Topical skin composition, topical skin composition for antibacterial and bactericidal effects against propionibacterium acnes, and topical skin composition for selective antibacterial and bactericidal effects against propionibacterium acnes

Abstract

To provide a composition containing isopropyl methylphenol and the like, which delivers excellent antibacterial and bactericidal effects against Propionibacterium acnes, exhibits reduced cloudiness under low-temperature conditions, and demonstrates excellent low-temperature stability.SOLUTION: A topical skin composition comprises (A) at least one selected from isopropyl methylphenol and the like, (B) at least one selected from pantothenic acid and the like, (C) at least one selected from polyethylene glycol fatty acid esters with the fatty acid chain length ranging from 12 to 16, and the like, and (D) at least one selected from polyethylene glycol fatty acid esters with the fatty acid chain length of 18, and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for external use on the skin, an antibacterial and bactericidal composition for external use on the skin against Propionibacterium acnes, and a selective antibacterial and bactericidal composition for external use on the skin against Propionibacterium acnes. [Background technology]

[0002] On the skin of healthy people, Staphylococcus epidermidis and Propionibacterium acnes exist as resident skin bacteria and play a role in maintaining skin homeostasis. Staphylococcus epidermidis is known as a beneficial resident bacteria because it strengthens the barrier function of the skin, maintains the moisturizing function, and has an antibacterial effect against pathogenic bacteria. On the other hand, Propionibacterium acnes is known to cause acne by excessive proliferation due to the blockage of pores and excessive secretion of sebum, and inflammation and other conditions caused by the fatty acids it produces. In the treatment of acne, a method is used in which inflammation is calmed by anti-inflammatory ingredients and Propionibacterium acnes is killed by bactericidal ingredients such as isopropyl methylphenol (IPMP), which has a bactericidal effect. However, there has been a demand for a skin topical composition that has a more excellent antibacterial and bactericidal effect against Propionibacterium acnes. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2011-231082 A Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention has been made in view of the above circumstances, and aims to provide a composition for external use on the skin, which is a composition containing isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride or hinokitiol and has excellent antibacterial and bactericidal effects against Propionibacterium acnes. Preferably, the present invention aims to provide a composition for external use on the skin which has excellent antibacterial and bactericidal effects against Propionibacterium acnes and has little effect on the growth of Staphylococcus epidermidis. Furthermore, the present invention aims to provide a composition for external use on the skin which is inhibited from becoming cloudy in a low-temperature environment and has excellent low-temperature stability. [Means for solving the problem]

[0005] As a result of intensive research by the present inventors to achieve the above-mentioned object, it has been found that the present invention is capable of producing a fatty acid ester having a fatty acid chain length of 12 to 16, which is selected from the group consisting of (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, as well as alkyl esters having a fatty acid chain length of 12 to 16. It has been found that by containing (A) one or more selected from polyoxyethylene alkyl ethers having a fatty acid chain length of 12 to 16, and (B) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, all of which have a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18, a topical skin composition having excellent antibacterial and bactericidal effects against P. acnes, and an antibacterial and bactericidal topical skin composition for P. acnes can be obtained. It has been found that, preferably, the above composition can provide a composition for external application to the skin that has excellent antibacterial and bactericidal effects against Propionibacterium acnes and has a low effect on the growth of Staphylococcus epidermidis, and a selective antibacterial and bactericidal composition for external application to the skin against Propionibacterium acnes. In addition, the inventors have found that a composition containing the above (A) to (C) causes clouding in a low-temperature environment, and have further found that the occurrence of clouding in a low-temperature environment can be suppressed by containing (D) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, all of which have a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18, and have arrived at the present invention.

[0006] Therefore, the present invention provides the following inventions. 1. (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each having a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each having an alkyl chain length of 12 to 16, and (D) One or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, each having a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18. A composition for external use on the skin comprising: 2. The composition for external skin application according to 1, wherein the mass ratio of the component (D) to the component (C) is 0.05 to 3. 3. The composition for external use on the skin according to 1 or 2, wherein the content of the component (A) is 0.01 to 0.5% by mass. 4. The composition for external skin application described in any one of 1 to 3, wherein the HLB of the component (C) is 10 to 15. 5. A composition for external use on the skin according to any one of claims 1 to 4, which is for treating acne. 6. (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each having a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each having an alkyl chain length of 12 to 16, and (D) One or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, each having a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18. An external skin composition for antibacterial and germicidal use against acne bacteria. 7. (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each having a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each having an alkyl chain length of 12 to 16, and (D) One or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, each having a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18. The present invention relates to a composition for external application to the skin for selective antibacterial and bactericidal action against Propionibacterium acnes, which has antibacterial and bactericidal action against Propionibacterium acnes but does not have antibacterial and bactericidal action against Staphylococcus epidermidis. Effect of the Invention

[0007] According to the present invention, it is possible to provide a composition for external application to the skin that has an excellent antibacterial and bactericidal effect against Propionibacterium acnes, is inhibited from generating cloudiness in a low-temperature environment, and has excellent low-temperature stability, and a composition for external application to the skin for selective antibacterial and bactericidal use against Propionibacterium acnes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below. Hereinafter, the "composition for external application to the skin", the "composition for external application to the skin for antibacterial and bactericidal use against Propionibacterium acnes", and the "selective antibacterial and bactericidal composition for external application to the skin for antibacterial and bactericidal use against Propionibacterium acnes" may be collectively referred to as the "composition". [Component (A)] The component (A) is one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, and can be used alone or in combination of two or more. These components are effective bactericides for diseases such as eczema, dermatitis, and acne that may be aggravated by bacteria or fungi, and are effective in treating and preventing acne by killing acne bacteria that aggravate symptoms and suppressing the progression of pimples and acne. Isopropylmethylphenol is preferred because it has a lower effect on the growth of Staphylococcus epidermidis.

