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WO2006106995A1 - Inhibiteur de la metalloproteinase comprenant un ingredient extrait d’amula - Google Patents

Inhibiteur de la metalloproteinase comprenant un ingredient extrait d’amula Download PDF

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Publication number
WO2006106995A1
WO2006106995A1 PCT/JP2006/306979 JP2006306979W WO2006106995A1 WO 2006106995 A1 WO2006106995 A1 WO 2006106995A1 JP 2006306979 W JP2006306979 W JP 2006306979W WO 2006106995 A1 WO2006106995 A1 WO 2006106995A1
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Prior art keywords
mmp
oil
patent document
solvent
inhibitor
Prior art date
Application number
PCT/JP2006/306979
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English (en)
Japanese (ja)
Inventor
Keisuke Kajita
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Kobayashi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kobayashi Pharmaceutical Co., Ltd. filed Critical Kobayashi Pharmaceutical Co., Ltd.
Publication of WO2006106995A1 publication Critical patent/WO2006106995A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • 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
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to a novel matrix meta-oral protease inhibitor.
  • the extracellular matrix is a biopolymer containing collagen, proteodarican, elastin and the like as main components, and plays a role in filling gaps existing between cells constituting the body tissue of mammals.
  • MMP matrix metaprotease
  • TMP tissue-derived meta-oral protease inhibitor
  • MMP plays a central role in the degradation of extracellular matrix in various pathologies such as cancer (cancer) disease, ulceration, rheumatoid arthritis, osteoporosis, periodontitis and gingivitis. Quality (see Non-Patent Document 1).
  • MMP whose activity has been enhanced by external stimuli such as ultraviolet rays, decomposes components important for maintaining the structure of the skin. Therefore, it has an aspect as a skin aging promoting factor that is activated by ultraviolet rays. Have both.
  • MMP is produced by a wide variety of cells, including collagenase (MMP-1 and MMP-8), stromelysin (MMP-3), gelatinase (MMP-2 and MMP-9), etc. 10 More than one kind of enzyme molecular species power S has been reported so far (see Non-Patent Document 2).
  • collagenase is not normally produced from epithelial cells, but it has been reported that it is expressed around the adhering epithelium and periodontal pocket epithelium of periodontal tissue (see Non-Patent Document 3). ).
  • gelatinase has been reported to be produced by epithelial cell force due to stimulation by lipopolysaccharide derived from periodontal disease-causing bacteria, and to degrade type IV collagen, which is a component of the basement membrane. In other words, this suggests that it is closely correlated with the progression of periodontal disease as well as the ability to increase MMP activity.
  • MMP inhibitors substances such as hydroxamic acid derivatives (see Patent Documents 1 and 2) and estaletin derivatives (see Patent Document 3) have been synthesized so far, and flavones derived from natural products have also been synthesized. Inhibitors containing sucrose and anthocyanins as active ingredients have also been proposed (see Patent Document 4). In addition, dexamethasone, a kind of darcocorticoids, has been synthesized as a substance that inhibits MMP production in cells (see Non-Patent Document 6).
  • an inhibitor Z substance derived from a natural product for the collagenase described above an inhibitor containing hexex or a thin load extract as an active ingredient (see Patent Document 5), nordihydroguaya retech acid is effective.
