ヘアクリーム、ヘアローション、ヘアートリートメント、髪パック、グロス、リップクリーム等が挙げられる。特に皮膚に長時間接触したまま使用するスキンケア化粧品に本発明は有効であるが、これに限定されない。また、前記機能性皮膚外用剤は医薬品または医薬部外品であってもよい。 <Processing to functional skin external preparation>
Preferred examples of functional skin external preparations include skin care cosmetics. Specifically, lotion, milky lotion, cream, foundation, eye shadow, lipstick, blush, hair cosmetic, emollient cream, emollient lotion, cream, cream rinse, cold cream, vanishing cream, lotion, pack agent, gel, face Packs, soaps, body soaps, shampoos, conditioners, rinses, bath agents, bath agents, face wash, face creams, shaving creams, hair creams, hair lotions, hair treatments, hair packs, gloss, lip balms and the like. The present invention is particularly effective for skin care cosmetics which are used while being in contact with the skin for a long time, but is not limited thereto. In addition, the functional skin external preparation may be a drug or quasi drug.
　なお、機能性皮膚外用剤の剤型については、任意であるが、例えば、化粧水、クリーム、軟膏、乳液、ファンデーション、オイル、パック、石鹸（薬用石鹸も含む）、ボディーソープ、口紅、爪化粧品、眉目化粧品、香水、洗顔料、口腔用類（歯磨き、マウスウオッシュ等）、防臭剤（腋臭、足臭等）、浴用剤、シャンプー、リンス、ヘアトニック、ヘアスプレー、染毛料等の剤型が挙げられる。 In addition, about the dosage form of a functional skin external preparation, although it is arbitrary, for example, a lotion, a cream, an ointment, a milk, a foundation, an oil, a pack, a soap (including medicated soap), a body soap, a lipstick, a nail cosmetics Cosmetics, perfumes, facial cleansers, oral cavity (toothpaste, mouthwash, etc.), deodorant (stardust, foot odor etc.), bath agent, shampoo, rinse, hair tonic, hair spray, hair dye etc. It can be mentioned.
　なお、本発明におけるポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を、例えばスキンケア化粧品の有効成分とする場合には、基材としての水分や油脂分以外に、防腐剤や抗菌剤、乳化剤、界面活性剤、ｐＨ調整剤等の成分調整剤や、香料成分、着色料等を、スキンケア化粧品の目的や用途に応じ適宜添加しても構わない。 In the case where at least one of the polyhydroxy aromatic carboxylic acid and the derivative thereof in the present invention is used as an active ingredient of, for example, skin care cosmetics, preservatives, antibacterial agents, emulsifiers, in addition to water and oil as a substrate. You may add suitably component adjustment agents, such as surfactant and a pH adjuster, a spice component, a coloring agent, etc. according to the objective and use of skin care cosmetics.
　＜抗菌剤等への加工＞
　本発明の抗菌剤は、各種組成物に配合されることにより、抗菌作用を発現する。
　本発明の抗菌剤は、本発明の効果を損なわない範囲内でいかなる組成物に配合されてもよいが、例えば、食品、化粧品、日用品、洗浄料、医薬品、医薬部外品等に配合される。 <Processing to antibacterial agents>
The antimicrobial agent of the present invention exhibits an antimicrobial effect by being blended in various compositions.
The antimicrobial agent of the present invention may be blended into any composition within the range not impairing the effects of the present invention, but it is blended, for example, in food, cosmetics, daily necessities, cleaning agents, medicines, quasi-drugs, etc. .
