JPH07233022A - External preparation for skin - Google Patents

Abstract

PURPOSE:To obtain an external preparation for skin by adding an amide of tranexamic acid and its salt to an ultraviolet absorber, thus showing reduced skin irritation caused by the ultraviolet absorber and markedly improved skinwhitening effect with high safety and stability. CONSTITUTION:The skin preparation comprises an ultraviolet absorber such as 2-hydroxy-4-methoxybenzophenone, and at least one from tranexamic acid amides of the formula (R1, R2 are H, a 1-18C alkyl, a 5-8C cycloalkyl, phenylalkyl, phenyl, R1 and R2 form together with N atom aziridine, azetidine, pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, morpholine) and its salts. The ultraviolet absorber is, for example, benzophenone, p-aminobenzoic acid or methoxycinnamic acid derivative. The amount of the ultraviolet absorber is 0.05 to 10wt.%; tranexomic acid derivative, 0.001 to 20wt.%, particularly 0.1 to 7wt.%.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a highly safe external preparation for skin which suppresses skin irritation of an ultraviolet absorber and has a significantly improved skin whitening effect.

[0002]

BACKGROUND OF THE INVENTION Although there are some unclear points about the mechanism of skin spots and the like, in general, melanin pigments are formed due to hormonal abnormalities and irritation of ultraviolet rays from the sun, and this is the skin. It is thought to be abnormally deposited inside. Treatments for such spots and bruises include substances that suppress the production of melanin, for example, a method of administering a large amount of vitamin C, a method of injecting glutathione or the like, or kojic acid,
Methods such as topical application of cysteine or the like in the form of an ointment, cream, lotion or the like have been adopted.
In Europe and America, hydroquinone preparations are used as medicines.

[0003]

However, the above-mentioned compounds, except for hydroquinone, exhibit an extremely slow effect, and thus the whitening effect is not sufficient. On the other hand, the effect of hydroquinone is tentatively recognized. , Its use is generally restricted due to its sensitizing potential. Furthermore, since an external preparation for the skin is applied to the skin and then exposed to sunlight, it is often blended with an ultraviolet absorber. There may be a problem depending on the type and individual differences.

In view of such circumstances, the present inventors have developed a skin external preparation which is excellent in safety, stability and skin whitening effect and which suppresses the skin irritation of the ultraviolet absorbent used together. As a result of extensive research aimed at, the amide of tranexamic acid and its salt are extremely safe and have good stability, and also surpass hydroquinone in terms of skin whitening effect. Acknowledging that it has an action of suppressing irritation, the present invention has been completed.

[0005]

That is, claim 1 of the present invention provides an ultraviolet absorber, and at least one of the amides of tranexamic acid represented by the following general formula 2 and salts thereof.
The external preparation for skin is characterized by containing at least one species.

[0006]

[Chemical 2] [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, a cycloalkyl group having 5 to 8 carbon atoms, or a phenylalkyl group (wherein the alkyl moiety is Has 1 to 3 carbon atoms, and the phenyl moiety may be substituted with 1 to 3 hydroxyl groups, lower alkyl groups, lower alkoxy groups, halogen atoms and amino groups), phenyl groups (wherein the phenyl group is 1 ~ 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom, an amino group may be substituted), or aziridine, azetidine, pyrrolidine formed by R ₁ and R ₂ together with a nitrogen atom, Shows a heterocyclic group of piperidine, hexahydroazepine, octahydroazocine or morpholine]

