JPH07233041A - Skin external preparation - Google Patents

Abstract

PURPOSE:To obtain a skin external preparation, remarkable in skin beautifying and whitening effects and having high safety by blending L-ascorbic acid (derivative), etc., with a specific amide derivative (salt) of tranexamic acid. CONSTITUTION:This skin external preparation is obtained by blending (A) 0.001-20wt.% one or more selected from the group consisting of L-ascorbic acid (derivative), a placental extract, kojic acid (derivative), azelaic acid (derivative), glucosamine (derivative) and a glycoside (derivative) of hydroquinone with (B) 0.001-20wt.% (preferably 0.1-7wt.%) amide derivative (salt) of tranexamic acid expressed by the formula (R1 is H or a lower alkyl; R2 is an alkyl, a cycloalkyl, an alkenyl, etc.). trans-4- Acetylaminomethylcyclohexanecarboxylic acid, etc., are cited as examples of the ingredient (B).

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 has a significantly improved skin whitening effect.

[0002]

2. Description of the Related Art Although there are some unclear points regarding the mechanism of skin stains and the like, in general, melanin pigments are formed due to hormonal abnormalities and irritation of ultraviolet rays from sunlight, and these are formed in the skin. It is considered to be abnormally deposited. In treating such spots and bruises, a substance that suppresses the production of melanin, for example, a method of administering a large amount of L-ascorbic acid, a method of injecting glutathione or the like, or an ointment, cream, lotion or the like of kojic acid or cysteine A method such as applying it locally in a form is adopted.

[0003]

However, many of them have problems in terms of stability, safety, odor, etc., and their expected effects are weak, so that they are not yet satisfactory. In view of such circumstances, the present inventors have conducted earnest studies to obtain a skin external preparation having a truly excellent whitening effect, and as a result, L-ascorbic acid and its derivative, placenta extract, kojic acid and its One or more selected from the group consisting of derivatives, azelaic acid and its derivatives, glucosamine and its derivatives, hydroquinone glycosides and its derivatives, and amides of tranexamic acid and their salts. It was found that a synergistic whitening effect can be obtained by using one kind or a combination of two or more kinds, and completed the present invention.

[0004]

That is, claim 1 of the present invention provides L-ascorbic acid and its derivatives, placenta extract, kojic acid and its derivatives, azelaic acid and its derivatives, glucosamine and its derivatives, and hydroquinone. One or more selected from the group consisting of glycosides and derivatives thereof and one or more selected from the group consisting of amides of tranexamic acid represented by the following general formula 2 and salts thereof. It is an external preparation for skin characterized by containing.

[0005]

[Chemical 2] Wherein the R ₁ is a hydrogen atom or a lower alkyl group, R ₂
Is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, a pyridyl group, a trifluoromethyl group,
Phenylalkyl group (wherein the alkyl part has 1 to 1 carbon atoms)
3, the phenyl moiety may be substituted with 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group), a phenyl group (wherein the phenyl group is 1 to 3 hydroxyl groups). , A lower alkyl group, a lower alkoxy group, a halogen atom, an amino group may be substituted) or a styryl group (wherein the phenyl moiety is 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom, an amino group). Group may be substituted))]