　その場合、他の成分とともに併用されてもよい。他の成分としては、例えば、砂糖、練乳、小麦粉、ショートニング、食塩、ブドウ糖、鶏卵、バター、マーガリン、水飴、カルシウム、鉄分、調味料、香辛料や油分（動植物油、鉱物油、エステル油、ワックス油、シリコーン油、高級アルコール、リン脂質類、脂肪酸類等）、界面活性剤（アニオン性、カチオン性、両性または非イオン性界面活性剤）、ビタミン類（ビタミンＡ群、ビタミンＢ群、葉酸類、ニコチン酸類、パントテン酸類、ビオチン類、ビタミンＣ群、ビタミンＤ群、ビタミンＥ群、その他フェルラ酸、γ－オリザノール等）、紫外線吸収剤（ｐ－アミノ安息香酸、アントラニル酸、サルチル酸、クマリン、ベンゾトリアゾール、テトラゾール、イミダゾリン、ピリミジン、ジオキサン、フラン、ピロン、カンファー、核酸、アラントインまたはそれらの誘導体、アミノ酸系化合物、シコニン、バイカリン、バイカレイン、ベルベリン等）、抗酸化剤（ステアリン酸エステル、ノルジヒドログアセレテン酸、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、パラヒドロキシアニソール、没食子酸プロピル、セサモール、セサモリン、ゴシポール等）、増粘剤（ヒドキシエチルセルロース、エチルセルロース、カルボキシエチルセルロース、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドキシプロピルセルロース、ニトロセルロース、ポリビニルアルコール、ポリビニルメチルエーテル、ポリビニルピロリドン、ポリビニルメタアクリレート、ポリアクリル酸塩、カルボキシビニルポリマー、アラビアゴム、トラガントゴム、寒天、カゼイン、デキストリン、ゼラチン、ペクチン、デンプン、アルギン酸またはその塩等）、保湿剤（プロピレングリコール、１，３－ブチレングリコール、ポリエチレングリコール、グリセリン、１，２－ペンタンジオール、ヘキシレングリコール、オクチレングリコール、コンドロイチン硫酸またはその塩、ヒアルロン酸またはその塩、乳酸ナトリウム等）、低級アルコール、多価アルコール、水溶性高分子、ｐＨ調整剤、防腐・防黴剤、着色料、香料、清涼剤、安定化剤、動・植物抽出物、動・植物性蛋白質またはその分解物、動・植物性多糖類またはその分解物、動・植物性糖蛋白質またはその分解物、微生物培養代謝成分、血流促進剤、消炎剤、抗炎症剤、抗アレルギー剤、細胞賦活剤、アミノ酸またはその塩、角質溶解剤、収斂剤、創傷治療剤、増泡剤、口腔用剤、消臭・脱臭剤、乳化剤等が挙げられる。なお、これらは１種で用いてもよくまたは２種以上を組み合わせて用いることができる。 In that case, it may be used together with other components. Other ingredients include, for example, sugar, condensed milk, flour, shortening, salt, glucose, chicken egg, butter, margarine, starch syrup, calcium, iron, seasonings, spices and oils (animal and vegetable oils, mineral oils, ester oils, wax oils , Silicone oils, higher alcohols, phospholipids, fatty acids, etc.), surfactants (anionic, cationic, amphoteric or nonionic surfactants), vitamins (vitamin group A, vitamin group B, folates, etc.) Nicotinic acids, pantothenic acids, biotins, vitamin C group, vitamin D group, vitamin E group, other ferulic acid, γ-oryzanol, etc., UV absorber (p-aminobenzoic acid, anthranilic acid, salicylic acid, coumarin, benzo) Triazole, tetrazole, imidazoline, pyrimidine, dioxane, furan, pyrone, camphor, nucleic acid Allantoin or derivatives thereof, amino acid compounds, shikonin, baicalin, baicalein, berberine etc., antioxidants (stearic acid esters, nordihydroguaselethenic acid, dibutylhydroxytoluene, butylhydroxyanisole, parahydroxyanisole, propyl gallate , Sesamol, sesamorin, gossypol etc., thickener (hydroxyethylcellulose, ethylcellulose, carboxyethylcellulose, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, nitrocellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, polyvinyl alcohol Methacrylate, polyacrylate, carboxyvinyl polymer, arabica Gum, tragacanth gum, agar, casein, dextrin, gelatin, pectin, starch, alginic acid or salts thereof, etc., moisturizers (propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerin, 1,2-pentanediol, hexylene Glycol, octylene glycol, chondroitin sulfate or its salts, hyaluronic acid or its salts, sodium lactate etc., lower alcohol, polyhydric alcohol, water-soluble polymer, pH adjuster, preservative / antifungal agent, coloring agent, flavor, Cooling agent, stabilizer, animal or plant extract, animal or plant protein or its degradation product, animal or plant polysaccharide or its degradation product, animal or plant glycoprotein or its degradation product, microorganism culture metabolism component, Blood flow promoter, anti-inflammatory agent, anti-inflammatory agent, anti-allergic agent, cell activator, amino acid or Salts, keratolytic agents, astringents, wound healing agents, foam boosters, oral agents, deodorant and deodorizing agents, emulsifying agents and the like. These may be used alone or in combination of two or more.