A second aspect of the present invention is the external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is a benzophenone type ultraviolet absorbent. A third aspect of the present invention is the external preparation for skin according to claim 1, wherein the ultraviolet absorber in the external preparation for skin is 2-hydroxy-4-methoxybenzophenone. Claim 4 of the present invention
Is the skin external preparation according to claim 1, wherein the UV absorbent in the skin external preparation is a p-aminobenzoic acid type UV absorbent. A fifth aspect of the present invention is the external preparation for skin according to claim 1, wherein the ultraviolet absorber in the external preparation for skin is octyl p-dimethylaminobenzoate.
A sixth aspect of the present invention is that the ultraviolet absorber in the external preparation for skin is a methoxycinnamic acid type ultraviolet absorber.
The external preparation for skin according to the item. Claim 7 of the present invention is the external preparation for skin according to claim 1, wherein the ultraviolet absorber in the external preparation for skin is octyl p-methoxycinnamate. Claim 8 of the present invention is the external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is glyceryl mono-2-ethylhexanoate di-p-methoxycinnamate. Claim 9 of the present invention is the external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is a dibenzoylmethane ultraviolet absorbent. According to claim 10 of the present invention, the ultraviolet absorber in the external preparation for skin is 4-
The external preparation for skin according to claim 1, which is tert-butyl-4'-methoxydibenzoylmethane. Claim 11 of the present invention is characterized in that the compounding amount of the ultraviolet absorber in the external preparation for skin is 0.05 to 10% by weight.
The external preparation for skin according to any one of items 1 to 10. According to a twelfth aspect of the present invention, the amide of tranexamic acid or a salt thereof in the external preparation for skin is represented by R ₁ and R ₂ in the above general formula _2.
5. The amides of tranexamic acid, which are the same or different and each is a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, or a salt thereof.
The external preparation for skin according to item 1. Claim 13 of the present invention
Is an amide of tranexamic acid or a salt thereof in the external preparation for skin, wherein R ₁ and R ₂ are the same or different in the general formula 2 above or a hydrogen atom or a phenyl group (wherein the phenyl group is 1 to 3 hydroxyl groups, The external preparation for skin according to any one of claims 1 to 11, which is an amide of tranexamic acid which may be substituted with an alkyl group, a lower alkoxy group, a halogen atom or an amino group) or a salt thereof. is there. In a fourteenth aspect of the present invention, the amide of tranexamic acid or a salt thereof in the external preparation for skin has R ₁ as a hydrogen atom and R ₂ as a phenyl group in the general formula 2 above (wherein the phenyl group is 1 to 3). The external preparation for skin according to any one of claims 1 to 11, which is an amide of tranexamic acid which may be substituted with a hydroxyl group or a lower alkoxy group) or a salt thereof. A fifteenth aspect of the present invention relates to aziridine, azetidine, pyrrolidine or piperidine, wherein the amide of tranexamic acid or a salt thereof in the external preparation for skin is formed by R ₁ and R ₂ in the general formula 2 together with a nitrogen atom. Claims 1. An amide of tranexamic acid, which is a heterocyclic group of hexahydroazepine, octahydroazocine, or morpholine, or a salt thereof.
The external preparation for skin according to items 11 to 11. According to a sixteenth aspect of the present invention, the amide of tranexamic acid or a salt thereof in the external preparation for skin is R ₁ and R ₂ in the above general formula _2.
12. An amide of tranexamic acid, which is a heterocyclic group of pyrrolidine or piperidine formed together with a nitrogen atom, or a salt thereof.
The external preparation for skin according to the item. Claim 17 of the present invention
The external preparation for skin according to any one of claims 1 to 16, wherein the content of at least one amide of tranexamic acid and a salt thereof in the external preparation for skin is 0.001 to 20% by weight. . Claim 18 of the present invention is the external preparation for skin, wherein the compounding amount of at least one or more amides of tranexamic acid and salts thereof is 0.1 to 7% by weight. The external preparation for skin according to 1. In a nineteenth aspect of the present invention, the compounding ratio of at least one or more of the amide of tranexamic acid and its salt and the ultraviolet absorber is such that the amide of tranexamic acid and its salt are based on 1 part by weight of the ultraviolet absorber. At least one kind is 0.1
Claim 1 characterized in that it is 60 parts by weight
Item is an external preparation for skin according to Items 18 to 18.

The structure of the present invention will be described in detail below. The amide of tranexamic acid and salts thereof according to the present invention,
For example, ActaPharm. Suecica, 7 , 441 (1970), J. Me.
It can be easily synthesized by a method such as d. Chem., 15 , 247 (1972).

That is, the amide of tranexamic acid is produced by reacting tranexamic acid or its reactive derivative with the amine. As the reactive derivative of tranexamic acid, acid chlorides, acid halides such as acid bromide, active esters such as p-nitrophenyl ester and N-hydroxysuccinimide ester, and mixed acid anhydrides are preferable. The reaction is preferably carried out in a solvent not involved in the reaction, for example, an organic solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, benzene and dimethylformamide at room temperature to the boiling point of the solvent for 1 to 8 hours. Alternatively, the amino group of tranexamic acid may be protected with a suitable protecting group such as a benzyloxycarbonyl group, and the protecting group may be removed by catalytic reduction or the like after amidation.

If desired, the compounds of the present invention produced as described above are inorganic acid salts such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, or acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Organic acid salts such as methanesulfonic acid and p-toluenesulfonic acid can be used.

