JP2011195494A - Composition containing proton pump inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition which is suitable for cosmetics (quasi drugs), foods and the like, and is used for preventing or improving pigmentation.SOLUTION: The composition is characterized by containing (1) a proton pump inhibitor and (2) an anti-inflammatory ingredient, and the composition is characterized by further containing a compound represented by general formula (wherein, Ris a 1 to 8C alkyl which may have a branched structure or a ring structure) and/or a pharmacologically acceptable salt thereof.

Description

The present invention relates to a composition comprising 1) a proton pump inhibitor and 2) an anti-inflammatory component, and more particularly to a skin external preparation suitable for preventing or improving pigmentation.

  Keeping the beauty of the skin beautiful against the deterioration of skin symptoms such as spots, wrinkles and sagging caused by factors such as aging, stress, and UV exposure is a very important concern for women. Various researches have been conducted to find a means for preventing or improving the deterioration of skin symptoms. In particular, it is known that stains, buckwheat, and pigmentation after sunburn occur due to markedly enhanced melanin production due to activation of pigment cells (melanocytes) present in the skin. In order to prevent or ameliorate these skin pigment-related problems, an external preparation for skin containing whitening ingredients such as ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone, arbutin, or catechol has been developed. (For example, see Non-Patent Document 1 and Non-Patent Document 2). However, although a certain whitening effect is recognized in these skin whitening agents containing these whitening components, none of them achieves a satisfactory whitening effect, and there are problems in terms of stability or safety. Some of them were there.

Examples of the mechanism of action of the component having the whitening action include tyrosinase inhibitors including catechols such as arbutin (for example, see Non-patent Document 3) and 4-n-butylresorcinol (for example, And non-patent document 3), tyrosinase expression inhibitor (for example, refer to Patent Document 1) by tyrosinase mRNA expression inhibitory action, tyrosinase enzyme degradation accelerator (for example, refer to Patent Document 2), etc. Is widely used. Further, by blending a plurality of the above-mentioned whitening agents (for example, see Patent Document 3), and further by combining the whitening agent with other active ingredients such as antioxidants (for example, see Patent Document 4). There are many attempts to enhance the whitening effect. However, in many cases, such a skin external preparation containing a plurality of whitening ingredients or other active ingredients does not have the expected enhancement of the whitening effect or has been confirmed to have the effect of enhancing the whitening effect. However, there is no certain result such as an additive effect or a synergistic effect, and the cause is not known at all. This is thought to be due in part to the fact that the mechanism of melanin production suppression is complex and not fully understood. For this reason, attention is focused on whitening ingredients having a new mechanism of action, and it is also expected to enhance the whitening effect by combining these ingredients having a new mechanism of action with existing whitening agents and other active ingredients. Has been sent.

The proton pump inhibitor is a proton pump that exists on a biological membrane, specifically, membrane ATPase (membrane H ⁺ -ATPase), which is a membrane protein that actively transports protons, and Na ⁺ / K ⁺ −. It plays a role in regulating proton concentration in cells or organelles by acting on Na ⁺ / H ⁺ exchange transport protein (NHE) etc. that works in conjunction with ATPase and passively transports protons (eg, non-patented) (Ref. 4). Furthermore, changes in proton concentration in cells or organelles greatly affect the functions and activities of various biomolecules that control biological functions (see, for example, Non-Patent Document 5). For this reason, biofunctional molecules that regulate proton concentration such as membrane H ⁺ -ATPase and Na ⁺ / H ⁺ exchange transport protein (NHE) involve various biofunctional molecules whose functions and activities are greatly affected by proton concentration. As a drug discovery target molecule for prophylactic or therapeutic drugs such as essential hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes, organ damage due to ischemia or ischemic reperfusion, cerebral ischemic damage, etc. Yes. On the other hand, in the skin, tyrosinase is a pH-dependent enzyme whose activity is adjusted by the proton concentration (pH) in cells or organelles. By bringing the inside of melanocytes close to neutrality, enzyme activity and melanin are obtained. It has been reported that the amount is affected (see, for example, Non-Patent Document 6). However, there is no known component that can be applied to cosmetics, which has a proton pump inhibitory action that adjusts the proton concentration in cells and organelles, and the whitening ingredient of cosmetics has such a proton pump inhibitory action. Nothing is known about the machine. Furthermore, a proton pump inhibitor that regulates proton concentration in cells or organelles induces acidification in melanocytes and reduces tyrosinase activity, thereby suppressing melanin production, including whitening. It was not known at all to be effective for skin pigment abnormality-related diseases.

In this situation, the present inventors have found that a plant extract having a proton pump inhibitory action has a melanin production inhibitory action. That is, according to the “proton pump inhibitor” (Japanese Patent Application No. 2009-050226, Japanese Patent Application No. 2009-219292) filed by the present applicant, the leguminous genus Hagi genus, Lamiaceae genus Tachycaria genus, leguminous genus Clara genus, ginger genus A plant extract obtained from a plant belonging to the genus Ginger, Araceae, Azalea, Uchinosidae, Hydrangea and Sarnococcidae Matsuhodo nuclei has a proton pump inhibitory action and a melanin production inhibitory action. It has been found that an external preparation for skin containing the extract obtained is more effective for the prevention or treatment of pigmented diseases such as whitening. In addition to being useful as a whitening agent having a new mechanism of action, such a proton pump inhibitor can be expected to enhance the whitening effect when combined with active ingredients such as antioxidants and anti-inflammatory agents. .

  On the other hand, glycyrrhetinic acid derivatives classified as an anti-inflammatory agent are perennial plants of the leguminous family that grow naturally in Eurasia such as southern Siberia, western China, South Korea, Japan, and Eastern Europe. As an anti-inflammatory analgesic, it is used for the treatment of allergic rhinitis, rhinitis and gastric ulcer. In licorice, there are subspecies such as Ural licorice, Siberian licorice and wild licorice, all of which contain glycyrrhetinic acids. In this invention, the glycyrrhetic acid derivative obtained by refine | purifying from what has become wild and grew naturally in Japan is used. The biological activity possessed by the glycyrrhetinic acid derivative includes an anti-inflammatory action, an antiviral action (see, for example, Patent Document 5), a melanin production inhibitory action (see, for example, Patent Document 6), and a rough skin improving action (for example, a patent). Reference 7) is known, and its application to cosmetics utilizing these activities is being made. However, cosmetics containing these compounds are not sufficiently satisfactory in whitening or roughening, and have problems in stability and safety. For this reason, pharmaceutical technology for efficiently utilizing the biological activity possessed by glycyrrhetinic acid derivatives, and formulation technology that ensures high efficacy and safety by combining with a whitening component having a new mechanism of action are desired. It is rare.

In addition, as described above, many attempts have been made to enhance the whitening effect by combining an existing component having a whitening effect and an active ingredient. In such attempts, when an existing whitening agent and anti-inflammatory agent are combined in a topical skin preparation, there is no effect of the combination, an additive effect, or a synergistic effect. There is no constant result, and the cause is not known at all. In addition, for a combined preparation of a substance having a proton pump inhibitory action and glycyrrhetinic acids, there are a few known orally administered drugs for the treatment of gastric ulcers and the like (see, for example, Patent Document 8), There is no known topical skin preparation. Therefore, a substance having a proton pump inhibitory action, which is a novel whitening mechanism, is not only expected as a new whitening agent, but also has a different action mechanism even when combined with a conventionally known anti-inflammatory agent or the like. Through the introduction, an additive or synergistic effect enhancement is expected.