[0006] According to claim 2 of the present invention, L-ascorbic acid and its derivative in the external preparation for skin according to claim 1 are L-.
Ascorbic acid, L-ascorbic acid phosphoric acid ester,
An external preparation for skin, which is L-ascorbic acid-2-sulfate or a salt thereof. A third aspect of the present invention is the external preparation for skin, wherein the glycoside of hydroquinone in the external preparation for skin according to claim 1 is hydroquinone β-D-glucose. According to a fourth aspect of the present invention, the amide of tranexamic acid and the salt thereof in the external preparation for skin according to the first to third aspects are the same as those in the above general formula 2, wherein R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is an alkyl. An external preparation for skin, which is an amide of tranexamic acid which is a group or a cycloalkyl group, or a salt thereof. According to a fifth aspect of the present invention, the amide of tranexamic acid and a salt thereof in the external preparation for skin according to the first to third aspects are the same as those in the above general formula 2, wherein R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is an alkenyl. A skin external preparation characterized by being an amide of tranexamic acid which is a group or a cycloalkenyl group, or a salt thereof. Claim 6 of the present invention
Is an amide of tranexamic acid and a salt thereof in the external preparation for skin according to claim 1 in the formula 2
_An external preparation for skin, wherein ₁ is a hydrogen atom or a lower alkyl group, and R ₂ is a pyridyl group, an amide of tranexamic acid or a salt thereof. Claim 7 of the present invention
Is an amide of tranexamic acid and a salt thereof in the external preparation for skin according to claim 1 in the formula 2
_An external preparation for skin, wherein ₁ is a hydrogen atom or a lower alkyl group, and R ₂ is a trifluoromethyl group, an amide of tranexamic acid or a salt thereof. According to claim 8 of the present invention, the amide of tranexamic acid and the salt thereof in the external preparation for skin according to claims 1 to 3 are represented by the general formula 2
Wherein R ₁ is a hydrogen atom or a lower alkyl group, and R ₂
Is a phenylalkyl group (where the alkyl part has 1 carbon
And the phenyl moiety is an amide of tranexamic acid which may be substituted with 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom and an amino group, or a salt thereof. It is a characteristic external preparation for skin. According to a ninth aspect of the present invention, the amide of tranexamic acid and a salt thereof in the external preparation for skin according to the first to third aspects are the same as those in the above general formula 2 in which R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is phenyl. Group (wherein the phenyl group is 1-3
An external dermatological agent characterized in that it is an amide of tranexamic acid, which may be substituted with a hydroxyl group, a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group) or a salt thereof. According to a tenth aspect of the present invention, the amide of tranexamic acid and a salt thereof in the external preparation for skin according to the first to third aspects are the same as those in the above general formula 2, wherein R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is styryl. A group (wherein the phenyl moiety is 1 to 3 hydroxyl groups, a lower alkyl group,
An external preparation for skin, which is an amide of tranexamic acid which may be substituted with a lower alkoxy group, a halogen atom or an amino group) or a salt thereof. Claim 11 of the present invention provides L-ascorbic acid and derivatives thereof, placenta extract, kojic acid and derivatives thereof, azelaic acid and derivatives thereof, glucosamine and derivatives thereof, hydroquinone in the external preparation for skin according to claims 1 to 10. The amount of one or more selected from the group consisting of glycosides and derivatives thereof of 0.
The external preparation for skin is characterized by being 001 to 20% by weight. In a twelfth aspect of the present invention, one or two or more compounded amounts selected from the group consisting of amides of tranexamic acid and salts thereof in the external preparation for skin according to claims 1 to 10 are the total amount of the external preparation for skin, The external preparation for skin is characterized by being 0.001 to 20% by weight. Claim 13 of the present invention
The amount of one or more selected from the group consisting of amides of tranexamic acid and salts thereof in the external preparation for skin according to claim 1 is 0.1, based on the total amount of the external preparation for skin.
It is an external preparation for skin characterized by being ~ 7% by weight.

The structure of the present invention will be described in detail below. The L-ascorbic acid used in the present invention is generally referred to as vitamin C, and has a strong reducing action to have a cell respiration action, an enzyme activating action, a collagen forming action, and a melanin reducing action. Examples of L-ascorbic acid derivatives include L-ascorbic acid monostearate and L
-Ascorbic acid monopalmitate, L-ascorbic acid monoalkyl ester such as L-ascorbic acid monooleate, L-ascorbic acid monophosphate ester, L
L-ascorbic acid monoester derivatives such as ascorbic acid-2-sulfate, L-ascorbic acid distearate, L-ascorbic acid dipalmitate, L
-Dialkyl esters such as ascorbic acid diolate, L-such as L-ascorbic acid diphosphate ester
Ascorbic acid diesters, L-ascorbic acid tristearate, L-ascorbic acid tripalmitate,
Examples thereof include trialkyl esters such as L-ascorbic acid trioleate, and ascorbic acid triesters such as L-ascorbic acid triphosphate.