[0009] The content of component (A) is preferably 0.005 to 0.5% by mass, more preferably 0.01 to 0.3% by mass, and even more preferably 0.05 to 0.3% by mass, based on the composition. By making it 0.01% by mass or more, it becomes easier to obtain a bactericidal and antibacterial effect against Propionibacterium acnes, and by making it 0.5% by mass or less, it becomes harder to inhibit the growth of Staphylococcus epidermidis. If it is within the range of 0.005 to 0.5% by mass, it is possible to obtain a bactericidal and antibacterial effect that is more excellent against Propionibacterium acnes and has a lower effect on the growth of Staphylococcus epidermidis, and thus a bactericidal and antibacterial power that is effective for acne treatment can be obtained.

[0010] [(B) Component] The component (B) is one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, and can be used alone or in combination of two or more. The component (B) has an excellent antibacterial and bactericidal effect against P. acnes and has a low effect on the growth of Staphylococcus epidermidis. Furthermore, by having the component (B) in combination, a selective antibacterial and bactericidal effect can be obtained against P. acnes and the effect on the growth of Staphylococcus epidermidis can be reduced.

[0011] From the viewpoint of effectiveness, panthenol and pantothenyl ethyl ether are preferred as component (B). Panthenol, a water-soluble vitamin, is known to have anti-inflammatory effects, activate skin cells, and enhance skin elasticity and moisture retention.

[0012] Panthenol and salts of pantothenic acid such as calcium pantothenate and sodium pantothenate are converted to pantothenic acid inside the skin and exert the above-mentioned pharmacological effects. Pantothenyl ethyl ether is the ethyl ether of panthenol, and like panthenol, is converted to pantothenic acid inside the body.

[0013] The content of component (B) is preferably 0.1 to 2% by mass, more preferably 0.3 to 2% by mass, based on the composition. By making it 0.1% by mass or more, the bactericidal and antibacterial effect against Propionibacterium acnes is further improved. Also, by making it 2% by mass or less, the effect on the growth of Staphylococcus epidermidis is reduced.

[0014] [(C) component] The component (C) is one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each of which has a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each of which has an alkyl chain length of 12 to 16, and can be used alone or in combination of two or more.

[0015] The fatty acid chain length or alkyl chain length of component (C) is 12 to 16, preferably 12 and 14, and more preferably 12. By making it equal to or greater than the above lower limit, irritation to the skin is further suppressed. By making it equal to or less than the above upper limit, the antibacterial and germicidal effect against P. acnes is further improved. The number of moles of polyoxyethylene added is preferably 6 to 40, more preferably 6 to 25, and even more preferably 10 to 15. By making it within the above upper and lower limits, the low temperature stability is further improved, the effect on the growth of Staphylococcus epidermidis is further reduced, and the germicidal and antibacterial effect against P. acnes is further improved. Furthermore, monoesters are preferred because they make it easier to obtain excellent antibacterial and germicidal effects against P. acnes.

[0016] The HLB (Hydrophile-Lipophile Balance) of the component (C) is preferably 10 to 15, more preferably 10 to 14, and even more preferably 10 to 13. By making it equal to or higher than the lower limit, the low-temperature stability is further improved. By making it within the above range, it becomes easier to interact with the cell wall and cell membrane of bacteria, so that it is easy to obtain excellent antibacterial and bactericidal effects against P. acnes and Staphylococcus aureus. HLB is an index of affinity for water and oil, and generally, the closer to 0, the higher the lipophilicity, and the closer to 20, the higher the hydrophilicity. HLB can be calculated by any of the Atlas method, Griffin method, Davis method, Kawakami method, etc., and the value published by the manufacturer for the product can be taken into consideration. The HLB in this specification is calculated in accordance with the actual measurement of the HLB value by the emulsification method described in "Handbook - Cosmetics and Pharmaceutical Raw Materials - Revised Edition", Nikko Chemicals Co., Ltd., revised edition published on February 1, 1977, pages 854-855. A specific method for determining the HLB value is to combine the above-mentioned component (C) with sorbitan monostearate (NIKKOL SS-10, HLB 4.7) as a standard emulsifier, keep the total amounts of these two types of emulsifiers constant, and emulsify liquid paraffin (HLB 10.1) to be emulsified by changing only the ratio. After leaving the mixture for one day and night, the optimal ratio of emulsifiers that is stable is determined from the amount of creaming, turbidity, and water separation from the lower layer, and the HLB value x of the above-mentioned component (C) is calculated using the following formula (1). y=(x×Amount used (mass%)+z×Amount used (mass%)) / 100...Formula (1) In the formula (1), "x" represents the HLB value of the component (C), "y" represents the HLB value of liquid paraffin, and "z" represents the HLB value of sorbitan monostearate (NIKKOL SS-10). The HLB value of liquid paraffin can be determined in a similar manner using a combination of sorbitan monostearate (NIKKOL SS-10, HLB 4.7) and POE sorbitan monostearate (NIKKOL TS-10, HLB 14.9).