Specific examples of substance names include trans-
4-aminomethylcyclohexanecarbonamide, 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, Nn- Butyl-trans-4-aminomethylcyclohexanecarbonamide, Nn-butyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride, Nn-propyl-trans-4-aminomethylcyclohexanecarbonamide, Nn- Propyl-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-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, trans-4-aminomethylcyclohexanecarbonylaziridineamide , Trans-4-aminomethylcyclohexanecarbonylaziridineamide hydrochloride, trans-4-aminomethylcyclohexanecarbonylazetidineamide, trans-4-aminomethylcyclohexanecarbonylazetidineamide hydrochloride, trans-4-aminomethylcyclohexanecarbonylpyrrolidineamide , Trans-4-aminomethylcyclohexanecarbonylpyrrolidineamide hydrochloride,
Trans-4-Aminomethylcyclohexanecarbonylpiperidineamide, trans-4-aminomethylcyclohexanecarbonylpiperidineamide hydrochloride, trans-4-aminomethylcyclohexanecarbonylhexahydroazepinamide, trans-4-aminomethylcyclohexanecarbonylhexahydroazepinamide hydrochloride Salt, trans-4-aminomethylcyclohexanecarbonyloctahydroazocinamide, trans-4-aminomethylcyclohexanecarbonyloctahydroazocinamide hydrochloride, trans-4-aminomethylcyclohexanecarbonylmorpholineamide, trans-4-aminomethylcyclohexane Carbonyl morpholine amide hydrochloride and the like can be mentioned.

The compounding amount of the amide of tranexamic acid and its salt compounded in the external preparation for skin according to the present invention is not particularly limited, but generally 0.0 to the total amount of external preparation for skin.
The amount is 01 to 20% by weight, preferably 0.1 to 7% by weight. If this blending amount is less than 0.001% by weight, the whitening effect of the skin external preparation and the effect of suppressing the skin irritation of the skin external preparation tend to be poor, and conversely, if the blending amount exceeds 20% by weight, it is effective. It is practically impossible to increase the amount of the compound, and it tends to be difficult to mix it with a skin external preparation.

The UV absorbers to be added to the external preparation for skin according to the present invention include benzophenone UV absorbers, p-aminobenzoic acid UV absorbers, methoxycinnamic acid UV absorbers, dibenzoylmethane UV absorbers, The following are examples of salicylic acid-based UV absorbers, and typical examples of such UV absorbers are shown.

(1) Benzophenone type ultraviolet absorber 2,4-dihydroxybenzophenone, 2,2'-dihydroxy-4-methoxybenzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2,
2 ', 4,4'-Tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-
4-methoxy-4'-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulfonate, 4-phenylbenzonone, 2-ethylhexyl-
4'-phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone

(2) p-Aminobenzoic acid type ultraviolet absorber p-aminobenzoic acid (hereinafter abbreviated as PABA), PABA
Monoglycerin ester, N, N-dipropoxy PAB
A ethyl ester, N, N-diethoxy PABA ethyl ester, N, N-dimethyl PABA ethyl ester,
N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA amyl ester, N, N-dimethyl PA
BA octyl ester

(3) Methoxycinnamic acid-based ultraviolet absorber: cinnamic acid octyl ester, 4-isopropylcinnamic acid ethyl ester, 2,5-diisopropylcinnamic acid methyl ester, 2,4-diisopropylcinnamic acid ethyl ester,
2,4-Diisopropylcinnamic acid methyl ester, p-methoxycinnamic acid propyl ester, p-methoxycinnamic acid isopropyl ester, p-methoxycinnamic acid isoamyl ester, p-methoxycinnamic acid octyl ester (p-methoxycinnamic acid 2-ethylhexyl Ester), p-methoxycinnamic acid 2-ethoxyethyl ester, p-methoxycinnamic acid cyclohexyl ester, sodium p-methoxycinnamate, potassium p-methoxycinnamate, di-p-methoxycinnamic acid mono-2-ethylhexanoic acid Glyceryl

(4) Dibenzoylmethane UV absorber 4-methoxy-4'-t-butyldibenzoylmethane,
4-methoxy-4'-methoxydibenzoylmethane, 4
-Isopropyldibenzoylmethane

(5) Salicylic Acid UV Absorber Salicylic acid amyl ester, salicylic acid menthyl ester, salicylic acid homomenthyl ester, salicylic acid octyl ester, salicylic acid phenyl ester, salicylic acid benzyl ester, salicylic acid ethylene glycol,
Dipropylene glycol salicylate

The amount of the ultraviolet absorber compounded in the external preparation for skin according to the present invention is not particularly limited, but it is generally 0.05 to 10% by weight, preferably 0.1% to the total amount of the external preparation for skin. Add 5 to 8% by weight. If this blending amount is too small, it is not possible to prevent sunburn, and the whitening effect of the amide of tranexamic acid and its salt tends to be offset, which is not preferable. It is not preferable because it tends to damage. The relative ratio between the amount of the ultraviolet absorber and the amount of the amide of tranexamic acid and the salt thereof is not particularly limited, either.
In order to suitably suppress the skin irritation of the ultraviolet absorber, it is preferable to add 0.1 to 60 parts by weight of the amide of tranexamic acid and its salt to 1 part by weight of the ultraviolet absorber.

