JPH08133956A - Skin preparation for external use - Google Patents

Abstract

PURPOSE: To obtain a skin preparation for external use containing, as active ingredients, Hederacoside and at least one kind of compound selected from L-ascorbic acid compounds, placenta extract, kojic acid compounds, azelaic acid compounds, glucosamine compounds, hydroquinone compounds and tranexamic acid compounds. CONSTITUTION: This skin preparation for external use contains, as active ingredients, 0.001-20wt.% of at least one kind of compound selected from L- ascorbic acid and derivatives therefrom, placenta extract, kojic acid and derivatives therefrom, azelaic acid and derivatives therefrom, glucosamine and derivatives therefrom, hydroquinone glycosides and derivatives therefrom, and tranexamic acid and derivatives therefrom and 0.001-20wt.% of Hederacoside and/or its salt. Combined use of the above two kinds of active ingredients results in the synergistic skin beautifying effect of this skin preparation with high safety. The skin preparation can be made into such formulations as solubilized system e.g. lotion, emulsified system e.g. milky lotion or cream, ointment or dispersion. The Hederacoside is a triterpenoid saponin obtainable from the extract of Sapindus mukurossi Gaertn. or Akebia quinata Decne.

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 Pigmentation of skin spots, freckles, etc. is caused by hormonal abnormalities and ultraviolet ray stimulation, which accelerates melanin production in epidermal pigment cells, resulting in excessive deposition of melanin on the epidermis. Occurs. To prevent stains and freckles, a substance that suppresses melanin production, such as L-
A method of administering a large amount of ascorbic acid, a method of injecting glutathione or the like, or a method of locally applying kojic acid, cysteine or the like in the form of an ointment, cream, lotion or the like is used.

[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 And one or more selected from the group consisting of derivatives, azelaic acid and its derivatives, glucosamine and its derivatives, hydroquinone glycosides and their derivatives, tranexamic acid and its derivatives, and hederacoside (Hederacosid)
It was found that a synergistic whitening effect can be obtained by using e) and / or a salt thereof together, 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. A skin external preparation containing one or more selected from the group consisting of glycosides and their derivatives, tranexamic acid and its derivatives, and Hederacoside and / or its salts.

According to a second aspect of the present invention, the L-ascorbic acid and its derivative in the external preparation for skin according to the first aspect 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.

[0006] Claim 4 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 in the external preparation for skin according to claims 1 to 3. Derivatives, hydroquinone glycosides and derivatives thereof, and one or more selected from the group consisting of tranexamic acid and its derivatives in an amount of 0.00
The external preparation for skin is characterized by being 1 to 20% by weight. According to claim 5 of the present invention, the compounding amount of Hederacoside and / or a salt thereof in the external preparation for skin according to claims 1 to 4 is 0.001-2 in the total amount of external preparation for skin.
The external preparation for skin is characterized by being 0% 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 called vitamin C, and due to its strong reducing action, exhibits an inhibitory action on the tyrosinase reaction, which is the rate-limiting step of melanin production, and exhibits a reducing action on melanin. Examples of L-ascorbic acid derivatives include L-ascorbic acid monoalkyl esters such as L-ascorbic acid monostearate, L-ascorbic acid monopalmitate and L-ascorbic acid monooleate, and L-ascorbic acid monophosphate. Acid ester, L-ascorbic acid monoester derivative such as L-ascorbic acid-2-sulfate ester, dialkyl ester such as L-ascorbic acid distearate, L-ascorbic acid dipalmitate, L-ascorbic acid dioleate, L-ascorbic acid Trialkyl esters such as L-ascorbic acid diesters such as diphosphates, L-ascorbic acid tristearate, L-ascorbic acid tripalmitate, L-ascorbic acid trioleate, L-ascorbic acid trilyl Ascorbic acid triester such as esters and the like.

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).

The derivative of tranexamic acid used in the present invention is a dimer of tranexamic acid (trans-4 hydrochloride).
-(Trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid), an ester form of tranexamic acid and hydroquinone (trans-
4-aminomethylcyclohexanecarboxylic acid 4'-hydroxyphenyl ester), ester form of tranexamic acid and gentisic acid (2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid and its salt), tranexamic acid Amide (trans-4-aminomethylcyclohexanecarboxylic acid methylamide and salts thereof, trans-4-acetylaminomethylcyclohexanecarboxylic acid and salts thereof, trans-4- (p-methoxybenzoyl) aminomethylcyclohexanecarboxylic acid and salts thereof , Transformer-4-
Guanidinomethylcyclohexanecarboxylic acid and salts thereof) and the like.

