WO2013176272A1 - Agent for the prevention and/or improvement of periodontal disease - Google Patents

Agent for the prevention and/or improvement of periodontal disease Download PDF

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Publication number
WO2013176272A1
WO2013176272A1 PCT/JP2013/064534 JP2013064534W WO2013176272A1 WO 2013176272 A1 WO2013176272 A1 WO 2013176272A1 JP 2013064534 W JP2013064534 W JP 2013064534W WO 2013176272 A1 WO2013176272 A1 WO 2013176272A1
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ascorbic acid
periodontal disease
agent
administration
food
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PCT/JP2013/064534
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French (fr)
Japanese (ja)
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翔子 田中
泰志 小池
伸介 片岡
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ライオン株式会社
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A23L33/15—Vitamins
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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

Definitions

  • the present invention relates to an agent for preventing and / or improving periodontal disease.
  • Periodontal disease is an inflammatory disease in which the periodontal tissues (gingiva, cementum, periodontal ligament, and alveolar bone) supporting the teeth are destroyed by infection with parasites (infectious bacteria). As periodontal disease progresses, it affects the generation of bad breath derived from bacteria, the destruction of gingival soft tissues such as periodontal ligament, and the destruction and absorption of periodontal tissues such as alveolar bone (Non-patent Document 1). At present, periodontal disease diagnosis is mainly performed by measuring alveolar bone resorption based on clinical indicators specified by X-ray imaging, dentist's visual inspection, and the like.
  • periodontal disease is a so-called bacterial infection caused by parasites (infectious bacteria), as a therapeutic agent for periodontal disease, bactericides, antibacterial agents, anti-plaque agents, anti-inflammatory agents, algin dipine inhibitors (patents) Reference 1) is used.
  • bactericides antibacterial agents, anti-plaque agents, anti-inflammatory agents, algin dipine inhibitors (patents) Reference 1) is used.
  • egg yolk-derived protein Patent Document 2 is known as a food having a therapeutic effect on periodontal disease.
  • L-ascorbic acid is known to be important for the synthesis of collagen in vivo, which is the main component of the bone matrix. That is, L-ascorbic acid is essential for the biosynthesis of amino acids specific to collagen, such as hydroxyproline and hydroxylysine. For example, when added to an osteoblast culture system, L-ascorbic acid promotes collagen synthesis, It is known to promote differentiation and bone formation.
  • Non-Patent Document 1 discloses that the stability of L-ascorbic acid 2-phosphate ester is higher than that of L-ascorbic acid, and that L-ascorbic acid 2-phosphate ester promotes the growth of cultured osteoblasts and It is described that it has a differentiation promoting effect.
  • periodontal disease As described above, the conventional prevention and treatment of periodontal disease has been performed focusing on the control of parasites (infectious bacteria), but their effects have not been sufficient. As a result, the incidence of periodontal disease is steadily increasing despite the decrease in the incidence of dental caries due to the spread of fluorine and the brushing habits.
  • Non-steroidal anti-inflammatory drugs are concerned about the spurious effects on the oral mucosa.
  • periodontal disease is recognized as a complication of diabetes.
  • periodontal disease is involved in not only the contribution of the parasite side but also the general background (health state) of the host side.
  • the present invention is intended to provide an active ingredient that can remarkably exert a therapeutic and preventive effect on periodontal disease and can be used as a food or drink.
  • the present inventors have found that symptoms such as periodontal disease (such as downward proliferation of gingival epithelium, periodontal pocket formation, and alveolar bone resorption) spontaneously develop in diabetic model mice. Further, when a test was conducted in which an L-ascorbic acid derivative was administered to animals, it was found that downward growth of the gingival epithelium, periodontal pocket formation, and alveolar bone resorption were suppressed. From these findings, it was concluded that a derivative of L-ascorbic acid is useful as an active ingredient for preventing and / or improving periodontal disease, and the present invention has been reached.
  • periodontal disease such as downward proliferation of gingival epithelium, periodontal pocket formation, and alveolar bone resorption
  • the present invention provides the following inventions.
  • An agent for preventing and / or improving periodontal disease comprising an ascorbic acid derivative as an active ingredient.
  • a composition for preventing and / or improving periodontal disease comprising an ascorbic acid derivative and a pharmacologically acceptable carrier.
  • [4] One type selected from the group consisting of an agent for preventing and / or improving periodontal disease according to [1] or [2] above, and a composition for preventing and / or improving periodontal disease according to [3] above Food / beverage products containing the above.
  • the present invention also provides the following [5] to [6].
  • [5] A method for preventing and / or improving periodontal disease by administering an ascorbic acid derivative.
  • [6] Use of an ascorbic acid derivative for producing an agent for preventing and / or improving periodontal disease.
  • the onset of periodontal disease can be prevented in advance, these risks can be reduced, and the symptoms can be improved after the onset of periodontal disease.
  • an alveolar pyorrhea and tooth loss can be prevented in advance, and the risk can be reduced.
  • FIG. 1 is a view showing a mesial side root portion under the lower first molar. The arrow indicates the distance (CEJ-AB) between the cement-enamel junction (CEJ) and the alveolar crest (AB).
  • FIG. 2 is a graph showing CEJ-AB in Example 1 (APM administration), Example 2 (A2G administration), Comparative Example 1 (DW administration) and Comparative Example 2 (DW administration, BL).
  • FIG. 3 is a graph showing epithelial downward proliferation of Example 1 (APM administration), Example 2 (A2G administration), Comparative Example 1 (DW administration) and Comparative Example 2 (DW administration, BL).
  • FIG. 4 is a graph showing periodontal pocket formation in Example 1 (APM administration), Example 2 (A2G administration), Comparative Example 1 (DW administration) and Comparative Example 2 (DW administration, BL).
  • the active ingredient in the present invention is an ascorbic acid derivative.
  • Ascorbic acid derivatives include a part of ascorbic acid ((R) -3,4-dihydroxy-5-((S) -1,2-dihydroxyethyl) furan-2 (5H) -one, vitamin C)
  • a compound obtained by substituting with an atom or a substituent of Ascorbic acid, which is the base of the ascorbic acid derivative may be any of D-form, L-form, and DL-form, but is preferably L-form.
  • the ascorbic acid derivative is not particularly limited as long as it can be used in the fields of pharmaceuticals, quasi drugs, cosmetics, and foods. Examples include ester derivatives of ascorbic acid or salts thereof, ether derivatives of ascorbic acid or salts thereof, and salts of ascorbic acid.
  • ester derivatives of ascorbic acid examples include esters of ascorbic acid and acids such as carboxylic acid, sulfuric acid, sulfonic acid, and phosphoric acid.
  • an esterification site part of ascorbic acid, each hydroxyl group of 2nd-position, 3-position, 5-position, and 6-position of ascorbic acid is mentioned, for example.
  • the number of ascorbic acid esterification sites may be one or more, and one or more hydroxy groups selected from the above hydroxy groups may be esterified. When the number of esterification sites is 2 or more, the type of acid forming the ester may be the same or different at each esterification site.
  • carboxylic acid examples include aliphatic carboxylic acids and aromatic carboxylic acids.
  • sulfonic acid examples include sulfonic acid and alkylsulfonic acid.
  • the alkyl sulfonic acid is usually an alkyl sulfonic acid having 1 to 6 carbon atoms, and examples thereof include methyl sulfonic acid and ethyl sulfonic acid.
