JP6412045B2 - Food composition and oral administration for periodontal disease prevention and / or improvement - Google Patents

Description

  The present invention relates to a preventive and / or therapeutic agent for periodontal disease.

  Periodontal disease is an inflammatory disease in which periodontal tissues (gingiva, cementum, periodontal ligament, and alveolar bone) supporting 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, the diagnosis of periodontal disease is mainly performed by measuring alveolar bone resorption by a clinical index such as X-ray imaging or visual inspection by a dentist.

  Once alveolar bone resorption occurs, 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-ascorbic acid is known to be important for the synthesis of collagen in vivo, which is a major component of the bone matrix. That is, L-ascorbic acid is essential for the biosynthesis of hydroxyproline and hydroxylysine, which are amino acids specific to collagen. For example, when added to an osteoblast culture system, collagen synthesis is promoted and osteoblast differentiation. It is known to promote bone formation.

  L-ascorbic acid has a drawback that it easily undergoes 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.

JP 2010-1228 A JP 2010-260794 A

Cell Biol Int. 2004; 28 (4): 255-65.

  As described above, conventional prevention and treatment of periodontal disease has been performed with a focus on the control of parasites (infectious bacteria), but their effects have not been sufficient. As a result, the incidence of periodontal disease has been steadily increasing despite the decrease in the incidence of caries due to the spread of fluoride and toothpaste habits.

  In addition, non-steroidal anti-inflammatory agents have been feared to have an adverse effect on the oral mucosa.

  On the other hand, 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.

  An object of the present invention is to provide an active ingredient that can remarkably exhibit the effect of treating and preventing periodontal disease and can be used as a food or drink.

  The present inventors have found that periodontal disease-like symptoms (such as downward proliferation of the gingival epithelium, periodontal pocket formation, and alveolar bone resorption) spontaneously develop in diabetic model mice. Moreover, when the test which administers an L-ascorbic acid derivative to an animal was conducted, it discovered that the downward proliferation of gingival epithelium, periodontal pocket formation, and alveolar bone resorption were each suppressed. From this finding, 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.

The present invention provides the following [1] to [3] and (1) to (11).
[1] An agent for preventing and / or treating periodontal disease comprising an ascorbic acid derivative as an active ingredient.
[2] The preventive and / or therapeutic agent for periodontal disease according to [1] above, wherein the ascorbic acid derivative is ascorbic acid phosphate magnesium salt and / or ascorbic acid-2-glucoside.
[3] A food and drink containing the preventive and / or therapeutic agent for periodontal disease according to [1] or [2].
(1) A food composition for preventing and / or improving periodontal disease comprising ascorbic acid-2-glucoside as an active ingredient (excluding chewing gum).
(2) A composition for alveolar bone resorption suppression containing ascorbic acid-2-glucoside as an active ingredient (excluding chewing gum).
(3) The food composition according to (2), wherein the alveolar bone resorption is alveolar bone resorption caused by diabetes.
(4) The food composition according to any one of (1) to (3), which contains 0.00001% by mass or more of ascorbic acid-2-glucoside.
(5) The food form according to any one of (1) to (4), wherein the dosage form is a liquid, syrup, tablet, capsule, granule, fine granule, soft capsule, or syrup. Composition.
(6) An oral administration agent for preventing and / or treating periodontal disease comprising ascorbic acid-2-glucoside as an active ingredient.
(7) An oral administration agent for suppressing alveolar bone resorption containing ascorbic acid-2-glucoside as an active ingredient.
(8) The agent according to (7), wherein the alveolar bone resorption is alveolar bone resorption caused by diabetes.
(9) The agent according to any one of (6) to (8), which contains 0.00001% by mass or more of ascorbic acid-2-glucoside.
(10) The agent according to any one of (6) to (9), wherein the dose of ascorbic acid-2-glucoside is 0.001 g / day to 100 g / day per adult.
(11) The agent according to any one of (6) to (10), wherein the dosage form is a liquid, syrup, tablet, capsule, granule, fine granule, soft capsule, or syrup.

  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.

FIG. 1 is a view showing a mesial side root portion under the lower first molar. An arrow part shows the distance (CEJ-AB) of a cement-enamel junction (CEJ) and an alveolar bone crest (AB). FIG. 2 is a graph showing CEJ-AB of 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.

  Examples of 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.

  Examples of the carboxylic acid include aliphatic carboxylic acids and aromatic carboxylic acids.

  Examples of the sulfonic acid include sulfonic acid and alkylsulfonic acid. The alkylsulfonic acid is usually an alkylsulfonic acid having 1 to 6 carbon atoms, and examples thereof include methylsulfonic acid and ethylsulfonic 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 monoesters of phosphoric acid; dialkyl esters of phosphoric acid (eg, the two hydrogens of phosphoric acid are methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl) Dialkyl group of phosphoric acid substituted with two alkyl groups selected from alkyl groups having 1 to 6 carbon atoms such as a group, isobutyl group, pentyl group, hexyl group, etc. Tel etc.) and the like. In the phosphoric acid dialkyl ester, the two alkyl groups may be the same or different from each other.

