JP6006537B2 - Skin external composition - Google Patents

Description

The present invention relates to an external composition for skin, and more particularly to an external composition for skin containing a whitening component.

Skin symptoms such as wrinkles, spots and sagging are skin aging symptoms that manifest with aging due to accumulation of physical stimuli such as temperature changes, ultraviolet rays and chemical exposure in addition to genetic factors. Such skin symptom greatly affects the appearance of others, so keeping the skin aesthetics is an important concern for people. Among these skin symptoms, it has been clarified that skin symptoms such as blotches, freckles, and pigmentation after sunburn are caused by increased melanin production by activation of pigment cells (melanocytes) present in the skin. . In addition, excessive or chronic enhancement of melanin production in melanocytes can be cured by inducing cell transport of keratinocytes by causing phenomena such as excessive transport of melanin to keratinocytes (keratinocytes), accumulation and delayed discharge. Causes pigmentation accompanied by exacerbation of skin symptoms such as hard spots, dullness, and delamination. In order to prevent or improve pigmentation including deterioration of skin symptoms caused by such increased melanin production, various active ingredients have been researched and developed. In particular, the development of ingredients having a whitening effect has been actively conducted. For example, whitening agents such as ascorbic acid, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, and catechols are known, and skins containing such ingredients are blended. External preparations are also widely used. In addition to research on whitening agents, detailed studies on pigmentation mechanisms have also been made, and whitening agents having various mechanisms based on the results, such as melanin production inhibitors (Patent Document 1), tyrosinase enzyme inhibition. Agents (Patent Document 2), tyrosinase enzyme gene expression inhibitors, α-MSH inhibitors (Patent Document 3), antioxidants (Patent Document 4) and the like have been reported.

On the other hand, it has been difficult to say that the whitening effect is sufficient in pigmentation involving the decrease in cell function of keratinocytes. However, the composition of a compound having a whitening component and a sterically bulky aromatic group or heteroaromatic group (particularly a diphenylmethyl group or a triphenylmethyl group) causes excessive transport and accumulation of melanin to keratinocytes due to enhanced melanin production. In recent years, it has been found to be effective against pigmentation accompanied by symptoms such as incurable healing, dullness, and rough skin caused by phenomena such as discharge delay (Patent Document 5).

On the other hand, as an attempt to achieve a higher whitening effect, studies have been made to improve skin permeability or storage (Patent Document 6) by devising prescription ingredients. In addition, it has been reported that skin permeability is controlled by a method using hydroxylated phospholipid or the like (Patent Document 7). However, even in these methods, in the case of a compound having an aromatic group or a heteroaromatic group having a sterically bulky chemical structure, skin permeation is limited or has a low rapid effect, and it is difficult to obtain a high whitening effect. It was. Therefore, a formulation and a dosage form that can realize high transdermal absorption of these compounds have been demanded.

JP 2008-208073 A JP 2009-196895 A JP 2001-220347 A JP 2010-037299 A JP 2012-001519 A JP 2007-332115 A JP 2008-115109 A

Skin that has a whitening effect and has a sterically bulky aromatic group or heteroaromatic group in the chemical structure, can achieve high transdermal absorbability, is highly stable as a preparation, and has excellent usability An object of the present invention was to provide a composition for external use.

In view of such a situation, the present inventors pay attention to emulsifiers, surfactants and oils, which have a great influence on the effects of transdermal absorption and formulation stability, and use these raw materials that can be used in the cosmetics field. As a result of investigation and diligent research aiming at a new composition for external use on the skin, it was found that a new composition for external use on the skin as shown below can solve the problem and completed the present invention. That is, the present invention is as follows.

