JP2006257012A - Torpent and external preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a torpent capable of being readily formulated without having influence on function and shape of a preparation and an external preparation for skin containing the torpent. <P>SOLUTION: The torpent comprises a glucose derivative, particularly a glucose derivative represented by general formula (I) (wherein R is a residue of 4-methoxyphenol, 4-carboxyphenol or 3-carboxyphenol). The external preparation for skin comprises the torpent. The external preparation for skin may further comprise an irritation causative agent [e.g. an oleagenous agent ingredient such as retinol and its derivative or an ultraviolet light absorber or an antiseptic agent] to the skin. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an irritation reducing agent comprising a glucose derivative and a skin external preparation containing the same. More specifically, the present invention relates to an irritation relieving agent and an external preparation for skin that can effectively relieve or prevent skin irritation and are excellent in stability, safety, and moisture retention.

  For skin external preparations, base components such as water, alcohols, salts, oils and fats, waxes, hydrocarbons, higher fatty acids, higher alcohols, silicone oils, powders, surfactants, emulsifiers, gelling agents, etc. In addition to various agents such as whitening agents, anti-aging agents, acne medications, astringents, skin roughening agents, vitamin preparations, preservatives and stabilizers, UV protection agents, pigments, and fragrances. Contains functional ingredients.

  Despite the fact that pharmaceutical preparations that ensure the safety of their use are designed to ensure their use, the topical skin preparation has many stimuli in its ingredients formulated for that purpose. Some people feel a slight irritation while still having a safe range of dosage. Some people, such as patients with lower alcohol sensitivity, feel hypersensitive to certain components (lower alcohol). Also, because of the so-called sensitive skin, you may feel sensitive irritation, or when you have rough skin, you may feel irritation due to the use of topical skin preparations, and in patients with atopic disease, you may feel excessive irritation due to the disease. is there. Furthermore, irritation may be caused not only by the ingredients but also by the combined formulation system. In addition, irritation may occur due to use in sensitive areas such as around the eyes, or irritation may be caused by usage methods such as rubbing the skin with a preparation containing powder. In addition, there may be a case where a stimulus is generated depending on the use environment, such as a case where a stimulus is generated due to use under severe conditions such as under strong sunlight.

  As described above, in the use of the external preparation for skin, there are various causes of irritation.

  Various methods for alleviating and preventing skin irritation have been studied so far.

  For example, various denatured alcohols were blended or used after aging for a certain period of time in order to alleviate the stimulation of lower alcohols. However, these methods were hardly effective. On the other hand, Japanese Patent Application Laid-Open No. 61-227514 (Patent Document 1) discloses a topical skin preparation in which a specific amount of hydroquinone glycoside (such as arbutin) and a lower alcohol are mixed to reduce the skin irritation of the lower alcohol. An agent is presented.

  Japanese Patent Laid-Open No. 10-36238 (Patent Document 2) discloses a method for suppressing / preventing irritant and / or erythematous skin symptoms using salicin, and Japanese Patent Laid-Open No. 10-36239 (Patent Document 3). Discloses a method for suppressing / preventing irritant and / or erythematous skin symptoms using ferulic acid glucoside. In particular, as a method for reducing irritation to lower alcohols, Japanese Patent No. 3308763 (Patent Document 4) discloses an alcohol stimulation mitigating agent containing a specific glucose derivative as an active ingredient.

JP-A 61-227514 Japanese Patent Laid-Open No. 10-36238 JP 10-36239 A Japanese Patent No. 3308763

  However, although the external preparation for skin shown in Patent Document 1 is excellent in the stimulating and mitigating effect of lower alcohol, the problem is that the preparation is colored over time, the problem that it is affected by the pH of the system at the time of blending, and the oxidation stability. Due to the problem of inferiority, there was a limitation on the formulation.

  The salicin disclosed in Patent Document 2 has a hydroxyl group at the benzylic position of the glucose binding group, and thus has problems in stability such as oxidation stability, light stability, and thermal stability. The ferulic acid glucoside shown in Patent Document 3 is difficult and expensive to produce, and has a problem in terms of stability of the preparation. Moreover, since it has a carboxyl group, there is a concern about the influence on the function and form of the preparation, such as formation of a metal salt, and there is a problem that the cis-trans conversion of the double bond occurs and the color changes to yellow.

  Many of the glucose derivatives shown in Patent Document 4 are difficult to produce and are not easy to prepare. In addition, there are problems such as coloration of the preparation over time and insufficient stimulation mitigating effect. Furthermore, among the disclosed glucose derivatives, a compound having an aldehyde group has problems such as poor oxidation stability and influence of pH. Those having a ketone skeleton have a problem in safety due to photosensitization, and further have a problem of being colored or condensed by acting with the formulation components under basicity. A compound having no functional group at the benzyl position has a problem in light stability and light safety. The glycoside of the hydroxyl group at the benzyl position is inferior in stability and has a problem of coloring over time. A compound having a double bond has a problem in oxidation stability. A compound having a methylenedioxy group has a problem in stability over time because it is easily decomposed. The described compounds having no substituent on the benzene ring are easy to produce, but do not have a sufficient stimulating effect.

  The method shown in Patent Document 4 obtains the effect of reducing lower alcohol stimulation by physical interaction between a glucose derivative and a lower alcohol aqueous solution. In fact, when the glucose derivative shown in Patent Document 4 is used, Such interaction did not occur except in the aqueous solution system, and therefore, there was no stimulus relaxation effect.