  • Examples of phosphoric acid include phosphoric acid, phosphoric acid monoester, and phosphoric acid diester, and the details are as follows: phosphoric acid; monoalkyl ester of phosphoric acid (for example, one hydrogen contained in phosphoric acid, An alkyl group selected from alkyl groups having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, t-butyl group, isobutyl group, pentyl group and hexyl group; Substituted phosphoric acid monoester); dialkyl ester of phosphoric acid (eg, the two hydrogens of phosphoric acid are methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl) Dialkyl phosphates substituted with two alkyl groups selected from alkyl groups having 1 to 6 carbon atoms,
  • ether derivatives of ascorbic acid include ascorbic acid glucoside (eg, ascorbic acid-2-glucoside).
  • the ascorbic acid derivative may be a salt of ascorbic acid or a salt of ascorbic acid derivative.
  • the salt include the following salts: various metal salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium, calcium and barium, and polyvalent metal salts such as aluminum; ammonium, Ammonium salts such as tricyclohexylammonium; various alkanolamine salts such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine;
  • Ascorbic acid derivatives preferably used in the present invention include L-ascorbic acid salts (for example, sodium salts), L-ascorbic acid phosphoric acid ester derivatives (for example, L-ascorbic acid monophosphate sodium salt, phosphoric acid L -Ascorbyl magnesium (ascorbic acid phosphate magnesium salt (APM)) and its salts, ascorbic acid glucoside (eg ascorbic acid-2-glucoside) and its salts, ascorbyl tetraisopalmitate (VCIP) and its salts Ascorbic acid-2-phosphate-6-palmitate (APPS) and salts thereof, and more preferably used ascorbic acid derivatives are sodium L-ascorbate, L-ascorbyl magnesium phosphate, Binic acid-2-glucoside (for example, ascorbic acid-2-O- ⁇ -glucoside (A2G)), and more preferably used ascorbic acid derivatives include L-ascorbyl magnesium phosphate,
  • an artificially synthesized product such as chemical synthesis may be used, or a commercially available product may be used.
  • the ascorbic acid derivative as an active ingredient in the present invention may be one kind or a combination of two or more kinds.
  • the dose of the periodontal disease prevention and / or ameliorating agent of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be appropriately changed according to various factors such as the age and condition of the administration target organism. Can do.
  • the preferred periodontal disease prevention and / or amelioration dose is preferably 0.001 g / day to 100 g / day as the amount of ascorbic acid derivative per adult.
  • the periodontal disease preventive and / or ameliorating agent of the present invention can be used as it is as a final product (for example, food and drink, pharmaceuticals, quasi drugs, etc.) Moreover, it can use as an additive for food-drinks, an additive for pharmaceuticals, and an additive for quasi drugs. Thereby, a periodontal disease prevention and / or improvement effect can be provided to food-drinks, a pharmaceutical, and a quasi-drug.
  • the agent of the present invention can be used as a composition in combination with a component (pharmacologically acceptable base) other than the active ingredient.
  • the composition may contain a component (pharmacologically acceptable base) other than the active component.
  • the composition can also be used as a final product (for example, food and drink, pharmaceuticals, quasi drugs, etc.) as it is. Moreover, it can use as an additive for food-drinks, an additive for pharmaceuticals, and an additive for quasi drugs. Thereby, effects, such as periodontal disease prevention and / or an improvement effect, can be provided to food / beverage products, pharmaceuticals, and quasi drugs.
  • components other than ascorbic acid derivatives include components that mainly ensure stability in storage and distribution (for example, storage stabilizers).
  • one or more types of components preferably about 1 to 3 types, more preferably 1 type selected from various components constituting the target final product (for example, foods and drinks, pharmaceuticals, quasi drugs, etc.) Degree).
  • Components other than the ascorbic acid derivative are not particularly limited as long as the object of the present invention is not impaired.
  • excipients disintegrants, binders, lubricants, coating agents, colorants, color formers, flavoring agents, flavoring agents, antioxidants, preservatives, flavoring agents, sour agents, sweeteners, strengthening Among ingredients, vitamins, swelling agents, thickeners, surfactants, etc., that do not impair various properties required for the formulation (eg, formulation stability)
  • the component other than the ascorbic acid derivative may be another component having a periodontal disease prevention and / or improvement effect.
  • the blending amount of the ascorbic acid derivative in the composition of the present invention is not particularly limited as long as it is a blending amount capable of exerting the effects of the present invention, but is generally 0.00001 mass with respect to the whole periodontal disease prevention and / or ameliorating agent. % Or more, preferably 0.001% by mass or more, more preferably 0.01% by mass or more, further preferably 0.1% by mass or more, and particularly preferably 1% by mass or more.
  • the upper limit of the compounding amount is preferably 35% by mass or less, more preferably 25% by mass or less, further preferably 20% by mass or less, and particularly preferably 15% by mass or less, with respect to the whole periodontal disease prevention and / or improving agent. It is.
  • the administration form of the preventive and / or ameliorating agent of the present invention and the composition containing the same is not particularly limited.
  • oral administration eg, oral administration, sublingual administration, etc.
  • parenteral administration intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, pulmonary administration, etc.
  • a less invasive dosage form is preferable, and oral administration is more preferable.
  • the agent for preventing and / or improving periodontal disease of the present invention is orally administered as a food or drink.
  • the dosage form of the composition of the present invention can be appropriately determined depending on whether it is a food or drink, a pharmaceutical product, or a quasi-drug, and is not particularly limited.
  • dosage forms for oral administration include liquid (liquid), syrup (syrup), tablets (tablets, tablets), capsules (capsules), powders (granules, fine granules), soft capsules (Soft capsule), solid, semi-liquid, cream, and paste.
  • the period of administration of the agent for preventing and / or improving periodontal disease of the present invention and the composition containing the same is not particularly limited. It may be administered before the onset of periodontal disease, or may be administered after the onset of periodontal disease. When it is administered after the onset of periodontal disease, it is preferably administered at the initial stage of onset.
  • the periodontal disease preventive and / or ameliorating agent of the present invention and a composition containing the same can prevent and / or improve periodontal disease as described below.
  • the onset of periodontal disease can be prevented before onset. After the onset of periodontal disease, the symptoms (gingival tissue lesions such as gingival epithelial growth and pocket formation; periodontal lesions such as alveolar bone resorption) can be improved (relieved). Therefore, it can be used as a food or drink or a medicine for periodontal disease prevention and / or improvement.
  • the cause of periodontal disease and the degree of progression of periodontal disease do not matter.
  • the periodontal disease preventive and / or ameliorating agent of the present invention is also effective for periodontal disease caused by diabetes.
  • the periodontal disease preventive and / or ameliorating agent of the present invention and a composition containing the same can prevent its onset before onset of periodontal disease. Moreover, after the onset of periodontal disease, the symptom can be improved (relieved).
  • the agent for preventing and / or improving periodontal disease of the present invention can prevent its onset before the onset of alveolar pyorrhea. In addition, after the onset of alveolar pyorrhea, the symptoms can be improved (relieved). Therefore, the periodontal disease prevention and / or improvement agent of the present invention can also be used as an alveolar bone resorption inhibitor, a gingival soft tissue change inhibitor, an alveolar abscess prevention and / or improvement agent.
  • the subject of ingestion of the agent for preventing and / or improving periodontal disease of the present invention and the composition containing the same is not particularly limited.
  • a subject who has already developed periodontal disease and periodontal disease, periodontal disease Subjects who are at risk for alveolar pyorrhea (such as the elderly, smokers, postmenopausal women, diabetics).
  • alveolar pyorrhea such as the elderly, smokers, postmenopausal women, diabetics.
  • even a subject who does not have any particular problem can be ingested on a daily basis for the purpose of preventing periodontal disease or alveolar pus leakage.
  • the periodontal disease preventive and / or ameliorating agent of the present invention and a composition containing the same can be used as various foods and drinks.
  • beverages soft drinks, carbonated drinks, nutrition drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.
  • confectionery fortunes, cakes, gums, candy, tablets, gummies, buns, sheep cakes, puddings, jelly, Ice cream, sherbet, etc.
