External composition

Abstract

To provide an external composition used for inhibition, prevention, prophylaxis or improvement of skin disease.SOLUTION: An external composition used for inhibition, prevention, prophylaxis or improvement of skin disease has (A) a heparin analog, (B) at least one selected from the group consisting of allantoin, pantothenic acid, vitamin A, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable derivative thereof, and (C) a nonionic surfactant.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for external use used for suppressing, preventing, prophylaxis or amelioration of skin diseases. [Background technology]

[0002] Itchy skin diseases include dry skin such as senile xerosis, atopic dermatitis, and housewives' eczema. Skin diseases, inflammatory skin diseases, skin pruritus, heat rash, chilblains, cracks, chapped skin, etc. are known. The skin of patients suffering from these skin diseases becomes sensitive to external stimuli and This is one of the reasons why the itch occurs repeatedly. This often leads to scratching behaviour.

[0003] For these symptoms, antihistamines and antipruritic ingredients such as crotamiton, heparin Moisturizing agents such as analogues and urea, anti-inflammatory ingredients such as allantoin and glycyrrhizinate Compositions for topical application to the skin containing the above as an active ingredient are widely used.

[0004] Of these, heparinoids have skin moisturizing effects and blood circulation promoting effects. In addition, the skin dryness symptoms are alleviated by the skin moisturizing effect of heparinoids. The heparinoids promote blood circulation in the area where they are used, improving blood circulation caused by circulatory disorders. Pain and swelling are reduced. For this reason, heparinoids are useful in the treatment of asteatosis, progressive keratoderma tylosum palmaris, and other conditions. , frostbite, hypertrophic scars and keloids, pain or inflammatory diseases due to circulatory disorders, thrombophlebitis Treatment or prevention of swelling, hematoma, tendonitis, muscle pain, arthritis, etc. after trauma (bruises, sprains, contusions) It is used in.

[0005] Patent Document 1 describes a skin topical composition containing crotamiton and a heparinoid that reduces dryness. It is described that the compound can improve itching associated with chronic skin diseases, inflammatory skin diseases, and the like.

[0006] Patent Document 2 describes a skin topical composition containing an antihistamine-containing preparation and a heparinoid. It is described that this can improve itching associated with dry skin diseases, inflammatory skin diseases, and the like.

[0007] Patent Document 3 discloses a skin treatment composition for external use that contains a nonsteroidal anti-inflammatory drug and a heparinoid. It is also described as being able to improve itching associated with dry skin diseases, inflammatory skin diseases, and the like.

[0008] Patent Document 4 describes a skin treatment containing a heparinoid, allantoin, and pantothenic acid. The present invention discloses a composition for external use. This skin preparation promotes normal differentiation of stratum corneum cells. It is stated that this can promote

[0009] Patent Document 5 discloses a skin care product containing vitamin A, edetic acid or its salt, and a heparinoid. A skin topical composition is disclosed. According to this skin topical composition, vitamin A is It is described that it can be contained stably.

[0010] By the way, excessive scratching behavior in response to itching can cause skin damage and inflammation. This can leave itchy marks on the skin. In some cases, these marks can be accompanied by pigmentation. Other cases where skin pigmentation can occur include burns, external wounds due to trauma, etc. After the wound has healed, pigmentation may appear (also called scarring). Imbalance, aging, sudden strong sunburn, chronic friction, etc. can also cause pigmentation on the skin. Skin pigmentation is an issue that must be addressed in order to be suppressed, prevented, prevented or improved from the standpoint of skin appearance or cosmetics. In addition, it is hoped that melanocytes in the dermis will produce excessive melanin. It is known that this can result in black, brown, or blue bruises. In addition, when the skin is injured due to trauma (bruises, sprains, contusions, etc.), not only does pigmentation occur, It can also cause hematomas (bruises caused by subcutaneous bleeding) and make pigmentation more noticeable.

[0011] A hematoma is a blood vessel formed when capillaries in the skin or subcutaneous tissue are ruptured due to trauma. Symptoms of a subcutaneous hematoma include a blue or purple discoloration of the area affected by the trauma. Although hematomas gradually disappear as blood vessels and tissues are repaired and exudates are removed, they may worsen with age. This can result in long-term recovery due to the combination of pigmentation and rash. Or, from a cosmetic point of view, to make the hematoma disappear or to make the color of the hematoma fade (lighten) early. For this reason, it is desirable to suppress, prevent, or improve pigmentation or hematoma. was. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] JP 2000-229852 A [Patent Document 2] JP 2000-229884 A [Patent Document 3] JP 2000-38352 A [Patent Document 4] JP 2011-231128 A [Patent Document 5] JP 2012-36183 A Summary of the Invention [Problem to be solved by the invention]

[0013] The object of the present invention is to provide a composition for external use that can be used to suppress, prevent, prevent, or improve skin diseases. The purpose is to provide. [Means for solving the problem]

[0014] A composition for external use used to suppress, prevent, prevent or improve skin diseases that solves the above problems is (A) heparinoids, (B) allantoin, pantothenic acid, vitamin A, and pharma- ceutically acceptable salts thereof, and pharma- ceutically acceptable derivatives thereof. and (C) a nonionic surfactant.

