JP2862911B2 - Topical melanin production inhibitor with excellent transdermal absorption - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to an external preparation for inhibiting melanin production, and more specifically, to an external preparation for inhibiting melanin production which has an effect of inhibiting melanin production and improving percutaneous absorption. About.

[Conventional technology]

Spots such as spots and freckles appearing on human skin are
It is known that it is mainly caused by the deposition of eumelanin.

Research on various fair skin cosmetics for the purpose of suppressing the production of melanin, which causes such spots and freckles, and for the purpose of whitening the entire skin has been conducted for a long time.

Examples thereof include blending peroxides such as hydrogen peroxide and zinc perborate into cosmetics, and blending vitamin C, cysteine, and colloidal sulfur into cosmetics. However, none of them has obtained satisfactory effects in terms of storage stability and whitening effect.

Over the years, the present inventors have repeated research on melanin production inhibitors such as fair skin cosmetics for removing spots such as spots and freckles that appear on human skin and enhancing the whitening effect of the entire skin. Factors related to normal human skin color include melanin, carotene, blood flow (oxidized and reduced hemoglobin), skin thickness and transparency, and light reflects, absorbs,
It scatters and becomes the color of the skin, but among these, melanin, especially brown or black melanin, has been elucidated to be the largest cause of pigmentation, and a substance that suppresses the production of this ramen has been identified. I've been exploring.

In their research, they found that kojic acid (5-oxy-2-oxymethyl-γ-pyrone) and its derivatives exhibited an extremely excellent melanin production-inhibiting action. (JP-B-56-18569, JP-A-54-92632, JP-A-54-92632)
JP-A-56-79616, JP-A-56-77272, JP-A-56-77272
No. 7776, JP-A-56-7710, JP-A-56-20330
JP, JP-B-63-34968).

These fair-skin cosmetics and external preparations are used in the form of products such as creams, lotions, emulsions, packs, lotions, ointments and cataplasms, all of which suppress excellent melanin production and have a whitening effect. It is used as a cosmetic or external preparation.

However, these cosmetics are sometimes required to have excellent absorption from the skin after use, that is, excellent transdermal absorption. In particular, cosmetics containing kojic acid or a kojic acid derivative as an active ingredient have no problem in ordinary use, but the absorbency immediately after use, that is, the initial transdermal absorbability is somewhat slow. Applications that should improve such tendency and be absorbed into the skin promptly after use, such as ointments, pastes, cataplasms, packs, creams, emulsions,
In applications such as lotions and essences, in order to further improve transdermal absorbability, a transdermal absorbability improver is added to the above-mentioned external preparation.

Such improvements include, for example, fatty acid esters of C ₁₀ -C _14, fatty acids, PEG (M <1000), although there has been known such as alcohols, the effect of suppressing melanin production There is no known compound that significantly improves transdermal absorption without impairment.

[Object of the invention]

Therefore, an object of the present invention is to provide a melanin production-inhibiting external preparation characterized by containing kojic acid and / or a kojic acid derivative and horse oil, which has improved melanin production-inhibiting effect and transdermal absorbability. It is in.

[Means for solving the problem]

Advantageous Effects of Invention According to the present invention, melanin excellent in transdermal absorbability, characterized in that an external preparation containing kojic acid and / or a kojic acid derivative is blended with 0.01 to 30% by weight of horse oil based on the external preparation. An external preparation for suppressing production is provided.

(Description of preferred embodiments of the invention)

Horse oil The most important technical feature of the present invention is kojic acid and / or
Alternatively, horse oil is blended as a transdermal absorption improver of a melanin production-inhibiting external preparation containing a kojic acid derivative as an active ingredient.

Horse oil is glycerin of glycerin and various fatty acids, and its fatty acid composition is substantially composed of the following components according to gas chromatography analysis.

Ingredient% Ingredient% C _{14: 0} 2.02 C _{18: 1} 41.46 C _{16: 0} 17.68 C _{18: 2} 30.49 C _{18: 0} 2.73 C _{18: 3} 1.12 C _{16: 1} 4.43 Other 0.07 Horse oil is kojic acid and / or When used in combination with a kojic acid derivative, it not only improves percutaneous absorbability, but also suppresses melanin production that kojic acid and kojic acid derivatives originally have,
It has also been found that the length can be significantly increased. Horse oil is used in combination with kojic acid and / or a kojic acid derivative,
The mechanism by which the melanogenesis inhibitory effect is marked is not yet clear, but it is thought that the _{C18: 1} component in horse oil may be involved.

