JPH09241154A - Preparation for external use for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a preparation for external use for the skin having excellent effect on skin whitening and color fading after pigmentation due to suntan, freckles and chloasma, etc., through suppressing melanogenesis, and also high in safety. SOLUTION: This preparation for external use for the skin contains 0.005-20wt.% of a compound of formula I (R is formula II or formula III). The compound of formula I, which has melanogenesis-suppressive effect and tyrosinase-inhibitory effect, is known as a precursor of γ-irone and α-irone, each being a perfume ingredient. Of the compounds of formula I, the compound where R is formula II is named as iriflorental, while the compound where R is formula III iripallidal. These compounds can be obtained by subjecting an Iridaceae plant, especially Iris florentina of the family Iridaceae to extraction with a solvent followed by partition and purification of the resultant extract.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for the skin, which is effective in inhibiting the production of melanin by blending a specific compound and preventing and improving pigmentation, spots, freckles, chloasma and the like after sunburn. .

[0002]

2. Description of the Related Art Although there are some unclear points about the mechanism of the occurrence of skin spots and the like, melanin pigments are generally formed due to hormonal abnormalities and stimulation of ultraviolet rays from sunlight. It is believed to be abnormally deposited within. This melanin pigment, which causes skin coloring, is produced in melanin-producing granules (melanosomes) in melanocytes (melanocytes) between the epidermis and dermis,
The generated melanin diffuses into adjacent cells by the osmotic effect. The biochemical reaction in this melanocyte is presumed to be as follows. That is, tyrosine, which is an essential amino acid, is converted into dopaquinone by the action of the enzyme tyrosinase, and the process in which it is converted to black melanin via a red pigment and a colorless pigment by an enzymatic or non-enzymatic oxidative action is a melanin pigment production process. Therefore, suppressing the action of tyrosinase, which is the first step of the reaction, is important for suppressing melanin production.

[0003]

However, compounds that suppress the tyrosinase action, except for hydroquinone, have very slow onset of their effects, so that the effect of improving skin pigmentation is not sufficient. On the other hand, although hydroquinone is recognized as having an effect, its use is generally restricted because of its sensitizing properties. Therefore, in order to improve its safety, attempts have been made to use higher fatty acid monoesters or alkyl monoethers (JP-A-58-154507), but the esters are decomposed by a hydrolase in the body. Therefore, it is not always safe, and ethers have not been sufficiently satisfactory in terms of safety.

[0004]

The inventors of the present invention investigated the melanin production inhibitory effect on various substances as a solution to these problems, and as a result, the following general formula (1)
It was found that the compound represented by the formula (3) has a melanin production inhibitory action and a tyrosinase inhibitory action, and completed the present invention. These compounds are known as precursors of γ-iron (γ-irone) and α-iron (α-irone), which are known as perfume ingredients, but there is no report on the melanin production inhibitory action of the compound itself. Unprecedentedly, the application to the skin external preparation is not known at all. The present inventors have completed the present invention based on the above findings.

That is, the present invention has the general formula (1):

[0006]

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(Where R is the following formula (2):

[0008]

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Or the following formula (3):

[0010]

[Chemical 6]

Represents the following. ) A compound for external use, which comprises the compound represented by The external preparation of the present invention is preferably a skin whitening external preparation.

The structure of the present invention will be described in detail below. Among the compounds represented by the above general formula (1) used in the present invention, those in which R is represented by the formula (2) are called iriflorenthal, and those represented by the formula (3) are iriparidal. be called.

[0013] These compounds are used in Iridaceae plants.
ae), especially Iris florenti, a plant of the iris genus
It is obtained by extracting na, Iris pallida, Iris germanica, etc. with an organic solvent, partitioning with ethyl acetate and water, and purifying the ethyl acetate phase by silica gel column chromatography or the like. Any solvent can be used as the extraction solvent as long as it is a solvent usually used for extraction. In particular, alcohols such as methanol and ethanol, hydroalcohols, organic solvents such as acetone and ethyl acetate can be used alone or in combination.

The compounding amount of the compound represented by the general formula (1) in the present invention is 0.005 to 2 in the total amount of the external preparation.
It is 0.0% by weight, preferably 0.01 to 10.0% by weight. If the amount is less than 0.005% by weight, the effects of the present invention are not sufficiently exhibited, and if the amount is more than 20.0% by weight, it is not preferable because formulation is difficult. Further, even if the content is 10.0% by weight or more, the effect is not so much improved.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, components that are usually used in external preparations for skin such as cosmetics and pharmaceuticals, for example, other whitening agents, moisturizers, antioxidants and oily ingredients. , UV absorber, surfactant, thickener,
Alcohols, powder components, coloring materials, aqueous components, water, various skin nutrients and the like can be appropriately blended as necessary.