[0017] Examples of polyethylene glycol fatty acid esters with fatty acid chain lengths of 12 to 16 include polyethylene glycol monolaurate (10EO) and polyethylene glycol monolaurate (12EO). The numbers in parentheses in the above-listed polyethylene glycol fatty acid esters indicate the average degree of polymerization of ethylene oxide, that is, the average number of repeating oxyethylene groups. The same applies to the following polyoxyethylene sorbit fatty acid esters and polyoxyethylene alkyl ethers.

[0018] Examples of polyoxyethylene sorbitol fatty acid esters having a fatty acid chain length of 12 to 16 include polyoxyethylene sorbitol monolaurate (6EO).

[0019] As the sorbitan fatty acid ester having a fatty acid chain length of 12 to 16, a fatty acid chain length of 12 is preferable. Also, a monoester is preferable. Specific examples thereof include sorbitan monolaurate.

[0020] Examples of polyglycerol fatty acid esters having a fatty acid chain length of 12 to 16 include polyglyceryl monolaurate and decaglyceryl monomyristate.

[0021] Examples of polyoxyethylene glycerin fatty acid esters having a fatty acid chain length of 12 to 16 include polyoxyethylene glyceryl laurate (9EO).

[0022] Examples of polyoxyethylene alkyl ethers having an alkyl chain length of 12 to 16 include lauromacrogol such as polyoxyethylene (4) lauryl ether and polyoxyethylene (9) lauryl ether; polyoxyethylene (10) cetyl ether; and the like.

[0023] As component (C), monoesters are preferred because they more easily provide antibacterial and bactericidal effects against acne bacteria.Moreover, polyethylene glycol monolaurate (10EO), polyethylene glycol monolaurate (12EO), decaglyceryl monomyristate, and polyoxyethylene (9) lauryl ether are preferred because they more easily provide antibacterial and bactericidal effects against acne bacteria.

[0024] The content of component (C) is preferably 0.1% by mass or more relative to the composition in order to obtain a better antibacterial and bactericidal effect against P. acnes, and is preferably 10% by mass or less, more preferably 0.3 to 6% by mass, and even more preferably 0.7 to 3% by mass in order to improve low-temperature stability and reduce the effect on the growth of Staphylococcus epidermidis. By making the content equal to or greater than the lower limit, the antibacterial and bactericidal effect against P. acnes is improved. By making the content equal to or less than the upper limit, the low-temperature stability is improved and the effect on the growth of Staphylococcus epidermidis is reduced.

[0025] [(D) component] The (D) component is one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, all of which have a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18, and can be used alone or in combination of two or more.

[0026] The fatty acid chain length or alkyl chain length of the (D) component is 18. The combination of the (C) component and the (D) component improves the low temperature stability of the composition. From the viewpoint of low temperature stability, the fatty acid chain or alkyl chain is preferably a structure having an unsaturated bond (e.g., oleic acid or an oleyl group) or a branched structure (e.g., isostearic acid or an isostearyl group). From the viewpoint of low temperature stability, the structure of the hydrophilic group is preferably polyoxyethylene or polyglycerin, and more preferably polyoxyethylene. From the viewpoint of low temperature stability, the lower limit of the number of moles of polyoxyethylene added is preferably 10 or more when the fatty acid chain or alkyl chain has an unsaturated bond or a branched structure, and is preferably 25 or more when it does not have an unsaturated bond or a branched structure (e.g., stearic acid or a stearyl group). The upper limit is not particularly limited, but is preferably 100 or less, more preferably 60 or less, since the effect of improving low temperature stability can be obtained with a smaller content.

[0027] The HLB (hydrophile-lipophile balance) of component (D) is preferably 10 to 20, and more preferably 11 to 18. By making it equal to or higher than the above lower limit, the low temperature stability is further improved. By making it equal to or lower than the above upper limit, the antibacterial and bactericidal effect against acne bacteria is further improved.

[0028] Examples of polyethylene glycol fatty acid esters having a fatty acid chain length of 18 include polyethylene glycol monooleate (10EO), polyethylene glycol monooleate (6EO), polyethylene glycol monostearate (10EO), polyethylene glycol monostearate (25EO), polyethylene glycol monostearate (40EO), and polyethylene glycol monostearate (100EO).

[0029] Examples of polyoxyethylene sorbitol fatty acid esters having a fatty acid chain length of 18 include polyoxyethylene sorbitol tetrastearate (60EO), polyoxyethylene sorbitol tetraoleate (60EO), polyoxyethylene sorbitol tetraoleate (40EO), and polyoxyethylene sorbitol tetraoleate (30EO).

