JP6237286B2 - Oral composition and oxidative stress inhibitor - Google Patents

Description

  The present invention relates to a composition for oral cavity and an oxidative stress inhibitor that have an improved oxidative stress-inhibiting effect of ascorbic acid phosphate ester or a salt thereof, and are excellent in an effect of inhibiting a living tissue such as gums from being damaged by oxidative stress.

  Periodontal disease is known to progress in the progression of enzymes, inflammatory mediators, active oxygen, etc. by damaging tissues. To prevent periodontal disease, cytotoxic factors such as those described above are used. It is important to block.

  Ascorbic acid phosphate ester or a salt thereof is known as a compound having an antioxidative action that protects a living tissue from oxidative stress by erasing excessive active oxygen produced in the living body. It was not enough.

By improving the antioxidant action of ascorbic acid phosphate ester or a salt thereof, it is expected to reduce cytotoxicity and effectively work for periodontal disease suppression.
Patent Document 1 (Japanese Patent Laid-Open No. 2013-129601) combines ascorbic acid phosphate ester or a salt thereof, a cationic polymer substance, isopropylmethylphenol and / or triclosan, and a specific nonionic surfactant. The dentifrice composition with improved oxidative stress inhibitory effect, Patent Document 2 (Japanese Patent Laid-Open No. 2012-180330), suppresses reactive oxygen injury of gingival fibroblasts by using arabitol in combination with ascorbic acid phosphate ester salt. Oral compositions with enhanced effects have been proposed.

  On the other hand, cyclodextrin is known as a compounding component of an oral composition. Patent Document 3 (Japanese Patent Laid-Open No. 2013-129641) discloses an oral composition containing cyclodextrin and polyglutamate and has an excellent effect of suppressing bad breath, and Patent Document 4 (Japanese Patent Laid-Open No. 2011-68607) discloses many. It has been proposed that the flavor can be improved by adding a specific amount of cyclodextrin to a composition for oral cavity containing a monohydric alcohol. Patent Document 5 (Japanese Patent Application Laid-Open No. 2007-169228) proposes that a specific cyclodextrin is effective for suppressing bad breath and suppressing inflammation of periodontal disease tissue. However, there is no mention of the involvement of cyclodextrin in the suppression of oxidative stress by ascorbic acid phosphate.

JP2013-129601A JP 2012-180330 A JP 2013-129641 A JP 2011-68607 A JP 2007-169228 A

  As described above, various techniques for improving the antioxidant action of ascorbic acid phosphate ester or a salt thereof have been proposed, but a new technique for improving the antioxidant action is desired.

  The present invention has been made in view of the above circumstances, and an oral composition that improves the oxidative stress suppression effect of ascorbic acid phosphate ester or a salt thereof, and is excellent in suppressing the damage of living tissues such as gums due to oxidative stress. It is an object to provide a product and an oxidative stress inhibitor.

  As a result of diligent studies to achieve the above object, the present inventors have found that when (A) ascorbic acid phosphate or a salt thereof and (B) cyclodextrin are used in combination, ascorbic acid phosphate or a salt thereof It has been found that the effect of suppressing oxidative stress is improved, and the effect of suppressing the damage of living tissues such as gums due to oxidative stress is excellent.

  When the fibroblasts that make up the gingiva are damaged by active oxygen, collagen fibers are destroyed and the cell growth function is lowered, and the gingiva is retracted and periodontal disease progresses. Under such circumstances, ascorbic acid phosphate ester or a salt thereof has an effect of protecting the living tissue from oxidative stress by erasing excess active oxygen produced in the living body. However, as shown in Comparative Examples described later, the effect of suppressing oxidative stress by ascorbic acid phosphate or a salt thereof alone is not sufficient, and oxidative stress cannot be suppressed by cyclodextrin alone. From these facts, ascorbic acid phosphate ester or a salt thereof is not considered to improve the oxidative stress suppression effect at all, but as shown in the examples, ascorbine is used in the present invention. When cyclodextrin is combined with an acid phosphate ester or a salt thereof, the oxidative stress suppressing effect is specifically and significantly enhanced, and the effect of suppressing oxidative stress injury is remarkably excellent.

  Furthermore, in this invention, it is more preferable that (A) component is ascorbic acid-2-phosphate magnesium. Moreover, as for the mixture ratio of (A) component and (B) component, it is more preferable that (A) / (B) is 0.1-20 as mass ratio.