  • Ingredients see Patent Document 6
  • Polypolenic Acid C as an active ingredient (see Patent Document 7)
  • tetracyclic triterpene 20-carboxy- 16-hydroxy- 21- nor- 5
  • Patent Document 1 Japanese Patent Publication No. 7-505387
  • Patent Document 2 JP-A-8-81443
  • Patent Document 3 JP-A-8-183785
  • Patent Document 4 JP-A-8-104628
  • Patent Document 5 JP-A-6-183990
  • Patent Document 6 Japanese Patent Laid-Open No. 4-217626
  • Patent Document 7 JP-A-9-40552
  • Patent Document 8 Japanese Patent Laid-Open No. 9-235293
  • Patent Document 9 Japanese Patent Laid-Open No. 2000-191487
  • Patent Document 10 Japanese Patent Laid-Open No. 2003-171307
  • Non-Patent Document 1 Nakata, Okada, "Respiration", 18, 4, pp.365-371 (1999)
  • Non-Patent Document 2 Yoshihara, Shinna, “Inflammation and Immunity", 2, pp.177-185 (1994)
  • Non-Patent Document 3 M. Kylmaniemi, et al: J. Dent Res., 75, pp. 919-926 (1996)
  • Non-Patent Document 4 M. Makela, et al: J. Dent Res., 73, pp. 1397-1406 (1994)
  • Non-Patent Document 5 A. Haerian, et al: J. ClinPeriodontoL, 22, pp.505-509 (1995)
  • Non-Patent Document 6 M. Kylmaniemi: J. Dent. Res., 75, pp.919-926 ( 1996)
  • An object of the present invention is to provide a novel MMP inhibitor that has an excellent inhibitory effect on MMP activity and improves the preventive and therapeutic effects of oral diseases such as gingivitis and periodontitis.
  • the gist of the present invention is a medicinal plant that has been well known since ancient times, and has been confirmed to be safe for humans.
  • Amla (Latin scientific name: Emblica officinalis Gaer tn. Myrobalan) is an MMP inhibitor containing a separated component obtained by extraction with a solvent.
  • the composition for oral cavity, foodstuffs, cosmetics, etc. which use the MMP inhibitor of this invention as an active ingredient are also provided.
  • the invention's effect [0013] According to the present invention, a novel MMP inhibitor that has an excellent inhibitory effect on MMP activity and is suitable for use in the prevention and treatment of oral diseases such as gingivitis and periodontitis is realized. .
  • oral compositions, foods, cosmetics, etc. that incorporate these MMP inhibitors as active ingredients, and eating or using them, the effects of MMP inhibitors can be enjoyed easily and continuously. Can do.
  • an MMP inhibitor comprising a separation component obtained by extracting amla with a solvent.
  • MMP inhibition refers to inhibition of enzyme activity of MMP and inhibition of production of MMP in Z or cells.
  • the inhibition of intracellular MMP production means that the MMP produced by cells constituting the periodontal tissue of mammals suffering from diseases such as gingivitis and periodontitis are extracellular cells that exist between the periodontal tissues. It is to inhibit a series of actions that break down the matrix and lead to destruction of the tissue.
  • Inhibition of MMP production means that cells constituting the periodontal tissue of mammals suffering from diseases such as gingivitis and periodontitis inhibit MMP production and accumulate MMP in the same tissue. By suppressing it, it means avoiding the destruction of periodontal tissue.
  • Amla is a medicinal plant that has been used as a tonic in India since ancient times.
  • the fruit contains about 3,000 mg of thermostable vitamin C, which is very well absorbed by the body, which is comparable to the total amount of vitamin C in 12 oranges. .
  • the fruit of Amla activates living tissue, increases red blood cell count, cleansing action in the mouth, hemostasis of gum bleeding, visual acuity improvement, bone regeneration, promotion of hair and nail growth, prevention of white hair formation, blood sugar level It is said to act on regulation and reduction of gastrointestinal inflammation.
  • the fruit of Amla is applied to an extraction process using a solvent.
  • the fruit applied in the extraction process can be applied to the extraction process as it is, or after being physically crushed, or if necessary, dried and pulverized into a powder. it can.
  • a solvent well known in the art can be used, for example, a lower alcohol, a polyhydric alcohol, a nonpolar solvent, a polar solvent, or the like is used. it can.
  • Examples of the lower alcohol include alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol, isopropyl alcohol, and butanol; examples of the polyhydric alcohol include glycerin and polyethylene glycol; and examples of the nonpolar solvent include pentane. Saturated hydrocarbons such as hexane, heptane, octane, nonane and decane; polar solvents include water, warm water (hot water), acetone, ethyl acetate, and methyl acetate.