In carrying out the present invention, one or more of these are appropriately selected and blended.

L- blended 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,
Glucosamine and its derivatives, hydroquinone glycosides and their derivatives, the amount of one or more selected from the group consisting of tranexamic acid and its derivatives is not particularly limited, but generally relative to the total amount of skin external preparation 0.001 to 20% by weight, preferably 0.01 to 10% by weight, and particularly preferably 0.1 to 7% by weight. If the content is less than 0.001% by weight, the whitening effect of the external preparation for skin tends to be poor, and conversely, if the content is more than 20% by weight, no increase in the effect can be expected and it is expected to be applied to the external preparation for skin. It also tends to be difficult to mix.

The Hederacosi according to the present invention
de) is Mukroji (Epinmei: Sapindus mukurossi Gae
rtn.) or Akebia quinata Decn
It is a triterpenoid saponin obtained from the extract of e.). Examples of the salt of hederacoside include alkaline earth metal salts such as sodium salt and potassium salt, basic amino acid or alkanolamine salt, and esters thereof, and specific examples thereof include hederacoside ammonium salt. .

Hederacoside and / or its salt may be incorporated into the external skin preparation as an extract of the above plant. The compounding amount of hederacoside and / or its salt is not particularly limited, but generally 0.001 to 20% by weight, preferably 0.1 to 5% by weight based on the total amount of the external preparation for skin.
Compound. 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.

[0018]

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, an effect test method and an evaluation method will be described prior to Examples. The whitening effect was judged from usage tests such as a whitening effect on the skin by cumulative application, elimination of stains 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 7 and Comparative Examples 1 to 1 having the following formulations
8 were tested. Samples of Examples 1 to 7 and Comparative Examples 1 to 8 (alcohol phase) wt% 95% ethanol 25.0 polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 preservative / antioxidant proper amount fragrance 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 alcohol phase are solubilized after preparation.

[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%

[0023]

[Table 2]

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 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 Hedelacoside 5.0 Preservative / antioxidant Appropriate amount Perfume Appropriate amount Ion-exchanged water Residual (production method) Add hederacoside, arbutin and propylene glycol to ion-exchanged water and heat to maintain at 70 ° C (water 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 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 Sucrose extract 10.0 Fragrance Suitable amount Preservative / antioxidant Suitable amount Ion-exchanged water Residue (production method) To ion-exchanged water Add Mucrose extract, placenta extract and propylene glycol and heat 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 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 Hederacoside potassium salt 0.1 Ion-exchanged water Residual fragrance Suitable amount Preservative / antioxidant Appropriate amount (manufacturing method) Hedelacoside potassium salt in ion-exchanged water , Kojic acid, soap powder and borax are added and heated to 70 ℃
Keep (water phase). Other ingredients are mixed, heated and melted at 70 ℃
Keep (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 Ethanol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative A proper amount of Akake extract 20.0 Ion-exchanged water Residual (Production method) A hydrous alcoholic extract of akebi and arbutin are dissolved in ion-exchanged water and ethanol under heating, and further water-soluble components below propylene glycol are dissolved and maintained 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, 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 Ethanol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative A suitable amount Hedelacoside alkanolamine Salt 7.0 Deionized water Residual (Production method) Dissolve the hederacoside alkanolamine salt in ion-exchanged water and ethanol with heating, and further dissolve the water-soluble components below propylene glycol and keep it at 70 ° C. ). 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 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 Ethanol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative Appropriate amount Placenta extract 5.0 Hedelacoside sodium salt 7.0 Ion Exchanged water Residual (manufacturing method) The sodium salt of hederacoside and the placenta extract are dissolved in ion-exchanged water and ethanol with heating, and the water-soluble components below propylene glycol are dissolved and 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 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 Glucerin 2.0 Ethyl alcohol 15.0 Carboxyvinyl polymer 0.3 Hydroxypropylcellulose 0.1 2-Aminomethylpropanol 0.1 Preservative Suitable amount Kojic acid 3.0 Hedelacoside 3.0 Ion-exchanged water Residual (Production method) Ion-exchanged water, hederacoside, and kojic acid 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, uniformly emulsified with a homomixer, and after emulsification, 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 Ethanol 10.0 Arbutin 20.0 Propylene glycol 5.0 Hederacoside potassium salt 1.0 Ion-exchanged water Residual fragrance Suitable amount Preservative / antioxidant Appropriate amount (Production method) Hedelacoside potassium salt, arbutin and propylene glycol are added to ion-exchanged water Addition by heating and melting and maintaining at 70 ° C (aqueous phase). Add perfume to ethanol and dissolve (alcohol 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 and preliminarily emulsified and homogenized with a homomixer. Add the alcohol phase while stirring. Then stir 3
Cool to 0 ° C.