  • processed fishery products kamaboko, chikuwa, hanpen, etc.
  • processed livestock products hamburg, ham, sausage, winner, cheese, butter, yogurt, fresh cream, cheese, margarine, etc.
  • soup powdered) Soup, liquid soup, etc.
  • staple foods rice, noodles (dried noodles, raw noodles), bread, cereals, etc.
  • seasonings mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.
  • the periodontal disease preventive and / or ameliorating agent of the present invention and the composition containing the same are used as health food, functional food, health supplement (supplement), nutritional supplement, specified health food, medical food, disease It can also be used as food and drink such as food for infants, food for infants, food for care, and food for elderly people. Among these, it is preferable to use as a health supplement, and more preferable to use as a tablet-like health supplement.
  • the administration method and administration period were the same as those of type 2 diabetes model mice.
  • APM used was a commercial product manufactured by Showa Denko.
  • A2G used was a commercial product manufactured by Hayashibara Biochemical Laboratory.
  • CEJ-AB of type 2 diabetes model mice was longer than the CEJ-AB of healthy mice (Comparative Example 2).
  • CEJ-AB of type 2 diabetes model mice administered with each of APM and A2G was shorter than CEJ-AB of type 2 diabetes model mice administered with distilled water (FIG. 2).
  • the influence of APM and A2G on the blood glucose level and body weight of each mouse was not particularly observed.
  • Periodontal pocket formation is seen in type 2 diabetes model mice. However, periodontal pocket formation of type 2 diabetes model mice administered with each of APM and A2G was smaller than periodontal pocket formation of type 2 diabetes model mice administered with distilled water (FIG. 4).

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Abstract

The purpose of the present invention is to provide an active ingredient which can notably exert an effect of treating and/or preventing periodontal diseases, and which can be used in food or beverages. The present invention provides: an agent for treating and/or preventing periodontal diseases, the agent containing an ascorbic acid derivative as the active ingredient; a composition for the prevention and/or improvement of periodontal diseases, the composition containing an ascorbic acid derivative and a pharmaceutically-acceptable carrier; and a food or beverage containing the agent for treating and/or preventing periodontal diseases or the composition for the prevention and/or improvement of periodontal diseases.

Description

歯周病予防および／または改善剤Periodontal disease prevention and / or improvement agent
　本発明は、歯周病予防および／または改善剤に関する。 The present invention relates to an agent for preventing and / or improving periodontal disease.
　歯周病は、パラサイト（感染菌）の感染により、歯を支持している歯周組織（歯肉、セメント質、歯根膜、および歯槽骨）が破壊される炎症性疾患である。歯周病が進行するにつれ、菌に由来する口臭の発生、歯根膜などの歯肉軟組織の破壊、歯槽骨などの歯周組織の破壊および吸収に波及する（非特許文献１）。現在、歯周病診断は、レントゲン撮影、歯科医の目視などから特定される臨床指標に基づく歯槽骨吸収量の測定による診断が主である。 Periodontal disease is an inflammatory disease in which the periodontal tissues (gingiva, cementum, periodontal ligament, and alveolar bone) supporting the teeth are destroyed by infection with parasites (infectious bacteria). As periodontal disease progresses, it affects the generation of bad breath derived from bacteria, the destruction of gingival soft tissues such as periodontal ligament, and the destruction and absorption of periodontal tissues such as alveolar bone (Non-patent Document 1). At present, periodontal disease diagnosis is mainly performed by measuring alveolar bone resorption based on clinical indicators specified by X-ray imaging, dentist's visual inspection, and the like.
　いったん歯槽骨吸収が起こると、その回復は容易ではない。そのため、歯槽骨吸収が起きる前に歯周病を治療し、予防することが求められる。歯周病はパラサイト（感染菌）による、いわゆる細菌感染症であることから、歯周病の治療薬として、従来、殺菌剤、抗菌剤、抗プラーク剤、抗炎症剤、アルジンジパイン阻害剤（特許文献１参照）が用いられている。歯周病の治療効果がある食品としては、従来、卵黄由来タンパク質（特許文献２）が知られている。 Once the alveolar bone resorption occurs, the recovery is not easy. Therefore, it is required to treat and prevent periodontal disease before alveolar bone resorption occurs. Since periodontal disease is a so-called bacterial infection caused by parasites (infectious bacteria), as a therapeutic agent for periodontal disease, bactericides, antibacterial agents, anti-plaque agents, anti-inflammatory agents, algin dipine inhibitors (patents) Reference 1) is used. Conventionally, egg yolk-derived protein (Patent Document 2) is known as a food having a therapeutic effect on periodontal disease.
　Ｌ－アスコルビン酸は、骨基質の主要成分である生体内でのコラーゲンの合成に重要であることが知られている。すなわち、Ｌ－アスコルビン酸は、ヒドロキシプロリン、ヒドロキシリジンなどの、コラーゲンに特異的なアミノ酸の生合成に必須であり、例えば骨芽細胞の培養系に添加するとコラーゲン合成を促進し、骨芽細胞の分化、骨形成を促進することが知られている。 L-ascorbic acid is known to be important for the synthesis of collagen in vivo, which is the main component of the bone matrix. That is, L-ascorbic acid is essential for the biosynthesis of amino acids specific to collagen, such as hydroxyproline and hydroxylysine. For example, when added to an osteoblast culture system, L-ascorbic acid promotes collagen synthesis, It is known to promote differentiation and bone formation.
　Ｌ－アスコルビン酸には、酸化分解を受け易く容易にその生理活性を失うという欠点がある。そこでＬ－アスコルビン酸を安定化させる方法として、糖誘導体、エステル誘導体などのＬ－アスコルビン酸誘導体が提案されている。非特許文献１には、Ｌ－アスコルビン酸２－リン酸エステルの安定性がＬ－アスコルビン酸と比較して高いこと、Ｌ－アスコルビン酸２－リン酸エステルが培養骨芽細胞の増殖促進効果および分化促進効果を有することが記載されている。 L-ascorbic acid has a drawback that it is susceptible to oxidative degradation and easily loses its physiological activity. Therefore, as a method for stabilizing L-ascorbic acid, L-ascorbic acid derivatives such as sugar derivatives and ester derivatives have been proposed. Non-Patent Document 1 discloses that the stability of L-ascorbic acid 2-phosphate ester is higher than that of L-ascorbic acid, and that L-ascorbic acid 2-phosphate ester promotes the growth of cultured osteoblasts and It is described that it has a differentiation promoting effect.
特開２０１０－１２２８号公報JP 2010-1228 A 特開２０１０－２６０７９４号公報JP 2010-260794 A
　上記の通り、従来の歯周病の予防および治療は、パラサイト（感染菌）の制御に着目して行われてきたが、それらの効果は十分ではなかった。その結果、フッ素の適用、歯磨き習慣等の普及により虫歯罹患率が低下しているにもかかわらず、歯周病罹患率は増加の一途をたどっている。 As described above, the conventional prevention and treatment of periodontal disease has been performed focusing on the control of parasites (infectious bacteria), but their effects have not been sufficient. As a result, the incidence of periodontal disease is steadily increasing despite the decrease in the incidence of dental caries due to the spread of fluorine and the brushing habits.
　非ステロイド系抗炎症剤については口腔粘膜への偽害作用が懸念されていた。 Non-steroidal anti-inflammatory drugs are concerned about the spurious effects on the oral mucosa.
　近年、歯周病と種々の全身疾患との関係が注目されている。例えば歯周病は糖尿病の合併症として認められている。つまり、歯周病はパラサイト側の寄与に加え、ホスト側の全身的背景（健康状態）も少なからず関与していることが推定されている。 In recent years, the relationship between periodontal disease and various systemic diseases has attracted attention. For example, periodontal disease is recognized as a complication of diabetes. In other words, it is estimated that periodontal disease is involved in not only the contribution of the parasite side but also the general background (health state) of the host side.