  • the solvent it is possible to select and use only one of the above-mentioned solvents, and it is also possible to use a combination of two or more kinds of solvents.
  • the degreasing extraction treatment with a non-polar solvent may be followed by the extraction treatment with an arbitrary solvent or the extraction treatment with a water-containing organic solvent. .
  • a method of immersing Amla fruit itself, a coarse powdered or cut product thereof, or a dried crushed product (powder) thereof in a solvent by cold immersion, digestion or the like, or heating and stirring.
  • extracting a method of obtaining an extract containing a desired separated component through filtration, and a bar-collation method can also be used.
  • the extract obtained as described above is used as it is, depending on the use mode, after removing unnecessary solid matter (solid content) by filtration or centrifugation, if necessary, or a solvent Can be used after partially evaporating and partially concentrated or dried.
  • the separated product obtained by concentrating or drying may be used after being purified by washing with a non-soluble solvent, or it may be used by further dissolving or suspending it in an appropriate solvent. You can also.
  • a fraction having a desired inhibitory activity is obtained and purified by using a conventional purification method such as a countercurrent distribution method or liquid chromatography. It is also possible to use it.
  • the solvent extract obtained as described above can be processed into a dried concentrated extract form by a usual drying means such as reduced pressure drying or freeze drying.
  • the MMP inhibitor of the present invention is effectively produced.
  • An oral composition is also provided.
  • the amount of the separated component obtained by extracting Amla in the oral composition of the present invention with a solvent is usually about 0.0001 to about 20% by weight, preferably about 0.0001 to about 20% by dry weight. It is prepared in the range of 10% by weight. This means that if the blending amount of the separated component is less than about 0.0001% by weight, the corresponding MMP inhibitory effect will not be expressed, while if it exceeds about 20% by weight, This is because the taste of the composition becomes unpleasant and the desired inhibitory effect cannot be obtained.
  • Examples of the pressure-sensitive adhesive include water-soluble polymer substances derived from polysaccharides, cellulose polymer substances, synthetic polymer substances, natural polymer substances, amino acid polymer substances, rubber polymer substances, and the like. Is available.
  • polysaccharides such as pullulan, pullulan derivatives and starch; hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methenoresenorelose, hydroxyethino retino resenorelose, canoleboxy methino rescenellose salts (carboxymethyl cellulose, Sodium carboxymethylcellulose and potassium ruboxymethylcellulose), methinoresanolose, ethyl cellulose, polyacrylic acid, polyacrylate (such as sodium polyacrylate and acrylic acid / octyl acrylate copolymer), meta Copolymers of acrylic acids (polymers of methacrylic acid and n-butyl acrylate, polymers of methacrylic acid
  • Examples of the refreshing agent include 1-menthol, cQ-menthol, heart force oil, camphor, heart force water, borneol, peppermint essential oil, spearmint essential oil, and the like that are usable in the present invention. Any one of these can be used alone, or two or more can be used in combination.
  • binders include sugars (such as glucose), sugar alcohols (such as sorbitol, xylitol, erythritol, mannitol), polybulurpyrrolidone, starches, macrogol, dextrin, tragacanth, gelatin, polybulul alcohol, Shellac, gum arabic, sodium alginate, hydroxypropylcellulose, and the like are available in the present invention, but are not limited to these. The above can also be used together.
  • saccharin sodium, stepioside, stevia extract, aspartame, xylitol, starch syrup, honey, sorbitol, maltitol, mannitol, sugars (lactose, sucrose, fructose, glucose, etc.) are claimed in the present invention.
  • the present invention is not limited to these, and any one of them can be used alone, or two or more can be used in combination.