In addition to the above-mentioned essential components, the external preparation for skin of the present invention contains other components usually used in external preparations for skin such as cosmetics and pharmaceuticals, such as oil, antioxidant, surfactant, moisturizer, fragrance, Water, alcohol, a thickener, an antiseptic, a coloring agent, a powder, a drug and the like can be appropriately blended as necessary.
The dosage form of the external preparation for skin according to the present invention is arbitrary, and for example, a solubilizing system such as lotion, an emulsifying system such as emulsion or cream, or an ointment or dispersion liquid can be used.

[0021]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but it goes without saying that the technical scope of the present invention is not limited to these examples. In the following examples, the blending amount is% by weight. First, the effect test method and evaluation method of the present invention will be described.

(1) Whitening effect (Test method) For 60 patients (females) with melasma,
An appropriate amount was applied to the affected area of the face twice a day for 12 weeks, and the degree of improvement of the affected area after 12 weeks was visually evaluated. 1 patient per group
It was divided into 0 groups into 6 groups, and the formulations shown in Examples 1 to 1 were used.
3 and Comparative Examples 4 to 6 were tested.

Samples of Examples 1 to 3 and Comparative Examples 1 to 6 (alcohol phase) wt% 95% ethyl alcohol 25.0 polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 preservative / antioxidant Agent Appropriate amount Perfume Appropriate amount Drug (listed in Table 1) 1.0 Ultraviolet absorber (listed in Table 2) 3.0 (water phase) Glycerin 5.0 Sodium hexametaphosphate proper amount Ion-exchanged water Residue (production method) Water phase, The alcohol phase is solubilized after preparation.

[0024]

[Table 1]

[0025]

[Table 2]

(Evaluation method) The degree of improvement of the affected area after use was judged based on the following judgment criteria. (Judgment) ⊚: When the rate of marked efficacy and efficacy among the subjects is 80% or more ◯: The rate of marked efficacy and efficacy among the subjects is 50 to 8
In the case of 0% Δ: The ratio of markedly effective and effective in the subjects is 30 to 5
0% x: When the ratio of excellent and effective in the subjects is less than 30%

As is clear from Table 3, it was confirmed that the example had a superior skin whitening effect as compared with the comparative example.

[0028]

[Table 3]

(2) Skin Irritation Inhibitory Effect (Test Method) The mitigating effect of tranexamic acid amide and its salt on the skin irritation (irritation) of a skin external preparation containing an ultraviolet absorber was examined at ages 19 to 26. 30 females in 1 group were divided into 10 groups, 3 groups, and the external preparation for skin of Examples 1 to 3 was applied to one side of the face, and Comparative Example 1 was applied to the other side.
After applying an appropriate amount of each of the skin external preparations (3) to (3), tennis was performed outdoors for 2 hours in the midsummer, and the degree of facial tingling at the time of publication was examined. (Evaluation method) The evaluation was made based on the following criteria. (Judgment criteria) 0: Nothing is felt ±: Slight tingling is felt +: tingling is felt −: Strongly tingling is felt

[0030]

[Table 4]

As is clear from Table 4, it was confirmed that the example had a superior effect of suppressing skin irritation as compared with the comparative example.

Example 4 Vanishing Cream Stearic Acid 5.0 Stearic Acid Alcohol 4.0 Stearic Acid Butyl Alcohol Ester 8.0 Glycerin Monostearic Acid Ester 2.0 p-Methoxycinnamic Acid Octyl Ester (UV Absorber) 5.0 Propylene Glycol 10.0 N-n-propyl-trans-4-aminomethyl cyclohexanecarbonamide 1.0 Caustic potash 0.2 Preservative / antioxidant Appropriate amount Perfume Appropriate amount Ion-exchanged water Residual (manufacturing method) N for ion-exchanged water -N-propyl-trans-
4-Aminomethylcyclohexanecarbonamide, propylene glycol and caustic potash are added and dissolved and heated to 70
Keep at ℃ (water phase). Mix other ingredients, heat and melt to 70
Keep at ℃ (oil phase). The oil phase is gradually added to the aqueous phase, and after the addition is completed, the temperature is maintained for a while to cause the reaction. After that, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C while stirring well.