Examples of the kojic acid derivative used in the present invention include kojic acid esters such as kojic acid alkyl ester and kojic acid ethers such as kojic acid alkyl ether.

Examples of the azelaic acid derivative used in the present invention include azelaic acid monoesters such as azelaic acid monoalkyl ester and azelaic acid diesters such as azelaic acid dialkyl ester.

Examples of the glucosamine derivative used in the present invention include glucosamine esters such as acetylglucosamine and glucosamine ethers such as glucosamine methyl ether.

Examples of the hydroquinone glycoside used in the present invention include hydroquinone α-D-glucose, hydroquinone β-D-glucose, hydroquinone α-L-glucose, hydroquinone β-L-glucose, and hydroquinone α-D. -Galactose, hydroquinone β-D-galactose, hydroquinone α-L-
Hexaglycoside glycosides such as galactose and hydroquinone β-L-galactose, hydroquinone α-D-ribose, hydroquinone β-D-ribose, hydroquinone α-L
-Ribose, hydroquinone β-L-ribose, hydroquinone α-D-arabinose, hydroquinone β-D
-Pentacarbon glycosides such as arabinose, hydroquinone α-L-arabinose and hydroquinone β-L-arabinose, hydroquinone α-D-glucosamine, hydroquinone β-D-glucosamine, hydroquinone α-L-
Glucosamine, hydroquinone β-L-glucosamine,
Aminoglycosides such as hydroquinone α-D-galactosamine, hydroquinone β-D-galactosamine, hydroquinone α-L-galactosamine, hydroquinone β-L-galactosamine, hydroquinone α-D-glucuronic acid, hydroquinone β-D-glucuronic acid , Hydroquinone α-L-glucuronic acid, hydroquinone β-L-
Glucuronic acid, hydroquinone α-D-galacturonic acid, hydroquinone β-D-galacturonic acid, hydroquinone α-L-galacturonic acid, hydroquinone β-L
-Uronic acid glycosides such as galacturonic acid can be mentioned, and derivatives thereof can include ester bodies such as acetylated products and ether bodies such as methylated products, but they have a whitening effect and are easily available. From the standpoint of properties, stability, etc., it is preferable to use hydroquinone β-D-glucose (generic name: arbutin, hereinafter referred to as arbutin).

In carrying out the present invention, one kind or two or more kinds are appropriately selected and mixed from these.

L- to be incorporated in the external preparation for skin according to the present invention
Ascorbic acid and its derivatives, placenta extract, kojic acid and its derivatives, azelaic acid and its derivatives,
The amount of one or more selected from the group consisting of glucosamine and its derivatives, glycosides of hydroquinone and its derivatives is not particularly limited, but generally 0.001 to 20 with respect to the total amount of the skin external preparation. %, Preferably 0.01 to 10% by weight, particularly preferably 0.1 to 7% by weight. If the blending amount is less than 0.001% by weight, the whitening effect of the external preparation for skin tends to be poor, and conversely,
Even if it is compounded in an amount exceeding 20% by weight, an increase in the effect cannot be expected substantially, and compounding into an external skin preparation tends to be difficult.

The amides of tranexamic acid and salts thereof according to the present invention include, for example, J. Med. Chem., 15 , 247 (197
2), JP-A-48-68541, JP-A-53-148536, JP-A-57-59847 and the like.

The compound of the present invention produced as described above is optionally combined with an inorganic salt such as sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt or an organic salt such as monoethanolamine, diethanolamine or triethanolamine. can do.