  Under such circumstances, there has been a strong demand for the development of a stimulant mitigating agent that does not affect the function and form of the preparation, is easy to formulate, and is excellent in safety and stability.

  Accordingly, the present invention provides an irritation relieving agent that does not affect the function and form of the preparation, is easy to formulate, is excellent in safety and stability, and excellent in irritation mitigation, and a skin external preparation containing the same. Objective.

  In order to solve the above-mentioned problems, the present invention provides a stimulant mitigating agent comprising a glucose derivative.

  In the present invention, the glucose derivative is represented by the following general formula (I):

(In the formula, R represents 4-methoxyphenol, 4-carboxyphenol, 3-carboxyphenol residue)
The said irritation reducing agent which is a compound represented by these is provided.

  Moreover, this invention provides the skin external preparation containing the said irritation reducing agent.

  Moreover, this invention provides the said skin external preparation whose skin external preparation further contains the irritation | stimulation substance to skin.

  Moreover, this invention provides the said skin external preparation whose irritation | stimulation substance to skin is a fat-soluble chemical | medical agent component.

  Moreover, this invention provides the said skin external preparation whose fat-soluble chemical | medical agent component is 1 type (s) or 2 or more types chosen from retinol and its derivative (s), a ultraviolet absorber, and antiseptic | preservative.

  INDUSTRIAL APPLICABILITY According to the present invention, an irritation mitigating agent and an external preparation for skin that are excellent in stability / safety and moisturizing properties are provided by reducing or preventing irritation caused by an irritating substance or preparation in an external preparation for skin and at the time of application.

  Hereinafter, the present invention will be described in detail.

  The glucose derivatives used in the present invention widely include those having a glucoside structure and that can be blended in cosmetics and pharmaceuticals. In the present invention, compounds represented by the following general formula (I) are particularly preferably used.

  In the general formula (I), R represents a residue of 4-methoxyphenol, 4-carboxyphenol, or 3-carboxyphenol.

  When R is a 4-methoxyphenol residue, the glucose derivative represented by the general formula (I) is specifically 4-methoxyphenyl-D-glucoside represented by the following formula (I-1).

  When R is a 4-carboxyphenol residue, the glucose derivative represented by the general formula (I) is specifically 4-carboxyphenyl-D-glucoside represented by the following formula (I-2).

  When R is a 3-carboxyphenol residue, the glucose derivative represented by the general formula (I) is specifically 3-carboxyphenyl-D-glucoside represented by the following formula (I-3).

  The binding mode between the substituent R of the glucose derivative and the sugar may be either α-bond or β-bond, but β-bond is preferred from the viewpoint of stability. However, it is not limited to this. A mixture thereof may also be used.

  Of the 4-methoxyphenylglucosides represented by the above formula (I-1), α-4-methoxyphenyl-D-glucoside (also referred to as “4-methoxyphenyl-α-D-glucoside”) is represented by the following formula ( I-1-a) and β-4-methoxyphenyl-D-glucoside (also referred to as “4-methoxyphenyl-β-D-glucoside”) are represented by the following formula (I-1-b).

  Among the 4-carboxyphenyl-D-glucosides represented by the above formula (I-2), α-4-carboxyphenyl-D-glucoside (also referred to as “4-carboxyphenyl-α-D-glucoside”) has the following formula. (I-2-a), and β-4-carboxyphenyl-D-glucoside (also referred to as “4-carboxyphenyl-β-D-glucoside”) is represented by the following formula (I-2-b). .

  Among the 3-carboxyphenyl-D-glucosides represented by the above formula (I-3), α-3-carboxyphenyl-D-glucoside (also referred to as “3-carboxyphenyl-α-D-glucoside”) has the following formula. (I-3-a), and β-3-carboxyphenyl-D-glucoside (also referred to as “3-carboxyphenyl-β-D-glucoside”) is represented by the following formula (I-3-b). .

  Each of the glucose derivatives used in the present invention can be obtained by a generally used chemical synthesis method, and can also be obtained by glucoside synthesis using an enzyme. Commercial products may also be used. The glucose derivative used in the present invention is commercially available from Aldrich, Tokyo Chemical Industry Co., Ltd., etc., and can be easily obtained.

  In addition, although the following method is mentioned as an example of a synthesis example, it is not limited to this.

[4-Methoxyphenyl-D-glucoside represented by the formula (I-1)]
Add 20 g of pentaacetyl-D-glucoside to 22.26 g of 4-methoxyphenol, add 1 cup of molybdophosphoric acid hydrate, heat up to 90 ° C., and heat and stir for 30 minutes. Unreacted 4-methoxyphenol is removed by distillation under reduced pressure, followed by extraction with 300 mL of ethyl acetate, and the organic layer is washed with a 10% aqueous sodium hydroxide solution. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue is purified with a column to obtain 15 g of 4-methoxyphenyl-D-glucoside tetraacetate.

Next, 15 g of the obtained 4-methoxyphenyl-D-glucoside tetraacetate is dissolved in 300 mL of methanol, 10 mL of sodium methoxide is added, and the mixture is stirred for 2 hours at room temperature. The mixture is neutralized with Amberlite IR120-B [H ⁺ ], then filtered off and concentrated under reduced pressure. The obtained residue is recrystallized with methanol to obtain 9.2 g of the desired 4-methoxyphenyl-D-glucoside.