Besides, sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extraction Substance, glabridin, hot water extract of fruits of fire thorns, various crude drugs, tocopherol acetate,
Drugs such as glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate,
Other whitening agents such as ascorbic acid glucoside, arbutin, kojic acid, glucose, fructose, mannose,
Sugars such as sucrose and trehalose can also be appropriately blended.

The external preparation for skin of the present invention may be any ointment, cream, emulsion, lotion, pack, bath agent or the like as long as it is a conventional external preparation for skin, and its form is not particularly limited.

[0018]

Next, the present invention will be described in more detail by way of examples. Note that the present invention is not limited by this. The compounding amount is% by weight. Prior to Examples, a method for producing the compound of the present invention, a test method for a melanin suppressing effect, a tyrosinase activity inhibiting effect, and a whitening effect and the results thereof will be described.

Iriflorental and Iripalidar
Manufacturing of

1. Production of Iriflorental Iris pallida (dry weight: 750 g) was extracted with methanol (10 liter) for 1 week at room temperature to obtain a methanol extract (47.5 g). This methanol extract was partitioned with ethyl acetate and water (1 l: 1 l), and the ethyl acetate phase was concentrated to obtain an extract (29.0 g). This extract was purified by silica gel chromatography (silica gel 900 g, elution solvent chloroform: methanol = 10: 1), and iriflorental (620 mg).
I got In this production example, iris florentina was produced using Iris pallida as a raw material.
Even if s germanica is used as a raw material, iriflorental can be produced in the same manner as above.

2. Production of Iriparidar Iris florentina (dry weight: 750 g) was extracted with methanol (10 liter) for 1 week at room temperature to obtain a methanol extract (52.5 g). This methanol extract was partitioned with ethyl acetate and water (1 l: 1 l), and the ethyl acetate phase was concentrated to obtain an extract (32.0 g). The extract was purified by silica gel chromatography (silica gel 900 g, elution solvent chloroform: methanol = 10: 1) to obtain iriparidal (760 mg). In this production example, Iris pallida or Iris gerger was produced using Iris florentina as a raw material.
Even if manica is used as a raw material, iriparidar can be produced in the same manner as above.

The following experiments were carried out using the obtained iriflorental and iriparidal.

Test Method and Results 1. Cell culture method B16 melanoma cultured cells derived from mice were used. 1
0% FBS and theophylline (0.09 mg / ml)
The cells were cultured in an Eagle MEM medium containing C. in a CO ₂ incubator (95% air, 5% carbon dioxide) at 37 ° C. After 24 hours of culturing, the sample solution containing the compound of the present invention (DMSO solution) was added at a sample concentration of 10 ^-2 to 10 ^-4.
Added so that the weight% is reached, and culturing is continued for another 3 days,
The visual determination of melanin production and the tyrosinase activity inhibitory effect were measured by the following methods.

2. Visual measurement of melanin amount A diffusion plate was placed on the lid of the well plate, and the intracellular melanin amount was observed with an inverted microscope, and compared with the case of a sample (reference) to which the compound of the present invention was not added. The results are shown in Table 1.

Further, as a reference example, the same test as above was carried out for hydroquinone, which is already known to have a melanin production inhibitory action. Table 1 also shows the results.

<Judgment Criteria> ○: White (amount of melanin) Δ: Slightly white (amount of melanin) ×: Reference (amount of melanin)

3. Measurement of tyrosinase activity Before measurement, the medium in the wells is removed and washed twice with 100 μl of PBS. 45 μl of 1% Triton-X in each well
(Rohm and Haas product name, surfactant) containing PBS is added. Shake the plate for 1 minute, break the cell membrane well, and use a microplate reader for 475n.
The absorbance at m was measured, and this was taken as the absorbance at 0 minutes. Then, 5 μl of 10 mM L-DOPA solution was quickly added, and the mixture was transferred to an incubator at 37 ° C. and reacted for 60 minutes. The plate was shaken for 1 minute, and the absorbance (475 nm) at 60 minutes was measured. The difference in the absorbance of the sample to which the compound of the present invention was added with respect to the difference in absorbance at 0 minute and 60 minutes in the case of the sample to which the compound of the present invention was not added (control) was defined as the tyrosinase activity rate (%). Table 1 shows the results.

Further, as a reference example, the same test as above was carried out on hydroquinone which is already known to have a tyrosinase activity inhibitory action. Table 1 also shows the results.