Specific examples of substance names include trans-
4-acetylaminomethylcyclohexanecarboxylic acid,
Trans-4-trifluoroacetylaminomethylcyclohexanecarboxylic acid, trans-4-propionylaminomethylcyclohexanecarboxylic acid, trans-4-
Butyrylaminomethylcyclohexanecarboxylic acid, trans-4-isobutyrylaminomethylcyclohexanecarboxylic acid, trans-4-valerylaminomethylcyclohexanecarboxylic acid, trans-4-isovalerylaminomethylcyclohexanecarboxylic acid, trans-4- Pivaloylaminomethylcyclohexanecarboxylic acid, trans-4-pentanoylaminomethylcyclohexanecarboxylic acid, trans-4-hexanoylaminomethylcyclohexanecarboxylic acid, trans-4- (2-hexenoylaminomethyl) cyclohexanecarboxylic acid, Trans-4-nonylaminomethylcyclohexanecarboxylic acid, trans-4- (9-tetradecenoylaminomethyl) cyclohexanecarboxylic acid, trans-4-decanoylaminomethyl Chlorohexanecarboxylic acid, trans-4-palmitoylaminomethylcyclohexanecarboxylic acid, trans-4-stearoylaminomethylcyclohexanecarboxylic acid, trans-4-oleoylaminomethylcyclohexanecarboxylic acid, trans-4-linoleoylaminomethylcyclohexanecarboxylic acid , Trans-4-linolenoylaminomethylcyclohexanecarboxylic acid, trans-4- (2,4,6-octatrienoylaminomethyl) cyclohexanecarboxylic acid, trans-4- (trans-4'-n-pentylcyclohexylcarbonyl) Aminomethyl) cyclohexanecarboxylic acid, trans-4- (trans-4′-isobutylcyclohexylcarbonylaminomethyl) cyclohexanecarboxylic acid, trans-4-benzoyl Mino methylcyclohexane carboxylic acid, trans-4- (3 ', 4'-
Dimethoxycinnamoylaminomethyl) cyclohexanecarboxylic acid, trans-4- (3 ', 4', 5'-trimethoxybenzoylaminomethyl) cyclohexanecarboxylic acid, trans-4- (3 ', 4'-dihydroxybenzoylaminomethyl) Cyclohexanecarboxylic acid, trans-4- (2'-hydroxybenzoylaminomethyl) cyclohexanecarboxylic acid, trans-4- (2 '
-Aminobenzoylaminomethyl) cyclohexanecarboxylic acid, trans-4- (2'-amino-5'-bromobenzoylaminomethyl) cyclohexanecarboxylic acid,
Examples include trans-4- (3'-pyridylcarbonylaminomethyl) cyclohexanecarboxylic acid.

The 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.

In the external preparation for skin of the present invention, in addition to the above-mentioned essential components, other components usually used in external preparations for skin such as cosmetics and pharmaceuticals, such as oil, humectant, ultraviolet absorber, antioxidant and surfactant. , An antiseptic, a moisturizer, a fragrance, water, an alcohol, a thickener and the like can be appropriately added if necessary. The dosage form of the external preparation for skin according to the present invention is arbitrary, for example, a solubilizing system such as lotion, an emulsion, an emulsion system such as cream,
Alternatively, any formulation such as an ointment or a dispersion can be used.

[0019]

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. The whitening effect was judged by a usage test such as a whitening effect on skin by cumulative application, elimination of spots and freckles.

(1) Whitening effect (Test method) One sample lotion was prepared in the morning and evening, with 20 subjects and 1 group each suffering from color blackness, stains, freckles, etc.
It was applied to the face every day for 3 months, and the whitening effect was examined after 3 months. Examples 1 to 6 and Comparative Examples 1 to 1 having the following formulations
7 were tested. Samples of Examples 1 to 6 and Comparative Examples 1 to 7 (alcohol phase) wt% 95% ethyl alcohol 25.0 polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 preservative / antioxidant proper amount Perfume Appropriate amount Drug (described in Table 1) (Aqueous phase) Glycerin 2.0 Propylene glycol 1.0 Ion-exchanged water Residual (Production method) The aqueous phase and the alcohol phase are prepared and then solubilized.