[4-Carboxyphenyl-D-glucoside represented by the formula (I-2)]
After adding 21.27 g of methyl 4-hydroxybenzoate and 25 g of pentaacetyl-D-glucoside to 100 mL of DME, add 1 cup of molybdophosphoric acid hydrate of micro spatula, warm to 90 ° C., and heat and stir for 30 minutes. After air cooling, extraction is performed with 300 mL of ethyl acetate, and the organic layer is washed with a 10% aqueous sodium hydroxide solution. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue is purified by a column to obtain 24.6 g of 4-methoxycarbonylphenyl-D-glucoside tetraacetate.

Next, 24.6 g of the obtained 4-methoxycarbonylphenyl-D-glucoside tetraacetate is dissolved in 300 mL of an aqueous THF solution, 10 g of sodium hydroxide is added, and the mixture is stirred for 2 hours at room temperature. The mixture is neutralized with Amberlite IR120-B [H ⁺ ], then filtered off and concentrated under reduced pressure. The obtained residue is recrystallized with methanol to obtain 15.4 g of the desired 4-carboxyphenyl-D-glucoside.

[3-Carboxyphenyl-D-glucoside represented by the formula (I-3)]
After adding 21.27 g of methyl 3-hydroxybenzoate and 25 g of pentaacetyl-D-glucoside to 100 mL of DME, add 1 cup of molybdophosphoric acid hydrate of micro spatula, warm to 90 ° C., and heat and stir for 30 minutes. After air cooling, extraction is performed with 300 mL of ethyl acetate, and the organic layer is washed with a 10% aqueous sodium hydroxide solution. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue is purified by a column to obtain 23.0 g of 3-methoxycarbonylphenyl-D-glucoside tetraacetate.

Next, 24.6 g of the obtained 3-methoxycarbonylphenyl-D-glucoside tetraacetate is dissolved in 300 mL of an aqueous THF solution, 10 g of sodium hydroxide is added, and the mixture is stirred for 2 hours at room temperature. The mixture is neutralized with Amberlite IR120-B [H ⁺ ], then filtered off and concentrated under reduced pressure. The obtained residue is recrystallized from methanol to obtain 14.4 g of the desired 3-carboxyphenyl-D-glucoside.

  The glucose derivative used in the present invention is inexpensive, has good usability when formulated in an external skin preparation, and is easy to design a formulation.

  In addition, the glucose derivative used in the present invention has no problem of coloring over time when blended in a preparation. Furthermore, since it is excellent in stability, the function and form of the preparation are retained, and the blending thereof is not limited. It is stable against oxidation, heat, pH, light, and the like. Since the stability of the obtained preparation is good, it can be blended even in preparations stored or used under harsh conditions such as high temperatures, in the sun, or severe changes in temperature. It is stable to light and can be blended in a preparation using any container. In addition, since it does not affect the physical properties of the components of the preparation system, it can take any form without impairing the form and function of the preparation and the feeling of use of the preparation.

  In addition, since the glucose derivative used in the present invention is amphiphilic because of its structure, it dissolves in any of an oil layer such as a wax or an oil component, an intermediate layer such as an aqueous layer, alcohols, or a layer in which they are mixed. Therefore, it can be blended in any pharmaceutical system.

  Such glucose derivatives are excellent in safety, so that they can also be applied to topical preparations used around the lips and eyes, which are concerned about the effects, and preparations for people who are sensitive to the preparations and those with diseases such as atopy. It can be formulated and has the effect of reducing or preventing their irritation.

  Furthermore, since the glucose derivative used in the present invention is excellent in moisturizing properties, the moisturizing effect of the preparation system is improved, and there is an advantage that an effect of improving or preventing rough skin is recognized.

  The irritation reducing agent comprising the glucose derivative of the present invention and the external preparation for skin containing the same are excellent in the effect of alleviating irritation of the irritation causing substance. The irritation-causing substance is not particularly limited as long as it is a component that can be generally blended into an external preparation for skin, but is particularly excellent in the irritation mitigating effect for fat-soluble drug components and preservatives.

  Although an example of a fat-soluble chemical | medical agent is shown below, it is not limited to these illustrations.

(1) Retinol and its derivatives Retinol (also known as vitamin A) has all-trans type or 1,3-cis type. Examples of the retinol derivative include, but are not limited to, retinol acetate (also known as vitamin A acetate), retinol palmitate (also known as vitamin A palmitate), and the like.

  The amount of retinol and its derivative is not particularly limited as long as it is an amount effective for exhibiting the effects of the component, but is usually about 0.0001 to 1.0% by mass in the external preparation for skin. Is more preferable, more preferably about 0.03 to 0.1% by mass, and particularly preferably about 0.05 to 0.1% by mass.