[0015] According to the above configuration, the topical composition contains the components (A), (B) and (C), The synergistic effect of these two substances suppresses melanin production. The effects of the present invention may be suppressed, prevented, prophylactically, or ameliorated. Effect of the Invention

[0016] According to the present invention, the topical composition contains components (A), (B) and (C), The synergistic effect of these ingredients suppresses, prevents, or improves pigmentation of the skin. can be done. [Brief description of the drawings]

[0017] [Figure 1] 1 is a graph showing the relationship between the amount of polyoxyethylene hydrogenated castor oil 50 and the rate of decrease in melanin production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Preferred embodiments of the present invention will be described in detail below. When indicating the relative amount of a specific ingredient, such as an ingredient added to a topical composition, "parts by weight" is used. " is used as the unit.

[0019] The topical composition E of this embodiment is effective for treating, for example, senile xerosis, atopic dermatitis, housewives' eczema, etc. Any dry skin disease, inflammatory skin disease, skin pruritus, heat rash, chilblains, cracks, chapped skin It is used as a skin medication applied to the affected areas of skin diseases accompanied by itching, such as

[0020] The topical composition E contains the following active ingredients (A), (B), and (C). It is combined.

[0021] The above component (A) is a heparinoid. Heparinoids have the effects of promoting blood circulation, It is known to have an inhibitory effect on fibroblast proliferation.

[0022] The heparinoids contained in the topical composition E are polysulfated heparin such as chondroitin polysulfate. Heparinoids are a general term for mucopolysaccharides. They contain an average of 0 It is preferable that the sulfate group has an average of 0.5 to 5 molecules, and preferably an average of 0.6 to 3 molecules.

[0023] As the heparinoid, a commercially available product that is generally available may be used as it is. By a method of sulfated mucopolysaccharides or by a method of extracting naturally occurring sulfated polysaccharides, Heparinoids can also be obtained. It is extracted and purified from the internal organs, including the bronchi, of animals such as cows and pigs using an aqueous carrier. The extract is then sulfated as necessary. Those listed in the non-pharmacopoeial drug standards are preferably used.

[0024] The molecular weight of the heparinoid is not particularly limited, but is usually 1,000 to 10,000. 000, and preferably 5000 to 1,000,000.

[0025] The ratio of the amount of component (A) contained in the topical composition E to the total amount of the topical composition E is As long as the effect of the present invention can be achieved, there is no particular limitation. For example, the content is 0.00001% by weight or more. The proportion of component (A) in the total amount of the topical composition E is 0.001% by weight or more. Preferably, 0.01% by weight or more is more preferable, and 0.05% by weight or more is even more preferable. Even more preferred is 0.1% by weight or more, and especially preferred is 0.3% by weight or more. In one embodiment, the ratio of the amount of component (A) to the total amount of the topical composition E is 0.45% by weight. The ratio of the amount of component (A) to the total amount of the topical composition E may be 0.00% or more. By making the amount of component (A) equal to or greater than 0.01% by weight, favorable effects can be obtained. The ratio of the total amount of the composition E for external use to the total amount of the composition E is 0.001% by weight or more. Furthermore, by making the content 0.01% by weight or more, an even more excellent effect can be obtained. The ratio of component (A) to the total amount of topical composition E is 10% by weight. % or less, more preferably 7% by weight or less, and even more preferably 5% by weight or less; The proportion of component (A) in the total amount of the topical composition E is particularly preferably 1% by weight or less. When the content is less than 10% by weight, the sticky feeling during use of the composition for external use E is suppressed, and Provides an excellent usability.

[0026] Ingredient (B) is allantoin, pantothenic acid, vitamin A, and their pharma- ceutical acceptable derivatives. and 1 or more selected from the group consisting of phenylalanine, ... Allantoin is an active ingredient that promotes wound healing. Pantothenic acid is It has the effect of assisting the metabolism of energy such as carbohydrates, proteins, and lipids, and activating cells. It is known to have useful physiological effects such as stimulating metabolism, moisturizing, and strengthening resistance. Vitamin A has the effect of promoting the disappearance of bruises caused by subcutaneous bleeding due to bruising, etc., or Component (B) is an active ingredient that has the effect of promoting fading. Component (B) can be used alone or in combination with other ingredients. Any combination of one or more species may be used.

[0027] Specific examples of allantoin salts that can be incorporated into the topical composition E include allantoin chlorhydrin, hydroxyaluminum, allantoin dihydroxyaluminum, etc.

[0028] Specific examples of allantoin derivatives that may be included in the topical composition E include allantoic acid, Dihydroxyaluminum Allantoinate, Allantoin Glycyrrhetin, Chlorohydride hydroxyaluminum allantoinate and the like.

[0029] Specific examples of salts of pantothenic acid that can be incorporated in the topical composition E include calcium pantothenate. Examples of suitable anti-inflammatory agents include sodium pantothenate and the like.

[0030] Specific examples of the pantothenic acid derivatives contained in the topical composition E include panthenol, pantothenic acid, pantothenyl ethyl ether, acetylpantothenyl ethyl ether, etc.

[0031] The vitamin A compounds contained in the topical composition E are retinol or retinoic acid esters. Retinol acetate, retinol palmitate, δ-retinoic acid tocopherol are preferred. Roles include:

[0032] Vitamin A is either isolated from natural sources such as animal materials or chemically synthesized. Vitamin A may also be used in the form of vitamin A oil. Vitamin A oil can be natural oil extracted and refined from animals, or vitamin A can be extracted from vegetable oils, etc. A typical example of the latter is vitamin A oil (1g (containing 30,000 or more vitamin A units (IU) per serving).