[0030] Examples of polyoxyethylene sorbitan fatty acid esters having a fatty acid chain length of 18 include polyoxyethylene sorbitan monooleate (20EO) and polyoxyethylene sorbitan trioleate (20EO).

[0031] Examples of polyglycerol fatty acid esters with a fatty acid chain length of 18 include polyglyceryl-10 monostearate, polyglyceryl-10 monooleate, polyglyceryl-10 monoisostearate, etc. The final numbers in the notations of the polyglycerol fatty acid esters exemplified above indicate the average degree of polymerization of glycerin.

[0032] Examples of polyoxyethylene glycerin fatty acid esters having a fatty acid chain length of 18 include polyoxyethylene glyceryl trioleate (20EO), polyoxyethylene glyceryl monostearate (15EO), and polyoxyethylene glyceryl isostearate (15EO).

[0033] Examples of polyoxyethylene hydrogenated castor oils having a fatty acid chain length of 18 include polyoxyethylene hydrogenated castor oil 60 (60EO), polyoxyethylene hydrogenated castor oil 80 (80EO), and polyoxyethylene hydrogenated castor oil 100 (100EO).

[0034] An example of a polyoxyethylene alkyl ether having an alkyl chain length of 18 is polyoxyethylene (10) oleyl ether.

[0035] As component (D), polyethylene glycol monooleate (10EO), polyethylene glycol monostearate (10EO to 100EO), polyglyceryl monoisostearate (10EO), polyoxyethylene glyceryl trioleate (20EO), and polyoxyethylene sorbitol tetraoleate (60EO) are preferred, since they further improve the low-temperature stability of the composition, further improve the bactericidal and antibacterial effects of components (A) to (C) against Propionibacterium acnes, and further reduce the effect on the growth of Staphylococcus epidermidis.

[0036] The content of component (D) is preferably 0.1 to 5% by mass, more preferably 0.2 to 3% by mass, and even more preferably 0.2 to 1% by mass, based on the composition. By making it equal to or more than the lower limit, low temperature stability is further improved. By making it equal to or less than the upper limit, antibacterial and bactericidal effects against acne bacteria are further improved.

[0037] The content mass ratio of the (D) component to the (C) component ((D) / (C)) is preferably 0.05 to 3, more preferably 0.1 to 1.5, even more preferably 0.13 to 1, particularly preferably 0.13 to 0.8, and most preferably 0.15 to 0.8. By making the content equal to or greater than the above lower limit, low temperature stability is further improved. By making the content equal to or less than the above upper limit, antibacterial and bactericidal effects against acne bacteria are further improved.

[0038] [Composition for external use on the skin, composition for external use on the skin for antibacterial and bactericidal use against acne bacteria, and composition for external use on the skin for selective antibacterial and bactericidal use against acne bacteria] The composition of the present invention has excellent antibacterial and bactericidal properties against acne bacteria when applied to the skin in an appropriate amount (generally 0.1 to 0.5 g [solid or semi-solid preparations such as creams and gels] or 1 to 5 mL [liquid preparations such as lotions and aerosols], depending on the application area). Preferably, the composition has excellent antibacterial and bactericidal properties against acne bacteria and has low effect on the growth of Staphylococcus epidermidis, a normal skin bacterium. In addition, acne bacteria are selectively antibacterial and bactericidal, and have low effect on the growth of Staphylococcus epidermidis, a normal skin bacterium. When Staphylococcus epidermidis is killed, the skin becomes easily dried and sebum secretion becomes excessive, which makes pores easily clogged and easily induces acne. Not only the anti-inflammatory and bactericidal components, but also the effect on the growth of Staphylococcus epidermidis, a normal skin bacterium, is low, so that a sufficient therapeutic effect against acne can be obtained.

[0039] The composition of the present invention is useful for treating acne, pimples, xerosis, dry skin in children, rough hands and fingers, cracks and chapped hands and feet, keratosis of elbows, knees, heels and ankles, chilblains (excluding sores), lumps and tightness of the skin after wounds and burns (excluding the face), itching, eczema, dermatitis, rashes, hives, heat rash, insect bites, etc., and also for preventing rough skin, chapped skin, heat rash, chilblains, cracks, chapped skin and acne, preventing oily skin, razor burn, preventing spots and freckles due to sunburn, preventing hot flashes after sunburn or snowburn, tightening the skin, cleansing the skin, toning the skin, and moisturizing the skin. It can be used in quasi-drugs having the effects and efficacy of keeping skin fresh, moisturizing the skin, protecting the skin, preventing dryness of the skin, etc., and in cosmetics having the effects and efficacy of cleaning the skin, preventing acne and heat rash, conditioning the skin, conditioning the skin texture, keeping the skin healthy, preventing rough skin, moisturizing the skin, replenishing and maintaining moisture and oil in the skin, maintaining flexibility of the skin, protecting the skin, preventing dryness of the skin, softening the skin, giving firmness to the skin, smoothing the skin, conditioning the skin after shaving, preventing sunburn, preventing spots and freckles caused by sunburn, making fine wrinkles caused by dryness less noticeable, etc. Among these, it is suitable as an external acne skin composition that prevents acne, treats acne, and improves acne symptoms, and a moisturizing external skin composition. It is also suitable as an external skin composition for selectively antibacterial and bactericidal action against Propionibacterium acnes, and has a low effect on the growth of Staphylococcus epidermidis. The criteria for "antibacterial / bactericidal" and "low effect on growth" will be based on the examples described below.