<1> 1) A composition for external use of skin, comprising a compound represented by the following general formula (Formula 1) and / or a pharmacologically acceptable salt thereof, and 2) a phospholipid.
Wherein A represents a di- or triarylmethyl group independently selected from the group consisting of unsubstituted or substituted aryl groups, X represents a nitrogen atom, NH group or oxygen atom, R ₁ represents a hydrogen atom, a hydrogen atom or a cyclic aliphatic hydrocarbon group or aromatic hydrocarbon group having 3 to 8 carbon atoms in which a carbon atom may be substituted with a hetero atom, and the above cyclic aliphatic hydrocarbon The ring of the group or aromatic hydrocarbon group also includes a ring formed by rebonding the other end of R ₁ to X only when X is a nitrogen atom. ]
<2> The external composition for skin according to <1>, comprising stearic acid.
<3> The external composition for skin according to <1> or <2>, which contains batyl alcohol.
<4> The external composition for skin according to any one of <1> to <3>, comprising isostearic acid.
<5> The external composition for skin according to any one of <1> to <4>, comprising 2-ethylhexyl isononanoate.

According to the present invention, a compound having a whitening effect having a sterically bulky aromatic group or heteroaromatic group in the chemical structure can achieve high transdermal absorbability and has high stability as a preparation, It is possible to provide a composition for external use with an excellent feeling of use.

<Compounds represented by the general formula (Formula 1) and / or pharmacologically acceptable salts thereof used in the present invention>
Among the compounds represented by the general formula (Formula 1), 1- (diphenylmethyl) imidazole, 1- (triphenylmethyl) imidazole, 2-[(diphenylmethyl) oxy] ethanol, 2 -[(Triphenylmethyl) oxy] ethanol, 2-[(diphenylmethyl) amino] ethanol, 2-[(triphenylmethyl) amino] ethanol, 2-[(diphenylmethyl) oxy] ethylamine 2-[(triphenylmethyl) oxy] ethylamine, 1- (diphenylmethyl) pyrrolidine, 1- (triphenylmethyl) pyrrolidine, 1- (diphenylmethyl) piperidine, 1- (triphenylmethyl) piperidine and / or them The pharmacologically acceptable salt of 2-[(triphenylmethyl) oxy] ethanol (formula 2), 1- (triphenylmethyl) is preferably exemplified. Le) piperidine (Formula 3) and / or their pharmacologically acceptable salts are more suitably be exemplified. As a manufacturing method, it has already been disclosed in Patent Document WO2010-074052 and is generally known. In the composition for external use of skin of this invention, you may contain individually 1 type among this compound, and may contain it in combination of 2 or more types. In the composition for external use of skin, the total amount is preferably 0.01 to 5% by mass, and more preferably 0.3 to 2% by mass in total.

2-[(Triphenylmethyl) oxy] ethanol

1- (Triphenylmethyl) piperidine

<Phospholipids used in the present invention>
Examples of the phospholipid used in the composition for external skin of the present invention include lecithin (phosphatidylcholine), phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and lysates thereof, and lecithin is more preferable. These may be natural, hydrogenated, or chemically synthesized. The may be a mixture containing phospholipids, and the like can be exemplified NIKKOL Nikoripiddo 81S (manufactured by Japan light Chemicals, Inc.).
In the external composition for skin of the present invention, the phospholipid is preferably contained in a total amount of 0.01 to 2% by mass, more preferably in a total amount of 0.1 to 0.3% by mass.

<Stearic acid used in the present invention>
Some stearic acids are already commercially available, and any stearic acid can be used without particular limitation as long as it is used in a composition for external use on the skin. In the external composition for skin of the present invention, stearic acid is preferably contained in an amount of 0.1 to 5% by mass, more preferably 1 to 3% by mass.

<Batylic alcohol used in the present invention>
There are already commercially available batyl alcohols, and any batyl alcohol can be used without particular limitation as long as it is used in an external composition for skin. In the external composition for skin of the present invention, batyl alcohol is preferably contained in an amount of 0.1 to 5% by mass, more preferably 1 to 3% by mass.