JP 2004-352647 A JP-A-06-100451 JP 2007-320851 A Japanese Patent Laid-Open No. 2004-083503 Japanese Patent Laid-Open No. 06-345748 JP 2004-300048 A JP-A-06-305932 JP 2003-206238 A

Supervised by Katsuyuki Takeda et al., “Usefulness of cosmetics, evaluation technology and future prospects”, published by Yakuji Nippo (2001) Control of melanin pigment and development of whitening agent, Fragrance Journal, No14 (1995) Pharmaceutical Journal, 112 (4), 276-282 (1992) Protein, Nucleic Acid, Enzyme, 34 (10), 1251 (1989) Smith, D. R .; Spaulding, D. T .; Glenn, H. M .; Fuller, B. B., Exp. Cell. Res., 2004, 298, 521-534. Janis Ancans et. Al., Experimental Cell Research, 268, 26-35 (2001)

  The present invention has been made under such circumstances, and provides a means for preventing the occurrence of pigmentation or a means for more effectively improving the pigmentation already formed.

In view of such circumstances, the present inventors have intensively studied and sought for a technique for preventing and improving pigmentation caused by ultraviolet irradiation, and as a result, 1) a proton pump inhibitor, 2) The present inventors have found that a composition containing an inflammatory component is excellent in these effects, and have completed the present invention. The present invention is as follows.
<1> A composition comprising 1) a proton pump inhibitor and 2) an anti-inflammatory component.
<2> The anti-inflammatory component is an extract obtained from a plant belonging to the genus Asteraceae, an extract obtained from a plant belonging to the genus Leguminosae, an extract obtained from a plant belonging to the genus Birchaceae, walnut family An extract obtained from a plant belonging to the above, a glycyrrhetinic acid derivative and a pharmacologically acceptable salt thereof, a grabridine derivative and a pharmacologically acceptable salt thereof, The composition according to <1>.
<3> Plants belonging to the genus Asteraceae, plants belonging to the genus Leguminosae, plants belonging to the genus Birchaceae, plants belonging to the walnut family, asteraceae The composition according to <1> or <2>, wherein the composition is a genus birch or walnut family Kouki.
<4> The glycyrrhetinic acid derivative is glycyrrhetinic acid and / or a pharmacologically acceptable salt thereof, alkyl glycyrrhetic acid and / or a pharmacologically acceptable salt thereof, and glycyrrhizic acid and a pharmacological thereof. <1> or <2>, wherein the composition is an acceptable salt.
<5> The glycyrrhetinic acid and its pharmacologically acceptable salt are stearyl glycyrrhetinate and / or its pharmacologically acceptable salt, and the glycyrrhizic acid and its salt are dipotassium glycyrrhizinate. <1>, <2> or <4>, wherein the composition is characterized by the above.
<6> The composition according to any one of <1> to <5>, wherein the proton pump inhibitor is obtained by extracting a plant body.
<7> The composition according to any one of <1> to <6>, wherein the plant extract having a proton pump inhibitory action is an extract of a plant listed below.
(Plant) Lamiaceae, Papaveraceae, Leguminous, Clara, Ginger, Ginger, Urochiaceae, Hachima, Yukinosida Hydrangea, Sarnokoshi, Matsuhodo Nucleus <8> Plants belonging to the genus Clara, Ginger family Ginger, Araceae department Ginger, Uridae family Hachima, Yukinosita family Hydrangea, Sarnosidaceae family Matsuhodo nuclei, Lamiaceae <1> to <7>, characterized in that it is a genus ginger, taro genus shobu, cucurbitaceae genus loofah, saxifrage family hydrangea amacha, sarnococcidae matsuhodo nuclei Composition.
<9> The composition according to any one of <1> to <8>, wherein the proton pump inhibitor has an action of acidifying melanocytes in melanocytes.
<10> The composition according to any one of <1> to <9>, wherein the plant extract having a proton pump inhibitory action acts on a Na ⁺ / H ⁺ exchange transport system.
<11> The composition according to any one of <1> to <10>, wherein the anti-inflammatory component is contained in an amount of 0.00001% by mass to 3% by mass with respect to the total amount of the composition.
<12> The plant extract having a proton pump inhibitory action is contained in an amount of 0.00001% by mass to 10% by mass with respect to the total amount of the composition, according to any one of <1> to <11> The composition as described.
<13> The compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof, wherein any one of <1> to <12> A composition according to 1.

（１）
[式中、R１は、分岐構造又は環構造を有していてもよい炭素数１〜８のアルキル基を表す]

(1)
[Wherein R 1 represents an alkyl group having 1 to 8 carbon atoms which may have a branched structure or a ring structure]

<14> The compound represented by the general formula (1) is 4-n-butylresorcinol and / or a pharmacologically acceptable salt thereof, <1> to <13> The composition according to any one of the above.
<15> The composition according to any one of <1> to <14>, further comprising a component preferable as a cosmetic.
<16> The composition according to any one of <1> to <15>, which is a cosmetic (including a quasi-drug).
<17> The composition according to any one of <1> to <16>, which is a skin external preparation.
<18> The external preparation for skin according to <17>, which is in the form of a water-in-oil emulsifier.
<19> The external preparation for skin according to <17> or <18>, which is for preventing pigmentation.
<20> The external preparation for skin according to <17> to <19>, which is used immediately after exposure to ultraviolet rays.
<21> A skin external preparation containing 1) a glycyrrhetinic acid derivative and / or a pharmacologically acceptable salt thereof, and 2) a proton pump inhibitor.

According to the present invention, it is possible to provide means for preventing or improving the occurrence of pigmentation after exposure to ultraviolet rays.

It is a figure which shows the examination result of the acidification (proton pump inhibitory effect) in the melanocyte of the plant extract of this invention.

<Proton pump inhibitor of the present invention>
The composition of the present invention comprises 1) a proton pump inhibitor and 2) an anti-inflammatory component. The proton pump inhibitor of the present invention includes a proton in a cell or organelle by directly or indirectly acting on a biological functional molecule involved in the regulation of proton concentration (pH) in the cell or organelle. It means a substance that adjusts the concentration (pH), and any substance having the proton pump inhibitory action can be applied without particular limitation. Specific examples of preferred proton pump inhibitors of the present invention include F-type ATPase groups present in the inner mitochondrial membrane, V-type ATPase groups present in cell membranes such as intracellular vacuoles, and plasma membranes. not play an active proton transport, such as P-type ATPase group present membrane H ⁺ -ATPase only, Na ^{+ /} K ⁺ ion pump and a conjugated manner works such -ATPase passively Na transport protons ⁺ / The component which acts on H ⁺ exchange transporter etc. and has the effect | action which adjusts a proton concentration can be illustrated suitably. Among the proton pump inhibitors of the present invention, more preferable examples include substances having an acidifying action in melanocytes in the “examination of melanocyte acidification (proton pump inhibitory action)” described later. The substance having an acidifying action in the melanocyte of the present invention means a substance in which the enhancement of the coloring intensity of the pH sensitive fluorescent dye is observed by visual observation with a fluorescence microscope.