[0040] In particular, in the case of a selective antibacterial and bactericidal composition for skin application against acne bacteria, from the viewpoint of reducing the influence on the growth of Staphylococcus epidermidis, it is preferable that the topical preparation is substantially free (at effective concentrations) of the bactericidal components in the composition, namely hydrogen peroxide, sodium hypochlorite, isopropanol, obanol, cetylpyridinium chloride, cresol, povidone iodine, iodine, sodium dichloroisocyanurate, and acrinol. Substantially free means less than 0.3% by mass, more preferably less than 0.1% by mass, even more preferably less than 0.01% by mass, and particularly preferably free (below the detection limit).

[0041] The dosage form of the composition of the present invention is not particularly limited as long as it can be applied transdermally, and may be any of liquid, solid, and semi-solid (gel, ointment, paste, and foam). The composition of the present invention may be any of medicines, quasi-drugs, cosmetics, and skin cleansing agents (face washes, etc.). Specific examples of the formulation form (dosage form) of the composition include ointments, creams, lotions, gels, emulsions, liquids, patches, sprays that are sprayed in the form of mist or foam, aerosols that are sprayed in the form of mist, powder, foam, or paste, and packs. Among these, ointments, creams, lotions, gels, aerosols, sprays, emulsions, and packs are preferred, and creams, lotions, emulsions, aerosols that are sprayed in the form of foam, and pump sprays that are sprayed in the form of foam are more preferred. The emulsified state of creams, milky lotions, etc. is not particularly limited, and may be any of W / O, O / W, W / O / W, and O / W / O. The appearance of the composition is preferably transparent to semi-transparent, since it is more effective in suppressing the occurrence of cloudiness in a low-temperature environment. In the present invention, "transparent" means that when a glass cell with an optical path length of 10 mm is used as the measurement cell and ion-exchanged water is placed in the control cell, the light transmittance at a wavelength of 660 nm is 95% or more, and "semi-transparent" means that the transmittance is 30% or more and less than 95%.

[0042] The pH of the composition of the present invention is preferably 3 or more, more preferably 3.5 or more, from the viewpoint of antibacterial and bactericidal activity against Propionibacterium acnes. The upper limit of the pH is preferably 10 or less, more preferably 9 or less, from the viewpoint of skin irritation. The pH is measured according to the General Tests of the Japanese Pharmacopoeia, 18th Edition (measurement temperature: 25°C).

[0043] The composition of the present invention may contain various active ingredients used in medicines, quasi-drugs, cosmetics, etc., as necessary, within the scope of not impairing the effects of the invention. For example, anti-inflammatory agents, antihistamines, antipruritic agents, wound healing agents, local anesthetics, vascular repair agents, keratin softeners, vitamins (excluding component (B)), surfactants (excluding components (C) and (D)), cooling agents, moisturizers, amino acids, etc., and examples of the following ingredients are possible. The balance may also include water.

[0044] Examples of anti-inflammatory agents include tranexamic acid, glycyrrhetinic acid, glycyrrhizic acid or a pharma- ceutically acceptable derivative thereof or a salt thereof (e.g., dipotassium glycyrrhizinate), licorice extract, steroid compounds (hydrocortisone, prednisolone, methylprednisolone, clobetasone, betamethasone, dexamethasone, cortisone, flumethasone, beclomethasone, fluticasone or a pharma- ceutically acceptable derivative thereof or a salt thereof), indomethacin, ibuprofen, ibuprofen piconol, bufexamac, ufenamate, piroxicam, ketoprofen, salicylic acid or a pharma- ceutically acceptable derivative thereof or a salt thereof, dimethylisopropylazulene, Angelica acutiloba extract, Lithospermum root extract, and the like.

[0045] Examples of the antihistamine include diphenhydramine, chlorpheniramine, mequitazine, azelastine, emedastine, ketotifen, or pharma- ceutically acceptable derivatives or salts thereof, etc. Preferred are diphenhydramine hydrochloride and chlorpheniramine maleate.

[0046] Examples of antipruritic agents include crotamiton, vanillylamide nonylate, capsaicin, benzyl nicotinate, capsicum tincture, etc. Examples of wound healing agents include allantoin, zinc oxide, etc. Examples of local anesthetics include lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, and the like. Examples of vasoconstrictors include naphazoline, tetrahydrozoline, methylephedrine or salts thereof. Examples of keratin softening agents include urea, sulfur, salicylic acid or its pharma- ceutical acceptable derivatives and salts thereof, nicotinamide, kaolin, bentonite, and the like.