<Isostearic acid used in the present invention>
Some isostearic acids are already on the market, and any isostearic acid can be used without particular limitation as long as it is used in a composition for external use on the skin. In the external composition for skin of the present invention, isostearic acid is preferably contained in an amount of 0.01 to 3% by mass, more preferably 0.1 to 1% by mass.

<2-ethylhexyl isononanoate used in the present invention>
There are some commercially available products of 2-ethylhexyl isononanoate, and any of them can be used without particular limitation as long as it is used in a composition for external use on the skin. In the composition for external use of the skin of the present invention, 2-ethylhexyl isononanoate is preferably contained in an amount of 1 to 20% by mass, more preferably 5 to 15% by mass.

The external composition for skin referred to in the present invention is not particularly limited as long as it is externally administered to the skin. For example, cosmetics including quasi-drugs, skin external goods and the like can be suitably exemplified. Of these, cosmetics are particularly preferred. In addition, the external composition for skin of the present invention can take any of the conventionally known emulsion dosage forms, essence dosage forms, cream dosage forms, and powder-containing dosage forms. As the cosmetic, any of basic cosmetics, hair cosmetics, and makeup cosmetics can be applied, but it is particularly preferable to apply to basic cosmetics.

In the composition for external use of the skin of the present invention, in addition to the above-mentioned components, optional components usually used in cosmetics and external preparations for skin can be contained. Examples of such optional ingredients include macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, and hardened coconut oil. Oil, wax, liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum, oil, wax, liquid wax, liquid paraffin, squalane, bean wax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax , Hydrocarbons such as microcrystalline wax, higher fatty acids such as oleic acid, lauric acid, myristic acid, palmitic acid, behenic acid, undecylenic acid, cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol Higher alcohols such as octyldodecanol, myristyl alcohol, cetostearyl alcohol, cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, diisostearyl malate, Di-2-ethylhexanoic acid ethylene glycol, dicaprate neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, triisostearic acid trimethylol Synthetic ester oils such as propane, tetra-2-ethylhexanoic acid pentane erythritol, dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane Chain polysiloxanes such as ethylene, cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexanesiloxane, amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, fluorine-modified polysiloxane Oils such as silicone oils such as modified polysiloxanes, fatty acid soap (sodium laurate, sodium palmitate, etc.), anionic surfactants such as potassium lauryl sulfate, alkylsulfuric triethanolamine ether, stearyltrimethylammonium chloride, Cationic surfactants such as benzalkonium chloride and laurylamine oxide, betaine surfactants (alkyl betaines, amide betaines, sulfobetaines, etc.), imidazoles Amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), amphoteric surfactants such as acylmethyl taurine, sorbitan fatty acid esters (sorbitan monostearate) , Sorbitan sesquioleate, etc.)
Glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (such as propylene glycol monostearate), hydrogenated castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, monostearic acid) Polyoxyethylene sorbitan, etc.), POE sorbite fatty acid esters (POE-sorbite monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate). etc)
POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Te Tronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), nonionic surfactants such as sucrose fatty acid ester, alkyl glucoside, polyethylene glycol, glycerin, 1,3-butylene glycol Erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1,2-he Polyhydric alcohols such as sundiol, 1,2-octanediol, moisturizing ingredients such as sodium pyrrolidonecarboxylate, lactic acid, sodium lactate, guar gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, xanthan gum , Curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylhydroxypropylcellulose, chondroitin sulfate, dermatan sulfate, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxy Methyl guar gum, dextran, keratosulfate, locust bean gum, succinoglucan, caronic acid, chitin, Thickeners such as tosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, carboxy vinyl polymer, alkyl-modified carboxy vinyl polymer, sodium polyacrylate, polyethylene glycol, bentonite, surface may be treated, mica, Powders such as talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, silicic anhydride (silica), aluminum oxide, barium sulfate, surface may be treated, bengara, yellow iron oxide, black iron oxide, Cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide inorganic pigments, surface may be treated, pearlescent agents such as titanium mica, fish phosphorus foil, bismuth oxychloride, red may be raked 202, Red 228, Red 226, Yellow 4, Blue 40 No. 4, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204 Organic dyes such as polyethylene powder, polymethyl methacrylate, nylon powder, organic powders such as organopolysiloxane elastomers, paraaminobenzoic acid UV absorbers, anthranilic acid UV absorbers, salicylic acid UV absorbers, cinnamon Acid UV absorber, benzophenone UV absorber, sugar UV absorber, 2- (2′-hydroxy-5′-t-octylphenyl) benzotriazole, 4-methoxy-4′-t-butyldibenzoylmethane ultraviolet absorbing agents and the like, ethanol, lower alcohols such as isopropanol, vitamin a or a derivative thereof, vitamin B Hydrochloride, vitamin _{B 6} tripalmitate, vitamin _{B 6} dioctanoate, vitamin _{B 2} or derivatives thereof, vitamin _{B 12,} vitamin B such as vitamin _{B 15} or a derivative thereof, alpha-tocopherol, beta-tocopherol, .gamma.-tocopherol, Preferable examples include vitamin E such as vitamin E acetate, vitamin D, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone and the like.