The proton pump inhibitor of the present invention means simple chemical substances, herbal medicines and extracts from animals and plants, and these components can contain only one kind or contain two or more kinds in combination. You can also. Here, the extract of the present invention means a general term for the extract itself, the fraction of the extract, the purified fraction, the extract or fraction, and the solvent-removed product of the purified product. Among these components, preferred examples of the chemical substance include omeprazole, lansoprazole, rabeprazole and / or pharmacologically acceptable salts thereof. Among these components, extracts obtained from herbal medicines and animals and plants include extracts obtained from plants belonging to the genus Lamiaceae, Leguminosae, based on the results of the study by the present inventors using the above method. An extract obtained from a plant belonging to the genus Clara, an extract obtained from a plant belonging to the genus Gingeraceae, an extract obtained from a plant belonging to the genus Araceae, an extract obtained from a plant belonging to the genus Cucurbitaceae, An extract obtained from a plant belonging to the genus Hydrangeaceae hydrangea, an extract obtained from the sorghum pine fungus nucleus, and the like can be preferably exemplified, and more preferably, Lamiaceae, Papaveraceae, Thymeaceae, Clara, Ginger, Ginger Ginger, taro genus genus genus, cucurbitaceae genus genus genus, saxifragaceae hydrangea genus Such as Runokoshikake Department Wolfiporia Extensa sclerotia Bukuryou it is suitably be exemplified. As a plant part used for preparation of the extract of such a plant, a plant body, an above-ground part, or a tree trunk part can be illustrated suitably. Such Lamiaceae genus Thymus is an evergreen small shrub native to Southern Europe and is native to the sub-alpine to alpine areas throughout Japan and is widely used as a spice for foods and the like. The Clariaceae Clara genus Clara is a perennial plant native to China and grows naturally in the sunny grasslands of Honshu, Shikoku and Kyushu. The root is a herb medicine “kujin”, which has effects such as healthy stomach and anti-inflammation. Ginger (Ginger) is a bulbous perennial plant native to tropical Asia. In Japan, it grows naturally in parts of Kyushu and Okinawa and is used as food. The Aceraceae is an evergreen perennial plant that is widely distributed from East Asia to all over Japan. The Cucurbitaceae genus Loma is a plant that originated in India and is said to have come to Japan via China, and is now cultivated in the south of central Honshu. The genus Hydrangea genus Achacha is a deciduous small shrub native to Japan and is cultivated in Honshu, Shikoku and Kyushu. The Sarcophagaceae matsuhodo fungus nuclei is a fungus native to East Asia and is native to China, Korea, Japan, and other countries. The extract obtained from the above-mentioned plant in the present invention can be prepared using a plant grown in Japan or a Japanese product sold as a herbal medicine raw material, Maruzen Co., Ltd., etc. It is also possible to purchase and use a commercial extract sold by a company that handles plant extracts. In the extraction, the plant body, the above-ground part, the tree trunk part, or the rhizome part is preferably processed in advance so as to improve the extraction efficiency by pulverization or chopping. The extract is 1 to 30 parts by mass of solvent with respect to 1 mass of plant body, above-ground part, tree trunk or rhizome part or its dried product, and if it is room temperature, it is several days, and if it is a temperature near the boiling point, it is several. Immerse for hours. After the immersion, the solution can be cooled to room temperature, insoluble matter can be removed if desired, and then the solvent can be removed by concentration under reduced pressure. Thereafter, fractionation and purification can be performed by column chromatography packed with silica gel or an ion exchange resin to obtain a desired extract.

  The extraction solvent is preferably a polar solvent, and alcohols such as water, ethanol, isopropyl alcohol, and butanol, and polyvalent alcohols such as 1,3-butanediol and polypropylene glycol. One or two or more selected from ketones such as alcohols, acetone and methyl ethyl ketone, and ethers such as diethyl ether and tetrahydrofuran can be preferably exemplified.

Further, the proton pump inhibitor of the present invention inhibits proton pump (membrane H ⁺ -ATPase) present in biological membranes, or Na ⁺ / H that works in combination with Na ⁺ / K ⁺ -ATPase that is an ion pump. ⁺ Acts on the exchange transport system and the like, and excels in acidifying action (proton pump inhibitory action) in cells or organelles by inhibiting proton transport in cells or organelles. Acidification in a cell or organelle affects the biological activity of pH-dependent functional molecules (eg, enzymes, ion channels, etc.) present in the cell. Acidification in cells or organelles reduces the enzyme activity of tyrosinase, one of the pH-dependent functional molecules, suppresses melanin production, and skin pigment abnormality related diseases such as whitening The prevention or improvement effect is expected. Such components include proton pump (membrane H ⁺ -ATPase) inhibitory action existing in biological membranes or protons such as Na ⁺ / H ⁺ exchange transport system that works in combination with Na ⁺ / K ⁺ -ATPase that is an ion pump. Acts on biomolecules responsible for transport, inhibits proton transport, induces acidification in cells or organelles, etc., has excellent accumulation and selectivity at the target site, high safety and stability Therefore, it is preferably used for medicines, foods, cosmetics and the like. In addition, such a component is combined with an anti-inflammatory agent and, further, a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof to prevent pigmentation. Or an improvement effect is shown. This is because the melanin production inhibitory action by the proton pump inhibitory action of such components is caused by the direct inhibitory action of the anti-inflammatory agent or the tyrosinase enzyme possessed by the compound represented by the general formula (1). Since the mechanism of action is different from the inhibitory action, the action works without interfering with each other, and thus exhibits a synergistic melanin production inhibitory action.

The content of the proton pump inhibitor in the composition of the present invention is 0.00001% by mass to 10% by mass, more preferably 0.0001% by mass to 5% by mass, and still more preferably 0.000% by mass to the total amount of the composition. It is more preferable to make it contain 001-3 mass%. This is because if the content of the proton pump inhibitor is too small, the melanin production inhibitory action through the proton pump inhibitory action (acidification action) in cells or organelles will not be achieved. In addition, there are cases where there is no combination effect with the compound represented by the general formula (1), and even if it is too much, there are cases where the effect reaches a peak and the degree of freedom of this system is impaired. . In addition, since such components have high selectivity and accumulation with respect to target molecules in cells or organelles, high safety is expected. For this reason, use for medicine, food, cosmetics and the like is preferable. Furthermore, in the external preparation for skin of the present invention, even when a proton pump inhibitor, especially, the above-mentioned plant extract is formulated for the purpose other than the proton pump inhibitory action such as moisturizing, the extract is used. In the case of having a proton pump inhibitory action, the structure and effect of the present invention are satisfied, and therefore it belongs to the technical scope of the present invention.

<Production Example 1: Method for producing plant extract having proton pump inhibitory action in the present invention>
The manufacturing method of the plant extract (plant extract obtained from the ginger family ginger genus ginger (ginger)) which has the proton pump inhibitory action of this invention is shown below. This extract was produced by immersing the rhizome of ginger Zingiber officinale Roscoe (Zingiberaceae) in ethanol. Specifically, about 600 mL of diluted ethanol (37-50%) is added to 200 g of ginger ginger (ginger), and left to stand until the soluble components are sufficiently dissolved. Wash the cloth, wash the residue with a small amount of diluted ethanol (37-50%), squeeze, combine the leachate and washings, leave for 2 days, filter, and further dilute ethanol (37 ˜50%) was added to produce a total volume of 1000 mL of this extract.

