JPH09255542A - Composition for oral cavity application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a composition for oral cavity application, containing tranexamic acid amide ant its salt, exhibiting excellent effect for the prevention and treatment of periodontosis and having high safety and usability. SOLUTION: This composition contains 0.001-10wt.% (based on the total composition) of a tranexamic acid amide of formula (R1 and R2 are each H, a 1-18C alkyl, a 5-8C cycloalkyl, benzyl or phenyl) and/or its salt as an active component. The compound of formula is highly effective for preventing the bleeding in chronic inflammation, suppressing edema, etc., and has excellent effect on periodontosis. The active component is properly compounded with a polishing agent, a moistening agent, a thickener, a surfactant, an oil, a lower alcohol, a perfume, a colorant, an antiseptic, an antioxidant, water, etc., and used in the form of dentifrice such as toothpaste, moist tooth powder or liquid dentifrice, pasta for oral cavity, mouth wash, mouth refreshing agent, chewing gum, etc. An example of the compound of formula is trans-4- aminomethylcyclohexanecarbonamide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an oral composition, and more particularly to an oral composition used for prevention and treatment of periodontal disease.

[0002]

BACKGROUND OF THE INVENTION Periodontal diseases such as periodontitis and alveolar pyorrhea are generally said to be chronic inflammation caused by chronic stimulation of periodontopathic bacteria or compounds produced by them. Yes I'm not sure yet. For these periodontal diseases, conventionally, oral compositions have been used in which anti-inflammatory agents such as allantoin and glycyrrhizic acid, antiplasmin agents such as ε-aminocaproic acid and tranexamic acid, hinokitiol, and sodium chloride are mixed.

[0003]

However, all of these are not sufficiently effective, and there are cases where the effects cannot be sufficiently exerted due to the relationship with other components to be blended, and there is a problem in stability. However, there is a problem that the usability of the compounded system may be deteriorated. Therefore, it was not always possible to obtain a satisfactory product. The present invention has been made in view of the above-mentioned problems of the prior art, and an object thereof is to provide an oral composition which is excellent in the preventive and therapeutic effects of periodontal disease, and which has good safety and usability.

[0004]

[Means for Solving the Problems] In order to achieve the above-mentioned object, as a result of intensive studies by the present inventors, the amide of tranexamic acid and its salt are highly effective in preventing bleeding and suppressing edema during chronic inflammation. The present invention was completed and the present invention was completed, recognizing that it has excellent effects on periodontal diseases. That is, the present invention is an oral composition characterized by containing at least one amide of tranexamic acid represented by the following general formula 2 and a salt thereof.

[0005]

Embedded image [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 18 carbon atoms, or 5 to 5 carbon atoms.
8 cycloalkyl group, benzyl group or phenyl group (provided that the phenyl moiety of the benzyl group and the phenyl group are 1 to
3 lower alkyl groups, lower alkoxy groups, hydroxyl groups, amino groups, and may be substituted with halogen atoms). ]

In the amide compound of tranexamic acid and the salt thereof of the above chemical formula 2, preferably, R ₁ and R ₂ are the same or different, and a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms. Or a cycloalkyl group having 5 to 8 carbon atoms, more preferably, R ₁ and R ₂ are the same or different,
It is a hydrogen atom, a methyl group or an ethyl group, and particularly preferably, R ₁ is a hydrogen atom and R ₂ is a methyl group. In addition, in the oral composition of the present invention, the amide of tranexamic acid represented by Chemical Formula 2 and a salt thereof are added in an amount of 0.
It is preferable to contain 001 to 10% by weight.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below. The amide form of tranexamic acid and its salt used in the present invention are known substances, for example, Acta Ph
arm. Suecica, 7,441 (1970), J. Med. Chem., 15, 24
7 (1972) and the like.

That is, the amino group of tranexamic acid is protected by a suitable protecting group such as a benzyloxycarbonyl group, and then the amine derivative is reacted with the protected compound or a reactive derivative of the protected compound to protect the tranexamic acid. The amide form of the body is produced. Examples of the reactive derivative of the protected form include acid chlorides, acid halides such as acid bromides, active ester forms such as N-hydroxysuccinimide ester and p-nitrophenyl ester, and mixed acid anhydrides with carbonic acid monoalkyl ester. Etc. are preferred. Thereafter, the protecting group is eliminated by catalytic reduction or the like to produce an amide of tranexamic acid.

The amide of tranexamic acid produced as described above is, if desired, an inorganic acid salt such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, or acetic acid, lactic acid, maleic acid,
Fumaric acid, tartaric acid, citric acid, methanesulfonic acid, p-
It may be an organic acid salt such as toluene sulfonic acid.