Horse oil production example 5000 kg of raw horse fat was cut into pieces, put into a rendering cooker, stirred at a vacuum of -500 mmHgG and a temperature of 105 to 110 ° C, and the eluted oil was fractionated by a centrifuge. The yield was 3800 kg.

The horse fat is vacuum-600mmHgG, temperature 9
Phosphoric acid (0.03%) was added with stirring at 3 ° C., and coagulated gum produced by treating for 30 minutes was centrifuged to remove gum.

The horse fat was trickled, passed through a dilute caustic soda solution at 92 ° C. in an alkaline treatment tank, and the free fatty acids were separated as soap and deoxidized.

This horse fat is vacuum-600mmHgG, oil temperature 110
While stirring at a temperature of 2 ° C., 2% of activated clay was added to carry out dye adsorption, followed by filtration. The decolorized horse fat was sent to a deodorization tower, and live steam was blown into the horse fat at a temperature of 25 ° C. and a degree of vacuum of 3 mmHgG, abs to evaporate volatile components. Thereby, most of the odors and the residual free fatty acids were separated.

The purified horse fat obtained by the above treatment has an acid value of 0.02 to
0.50, saponification value 180-220, iodine value 60-80, melting point 25-32 ° C,
It has a peroxide value of 0.01 to 10.0.

The percentages described in the above Examples and Production Examples are percentages by weight.

Kojic acid As previously described, kojic acid is excellent in the melanin production inhibitory action.
As described in detail in JP-A-569, it is used as an active ingredient of fair-skinned cosmetics or as an external preparation such as an ointment as disclosed in JP-B-61-1047.

As kojic acid A pure product of 5-oxy-2-hydroxymethyl-γ-pyrone represented by, a fermentation solution containing kojic acid as a main component obtained by culturing a strain having a kojic acid-producing ability, a concentrated solution of the fermentation solution, and A product obtained by extracting and crystallizing kojic acid from the fermentation solution is used.

Examples of such a strain having a kojic acid-producing ability include, for example, Aspergillus albus, Aspergillus candidas, Aspergillus oryzae, Aspergillus nidulans Aspergillus parasiteicas, Aspergillus awamori, Aspergillus tamari, Aspergillus newpus, and Aspergillus newpus. Strains of the genus Aspergillus, such as Aspergillus wenchi, Aspergillus glaucus, Aspergillus clavatus, Aspergillus fumigatus, Aspergillus digantus, strains of the genus Penicillium such as Penicillium dalay, strains of the genus Escalikia such as Escalikia coli. Acetobacter strains such as acetyl, Acetobacter gluconicas, Acetobacter xylinum, etc. Konobakuta-Roshiusu, strain, etc. of Gluconobacter, such as Gluconobacter, Gurunikasu is preferably used.

In addition, the medium composition of these strains usually includes sucrose, sucrose, fructose, glucose, starch, maltose, glycerin, mannitol, rhamnose, xylose, gluconic acid, arabinose, dihydroxyacetone, inosit, lactose, ethanol and the like. About 2 to 15% (weight%, the same applies hereinafter), about 0.1 to 1% of a nitrogen source such as ammonia sulfate, polypeptone, sodium nitrate, baker's yeast extract, brewer's yeast extract, and 0.01 to 1% of a magnesium source such as magnesium sulfate. 0.5%, Phosphorus and potassium sources such as potassium monohydrogen phosphate and potassium dihydrogen phosphate are 0.01 to 0.1%, and other inorganic salts such as ferric sulfate, ferric chloride, sodium chloride and calcium chloride are about 0.001 to 0.005%. May be employed.

Kojic acid derivative As the kojic acid derivative used in the present invention,
2-methoxymethyl-5-hydroxy-4H-pyran-4
-One, 2-methoxymethyl-5-hydroxy-4H-pyran-4-one, 2-benzoyloxymethyl-5-hydroxy-4H-pyran-4-one, 2-cinnamoyloxymethyl-5-hydroxy-4H -Pyran-4-one,
2-phenoxymethyl-5-hydroxy-4H-pyran-
4-one or (Wherein, R is a saturated or unsaturated aliphatic hydrocarbon group).