  The plant extract having a proton pump inhibitory action of the present invention can be produced according to the production example of the plant extract obtained from the above-mentioned Ginger family ginger (Ginger), Maruzen Co., Ltd., Ichimaru Falcos Co., Ltd. Extracts marketed by companies can be purchased and used.

<Test Example 1: Examination of acidification (proton pump inhibitory action) in melanocytes using the plant extract of the present invention>
Regarding the plant extract of the present invention, live cell acidification (proton pump inhibitory action) was detected according to the following procedure. Normal human melanocytes (Kurabo Co., Ltd.) are seeded in a 4-well Lab-Tek chamber slide (Thormo Fisher Scientific) at 10000 cells / cm ^2, and the next day, the medium containing the evaluation substance is replaced with 0.5 mL / well and incubated for 30 minutes. did. A sample containing no evaluation substance as a control was prepared in the same manner as described above. Thereafter, Lysosensor 189 (Molecular Probes: final concentration 1 μM) was added and incubated for 15 minutes. After completion of the culture, the cells were washed with PBS and fixed with 4% paraformaldehyde for 15 minutes at room temperature. Thereafter, the sample was sealed with a slide glass and observed with a fluorescence microscope (Karlzeitz). In the present invention, a substance having a proton pump inhibitory action means that the color intensity of a pH-sensitive fluorescent dye is visually observed with a fluorescence microscope in the detection of acidification (proton pump inhibitory action) in melanocytes using human normal melanocytes. It means a case where an increase in emission intensity is observed by observation. The results are shown in FIG.

If the fluorescence intensity (green) of Lysosensor 189 is enhanced by the evaluation substance treatment as compared to the control of the evaluation substance non-treatment, it is considered that the acidification in normal human melanocytes is enhanced.

In FIG. 1, the fluorescent color intensity indicating the acidification degree is weak in the control. On the other hand, when the plant extract of the present invention is treated, the fluorescence intensity is enhanced. Therefore, it was found that the plant extract of the present invention has a remarkable acidifying action (proton pump inhibitory action) in melanocytes.

<Test Example 2: Melanin production inhibitory action evaluation of plant extract of the present invention>
Using the plant extract of the present invention, the melanin production inhibitory action was evaluated according to the method described below. 22500 (cells / cm ² ) of normal human melanocytes (Kurabo Co., Ltd.) are seeded in a 24-well plate. The next day, the medium was replaced with a medium 0.5 containing evaluated substances (mL / well), to continue adding cultured ^{0.25 (μCi) 2- [2- 14} C] thiouracil (GE Healthcare Bio-Sciences) . Four days after seeding, the medium was removed, and the plate was washed once with PBS. Then, in order to evaluate cell viability, the medium was replaced with a medium to which a viable cell count reagent SF (Nacalai Tesque) was added, The color reaction was carried out for 3 hours. After the reaction, the absorbance at 450 (nm) was measured using a microplate reader Benchmark Plus (Bio-Rad Laboratories). A sample containing no evaluation substance as a control was prepared in the same manner as described above, and the percentage of absorbance of the sample containing each evaluation substance relative to the control was determined to obtain the cell viability. After measuring the absorbance to measure the amount of melanin, the plate was washed once with PBS, TCA was added, the cells were lysed, distilled water was added, and the solution was transferred to a vial. After leaving it on ice, it was centrifuged at 15000 rpm for 5 minutes, and then the supernatant was removed. Again, 10% TCA 500 (μL) was added to each vial and left on ice for 15 minutes. After centrifugation at 15000 rpm for 5 minutes, the supernatant was removed. Aquazol-2 (Perkin Elmer) 1 (mL) was added to the residue, and the radiation dose was measured with a liquid scintillation counter LSC-6100 (Aloka). A sample containing no evaluation substance as a control was prepared in the same manner as described above, and the percentage of the radiation dose of the sample containing the evaluation substance relative to the control was determined and used as the melanin amount (%). The 50% inhibitory concentration (IC ₅₀ value) of melanin production was calculated using SAS software version 9.1.3 (SAS Institute Inc.) within the range where cytotoxicity was not observed. In the present invention, the substance having an inhibitory action on melanin production refers to an evaluation of the inhibitory action on melanin production using the normal human melanocytes, wherein the amount of melanin produced is 50% or less compared to control at a concentration where cytotoxicity is not observed. It means a case where it has an action of lowering the level. This is because when a substance having a low melanin production inhibitory effect is blended, the expected melanin production inhibitory effect does not appear. The results are shown in Table 1.

  From the results in Table 1, the positive control hydroquinone exhibited a melanin production inhibitory action, confirming the objectivity of this evaluation system. It was found that all the plant extracts of the present invention have a remarkable melanin production inhibitory action.

From the results shown in FIG. 1, it was found that the plant extract of the present invention showed a remarkable acidifying action (proton pump inhibitory action) in melanocytes. In addition, based on the results of FIG. 1 and Table 1, as an alternative value of the melanin production suppression action of the mechanism that inhibits tyrosinase activity in melanocytes by acidification in melanocytes via proton pump inhibition action, It can also be seen that the acidification action within this melasite can be used. The component having such an action is regarded as a melanin production inhibitor whose mechanism is a proton pump inhibitory action. In the composition of the present invention, a proton pump inhibitor is used with a melanin production inhibitor whose mechanism is such a proton pump inhibitory action. Treat as an agent. This is because acidifying the pH in such melanocytes and reducing the tyrosinase activity are related to the effect of the present invention.

<Anti-inflammatory component of the present invention>
The composition of the present invention comprises 1) a proton pump inhibitor and 2) an anti-inflammatory component. As the anti-inflammatory component of the present invention, any substance having an anti-inflammatory action can be applied without any particular limitation. For example, an extract of the asteraceae chamomile genus chamomile (chamomile), an extract of asteraceae burdock burdock, Anti-inflammation such as clarinon, glabrizine, glycyrrhizic acid, glycyrrhetinic acid, etc. in addition to plant extracts with anti-inflammatory activity such as birch extract, birch extract, walnut extract, legume extract Principal components contained in the plant extract can be exemplified preferably, more preferably a plant extract obtained from the asteraceae burdock burdock, a plant extract obtained from the leguminous clara genus kudin, obtained from the birch family birch genus birch Selected from plant extracts obtained from walnuts, glycyrrhetinic acid derivatives and derivatives thereof It shall have be preferably exemplified, more preferably, glycyrrhizic acid and salts thereof, glycyrrhetinic acid alkyl and its salts, and, glycyrrhetinic acid and salts thereof suitably be exemplified. The plant extract having an anti-inflammatory action of the present invention is added with 1 to 20 times the amount of a plant or a processed product thereof using a lower alcohol such as water or ethanol as a solvent, and if necessary, stirring is appropriately added. After immersion for several days at room temperature or several hours at a temperature near the boiling point, the insoluble matter is removed by filtration or the like, and then the solvent is removed by distillation under reduced pressure or the like. Etc. can be purified and fractionated by column chromatography or the like using them as a carrier. Preferable plant parts for preparing a plant extract include flower buds for Compositae chamomile chamomile, roots for Compositae burdock, root stem for leguminous clams, and birch, birch birch. In the case of the genus birch, the bark, in the case of the walnut family, the leaf part, and in the case of the legume licorice, the rhizome is preferably exemplified. Glycyrrhetinic acid derivatives such as glycyrrhizic acid and its salts, alkyl glycyrrhetinic acid and its salts, glycyrrhizic acid and its salts have melanin production inhibitory action, moisturizing action and the like in addition to anti-inflammatory action. The present invention has an excellent inhibitory effect on pigmentation caused by exposure to ultraviolet rays. However, when an external preparation for skin is used for such applications, there is a high possibility of causing inflammation due to exposure to ultraviolet rays. The reaction and the various skin reactions that accompany it enhance melanin production. Therefore, by containing a component having such an anti-inflammatory action, the inflammation subsides or further inflammation is suppressed, and an increase in the amount of transdermal water transpiration is suppressed. That is, the appearance of rough skin after inflammation is also suppressed. In addition, the pigmentation can be prevented from becoming serious.