[0033] The amount of component (B) contained in the topical composition E (when two or more components are contained as component (B) In the case where the composition is combined with other ingredients, the ratio of the total amount of the composition for external use E to the total amount of the composition for external use E is, for example, In addition to the amount of component (B) contained in the topical composition E, the amount of component (B) is 0.0001% by weight or more. The proportion of the composition E in the total amount is preferably 0.001% by weight or more, and more preferably 0.04% by weight or more. More preferably, the amount is 0.05% by weight or more, even more preferably, 0.5% by weight or more. The total amount of the component (B) in the composition for external use E is preferably 1.5% by weight or more, and particularly preferably 1.5% by weight or more. A preferable effect can be obtained by making the ratio of the total amount 0.0001% by weight or more. By setting the content to 0.001% by weight or more, a more excellent effect can be obtained. In addition, the proportion of the component (B) in the total amount of the topical composition E is preferably 10% by weight or less, and 7 times the weight of the component (B) in the total amount of the topical composition E. It is more preferable that the amount of the composition for external use is 5% by weight or less, and further preferably 5% by weight or less. Composition E has a good feeling when used. By making the ratio of the component (I) to 10% by weight or less, a more excellent feeling of use can be obtained. The content of component (B) is, for example, 0.0001 to 25 parts by weight per part by weight of component (A). The content of component (B) is 0.01 to 10 parts by weight per part by weight of component (A). It is preferable that the content is 0.05 to 5 parts by weight, and more preferable that the content is 0.1 to 2 It is more preferable that the content is 10 parts by weight.

[0034] Component (C) is a nonionic surfactant. Component (C) may be used alone. Any combination of two or more of them may also be used.

[0035] Nonionic surfactants include ester-based nonionic surfactants and ether-based nonionic surfactants. Examples of such surfactants include ionic surfactants, alkyl glycosides, and silicone surfactants.

[0036] Ester-based nonionic surfactants include sorbitan fatty acid esters and glyceryl fatty acid esters, polyglycerol fatty acid esters, polyglycerol fatty acids, Pyrene glycol fatty acid esters, hydrogenated castor oil derivatives, polyoxyethylene sorbita fatty acid esters, polyoxyethylene monococonut oil fatty acid glyceryl, etc.

[0037] Examples of sorbitan fatty acid esters include nonionic surfactants such as For example, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopal Mitate, Sorbitan Monostearate, Diglycerol Penta-2-ethylhexyl sorbitan, diglycerol sorbitan tetra-2-ethylhexyl acid, and the like. Examples of glycerin fatty acid esters include glyceryl monostearate, Examples of polyglycerol fatty acid esters include glycerol, malic acid, etc. For example, polyglyceryl monostearate, polyglyceryl monoisostearate, diglyceryl stearate, Polyglyceryl isostearate, Polyglyceryl monolaurate, Polyglyceryl monooleate glyceryl, polyglyceryl monomyristate, etc. Polyglycerol fatty acids Examples of the polyglyceryl monostearate and polyglyceryl monoisostearate are Polyglyceryl diisostearate, Polyglyceryl monolaurate, Monooleate Examples of the fatty acid esters include polyglyceryl phosphate and glycerin fatty acid esters. Examples of fatty acid esters include propylene glycol monostearate, polyethylene Examples of hydrogenated castor oil derivatives include: Polyoxyethylene hydrogenated castor oil 40 (HCO-40), Polyoxyethylene hydrogenated castor oil Oil 50 (HCO-50), Polyoxyethylene hydrogenated castor oil 60 (HCO-60), Poly Examples include polyoxyethylene hydrogenated castor oil such as oxyethylene hydrogenated castor oil 80. Examples of polyoxyethylene sorbitan fatty acid esters include poly(monolauryl)ate, Polyoxyethylene (20) sorbitan (polysorbate 20), polyoxyethylene monostearate Oxyethylene (20) sorbitan (polysorbate 60), polyoxyethylene monooleate Polyethylene (20) Sorbitan (Polysorbate 80), Polyoxyethylene Isostearate (20) Sorbitan, etc.

[0038] Examples of ether-based nonionic surfactants include glycerin alkyl ethers, Polyoxyalkylene alkyl ether, polyoxyethylene polycyclic phenyl ether, etc. Some examples include:

[0039] Examples of polyoxyalkylene alkyl ethers include polyoxyethylene alkyl ethers. ether, polyoxyethylene alkylphenyl ether, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether , polyoxyethylene tridecyl ether, polyoxyethylene castor oil ether, poly Oxyethylene-2-ethylhexyl ether, polyoxyethylene stearyl ether , polyoxyethylene oleyl ether, polyoxyethylene behenyl ether, etc. can be done.

[0040] Examples of alkyl glycosides include octyl glycoside, decyl glycoside, lauroyl glycoside, and lauric acid glycoside. Examples include aryl glycosides.

[0041] Examples of silicone surfactants include polyoxyethylene methylpolysiloxane. Copolymer, Lauryl PEG-9 Polydimethylsiloxyethyl Dimethicone, PEG-9 Polydimethylsiloxyethyl Dimethicone Dimethylsiloxyethyl dimethicone and the like.