In the formula, as the saturated or unsaturated aliphatic hydrocarbon group represented by R, a saturated or unsaturated aliphatic carboxylic acid is exemplified.

Examples of the saturated aliphatic carboxylic acid include acetic acid, propionic acid, n-valeric acid, iso-valeric acid, methyl ethyl acetic acid,
Trimethylacetic acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid,
Palmitic acid, margaric acid, stearic acid, non-deleric acid, arachiic acid or lignoceric acid are used, but in order to reduce the skin irritation of the acid, a saturated aliphatic carboxylic acid having C ₈ or more, especially C _{14-20 is preferred.} It is preferred to use a saturated aliphatic carboxylic acid of Incidentally, C ₂₀ greater than the aliphatic carboxylic acids, particularly but not their use is limited, because its availability is very difficult, not preferable from the top of the production cost.

In addition to these saturated fatty acid carboxylic acids, for example, unsaturated aliphatic carboxylic acids such as linoleic acid, linolenic acid, maleic acid, fumaric acid, olefin acid and arachidonic acid are all used without any particular limitation.

In the present invention, the horse oil, kojic acid and / or kojic acid derivative may be added in an amount of cream, lotion, emulsion,
In the case of cosmetics such as packs, lotions, essences, and the like, and in the case of use as external preparations such as ointments, cataplasms, pasta preparations, etc.
~ 30 wt%, preferably 0.5-20 wt%, kojic acid and / or kojic acid derivative is 0.01-4.0 wt%, preferably
It is blended in the range of 0.5 to 2.0% by weight.

As described above, the melanin production-inhibiting external preparation of the present invention includes creams, lotions, emulsions, packs, lotions,
Ointments, poultices, pasta and the like are used in the form of horse oil and kojic acid and / or kojic acid derivatives, together with bases and auxiliaries used for each external preparation. In the case of an external preparation in which the water phase and the oil phase are prepared in advance and then mixed later, horse oil is contained in the oil phase, kojic acid and Preferably, the kojic acid derivative is blended in the aqueous phase.

Example of preparation of external preparation ・ Cream As the aqueous phase, prepare a mixture of purified water and a humectant such as glycerin or sorbite, and add kojic acid and / or
Alternatively, a required amount of a kojic acid derivative is blended.

On the other hand, as the oil phase, solid oils such as beeswax, paraffin, microcrystalline wax, ceresin, higher fatty acids, and hardened oils, and squalane, liquid paraffin,
A mixture is prepared by mixing horse oil with liquid components such as various ester oils and oil components such as preservatives and surfactants.

Next, the aqueous phase is gradually heated, and when the temperature reaches about 80 ° C., the oil phase heated to approximately the same temperature is added little by little to this, and emulsified to obtain a cream.

・ Ointment A hydrophilic component consisting of a moisturizing agent such as kojic acid and / or a kojic acid derivative, glycerin or sorbitol is added to purified water to form an aqueous phase.

The oil phase consists of solid components such as beeswax, paraffin, microcrystalline wax, ceresin, higher fatty acids and hardened oils, semi-solid oils such as petrolatum, lanolin and glyceride, and liquid oils such as squalane, liquid paraffin and various ester oils. It is prepared by adding horse oil along with oily components such as preservatives and surfactants. Next, the aqueous phase is gently stirred while heating. When the temperature reaches about 80 ° C., the oil phase, which has been heated to the same degree, is gradually added to obtain an ointment.

〔Example〕

 Hereinafter, the present invention will be described by way of examples.

Examples 1 and 2 Creams were prepared according to the formulation examples shown in Formulation Examples 1 and 2.