  The glycyrrhetinic acid derivative is a known ingredient as an quasi-drug active ingredient. Examples of alkyl glycyrrhetinate and / or pharmacologically acceptable salts thereof include stearyl glycyrrhetinate and lauryl glycyrrhetinate. And / or pharmacologically acceptable salts thereof, and the like. Glycyrrhizic acid and / or a salt thereof can be preferably exemplified by glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate and the like. Stearyl glycyrrhizinate and dipotassium glycyrrhizinate are preferred. This is because it is already known that there are many examples of use and high safety. The preferable content of such components is 0.00001% by mass to 3% by mass, more preferably 0.0001% by mass to 2% by mass, and still more preferably 0.001-1% with respect to the total amount of the external preparation for skin. % By mass. This is because if the amount is too small, the above-described effect may not be achieved, and if the amount is too large, the effect may reach its peak and the degree of freedom of the system may be impaired. Such an ingredient exhibits an anti-inflammatory action, a melanin production inhibitory action, a rough skin improving action, etc. on the skin. In the composition of the present invention, the above-described proton pump inhibitor, and further the general formula (1) ) And / or their pharmacologically acceptable salts, it has an excellent effect on the prevention or improvement of pigmentation (stains, buckwheat, dark black, etc.) that occurs after exposure to ultraviolet rays.

Such an ingredient exhibits an anti-inflammatory action, a melanin production inhibitory action, a rough skin improving action, etc. on the skin, but in the composition of the present invention, it works together with the proton pump inhibitor and is a pigment produced by exposure to ultraviolet rays. It has an excellent effect on prevention or improvement of deposition (stain, buckwheat, dark black, etc.). When these ingredients are contained together with a proton pump inhibitor, when administered as a skin external preparation against skin inflammation such as immediately after sunburn, the inflammation is suppressed more quickly, and the skin barrier function is restored. As a result, the melanin production inhibitory effect of the external preparation for skin of the present invention is also improved. That is, the external preparation for skin of such a form is preferable as an external preparation for preventing pigmentation caused by ultraviolet rays even when the skin is inflamed.

<Composition of the present invention>
The composition of the present invention comprises 1) a proton pump inhibitor and 2) an anti-inflammatory agent as essential components. In preparing the composition containing the essential ingredients, in addition to the essential ingredients, optional ingredients that are usually used in the preparation of pharmaceuticals, cosmetics, foods, and beverages can be contained. Moreover, as an administration route of the composition of the present invention, either oral administration or transdermal administration is possible. Moreover, when such a component is continuously administered, and further considering safety, it is preferably administered transdermally. As long as it is administered transcutaneously, it can be applied without any particular limitation. For example, cosmetics including quasi-drugs, external medicines for skin, sundry goods and the like can be preferably exemplified. This is because the external preparation for skin of the present invention has an unparalleled feeling of use and is particularly suitable for cosmetics where the feeling of use is important. The cosmetic is not particularly limited as long as the water-in-oil emulsifier form can be applied. For example, basic cosmetics such as essence, milky lotion, cream, under-makeup, foundation, -Makeup cosmetics such as kukara, mascara, and eyeliner, and hair cosmetics such as hair cream can be preferably exemplified.

In the composition of the present invention, in addition to the above essential components, in order to more effectively improve pigmentation, in particular, means for preventing the occurrence of pigmentation after ultraviolet irradiation, or to improve pigmentation that has been achieved. It is preferable to contain the compound represented by the formula (1) and / or a pharmacologically acceptable salt thereof. The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof is excellent in the direct inhibitory action of tyrosinase enzyme, and the proton pump inhibitor and the anti-inflammatory agent are It exerts an inhibitory effect on melanin production through different mechanisms of action.

  Here, the compound represented by the general formula (1) will be described. In the formula, R1 represents an alkyl group having 1 to 8 carbon atoms which may have a branched structure or a cyclic structure. Are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, amyl group, isoamyl group, n-hexyl group, n-heptyl group. N-octyl group, isooctyl group, 1-methylpropyl group, 1-methylbutyl group, 1-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1-isopropyl-2-methylpropyl group, 1,1- Dimethyl-3-methylbutyl group, 1-butylpentyl group, 1-isobutyl-3-methylbutyl group, isostearyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group Etc. Le group can preferably be mentioned, these among, n- butyl group are particularly preferred examples. Among the compounds represented by the general formula (1), preferred examples include 4-butylresorcinol and / or a pharmacologically acceptable salt thereof. Such a compound exhibits a melanin production-inhibiting action by inhibiting the tyrosinase enzyme that directly inhibits the key enzyme tyrosinase in the melanin production process, and is added to the composition together with the proton pump inhibitor and the anti-inflammatory agent. By doing so, an excellent effect of preventing or improving pigmentation is exhibited.

The compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof, in particular, 4-alkylresorcinol is obtained by converting a corresponding carboxylic acid having an alkyl group and resorcin into zinc chloride. A known synthesis method (for example, a method of condensing and reducing with zinc amalgam / hydrochloric acid, or a method of condensing an alcohol having a corresponding alkyl group and resorcin at a high temperature of 200 to 400 ° C. (for example, Bitter, LA; Peiner, V. Trudy-Nauchono- Issledovatel 'skii Institut Slantsev (1969), No. 18, 127-134, JP 2006-124358 A, JP 2006-124357 A Can be produced according to the above-mentioned), or can be purchased as a commercially available reagent.

In addition, the compound represented by the general formula (1) thus obtained can be used as it is, or is treated with a pharmacologically acceptable acid or base to be converted into a salt form and used as a salt. It is also possible to use it. For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonate and benzene sulfonate, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, Preferred examples include organic amine salts such as monoethanolamine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginate salts. These components can be contained alone or in combination of two or more. The content of the compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof is 0.0001% by mass to 5% by mass, more preferably 0.001% by mass with respect to the total amount of the composition. It is more preferable to contain 001 mass%-3 mass%, More preferably, 0.01-1 mass%. This is because, if the content of the compound represented by the general formula (1) and / or the pharmacologically acceptable salt thereof is too small, the compound has a direct inhibitory action on the tyrosinase enzyme, and This is because there is a case where the combined effect with the proton pump inhibitor and the anti-inflammatory component is not achieved, and even when the amount is too much, the effect reaches a peak and the degree of freedom of this system may be impaired. .