(2) Ultraviolet absorber The ultraviolet absorber is not particularly limited as long as it can be generally used in cosmetics, pharmaceuticals and the like. Specifically, a benzoic acid-based ultraviolet absorber (for example, paraaminobenzoic acid (hereinafter abbreviated as PABA), PABA monoglycerin ester, N, N-dipropoxy PABA ethyl ester, N, N-diethoxy PABA ethyl ester, N, N-dimethyl PABA ethyl ester, N, N-dimethyl PABA butyl ester, N, N-dimethyl PABA ethyl ester, etc.); anthranilic acid-based UV absorbers (for example, homomenthyl-N-acetylanthranylate, etc.); salicylic acid-based UV Absorbents (for example, amyl salicylate, menthyl salicylate, homomenthyl salicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, p-isopropanol phenyl salicylate, etc.); cinnamic acid UV absorbers (for example, octyl Rumethoxycinnamate, di-paramethoxycinnamic acid-glyceryl mono-2-ethylhexanoate, octylcinnamate, ethyl-4-isopropylcinnamate, methyl-2,5-diisopropylcinnamate, ethyl-2,4- Diisopropyl cinnamate, methyl-2,4-diisopropyl cinnamate, propyl-p-methoxycinnamate, isopropyl-p-methoxycinnamate, isoamyl-p-methoxycinnamate, octyl-p-methoxycinnamate (2-ethylhexyl- p-methoxycinnamate), 2-ethoxyethyl-p-methoxycinnamate, cyclohexyl-p-methoxycinnamate, ethyl-α-cyano-β-phenylcinnamate, 2-ethylhexyl-α-cyano-β-phenylcinna Mate Glyceryl mono-2-ethylhexanoyl-diparamethoxycinnamate, 3,4,5-trimethoxycinnamic acid-3-methyl-4- [methylbis (trimethylsiloxy) silyl] butyl, trimethoxycinnamic acid Methylbis (trimethylsiloxy) silylisopentyl, etc.); benzophenone ultraviolet absorbers (for example, 2,4-dihydroxybenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone, 2,2′-dihydroxy-4,4′-) Dimethoxybenzophenone, 2,2 ′, 4,4′-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxy-4′-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone-5 -Sulfonate, 4-phenylbenzophenone 2-ethylhexyl-4′-phenyl-benzophenone-2-carboxylate, 2-hydroxy-4-n-octoxybenzophenone, 4-hydroxy-3-carboxybenzophenone, etc.); 3- (4′-methylbenzylidene) -d , L-camphor, 3-benzylidene-d, l-camphor; 2-phenyl-5-methylbenzoxazole; 2,2'-hydroxy-5-methylphenylbenzotriazole; 2- (2'-hydroxy-5 ' -(2-octylphenyl) benzotriazole; 2- (2'-hydroxy-5'-methylphenylbenzotriazole;dibenzalazine;dianisoylmethane;4-methoxy-4'-t-butyldibenzoylmethane; , 3-dimethyl-2-norbornylidene) -3-pentan-2-one and the like. .

  Especially in this invention, it uses suitably for the irritation | stimulation relaxation of the following ultraviolet absorber which has irritation. For example, octylmethoxycinnamate (a commercial product is exemplified by “Pulsol MCX”), t-butylmethoxydibenzoylmethane (a commercial product is exemplified by “Pulsol 1789”), paradimethylaminobenzoic acid 2-ethylhexyl (a commercially available product is exemplified by “escalol 507D”) and paradimethylaminobenzoic acid methyl (a commercially available product is exemplified by “escalol 506” and the like).

  The blending amount of the ultraviolet absorber is not particularly limited as long as it is an amount effective for exerting the effect of the component, but is usually preferably about 0.1 to 20% by mass in the external preparation for skin. In particular, about 1.0-10 mass% is preferable.

(3) Preservatives Phenoxyethanol, benzoic acid and its salts, salicylic acid and its salts, phenol, sorbic acid and its salts, dehydroacetic acid and its salts, paraoxybenzoic acid esters (for example, methylparaben, ethylparaben, butylparaben, etc.), chloro Cresol, hexachlorophene, resorcinol, isopropylmethylphenol, orthophenylphenol, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkylisoquinolium bromide, trichloricarbanilide, halocarban, photosensitizer 201, trichlorohydroxydiphenyl ether (Triclosan), methylchloroisothiazolinone / methylisothiazolinone solution, bisabolol, alkyldiaminoethylglycine hydrochloride, tri Examples include chloro salicylanilide (TCSA) and tribromo salicylanilide (TBS).

  The blending amount of glucose derivatives for mitigating stimuli such as fat-soluble drug components (retinol and its derivatives, UV absorbers, preservatives, etc.) is appropriately determined according to the blending amount of these stimulating substances. The

  The glucose derivative to be blended in the present invention is preferably about 0.1% by mass or more, more preferably about 0.5% by mass or more, based on the total amount of the external preparation for skin. Moreover, it is preferable that the upper limit of a compounding quantity shall be about 20.0 mass% or less, More preferably, it is about 10.0 mass% or less.

  The external preparation for skin of the present invention has an effect of mitigating and preventing irritation to sensitive skin and atopic patients, and also mitigates irritation caused by active agents and preparations.

  Since the glucose derivative blended in the present invention is excellent in stability and does not affect other components in the preparation, nor is the glucose derivative itself affected, this skin external preparation is generally blended in cosmetics and pharmaceuticals. Any ingredient that can be made can be broadly blended. For example, UV absorbers, moisturizers, vitamins, whitening agents, astringents, refreshing agents, medicinal ingredients such as various extracts, surfactants, liquid fats, solid fats, waxes, ester oils, hydrocarbon oils, Examples include, but are not limited to, silicones, sterols, water-soluble polymers, oil-soluble polymers, chelating agents, neutralizing agents, pH adjusters, antioxidants, antibacterial agents, powders, perfumes, and pigments. is not.

  The preparation form of the external preparation for skin of the present invention is not limited, and for example, any property such as liquid, gel, paste, emulsion, cream, powder, solid, solution system, solubilization Any type of dosage form such as a system, an emulsifying system, a powder dispersion system, a water-oil two-layer system, a water-oil-powder three-layer system, a gel, and an aerosol is applied.

  The use form is also arbitrary. For example, it can be used for makeup cosmetics, aromatic cosmetics, bath preparations, etc. in addition to facial cosmetics and foundations such as lotions, emulsions, creams, cosmetics, packs, etc. Of course, it is not limited to the examples.