Formulation Example 1) (%) Polyoxyethylene oleyl ether (POEO) 1.60 Glycerin monostearate 3.00 Salami beeswax 2.80 Cetanol 3.00 Stearic acid 1.75 Horse oil 2.00 Liquid paraffin 7.10 Parsol 1789 0.50 Squalane 4.50 Glycerin 2.50 Carbopol 940 0.08 Crewat N 0.01 Koji Acid 1.00 Purified water 70.16 Formulation example 2) (%) Polyoxyethylene hydrogenated castor oil 2.00 Glycerin monostearate 3.50 Microcrystalline wax 3.50 Horse oil 2.00 Behenyl alcohol 4.00 Vaseline 3.30 Parsol 1789 0.50 Liquid paraffin 8.20 Carbopol 940 0.10 1,3-BG 7.00 Crewat N (EDTA) 0.01 Kojic acid 1.00 Purified water 64.89 Formulation example 3) (%) Polyoxyethylene oleyl ether (POEO) 1.60 Glycerin monostearate 3.00 Salami beeswax 2.80 Cetanol 3.00 Stearic acid 1.75 Horse oil 2.00 Kojic acid derivatives (esters and ethers) 1.00 Liquid paraffin 7.10 Parsol 1789 0.50 Squalane 4.50 Glycerin 2.50 Carbopol 940 0.08 Crewath N (EDTA) 0.01 Purified water 76.16 The cream prepared according to the above formulation was used as a hairless mouse (No. An in vitro percutaneous absorption experiment using a Franz cell was performed on the skin of the back of a 7-week-old male), the mouse skin was filtered, and kojic acid and C ₁₈ that reached the receptor solution were filtered.
As a result of quantifying the time-dependent concentration change of (total amount) by HPLC, the results of Formulation Example 1) were obtained as shown in FIG.
The results shown in FIG.

Formulation Example 3) KA derivatives (kojic acid stearic acid ester and 2-ethoxymethyl-5-hydroxy-4H)
-Pyran-4-one) is shown in FIG.

DBT test-1 6 males aged 24 to 84 years and 4 females aged 22 to 29 years, total 10
A left subject's inner left arm was irradiated with a UV lamp, and immediately after that, the creams prepared according to Formulation Examples 1) and 2) were applied three times daily (9 o'clock, 15 o'clock, 21 o'clock). Control is KA
(-)-Horse oil (-), KA (-), Horse oil (-). The judgment was made by visually observing the degree of pigmentation one month later. The result is "KA (-)" for horse oil only, "slightly effective"
There were only two cases and the others were invalid,
In the case of KA only {horse oil (-)}, "valid" 3 cases, "slightly valid" 4 cases, "invalid" 3 cases, and KA + horse oil,
Five cases were "effective", four cases were "slightly effective", and one case was "ineffective", and the effect of using kojic acid and horse oil together was confirmed.

DBT test-2 7 males aged 25 to 84 years and 3 females aged 21 to 29 years, total 10
Using the inside of the left arm of one subject, U
The degree of inhibition of pigmentation after V irradiation was observed.

The cream prepared according to Formulation Example 3) was used, and horse oil (-) cream and horse oil (-). KA were used as controls.
Derivative (-) cream was used. As the KA derivative, a stearic acid ester of kojic acid and 2-ethoxymethyl-5-hydroxy-4H-pyran-4-one were used.

The results are as follows: in the case of only the KA derivative (stearic acid ester of kojic acid) {horse oil (-)}, “effective” 2 cases, “slightly effective” 4 cases, “ineffective” 4 cases, 2-ethoxymethyl-
In the case of only 5-hydroxy-4H-pyran-4-one,
｛Horse oil (-)｝, “effective” 3 cases, “slightly effective” 4
In contrast to the three cases of "invalid", in the system to which horse oil was added, there were four cases of "valid", four cases of "slightly valid", and two cases of "invalid". Similar to the DBT test-1, the addition of horse oil suppressed the degree of pigmentation.

〔The invention's effect〕

ADVANTAGE OF THE INVENTION According to this invention, the percutaneous absorption of an external preparation, especially the initial percutaneous absorption is improved by mix | blending horse oil with the melanin production suppression external preparation which has a kojic acid and / or a kojic acid derivative as an active ingredient. In addition, kojic acid and / or a kojic acid derivative can have a significantly increased melanin production-inhibiting effect.

[Brief description of the drawings]

1 to 3 show the results of a transdermal absorption experiment of the creams prepared according to Formulation Examples 1) to 3).

Claims (1)

(57) [Claims] 1. A melanin production having excellent transdermal absorbability, characterized in that an external preparation containing kojic acid and / or a kojic acid derivative is blended with 0.01 to 30% by weight of horse oil based on the external preparation. External preparation for control