The external preparation for skin of the present invention preferably contains an emulsifier for forming a water-in-oil emulsifier form in addition to the essential components. Examples of the emulsifier include organically modified clay minerals and diglycerin monooleate. And triglycerin diisostearate can be suitably exemplified. When diglycerin monooleate is used as an emulsifier, the amount for emulsification is added to the amount as an essential component, and the role for stabilization and the role for emulsification are combined. You can also.

In the organically modified clay mineral, organically modified means that a part of the organic compound is bonded to a part of the clay mineral to form a strong or loose bond through a covalent bond or an ionic bond. This means that some or all of the mineral is imparted to the clay mineral. Examples of such modifications include a method of bonding a quaternary amine group and an anion portion of the clay mineral, a method of bonding a carboxyl group and a cation portion of the clay mineral, etc. And a method of binding a quaternary amine group and an anion portion of a clay mineral is particularly preferable.

Although it does not necessarily limit as a compound which has a quaternary amino group which modifies a clay mineral, The compound called quaternium is illustrated. Quotanium is a low molecular weight substituted quaternary ammonium salt, and is preferably a cosmetic raw material registered in International Standard Cosmetic Ingredients (INCI). Furthermore, the compound having a quaternary amino group that modifies the clay mineral is preferably a quaternium compound contained in a conventional external skin preparation among quaternium compounds. Preferred examples of the quaternium compound used in conventional external preparations for skin include stearyl trimethyl ammonium chloride and dimethyl distearyl ammonium chloride. Stearyl trimethyl ammonium chloride, dimethyl distearyl ammonium chloride and the like are preferable because they can form a stable water-in-oil emulsion structure together with clay minerals.

On the other hand, as a clay mineral (unmodified clay mineral) modified with a compound having a quaternary amino group, any clay mineral contained in a conventional external preparation for skin can be used without particular limitation. Examples of clay minerals contained in conventional external preparations for skin include smectite-type hectorite, bentonite and montmorillonite; kaolinite; illite; marine clay mineral (sea mud); dezatroze clay mineral; Preferably mentioned. Among these, bentonite, hectorite, montmorillonite or kaolinite which can stabilize the water-in-oil emulsion structure is preferably exemplified.

An example of a method for producing a clay mineral modified with a compound having a quaternary amino group contained in the external preparation for skin of the present invention will be described below. The unmodified clay mineral is dispersed in a dispersion medium. The dispersant is preferably an aqueous solvent, and may be water. A compound having a quaternary amino group is further added to the dispersion containing the dispersed unmodified clay mineral and stirred well. The compound having a quaternary amino group may be added after being dissolved in water. The amount of the compound having a quaternary amino group to be added is preferably 0.01 to 20% by mass, and more preferably 0.05 to 15% by mass with respect to the amount of the dispersed unmodified clay mineral. This is because by taking such a configuration, a preferable feeling of use is exhibited in the emulsification system. After stirring, the dispersoid is filtered, dehydrated and dried to obtain the modified clay mineral in the present invention. Or the modified clay mineral in this invention can also be obtained by removing a dispersing agent by concentrating under reduced pressure without filtering a dispersoid, and making it dry. The obtained modified clay mineral is preferably pulverized to a desired size (preferably having a particle size of 1 to 1000 μm) and contained in the skin external preparation of the present invention.

The modified clay mineral in the present invention can be prepared and used as described above, but a commercially available one can also be used. Some modified clay minerals on the market are used as external preparations for skin such as cosmetics. Preferable examples of commercially available modified clay minerals include dimethyl distearyl ammonium modified hectorite sold under the name “Benton 38V” by Elementis.

In the skin external preparation of this invention, this component is contained preferably 0.01-10 mass%, More preferably 0.05-5 mass% is contained. Such an ingredient acts as an emulsifier in the above-mentioned content range to form a high internal phase water-in-oil emulsifier form.

When diglycerin monooleate and / or triglycerin diisostearate is contained as an emulsifier, a polyhydric alcohol such as a multi-toll or sorbitol having a mass of 0.5 to 2 times the mass of the emulsifier. -It is preferable to contain together. Preferred examples of the raw material for the diglycerin monooleate cosmetics include “Nikko DGMO-C” (manufactured by Nippon Surfactant Co., Ltd.), and triglycerin diisostearate for cosmetics. Preferred examples of the raw material include “Emerest 2452” (manufactured by Emery). The preferable content of this component is 1 to 10% by mass, more preferably 2 to 7% by mass, based on the total amount of the external preparation for skin. This is because if the amount is out of the range, emulsification may not be possible or stability may be impaired.

Since the external preparation for skin of the present invention takes the form of a water-in-oil emulsifier form, in order to compensate for the drawbacks of the feeling of use and finish of the water-in-oil emulsifier form, silicone, particularly preferably cyclomethicone and / or It is preferable to contain dimethicone having a viscosity of 1 mPa · s or less, and the content of the silicone is preferably 10 to 50% by mass, more preferably 20 to 40% with respect to the total amount of the cosmetic. The sum of the contents of cyclomethicone and dimethicone having a viscosity of 1 mPa · s or less is 50% by mass or more, more preferably 55% by mass or more, based on the total amount of the oil phase.

Moreover, in the skin external preparation of this invention, when using the said organic modified clay mineral as an emulsifier, in the meaning which assists the emulsification effect | action of the said organic modified clay mineral, POE modified methylpolysiloxane, POP modified methylpolysiloxane, POP · POE A suitable example is the inclusion of a polyether-modified methylpolysiloxane such as a modified methylpolysiloxane. The preferable content of such polyether-modified methylpolysiloxane is more preferably 0.5 to 5% by mass and 1 to 3% by mass.

When the organically modified clay mineral is used as an emulsifier, a preferred optional component other than the above-described components can be exemplified by a polyhydric alcohol that can stabilize the emulsified state. Particularly preferred are glycerin, diglycerin, dipropylene glycol, 1,3-butylene glycol and the like. Such a component may contain only one species or may contain two or more species in combination. A preferable content is 5-30 mass% with respect to the total amount of skin external preparations in total, More preferably, it is 10-25 mass%. In addition, 1 to 7% by mass of one or more selected from 1,2-pentanediol, 1,2-hexanediol, and 1,2-octanediol can also be contained. It is preferable from the viewpoint of improving power.