<Production Example of Composition for External Use of Skin of the Present Invention>
The composition for external use of the skin of the present invention was prepared according to the formulation shown below. That is, after (A) of Example 1 in Table 1 was heated and dissolved at 60 ° C., the mixture was stirred and mixed at 5000 rpm for 5 minutes in an emulsifier while adding (B) to (A), and the aqueous phase 1 was prepared. Then, (C) was heated and dissolved at 80 ° C., and then gradually added to the aqueous phase 1 and stirred and mixed at 3000 rpm for 10 minutes in an emulsifier. Thereafter, the stirring and mixing of the emulsifier was reduced to 1000 rpm and cooled to 30 ° C. to obtain the emulsion of Example 1.

<External skin composition of the present invention>
Example 2 was prepared by substituting 2-[(triphenylmethyl) oxy] ethanol with 1- (triphenylmethyl) piperidine for Example 1. Moreover, the lecithin, the stearic acid, and the batyl alcohol were deleted with respect to Example 1, 2, and Example 3, 4 which mix | blended NIKKOL Nikolipid 81S was also prepared. Furthermore, compared with Examples 1 and 2, Comparative Examples 1 and 2 in which lecithin was deleted, Examples 5 and 6 in which the amount of lecithin was increased , and Comparative Examples 3 and 4 , Comparative Examples 5 and 6 in which lecithin was substituted with hydroxylated lecithin, Comparative Examples 7 and 8 in which stearic acid was removed, Examples 7 and 8 in which the amount of stearic acid was increased , and Comparative Examples 9 and 10 , Comparative Examples 11 and 12 in which batyl alcohol was deleted , and Examples 9 and 10 in which batyl alcohol was increased And Comparative Examples 13 and 14 , Comparative Examples 15 and 16 in which batyl alcohol was replaced with cetyl alcohol, Comparative Examples 17 and 18 in which isostearic acid was removed , Examples 11 and 12 in which the amount of isostearic acid was increased , and Comparative Examples 19 and 20 Comparative example 21 and 22 remove the stearic acid and isostearic acid, Comparative examples 23 and 24 were all replaced with stearic acid and isostearic acid lauric acid Comparative Example 25 and 26 remove the isononanoic acid 2-ethylhexyl, examples 13 and 14 was increased isononanoic acid 2-ethylhexyl, comparative examples 27 and 28 was substituted for isononanoate, 2-ethylhexyl to tri-2-ethylhexanoate glycerin Comparative Examples 29 and 30 in which isostearic acid and 2-ethylhexyl isononanoate were omitted were also prepared. It shows in Tables 1-3.