  The external preparation for skin of the present invention reduces or prevents irritation caused by an irritating substance or preparation in external preparation for skin and irritation at the time of application, and is excellent in stability, safety and moisture retention.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Unless otherwise specified, the amount is shown in mass%.

  First, the test method and evaluation criteria used in this example will be described.

[Irritation mitigation]
The following continuous skin irritation test was performed and evaluated.
(Test method)
(1) A stimulus-causing substance and a stimulant mitigating agent were blended (in the control examples 1 and 2 (control), no stimulating mitigating agent was blended), and 0.05 mL of each sample (test solution) was applied to the back 2 × 2 cm of the guinea pig (1 Second application).
(2) A second coating was performed 24 hours later.
(3) A third coating was performed 24 hours later.
(Evaluation methods)
Before the second application (= 24 hours after the first application), before the third application (= 24 hours after the second application), and 24 hours after the third application, the skin condition (erythema and edema), respectively. The skin reaction) was observed with the naked eye.

Irritation relaxation was evaluated according to the following criteria, and the average of the three scores was used as the skin reaction score.
(Evaluation criteria for skin reaction)
(Degree of skin reaction) Score No erythema was observed 0
Slight erythema was observed 1
Obvious erythema was observed 2
Strong erythema or slight edema and crusts were observed 3
Obvious edema and crusts were observed 4

[Formulation stability]
Each sample (test solution) was formulated with a stimulus-causing substance and a stimulant-relief agent (no stimulus-relief agent was added to the samples of Control Examples 1 and 2 (control)), and injected into a screw tube (capacity 50 mL) at 50 ° C. for 1 month. The samples were allowed to stand under the conditions of sun exposure (50 MJ), and the appearance of each sample was observed with the naked eye and evaluated according to the following criteria.
(Stability evaluation criteria)
○: There was no particular problem in the appearance, and no coloring or separation was observed. Δ: Some coloring or separation was observed in the appearance, but there was no problem in practical use. ×: There was considerable coloring or separation in the appearance.

(Control Example 1, Comparative Examples 1-4, Examples 1-3)
A sample (not prepared in the control example 1 (control)) was prepared by a conventional method with the composition shown in the following Tables 1 and 2 in which the stimulus-causing substance and the stimulus-relaxing agent were blended, and the above test method was prepared using this sample. Based on the evaluation criteria, irritation relaxation and stability were evaluated. FIG. 1 shows the result of stimulus relaxation and Table 3 shows the result of stability.

  In Tables 1 and 2, the test compounds (stimulation mitigating agents) used in Comparative Examples 1 to 4 are represented by the following chemical formulas. In Examples 1 to 3, β-4-methoxyphenyl-D-glucoside represented by the above formula (I-1-b), and β-4-carboxyphenyl-D- represented by the above formula (I-2-b). Glucosides and β-3-carboxyphenyl-D-glucoside represented by the above formula (I-3-b) were used.

  Each of these compounds was prepared as follows.

[Β-4-methoxyphenyl-D-glucoside represented by the formula (I-1-b)]
20 g of pentaacetyl-D-glucoside was added to 22.26 g of β-4-methoxyphenol, and 1 cup of molybdophosphoric acid hydrate was added, and the mixture was heated to 90 ° C. and stirred for 30 minutes. Unreacted β-4-methoxyphenol was removed by distillation under reduced pressure, followed by extraction with 300 mL of ethyl acetate, and the organic layer was washed with a 10% aqueous sodium hydroxide solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified with a column to obtain 15 g of β-4-methoxyphenyl-D-glucoside tetraacetate.

Next, 15 g of the obtained β-4-methoxyphenyl-D-glucoside tetraacetate was dissolved in 300 mL of methanol, 10 mL of sodium methoxide was added, and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with Amberlite IR120-B [H ⁺ ], then filtered off and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to obtain 9.2 g of the intended β-4-methoxyphenyl-D-glucoside.

[Β-4-carboxyphenyl-D-glucoside represented by the formula (I-2-b)]
After adding 21.27 g of methyl β-4-hydroxybenzoate and 25 g of pentaacetyl-D-glucoside to 100 mL of DME, add 1 cup of microspatula molybdophosphate hydrate, heated to 90 ° C. and stirred for 30 minutes. did. After air cooling, extraction was performed with 300 mL of ethyl acetate, and the organic layer was washed with a 10% aqueous sodium hydroxide solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified on a column to obtain 24.6 g of β-4-methoxycarbonylphenyl-D-glucoside tetraacetate.

Next, 24.6 g of the obtained β-4-methoxycarbonylphenyl-D-glucoside tetraacetate was dissolved in 300 mL of an aqueous THF solution, 10 g of sodium hydroxide was added, and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with Amberlite IR120-B [H ⁺ ], then filtered off and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to obtain 15.4 g of the intended β-4-carboxyphenyl-D-glucoside.

[Β-3-carboxyphenyl-D-glucoside represented by the formula (I-3-b)]
After adding 21.27 g of methyl β-3-hydroxybenzoate and 25 g of pentaacetyl-D-glucoside to 100 mL of DME, add 1 microboil of molybdophosphoric acid hydrate, heat to 90 ° C. and stir for 30 minutes. did. After air cooling, extraction was performed with 300 mL of ethyl acetate, and the organic layer was washed with a 10% aqueous sodium hydroxide solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was purified with a column to obtain 23.0 g of β-3-methoxycarbonylphenyl-D-glucoside tetraacetate.