　なお、本発明の抗菌剤をその他の組成物に配合した場合の剤型については、任意である。例えば、経口薬剤、繊維製品（シーツ類、衣類等）、衛生綿類、ウエットティッシュや拭き取り用ペーパー類、除菌用クロスのような不織布、口腔用組成物（ガム、キャンデー等）、かまぼこ、ちくわのような水産ねり製品、ソーセージ、ハムのような畜産製品、洋菓子類、和菓子類、中華めん、うどん、そばのようなめん類、ソース、醤油、たれのような調味料、惣菜、ジュース、スープのような一般的な飲食類等の剤型とすることができる。 In addition, about the dosage form at the time of mix | blending the antibacterial agent of this invention to another composition, it is arbitrary. For example, oral medicine, textiles (sheets, clothes, etc.), sanitary cotton, wet tissues and wiping papers, non-woven fabrics such as sterilization cloths, oral compositions (gum, candy, etc.), kamaboko, chikuwa Such as fishery products such as fishery products, sausages, ham-like livestock products, western-style confectionery, Japanese-style confectionery, Chinese-style confectionery, Chinese noodles, udon, buckwheat noodles, sauces, soy sauce, seasonings such as sauce, sugar beet, juice, soup and so on It can be made into the dosage form of such as general food and drink.
　また、本発明の抗菌剤を配合した各種組成物の形態は、任意であるが、例えば、溶液状、クリーム状、ペースト状、ゲル状、ジェル状、泡状、固形状、粉末状等の形態とされる。 The form of various compositions containing the antibacterial agent of the present invention is arbitrary, but for example, forms such as solution, cream, paste, gel, gel, foam, solid, powder and the like It is assumed.
　また、本発明の抗菌剤を配合した各種組成物の目的、用途および用法によっては、本発明の抗菌剤を含有する液状組成物の使用方法に噴霧または蒸散を適用することも可能である。この場合、所期の効果および効能に応じて、本発明の抗菌剤は液状組成物に含有されるその他の成分とともに噴霧または蒸散してもよく、噴霧または蒸散されずに液状組成物に残存しても構わない。 In addition, depending on the purpose, use and usage of various compositions containing the antibacterial agent of the present invention, it is also possible to apply spraying or transpiration to the method of using the liquid composition containing the antibacterial agent of the present invention. In this case, depending on the desired effect and efficacy, the antimicrobial agent of the present invention may be sprayed or evaporated together with other components contained in the liquid composition, and remains in the liquid composition without being sprayed or evaporated. It does not matter.
　以下、実施例に基づいて本発明をより具体的に説明する。
　＜バイオプロセスによる３，４－ジヒドロキシ安息香酸の製造＞
　１０Ｌジャーファーメンターでのバイオプロセスにより、３，４－ジヒドロキシ安息香酸の製造を行った。培地としてＬＢ培地を用いた。また、植物由来糖類（原料）として、サトウキビのしぼりかすから精製した糖を用いた。この糖を１０％の割合でＬＢ培地に溶解させた培養液を調製した。この培養液をｐＨ７／３３℃の条件下で４８時間バイオプロセスに供し、３，４－ジヒドロキシ安息香酸を５３．６ｍＭ（８．２５ｇ／Ｌ）含有する培養液を得た。 Hereinafter, the present invention will be more specifically described based on examples.
<Production of 3,4-dihydroxybenzoic acid by bioprocess>
Production of 3,4-dihydroxybenzoic acid was carried out by bioprocess in a 10 L jar fermenter. LB medium was used as the medium. Further, as the plant-derived saccharide (raw material), sugar purified from sugarcane sorghum was used. A culture solution in which this sugar was dissolved in LB medium at a rate of 10% was prepared. This culture broth was subjected to a bioprocess at pH 7/33 ° C. for 48 hours to obtain a culture broth containing 53.6 mM (8.25 g / L) of 3,4-dihydroxybenzoic acid.