[0021]

[Table 1]

(Judgment Criteria) Effectiveness: Pigmentation was almost inconspicuous. Effective; Very thin. Somewhat effective: Somewhat thin. Ineffective: No change (judgment) ◎: When the ratio of effective and effective (effective rate) among the subjects is 80% or more ○: The ratio of effective and effective (effective rate) among the tested Is 50% or more and less than 80%. Δ: Remarkable and effective ratio among test subjects (effective ratio) is 30% or more and less than 50% ×: Remarkable and effective ratio among test subjects (Effective rate) is less than 30%

As is clear from Table 2, it was confirmed that the example had a superior skin whitening effect as compared with the comparative example.

Example 7 Vanishing Cream Stearic Acid 5.0 Stearic Acid Alcohol 4.0 Stearic Acid Butyl Alcohol Ester 8.0 Glycerin Monostearate 2.0 Ascorbate Distearate 1.0 Propylene Glycol 10.0 trans-4- ( 2,4,6-octatrienoylaminomethyl) cyclohexanecarboxylic acid 1.0 Preservative / antioxidant Appropriate amount Perfume Appropriate amount Ion-exchanged water Residual (production method) Trans-4- (2,4,2) 6-
Octatrienoylaminomethyl) cyclohexanecarboxylic acid and propylene glycol are added and dissolved, and the mixture is heated and kept at 70 ° C. (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° C. (oil phase). Gradually add the oil phase to the aqueous phase,
After all the additions are completed, the temperature is kept 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 8 Vanishing Cream Stearic Acid 6.0 Sorbitan Monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan Monostearate 1.5 Arbutin 7.0 Propylene Glucol 10.0 trans-4- (3'-Pyridylcarbonylaminomethyl) Cyclohexanecarboxylic acid 5.0 Preservative / antioxidant Appropriate amount Perfume Appropriate amount Ion-exchanged water Residual (production method) Trans-4- (3'-pyridylcarbonylaminomethyl) in ion-exchanged water ) Cyclohexanecarboxylic acid, arbutin and propylene glycol are added and heated and kept 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 9 Neutral Cream Stearyl Alcohol 7.0 Stearic Acid 2.0 Hydrogenated Lanolin 2.0 Squalane 5.0 2-Octyldedeserial Call 6.0 Polyoxyethylene (25 mol) Cetyl Alcohol Ether 3 0.0 Glycerin monostearate 2.0 Placenta extract 0.1 Propylene glycol 5.0 Trans-4- (3 ', 4'-dimethoxycinnamoyl aminomethyl) cyclohexanecarboxylic acid 10.0 Fragrance Suitable amount Preservative Antioxidant Appropriate amount Ion-exchanged water Residual (production method) Trans-4- (3 ', 4'-
Dimethoxycinnamoylaminomethyl) cyclohexanecarboxylic acid, placenta extract and propylene glycol are added and heated to 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 10 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 Kojic acid 2.0 Soap powder 0.1 Borax 0.2 trans-4-trifluoroacetylaminomethyl cyclohexanecarboxylic acid 0.1 Ion-exchanged water Residual fragrance Suitable amount Preservative / antioxidant Suitable amount (production method) Ion exchange Trans-4-trifluoroacetylaminomethylcyclohexanecarboxylic acid, kojic acid, soap powder and borax are added to water and dissolved by heating to maintain the temperature at 70 ° C (aqueous phase). The other ingredients are mixed, heated and melted and maintained at 70 ° 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 11 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 Propylene glycol 5.0 Arbutin 2.0 Glycerin 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative A suitable amount trans-4- (3'-p- Hydroxyphenyl propionylaminomethyl) cyclohexanecarboxylic acid 20.0 Ion-exchanged water Residual (production method) Ion-exchanged water and ethanol trans-4-
(3′-p-Hydroxyphenylpropionylaminomethyl) cyclohexanecarboxylic acid and arbutin are dissolved by heating, and water-soluble components below propylene glycol are dissolved and maintained 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 12 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 Propylene glycol 5.0 Sodium ascorbic acid-2-sulfate 5.0 Glycerin 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative proper amount trans-4- (3 ', 4'-dihydroxybenzoyl aminomethyl) cyclohexanecarboxylic acid 7.0 Ion-exchanged water Residual (Production method) Ion-exchanged water and ethanol trans-4-
(3 ', 4'-dihydroxybenzoylaminomethyl)
Cyclohexanecarboxylic acid is dissolved by heating, and then water-soluble components below propylene glycol are dissolved and maintained at 70 ° C (aqueous phase). Mix with other oily ingredients, heat and melt to 70
Keep at ℃ (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 13 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 Propylene glycol 5.0 Glycerin 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative Suitable amount Placental extract 5.0 Trans-4-linolenoylamino Methyl cyclohexanecarboxylic acid 7.0 Ion-exchanged water Residual (production method) Trans-4-linolenoylaminomethylcyclohexanecarboxylic acid and placenta extract are dissolved in ion-exchanged water and ethanol under heating, and water solubility of propylene glycol or less Dissolve the ingredients, 70 ℃ Keep (water phase).
Other oily ingredients are mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsification is performed, and the mixture is homogenized with a homomixer.
Cool to ° C.