Next, 24.6 g of the obtained β-3-methoxycarbonylphenyl-D-glucoside tetraacetate was dissolved in 300 mL of an aqueous THF solution, 10 g of sodium hydroxide was added, and the mixture was stirred at room temperature for 2 hours. The mixture was neutralized with Amberlite IR120-B [H ⁺ ], then filtered off and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to obtain 14.4 g of the intended β-3-carboxyphenyl-D-glucoside.

(Comparative Example 1)
Arbutin (a compound represented by the following formula (II)) was used.

(Comparative Example 2)
Salicin (a compound represented by the following formula (III)) was used.

(Comparative Example 3)
Methyl glucoside (a compound represented by the following formula (IV)) was used.

(Comparative Example 4)
Benzylglucoside (a compound represented by the following formula (V)) was used.

  As is clear from the results of FIG. 1 and Table 3, both of the control example 1 in which no stimulant mitigating agent is blended and the comparative examples 1 to 4 in which other stimulating mitigating agents are blended have both the stimulus mitigating effect and long-term stability. However, in Examples 1 to 3, in which a glucose derivative was blended as a stimulus-relaxing agent, it was confirmed that both the stimulus-relaxing effect and the long-term stability were combined. That is, according to the present invention, it is possible to obtain a stimulating and moisturizing effect over a long period of time without affecting the function and form of the preparation.

(Control Example 2, Comparative Examples 5-8, Examples 4-6)
A sample (not prepared with a stimulant mitigating agent in the control example 2 sample (control)) was prepared by a conventional method with the composition shown in the following Tables 4 to 5 in which an irritation causing substance and an irritation mitigating agent were blended, and the above-described test method using this Based on the evaluation criteria, irritation relaxation and stability were evaluated. FIG. 2 shows the result of stimulus relaxation, and Table 6 shows the result of stability.

  In Tables 4 to 5, the test compounds (stimulation mitigating agents) used in Comparative Examples 5 to 8 are represented by the chemical formulas shown in the above formulas (II) to (V), respectively. In Examples 4 to 6, as in Examples 1 to 3, glucose derivatives represented by the above formulas (I-1-b), (I-2-b), and (I-3-b) were used.

  As is apparent from the results of FIG. 2 and Table 6, both of Control Example 2 in which no stimulant mitigating agent was blended and Comparative Examples 5 to 8 in which other stimulating mitigating agents were blended had both the stimulus mitigating effect and long-term stability. However, it was confirmed that Examples 4 to 6 in which a glucose derivative was blended as a stimulus relaxation agent had both a stimulus relaxation effect and a long-term stability. That is, according to the present invention, it is possible to obtain a stimulating and moisturizing effect over a long period of time without affecting the function and form of the preparation.

  The formulation example of the skin external preparation which mix | blended the irritation reducing agent of this invention is given to the following.

Example 7 Lipstick (combination component) (mass%)
Solid paraffin 8.0
Carnauba wax 2.0
Candelilla Row 4.0
Microcrystalline wax 6.0
Hydrogenated lanolin 15.0
Glyceryl diisostearate 30.0
4-Carboxyphenyl glucoside 1.0
Retinol 1.0
BHT 0.3
Formulated colorant (red) 7.0
Perfume appropriate amount Isopropyl palmitate Residue

Example 8 lotion (combination component) (mass%)
Retinol 0.0001
Oleyl alcohol 0.001
α-Tocopherol 0.005
POE (20) Octyldodecanol 0.8
Ethanol 8.0
4-Methoxyphenylglucoside 1.0
Methylparaben 0.15
Lactic acid 0.03
Sodium lactate 0.07
Purified water residue

Example 9 irinkle oil (combined component) (mass%)
Olive oil 40.0
2-Ethylhexanoic acid triglyceride 26.0
Squalane 30.0
3-Carboxyphenyl glucoside 1.0
δ-tocopherol 1.0
Retinol 0.1
Retinol palmitate 0.1

Example 10 Night cream (combination component) (mass%)
Squalane 15.0
Isopropyl myristate 5.0
Silicon dioxide 3.0
Vaseline 6.0
Glyceryl monoisostearate 2.0
POE (7) hydrogenated castor oil 1.5
Propylparaben 0.2
Retinol 0.4
4-Carboxyphenyl glucoside 1.5
Glycerin 17.0
Purified water residue

Example 11 Latex (combined component) (mass%)
(Phase A)
Squalane 5.0
Oleil Olate 3.0
Glycerin 2.0
Sorbitan sesquioleate 0.8
Polyoxyethylene oleyl ether (20EO) 1.2
Retinol 0.1
Cetyl octanoate 0.5
Fragrance 0.3
Methylparaben 0.2
(Phase B)
1,3 Butylene glycol 4.5
Ethanol 3.0
4-Methoxyphenylglucoside 1.0
Carboxyvinylpollimer 0.2
Potassium hydroxide 0.1
L-arginine L-aspartate 0.01
Turmeric extract (dry mass) 0.001
Sodium hexametaphosphate 0.05
4-Carboxyphenyl-D-glucoside 2.0
Purified water residue

Example 12 Eye cream (combination component) (mass%)
Glycerol 14.0
4-Methoxyphenylglucoside 1.5
Carboxyvinyl polymer 0.1
Polyoxybehenyl ether 1.0
Behenyl alcohol 4.0
Stearyl alcohol 2.0
Vaseline 5.0
Dimethicone 5.0
Retinol acetate 0.17
Tocopherol acetate 0.5
Evening primrose oil 0.2
Hyaluronic acid 0.1
MPC copolymer 3.0
Trimentilla extract 0.1
Magnesium ascorbate phosphate 0.1
Hydrolyzed eggshell membrane 0.1
Silica 3.0
Edetate 0.1
Paraben 0.2
Perfume 0.03
Ion exchange water