[0042] The HLB value of nonionic surfactants is based on the value measured by the Kawakami method. The LB value is preferably 8 or more, and more preferably 9 or more, in order to improve compatibility with the skin. In particular, those having a molecular weight of 10 or more are preferred. In other words, the nonionic surfactant must be hydrophobic. It is preferable that

[0043] In the topical composition E, the amount of component (C) (two or more components are included as component (C)) In the case where the total amount of each of the above ingredients is used, the ratio of the total amount of each ingredient to the total amount of the topical composition E is 0.000 1% by weight or more is preferable, 0.005% by weight or more is more preferable, and 0.01% by weight or more is The amount of component (C) in the composition for topical use is more preferably 0.05% by weight or more, and particularly preferably 0.05% by weight or more. By making the ratio of E to the total amount 0.0001% by weight or more, a more excellent effect can be obtained. The proportion of component (C) in the total amount of the topical composition E is 25% by weight or more. The content is preferably 10% by weight or less, more preferably 5% by weight or less. The proportion of the amount of C) in the total amount of the topical composition E is 25% by weight or less. The sticky feeling when using the composition E is suppressed, and a better feeling of use is obtained. The content of (C) is, for example, 0.1 to 80 parts by weight per part by weight of component (A). The component (C) is preferably contained in an amount of 1 to 50 parts by weight per 1 part by weight of the component (A). Preferably, the content is 5 to 40 parts by weight, and more preferably, 6 to 35 parts by weight. It is even more preferable.

[0044] Composition E for external use contains the above-mentioned components (A), (B), and (C), and therefore: For example, in cases of skin diseases accompanied by itching, it can suppress pigmentation in the skin after scratching the affected area. The topical composition E can prevent, prevent, or improve the above-mentioned symptoms. The combination of (B) and (C) helps to eliminate hematomas that occur due to bruises, etc. and / or may accelerate fading.

[0045] Composition E for external use may contain, as necessary, In addition to the essential ingredients listed above, it also contains non-steroidal anti-inflammatory agents, vitamins, anti-inflammatory and analgesic agents, antifungal agents, and Steroid agent, local anesthetic, antibacterial agent, antiviral agent, keratin softener, moisturizer, astringent, antioxidant Various active ingredients such as moisturizers, moisturizers, and fresheners can be blended. is not particularly limited as long as the effects of the present invention are achieved, but is preferably within the upper limit of the pharma- ceutical acceptable range. The amount is appropriately selected within the limits.

[0046] In addition to the above active ingredients, topical composition E contains water-soluble ingredients that are usually used in topical compositions. Preservatives, pH adjusters, thickeners, antioxidants, etc. can be appropriately blended as necessary. .

[0047] The dosage form of the external composition E may be, for example, an ointment, a cream, a gel, an emulsion, or an external liquid. Examples of the preparations include patches, solid preparations, poultices, packs, tapes, etc.

[0048] The topical composition E can be prepared by the usual method for each formulation. Known excipients and other ingredients necessary for preparation of the desired formulation are appropriately blended.

[0049] The amount of topical composition E to be applied to the skin and the method of use are not particularly limited. For example, the topical composition E may be applied several times a day (e.g., 1 to 5 times, preferably 1 to 3 times), with an appropriate amount (e.g., about 0.05 to 5 g) per time. The amount of topical composition E to be applied to the skin and the method of use should be determined according to the skin of the subject. The application period varies depending on the condition, age, sex, etc. The application period is, for example, about 2 weeks to 6 months, preferably The period of application may be about 1 to 6 months. Composition E for external use is effective in treating the condition where melanin production is promoted by itching. Those at risk of developing skin pigmentation, or those who are at risk of developing skin pigmentation due to melanin production being promoted by itching. It can be preferably used for people with abnormal skin pigmentation.

[0050] The topical composition E according to the present embodiment is effective for treating, for example, senile xerosis, atopic dermatitis, housewives, Dry skin diseases such as eczema, inflammatory skin diseases, skin pruritus, heat rash, chilblains, cracks, It is explained that it is used as a skin medication to be applied to areas affected by skin diseases such as chapped skin that are accompanied by itching. However, the use of the topical composition E is not particularly limited thereto. For example, the topical composition E can be used as Discoloration of the skin after healing of external wounds, such as burns or trauma (e.g. scars) The composition E for external use may be used as a skin drug to be applied to the skin. For pigmentation caused by irregularities in the lance, aging, sudden strong sunburn, chronic friction, etc. It can also be used as a topical medicine for external application. Pigmentation occurs after a skin imbalance, aging, sudden strong sunburn, chronic friction, etc. Even before pigmentation occurs, topical composition E is applied to the skin for the purpose of preventing or preventing pigmentation. In addition, if you have symptoms of bruises (e.g., black bruises, brown bruises, blue bruises), apply the topical composition E to Composition E for topical use may be applied to areas of the skin where bruising may occur, or for the purpose of preventing or preventing bruising. You may do so. EXAMPLES

[0051] Examples and comparative examples prepared in Evaluation Test I and Evaluation Test II are shown below to specifically illustrate the present invention. The present invention is not limited to the following examples. A cell lysate containing melanoma cells was prepared, and the amount of melanin produced per cell was measured to determine the melanin level. By evaluating the effect of reducing ranin production, it is possible to suppress, prevent, or prevent pigmentation. The present invention is intended to be an indicator of the effect of preventing or improving pigmentation from the viewpoint of suppressing melanin production. Evaluation is underway.

[0052] (Evaluation Test I) (Sample preparation) First, prepare DMEM (Dulbecco's modified Eagle) medium containing 10% FBS (fetal bovine serum). Using a 100% PBS-MS assay, mouse-derived B16 melanoma cells were cultured in 6-well plates (15 cells per well). 3 mL of mouse-derived B16 melanoma cells were seeded in each well (53 mL). Density is 3.0×10 4 The plate was then cultured at 3 The cells were cultured for one day at 7°C in an environment of 5% carbon dioxide and 95% air.