[0010] Specific examples of substance names include trans-
4-aminomethylcyclohexanecarbonamide, trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N-methyl-trans-4-aminomethylcyclohexanecarbonamide, N-methyl-trans-4
-Aminomethylcyclohexanecarbonamide hydrochloride,
N-ethyl-trans-4-aminomethylcyclohexanecarbonamide, N-ethyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, Nn-
Propyl-trans-4-aminomethylcyclohexanecarbonamide, Nn-Propyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N-
iso-propyl-trans-4-aminomethylcyclohexanecarbonamide, N-iso-propyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, Nn-butyl-trans-4-aminomethylcyclohexanecarbonamide, N- n-butyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, Nn-hexyl-trans-4-aminomethylcyclohexanecarbonamide, Nn-hexyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, Nn-heptyl-trans-4-aminomethylcyclohexanecarbonamide, Nn-heptyl-
Trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N-cyclohexyl-trans-4-aminomethylcyclohexanecarbonamide, N-cyclohexyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N, N-dicyclohexyl-trans- 4-Aminomethylcyclohexanecarbonamide, N, N-dicyclohexyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N, N-
Diethyl-trans-4-aminomethylcyclohexanecarbonamide, N, N-diethyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N,
N-dimethyl-trans-4-aminomethylcyclohexanecarbonamide, N, N-dimethyl-trans-4
-Aminomethylcyclohexanecarbonamide hydrochloride,
N-benzyl-trans-4-aminomethylcyclohexanecarbonamide, N-benzyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N-
(4'-Methoxyphenyl) -trans-4-aminomethylcyclohexanecarbonamide, N- (4'-methoxyphenyl) -trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N- (4'-ethoxyphenyl)- Trans-4-aminomethylcyclohexanecarbonamide, N- (4'-ethoxyphenyl) -trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N- (2'-methylphenyl) -trans-
4-aminomethylcyclohexanecarbonamide, N-
(2'-methylphenyl) -trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N- (3'-
Methylphenyl) -trans-4-aminomethylcyclohexanecarbonamide, N- (3'-methylphenyl) -trans-4-aminomethylcyclohexanecarbonamide hydrochloride, N- (4'-chlorophenyl) -trans-4-amino Methylcyclohexanecarbonamide, N- (4'-chlorophenyl) -trans-4-aminomethylcyclohexanecarbonamide hydrochloride and the like can be mentioned.

The oral composition of the present invention contains at least one amide of tranexamic acid and the salt thereof thus obtained, and the compounding amount thereof is preferably 0.1% based on the total amount of the oral composition. It is 001 to 10% by weight, more preferably 0.01 to 5% by weight. If the amide of tranexamic acid and its salt are less than 0.001% by weight, the effect of the present invention cannot be sufficiently obtained. On the other hand, if the amount exceeds 10% by weight, the effect cannot be expected to increase.

The oral composition of the present invention contains, in addition to the above-mentioned essential components, if necessary, depending on the shape of the composition.
Abrasives such as dicalcium phosphate, silica, wetting agents such as glycerin, sorbitol, propylene glycol,
Carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, carrageenan, thickeners such as sodium polyacrylate, sodium lauryl sulfate, sucrose fatty acid ester, surfactants such as lauroyl sarcosinate, higher alcohols, oils such as waxes, lower alcohols, Ingredients normally used in oral compositions such as fragrances, pigments, preservatives, antioxidants, and water can be added. Further, the dosage form of the composition for oral cavity of the present invention is optional,
It can be used as a toothpaste, a moisturized toothpaste, a toothpaste such as a water toothpaste, an oral pasta, a mouthwash, a mouth refreshing agent, a chewing gum and the like.

[0013]

EXAMPLES Next, the present invention will be described in more detail with reference to examples. The present invention is not limited by this. The compounding amount is% by weight.

Examination of the effect of improving periodontal disease With the formulation shown in Table 1, toothpaste was prepared and examined by a conventional method. The test method and evaluation method were as follows. (Test method) Gum swelling and bleeding symptoms, age 3
The test was carried out by 25 male and 25 female subjects aged 0 to 54. With the toothpaste of Examples 1 to 3 and Comparative Example 1, brushing was performed 3 times a day for 3 minutes for 14 days. During this period, the use of other oral compositions was prohibited, and no brushing instruction was given.

(Evaluation method) The effect of improving gum swelling and bleeding symptoms after use was evaluated based on the following criteria. (Criteria) Effectiveness: Gum swelling and bleeding are significantly improved Effectiveness: Gum swelling and bleeding are improved Slightly effective: Gum swelling and bleeding are improved Ineffective: No change before and after use ) ⊚: When the ratio of markedly effective and effective among the subjects is 80% or more ◯: The ratio of markedly effective and effective among the subjects is 50 to 80
In the case of%, Δ: the ratio of markedly effective or effective among the subjects is 30 to 50
%: X: When the ratio of markedly effective or effective in the subject is 30% or less

[0016]

[Table 1] ──────────────────────────────────── Example 1 Example 2 Example 3 Comparison Example 1 ──────────────────────────────────── Glycerin 10.0 10.0 10.0 10.0 10. 0 dibasic calcium phosphate dihydrate 40.0 40.0 40.0 40.0 sorbit 10.0 10.0 10.0 10.0 10.0 carboxymethylcellulose sodium 1.5 1.5 1.5 1.5 1.5 saccharin sodium 0 1 0.1 0.1 0.1 0.1 N-methyl-trans-4-aminomethylcyclohexanecarbaminamide hydrochloride 1.0 --- N, N-Dimethyl-trans-4-aminomethylcyclohexanecarbaminamide hydrochloride- 1.0-Nn-Propyl-trans-4-aminomethylsilane Rohexane Carbone Amide − − 1.0 − Fragrance Suitable amount Suitable amount Suitable amount Suitable amount Purified water Residual residue Residual residue Residual residue ────────────────────── ─────────────── Periodontal disease improvement effect ◎ ◎ ◎ ◎ × ─────────────────────────── ──────────