　本発明は、歯周病の治療および予防効果を顕著に発揮することができ、飲食品としても利用可能な有効成分の提供を目的とする。 The present invention is intended to provide an active ingredient that can remarkably exert a therapeutic and preventive effect on periodontal disease and can be used as a food or drink.
　本発明者らは、糖尿病モデルマウスにおいて、加齢とともに（歯肉上皮の下方増殖、歯周ポケット形成、歯槽骨吸収などの）歯周病等の症状が自然発症することを見出した。また、Ｌ－アスコルビン酸誘導体を動物に投与する試験を行ったところ、歯肉上皮の下方増殖、歯周ポケット形成、歯槽骨吸収がそれぞれ抑制されることを見出した。これらの知見から、Ｌ－アスコルビン酸の誘導体が歯周病の予防および／または改善薬の有効成分として有用であるとの結論に達し、本発明に到達した。 The present inventors have found that symptoms such as periodontal disease (such as downward proliferation of gingival epithelium, periodontal pocket formation, and alveolar bone resorption) spontaneously develop in diabetic model mice. Further, when a test was conducted in which an L-ascorbic acid derivative was administered to animals, it was found that downward growth of the gingival epithelium, periodontal pocket formation, and alveolar bone resorption were suppressed. From these findings, it was concluded that a derivative of L-ascorbic acid is useful as an active ingredient for preventing and / or improving periodontal disease, and the present invention has been reached.
　本発明は、以下の発明を提供する。
〔１〕アスコルビン酸誘導体を有効成分として含む歯周病予防および／または改善剤。
〔２〕アスコルビン酸誘導体が、アスコルビン酸リン酸エステルマグネシウム塩および／またはアスコルビン酸－２－グルコシドである上記〔１〕に記載の歯周病予防および／または改善剤。
〔３〕アスコルビン酸誘導体と薬理学的に許容される担体とを含有する歯周病予防および／または改善組成物。
〔４〕上記〔１〕または〔２〕に記載の歯周病予防および／または改善剤、ならびに上記〔３〕に記載の歯周病予防および／または改善組成物からなる群より選ばれる１種以上を含有する飲食品。 The present invention provides the following inventions.
[1] An agent for preventing and / or improving periodontal disease comprising an ascorbic acid derivative as an active ingredient.
[2] The periodontal disease preventive and / or ameliorating agent according to the above [1], wherein the ascorbic acid derivative is ascorbic acid phosphate magnesium salt and / or ascorbic acid-2-glucoside.
[3] A composition for preventing and / or improving periodontal disease comprising an ascorbic acid derivative and a pharmacologically acceptable carrier.
[4] One type selected from the group consisting of an agent for preventing and / or improving periodontal disease according to [1] or [2] above, and a composition for preventing and / or improving periodontal disease according to [3] above Food / beverage products containing the above.
　本発明は以下の〔５〕～〔６〕も提供する。
〔５〕アスコルビン酸誘導体を投与して歯周病を予防および／または改善する方法。
〔６〕歯周病予防および／または改善剤を製造するための、アスコルビン酸誘導体の使用。 The present invention also provides the following [5] to [6].
[5] A method for preventing and / or improving periodontal disease by administering an ascorbic acid derivative.
[6] Use of an ascorbic acid derivative for producing an agent for preventing and / or improving periodontal disease.
　本発明によれば、歯周病の発症を未然に予防することができ、これらのリスクを軽減することができ、歯周病の発症後には症状を改善することができる。これにより、歯槽膿漏および歯の喪失を未然に予防し、リスクを軽減することができる。 According to the present invention, the onset of periodontal disease can be prevented in advance, these risks can be reduced, and the symptoms can be improved after the onset of periodontal disease. Thereby, an alveolar pyorrhea and tooth loss can be prevented in advance, and the risk can be reduced.
図１は、下顎第１臼歯の下側の近心側歯根部分を示す図である。矢印部分は、セメント－エナメルジャンクション（ＣＥＪ）と歯槽骨頂（ＡＢ）の距離（ＣＥＪ－ＡＢ）を示す。FIG. 1 is a view showing a mesial side root portion under the lower first molar. The arrow indicates the distance (CEJ-AB) between the cement-enamel junction (CEJ) and the alveolar crest (AB). 図２は、実施例１（ＡＰＭ投与）、実施例２（Ａ２Ｇ投与）、比較例１（ＤＷ投与）および比較例２（ＤＷ投与、ＢＬ）の、ＣＥＪ－ＡＢを示すグラフである。FIG. 2 is a graph showing CEJ-AB in Example 1 (APM administration), Example 2 (A2G administration), Comparative Example 1 (DW administration) and Comparative Example 2 (DW administration, BL). 図３は、実施例１（ＡＰＭ投与）、実施例２（Ａ２Ｇ投与）、比較例１（ＤＷ投与）および比較例２（ＤＷ投与、ＢＬ）の、上皮下方増殖を示すグラフである。FIG. 3 is a graph showing epithelial downward proliferation of Example 1 (APM administration), Example 2 (A2G administration), Comparative Example 1 (DW administration) and Comparative Example 2 (DW administration, BL). 図４は、実施例１（ＡＰＭ投与）、実施例２（Ａ２Ｇ投与）、比較例１（ＤＷ投与）および比較例２（ＤＷ投与、ＢＬ）の、歯周ポケット形成を示すグラフである。FIG. 4 is a graph showing periodontal pocket formation in Example 1 (APM administration), Example 2 (A2G administration), Comparative Example 1 (DW administration) and Comparative Example 2 (DW administration, BL).
　本発明における有効成分は、アスコルビン酸誘導体である。アスコルビン酸誘導体とは、アスコルビン酸（（Ｒ）－３，４－ジヒドロキシ－５－（（Ｓ）－１，２－ジヒドロキシエチル）フラン－２（５Ｈ）－オン、ビタミンＣ）の一部が他の原子または置換基で置換されて得られる化合物を意味する。アスコルビン酸誘導体の母体であるアスコルビン酸はＤ体、Ｌ体、ＤＬ体のいずれであってもよいが、好ましくはＬ体である。アスコルビン酸誘導体は、医薬品、医薬部外品、化粧品または食品の分野において用いることができれば特に限定されない。例えば、アスコルビン酸のエステル誘導体またはその塩、アスコルビン酸のエーテル誘導体またはその塩、アスコルビン酸の塩等が挙げられる。 The active ingredient in the present invention is an ascorbic acid derivative. Ascorbic acid derivatives include a part of ascorbic acid ((R) -3,4-dihydroxy-5-((S) -1,2-dihydroxyethyl) furan-2 (5H) -one, vitamin C) A compound obtained by substituting with an atom or a substituent of Ascorbic acid, which is the base of the ascorbic acid derivative, may be any of D-form, L-form, and DL-form, but is preferably L-form. The ascorbic acid derivative is not particularly limited as long as it can be used in the fields of pharmaceuticals, quasi drugs, cosmetics, and foods. Examples include ester derivatives of ascorbic acid or salts thereof, ether derivatives of ascorbic acid or salts thereof, and salts of ascorbic acid.