[0047] Vitamin preparations other than component (B) include vitamin A group [retinol and its pharma- ceutical acceptable derivatives and their salts (e.g., retinol palmitate, retinol acetate, retinol, retinal, retinoic acid, retinoids, etc.)], vitamin B 6 Vitamin C [ascorbic acid and its pharma- ceutical acceptable derivatives and their salts (e.g., ascorbic acid, sodium ascorbate, magnesium ascorbate phosphate, trisodium ascorbyl palmitate phosphate, erythorbic acid, ascorbic acid 2-glucoside, ascorbyl palmitate, etc.)], Vitamin E [tocopherol and its pharma-ceutical acceptable derivatives and their salts (e.g., ascorbic acid, sodium ascorbate, magnesium ascorbate phosphate, trisodium ascorbyl palmitate phosphate, erythorbic acid, ascorbic acid 2-glucoside, ascorbyl palmitate, etc.)], Tolerable derivatives and their salts (e.g., d-α-tocopherol, dl-α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, mixed tocopherols, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, vitamin E acetate (tocopherol acetate), vitamin E nicotinate, vitamin E succinate, vitamin E linoleate, natural vitamin E, etc.), vitamin B 1 [Thiamine and its pharma- ceutical acceptable derivatives and their salts (e.g., thiamine hydrochloride, thiamine nitrate, etc.)], vitamin B 2 [Riboflavin and its pharma- ceutical acceptable derivatives and salts thereof (e.g., riboflavin phosphate, riboflavin sodium phosphate, riboflavin butyrate, and sodium flavin adenine dinucleotide)], vitamin B 3 [Nicotinic acid and its pharma- ceutical acceptable derivatives and their salts (nicotinamide, benzyl nicotinate, etc.)], vitamin B 12class [cobalamin and its derivatives and their pharma- ceutical acceptable derivatives and salts thereof (e.g., cyanocobalamin, mecobalamin, hydroxocobalamin hydrochloride, etc.)], biotin, folic acid and its pharma-ceutical acceptable derivatives and salts thereof, vitamin D class [calciferol and its pharma-ceutical acceptable derivatives and salts thereof (e.g., ergocalciferol, cholecalciferol, etc.)], other vitamins (e.g., hesperidin, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, inositol, and its pharma-ceutical acceptable derivatives and salts thereof).

[0048] Examples of the surfactant other than the components (C) and (D) include nonionic surfactants other than the components (C) and (D), ionic surfactants, etc. Examples of the nonionic surfactant include glycerin fatty acid esters such as self-emulsifying glyceryl monostearate, sorbitan fatty acid esters with a fatty acid chain length of 18 such as sorbitan monostearate and sorbitan monooleate, polyoxyethylene polyoxypropylene alkyl ethers such as polyoxyethylene (20EO) polyoxypropylene (4PO) cetyl ether, fatty acid alkanolamides such as coconut oil fatty acid diethanolamide, sucrose fatty acid esters, and alkyl glucosides. Among the ionic surfactants, the anionic surfactants include fatty acid soaps such as laurate, myristate, palmitate, and stearate, alkyl sulfates such as lauryl sulfate, alkyl ether sulfates such as laureth sulfate, amino acid surfactants such as cocoyl alanine salt, cocoyl glutamine salt, and cocoyl sarcosine salt, and lauroyl methyl taurine salt, and the types of salts include alkali metal salts such as sodium and potassium, and triethanolamine salt.The amphoteric surfactants include betaines such as cocamidopropyl betaine.

[0049] When a surfactant other than the components (C) and (D) is contained, the content in the composition for external use on skin is preferably low in order to further reduce the influence on the growth of Staphylococcus epidermidis. Specifically, the content is preferably less than 3% by mass in the composition, more preferably less than 0.5% by mass, even more preferably 0.01% by mass or less, and particularly preferably none (below the detection limit).

[0050] Examples of the freshening agents include 1-menthol, camphor, borneol or related substances thereof, fennel oil, eucalyptus oil, peppermint oil, spearmint oil, and the like.

[0051] Examples of moisturizing agents include polyhydric alcohols (glycerin, 1,3-butylene glycol, 1,2-pentanediol, etc.), sugar alcohols (sorbitol, etc.), hyaluronic acid or derivatives thereof, heparinoids, polymeric compounds (collagen, chitosan, etc.), amino acids, natural moisturizing factors (sodium lactate, urea, etc.), ceramides, vegetable oils (olive oil, etc.), and plant extracts (soybean extract, chamomile extract, aloe extract, etc.).

[0052] Examples of amino acids include glutamic acid, aspartic acid, glycine, alanine, serine, aminoethylsulfonic acid (taurine), and pharma- ceutical acceptable salts thereof (eg, ephedrine hydrochloride, methylephenoline hydrochloride, etc.).