[0029]

[Table 1] ──────────────────────────────────── Test melanogenesis visual evaluation Tyrosinase activity rate ( %) ──────── ─────────── ─────────── Concentration (wt%) 10 ^-4 10 ^-3 10 ^-2 10 ^-4 10 ^-3 10 ^-2 ──────────────────────────────────── Iriflorenthal × ○ ◎ 91 69 38 Iriparidal × ○ ◎ 87 44 21 Hydroquinone × ○ ○ 92 60 51 ────────────────────────────────────

5. Whitening effect test [Test method] Each of the 64 subjects exposed to the sunlight in the summer for 4 hours (2 hours per day for 2 days) was subjected to the sunlight for 5 days from the day 5 days after the day when the skin was exposed to the sunlight. Was applied once each morning and evening for 4 weeks. The panel was divided into 8 groups, and 8 groups were prepared. (Alcohol phase) 95% Ethyl alcohol 55.0% by weight Polyoxyethylene (25 moles) hydrogenated castor oil ether 2.0 Antioxidant / preservative proper amount Fragrance proper amount drug (listed in Table 2) (water phase) glycerin 5.0 Sodium hexametaphosphate Suitable amount Ion-exchanged water Residue <Production method> An aqueous phase and an alcohol phase are prepared, respectively, and then both are mixed and solubilized.

[Evaluation Method] The lightening effect after use was judged based on the following judgment criteria. <Judgment criteria> ：: When the ratio showing significant effect and effectiveness among the subjects is 80% or more 割 合: The ratio showing significant effect and effectiveness among the subjects is 50% or more
Less than 80% △: The proportion of the test subjects showing excellent and effective is 30% or more
When less than 50% x: When the ratio of markedly effective or effective among the subjects is less than 30%

Samples having the blending composition described in the above test method were prepared and the whitening effect was compared using the agents shown in Table 2.
The results are shown in Table 2.

[0033]

[Table 2] ────────────────────────── Drug compounding amount (% by weight) Effect ─────────── ─────────────── Additive- × Hydroquinone 1.0 △ Iriflorental 0.1 ○ Iriflorental 1.0 ○ Iriflorental 10.0 ◎ Iriparidal 0.1 ○ Iriparidal 1.0 ○ Iriparidar 10.0 ◎ ──────────────────────────

As is clear from Table 2, the effect after exposure to sunlight is recognized that the addition of the compound of the present invention prevents excessive deposition of melanin pigment and prevents darkening. Was given.

Example 1 Cream (Formulation) Stearic acid 5.0% by weight Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Iriflorenthal 0.01 Caustic potash 0.1. 2 Sodium bisulfite 0.01 Preservative Suitable amount Perfume Suitable amount Ion-exchanged water Residual (production method) Add propylene glycol, iriflorental and caustic potash to ion-exchanged water, dissolve and heat to 70 ° C.
Keep (water phase). Mix other ingredients, heat and melt at 70 ° C
(Oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction.
Then, it is uniformly emulsified with a homomixer and cooled to 30 ° C. with thorough stirring.

Example 2 Cream (Formulation) Stearic acid 2.0% by weight Stearyl alcohol 7.0 Hydrogenated lanolin 2.0 Squalane 5.0 2-Octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) cetyl alcohol ether 3.0 glycerin monostearate 2.0 propylene glycol 5.0 iriparidal 0.05 sodium bisulfite 0.03 ethylparaben 0.3 fragrance suitable amount ion-exchanged water residual (manufacturing method) propylene glycol is added to ion-exchanged water,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the aqueous phase to carry out preliminary emulsification, and the mixture is uniformly emulsified with a homomixer and then cooled to 30 ° C. with thorough stirring.

Example 3 Cream (Formulation) Solid paraffin 5.0% by weight Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) sorbitan monolaurate 2 0.0 Soap powder 0.1 Borax 0.2 Iriparidal 0.05 Iriflorental 0.05 Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Fragrance Ion-exchanged water Residual (production method) Soap powder and borax in ion-exchanged water In addition, the mixture was heated and melted and maintained at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase while stirring to carry out the reaction. After the reaction is completed, the mixture is uniformly emulsified with a homomixer, and after emulsification, the mixture is cooled to 30 ° C. with thorough stirring.

Example 4 Emulsion (formulation) Stearic acid 2.5% by weight Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) monooleate 2.0 Polyethylene glycol 1500 3. 0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Brand name: Carbopol 941, BFGoodrich Chemical company) Iriparidar 0.01 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Suitable amount Ion-exchanged water Residual (manufacturing method) Small amount The carboxyvinyl polymer is dissolved in the ion-exchanged water of (A phase). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, dissolved by heating, and kept at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase to perform preliminary emulsification, the phase A is added, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring well.