Example 5 Vanishing cream Stearic acid 6.0 Sorbitan monostearate 2.0 Polyoxyethylene (20 mol) sorbitan monostearate 1.5 Acid ester 2-hydroxy-4-methoxybenzophenone (UV absorber) 8 0.0 Propylene glycol 10.0 N, N-diethyl-trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 5.0 Preservative / antioxidant Appropriate amount Perfume Appropriate amount Ion-exchanged water Residual (production method) Ion-exchanged water N, N-diethyl-trans-
4-Aminomethylcyclohexanecarbonamide hydrochloride and propylene glycol are added and heated to maintain at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). Add the oil phase to the aqueous phase and perform pre-emulsification, homogenize with a homomixer, then stir well at 30 ° C.
Cool down.

Example 6 Neutral Cream Stearyl Alcohol 7.0 Stearic Acid 2.0 Hydrogenated Lanolin 2.0 Squalane 5.0 2-Octyldodeserial Call 6.0 Polyoxyethylene (25 mol) Cetyl Alcohol Ether 3 0.0 Glycerin monostearate 2.0 N, N-dimethyl PABA octyl ester (ultraviolet absorber) 3.0 Propylene glycol 5.0 trans-4-aminomethylcyclohexane carbonylpiperidine amide hydrochloride 10.0 Perfume Suitable amount Preservative Agents / Antioxidants Appropriate amount Ion-exchanged water Residue (Production method) Trans-4-aminomethylcyclohexanecarbonylpiperidineamide hydrochloride and propylene glycol are added to ion-exchanged water and heated to maintain at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). The oil phase is added to the aqueous phase for preliminary emulsification, and the mixture is uniformly emulsified with a homomixer and then cooled to 30 ° C. while stirring well.

Example 7 Cold cream Solid paraffin 5.0 Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) 2.0 Sorbitan monolaurate 4-Methoxy-4'-t-butyldibenzoylmethane 3.0 (UV absorber) Soap powder 0.1 Borax 0.2 N- (4'-methoxyphenyl) -trans-4-aminomethyl cyclohexanecarbonamide 3 0.0 Ion-exchanged water Residual fragrance Appropriate amount Preservative / antioxidant Appropriate amount (Production method) N- (4'-methoxyphenyl) -trans-4-aminomethylcyclohexanecarbonamide, soap powder and borax are added to ion-exchanged water. Add heat and melt to 7
Keep at 0 ° C (aqueous phase). Mix other ingredients and heat to melt
Keep at 0 ° C (oil phase). The oil phase is stirred into the water phase and gradually added to carry out the reaction. After completion of the reaction, the mixture is uniformly emulsified with a homomixer, and after emulsification, the mixture is cooled to 30 ° C. with thorough stirring.

Example 8 Emulsion Polyoxyethylene (20 moles) Polyoxypropylene (2 moles) Cetyl alcohol 1.0 Silicone KF96 (20cs) (Shin-Etsu Chemical) 2.0 Liquid paraffin (medium viscosity) 3.0 2- Hydroxy-4-methoxybenzophenone 5.0 (UV absorber) Propylene glycol 5.0 Glycerin 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative Appropriate amount N-ethyl-trans-4-aminomethylcyclohexane carbonamide hydrochloride 3.0 Ion-exchanged water Residue (production method) N-ethyl-trans-4-aminomethylcyclohexanecarbonamide hydrochloride is added to ion-exchanged water and ethanol. Dissolve by heating and By dissolving the following water-soluble ingredients propylene glycol, kept at 70 ° C. (aqueous phase). Other oily ingredients are mixed, heated and melted and kept at 70 ° C. (oil phase).
The oil phase is added to the aqueous phase, preliminarily emulsified, homogeneously emulsified with a homomixer, and after emulsification, cooled to 30 ° C. with thorough stirring.