Accordingly, the present invention provides the following oral composition and oxidative stress inhibitor.
[1]
(A) and ascorbic acid phosphate ester or a salt thereof, (B) containing a cyclodextrin composition for oral, characterized in 0.1-20 der Rukoto as mass ratio (A) / (B) object.
[2]
(A) and ascorbic acid phosphate ester or a salt thereof, (B) Ri Do and a cyclodextrin, (A) / (B) is an oral oxidative stress inhibitor Ru 0.1-20 der as a mass ratio.

  ADVANTAGE OF THE INVENTION According to this invention, the composition for oral cavity and the oxidative stress inhibitor which the oxidative stress inhibitory effect of ascorbic acid phosphate ester or its salt improves, and the biological tissue, such as gums, is excellent in the inhibitory effect by oxidative stress Can provide. This composition for oral cavity and oxidative stress inhibitor can be effectively used for prevention or suppression of periodontal disease.

  The present invention will be described in further detail below. The present invention is characterized in that (A) ascorbic acid phosphate ester or a salt thereof and (B) cyclodextrin are used in combination.

(A) Ascorbic acid phosphate of component (A) is one in which one or more of the hydroxyl groups at positions 2, 3, 5, and 6 of ascorbic acid is an ester of a compound such as phosphoric acid or polyphosphoric acid. In particular, a derivative in which the hydroxyl group at the 2-position or 3-position of ascorbic acid is converted to a phosphate ester is more preferable in terms of stability.
Examples of the ascorbic acid phosphate include ascorbic acid-2-phosphate, ascorbic acid-3-phosphate, ascorbic acid-6-phosphate, ascorbic acid-2-polyphosphate, and the like. In addition, examples of the salts include alkali metal salts and alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, and magnesium salt. Particularly preferred are magnesium salt and sodium salt, and more preferred is magnesium salt. .

  (A) Ascorbic acid phosphate or a salt thereof is preferably a magnesium salt or sodium salt of ascorbic acid-2-phosphate suitable for oral use, particularly ascorbic acid-2-phosphate having good stability. Ester magnesium is preferred.

  (A) The compounding quantity of ascorbic acid phosphate ester or its salt is preferably 0.1 to 2% (mass%, the same applies hereinafter) of the whole composition, more preferably 0.2 to 2%, and still more preferably. 0.3-2%. The greater the amount, the better the oxidative stress inhibitory effect. When 0.1% or more is added, the oxidative stress inhibitory effect is sufficiently manifested. 2% or less is suitable for suppressing discoloration and taste deterioration of the preparation. In addition, it is preferable because it is easily available and economical.

  Examples of (B) cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and α-cyclodextrin and γ-cyclodextrin are more preferable from the viewpoint of solubility in water.

  (B) As for the compounding quantity of cyclodextrin, 0.1 to 1% of the whole composition is preferable, More preferably, it is 0.2 to 1%. When 0.1% or more is blended, the effect of suppressing oxidative stress is sufficiently exhibited, and when it is 1% or less, it is suitable for suppressing the decrease in the effect of suppressing oxidative stress.

  In the present invention, the blending ratio of the component (A) and the component (B) is preferably such that (A) / (B) is 0.1 to 20, more preferably 0.2 to 20, More preferably, it is 0.3-20. Within this ratio range, the effect of suppressing oxidative stress is excellent. If it is less than 0.1, the effect of suppressing oxidative stress is not improved. If it exceeds 20, discoloration of the preparation occurs and it is not suitable for use.

The oral composition of the present invention can be prepared in the form of a liquid, liquid, paste, etc., and can be prepared as a toothpaste such as toothpaste, liquid toothpaste, liquid toothpaste, moisturized toothpaste, mouthwash, etc. Suitable as an agent, especially a toothpaste.
In this case, in addition to the said component, this invention composition can mix | blend a well-known component suitably in the range which does not prevent the effect of this invention. Specifically, the dentifrice contains, for example, an abrasive, a binder, a thickener, a surfactant, a sweetener, an antiseptic, a colorant, a fragrance, an active ingredient, a solvent such as water, a pH adjuster, and the like. Can do. The mouthwash may contain a wetting agent, a surfactant, a solvent such as water, a buffering agent, an antiseptic, a bactericidal agent, a fragrance, a sweetening agent, a pigment, and an active ingredient.