Example 13 Sunscreen (combination component) (mass%)
Octyl methoxycinnamate 7.5
3-Carboxyphenyl glucoside 2.0
t-Butylmethoxydibenzoylmethane 0.1
Titanium dioxide 5.0
Decamethylcyclopentasiloxane 30.0
POE / methylpolysiloxane copolymer 3.0
Organically modified montmorillonite 0.8
1,3-butylene glycol 5.0
Arbutin 5.0
Methylparaben 0.1
Perfume appropriate amount Purified water residue

Example 14 Cream (combination component) (mass%)
(Phase A)
Squalane 6.0
Vaseline 5.0
Stearyl alcohol 3.0
Stearic acid 3.0
Glyceryl monostearate 3.0
Polyethyl acrylate 1.0
t-Butylmethoxybenzoylmethane 7.5
Polyamide resin powder 5.0
Ethanol 40.0
Phenoxyethanol 0.3
Perfume proper amount (Phase B)
1,3-butylene glycol 7.0
4-Carboxyphenyl glucoside 1.5
Edetate trisodium 0.05
Cationic thickener 3.0
Lactic acid 0.6
Purified water residue (production method)
The ingredients of phase A are heated and melted and phase B is added with stirring. The mixture is processed with a homomixer to make the emulsified particles fine, and then rapidly cooled with stirring to obtain a cream.

Example 15 Lotion (combination component) (mass%)
(Phase A)
Octyl methoxycinnamate 2.0
POE (20) oleyl alcohol ether 0.5
Ethanol 60.0
Perfume appropriate amount Phenoxyethanol 0.3
(Phase B)
Sorbit 4.0
Dipropylene glycol 6.0
4-Methoxyphenylglucoside 1.0
Lactic acid 0.1
Citric acid 0.1
Sodium citrate 0.05
Hydroxymethoxybenzophenone Sodium sulfonate proper amount Trisodium edetate proper amount Purified water Residue (Production method)
Prepare Phase B. On the other hand, octyl methoxycinnamate, POE (20) oleyl alcohol ether, fragrance and preservative are dissolved in ethanol to prepare phase A. The A phase is added to the B phase to solubilize, and filtered to obtain a lotion.

Example 16 Emulsion (combined component) (mass%)
(Phase A)
Stearic acid 2.0
Cetyl alcohol 0.5
Liquid paraffin 10.0
Polyoxyethylene (10) oleate 1.0
Sorbitan triolate 1.0
Octyl methoxycinnamate 3.0
Isopropyl myristate 2.0
Silica 3.0
Isopropylphenol 0.2
Perfume proper amount (Phase B)
Dipropylene glycol 5.0
3-Carboxyphenyl glucoside 1.5
Triethanolamine 1.0
Hectorite 1.0
Citric acid 0.2
Ethanol 55.0
Purified water residue (production method)
Prepare Phase B and keep at 70 ° C. The components of phase A are mixed, heated and melted and kept at 70 ° C. Add phase A to phase B, uniformly emulsify with a homomixer, and cool rapidly with stirring to obtain an emulsion.

Example 17 Sunscreen Hair Gel (Compound Component) (mass%)
(Phase A)
Water-soluble polymer (“Carbopol 940”) 0.6
(Phase B)
Purified water residue 4-methoxyphenyl glucoside 1.0
(Phase C)
Triethanolamine 0.1
(Phase D)
Ethanol 14.0
Octyl methoxycinnamate 7.5
Methoxyethyl acrylate / hydroxyethyl acrylate / butyl acrylate copolymer 1.0
Polyethylene glycol 1.0
Dimethicone copolymer 4.0
Methylparaben 0.25
Propylparaben 0.05
Perfume appropriate amount (Manufacturing method)
A phase is stirred and dissolved in B phase, and after adding C phase, it disperses with a disperser. Add Phase D to this and stir to obtain the desired hair gel.

Example 18 Sunscreen Emulsification Foundation (Compound Component) (mass%)
(Phase A)
Purified water residue 4-methoxyphenyl glucoside 1.5
1,3-butylene glycol 5.0
Ethanol 7.0
(Phase B)
Talc 7.0
Titanium dioxide 10.0
Zinc oxide 2.0
Silica anhydride 2.0
Nylon powder 4.0
Color pigment 2.0
(Phase C)
Paramethoxycinnamate 15.0
Octamethylcyclotetrasiloxane 10.0
Rosin pentaerythlit ester 1.5
Neopentyl glycol diisooctanoate 5.0
Glycerin triisooctanoate 2.0
Polyoxyethylene-modified dimethylpolysiloxane 1.5
Trimethylsiloxysilicate resin 5.0
(Manufacturing method)
After stirring the A phase, the sufficiently mixed and ground B phase is added and homomixed. After dissolving phase C, a homomixer treatment is added thereto to obtain a sunscreen emulsified foundation.