Example 9 Emulsion Polyoxyethylene (20 mol) Polyoxypropylene (2 mol) Cetyl alcohol 1.0 Silicone KF96 (20 cs) (Shin-Etsu Chemical) 2.0 Liquid paraffin (medium viscosity) 3.0 N, N-dimethyl PABA-octyl ester (UV absorber) 5.0 Propylene glycol 5.0 Glycerin 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropyl cellulose 0.1 2-Aminomethylpropanol 0.1 Antiseptic Agent Appropriate amount N- (4'-ethoxyphenyl) -trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 7.0 Ion-exchanged water Residue (production method) N- (4'-ethoxyphenyl) in ion-exchanged water and ethanol -Trans-4-aminomethylcyclohexane calc The N'amido hydrochloride was dissolved with heating, and further dissolving the following water-soluble ingredients propylene glycol, kept at 70 ° C. (aqueous phase). Mix with other oily ingredients, heat and melt to 7
Keep at 0 ° C (oil phase). The oil phase is added to the aqueous phase, preliminarily emulsified, uniformly emulsified with a homomixer, and after emulsification, cooled to 30 ° C. with thorough stirring.

Example 10 Emulsion Polyoxyethylene (20 mol) Polyoxypropylene (2 mol) Cetyl alcohol 1.0 Silicone KF96 (20 cs) (Shin-Etsu Chemical) 2.0 Liquid paraffin (medium viscosity) 3.0 4- Methoxy-4′-t-butyldibenzoylmethane 5.0 (UV absorber) Propylene glycol 5.0 Glucerine 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative Appropriate amount trans-4-aminomethylcyclohexane carbonylpyrrolidineamide 20.0 Ion-exchanged water Residue (production method) Dissolve trans-4-aminomethylcyclohexanecarbonylpyrrolidineamide in ion-exchanged water and ethanol with heating, Further prop By dissolving the following water-soluble components glycol, kept at 70 ° C. (aqueous phase). Other oily ingredients are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the aqueous phase, preliminarily emulsified, uniformly emulsified with a homomixer, and after emulsification, cooled to 30 ° C. with thorough stirring.

Example 11 Emulsion Stearic acid 1.5 Cetyl alcohol 0.5 Beeswax 2.0 Polyoxyethylene (20 mol) monooleate 1.0 Glycerin monostearate 1.0 Quinceseed extract ( 5% aqueous solution) 20.0 ethyl alcohol 10.0 di-p-methoxycinnamic acid mono-2-ethylhexanoate glyceryl (ultraviolet absorber) 5.0 propylene glycol 5.0 N, N-dimethyl-trans-4- Aminomethyl cyclohexanecarbonamide hydrochloride 8.0 Ion-exchanged water Residual fragrance Suitable amount Preservative / antioxidant Appropriate amount (manufacturing method) N-N-dimethyl-trans-in ion-exchanged water
4-Aminomethylcyclohexanecarbonamide hydrochloride and propylene glycol are added and dissolved by heating to maintain the temperature at 70 ° C (aqueous phase). Add perfume and ultraviolet absorber to ethyl alcohol and dissolve (alcohol phase). Other ingredients except the quince seed extract are mixed, heated and melted and kept at 70 ° C (oil phase). The oil phase is added to the water phase and preliminarily emulsified and homogenized with a homomixer. While stirring, add the alcohol phase and the quince seed extract. Then, cool to 30 ° C. with stirring.

Example 12 Emulsion Microcrystalline wax 1.0 Beeswax 2.0 Lanolin 2.0 Liquid paraffin 20.0 Squalane 10.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol) 1.0 Sorbitan monooleate 4-Methoxy-4'-t-butylbenzoylmethane 5.0 (UV absorber) Di-p-methoxycinnamic acid mono-2-ethylhexanoate 5.0 Glyceryl (UV absorber) Propylene glycol 7.0 N-benzyl-trans-4-aminomethyl cyclohexanecarbonamide 2.0 Ion-exchanged water Residual fragrance Suitable amount Preservative / antioxidant Appropriate amount (manufacturing method) N-benzyl-trans-4-in ion-exchanged water
Aminomethylcyclohexanecarbonamide and propylene glycol are added and heated to maintain 70 ° C (aqueous phase).
The other ingredients are mixed, dissolved by heating and kept at 70 ° C. (oil phase).
While stirring the oil phase, gradually add the water phase to this oil phase,
Emulsify uniformly with a homomixer. After emulsification, cool to 30 ° C while stirring well.