[0053] Then, the medium was replaced with fresh DMEM medium, and the cells were cultured using 10% FBS-containing DMEM medium. The test drug thus prepared was added to each well so that the final concentration became the specified value. The type and concentration of the test drug to be added differs depending on each Example, Comparative Example, and Reference Example. The samples were then incubated for an additional 3 days. The final volume of the plate was Each well contained approximately 3 mL.

[0054] After the incubation, the supernatant of each well was removed, and the sample was washed once with PBS(-). Then, 600 μL of 0.1N NaOH was added to each well and the plate was left to stand at room temperature for 24 hours. As a result, the cells in the plate were lysed, and a cell lysate was obtained. The ranin pigment was completely dissolved by the alkaline treatment.

[0055] (Test Drug) In each of Examples 1 to 12 and Comparative Examples 2 to 17, The concentrations of components (A) to (C) in the cell lysis solution were adjusted so that the final concentrations were as shown below. The test drug prepared was used. In Comparative Example 1, no test drug was added. The final concentrations of components (A) to (C) contained in each cell lysis solution are shown in Tables 1 to 6. show.

[0056] Comparative Example 1 Comparative Example 1 was a test drug to which none of components (A) to (C) was added.

[0057] (Comparative Examples 2 to 3) As the test drug, a drug containing only component (A) among components (A) to (C) was used as Comparative Example 2. In Comparative Examples 2 and 3, the final concentration of the heparinoid was 0.006 times that of the heparinoid. % by volume and 0.002% by weight.

[0058] (Comparative Examples 4 to 7) As the test drug, a drug containing only component (B) among components (A) to (C) was used as Comparative Example 4. In Comparative Example 4, the final concentration of panthenol was adjusted to 0.01% by weight. In addition, in Comparative Examples 5, 6 and 7, the final concentrations of allantoin were 0.01% by weight and 0. The concentrations were adjusted to 0.02% by weight and 0.1% by weight.

[0059] (Comparative Examples 8 to 11) As the test drug, a drug containing only component (C) among components (A) to (C) was used as Comparative Example 8. In Comparative Examples 8, 9 and 10, the final concentration of polyoxyethylene hydrogenated castor oil 50 was The concentrations were adjusted to 0.004%, 0.01%, and 0.04% by weight, respectively. In Comparative Example 11, the final concentration of polysorbate 60 was adjusted to 0.02% by weight. Made.

[0060] (Comparative Examples 12 to 13) The test drug contains only components (A) and (B) of components (A) to (C). The results are shown as Comparative Examples 12 and 13. Comparative Example 12 has a final concentration of the heparinoid of 0.006 times. The final concentration of the mixture was adjusted to 0.01% by weight. 13 has a final concentration of heparinoid of 0.006% by weight and a final concentration of allantoin of 0. It was prepared to be .02% by weight.

[0061] (Comparative Example 14) The test drug contains only components (A) and (C) among components (A) to (C). The result was designated Comparative Example 14. Comparative Example 14 was carried out with the final concentration of the heparinoid being 0.006% by weight, and and polyoxyethylene hydrogenated castor oil 50 were adjusted to a final concentration of 0.04% by weight. .

[0062] (Comparative Examples 15 to 17) The test drug contains only components (B) and (C) among components (A) to (C). The results are shown as Comparative Examples 15 to 17. Comparative Example 15 has a final panthenol concentration of 0.01% by weight, and The final concentration of polysorbate 60 was adjusted to 0.02% by weight. The final concentration of allantoin was 0.02% by weight, and the final concentration of polyoxyethylene hydrogenated castor oil 50 was 0.02% by weight. The concentration was adjusted to 0.04% by weight. In Comparative Example 17, the final concentration of allantoin was The final concentration of polyoxyethylene hydrogenated castor oil 50 was 0.04% by weight. It was prepared so that

[0063] (Examples 1 to 4) The test drug for component (A) was a heparinoid, and the test drug for component (B) was Allantoin. The test drug (C) was mixed with polyoxyethylene hydrogenated castor oil 50. These were referred to as Examples 1 to 4. In Examples 1 to 4, the final concentration of the heparinoid was 0.006 wt. The final concentration of allantoin was adjusted to be 1.0% in Examples 1 to 3. The blending amount was adjusted to 0.02% by weight in Example 1 and 0.1% by weight in Example 2. The ratio of the amount of component (B) to the amount of component (A) was 3. 33 in Example 2 and 16.7 in Example 4. The final concentrations of the compounds in Examples 1, 2, 3 and 4 were 0.01% by weight, 0.01% by weight, and 0.01% by weight, respectively. The components were prepared so as to have concentrations of 0.04%, 0.2% and 0.1% by weight. The ratio of the amount of component (A) to the amount of component (A) was 1.67 parts by weight in each of Examples 1 to 4. , 6.67 parts by weight, 33.3 parts by weight, and 16.7 parts by weight.

[0064] (Examples 5 to 9) The test drug for component (A) was a heparinoid, and the test drug for component (B) was Panthenol. The test drug (component (C)) was mixed with polyoxyethylene hydrogenated castor oil 50. The final concentration of the heparinoid was 0. In Examples 7 to 9, the blending amount was adjusted to 0.006% by weight, and in Examples 7 to 9, the blending amount was adjusted to 0.002% by weight. In Examples 5 to 9, panthenol was added to give a final concentration of 0.01% by weight. The ratio of the amount of component (B) to the amount of component (A) was the same as in Example 5 and In Examples 7 to 9, the ratio was 5. The final concentration of each of Examples 5, 6, 7, 8 and 9 was 0.01 times. %, 0.04% by weight, 0.004% by weight, 0.01% by weight and 0.04% by weight. The ratio of the amount of component (C) to the amount of component (A) was the same as in Examples 5 to 10. 9 at 1.67 parts by weight, 6.67 parts by weight, 2 parts by weight, 5 parts by weight, and 20 parts by weight, respectively be.