　アスコルビン酸のエステル誘導体としては例えば、アスコルビン酸と、カルボン酸、硫酸、スルホン酸、リン酸等の酸とのエステルが挙げられる。アスコルビン酸のエステル化部位としては、例えば、アスコルビン酸の２位、３位、５位及び６位の各ヒドロキシ基が挙げられる。アスコルビン酸のエステル誘導体において、アスコルビン酸のエステル化部位は１以上であればよく、上記各ヒドロキシ基から選ばれる１以上のヒドロキシ基がエステル化されていてもよい。エステル化部位が２以上の場合、エステルを形成する酸の種類は、それぞれのエステル化部位において同一でも異なっていてもよい。 Examples of the ester derivatives of ascorbic acid include esters of ascorbic acid and acids such as carboxylic acid, sulfuric acid, sulfonic acid, and phosphoric acid. As an esterification site | part of ascorbic acid, each hydroxyl group of 2nd-position, 3-position, 5-position, and 6-position of ascorbic acid is mentioned, for example. In the ester derivative of ascorbic acid, the number of ascorbic acid esterification sites may be one or more, and one or more hydroxy groups selected from the above hydroxy groups may be esterified. When the number of esterification sites is 2 or more, the type of acid forming the ester may be the same or different at each esterification site.
　カルボン酸としては例えば、脂肪族カルボン酸、芳香族カルボン酸等が挙げられる。 Examples of the carboxylic acid include aliphatic carboxylic acids and aromatic carboxylic acids.
　スルホン酸としては例えば、スルホン酸、アルキルスルホン酸等が挙げられる。アルキルスルホン酸は、通常、炭素原子数１～６のアルキルスルホン酸であり、例えば、メチルスルホン酸、エチルスルホン酸等が挙げられる。 Examples of the sulfonic acid include sulfonic acid and alkylsulfonic acid. The alkyl sulfonic acid is usually an alkyl sulfonic acid having 1 to 6 carbon atoms, and examples thereof include methyl sulfonic acid and ethyl sulfonic acid.
　リン酸としては例えば、リン酸、リン酸モノエステル、リン酸ジエステルが挙げられ、詳しくは以下の通りである：リン酸；リン酸のモノアルキルエステル（例、リン酸が有する１つの水素が、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓ－ブチル基、ｔ－ブチル基、イソブチル基、ペンチル基、ヘキシル基等の炭素原子数１～６のアルキル基から選ばれるアルキル基で置換されているリン酸モノエステル）；リン酸のジアルキルエステル（例、リン酸が有する２つの水素が、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｓ－ブチル基、ｔ－ブチル基、イソブチル基、ペンチル基、ヘキシル基等の炭素原子数１～６のアルキル基から選ばれる２つのアルキル基で置換されているリン酸のジアルキルエステル等）等。上記リン酸のジアルキルエステルにおいて、２つのアルキル基は互いに同一であってもよいし異なっていてもよい。 Examples of phosphoric acid include phosphoric acid, phosphoric acid monoester, and phosphoric acid diester, and the details are as follows: phosphoric acid; monoalkyl ester of phosphoric acid (for example, one hydrogen contained in phosphoric acid, An alkyl group selected from alkyl groups having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, t-butyl group, isobutyl group, pentyl group and hexyl group; Substituted phosphoric acid monoester); dialkyl ester of phosphoric acid (eg, the two hydrogens of phosphoric acid are methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl) Dialkyl phosphates substituted with two alkyl groups selected from alkyl groups having 1 to 6 carbon atoms, such as an isobutyl group, an isobutyl group, a pentyl group, and a hexyl group Ester, etc.), and the like. In the phosphoric acid dialkyl ester, the two alkyl groups may be the same or different from each other.
　アスコルビン酸のエーテル誘導体としては例えば、アスコルビン酸グルコシド（例、アスコルビン酸－２－グルコシド）などが挙げられる。 Examples of ether derivatives of ascorbic acid include ascorbic acid glucoside (eg, ascorbic acid-2-glucoside).
　アスコルビン酸誘導体は、アスコルビン酸の塩またはアスコルビン酸誘導体の塩であってもよい。塩としては例えば下記の塩が挙げられる：ナトリウム、カリウム等のアルカリ金属塩、マグネシウム、カルシウム、バリウム等のアルカリ土類金属塩、およびアルミニウム等の多価金属塩などの各種の金属塩；アンモニウム、トリシクロヘキシルアンモニウム等のアンモニウム塩；モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、モノイソプロパノールアミン、ジイソプロパノールアミン、トリイソプロパノールアミン等の各種のアルカノールアミン塩等。 The ascorbic acid derivative may be a salt of ascorbic acid or a salt of ascorbic acid derivative. Examples of the salt include the following salts: various metal salts such as alkali metal salts such as sodium and potassium, alkaline earth metal salts such as magnesium, calcium and barium, and polyvalent metal salts such as aluminum; ammonium, Ammonium salts such as tricyclohexylammonium; various alkanolamine salts such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine;
　本発明において好ましく用いられるアスコルビン酸誘導体は、Ｌ－アスコルビン酸の塩（例えば、ナトリウム塩など）、Ｌ－アスコルビン酸のリン酸エステル誘導体（例えば、Ｌ－アスコルビン酸モノリン酸エステルナトリウム塩、リン酸Ｌ－アスコルビルマグネシウム（アスコルビン酸リン酸エステルマグネシウム塩（ＡＰＭ））など）およびその塩、アスコルビン酸グルコシド（例えば、アスコルビン酸－２－グルコシドなど）およびその塩、テトライソパルミチン酸アスコルビル（ＶＣＩＰ）およびその塩、アスコルビン酸－２－リン酸－６－パルミチン酸エステル（ＡＰＰＳ）およびその塩であり、より好ましく用いられるアスコルビン酸誘導体は、Ｌ－アスコルビン酸ナトリウム、リン酸Ｌ－アスコルビルマグネシウム、アスコルビン酸－２－グルコシド（例えば、アスコルビン酸－２－Ｏ－α－グルコシド（Ａ２Ｇ））であり、さらに好ましく用いられるアスコルビン酸誘導体は、リン酸Ｌ－アスコルビルマグネシウム、アスコルビン酸－２－グルコシド（例えば、アスコルビン酸－２－Ｏ－α－グルコシド）（Ａ２Ｇ）である。 Ascorbic acid derivatives preferably used in the present invention include L-ascorbic acid salts (for example, sodium salts), L-ascorbic acid phosphoric acid ester derivatives (for example, L-ascorbic acid monophosphate sodium salt, phosphoric acid L -Ascorbyl magnesium (ascorbic acid phosphate magnesium salt (APM)) and its salts, ascorbic acid glucoside (eg ascorbic acid-2-glucoside) and its salts, ascorbyl tetraisopalmitate (VCIP) and its salts Ascorbic acid-2-phosphate-6-palmitate (APPS) and salts thereof, and more preferably used ascorbic acid derivatives are sodium L-ascorbate, L-ascorbyl magnesium phosphate, Binic acid-2-glucoside (for example, ascorbic acid-2-O-α-glucoside (A2G)), and more preferably used ascorbic acid derivatives include L-ascorbyl magnesium phosphate, ascorbic acid-2-glucoside (for example, Ascorbic acid-2-O-α-glucoside) (A2G).
　アスコルビン酸誘導体は、化学合成などにより人工的に合成されたものを用いてもよいし、市販品を用いてもよい。 As the ascorbic acid derivative, an artificially synthesized product such as chemical synthesis may be used, or a commercially available product may be used.
　本発明における有効成分としてのアスコルビン酸誘導体は、１種類であってもよいし２種類以上の組み合わせであってもよい。 The ascorbic acid derivative as an active ingredient in the present invention may be one kind or a combination of two or more kinds.