Example 13 Jelly 95% Ethyl alcohol 10.0 Dipropylene glycol 15.0 Polyoxyethylene (15 mol) oleyl alcohol ether 2.0 4-Methoxy-4′-t-butyl-dibenzoylmethane 0.5 (Ultraviolet absorber) 2-Hydroxy-4-methoxycinnamic acid octyl ester 0.5 (Ultraviolet absorber) Carboxyvinyl polymer (trade name: Carbopol 941) 1.0 Caustic potassium 0.15 L-Arginine 0.1 N- (4'-Hydroxyphenyl) -trans-4-aminomethylcyclohexanecarbonamide hydrochloride 20.0 Fragrance, appropriate amount, preservative, appropriate amount, ion-exchanged water, residual (manufacturing method) N- (4'-hydroxyphenyl) in ion-exchanged water -Trans-4-aminomethylcyclohexanecarbonamide hydrochloride and carboxylic acid The Boporu 941 was uniformly dissolved, whereas 95% ethanol dipropylene glycol,
Polyoxyethylene (15 mol) oleyl alcohol ether and other components are dissolved and added to the aqueous phase. Then, it is thickened by neutralizing with caustic potash and L-arginine.

Example 14 Peel-off type pack (alcohol phase) 95% ethanol 10.0 polyoxyethylene (15 mol) oleyl alcohol ether 2.0 di-p-methoxycinnamic acid mono-2-ethylhexanoic acid 0.5 glyceryl (Ultraviolet absorber) Preservative Suitable amount Fragrance Suitable amount (Aqueous phase) N-cyclohexyl-trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 3.0 Polyvinyl alcohol 12.0 Glycerin 3.0 Polyethylene glycol 1500 1.0 Ion-exchanged water residue (manufacturing method) Prepare an aqueous phase at 80 ° C and cool to 50 ° C.
Then, the alcohol phase prepared at room temperature is added, mixed uniformly and allowed to cool.

Example 15 Powder-containing pack (alcohol phase) 95% ethanol 2.0 Preservative proper amount fragrance proper amount colorant proper amount 4-methoxy-4′-t-butyl-dibenzoylmethane 1.0 (UV ray Absorber) 2-Hydroxy-4-methoxycinnamic acid octyl ester 1.0 (UV absorber) (Aqueous phase) N-methyl-trans-4-aminomethyl cyclohexanecarbonamide hydrochloride 7.0 Propylene glycol 7.0 Zinc Hana 25.0 Kaolin 20.0 Ion-exchanged water Residual (manufacturing method) A water phase is uniformly prepared at room temperature. Then, the alcohol phase prepared at room temperature is added and uniformly mixed.

Example 16 Water-absorbing ointment Vaseline 40.0 Stearyl alcohol 18.0 Mokurou 20.0 Polyoxyethylene (10 mol) monooleate 0.25 Glycerine monostearate 0.25 2-Hydroxy-4-methoxy Benzophenone (ultraviolet absorber) 1.0 N, N-di-n-propyl-trans-4-aminomethyl cyclohexanecarbonamide 10.0 Ion-exchanged water Residue (production method) N, N-di-n in ion-exchanged water -Propyl-trans-4-aminomethylcyclohexanecarbonamide is added and kept at 70 ° C (aqueous phase). Other components are mixed and dissolved at 70 ° C. (oil phase). The oil phase is added to the above aqueous phase, the mixture is uniformly emulsified with a homomixer, and then cooled.

The external preparations for skin obtained in the present invention were all found to be effective in the whitening effect test and the skin irritation inhibitory effect test carried out in Examples 1 to 3.

[0046]

The external preparation for skin comprising the ultraviolet absorbent according to the present invention and the amide of tranexamic acid and a salt thereof suppresses the skin irritation of the ultraviolet absorbent and significantly improves the skin whitening effect. It is a highly safe external preparation for skin.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical indication location A61K 7/44 C09K 3/00 104 Z (72) Inventor Yuki Shibata Shinhacho, Kohoku-ku, Yokohama-shi, Kanagawa 1050 Incorporated Shiseido Daiichi Research Center (72) Inventor Rumiko Kaku In Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa 1050 Incorporated Shiseido Daiichi Research Center (72) Inventor Mariko Sugiyama Kohoku, Yokohama-shi Kanagawa Shibaido Daiichi Research Center, 1050 Shinba, Tokyo (72) Inventor Maki Mori In Shiseido Daiichi Research Center, 1050 Nibacho, Kohoku-ku, Yokohama-shi, Kanagawa (72) Inventor Kenji Kitamura Kanagawa Shiseido Daiichi Research Center, Inc. 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Japan

Claims (19)