[0065] (Examples 10 to 12) As ingredient (C), polysorbate 6 is used instead of polyoxyethylene hydrogenated castor oil 50. The same procedure as in Example 5 was repeated except that 0.01 was added to the mixture so that the final concentration was 0.02% by weight. The sample to which the test drug was added in the same proportion as in Example 10 was prepared. The ratio of component (C) to the amount of component (A) is 1.67 and 3.33, respectively. In addition, allantoin was used instead of panthenol as ingredient (B), and the final concentration was 0. The test drug was added in the same formulation as in Example 10, except that it was prepared to be 0.01% by weight. The sample to which the component (B) and the component (C) were added was designated as Example 11. The ratios to the amounts are 1.67 and 3.33, respectively. Polysorbate 60 was added instead of polyoxyethylene hydrogenated castor oil 50, and the final concentration The test drug was prepared in the same composition as in Example 8, except that the concentration was adjusted to 0.01% by weight. The sample to which the component (B) and the component (C) were added was designated as Example 12. The proportions relative to the blend amounts are 5 parts by weight and 5 parts by weight, respectively.

[0066] (Evaluation method) The cell lysates of the examples and comparative examples were analyzed using an absorbance measuring device (Corona Electric Co., Ltd., Using a microplate reader (SH-9000Lab), 475 nM of the obtained cell lysate was The absorbance at 100 nm was measured and used as an index of the amount of melanin produced. The amount is the amount of melanin that all melanoma cells have.

[0067] In addition, the cell lysates of the Examples and Comparative Examples were analyzed using a BCA protein quantification kit (ThermoFisher). BCA Protein Assay Ready, manufactured by Shar Scientific Co., Ltd. The protein content of each cell lysate was quantified using the gent. The amount of protein in the cells was measured, and this measurement was used as an indicator of the number of melanoma cells in the whole cell lysate. This was the target.

[0068] To evaluate the amount of melanin per melanoma cell, the absorbance was calculated as shown in the following formula: The amount of melanin produced was divided by the amount of protein, and this value was used as the standard value for the amount of melanin. The melanin amount standard value was evaluated as a relative value.

[0069] (Melanin amount standard value) = (Melanin production amount) / (protein amount) Specifically, for Comparative Examples 1 to 3, the melanin amount reference value of Comparative Example 1 was set to the reference value m0(1 00). The melanin amount standard value m in Comparative Examples 2 and 3 was set to the melanin amount standard value m in Comparative Example 1. The melanin production in Comparative Examples 2 and 3 was calculated by dividing the measured value by m0 and subtracting it from 1 to obtain a percentage. The rate of decrease in the amount was r.

[0070] Regarding the melanin production reduction rate r in Examples 1 to 6, Examples 10 to 12, and Comparative Examples 4 to 17, The melanin amount standard value m was set at 0.0 The standard value of melanin amount when added to be 0.6% by weight m 0.006 Divide it by 1 The value subtracted from the above was expressed as a percentage. The melanin amount standard value m was set at 0.00 for the final concentration of only the heparinoid as the test drug. The standard value m of melanin when added to make 2% by weight 0.002a Divide it by 1 The percentage was calculated by subtracting r from r. The formula for calculating the melanin production reduction rate r is shown below.

[0071]

number

[0072] (Evaluation Results) The evaluation results are shown in Tables 1 to 6.

[0073] [Table 1]

[0074] [Table 2]

[0075] [Table 3]

[0076] [Table 4]

[0077] [Table 5]

[0078] [Table 6]

[0079] According to Table 1, Comparative Example 1, which does not contain a heparinoid in the cell lysate, and Comparative Example 2, which contains a heparinoid When compared with Comparative Examples 2 and 3, in which the final concentration of the heparinoid was 0.006 The effect of reducing the amount of melanin produced in Comparative Example 2, which is % by weight, is less than that in Comparative Example 1. On the other hand, Comparative Example 3, in which the final concentration of the heparinoid was 0.002% by weight, showed a higher concentration than Comparative Example 1. The effect of reducing melanin production was slightly increased. Even when heparinoids are used alone, they do not contribute to reducing melanin production. It is clear that this is not the case.

[0080] According to Table 2, when the cell lysate contains ingredient (B) allantoin or panthenol, In all of the comparative examples 4 to 7, the heparinoid was added alone. It can be seen that the amount of melanin produced increases when allantoin or When panthenol is used alone, it has no effect of reducing melanin production. I realize that this is not possible.

[0081] In addition, according to Table 3, the cell lysate contains component (C), polyoxyethylene hydrogenated castor oil. In Comparative Examples 8 to 11, which contained polysorbate 50 or polysorbate 60, It can be seen that the amount of melanin produced is increased compared to when the substance is used alone. Therefore, when polyoxyethylene hydrogenated castor oil 50 or polysorbate 60 was added to the cell lysate, It has been found that when used alone, it has no effect at all in reducing melanin production. Light.