　本発明の歯周病予防および／または改善剤の投与量は、本発明の効果を損なわない限り特に制限は無く、また適応される被投与生体の年齢、状態などの種々の要因により適宜変えることができる。目的の効果を得るために好ましい歯周病予防および／または改善剤の投与量は、成人１人当たりのアスコルビン酸誘導体の量として０．００１ｇ／日～１００ｇ／日であることが好ましい。 The dose of the periodontal disease prevention and / or ameliorating agent of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and may be appropriately changed according to various factors such as the age and condition of the administration target organism. Can do. In order to obtain the desired effect, the preferred periodontal disease prevention and / or amelioration dose is preferably 0.001 g / day to 100 g / day as the amount of ascorbic acid derivative per adult.
　本発明の歯周病予防および／または改善剤は、そのままの形態で、最終製品（例えば、飲食品、医薬品、医薬部外品など）として用いることもできる。また、飲食品用の添加剤、医薬用の添加剤、医薬部外品用の添加剤として用いることができる。これにより、飲食品、医薬品、医薬部外品に、歯周病予防および／または改善効果を付与することができる。本発明の剤は、有効成分以外の成分（薬理学的に許容される基剤）と組み合わせた組成物として利用することができる。当該組成物は、有効成分以外の成分（薬理学的に許容される基剤）を含んでいてもよい。当該組成物は、そのままの形態で最終製品（例えば、飲食品、医薬品、医薬部外品など）として用いることもできる。また、飲食品用の添加剤、医薬用の添加剤、医薬部外品用の添加剤として用いることができる。これにより、飲食品、医薬品、医薬部外品に、歯周病予防および／または改善効果等の作用を付与することができる。 The periodontal disease preventive and / or ameliorating agent of the present invention can be used as it is as a final product (for example, food and drink, pharmaceuticals, quasi drugs, etc.) Moreover, it can use as an additive for food-drinks, an additive for pharmaceuticals, and an additive for quasi drugs. Thereby, a periodontal disease prevention and / or improvement effect can be provided to food-drinks, a pharmaceutical, and a quasi-drug. The agent of the present invention can be used as a composition in combination with a component (pharmacologically acceptable base) other than the active ingredient. The composition may contain a component (pharmacologically acceptable base) other than the active component. The composition can also be used as a final product (for example, food and drink, pharmaceuticals, quasi drugs, etc.) as it is. Moreover, it can use as an additive for food-drinks, an additive for pharmaceuticals, and an additive for quasi drugs. Thereby, effects, such as periodontal disease prevention and / or an improvement effect, can be provided to food / beverage products, pharmaceuticals, and quasi drugs.
　アスコルビン酸誘導体以外の成分（薬理学的に許容される基剤）の成分の一例としては、主に貯蔵および流通における安定性を確保する成分（例えば保存安定剤など）が挙げられる。その他、目的の最終製品（例えば、飲食品、医薬品、医薬部外品など）を構成する諸成分から選ばれる１または２以上の種類の成分（好ましくは１～３種類程度、より好ましくは１種類程度）を含有していてもよい。 Examples of components other than ascorbic acid derivatives (pharmacologically acceptable base) include components that mainly ensure stability in storage and distribution (for example, storage stabilizers). In addition, one or more types of components (preferably about 1 to 3 types, more preferably 1 type) selected from various components constituting the target final product (for example, foods and drinks, pharmaceuticals, quasi drugs, etc.) Degree).
　アスコルビン酸誘導体以外の成分は、本発明の目的を損なわない限り、特に限定されない。例えば、賦形剤、崩壊剤、結合剤、滑沢剤、コーティング剤、着色剤、発色剤、矯味剤、着香剤、酸化防止剤、防腐剤、呈味剤、酸味剤、甘味剤、強化剤、ビタミン剤、膨張剤、増粘剤、界面活性剤などの中から、製剤に必要な諸特性（例えば、製剤安定性）を損なわない成分であって、最終製品（例えば、医薬品、医薬部外品、飲食品など）の剤形に応じた成分を１種または２種以上選択することができる。また、アスコルビン酸誘導体以外の成分は、歯周病予防および／または改善効果を有する他の成分であってもよい。 Components other than the ascorbic acid derivative are not particularly limited as long as the object of the present invention is not impaired. For example, excipients, disintegrants, binders, lubricants, coating agents, colorants, color formers, flavoring agents, flavoring agents, antioxidants, preservatives, flavoring agents, sour agents, sweeteners, strengthening Among ingredients, vitamins, swelling agents, thickeners, surfactants, etc., that do not impair various properties required for the formulation (eg, formulation stability) One type or two or more types of components can be selected according to the dosage form of the external product, food and drink, and the like. In addition, the component other than the ascorbic acid derivative may be another component having a periodontal disease prevention and / or improvement effect.
　本発明の組成物におけるアスコルビン酸誘導体の配合量は、本発明の効果を奏し得る配合量である限り特に制限されないが、通常は歯周病予防および／または改善剤全体に対して０．００００１質量％以上、好ましくは０．００１質量％以上、より好ましくは、０．０１質量％以上、さらに好ましくは０．１質量％以上、特に好ましくは１質量％以上である。配合量の上限は、歯周病予防および／または改善剤全体に対して、好ましくは３５質量％以下、より好ましくは２５質量％以下、さらに好ましくは２０質量％以下、特に好ましくは１５質量％以下である。 The blending amount of the ascorbic acid derivative in the composition of the present invention is not particularly limited as long as it is a blending amount capable of exerting the effects of the present invention, but is generally 0.00001 mass with respect to the whole periodontal disease prevention and / or ameliorating agent. % Or more, preferably 0.001% by mass or more, more preferably 0.01% by mass or more, further preferably 0.1% by mass or more, and particularly preferably 1% by mass or more. The upper limit of the compounding amount is preferably 35% by mass or less, more preferably 25% by mass or less, further preferably 20% by mass or less, and particularly preferably 15% by mass or less, with respect to the whole periodontal disease prevention and / or improving agent. It is.
　本発明の歯周病予防および／または改善剤ならびにこれを含む組成物の投与形態は特に限定されない。例えば、経口投与（例えば、口腔内投与、舌下投与など）、非経口投与（静脈内投与、筋肉内投与、皮下投与、経皮投与、経鼻投与、経肺投与など）などが挙げられる。これらの中でも侵襲性の少ない投与形態が好ましく、経口投与であることがより好ましい。本発明の歯周病予防および／または改善剤は飲食品として経口投与されることがさらに好ましい。 The administration form of the preventive and / or ameliorating agent of the present invention and the composition containing the same is not particularly limited. For example, oral administration (eg, oral administration, sublingual administration, etc.), parenteral administration (intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, pulmonary administration, etc.) and the like can be mentioned. Among these, a less invasive dosage form is preferable, and oral administration is more preferable. More preferably, the agent for preventing and / or improving periodontal disease of the present invention is orally administered as a food or drink.
　本発明の組成物の剤形は、飲食品、医薬品および医薬部外品のいずれとするかによって適宜決定することができ、特に限定されない。経口投与される際の剤形の例としては、液状（液剤）、シロップ状（シロップ剤）、錠（錠剤、タブレット）、カプセル状（カプセル剤）、粉末状（顆粒、細粒）、ソフトカプセル状（ソフトカプセル剤）、固形状、半液体状、クリーム状、ペースト状が挙げられる。 The dosage form of the composition of the present invention can be appropriately determined depending on whether it is a food or drink, a pharmaceutical product, or a quasi-drug, and is not particularly limited. Examples of dosage forms for oral administration include liquid (liquid), syrup (syrup), tablets (tablets, tablets), capsules (capsules), powders (granules, fine granules), soft capsules (Soft capsule), solid, semi-liquid, cream, and paste.
　本発明の歯周病予防および／または改善剤ならびにこれを含む組成物の投与時期は特に限定されない。歯周病が発症する前に投与されてもよいし、歯周病の発症後に投与されてもよい。歯周病の発症後に投与する場合には、発症初期に投与されることが好ましい。 The period of administration of the agent for preventing and / or improving periodontal disease of the present invention and the composition containing the same is not particularly limited. It may be administered before the onset of periodontal disease, or may be administered after the onset of periodontal disease. When it is administered after the onset of periodontal disease, it is preferably administered at the initial stage of onset.