Example 5 Emulsion (formulation) Microcrystalline wax 1.0 wt% Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol ) Sorbitan monooleate 1.0 propylene glycol 7.0 iriparidal 10.0 sodium bisulfite 0.01 ethylparaben 0.3 fragrance suitable amount ion-exchanged water residual (manufacturing method) propylene glycol is added to ion-exchanged water,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added thereto, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C with good stirring.

Example 6 Jelly (formulation) 95% ethyl alcohol 10.0% by weight dipropylene glycol 15.0 polyoxyethylene (50 mol) oleyl alcohol ether 2.0 carboxyvinyl polymer 1.0 (trade name: Carbopol 940, BFGoodrich Chemical company) Caustic soda 0.15 L-Arginine 0.1 Iriflorental 7.0 Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05 Ethylenediaminetetraacetate ・ 3 sodium ・ diwater 0.05 Methylparaben 0 .. 2. Fragrance, appropriate amount, ion-exchanged water, residual (manufacturing method) Carbopol 940 is uniformly dissolved in ion-exchanged water, while iriflorental is added to 95% ethanol.
Polyoxyethylene (50 mol) oleyl alcohol ether is dissolved and added to the aqueous phase. Next, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 7 Beauty Serum (Formulation) (Phase A) Ethyl Alcohol (95%) 10.0% by Weight Polyoxyethylene (20 mol) Octyldodecanol 1.0 Pantotenyl Ethyl Ether 0.1 Iriparidar 1.5 Methylparaben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium hydrogen sulfite 0.03 Carboxyvinyl polymer 0.2 (trade name: Carbopol 940, BFGoodrich Chemical company) Purified water Residual (manufacturing method) Dissolve Phases A and C uniformly,
Add phases and solubilize. Next, after adding the phase B, filling is performed.

Example 8 Pack (Formulation) (Phase A) Dipropylene glycol 5.0 wt% Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) Iriparidar 0.01 Olive oil 5.0 Tocopherol acetate 0 .2 Ethyl paraben 0.2 Perfume 0.2 (Phase C) Sodium hydrogen sulfite 0.03 Polyvinyl alcohol 13.0 (Saponification degree 90, degree of polymerization 2,000) Ethanol 7.0 Purified water Residual (production method) Phase A , Phase B, and phase C are uniformly dissolved,
Add phase B to phase and solubilize. Next, this is added to the C phase and then filled.

Example 9 Solid Foundation (Formulation) Talc 43.1 wt% Kaolin 15.0 Sericite 10.0 Zinc white 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8 0.0 isostearic acid 4.0 POE sorbitan monooleate 3.0 isocetyl octanoate 2.0 iriflorental 1.0 preservative appropriate amount perfume appropriate amount (production method) Talc to black iron oxide powder components are sufficiently mixed with a blender, To this, an oily component of squalane to isocetyl octoate, iriflorental, a preservative and a fragrance are added, and the mixture is kneaded well, then filled into a container and molded.

Example 10 Emulsion type foundation (cream type) (Formulation) (Powder part) Titanium dioxide 10.3% by weight Sericite 5.4 Kaolin 3.0 Yellow iron oxide 0.8 Bengala 0.3 Black iron oxide 0.2 (oil phase) decamethylcyclopentasiloxane 11.5 liquid paraffin 4.5 polyoxyethylene-modified dimethylpolysiloxane 4.0 (water phase) purified water 50.0 1,3-butylene glycol 4.5 iriparidal 1.5 Sorbitan sesquioleate 3.0 Preservative Suitable amount Perfume Suitable amount (Manufacturing method) After heating and stirring the aqueous phase, a powder portion thoroughly mixed and pulverized is added and treated with a homomixer. Further, the oil phase mixed by heating is added, and the mixture is treated with a homomixer. Then, a fragrance is added with stirring, and the mixture is cooled to room temperature.

[0045]

Industrial Applicability As described above, the external preparation for skin of the present invention has a melanin production inhibitory action and a tyrosinase activity inhibitory action, and it causes lightening of pigmentation, stains, freckles, melasma etc. after sunburn. It is an external preparation for skin that has excellent whitening effect and safety.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location // C07C 47/267 9049-4H C07C 47/267 C07M 7:00

Claims (3)

[Claims] 1. General formula (1): (In the formula, R is the following formula (2): Or the following formula (3): Represents ) An external preparation for skin, comprising one or two compounds represented by the formula (1). 2. The external preparation for skin according to claim 1, wherein the compounding amount of the compound represented by the general formula (1) is 0.005 to 20.0% by weight. 3. The external preparation for skin according to claim 1, which is an external preparation for whitening skin.