As is clear from the above results, Comparative Example 1
There was no improvement in gum swelling or bleeding. On the other hand, when Examples 1 to 3 were used, not less than 80% of the subjects showed remarkable improvement in gum swelling and bleeding. Therefore,
It was suggested that the oral composition of the present invention exhibits bleeding prevention and edema inhibitory effects during chronic inflammation, and is effective in preventing and improving periodontal disease.

A more preferred embodiment of the present invention will be described below. The present invention is not limited to these. In addition, unless otherwise specified, the compounding amount is shown by weight%.
All compositions showed sufficient periodontal disease improving effect.

Example 4 Toothpaste Silica 20.0% by weight Sorbit 50.0 Carrageenan 0.5 N-benzyl-trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 0.1 N-Ethyl-trans-4- Aminomethyl cyclohexanecarbonamide hydrochloride 0.001 Sodium carboxymethylcellulose 1.0 Sodium lauryl sulfate 1.8 Sodium saccharin 0.08 Methyl paraoxybenzoate 0.2 Perfume 0.9 Purified water Residue

Example 5 Oral Pasta Wasserin 10.0% by Weight Propylene Glycol 7.0 Stearyl Alcohol 10.0 N- (p-methoxy) phenyl-trans-4-aminomethylcyclohexanecarbonamide 0.001 N-Methyl- Trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 0.5 polyethylene glycol 1500 30.0 hinokitiol 0.1 polyethylene glycol 400 balance

Example 6 Mouthwash Ethyl alcohol 10.0% by weight Sodium saccharin 0.05 Perfume 0.8 Polyoxyethylene (20 mol) sorbitan lauric acid ester 1.0 N-methyl-trans-4-aminomethyl cyclohexanecarbonamide Hydrochloride 1.0 Purified water Residual

Example 7 Oral cooling agent (spray type) Ethyl alcohol 40.0% by weight Saccharin sodium 0.1 Sorbit 10.0 Perfume 1.0 Polyoxyethylene (20 mol) hydrogenated castor oil 0.7 Chlorhexidine hydrochloride 0.05 N -Methyl-trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 0.05 Purified water Residual

Example 8 Chewing gum gum base 25.0% by weight Calcium carbonate 2.0 Fragrance 1.0 Copper chlorophyll 0.05 N-Methyl-trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 0.1 Sorbit powder balance

[0024]

As described above, since the oral composition of the present invention contains the amide of tranexamic acid and its salt, it exhibits high efficacy in preventing bleeding during chronic inflammation, suppressing edema and the like. It is a novel oral composition which is excellent in the preventive and therapeutic effects of periodontal disease and has good safety and usability.

Front page continuation (72) Inventor Yuki Shibata, 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa, Shiseido Daiichi Research Center Co., Ltd. (72) Naomi Tanaka 1050, Shinba-cho, Kohoku-ku, Yokohama, Kanagawa Shiseido Daiichi Research Center (72) Inventor Rumiko Fujiwara 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Daiichi Research Center (72) Inventor Kenji Kitamura 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Daiichi Research Center Co., Ltd.

Claims (5)

[Claims] 1. An oral composition comprising at least one amide of tranexamic acid represented by the following general formula 1 and a salt thereof. Embedded image [In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a linear or branched alkyl group having 1 to 18 carbon atoms, or 5 to 5 carbon atoms.
8 cycloalkyl group, benzyl group or phenyl group (provided that the phenyl moiety of the benzyl group and the phenyl group are 1 to
3 lower alkyl groups, lower alkoxy groups, hydroxyl groups, amino groups, and may be substituted with halogen atoms). ] 2. The oral composition according to claim 1, wherein
R ₁ and R ₂ are the same or different, and are a hydrogen atom and a carbon number of 1 to 6
An oral composition comprising at least one or more of an amide of tranexamic acid which is a linear or branched alkyl group or a cycloalkyl group having 5 to 8 carbon atoms and a salt thereof. 3. The oral composition according to claim 1, wherein R
An oral composition comprising 1 or more of at least one amide of tranexamic acid and a salt thereof in which ₁ and R ₂ are the same or different and each is a hydrogen atom, a methyl group or an ethyl group. 4. The oral composition according to claim 1, wherein
An oral composition comprising at least one amide of tranexamic acid in which R ₁ is a hydrogen atom and R ₂ is a methyl group, and a salt thereof. 5. The oral composition according to any one of claims 1 to 4, wherein the amide of tranexamic acid represented by the general formula 1 and its salt are contained in an amount of 0.001 to 1 in the total amount of the composition.
A composition for oral cavity, which is blended in an amount of 0% by weight.