  Examples of abrasives include silica-based abrasives such as crystalline silica, amorphous silica, silica gel, and aluminosilicate, calcium hydrogen phosphate-based abrasives, calcium carbonate, aluminum hydroxide, alumina, synthetic resin-based abrasives, etc. It is done. The compounding amount of the abrasive is usually preferably 2 to 40%, particularly 5 to 20% for dentifrice. In addition, a polishing agent is not normally mix | blended with a mouthwash.

  Examples of the binder include cellulose binders such as sodium carboxymethyl cellulose, methyl cellulose, and hydroxyethyl cellulose; gums such as carrageenan, xanthan gum, and gum arabic; organic binders such as sodium alginate and sodium polyacrylate; gels Inorganic binders such as gelatinizing silica and gelling aluminum silica can be mentioned. The amount of these binders is usually 0.01 to 10%.

  Examples of the thickening agent (wetting agent) include sugar alcohols such as sorbitol and xylitol, and polyhydric alcohols such as propylene glycol, glycerin and polyethylene glycol. These compounding quantities are 10 to 60% normally.

As the surfactant, an anionic surfactant, nonionic surfactant, amphoteric surfactant and the like can be blended. In addition, an anionic surfactant such as sodium lauryl sulfate is suitably blended in the dentifrice.
Examples of the anionic surfactant include alkyl sulfates such as sodium lauryl sulfate and sodium myristyl sulfate, N-acyl amino acid salts, α-olefin sulfonates, N-acyl sulfonates, sulfates of glycerin fatty acid esters, and the like. Can be mentioned.
Nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, glycerin ester polyoxyethylene ether, sucrose fatty acid ester, polyoxyethylene-polyoxypropylene block copolymer, alkylolamide Etc. Examples of amphoteric surfactants include betaine acetate types such as alkyldimethylaminoacetic acid betaines and fatty acid amidopropyldimethylaminoacetic acid betaines, and imidazoline types such as N-fatty acid acyl-N-carboxymethyl-N-hydroxyethylethylenediamine salts.
Surfactant can use 1 type (s) or 2 or more types, and a compounding quantity is 0 to 10% normally, Especially 0.01 to 5%.

Examples of sweeteners include saccharin sodium and stevioside.
Examples of the preservative include paraoxybenzoic acid esters such as sodium benzoate, methyl paraben, ethyl paraben, and butyl paraben.
Examples of the colorant include red No. 2, No. 3, blue No. 1, titanium oxide and the like.

Perfumes include peppermint oil, spearmint oil, anise oil, eucalyptus oil, winter green oil, cassia oil, clove oil, thyme oil, sage oil, lemon oil, orange oil, peppermint oil, cardamom oil, coriander oil, mandarin oil, Lime oil, lavender oil, rosemary oil, laurel oil, camomil oil, caraway oil, marjoram oil, bay oil, lemongrass oil, origanum oil, pine needle oil, neroli oil, rose oil, jasmine oil, grapefruit oil, sweetie Natural fragrances such as oil, coconut oil, Iris concrete, absolute peppermint, absolute rose, orange flower, and processing of these natural fragrances (front reservoir cut, rear reservoir cut, fractional distillation, liquid-liquid extraction, essence, Powdered fragrances, etc.) and l-ment , Carboxyl, Anethole, Cineol, Methyl salicylate, Synamic aldehyde, Eugenol, 3-1-Mentoxypropane-1,2-diol, Thymol, Linalol, Linaryl acetate, Limonene, Menthone, Menthyl acetate, N-Substituted Paramentan-3-carboxamide, pinene, octylaldehyde, citral, pulegone, carbyl acetate, anisaldehyde, ethyl acetate, ethyl butyrate, allyl cyclohexane propionate, methyl anthranilate, ethyl methyl phenyl glycidate, vanillin, undeca Lactone, hexanal, butanol, isoamyl alcohol, hexenol, dimethyl sulfide, cycloten, furfural, trimethylpyrazine, ethyl lactate, Oral compositions such as single flavors such as chilled thioacetate, and strawberry flavors, apple flavors, banana flavors, pineapple flavors, grape flavors, mango flavors, butter flavors, milk flavors, fruit mix flavors, tropical fruit flavors, etc. It can be used in combination with known fragrance materials used for products.
Although the compounding quantity of a fragrance | flavor is not specifically limited, It is preferable to use said fragrance | flavor raw material 0.000001 to 1% in a composition. Moreover, as a fragrance | flavor for oral compositions using the said fragrance | flavor raw material, it is preferable to use 0.1 to 2.0% in a composition.