Example 14 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 Propylene glycol 5.0 Glucerine 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative Suitable amount Kojic acid 3.0 Trans-4- (2'-amino) Benzoylaminomethyl) Sodium cyclohexanecarboxylate 3.0 Ion-exchanged water Residue (production method) Trans-4-ion in ion-exchanged water and ethanol
Sodium (2'-aminobenzoylaminomethyl) cyclohexanecarboxylate and kojic acid were dissolved by heating,
Furthermore, the water-soluble components below propylene glycol are dissolved and kept at 70 ° C. (aqueous phase). Other oily ingredients are mixed, heated and melted and kept at 70 ° C. (oil phase). Add the oil phase to the water phase,
Preliminary emulsification is performed, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. with thorough stirring.

Example 15 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 Arbutin 20.0 Propylene glycol 5.0 Trans-4-propionylaminomethyl cyclohexanecarboxylic acid ethyl ester 1.0 Ion-exchanged water Residual fragrance Suitable amount Preservative / antioxidant Appropriate amount (manufacturing method) Trans-4-propionylaminomethylcyclohexanecarboxylic acid ethyl ester in ion-exchanged water,
Arbutin and propylene glycol are added, and the mixture is heated and dissolved and maintained at 70 ° C (aqueous phase). Add fragrance 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 16 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 Arbutin 5.0 Kojic acid 5,0 Propylene glycol 7.0 Trans-4- (4'-hydroxybenzoyl aminomethyl) cyclohexanecarboxylic acid 2.0 Ion-exchanged water Residual fragrance Suitable amount Preservative / oxidation Inhibitor A suitable amount (production method) Trans-4- (4'-hydroxybenzoylaminomethyl) cyclohexanecarboxylic acid, arbutin, kojic acid and propylene glycol are added to ion-exchanged water and heated to maintain it at 70 ° C (aqueous phase). The other ingredients are mixed, dissolved by heating and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added to this oil phase, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C while stirring well.