  Examples of 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. 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;

  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 ester magnesium salt (APM) and the like) and salts thereof, Ascorbic acid glucoside (eg ascorbic acid-2-glucoside and the like) and salts thereof, Ascorbyl tetraisopalmitate (VCIP) and salts thereof Ascorbic acid-2-phosphate-6-palmitate (APPS) and salts thereof, and more preferably used ascorbic acid derivatives are sodium L-ascorbate, magnesium L-ascorbyl phosphate, ascorb Acid 2-glucoside (for example, ascorbic acid-2-O-α-glucoside), 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).

  As the ascorbic acid derivative, one artificially synthesized by chemical synthesis or the like 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 compounding amount of the ascorbic acid derivative in the preventive and / or ameliorating agent of the present invention is not particularly limited as long as it is a compounding amount capable of achieving the effects of the present invention, but usually the whole periodontal disease preventing and / or improving agent 0.00001% by mass or more, preferably 0.001% by mass or more, more preferably 0.01% by mass or more, still more 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 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.

  The agent for preventing and / or improving periodontal disease 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 periodontal disease preventive and / or ameliorating agent of the present invention may have an ascorbic acid derivative as an active ingredient, and may have a component (pharmacologically acceptable base) other than the ascorbic acid derivative. As an example of other components, there may be mentioned components (for example, storage stabilizers) that mainly ensure stability in storage and distribution. In addition, one or two 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 contained in the periodontal disease prevention and / or ameliorating agent of the present invention 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 From various agents, vitamins, swelling agents, thickeners, surfactants, etc. that do not impair the properties required for the formulation (for example, stability of the formulation). One type or two or more types 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.

  The dosage form of the preventive and / or ameliorating agent of the present invention 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.

  The dosage form of the periodontal disease preventive and / or ameliorating agent 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), syrup (syrup), solid, semi-liquid, cream, and paste.

  The timing of administration of the periodontal disease prevention and / or ameliorating agent of the present invention 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 agent for preventing and / or improving periodontal disease of the present invention can prevent and / or improve periodontal disease as described below. First, the onset of periodontal disease can be prevented. Further, after the onset of periodontal disease, the symptoms (gum tissue lesions such as gingival epithelial downward proliferation 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.

  The agent for preventing and / or improving periodontal disease of the present invention can prevent its onset before onset of periodontal disease. Moreover, after the onset of periodontal disease, the symptom can be improved (relieved). Further, the preventive and / or ameliorating agent for 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 periodontal disease prevention and / or amelioration agent of the present invention is not particularly limited. For example, the subject who has already developed periodontal disease and alveolar pus leak, the risk of periodontal disease and alveolar pus leak There are certain subjects (old people, smokers, postmenopausal women, diabetics, etc.). 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.

  The agent for preventing and / or improving periodontal disease of the present invention 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, wiener, cheese, butter, yogurt, fresh cream, cheese, margarine, fermented milk, etc.), soup (Powder soup, liquid soup, etc.), staple foods (rice, noodles (dried noodles, raw noodles), bread, cereals, etc.), seasonings (mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.). Further, the preventive and / or improving agent for periodontal disease of the present invention is a health food, a functional food, a health supplement (supplement), a nutritional supplement, a food for specified health use, a medical food, a food for a sick person, and an infant. It can also be used as food and drink such as food, food for nursing 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.

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).

  Meanwhile, 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 used was a commercial product manufactured by Showa Denko KK. A2G used was a commercial product manufactured by Hayashibara Biochemical Laboratory.

(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.

  CEJ-AB of type 2 diabetes model mice (Examples 1, 2 and Comparative Example 1) was longer than 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.

  This result shows that ascorbic acid derivatives reduce 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) 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) 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.

  Gingival epithelial downward proliferation 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) Evaluation of presence or absence of periodontal pocket formation (FIG. 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.

  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) Summary These results indicate that ascorbic acid derivatives reduce gingival epithelial downward growth 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 (7)

Look containing ascorbic acid 2-glucoside as an active ingredient from 0.00001 to 35 wt%, not including vitamin E, periodontal pocket formation inhibiting food composition resulting from diabetes (except for chewing gum).   The composition for foodstuffs of Claim 1 which contains 1-35 mass% ascorbic acid-2-glucoside.   The food composition according to claim 1 or 2, wherein the dosage form is a liquid, syrup, tablet, capsule, granule, fine granule, soft capsule, or syrup. Look containing ascorbic acid 2-glucoside as an active ingredient from 0.00001 to 35 wt%, not including vitamin E, oral dosage for periodontal pocket formation inhibition resulting from diabetes.   The agent of Claim 4 containing 1-35 mass% of ascorbic acid-2-glucoside.   The agent according to claim 4 or 5, wherein the dose of ascorbic acid-2-glucoside is 0.001 g / day to 100 g / day per adult.   The agent according to any one of claims 4 to 6, wherein the dosage form is a liquid, a syrup, a tablet, a capsule, a granule, a fine granule, a soft capsule, or a syrup.