In addition to the above, the external preparation for skin of the present invention may contain any commonly used optional component as long as the effects of the present invention are not impaired. Such optional ingredients include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm oil, palm oil, liquid Lanolin, hydrogenated coconut oil, hydrogenated oil, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, oils, waxes; liquid paraffin, squalane, pristane, ozokerite, Hydrocarbons such as paraffin, ceresin, petrolatum, microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol -Le, Isosteari Higher alcohols such as alcohol, behenyl alcohol, octyl decanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, Di-2-ethylhexyl sebacate, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, tri-2- Oil agents such as synthetic ester oils such as glycerin ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentane erythritol tetra-2-ethylhexanoate; fatty acid soap (Natrilaurate) Anionic surfactants such as potassium lauryl sulfate, triethanolamine ether alkyl sulfate; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide; imidazoline series Amphoteric surfactants (such as 2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt), betaine surfactants (such as alkyl betaines, amide betaines, sulfobetaines), acylmethyl taurines, etc. Amphoteric surfactants; sorbitan fatty acid esters (such as sorbitan monostearate, sorbitan sesquioleate), glycerin fatty acids (such as glyceryl monostearate), propylene glycol fatty acid esters (monostearic acid) Propylene glycol, etc.), hydrogenated castor oil derivative, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE- Sorbit monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ether (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether) Tel), Tetro Non-ionic surfactants such as sucrose fatty acid esters such as sucrose laurate, alkyl glucoside, POE castor oil and hydrogenated castor oil derivatives (POE castor oil, POE hydrogenated castor oil, etc.); Polyhydric alcohols such as glycerol, glycerin, erythritol, sorbitol, xylitol, maltitol, propylene glycol, 2,4-hexanediol; sodium pyrrolidone carboxylate, lactic acid, sodium lactate Moisturizing components such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, etc .; surface May be treated, bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, oxide Inorganic pigments such as zinc oxide and zinc oxide; paroles such as titanium mica, fish phosphorus foil, bismuth oxychloride, etc. whose surface may be treated; red No. 202, red which may be laked 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 Organic dyes such as green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; paraaminobenzoic acid UV absorbers; anthranils Acid UV absorbers; salicylic acid UV absorbers; cinnamic acid UV absorbers; benzophenone UV absorbers; sugar UV absorbers; 2- (2'-hydroxy-5'- UV absorbers such as t-octylphenyl) benzotriazole and 4-methoxy-4′-t-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; vitamin A or a derivative thereof; Vitamin B types such as vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or derivatives thereof, vitamin B12, vitamin B15 or derivatives thereof; α-tocopherol, β-tocopherol, γ -Vitamin E such as tocopherol, vitamin E acetate, vitamin D, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone, etc .; antibacterial agents such as phenoxyethanol; EDTA, EDTA2Na, EDTA3Na Edetates (ethylenediaminetetraacetate) such as EDTA4Na; hydroxy esters such as HEDTA3Na Pentetate (diethylenetriaminepentaacetate); phytic acid; salts of phosphonic acid such as etidronic acid and its sodium salt; sodium oxalate; polypolyamino acids such as polyaspartic acid and polyglutamic acid; Sodium citrate, sodium metaphosphate, phosphoric acid; sodium citrate, citric acid, alanine, dihydroxyethylglycine, gluconic acid, ascorbic acid, succinic acid, tartaric acid and other chelating agents; citric acid, sodium citrate, lactic acid, lactic acid Sodium, glycolic acid, succinic acid, acetic acid, sodium acetate, malic acid, tartaric acid, fumaric acid, phosphoric acid, hydrochloric acid, sulfuric acid, monoethanolamine, diethanolamine, triethanolamine, isopropanolamine, triisopropanolamine, -Amino-2-methyl-1,3-propanediol, 2-amino-2-hydroxymethyl-1,3-propanediol, arginine, sodium hydroxide, potassium hydroxide, aqueous ammonia, guanidine carbonate, ammonium carbonate, etc. A pH adjuster etc. can be illustrated preferably.

In addition to these, as a particularly preferable component, polyether-modified silicone can be exemplified in the sense of assisting the emulsifiability of the organically modified clay mineral. Preferred examples of the polyether-modified silicone include polyethylene glycol-modified methyl siloxane, polypropylene glycol-modified methyl siloxane, polyethylene glycol / polypropylene glycol-modified methyl siloxane, and the like. Particularly preferred is polyethylene glycol (10) -modified methylsiloxane, for example, “Silicon KF6017” manufactured by Shin-Etsu Chemical Co., Ltd. exists as a commercial product. A preferable content of such a polyether-modified silicone is 0.5 to 30% by mass, and more preferably 1 to 25% by mass, based on the total amount of the external preparation for skin.

The skin external preparation of this invention can manufacture the skin external preparation of this invention by processing the above-mentioned component in accordance with a conventional method.

Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

<Manufacture example 2: The manufacturing method of the skin external preparation of this invention>
According to the formulations shown in Table 2 and Table 3, a water-in-oil emulsified cosmetic preparation, which is the composition of the present invention (external preparation for skin), was produced. That is, each of the components (a), (b), and (c) is heated to 80 ° C., and (d) is added and dissolved in (b), kneaded to form a gel, and added to (b), diluted, and gradually stirred with stirring. The mixture was emulsified with water, stirred and cooled to prepare water-in-oil emulsifier type cosmetics 1 to 7, which are external preparations for skin of the present invention. Furthermore, in the prescription components of Table 2, Comparative Example 1 in which “the proton pump inhibitor of the present invention” was replaced with water, Comparative Example 2 in which “the anti-inflammatory agent of the present invention” (dipotassium glycyrrhizinate) was replaced with water, “ Comparative Example 3 was prepared in which the proton pump inhibitor of the present invention and the anti-inflammatory agent of the present invention (dipotassium glycyrrhizinate) were both replaced with water.

<Test Example 3: Examination of preventive effect on pigmentation after UV irradiation>
According to the following procedure, the pigmentation inhibitory effect by ultraviolet irradiation of cosmetics 1-7 and Comparative Examples 1-3 was evaluated. Panels who participated freely were divided into two upper and lower sections of 1.5 cm x 1.5 cm on the inner side of both upper arms, for a total of 11 locations, and UV irradiation with a minimum amount of erythema (1 MED) once a day for 3 days Irradiated 3 times in succession. From 1 day after the completion of irradiation, 50 μL of sample was applied once a day for 28 consecutive days. One site was an untreated site. 24 hours after the completion of application, the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and ΔL * value relative to the L value of the untreated site was calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 4. Thereby, it turns out that the cosmetics 1-7 which are the external preparations of this invention show the outstanding pigmentation inhibitory effect. From these results, in the topical skin preparation of the present invention, as the proton pump inhibitor, an extract of a plant belonging to the genus Ginger family, a plant belonging to the leguminous family Clara genus, or an extract of a plant belonging to the genus Hydrangeaceae family is used. It turns out to be particularly preferable. Among these, an extract of a plant belonging to the genus Ginger is particularly preferable.

From the results shown in Table 4, the skin external preparation containing both the “anti-inflammatory agent of the present invention” (dipotassium glycyrrhizinate) and the “proton pump inhibitor of the present invention” has a remarkable effect on pigmentation after ultraviolet irradiation. Was recognized. Thus, the combined effect of the proton pump inhibitor and the anti-inflammatory component of the present invention can improve the effect of suppressing pigmentation due to ultraviolet irradiation.

  A cosmetic 8 was prepared by replacing dipotassium clityrrhizinate, which is the “anti-inflammatory agent of the present invention”, with “stearyl glycyrrhetinate” among the ingredients of the cosmetic 3 described in Tables 2 and 3 above. When the preventive effect against pigmentation after ultraviolet irradiation was examined according to the method shown in No. 2, the ΔL * value was 1.12. The external preparation for skin was found to have an excellent preventive effect on pigmentation after ultraviolet irradiation. It can also be seen that stearyl glutylretinate is particularly preferred in the water-in-oil emulsion system.

Among the prescription ingredients of cosmetic 3 shown in Tables 2 and 3 above, the concentrations of “proton pump inhibitor of the present invention” (extract obtained from Ginger family ginger) and “dipotassium glycyrrhizinate” Cosmetics 9 to 12 having the concentrations changed to those shown in Table 5 were prepared. In addition, the increase / decrease amount of the mass% regarding both components was adjusted with the mass% of water.