Example 17 Jelly 95% Ethyl alcohol 10.0 Dipropylene glycol 15.0 Polyoxyethylene (15 mol) Oleyl alcohol ether 2.0 Arbutin 0.5 Ascorbic acid distearate 0.5 Carboxyvinyl polymer (commodity) Name: Carbopol 941) 1.0 Caustic potassium 0.15 L-arginine 0.1 trans-4- (4'-methoxycinnamoyl aminomethyl) cyclohexanecarboxylic acid 1.0 trans-4- (3'-pyridylcarbonylamino) Methyl) Cyclohexanecarboxylic acid 1.0 Fragrance Suitable amount Preservative Suitable amount Ion-exchanged water Residue (production method) Trans-4- (4'-methoxycinnamoylaminomethyl) cyclohexanecarboxylic acid, trans-4- ( 3'-pyridylcarbonyl Aminomethyl) cyclohexanecarboxylic acid, arbutin and carbopol 941 are uniformly dissolved, while dipropylene glycol, polyoxyethylene (1
5 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 18 Peel-off type pack (alcohol phase) 95% ethanol 10.0 polyoxyethylene (15 mol) oleyl alcohol ether 2.0 preservative proper amount flavoring substance proper amount (water phase) trans-4- (4 '-Hydroxyphenylacetyl aminomethyl) cyclohexanecarboxylic acid 3.0 Arbutin 1.0 Polyvinyl alcohol 12.0 Glycerin 3.0 Polyethylene glycol 1500 1.0 Ion-exchanged water Residual (manufacturing method) Prepare an aqueous phase at 80 ° C. , Cool to 50 ° C.
Then, the alcohol phase prepared at room temperature is added, mixed uniformly and allowed to cool.

Example 19 Pack containing powder (alcohol phase) 95% ethanol 2.0 Preservative proper amount Fragrance proper amount colorant proper amount ascorbic acid dioleate 1.0 (aqueous phase) trans-4-palmitoylaminomethyl Cyclohexanecarboxylic acid 7.0 Arbutin 1.0 Propylene glycol 7.0 Zinc white 25.0 Kaolin 20.0 Ion-exchanged water Residual (production method) An aqueous phase is uniformly prepared at room temperature. Then, the alcohol phase prepared at room temperature is added and uniformly mixed.

Example 20 Water-absorbing ointment Vaseline 40.0 Stearyl alcohol 18.0 Mokurou 20.0 Polyoxyethylene (10 mol) monooleate 0.25 Glycerin monostearate 0.25 Placenta extract 1.0 trans -4- (trans-4'-n-pentylcyclohexylcarbonylaminomethyl) cyclohexanecarboxylic acid 10.0 Ion-exchanged water Residual (production method) Trans-4- (trans-) in ion-exchanged water
4′-n-pentylcyclohexylcarbonylaminomethyl) cyclohexanecarboxylic acid, placenta extract,
Keep 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 by the present invention were all found to be effective in the whitening effect test carried out in Examples 1 to 6.

[0039]

The L-ascorbic acid and its derivatives, the placenta extract, kojic acid and its derivatives according to the present invention,
One or more selected from the group consisting of azelaic acid and its derivatives, glucosamine and its derivatives, hydroquinone glycosides and their derivatives, and one selected from the group consisting of amides of tranexamic acid and its salts, or The skin external preparation containing two or more kinds is a highly safe skin external preparation with significantly improved skin whitening effect.

[Table 2]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 7/00 FX X // C07C 233/47 7106-4H 233/48 7106-4H 233/49 7106 −4H 233/50 7106−4H 233/51 7106−4H 233/81 7106−4H (72) Inventor Yuki Shibata 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Within Shiseido Daiichi Research Center (72) Invention Rumiko Kaku, 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa, Shiseido Daiichi Research Center, Inc. (72) Inventor Takeshi Hariya, 1050, Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa (Shiseido Daiichi, Research Center, Inc.) 72) Inventor Hiroshi Kobayashi, Shiseido Daiichi Research Center, 1050 Shinba-cho, Kohoku-ku, Yokohama City, Kanagawa Prefecture (72) Inventor Kenji Kitamura Yokohama City, Kanagawa Prefecture Shiseido Daiichi Research Center Co., Ltd. 1050 Shinba-cho, Kohoku Ward