<Test Example 1 Evaluation of transdermal absorbability of external composition for skin>
Six portions of 1 cm × 1 cm were provided on the inner part of the forearm of 15 panelists, and 7 μL of the test sample, which was the above-prepared external composition for the skin, was applied to each panel and allowed to stand at 20 ° C. for 1 hour, followed by tetrahydrofuran (THF). The skin was wiped off with absorbent cotton impregnated with 100% of this cotton, and this absorbent cotton was extracted three times with 100 ml of THF to recover 2-[(triphenylmethyl) oxy] ethanol or 1- (triphenylmethyl) piperidine in the extract. The amount was quantified by high performance liquid chromatography. The recovery rate was defined as transdermal absorbability (the lower the value, the higher the transdermal absorbability). Each test sample was evaluated twice, and the averages are shown in Tables 1 to 3.

<Test Example 2 Appearance, color and odor evaluation of composition for external use on skin>
After preparing the test sample, it was stored at 50 ° C. One week after the preparation, appearance, color and odor were evaluated. However, on the day before the evaluation, the test sample stored at 50 ° C. was stored at 20 ° C. for 24 hours and evaluated. In terms of appearance, the absolute evaluation was evaluated by comparing the color and odor with those separately stored at 5 ° C. The criteria for each evaluation are shown below. The results are shown in Tables 1-3.

[Appearance evaluation]
0: Emulsified neatly.
1: Although emulsified, the emulsified particles are enlarged and the transparency is enhanced.
2: Emulsification failure is observed (less than 5% of the total).
3: Emulsification is broken and oil is separated.

[Color and smell evaluation]
0: Same as 5 ° C.
1: There is a slight difference compared to 5 ° C. It is a level that cannot be understood unless compared with 5 ° C.
2: A difference is seen compared with 5 degreeC. Even if it is not compared with 5 ° C., it can be easily understood.
3: Discoloration or odor change is remarkable. It is not suitable as a composition for external use on the skin.

<Test Example 3 Skin feel evaluation of composition for external use>
A questionnaire was conducted regarding the feeling of use of the composition for external use on the skin. The evaluation criteria are shown below. In addition, Tables 1 to 3 show the most frequent results for five people.
A: There is no stickiness and it is a very good feeling.
B: Although it feels a little sticky, it is a relatively good feeling.
C: A feeling of stickiness is felt and the feeling of use is bad.
D: A feeling of stickiness is considerably felt, and it is a very bad feeling of use. It is not suitable as a composition for external use on the skin.

From the results of Tables 1 to 3, according to the present invention, high transdermal absorption can be realized even in a compound having a sterically bulky aromatic group or heteroaromatic group having an excellent whitening effect on the skin. In addition, it can be seen that a composition for external use of skin having high stability as a preparation and excellent usability can be provided.

The present invention relates to an external preparation for skin, and more specifically, can be applied to an external preparation for skin containing a whitening component.

Claims (3)

1) A compound represented by the following general formula (Formula 1) and / or a pharmacologically acceptable salt thereof,
2) 0.01-2% by weight of lecithin,
3) 0.1-5% by weight stearic acid,
4) 0.1-5% by weight of batyl alcohol,
5) 0.01-3 mass% isostearic acid, and
6) A composition for external use on skin , comprising 2-ethylhexyl isononanoate .
[In the formula, A represents a di- or triarylmethyl group each independently selected from the group consisting of an aryl group having unsubstituted or substituted group, X represents a nitrogen atom or an NH group or an oxygen atom, R ₁ are water atom or a carbon atom represents a cyclic or chain aliphatic hydrocarbon group having a nitrogen atom or an oxygen atom carbon atoms which may be substituted with 3-8, aliphatic hydrocarbon group of the cyclic The ring also includes a ring formed by rebonding the other end of R ₁ to X only when X is a nitrogen atom. ] The skin external application according to claim 1, wherein the content of the compound represented by 1) the general formula (Chemical Formula 1) and / or a pharmacologically acceptable salt thereof is 0.01 to 5% by mass. Composition. The composition for external use of the skin according to claim 1 or 2 , wherein the content of 6) 2-ethylhexyl isononanoate is 1 to 20% by mass .