[0082] Therefore, ingredients (A), (B) and (C) have no effect of reducing melanin production when used alone. It can be seen that it does not have

[0083] According to Table 4, the ingredients (A) and (B) are mixed, but the ingredient (C) is not mixed. Comparative Example 12 and Comparative Example 13, in which the components (A) and (C) were blended but the components ( Comparative Example 14 in which component (B) was not blended, and Comparative Example 15 in which component (B) and component (C) were blended However, in all of Comparative Examples 15 to 17, which do not contain component (A), the heparinoid is a single component. It can be seen that the amount of melanin produced is increased compared to when it is mixed alone. Therefore, even if two of the ingredients (A), (B), and (C) are combined, melanin production is not increased. It can be seen that it has no effect on reducing the amount.

[0084] According to Tables 5 and 6, all of the components (A), (B) and (C) were added to the cell lysate. In Examples 1 to 12, the amount of melanin was reduced compared to when a heparinoid was used alone. It can be seen that the amount of melanin produced is reduced. Therefore, it is a component that is not effective in suppressing melanin production. Only when components (B) and (C) are combined with (A) can melanin be produced. It can be seen that the effect of reducing the amount of production is obtained.

[0085] In addition, JP 2011-231128 A discloses that a skin external preparation contains a heparinoid, arabinopeptide, and cyclohexylglycerol. It is disclosed that the formulation contains anthoin and pantothenic acid, and monostearin as an additive. It is disclosed that a surfactant such as sorbitan acetate is blended. Publication No. 6183 describes a topical ointment containing heparinoids, allantoin, and pantothenic acid. The composition for topical use is disclosed, and the composition for topical use contains, as optional ingredients, allantoin, pantothenic acid, and In other words, the composition for external use according to the present invention can be formulated with a surfactant. It is known to combine all of the components (A), (B) and (C). The literature states that the combination of ingredients (A), (B) and (C) suppresses melanin production. The effect of suppressing melanin production is not disclosed in the present invention. It was first discovered by these researchers.

[0086] The topical composition contains components (A), (B) and (C), and thereby induces melanin production in melanocytes. It has the effect of reducing ranin production, so it suppresses or prevents skin pigmentation. It can be seen that the effect of preventing the formation of sebum is obtained. In addition, the composition for external use contains components (A), (B) and ( C) reduces melanin production, so that keratinocytes in the basal layer of the skin During cell turnover, the amount of melanin produced by new cells decreases. It can be seen that the effect of preventing and improving skin pigmentation can be obtained. The composition contains components (A), (B) and (C) to stimulate melanin production in melanocytes. It has the effect of reducing the amount of keratinocytes in the dermis, so it is also effective in reducing bruises (e.g., black bruises, brown bruises, It has been found to be effective in preventing and improving pigmentation caused by bruises.

[0087] Next, Examples 1 to 5, in which polyoxyethylene hydrogenated castor oil 50 was blended as component (C), were used. Consider 3, 5-9. Figure 1 shows the relationship between the amount of polyoxyethylene hydrogenated castor oil 50 and the 1 is a graph showing the relationship between the rate of decrease in the amount of ranin produced and the amount of E1 to E3 and E5 in the graph. 〜E9 are data on the reduction rate of melanin production in Examples 1 to 3 and Examples 5 to 9, respectively. The component (A) is a heparinoid (final concentration: 0.006% by weight). Allantoin (final concentration: 0.02% by weight) was added as component (B), and component (C) The broken line L1 shows a comparison of Examples 1 to 3 in which only the amount of component (A) was changed. Heparinoids (final concentration: 0.006% by weight) were added, and Panthenol was added as component (B). Example 5 and Example 6 in which only the amount of component (C) was changed, The comparison of the samples with 6 is shown by the dashed line L2. Furthermore, a heparinoid (final concentration: 0 0.002% by weight) was blended, and panthenol (final concentration: 0.01% by weight) was blended as component (B). The solid line L3 shows a comparison of Examples 7 to 9 in which only the amount of component (C) was changed.

[0088] From the graph in FIG. 1, the dashed line L1, dashed line L2, and solid line L3 all show the polysaccharides in the cell lysate. When the blending amount of trioxyethylene hydrogenated castor oil 50 was 0.04% by weight, the melanin production It can be seen that the reduction rate is improved to nearly 40%. When the amount of hydrogenated castor oil 50 is increased to more than 0.04% by weight, the melanin production reduction rate As a result, the change in the rate of decrease in melanin production is 0.04% by weight. It can be seen that the results change significantly depending on the amount of polyoxyethylene hydrogenated castor oil 50 added. Therefore, the blending amount of 0.04% by weight of polyoxyethylene hydrogenated castor oil 50 is This is the inflection point for the rate of change in the rate of decrease in melanin production, and the rate of decrease in melanin production has increased to about 40%. Therefore, the types and amounts of components (A) and (B) are of critical importance. Regardless of this, when the amount of component (C) is 0.04% by weight or more, excellent melanin production is achieved. From this, it can be seen that the reduction rate of polyoxyethylene hydrogenated castor oil 50 can be obtained. The lower limit of the blend amount is more preferably 0.04% by weight or more.

[0089] For this reason, the composition of components (A) and (B) in the topical composition for actual use is Regardless of the total amount and type, when the amount of component (C) is equal to or greater than a specified concentration, the composition has particularly excellent properties. It is believed that this has the effect of reducing melanin production.

[0090] (Evaluation Test II) Next, Example 13 and Comparative Examples 18 to 19 prepared in Evaluation Test II will be described. do.

[0091] (Sample preparation) In the dissolution treatment of melanoma cells, the concentration of NaOH added to each well was 4N. The samples were prepared in the same manner as in Evaluation Test I, except that the dissolution treatment conditions were 60°C and 3 hours. A pool was created.