Example 19 Sunscreen (combination component) (mass%)
Octyl methoxycinnamate 7.5
t-Butylmethoxydibenzoylmethane 0.1
Titanium dioxide 5.0
Decamethylcyclopentasiloxane 30.0
POE / methylpolysiloxane copolymer 3.0
Organically modified montmorillonite 0.8
4-Methoxyphenylglucoside 1.0
1,3-butylene glycol 5.0
Arbutin 5.0
Butylparaben 0.1
Perfume appropriate amount Purified water residue

Example 20 Cream (combination component) (mass%)
(Phase A)
Squalane 6.0
Vaseline 5.0
Stearyl alcohol 3.0
Stearic acid 3.0
Glyceryl monostearate 3.0
Polyethyl acrylate 1.0
t-Butylmethoxybenzoylmethane 7.5
Polyamide resin powder 5.0
Ethanol 40.0
Methylparaben 0.1
Ethylparaben 0.05
Perfume proper amount (Phase B)
1,3-butylene glycol 7.0
3-Carboxyphenyl glucoside 1.0
Edetate trisodium 0.05
Cationic thickener 3.0
Lactic acid 0.6
Purified water residue (production method)
The components of phase A are heated and melted, and phase B is added with stirring. The mixture is processed with a homomixer to make the emulsified particles fine, and then rapidly cooled with stirring to obtain a cream.

Example 21 lotion (combination component) (mass%)
(Phase A)
Octyl methoxycinnamate 2.0
POE (20) oleyl alcohol ether 0.5
Ethanol 60.0
Perfume Amount Methylparaben 0.05
(Phase B)
Sorbit 4.0
Dipropylene glycol 6.0
4-Methoxyphenylglucoside 2.0
Lactic acid 0.1
Citric acid 0.1
Sodium citrate 0.05
Hydroxymethoxybenzophenone Sodium sulfonate proper amount Trisodium edetate proper amount Purified water Residue (Production method)
Prepare Phase B. On the other hand, octyl methoxycinnamate, POE (20) oleyl alcohol ether, fragrance and preservative are dissolved in ethanol to prepare phase A. The A phase is added to the B phase to solubilize, and filtered to obtain a lotion.

Example 22 Latex (combined component) (mass%)
(Phase A)
Stearic acid 2.0
Cetyl alcohol 0.5
Liquid paraffin 10.0
Polyoxyethylene (10) oleate 1.0
Sorbitan triolate 1.0
Octyl methoxycinnamate 3.0
Isopropyl myristate 2.0
Silica 3.0
Phenoxyethanol 0.5
Perfume proper amount (Phase B)
Dipropylene glycol 5.0
4-Methoxyphenylglucoside 5.0
Triethanolamine 1.0
Hectorite 1.0
Citric acid 0.2
Ethanol 55.0
Purified water residue (production method)
Prepare Phase B and keep at 70 ° C. The components of phase A are mixed, heated and melted and kept at 70 ° C. Add phase A to phase B, uniformly emulsify with a homomixer, and cool rapidly with stirring to obtain an emulsion.

Example 23 Sunscreen Hair Gel (Compound Component) (mass%)
(Phase A)
Water-soluble polymer (“Carbopol 940”) 0.6
(Phase B)
Purified water residue 4-methoxyphenyl glucoside 1.5
(Phase C)
Triethanolamine 0.1
(Phase D)
Ethanol 14.0
Octyl methoxycinnamate 7.5
Polybutylene glycol 4800 4.0
Methoxyethyl acrylate / hydroxyethyl acrylate / butyl acrylate copolymer 1.0
Polyethylene glycol 1.0
Dimethicone copolymer 4.0
Methylparaben 0.25
Propylparaben 0.05
Perfume appropriate amount (Manufacturing method)
A phase is stirred and dissolved in B phase, and after adding C phase, it disperses with a disperser. Add Phase D to this and stir to obtain the desired hair gel.

Example 24 Sunscreen Emulsification Foundation (Compound Component) (mass%)
(Phase A)
Purified water residue 3-Carboxyphenyl glucoside 1.0
1,3-butylene glycol 5.0
Ethanol 7.0
(Phase B)
Talc 7.0
Titanium dioxide 10.0
Zinc oxide 2.0
Silica anhydride 2.0
Nylon powder 4.0
Color pigment 2.0
(Phase C)
Paramethoxycinnamate 15.0
Octamethylcyclotetrasiloxane 10.0
Rosin pentaerythlit ester 1.5
Neopentyl glycol diisooctanoate 5.0
Glycerin triisooctanoate 2.0
Polyoxyethylene-modified dimethylpolysiloxane 1.5
Trimethylsiloxysilicate resin 5.0
(Manufacturing method)
After stirring the A phase, the sufficiently mixed and ground B phase is added and homomixed. After dissolving phase C, a homomixer treatment is added thereto to obtain a sunscreen emulsified foundation.

It is a graph which shows the irritation | stimulation relaxation effect in the comparative example 1, Comparative Examples 1-4, and Examples 1-3. It is a graph which shows the irritation | stimulation relaxation effect in the control example 2, Comparative Examples 5-8, and Examples 4-6.

Claims (6)

  An irritation reducing agent comprising a glucose derivative. The glucose derivative is represented by the following general formula (I)

(In the formula, R represents 4-methoxyphenol, 4-carboxyphenol, 3-carboxyphenol residue)
The irritation reducing agent of Claim 1 which is a compound represented by these.   The skin external preparation containing the irritation reducing agent of Claim 1 or 2.   The external preparation for skin according to claim 3, wherein the external preparation for skin further contains a substance that causes irritation to the skin.   The skin external preparation according to claim 4, wherein the substance that causes irritation to the skin is a fat-soluble drug component.   The skin external preparation according to claim 5, wherein the fat-soluble drug component is one or more selected from retinol and derivatives thereof, ultraviolet absorbers and preservatives.

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