　＜培養液から濃縮精製プロセスを経て３，４－ジヒドロキシ安息香酸の回収＞
　バイオプロセスにより得られた培養液を、減圧濃縮により総固形分濃度が１５～３０質量％となるように濃縮処理を行った。減圧度を１００～５０００Ｐａ、液温を３０～８０℃とし、減圧蒸留設備による濃縮処理を行った。濃縮度は処理時間に依存するが、６～８時間の濃縮処理により総固形分濃度が１５～３０質量％の濃縮液を回収した。この濃縮液に塩酸を添加してｐＨ４以下とし、さらに０℃～室温に冷却した。晶析物を濾過により回収し、適宜洗浄ののち、減圧乾燥を行い、純度９９％以上の高純度３，４－ジヒドロキシ安息香酸を回収した。 <Recovery of 3,4-dihydroxybenzoic acid from culture broth through concentration and purification process>
The culture broth obtained by the bioprocess was concentrated under reduced pressure to a total solid concentration of 15 to 30% by mass. The pressure reduction degree was 100 to 5000 Pa, the liquid temperature was 30 to 80 ° C., and concentration processing was performed using a vacuum distillation apparatus. The degree of concentration depends on the treatment time, but a concentration of 15 to 30% by mass of a total solid concentration was recovered by concentration for 6 to 8 hours. Hydrochloric acid was added to the concentrate to adjust the pH to 4 or less, and the mixture was further cooled to 0 ° C. to room temperature. The crystallized material was recovered by filtration, appropriately washed and then dried under reduced pressure to recover high purity 3,4-dihydroxybenzoic acid having a purity of 99% or more.
　＜３，４－ジヒドロキシ安息香酸を有効成分として含有する機能性皮膚外用剤の評価＞
　機能性皮膚外用剤の具体例として、上記３，４－ジヒドロキシ安息香酸を含む化粧水を調製した。具体的には、３，４－ジヒドロキシ安息香酸０．１％、グリセリン５．０％、プロピレングリコール４．０％、エタノール８．０％、クエン酸０．０１％、クエン酸ナトリウム０．１％、ヒアルロン酸ナトリウム２．０％、リン酸化糖カリウム５．０％、さらに香料および防腐剤を適量含有する化粧水を調製した。この化粧水は、石油由来の不純物を含まないものであった。 <Evaluation of functional skin external preparation containing 3,4-dihydroxybenzoic acid as an active ingredient>
As a specific example of the functional external skin preparation, a lotion containing the 3,4-dihydroxybenzoic acid was prepared. Specifically, 3,4-dihydroxybenzoic acid 0.1%, glycerin 5.0%, propylene glycol 4.0%, ethanol 8.0%, citric acid 0.01%, sodium citrate 0.1% A lotion containing 2.0% sodium hyaluronate, 5.0% potassium phosphate potassium, and an appropriate amount of a fragrance and a preservative was prepared. This lotion did not contain petroleum-derived impurities.
　＜３，４－ジヒドロキシ安息香酸を有効成分として含有する抗菌剤の評価＞
　抗菌剤による抗菌効果を評価するため、各種の菌に対する抗菌剤の薬剤感受性検査を行った。各種試験菌（大腸菌（Escherichia coli）、緑膿菌（Pseudomonas aeruginosa）、黄色ブドウ球菌（Staphylococcus aureus）、カンジダ菌（Candida albicans）、黒コウジカビ（Aspergillus niger））に対する最小発育阻止濃度（ＭＩＣ）を求めたところ、全ての試験菌に対して良好な抗菌性を示した。 <Evaluation of antibacterial agent containing 3,4-dihydroxybenzoic acid as an active ingredient>
In order to evaluate the antimicrobial effect of the antimicrobial agent, drug sensitivity test of the antimicrobial agent to various bacteria was conducted. The minimum inhibitory concentration (MIC) against various test bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Aspergillus niger) was determined. As a result, it showed good antibacterial activity against all test bacteria.