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 Tranexamic acid 5,0 Propylene glycol 7.0 Hedelacoside sodium salt 2.0 Ion-exchanged water Residual perfume proper amount Preservative / antioxidant proper amount (production method) For ion-exchanged water Hederacoside sodium salt,
Arbutin, tranexamic acid and propylene glycol are added and heated to 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% ethanol 10.0 Dipropylene glycol 15.0 Polyoxyethylene (15 mol) oleyl alcohol ether 2.0 Arbutin 0.5 Ascorbic acid distearate 0.5 Carboxyvinyl polymer (trade name) : Carbopol 941) 1.0 Caustic potash 0.15 L-Arginine 0.1 Sucrose extract 1.0 Scutellaria extract 1.0 Perfume Adequate amount of preservative Adequate amount of ion-exchanged water Residue (production method) The extract, akebi extract, arbutin and carbopol 941 were uniformly dissolved, while dipropylene glycol in 95% ethanol,
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 18 Peel-off type pack (alcohol phase) 95% ethanol 10.0 Polyoxyethylene (15 mol) oleyl alcohol ether 2.0 Preservative proper amount Fragrance proper amount (water phase) hederacoside 3.0 Arbutin 1 0.0 Polyvinyl alcohol 12.0 Glycerin 3.0 Polyethylene glycol 1500 1.0 Ion-exchanged water Residue (production 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 19 Powder-containing pack (alcohol phase) 95% ethanol 2.0 Preservative proper amount fragrance proper amount colorant proper amount ascorbic acid dioleate 1.0 (aqueous phase) hederacoside ammonium salt 7. 0 Arbutin 1.0 Propylene glycol 7.0 Zinc white 25.0 Kaolin 20.0 Ion-exchanged water Residual (production method) A water 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 Muculodi Extract 10.0 Ion-exchanged water Residual (manufacturing method) The mukurodi extract and placenta extract are added to ion-exchanged water, and the mixture is 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 by the present invention were all found to be effective in the whitening effect test conducted in Examples 1 to 7.

[0039]

The external preparation for skin according to the present invention is a highly safe external preparation for skin with significantly improved skin whitening effect.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 7/00 C F 31/19 9455-4C 31/195 9455-4C 31/35 31/375 31/70 35 / 50 7431-4C 35/78 ADA C 8217-4C

Claims (5)

[Claims] 1. 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, tranexamic acid and its derivative. An external preparation for skin, which comprises one or more selected from the group and Hederacoside and / or a salt thereof. 2. L-ascorbic acid and its derivatives are L
The external preparation for skin according to claim 1, which is-ascorbic acid, L-ascorbic acid phosphoric acid ester, L-ascorbic acid-2-sulfuric acid ester or a salt thereof. 3. The external preparation for skin according to claim 1, wherein the glycoside of hydroquinone is hydroquinone β-D-glucose. 4. 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, tranexamic acid and its derivative. The amount of one or more selected from the group is 0.001 to 20 in the total amount of the external preparation for skin.
The external preparation for skin according to any one of claims 1 to 3, wherein the external preparation is in a weight percentage. 5. Hederacoside and / or
Or the amount of the salt is 0.001 in the total amount of the external preparation for skin.
The external preparation for skin according to any one of claims 1 to 4, wherein the external preparation is about 20% by weight.