[0092] (Test Drug) In each of Example 13 and Comparative Examples 18 to 19, the test drug was added to the cell lysate. The test substance was prepared so that the final concentrations of the components (A) to (C) contained therein were the values ​​shown below. The final concentrations of components (A) to (C) in each cell lysate were The details are also shown in Table 7.

[0093] (Comparative Examples 18 and 19) As the test drug, a drug containing only component (A) among components (A) to (C) was used as Comparative Example 1. In Comparative Example 18, the final concentration of the heparinoid was adjusted to 0.002% by weight. In addition, the test drug was prepared by adding only component (B) out of components (A) to (C). The result was designated Comparative Example 19. In Comparative Example 19, the final concentration of vitamin A oil was 0.003% by weight. It was prepared as follows.

[0094] (Example 13) The test drug for component (A) was a heparinoid, and the test drug for component (B) was vitamin A. The oil was mixed with polyoxyethylene hydrogenated castor oil 40 as the test drug for ingredient (C). In Example 13, the final concentration of the heparinoid was 0.002% by weight. The final concentration of vitamin A oil was 0.003% by weight, and polyoxyethylene hydrogenated castor oil 40 The amount of component (B) was adjusted so that the final concentration was 0.16% by weight. The ratio of the amount of (A) to the amount of (A) is 1.5 parts by weight. The proportion of component (A) in the blend is 80 parts by weight.

[0095] (Evaluation method) The absorbance of the cell lysates of Example 13 and Comparative Examples 18 to 19 was measured in the same manner as in Evaluation Test I. From these results, the following formula was used as in Evaluation Test I: Based on this, a melanin amount standard value was obtained.

[0096] (Melanin amount standard value) = (Melanin production amount) / (protein amount)

[0097] The melanin amount standard value of Comparative Example 18 is m 0.002b In addition, Example 13 or Comparative Example The melanin amount standard value m of Comparative Example 19 and the melanin amount standard value m of Comparative Example 18 0.002b Using The melanin production reduction rate r of Example 13 or Comparative Example 19 was calculated.

[0098]

number

[0099] (Evaluation Results) The results of these evaluations are shown in Table 7.

[0100] [Table 7]

[0101] According to Table 7, even when vitamin A oil was added as ingredient (B), the It has been shown that the use of this product in combination with component (C) has the effect of reducing melanin production. It was criticized. [Industrial Applicability]

[0102] The present invention is useful for a composition for external use used to suppress, prevent, prevent or improve skin diseases. It is.

Claims

1. A composition for external use used for suppressing, preventing, preventing or improving skin pigmentation, comprising: (A) a heparinoid; (B) one or more selected from the group consisting of allantoin, pharma- ceutically acceptable derivatives of allantoin, and pharma-ceutically acceptable salts thereof; (C) a nonionic surfactant; A topical composition comprising: Pharmaceutically acceptable derivatives of allantoin are allantoic acid, dihydroxyaluminum allantoinate, allantoin glycyrrhetin, or chlorohydroxyaluminum allantoinate; (C) the nonionic surfactant comprises at least one selected from polyoxyethylene hydrogenated castor oil and polysorbate 60; The proportion of the component (A) in the total amount of the composition for external use is 0.006 to 1% by weight, The proportion of the component (B) in the total amount of the composition for external use is 0.01 to 5% by weight, The proportion of the component (C) in the total amount of the composition for external use is 0.01 to 10% by weight, The content of component (B) is 0.1 to 25 parts by weight per part by weight of component (A), A composition for external use (excluding the following compositions) in which the content of component (C) is 0.1 to 80 parts by weight per 1 part by weight of component (A). (1) A pharmaceutical composition for external application comprising a heparinoid, one or more substances selected from the group consisting of allantoin, pharma- ceutically acceptable derivatives of allantoin, and pharma- ceutically acceptable salts thereof, and one or more substances selected from the group consisting of pantothenic acid, panthenol, pantothenyl ethyl ether, acetylpantothenyl ethyl ether, and pharma-ceutically acceptable salts thereof. (2) A composition for external use comprising at least one vitamin A selected from retinol, retinal, retinoic acid, their dehydrogenated forms, their esters, and provitamin A, and a heparinoid. (3) Compositions containing diphenhydramine or a salt thereof (4) A composition comprising a polyhydric alcohol and solid particles having an average particle size of 10 to 3,000 μm, the content of the polyhydric alcohol being 30 to 90% by mass in the composition. (5) A composition comprising tocopherol acetate, squalane, jojoba oil, acrylic acid / alkyl methacrylate copolymer, and polyglyceryl pentaoleate. (6) A composition containing at least one selected from the group consisting of acyclovir, vidarabine, penciclovir, famciclovir, valacyclovir, and salts thereof.

2. The topical composition according to claim 1, used for inhibiting, preventing, prophylaxis or amelioration of pigmentation caused by itchy skin diseases, pigmentation after wounds have healed, pigmentation due to hormonal imbalance, pigmentation due to aging, pigmentation due to sunburn, pigmentation due to friction, or pigmentation due to bruises.

3. An external composition described in claim 1 or 2, containing 1 to 50 parts by weight of component (C) per 1 part by weight of component (A).

4. An external composition described in any of claims 1 to 3, wherein the allantoin, its pharma-ceutically acceptable salt, and their pharma-ceutically acceptable derivatives comprise one or more selected from the group consisting of allantoin, chlorohydroxyaluminum allantoinate, and dihydroxyaluminum allantoinate.

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