　なお、この評価に使用した抗菌剤は、上記３，４－ジヒドロキシ安息香酸を含む化粧水であった。具体的には、抗菌剤は、３，４－ジヒドロキシ安息香酸０．１％、グリセリン５．０％、プロピレングリコール４．０％、エタノール８．０％、クエン酸０．０１％、クエン酸ナトリウム０．１％、ヒアルロン酸ナトリウム２．０％、リン酸化糖カリウム５．０％、さらに香料を適量含有する化粧水であった。この化粧水は、石油由来の不純物を含まず、有効成分として、３，４－ジヒドロキシ安息香酸（ポリヒドロキシ芳香族カルボン酸）のみを含んでいた。このため、石油由来の不純物を含む抗菌剤に比べて、より安全な抗菌剤を提供することができた。さらに、有効成分を２以上含む抗菌剤に比べて、有効成分同士の相互作用による影響がなく、抗菌作用を確実に発揮し得る抗菌剤を提供することができたと考えられる。このため、本発明は、抗菌のための機能性皮膚外用剤における、植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方の使用に関するということもできる。 The antibacterial agent used for this evaluation was a lotion containing the 3,4-dihydroxybenzoic acid. Specifically, the antibacterial agent is 3,4-dihydroxybenzoic acid 0.1%, glycerin 5.0%, propylene glycol 4.0%, ethanol 8.0%, citric acid 0.01%, sodium citrate It was a lotion containing 0.1%, sodium hyaluronate 2.0%, phosphated potassium phosphate 5.0%, and an appropriate amount of perfume. This lotion did not contain petroleum-derived impurities and contained only 3,4-dihydroxybenzoic acid (polyhydroxy aromatic carboxylic acid) as an active ingredient. For this reason, the safer antibacterial agent was able to be provided compared with the antibacterial agent containing the impurity derived from petroleum. Furthermore, compared with the antibacterial agent containing 2 or more of active ingredients, it is thought that there was no influence by interaction of active ingredients, and the antibacterial agent which can exhibit an antimicrobial effect reliably could be provided. Therefore, it can be said that the present invention relates to the use of at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof in functional skin external preparations for antibacterial.
　本発明によれば、ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有し、石油由来の不純物を含まない機能性皮膚外用剤および抗菌剤を提供することができる。また、これらの機能性皮膚外用剤または抗菌剤の有効成分として用いることが可能な、ポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法を提供することができる。したがって、本発明は、産業上の利用可能性を有する。 According to the present invention, it is possible to provide a functional external preparation for skin and an antimicrobial agent which contains at least one of polyhydroxyaromatic carboxylic acid and its derivative as an active ingredient and does not contain petroleum-derived impurities. Moreover, the manufacturing method of polyhydroxy aromatic carboxylic acid or its derivative (s) which can be used as an active ingredient of these functional skin external preparations or an antimicrobial agent can be provided. Thus, the present invention has industrial applicability.

Claims (10)

  1. 　植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有することを特徴とする機能性皮膚外用剤。 A functional external skin preparation comprising as an active ingredient at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof.
  2. 　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、下記一般式（１）で表される化合物である請求項１に記載の機能性皮膚外用剤。
    Figure JPOXMLDOC01-appb-C000001
     ［前記一般式（１）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかを表し、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。］     The functional skin external preparation according to claim 1, wherein the polyhydroxy aromatic carboxylic acid and the derivative thereof are a compound represented by the following general formula (1).
    Figure JPOXMLDOC01-appb-C000001
     [In the above general formula (1), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. ]
  3. 　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、下記一般式（２）で表される化合物である請求項１に記載の機能性皮膚外用剤。
    Figure JPOXMLDOC01-appb-C000002
     ［前記一般式（２）中、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６は、独立して、Ｈ、ＣＨ３、ＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）、ＯＨ、ＳＨ、ＣＯＯＨ、ＯＣＨ３、およびＯＣＨ２Ｒ（Ｒは１つ以上の炭素原子を含む置換基）のうちのいずれかであり、Ｘ２、Ｘ３、Ｘ４、Ｘ５およびＸ６のうちの少なくとも１つ以上はＯＨである。また、一般式（２）のＲ１は炭素数１～６の脂肪族アルキル基またはアルキレン基である。］     The functional skin external preparation according to claim 1, wherein the polyhydroxy aromatic carboxylic acid and the derivative thereof are a compound represented by the following general formula (2).