  • Natural flavors (spearmint oil, varnish oil, eucalyptus oil, wintergreen oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, heart power oil, power rudamon oil, Coriander oil, mandarin oil, lime oil, lavender oil, rosemary oil, laurel oil, camomil oil, caraway oil, marjoram oil, bay oil, lemongrass oil, orina gum oil, pine-dollar oil, etc.), synthetic Perfume (Carbon, Anethole, Cineol, Methyl salicylate, Cynamic aldehyde, Eugenol, Thymol, Linalol, Linalyl acetate, Limonene, Menthone, Menthyl acetate, Pinene, Octylaldehyde, Citral, Pregon, Calbele acetate, Anisaldehyde Natural fragrances listed above and , Or the like blended fragrance obtained by mixing the selected fragrance arbitrarily
  • disintegrants include starches, methylcellulose, crystalline cellulose, cellulose derivatives (such as sodium carboxymethylcellulose), alginic acid, alginates, carbonates, organic acids, polyvinylpyrrolidone, and crosslinked polybutyropyrrolidone in the present invention. It can be used, but not limited to these, only one of these can be used, or two or more can be used in combination.
  • Lubricants include talc, metal sarcophagus, fatty acids (such as stearic acid), stearates (such as magnesium stearate), talc, sucrose fatty acid esters, hydrous silicon dioxide, light anhydrous key acid, dry water Acid-aluminum gel, macrogol, etc. can be used in the present invention, but are not limited to these, use only one of these V, or use two or more together You can also.
  • blue No. 1, yellow No. 4, titanium dioxide, copper chlorophyllin sodium and the like are usable in the invention of the present application. Can be used, or two or more types can be used in combination.
  • preservatives include benzoic acids, salicylic acids, sorbic acids, norabens, cetylpyridinium chloride, decalinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine chloride, chlorhexidine darconate, isopropylmethylphenol, Forces that can be used in the present invention, such as trickle san, hinokitiol, phenol, etc., are not limited to these. Any one of these forces can be used, or two or more can be used in combination.
  • sustained release modifier polyvinyl acetate, ethyl cellulose, aminoalkyl metaacrylate copolymer and the like that can be used in the present invention S, and any one of these not limited to these 1 It is possible to use only one type or use both.
  • sucrose fatty acid ester polyoxyethylene hydrogenated castor oil, sorbitan monostearate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol and the like can be used in the present invention.
  • a certain force is not limited to these. Either one of these may be used, or two or more may be used. The above can also be used together.
  • solubilizer glycerin, concentrated glycerin, propylene glycol, ethanol, fluidized oil ⁇ raffin, purified water, macrogol, polysorbate, etc.
  • solubilizer glycerin, concentrated glycerin, propylene glycol, ethanol, fluidized oil ⁇ raffin, purified water, macrogol, polysorbate, etc.
  • Either one of these forces can be used, or two or more can be used in combination.
  • wetting agent glycerin, propylene glycol, sorbitol liquid, water, ethanol, dilute ethanol and the like are usable in the present invention. Or, use two or more types together.
  • lactic acid pantothenic acid, phosphate, malic acid, citrate, and the like can be used in the invention of the present application. Can be used, or two or more types can be used in combination.
  • any of tablets, pills, granules, solutions, sheets, gels, pastes and the like can be used.
  • periodontitis, gingivitis, periodontitis, wisdom teeth can be obtained by using a toothpaste, mouthwash, oral pasta, troche, etc.
  • a toothpaste, mouthwash, oral pasta, troche, etc. Can effectively deal with prevention and treatment of oral diseases caused by destruction of periodontal tissues such as peritonitis and peri-implantitis
  • Wikiyo Fraeniculum vulgare
  • MMP-2 Active, Human
  • MMP-9 Recombinant, Active (67kD) j (5 ⁇ g, CA LBIOCHEM, catalog # PF140), 30 mM
  • HEPES pH 7.4 [contains 5 mM calcium chloride, 0.2 M sodium chloride, 0.02% sodium azide] Prepared with 2 ml and stored at -20 ° C.
  • MMP-2 sample and MMP-9 sample placed the MMP-2 sample and MMP-9 sample converted to SDS with Tris-HCl (pH 6.8) [containing 10% SDS and 50% glycerol] in the grooves for 2.0 1, 1.5 1 sample application, respectively.