　本発明の歯周病予防および／または改善剤ならびにこれを含む組成物は、下記のとおり歯周病を予防および／または改善することができる。歯周病の発症前はその発症を予防することができる。歯周病の発症後にはその症状（歯肉上皮下方増殖、ポケット形成などの歯肉組織の病変；歯槽骨吸収などの歯周組織の病変）を改善（緩和）することができる。そのため、歯周病予防および／または改善用の飲食品もしくは医薬品として利用できる。歯周病の原因、歯周病の進行の程度は問わない。例えば、糖尿病に起因する歯周病にも、本発明の歯周病予防および／または改善剤は有効である。 The periodontal disease preventive and / or ameliorating agent of the present invention and a composition containing the same can prevent and / or improve periodontal disease as described below. The onset of periodontal disease can be prevented before onset. After the onset of periodontal disease, the symptoms (gingival tissue lesions such as gingival epithelial growth and pocket formation; periodontal lesions such as alveolar bone resorption) can be improved (relieved). Therefore, it can be used as a food or drink or a medicine for periodontal disease prevention and / or improvement. The cause of periodontal disease and the degree of progression of periodontal disease do not matter. For example, the periodontal disease preventive and / or ameliorating agent of the present invention is also effective for periodontal disease caused by diabetes.
　本発明の歯周病予防および／または改善剤ならびにこれを含む組成物は、歯周病の発症前はその発症を予防することができる。また、歯周病の発症後にはその症状を改善（緩和）することができる。本発明の歯周病予防および／または改善剤は、歯槽膿漏の発症前はその発症を予防することができる。また、歯槽膿漏の発症後にはその症状を改善（緩和）することができる。したがって、本発明の歯周病予防および／または改善剤は、歯槽骨吸収抑制剤、歯肉軟組織の変化抑制剤、歯槽膿漏予防および／または改善剤としても利用できる。 The periodontal disease preventive and / or ameliorating agent of the present invention and a composition containing the same can prevent its onset before onset of periodontal disease. Moreover, after the onset of periodontal disease, the symptom can be improved (relieved). The agent for preventing and / or improving periodontal disease of the present invention can prevent its onset before the onset of alveolar pyorrhea. In addition, after the onset of alveolar pyorrhea, the symptoms can be improved (relieved). Therefore, the periodontal disease prevention and / or improvement agent of the present invention can also be used as an alveolar bone resorption inhibitor, a gingival soft tissue change inhibitor, an alveolar abscess prevention and / or improvement agent.
　本発明の歯周病予防および／または改善剤ならびにこれを含む組成物の摂取対象者は特に限定されないが、例えば、歯周病、歯槽膿漏を既に発症している対象者、歯周病、歯槽膿漏のリスクがある対象者（高齢者、喫煙者、閉経後の女性、糖尿病患者など）が挙げられる。また、特段の問題のない対象者であっても、歯周病または歯槽膿漏の予防を目的として日常的に摂取することができる。 The subject of ingestion of the agent for preventing and / or improving periodontal disease of the present invention and the composition containing the same is not particularly limited. For example, a subject who has already developed periodontal disease and periodontal disease, periodontal disease, Subjects who are at risk for alveolar pyorrhea (such as the elderly, smokers, postmenopausal women, diabetics). Moreover, even a subject who does not have any particular problem can be ingested on a daily basis for the purpose of preventing periodontal disease or alveolar pus leakage.
　本発明の歯周病予防および／または改善剤ならびにこれを含む組成物は、各種飲食品として利用することができる。例えば、飲料（清涼飲料、炭酸飲料、栄養飲料、粉末飲料、果実飲料、乳飲料、ゼリー飲料など）、菓子類（クッキー、ケーキ、ガム、キャンディー、タブレット、グミ、饅頭、羊羹、プリン、ゼリー、アイスクリーム、シャーベットなど）、水産加工品（かまぼこ、ちくわ、はんぺんなど）、畜産加工品（ハンバーグ、ハム、ソーセージ、ウィンナー、チーズ、バター、ヨーグルト、生クリーム、チーズ、マーガリンなど）、スープ（粉末状スープ、液状スープなど）、主食類（ご飯類、麺（乾麺、生麺）、パン、シリアルなど）、調味料（マヨネーズ、ショートニング、ドレッシング、ソース、たれ、しょうゆなど）が挙げられる。更に、本発明の歯周病予防および／または改善剤ならびにこれを含む組成物は、健康食品、機能性食品、健康補助食品（サプリメント）、栄養補助食品、特定保健用食品、医療用食品、病者用食品、乳児用食品、介護用食品、高齢者用食品等の飲食品として利用することもできる。これらのうち、健康補助食品として利用することが好ましく、タブレット状の健康補助食品として利用することがより好ましい。 The periodontal disease preventive and / or ameliorating agent of the present invention and a composition containing the same can be used as various foods and drinks. For example, beverages (soft drinks, carbonated drinks, nutrition drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.), confectionery (cookies, cakes, gums, candy, tablets, gummies, buns, sheep cakes, puddings, jelly, Ice cream, sherbet, etc.), processed fishery products (kamaboko, chikuwa, hanpen, etc.), processed livestock products (hamburg, ham, sausage, winner, cheese, butter, yogurt, fresh cream, cheese, margarine, etc.), soup (powdered) Soup, liquid soup, etc.), staple foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.). Furthermore, the periodontal disease preventive and / or ameliorating agent of the present invention and the composition containing the same are used as health food, functional food, health supplement (supplement), nutritional supplement, specified health food, medical food, disease It can also be used as food and drink such as food for infants, food for infants, food for care, and food for elderly people. Among these, it is preferable to use as a health supplement, and more preferable to use as a tablet-like health supplement.
実施例１および２、ならびに比較例１および２
　２型糖尿病モデルマウス（ＫＫＡｙマウス（８週齢、オス））を３つの試験群に分け（ｎ＝８－９）、それぞれの試験群に１％（Ｗ／Ｖ）アスコルビン酸リン酸エステルＭｇ塩（ＡＰＭ）（実施例１）（ｎ＝８）、１％（Ｗ／Ｖ）アスコルビン酸－２－Ｏ－α－グルコシド（Ａ２Ｇ）（実施例２）（ｎ＝９）、蒸留水（ＤＷ）（比較例１）（ｎ＝９）を投与した。投与方法は、飲み水として自由摂取とした。投与期間は１４週間（２２週齢時に終了）とした。 Examples 1 and 2 and Comparative Examples 1 and 2
Type 2 diabetes model mice (KKAy mice (8 weeks old, male)) were divided into 3 test groups (n = 8-9), and 1% (W / V) ascorbic acid phosphate Mg salt in each test group (APM) (Example 1) (n = 8), 1% (W / V) ascorbic acid-2-O-α-glucoside (A2G) (Example 2) (n = 9), distilled water (DW) (Comparative Example 1) (n = 9) was administered. The administration method was free intake as drinking water. The administration period was 14 weeks (finished at the age of 22 weeks).
　一方、健常マウス（Ｃ５７ＢＬ／６マウス（８週齢、オス））に蒸留水（ＤＷ）を投与した（比較例２）（ｎ＝９）。投与方法及び投与期間は２型糖尿病モデルマウスと同様とした。 On the other hand, distilled water (DW) was administered to healthy mice (C57BL / 6 mice (8 weeks old, male)) (Comparative Example 2) (n = 9). The administration method and administration period were the same as those of type 2 diabetes model mice.