    Figure JPOXMLDOC01-appb-C000002
     [In the above general formula (2), X 2 , X 3 , X 4 , X 5 and X 6 are independently H, CH 3 , CH 2 R (R is a substituent containing one or more carbon atoms X 2 , X 3 , X 4 , X 5 and X), OH, SH, COOH, OCH 3 , and OCH 2 R (wherein R is a substituent containing one or more carbon atoms); At least one or more of 6 is OH. Further, R 1 in the general formula (2) is an aliphatic alkyl group having 1 to 6 carbon atoms or an alkylene group. ]
  4. 　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、２－ヒドロキシ安息香酸、３－ヒドロキシ安息香酸、４－ヒドロキシ安息香酸、２，３－ジヒドロキシ安息香酸、２，４－ジヒドロキシ安息香酸、２，５－ジヒドロキシ安息香酸、２，６－ジヒドロキシ安息香酸、３，４－ジヒドロキシ安息香酸および３，５－ジヒドロキシ安息香酸からなる群から選択される少なくとも１種である請求項２に記載の機能性皮膚外用剤。 The said polyhydroxy aromatic carboxylic acid and its derivative are 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5- The functional external skin preparation according to claim 2, which is at least one selected from the group consisting of dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid. .
  5. 　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体が、３－（２，３－ジヒドロキシ）プロパン－２－エノール酸、３－（２－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸、および３－（４－ヒドロキシ－３－メトキシフェニル）プロパン－２－エノール酸からなる群から選択される少なくとも１種である請求項３に記載の機能性皮膚外用剤。 The polyhydroxy aromatic carboxylic acid and its derivative are 3- (2,3-dihydroxy) propane-2-enolic acid, 3- (2-hydroxy-3-methoxyphenyl) propane-2-enolic acid, and 3- The functional external skin preparation according to claim 3, which is at least one selected from the group consisting of (4-hydroxy-3-methoxyphenyl) propane-2-enolic acid.
  6. 　前記一般式（２）のＲ１は、分岐または環状構造を含む請求項３に記載の機能性皮膚外用剤。 The functional skin external preparation according to claim 3, wherein R 1 in the general formula (2) contains a branched or cyclic structure.
  7. 　前記微生物が、大腸菌、枯草菌、黄色ブドウ球菌、コリネ菌、放線菌、ラン藻菌、メタン生成菌、好塩菌、高温好酸菌、耐熱性好酸菌、抗酸菌、カビ、酵母またはそれらの形質転換体である請求項１に記載の機能性皮膚外用剤。 The microorganism is Escherichia coli, Bacillus subtilis, Staphylococcus aureus, coryneform bacteria, actinomycetes, cyanobacteria, methanogens, halophilic bacteria, thermophilic acid-fast bacteria, heat-resistant acid-fast bacteria, acid-fast bacteria, fungi, yeasts or The functional skin external preparation according to claim 1, which is a transformant thereof.
  8. 　前記植物由来糖類の原料が、非可食のバイオマス資源である請求項１ないし７のいずれか１項に記載の機能性皮膚外用剤。 The functional skin external preparation according to any one of claims 1 to 7, wherein the plant-derived saccharide raw material is a non-edible biomass resource.
  9. 　植物由来糖類および微生物を由来とするポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を有効成分として含有することを特徴とする抗菌剤。 An antibacterial agent comprising, as an active ingredient, at least one of plant-derived saccharides and polyhydroxyaromatic carboxylic acids derived from microorganisms and derivatives thereof.
  10. 　機能性皮膚外用剤または抗菌剤の有効成分として用いられる、ポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法であって、
    　前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を生成するように、植物由来糖類と、微生物とを含む培養液を調製する工程と、
    　前記培養液を濃縮して濃縮液を得る工程と、
    　前記濃縮液から晶析法、沈殿法、抽出法、昇華精製法または蒸留法により前記ポリヒドロキシ芳香族カルボン酸およびその誘導体の少なくとも一方を回収する工程と、
    を含むポリヒドロキシ芳香族カルボン酸またはその誘導体の製造方法。     A method for producing a polyhydroxy aromatic carboxylic acid or a derivative thereof, which is used as an active ingredient of a functional external skin preparation or an antibacterial agent,
    Preparing a culture solution containing a plant-derived saccharide and a microorganism to produce at least one of the polyhydroxy aromatic carboxylic acid and a derivative thereof;
    Concentrating the culture to obtain a concentrate;
    Recovering at least one of the polyhydroxy aromatic carboxylic acid and its derivative from the concentrate by a crystallization method, a precipitation method, an extraction method, a sublimation purification method or a distillation method;
    A process for producing a polyhydroxyaromatic carboxylic acid or derivative thereof comprising
PCT/JP2018/031594 2017-08-30 2018-08-27 Functional skin preparation for external use, antimicrobial agent and method for producing aromatic polyhydroxycarboxylic acid or derivative thereof WO2019044773A1 (en)

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