  • Gelatin zymography was performed under an electric load condition of 250 V and 20 mA.
  • a buffer solution for the electrophoresis phase of SDS-PAGE a buffer solution containing 25 mM Tris, 192 mM glycine, and 0.1% SDS was used. After finishing electrophoresis, 2.5% Triton
  • the separation gel was immersed twice in a solution of X-IOO (SIGMA) at room temperature for 30 minutes to remove SDS. Then 50 mM Tris-HCl containing 200 mM sodium chloride, 5 mM calcium chloride, 0.02% sodium azide
  • Example A gel for concentration [3% acrylamide ⁇ .8% bisacrylamide, 0.125M Tris-HCl (pH 6.8), 0.100% SDS, 0.095% APS, 0.250% TEMED], and incubated at 37 ° C for 19 hours. At this time, the sample solution of each dry extract (concentration of 1% and 0.1%) prepared in Example A was added to the Tris-HCl buffer.
  • FIG. 1 (a) shows that Amla (Emblica officinalis
  • Fig. 1 (b) shows the separated components obtained by extracting Wikiu (Foeniculum vulgare Mill.) With a solvent. This is the test area used. Then, the direction of the center line of the broken line added on each gel, the MMP-2 sample force is applied to the left lane, and the MMP-9 sample is placed in the right lane and subjected to electrophoresis. . Also, no MMP inhibitory component was included! /, The gel was used as a negative control, and the 0-phenantorin (ImM) gel was used as a positive control.
  • Wikiu Freeniculum vulgare Mill.
  • the MMP inhibitor of the present invention containing a separation component obtained by extracting Ammura (Emblica officinalis Gaertn.) With a solvent can exert an MMP inhibitory effect. confirmed. Further, the MMP inhibitor of the present invention has a low concentration. Nevertheless, it had sufficient MMP inhibitory activity for practical use.
  • compositions for oral cavity were prepared by blending an amla extract (1.0%).
  • the unit of the component blending amount in this example is expressed in wt% unless otherwise specified.
  • Toothpastes were prepared by mixing and kneading the materials shown in Table 3 below at room temperature.
  • the unit of the compounding amount in this example is expressed in weight% unless otherwise specified.
  • the unit of the component blending amount in this example is expressed in weight% unless otherwise specified.
  • a lotion was prepared by mixing the materials shown in Table 8 below at room temperature.
  • the MMP inhibitor of the present invention is useful as a means for preventing and treating oral diseases such as gingivitis and periodontitis.
  • FIG. L (a) Amla (Emblica officinalis Gaertn.) And (b) Wikiyo (Foeniculum vulgare Mill.

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Abstract

Les problèmes à résoudre dans le cadre de la présente invention consistent en un nouvel inhibiteur de la métalloprotéinase (MMP) ayant un excellent effet inhibiteur sur une activité de la MMP. La solution apportée par l'invention consiste en un inhibiteur MMP comprenant un ingrédient produit en extrayant un fruit d’amula (Emblica officinalis Gaertn.) avec un solvant ; et une composition pour utilisation orale, un aliment et un produit cosmétique comprenant l’inhibiteur de la MMP.
PCT/JP2006/306979 2005-03-31 2006-03-31 Inhibiteur de la metalloproteinase comprenant un ingredient extrait d’amula WO2006106995A1 (fr)

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JP2005103702A JP2006282561A (ja) 2005-03-31 2005-03-31 アムラの抽出成分を配合したマトリックスメタロプロテアーゼ阻害剤
JP2005-103702 2005-03-31

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JP5294536B2 (ja) * 2005-03-31 2013-09-18 小林製薬株式会社 歯肉上皮細胞伸展阻害剤
JP2008143784A (ja) * 2006-12-06 2008-06-26 B & C Laboratories Inc 細胞増殖促進剤
JP5657201B2 (ja) * 2008-09-30 2015-01-21 サンメディカル株式会社 酵素阻害作用または酵素阻害作用と抗菌作用とを有する歯科用組成物

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