  Regarding cosmetics 9 to 12 produced according to the prescriptions in Tables 2 and 5, the preventive effect on pigmentation after ultraviolet irradiation was examined according to the method described in Example 2. The results are shown in Table 6. From the results of Table 6, cosmetic 9 containing both the “proton pump inhibitor of the present invention” (an extract obtained from Ginger ginger) and the “anti-inflammatory agent of the present invention” (dipotassium glycyrrhizinate). In -12, the preventive effect against pigmentation by ultraviolet irradiation by the combination of both components was confirmed. From the results of Table 6, it can be seen that the external preparation for skin containing 1) a proton pump inhibitor and 2) an anti-inflammatory component has an excellent inhibitory effect on pigmentation due to ultraviolet irradiation.

Cosmetics 13 in which “Benton 38V” is replaced with “Silicon KF6017” and “1,3-butylene glycol” is replaced with “polyethylene glycol” in the prescription ingredients of Cosmetic 3 shown in Table 2 and Table 3. 400 ”was prepared, and the effect of preventing pigmentation by ultraviolet irradiation was examined according to the method described in Example 2. As a result, the cosmetic 13 had a ΔL * value of 0.35, The cosmetic 14 had a ΔL * value of 0.32, and almost no protective effect against pigmentation after ultraviolet irradiation was observed in any cosmetic.

<Manufacture example 3: The manufacturing method of the composition (skin external preparation) of this invention>
According to the formulations shown in Tables 7 and 8, lotion-form cosmetics (cosmetics 15 to 21) were prepared.

According to the formulations shown in Table 9 and Table 10 below, essence dosage form cosmetics (cosmetics 22 to 28) were prepared. That is, the ingredients of A, B and C are heated to 75 ° C., B is added to B, neutralized and thickened, C is gradually added, emulsified, and the particles are homogenized by a homomixer and stirred. Then, it was cooled to obtain an essence cosmetic that is an external preparation for skin of the present invention.

  A cosmetic 29 in the form of a water-in-oil emulsifier was prepared according to the formulation shown in Table 11, and the pigmentation inhibitory effect after ultraviolet irradiation was examined according to the method shown in Example 2. The ΔL * value was 1.71 was shown. From these results, 1) a proton pump inhibitor, 2) an anti-inflammatory component (dipotassium glycyrrhizinate), 3) a compound represented by the general formula (1) and / or a pharmacologically acceptable salt thereof. It was found that the skin external preparation (cosmetic 29) containing (4-butylresorcinol) has an excellent pigmentation-inhibiting effect after ultraviolet irradiation. This is considered to be a result that an excellent effect was exhibited by using each component in combination in addition to the pigmentation-inhibiting action after ultraviolet irradiation of each component.

<Method for Producing Composition (Food) of the Present Invention>
According to the prescription shown in Table 12 and Table 13, health food 1-7 was produced. That is, the prescription ingredients were tumbled phase granulated with 10 parts by weight of water (“New Malmerizer” manufactured by Fuji Powder Co., Ltd.) and tableted to obtain a tablet-like health food. In addition, the unit of the numerical value in a table | surface represents a weight part.

  The present invention can be applied to an external preparation for skin useful for preventing or improving pigmentation.

Claims (21)

A composition comprising 1) a proton pump inhibitor and 2) an anti-inflammatory component. The anti-inflammatory component is an extract obtained from a plant belonging to the genus Asteraceae, an extract obtained from a plant belonging to the leguminous genus, an extract obtained from a plant belonging to the genus Birchaceae, a plant belonging to the walnut family The extract obtained from the above, glycyrrhetinic acid derivatives and pharmacologically acceptable salts thereof, grabridine derivatives and pharmacologically acceptable salts thereof, A composition according to 1. The plant belonging to the genus Asteraceae, the plant belonging to the Leguminosae genus, the plant belonging to the Birchaceae birch genus, the plant belonging to the walnut family, the Asteraceae burdock, the Legumeaceae licorice, the Birchaceae birch genus birch, The composition according to claim 1, wherein the composition is a walnut family. The glycyrrhetinic acid derivative is glycyrrhetinic acid and / or a pharmacologically acceptable salt thereof, alkyl glycyrrhetinic acid and / or a pharmacologically acceptable salt thereof, and glycyrrhizic acid and a pharmacologically acceptable salt thereof. The composition according to claim 1, wherein the composition is a salt. The glycyrrhetinic acid and its pharmacologically acceptable salt are stearyl glycyrrhetinate and / or its pharmacologically acceptable salt, and the glycyrrhizic acid and its salt are dipotassium glycyrrhizinate. The composition according to claim 1, 2, or 4. The composition according to any one of claims 1 to 5, wherein the proton pump inhibitor is obtained by extracting a plant body. The composition according to any one of claims 1 to 6, wherein the plant extract having a proton pump inhibitory action is an extract of a plant listed below.
(Plant) Lamiaceae Tachytaceae, Leguminosae Clara, Gingeraceae Ginger, Araceae Drosophila, Cucurbitaceae Hechima, Yukinosidae Hydrangea, Sarnococcidae The plant belonging to the family Lamiaceae, Papaveraceae, Leguminosae, Clara, Ginger, Ginger, Araceae, Ganoderma, Horishima, Hydrangea, Hydrangea, Sarnosidaceae The genus Clara genus Clara, Ginger genus Ginger genus Ginger, taro genus ginger genus cucumber, cucurbitaceae genus genus Hachima, saxifrage family hydrangea genus amacha, sarnococcidae matsuhodo nuclei A composition according to claim 1. The composition according to any one of claims 1 to 8, wherein the proton pump inhibitor has an action of acidifying the inside of melanocytes in melanocytes. The composition according to any one of claims 1 to 9, wherein the plant extract having a proton pump inhibitory action acts on a Na ⁺ / H ⁺ exchange transport system. The said anti-inflammatory component contains 0.00001 mass%-3 mass% with respect to the composition whole quantity, The composition as described in any one of Claims 1-10 characterized by the above-mentioned. The composition according to any one of claims 1 to 11, wherein the plant extract having a proton pump inhibitory action is contained in an amount of 0.00001 mass% to 10 mass% based on the total amount of the composition. The composition according to any one of claims 1 to 12, further comprising a compound represented by the following general formula (1) and / or a pharmacologically acceptable salt thereof. .

(1)
[Wherein R 1 represents an alkyl group having 1 to 8 carbon atoms which may have a branched structure or a ring structure] 14. The compound represented by the general formula (1) is 4-n-butylresorcinol and / or a pharmaceutically acceptable salt thereof. A composition according to 1. Furthermore, a composition preferable as cosmetics is contained, The composition as described in any one of Claims 1-14 characterized by the above-mentioned. The composition according to any one of claims 1 to 15, wherein the composition is a cosmetic (however, including a quasi-drug). It is a skin external preparation, The composition as described in any one of Claims 1-16 characterized by the above-mentioned. The topical skin preparation according to claim 17, which is in the form of a water-in-oil emulsifier. The external preparation for skin according to claim 17 or 18, wherein the preparation is for preventing pigmentation. The external preparation for skin according to claim 17 for use immediately after exposure to ultraviolet rays. An external preparation for skin containing 1) a glycyrrhetinic acid derivative and / or a pharmacologically acceptable salt thereof, and 2) a proton pump inhibitor.

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