[Claims] 1. An external preparation for skin comprising an ultraviolet absorber and at least one or more amides of tranexamic acid represented by the following general formula 1 and salts thereof. [Chemical 1] [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, a cycloalkyl group having 5 to 8 carbon atoms, or a phenylalkyl group (wherein the alkyl moiety is Has 1 to 3 carbon atoms, and the phenyl moiety may be substituted with 1 to 3 hydroxyl groups, lower alkyl groups, lower alkoxy groups, halogen atoms and amino groups), phenyl groups (wherein the phenyl group is 1 ~ 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom, an amino group may be substituted), or aziridine, azetidine, pyrrolidine formed by R ₁ and R ₂ together with a nitrogen atom, Shows a heterocyclic group of piperidine, hexahydroazepine, octahydroazocine or morpholine] 2. The external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is a benzophenone-based ultraviolet absorbent. 3. The external preparation for skin according to claim 1, wherein the ultraviolet absorber in the external preparation for skin is 2-hydroxy-4-methoxybenzophenone. 4. The external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is a p-aminobenzoic acid-based ultraviolet absorbent. 5. The external preparation for skin according to claim 1, wherein the ultraviolet absorber in the external preparation for skin is octyl p-dimethylaminobenzoate. 6. The external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is a methoxycinnamic acid-based ultraviolet absorbent. 7. The external skin preparation according to claim 1, wherein the ultraviolet absorber in the external skin preparation is octyl p-methoxycinnamate. 8. The external preparation for skin according to claim 1, wherein the ultraviolet absorber in the external preparation for skin is glyceryl mono-2-ethylhexanoate di-p-methoxycinnamate. 9. The external preparation for skin according to claim 1, wherein the ultraviolet absorbent in the external preparation for skin is a dibenzoylmethane ultraviolet absorbent. 10. The ultraviolet absorber in the external preparation for skin is 4-tert.
The external preparation for skin according to claim 1, which is -butyl-4'-methoxydibenzoylmethane. 11. The external preparation for skin according to any one of claims 1 to 10, wherein the content of the ultraviolet absorber in the external preparation for skin is 0.05 to 10% by weight. 12. An amide form of tranexamic acid or a salt thereof in an external preparation for skin is the same as or different from R ₁ and R ₂ in the general formula 1 of claim 1 in which R ₁ and R ₂ are hydrogen atoms or have 1 to 3 carbon atoms. The external skin preparation according to any one of claims 1 to 11, which is an amide of tranexamic acid having a linear or branched alkyl group or a salt thereof. 13. An amide of tranexamic acid or a salt thereof in an external preparation for skin is the same as or different from R ₁ and R ₂ in the general formula 1 of claim 1, wherein a hydrogen atom or a phenyl group (here, phenyl) is used. The group is 1 to 3 hydroxyl groups,
The external preparation for skin according to any one of claims 1 to 11, which is an amide of tranexamic acid which may be substituted with a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group, or a salt thereof. . 14. An amide of tranexamic acid or a salt thereof in an external preparation for skin is represented by the general formula 1 of claim 1 in which R ₁ is a hydrogen atom and R ₂ is a phenyl group (wherein the phenyl group is 1 The external preparation for skin according to any one of claims 1 to 11, which is an amide of tranexamic acid having 3 to 3 hydroxyl groups or a lower alkoxy group) or a salt thereof. 15. An aziridine or azetidine, wherein the amide of tranexamic acid or a salt thereof in the external preparation for skin is formed by R ₁ and R ₂ together with a nitrogen atom in the general formula 1 of claim 1. 12. An amide of tranexamic acid, which is a heterocyclic group of pyrrolidine, piperidine, hexahydroazepine, octahydroazocine, or morpholine, or a salt thereof.
The external preparation for skin according to the item. 16. A pyrrolidine or piperidine in which the amide form of tranexamic acid or a salt thereof in the external preparation for skin is formed by R ₁ and R ₂ together with a nitrogen atom in the general formula 1 of claim 1. The external preparation for skin according to any one of claims 1 to 11, which is an amide of tranexamic acid, which is the heterocyclic group, or a salt thereof. 17. A compounding amount of at least one amide of tranexamic acid and a salt thereof in an external preparation for skin is 0.0.
01 to 20% by weight of claims 1 to 1
The external skin preparation according to item 6. 18. The amount of at least one amide of tranexamic acid and a salt thereof contained in the external preparation for skin is 0.1.
The external preparation for skin according to any one of claims 1 to 16, which is -7% by weight. 19. A compounding ratio of at least one or more of an amide of tranexamic acid and a salt thereof and an ultraviolet absorber,
The amide compound of tranexamic acid and at least one or more salts thereof are 0.1 to 60 parts by weight with respect to 1 part by weight of the ultraviolet absorber. Skin external preparation.