Claims (13)

[Claims] 1. A kind selected from the group consisting of L-ascorbic acid and its derivative, placenta extract, kojic acid and its derivative, azelaic acid and its derivative, glucosamine and its derivative, hydroquinone glycoside and its derivative. Alternatively, a skin external preparation containing two or more kinds and one or more kinds selected from the group consisting of amides of tranexamic acid represented by the following general formula 1 and salts thereof. [Chemical 1] Wherein the R ₁ is a hydrogen atom or a lower alkyl group, R ₂
Is an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, a pyridyl group, a trifluoromethyl group,
Phenylalkyl group (wherein the alkyl part has 1 to 1 carbon atoms)
3, the phenyl moiety may be substituted with 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group), a phenyl group (wherein the phenyl group is 1 to 3 hydroxyl groups). , A lower alkyl group, a lower alkoxy group, a halogen atom, an amino group may be substituted) or a styryl group (wherein the phenyl moiety is 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom, an amino group). Group may be substituted))] 2. The L-ascorbic acid and its derivative in the external preparation for skin according to claim 1 are L-ascorbic acid and L-
Ascorbic acid phosphate, L-ascorbic acid-
A skin external preparation characterized by being a 2-sulfate or a salt thereof. 3. An external preparation for skin, wherein the glycoside of hydroquinone in the external preparation for skin according to claim 1 is hydroquinone β-D-glucose. 4. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to any one of claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , An external dermatological agent characterized by being an amide of tranexamic acid in which R ₂ is an alkyl group or a cycloalkyl group, or a salt thereof. 5. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to any one of claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , An amide of tranexamic acid, wherein R ₂ is an alkenyl group or a cycloalkenyl group, or a salt thereof. 6. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , An external dermatological agent characterized by being an amide of tranexamic acid in which R ₂ is a pyridyl group or a salt thereof. 7. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to any one of claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , An amide of tranexamic acid, wherein R ₂ is a trifluoromethyl group, or a salt thereof. 8. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to any one of claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , R ₂ is a phenylalkyl group (wherein the alkyl part has 1 to 3 carbon atoms and the phenyl part has 1 to 3 carbon atoms).
An external preparation for skin, which is an amide form of tranexamic acid having three hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group) or a salt thereof. 9. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to any one of claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , R ₂ is a phenyl group (wherein the phenyl group may be substituted with 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group)
An external preparation for skin, which is an amide of tranexamic acid or a salt thereof. 10. An amide of tranexamic acid and a salt thereof in the external preparation for skin according to any one of claims 1 to 3, wherein R ₁ is a hydrogen atom or a lower alkyl group in the general formula 1 according to claim 1. , R ₂ is a styryl group (wherein the phenyl moiety may be substituted with 1 to 3 hydroxyl groups, a lower alkyl group, a lower alkoxy group, a halogen atom or an amino group), or an amide of tranexamic acid or a salt thereof. An external preparation for skin characterized by being 11. L-ascorbic acid and its derivative, placenta extract, kojic acid and its derivative, azelaic acid and its derivative, glucosamine and its derivative, hydroquinone glycoside in the external preparation for skin according to any one of claims 1 to 10. The amount of one or more selected from the group consisting of the body and its derivatives is 0.001 in the total amount of the skin external preparation.
An external preparation for skin, which is -20% by weight. 12. The external preparation for skin according to claim 1, wherein the compounded amount of one or more selected from the group consisting of amides of tranexamic acid and salts thereof in the external preparation for skin is 0.001 in the total amount of the external preparation for skin. An external preparation for skin, which is -20% by weight. 13. The external preparation for skin according to claim 1, wherein the compounded amount of one or two or more kinds selected from the group consisting of amides of tranexamic acid and salts thereof in the external preparation for skin is 0.1. The external preparation for skin is characterized in that the content is -7% by weight.