[0053] Others include hydrocarbons such as petrolatum, paraffin, liquid paraffin, squalane, ceresin, gelling hydrocarbons, and microcrystalline wax; higher fatty acids such as stearic acid, isostearic acid, myristic acid, palmitic acid, oleic acid, and behenic acid; higher fatty alcohols such as cetanol, stearyl alcohol, and behenyl alcohol; fatty acid ester oils such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, and diisopropyl adipate; triglycerin fatty acid esters such as glycerin triisooctanoate and tri(caprylic / capric acid)glyceryl; Polyhydric alcohols such as propylene glycol and polyethylene glycol; organic solvents such as acetone, methyl ethyl ketone, and ethyl acetate; pH adjusters such as diisopropanolamine, triethanolamine, lauric acid diethanolamide, sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, potassium dihydrogen phosphate, and sodium hydrogen phosphate; chelating agents such as disodium edetate, ethylenediaminetetraacetate, edetate, pyrophosphate, hexametaphosphate, citric acid, tartaric acid, and gluconic acid; preservatives such as parabens (methylparaben, ethylparaben, butylparaben), boric acid, and borax;Cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carmellose, croscarmellose, ethyl cellulose, and methyl cellulose, processed starches such as partially pregelatinized starch, polyvinyl alcohol, polyvinyl methyl ether, polyvinylpyrrolidone, crospovidone, polyethylene glycol, xanthan gum, carrageenan, sodium alginate, gum arabic, guar gum, tamarind gum, karaya gum, carob gum, tragacanth gum, locust bean gum, pullulan, gelatin, carboxyvinyl polymer, acrylic acid / alkyl methacrylate copolymer, polyacrylonitrile, polyacrylonitrile, polystyrene, polystyrene, polystyrene-poly ... Examples of thickeners include sodium acrylate, hydroxyethyl acrylate / acryloyldimethyl taurate crosslinked polymer, quince seed, casein, dextrin, sodium pectinate, dimethylacrylamide / acryloyldimethyl taurate crosslinked polymer, dialkyldimethylammonium cellulose sulfate, bentonite, hectorite, magnesium aluminosilicate, laponite, and anhydrous silicic acid; blended fragrances such as citrus fragrance, floral fragrance, and rose fragrance; essential oils (natural fragrances) such as peppermint oil, eucalyptus oil, bergamot oil, rose oil, rosemary oil, lavender oil, and lemon oil; and pearling agents such as ethylene glycol distearate.

[0054] The skin external composition of the present invention can be obtained by mixing the above (A) to (D) and, if necessary, optional ingredients with water (the balance). Furthermore, the pH can be adjusted to a set pH by using a pH adjuster. EXAMPLES

[0055] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, "%" in the composition indicates mass % and the ratio indicates mass ratio.

[0056] [Examples and Comparative Examples] The components shown in the table below were dissolved in purified water to prepare a skin topical composition (liquid). The pH of the obtained skin topical composition was measured in accordance with the General Test Methods of the Japanese Pharmacopoeia, 18th Edition (measurement temperature: 25°C), and further evaluated as described below. The results are also shown in the table. The pH of each Example and Comparative Example was 4 to 7.

[0057] [Antibacterial activity evaluation method] Inhibitory concentration (MIC) evaluation The antibacterial effects were evaluated by the broth microdilution method using a Staphylococcus epidermidis isolate (Staphylococcus epidermidis), which is considered to be a beneficial bacteria, and a Cutibacterium acnes isolate (Klebsiella acnes), which is an opportunistic bacteria. (1) Bacterial liquid preparation The following bacterial strains were each scraped off with a platinum loop, and Staphylococcus epidermidis was inoculated into SCD liquid medium (Shioya MS Co., Ltd.), and Klebsiella acnes was inoculated into GAM liquid medium (Nissui Pharmaceutical Co., Ltd.). Staphylococcus epidermidis was pre-cultured under aerobic conditions at 37°C for 24 hours, and Klebsiella acnes was pre-cultured under anaerobic conditions for 48 hours. The pre-cultured bacterial solutions were each inoculated at 2 x 10 5 Staphylococcus epidermidis was prepared in 2× SCD liquid medium at CFU / mL, and Propionibacterium acnes was prepared in 2× modified GAM bouillon liquid medium (Nissui Pharmaceutical Co., Ltd.). Staphylococcus epidermidis: Staphylococcus epidermidis NBRC 12993 Acne bacteria: Cutibacterium acnes NBRC 107605 Both of the above two strains were obtained from the National Institute of Technology and Evaluation (NBRC). (2) Test solution Compositions obtained in the examples and comparative examples (3) Test method 100 μL of the test solution was added to a 96-well round-bottom microplate, serially diluted with purified water in a 2-fold dilution series, and 100 μL of the bacterial solution prepared in (1) was inoculated thereto (final bacterial concentration 1 × 10 4CFU / mL). Staphylococcus epidermidis was then cultured at 32.5℃ under aerobic conditions, and Klebsiella acnes was cultured at 37℃ under anaerobic conditions, and the results were evaluated after 24 hours for Staphylococcus epidermidis and 48 hours for Klebsiella acnes. The table shows the minimum inhibitory concentration (dilution ratio) for Klebsiella acnes. A dilution ratio of 32 or more is preferable, and 64 or more is more preferable.

[0058] (4) Judgment criteria <Criteria for determining positive growth> If turbidity or precipitate with a diameter of 1 mm or more is observed with the naked eye When two or more precipitate lumps are found even if the diameter of the precipitate is less than 1 mm <Criteria for determining negative growth> When no turbidity or precipitation is visible to the naked eye If there is a precipitate, but it is less than 1mm in diameter and there is only one The inhibitory concentration (MIC) for a test bacterium is expressed as the minimum dilution concentration in the concentration series that inhibited the growth of the test bacterium (growth negative). In the examples of the present invention, in Examples 1 to 15, Staphylococcus epidermidis was positive for growth at 2-fold dilution, while in Examples 16 to 22, Staphylococcus epidermidis was negative for growth at 2-fold dilution.