  Active ingredients (medicinal ingredients) include non-ionic and cationic antibacterial and antibacterial agents such as isopropylmethylphenol, triclosan and cetylpyridinium chloride, anti-inflammatory agents such as tranexamic acid and dipotassium glycyrrhizin, dextranase, Enzyme agents such as mutanase, fluorine-containing compounds such as sodium fluoride and sodium monofluorophosphate, hypersensitivity inhibitors such as ascorbic acid, aluminum lactate and potassium nitrate, condensed phosphates, calculus preventives, glycyrrhizic acid and its salts, Sodium chloride and the like can be used within a pharmaceutically acceptable range.

As the pH adjuster, an appropriate amount of citric acid, phosphoric acid, malic acid or salts thereof, an acid such as sodium hydroxide, potassium hydroxide, sodium carbonate or the like, or a buffering agent can be blended.
In addition, these arbitrary components can be mix | blended with a normal quantity in the range which does not impair the effect of this invention.

Moreover, this invention provides the oxidative stress inhibitor which consists of (A) ascorbic-acid phosphate ester or its salt, and (B) cyclodextrin. This oxidative stress inhibitor can be suitably used for oral use.
In addition, details, such as a compounding component, its compounding quantity, a ratio, are all the same as the above.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, “%” means “% by mass” unless otherwise specified.

[Examples and Comparative Examples]
Dentifrice compositions having the compositions shown in Tables 1 and 2 were prepared by conventional methods and evaluated by the following methods. The results are shown in the table.

Evaluation Method of Oxidative Stress Inhibitory Effect 10 g of the prepared dentifrice composition was weighed, artificial saliva (30 mL) was added and stirred, and then centrifuged (10,000 rpm, 20 min.), And the resulting supernatant was used as a sample solution. .
Next, commercially available gingival fibroblasts Gin-1 (manufactured by DS Pharma Biomedical Co., Ltd.) in a 10% fetal bovine serum (FBS) -containing Dulbecco's Modified Eagle Medium (D-MEM) at 37 ° C., 5% CO Pre-cultured under the conditions of ₂ . 400 μL of Gin-1 prepared to 5 × 10 ⁴ cells / mL was seeded in a 48-well plate and further cultured for 24 hours. After removing the culture solution, 400 μL of each prepared sample solution was added (diluted 50-fold with 10% FBS-containing D-MEM) and treated with a drug for 12 hours. After completion of the treatment, the sample solution was removed, and 400 μL of a solution containing 1 mM hydrogen peroxide (D-MEM containing 10% FBS) was added and treated for 60 minutes. After removing the solution, 200 μL of a cell activity reagent (Calcinin AM; manufactured by Invitrogen) was added and incubated at 37 ° C. under 5% CO ₂ for 30 minutes.
Thereafter, the fluorescence intensity was measured under conditions of Ex / Em = 485 nm / 538 nm using a plate reader (Fluoroskan Ascent; manufactured by Labsystems). The result calculated from the following formula was defined as the oxidative stress suppression rate.

Oxidative stress suppression evaluation was performed at n = 10, an average value was calculated, and evaluation was performed using the following scores.
Grades;
Oxidative stress suppression rate ◎: 70% or more ○: 50% or more and less than 70% △: 30% or more and less than 50% ×: Less than 30%

A prescription example is shown below.
[Formulation example] Mouthwash (A) Ascorbic acid-2-phosphate magnesium 0.3%
(B) α-cyclodextrin 0.3
Polyoxyethylene hydrogenated castor oil (60) 0.5
Propylene glycol 3
Glycerin 4.5
Xylitol 3
Ethanol 2
Citric acid 0.07
Sodium citrate 0.25
Saccharin sodium 0.004
Fragrance 0.2
Purified water balance
Total 100.0%
(A) / (B) Mass ratio 1

Claims (4)

(A) and ascorbic acid phosphate ester or a salt thereof, (B) containing a cyclodextrin composition for oral, characterized 0.1 to 20 der Rukoto as mass ratio (A) / (B) object.   The composition for oral cavity according to claim 1, wherein the (A) component ascorbic acid phosphate or a salt thereof is magnesium ascorbyl phosphate.   The composition for oral cavity according to claim 1 or 2, comprising 0.1 to 2% by mass of component (A) and 0.1 to 1% by mass of component (B). (A) and ascorbic acid phosphate ester or a salt thereof, (B) Ri Do and a cyclodextrin, (A) / (B) is an oral oxidative stress inhibitor Ru 0.1-20 der as a mass ratio.