　ＡＰＭは昭和電工株式会社製の市販品を用いた。Ａ２Ｇは林原生物化学研究所製の市販品を用いた。 APM used was a commercial product manufactured by Showa Denko. A2G used was a commercial product manufactured by Hayashibara Biochemical Laboratory.
（１）歯槽骨吸収抑制（歯周病予防）の評価（図２）
　投与期間終了後に各マウスの下顎第１臼歯の舌側の近心側歯根部分の断層画像をＸ線ＣＴにより撮影し、セメント－エナメルジャンクション（ＣＥＪ）と歯槽骨頂（ＡＢ）の距離（ＣＥＪ－ＡＢ、図１の矢印で示す部分の距離）を測定した。測定値から各試験群の平均値を算出した。結果を図２に示す。 (1) Evaluation of alveolar bone resorption suppression (periodontal disease prevention) (Fig. 2)
After the administration period, a tomographic image of the lingual mesial root of the lower first molar of each mouse was taken by X-ray CT, and the distance between the cement-enamel junction (CEJ) and the alveolar crest (AB) (CEJ-AB). The distance of the portion indicated by the arrow in FIG. The average value of each test group was calculated from the measured values. The results are shown in FIG.
　２型糖尿病モデルマウス（実施例１、２および比較例１）のＣＥＪ－ＡＢは、健常マウス（比較例２）のＣＥＪ－ＡＢよりも長かった。しかし、ＡＰＭ及びＡ２Ｇのそれぞれを投与した２型糖尿病モデルマウスのＣＥＪ－ＡＢは、蒸留水を投与した２型糖尿病モデルマウスのＣＥＪ－ＡＢよりも短かった（図２）。なお、各マウスの血糖値、体重へのＡＰＭ及びＡ２Ｇの影響は、特に見られなかった。 The CEJ-AB of type 2 diabetes model mice (Examples 1 and 2 and Comparative Example 1) was longer than the CEJ-AB of healthy mice (Comparative Example 2). However, CEJ-AB of type 2 diabetes model mice administered with each of APM and A2G was shorter than CEJ-AB of type 2 diabetes model mice administered with distilled water (FIG. 2). In addition, the influence of APM and A2G on the blood glucose level and body weight of each mouse was not particularly observed.
　この結果は、アスコルビン酸誘導体が、糖尿病患者における歯槽骨吸収を軽減することを示している。また、この結果は、アスコルビン酸誘導体が、糖尿病に起因する歯周病の症状を予防または改善する可能性、および、糖尿病に起因する歯の喪失のリスクを軽減する可能性を有することを示している。 This result indicates that the ascorbic acid derivative reduces alveolar bone resorption in diabetic patients. The results also show that ascorbic acid derivatives have the potential to prevent or ameliorate periodontal disease symptoms due to diabetes and reduce the risk of tooth loss due to diabetes. Yes.
（２）歯周ポケット形成抑制（歯周病予防）の評価（図３および４）
　投与期間終了後に各マウスの下顎を採取した。左右に分割し、切歯をトリミング後、定法により固定、脱灰、パラフィン包埋してヘマトキシリン／エオジン染色を行った。 (2) Evaluation of periodontal pocket formation inhibition (periodontal disease prevention) (FIGS. 3 and 4)
After the administration period, the lower jaw of each mouse was collected. After dividing into left and right, trimming the incisor, fixing, demineralization, embedding in paraffin and staining with hematoxylin / eosin after regular trimming.
（２－１）歯肉上皮下方増殖の評価（図３）
　上記組織切片について、下顎第１臼歯のＣＥＪと付着上皮下端の距離を測定し、各試験区の平均値を算出した。結果を図３に示す。 (2-1) Evaluation of gingival epithelial downward proliferation (FIG. 3)
For the tissue section, the distance between the CEJ of the lower first molar and the lower end of the attached epithelium was measured, and the average value of each test section was calculated. The results are shown in FIG.
　２型糖尿病モデルマウスでは歯肉上皮下方増殖が見られる。しかし、ＡＰＭ及びＡ２Ｇのそれぞれを投与した２型糖尿病モデルマウスの歯肉上皮下方増殖は、蒸留水を投与した２型糖尿病モデルマウスの歯肉上皮下方増殖よりも小さかった（図３）。 下方 Gingival epithelial growth is seen in type 2 diabetes model mice. However, the downward growth of the gingival epithelium of the type 2 diabetes model mouse administered with each of APM and A2G was smaller than the downward growth of the gingival epithelium of the type 2 diabetes model mouse administered with distilled water (FIG. 3).
（２－２）歯周ポケット形成の有無の評価（図４）
　上記組織切片について、下顎第１臼歯のＣＥＪと付着上皮接着上端の距離を測定し、各試験区の平均値を算出した。結果を図４に示す。 (2-2) Evaluation of periodontal pocket formation (Figure 4)
With respect to the tissue section, the distance between the CEJ of the lower first molar and the upper end of the adhering epithelium was measured, and the average value of each test section was calculated. The results are shown in FIG.
　２型糖尿病モデルマウスでは歯周ポケット形成が見られる。しかし、ＡＰＭ及びＡ２Ｇのそれぞれを投与した２型糖尿病モデルマウスの歯周ポケット形成は、蒸留水を投与した２型糖尿病モデルマウスの歯周ポケット形成よりも小さかった（図４）。 Periodontal pocket formation is seen in type 2 diabetes model mice. However, periodontal pocket formation of type 2 diabetes model mice administered with each of APM and A2G was smaller than periodontal pocket formation of type 2 diabetes model mice administered with distilled water (FIG. 4).
（２－３）まとめ
　これらの結果は、アスコルビン酸誘導体が、糖尿病患者における歯肉上皮下方増殖および歯周ポケット形成を軽減することを示している。また、この結果は、アスコルビン酸誘導体が、糖尿病に起因する歯槽膿漏の症状を予防または改善する可能性、および、糖尿病に起因する歯の喪失のリスクを軽減する可能性を有することを示している。 (2-3) Summary These results indicate that ascorbic acid derivatives reduce gingival epithelial proliferation and periodontal pocket formation in diabetic patients. The results also show that ascorbic acid derivatives have the potential to prevent or ameliorate symptoms of alveolar pyorrhea due to diabetes and reduce the risk of tooth loss due to diabetes. Yes.

Claims (4)

  1. 　アスコルビン酸誘導体を有効成分として含む歯周病予防および／または改善剤。 An agent for preventing and / or improving periodontal disease comprising an ascorbic acid derivative as an active ingredient.
  2. 　アスコルビン酸誘導体が、アスコルビン酸リン酸エステルマグネシウム塩および／またはアスコルビン酸－２－グルコシドである請求項１に記載の歯周病予防および／または改善剤。 The agent for preventing and / or improving periodontal disease according to claim 1, wherein the ascorbic acid derivative is magnesium magnesium ascorbate and / or ascorbic acid-2-glucoside.
  3. 　アスコルビン酸誘導体と薬理学的に許容される担体とを含有する歯周病予防および／または改善組成物。 Periodontal disease prevention and / or improvement composition containing an ascorbic acid derivative and a pharmacologically acceptable carrier.
  4. 　請求項１または２に記載の歯周病予防および／または改善剤、ならびに請求項３に記載の歯周病予防および／または改善組成物からなる群より選ばれる１種以上を含有する飲食品。 A food or drink containing at least one selected from the group consisting of an agent for preventing and / or improving periodontal disease according to claim 1 and a composition for preventing and / or improving periodontal disease according to claim 3.
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Citations (2)

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JPS6296408A (en) * 1985-10-23 1987-05-02 Showa Denko Kk Drug for oral cavity
JPH04182419A (en) * 1990-11-19 1992-06-30 Hayashibara Biochem Lab Inc Composition for oral cavity use

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