[0059] [Low temperature stability] 50 g of the composition for external use on the skin was filled into a glass vial (capacity 50 mL), the vial was sealed with a lid, and then stored for one month at 25° C. and 5° C. Immediately after being taken out of the storage chamber, the appearance of the composition for external use on the skin was observed and evaluated according to the following evaluation criteria. <Low temperature stability evaluation criteria> ○: No or very little change in the 5℃ sample compared to the 25℃ sample, and the appearance is transparent ×: Compared to the sample stored at 25℃, the sample stored at 5℃ is clearly cloudy or has a precipitate at the bottom of the container.

[0060] [Table 1]

[0061] [Table 2]

[0062] [Table 3]

[0063] [Table 4]

[0064] The raw materials used in preparing the examples and comparative examples are listed below. The terms "Japanese Pharmacopoeia", "Extra-Pharmacopoeia Regulations", "Drug Additive Regulations", and "Extra-Raw Material Regulations" below refer to raw materials that comply with the 18th Revised Japanese Pharmacopoeia Standards, Japanese Pharmacopoeia Extra-Pharmacopoeia Standards, Pharmaceutical Additives Standards (2018), and Quasi-Drug Raw Materials Standards (2021), respectively. Isopropyl methylphenol: Isopropyl methylphenol, manufactured by Osaka Kasei Co., Ltd. Benzethonium chloride: Japanese Pharmacopoeia, Benzethonium chloride manufactured by Lonza Co., Ltd. Benzalkonium chloride: Reagent, Benzalkonium chloride, MP Biomedicals Chlorhexidine dihydrochloride: Reagent, chlorhexidine dihydrochloride Combi-Blocks Hinokitiol: Tonoharaki, Hinokitiol, manufactured by Takasago Chemical Co., Ltd. Panthenol: D-pantothenyl alcohol, manufactured by DSM Co., Ltd. Polyethylene glycol monolaurate (10): (HLB=12.5), manufactured by Nikko Chemicals Co., Ltd. Polyethylene glycol monolaurate (12): (HLB=13.7), foreign standard, Emanon 1112, Kao Corporation Polyethylene glycol monooleate (10): (HLB=11.0), manufactured by Nikko Chemicals Co., Ltd. Polyethylene glycol monostearate (25): (HLB=15.0), manufactured by Nikko Chemicals Co., Ltd. Polyethylene glycol monostearate (40): (HLB=17.5), manufactured by Nikko Chemicals Co., Ltd. Polyethylene glycol monostearate (100): (HLB=17), manufactured by EMALEX 8100R, manufactured by Nippon Emulsion Co., Ltd. Polyglyceryl monoisostearate (10): (HLB=12.0), manufactured by Nikko Chemicals Co., Ltd. Polyoxyethylene glyceryl trioleate (20): (HLB=14), Tonoharaki, EMALEX GWO-120, manufactured by Nippon Emulsion Co., Ltd. Polyoxyethylene sorbitol tetraoleate (60): (HLB=14.0), Tonoharaki, NIKKOL GO-460V, Nikko Chemicals Co., Ltd. 1,3-Butylene glycol, foreign standard, 1,3-butylene glycol, manufactured by Daicel Corporation

Claims

1. (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each having a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each having an alkyl chain length of 12 to 16; and (D) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, each of which has a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18. A composition for external use on the skin comprising:

2. The composition for external use on skin according to claim 1, wherein the mass ratio of the component (D) to the component (C) is 0.05 to 3.

3. The composition for external use on the skin according to claim 1, wherein the content of the component (A) is 0.01 to 0.5% by mass.

4. The composition for external use on skin according to claim 1, wherein the HLB of the component (C) is 10 to 15.

5. The composition for external application to the skin according to any one of claims 1 to 4, which is for treating acne.

6. (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each having a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each having an alkyl chain length of 12 to 16; and (D) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, each of which has a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18. An antibacterial and germicidal composition for topical application to the skin for treating acne bacteria comprising the compound.

7. (A) one or more selected from isopropylmethylphenol, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, and hinokitiol, (B) one or more selected from pantothenic acid, calcium pantothenate, sodium pantothenate, panthenol, and pantothenyl ethyl ether, (C) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, and polyoxyethylene glycerin fatty acid esters, each having a fatty acid chain length of 12 to 16, and polyoxyethylene alkyl ethers, each having an alkyl chain length of 12 to 16; and (D) one or more selected from polyethylene glycol fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, and polyoxyethylene hydrogenated castor oil, each of which has a fatty acid chain length of 18, and polyoxyethylene alkyl ethers having an alkyl chain length of 18. The present invention relates to an external skin composition for selectively inhibiting and killing acne bacteria, which contains the compound (I) and has antibacterial and bactericidal properties against acne bacteria but not against Staphylococcus epidermidis.

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