External components

Abstract

A topical composition containing (A) adapalene and / or its salt and (B) at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas, and mucopolysaccharides and its salts exhibits good dispersibility of adapalene and / or its salt. This topical composition may further contain (C) a polyhydric alcohol, (D) an emulsifier, and / or (E) a hydrocarbon base.

Description

[Technical Field]

[0001] The present invention relates to a topical composition comprising adapalene and / or a salt thereof. [Background technology]

[0002] Adapalene is a derivative of naphthalenecarboxylic acid and is used as an active ingredient in topical treatments for acne vulgaris. Acne vulgaris develops as comedones due to increased sebum secretion from the pilosebaceous system and blockage of hair follicles due to hyperkeratinization, which then progresses to an inflammatory rash. Adapalene suppresses comedonal formation by controlling epidermal keratinization and improving pore blockage. Deferin Gel 0.1% (trade name) (Galderma Inc.) is a known topical agent containing adapalene as an active ingredient. Deferin Gel 0.1% contains additives such as propylene glycol, methyl parahydroxybenzoate, carboxyvinyl polymer, polyoxyethylene (20) polyoxypropylene (20) glycol, sodium edetate hydrate, and sodium hydroxide (Non-Patent Document 1). In developing topical preparations, if the dispersibility of the ingredients in the topical preparation is poor, it is difficult to apply the ingredients uniformly. Also, if the ingredients aggregate in the topical preparation, the contact area of ​​the ingredients with the skin becomes small, making it difficult to achieve the desired medicinal effect. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Deferin Gel 0.1% Package Insert Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have found that the dispersibility of adapalene and / or a salt thereof in a topical composition is extremely poor. Therefore, an object of the present invention is to provide a topical composition containing adapalene and / or a salt thereof, in which the dispersibility of adapalene and / or a salt thereof is good. [Means for solving the problem]

[0005] The present inventors have conducted extensive research to solve the above-mentioned problems and have found that the dispersibility of adapalene and / or its salt in an external use composition containing (A) adapalene and / or its salt can be improved by adding (B) at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas, and mucopolysaccharides and its salts to the external use composition containing (A) adapalene and / or its salt.

[0006] The present invention was completed based on the above findings, and provides the following topical composition and method for improving the dispersibility of adapalene and / or a salt thereof. Item 1. A composition for external use containing (A) adapalene and / or a salt thereof, and (B) at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof. Item 2. The composition for external use according to Item 1, containing 0.001 to 1% by weight of component (A). Item 3. The composition for external use according to Item 1 or 2, containing 0.0001 to 20% by weight of component (B). Item 4. The composition for external use according to any one of Items 1 to 3, further comprising (C) a polyhydric alcohol. Item 5. The topical composition according to Item 4, wherein component (C) is at least one selected from the group consisting of dipropylene glycol, glycerin, 1,3-butylene glycol, and polyethylene glycol. Item 6. The composition for external use according to any one of Items 1 to 5, further comprising (D) an emulsifier. Item 7. The topical composition for external use according to Item 6, wherein the emulsifier (D) is at least one selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ether, and polyoxyethylene sorbitan fatty acid esters. Item 8. The composition for external use according to any one of Items 1 to 7, further comprising (E) a hydrocarbon base. Item 9. The composition for external use according to any one of Items 1 to 8, wherein the composition is in the form of a liquid, suspension, emulsion, cream, gel, lotion, spray, or aerosol. Item 10. A method for improving the dispersibility of adapalene and / or a salt thereof in a topical composition, comprising adding (A) to a topical composition containing adapalene and / or a salt thereof at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof. [Effects of the Invention]

[0007] Adapalene and / or its salts generally have very poor dispersibility in topical compositions, but the topical composition of the present invention further contains a component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas, and mucopolysaccharides and its salts, thereby improving the dispersibility and dispersion retention of adapalene and / or its salts. These components are moisturizing factors naturally present in the skin and are incorporated into cosmetics and the like as moisturizing agents. It is surprising that such moisturizing components improve the dispersibility of adapalene and / or its salts.

[0008] The topical composition of the present invention has good dispersibility of adapalene and / or its salt, so that the amount of adapalene and / or its salt applied is uniform when the topical composition is applied. Furthermore, the high dispersibility and uniformity of adapalene and / or its salt are maintained during the preparation of the formulation, facilitating the preparation. Furthermore, while components with poor dispersibility in topical compositions generally undergo significant aggregation when the composition is applied and dried, the composition of the present invention effectively suppresses aggregation of adapalene and / or its salt in the dried state after application. The topical composition of the present invention improves the dispersibility of adapalene and / or its salts by including factors naturally present in the skin or their analogs, such as ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid, lactic acid and its salts, ureas, and mucopolysaccharides and its salts. Therefore, to improve dispersibility, it is not necessary to add ingredients that are not necessary for the skin. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention will be described in detail below. The composition of the present invention is a topical composition containing (A) adapalene and / or a salt thereof, and (B) at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas, and mucopolysaccharides and its salts.

[0010] Adapalene and its salts The salt of adapalene may be any pharmaceutically or physiologically acceptable salt, and may include salts with organic bases (organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt, etc.), salts with inorganic bases (ammonium salt; alkali metal salts such as sodium salt, potassium salt, alkaline earth metal salts such as calcium salt, magnesium salt, metal salts such as zinc salt, aluminum salt, etc.).When the composition of the present invention contains a salt of adapalene, it may be formulated as a salt of adapalene, or it may be a salt formed in the composition as a result of separately formulating adapalene and an organic or inorganic base. Among adapalene and its salts, adapalene and salts of adapalene and inorganic bases are preferred, with adapalene being more preferred.

[0011] The content of adapalene and / or its salt is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, more preferably 0.05% by weight or more, and even more preferably 0.1% by weight or more, based on the total amount of the composition. It is also preferably 1% by weight or less, more preferably 0.3% by weight or less, and even more preferably 0.15% by weight or less. 0.1% by weight is the most preferred. Within this range, the appropriate pharmacological activity of adapalene and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt can be sufficiently achieved. The content of adapalene and / or a salt thereof may be 0.001 to 1 wt%, 0.001 to 0.3 wt%, 0.001 to 0.15 wt%, 0.01 to 1 wt%, 0.01 to 0.3 wt%, 0.01 to 0.15 wt%, 0.05 to 1 wt%, 0.05 to 0.3 wt%, 0.05 to 0.15 wt%, 0.1 to 1 wt%, 0.1 to 0.3 wt%, or 0.1 to 0.15 wt%, relative to the total amount of the composition.

[0012] Ceramides Examples of ceramides include sphingosine, phytosphingosine, ceramides in which a fatty acid is amide-bonded to sphingosine, sphingoglycolipids in which a sugar is bonded to a ceramide (typically, cerebrosides), sphingophospholipids in which a phosphate and a base are bonded to a ceramide (typically, sphingomyelin), synthetic ceramides having a structure similar to ceramide (N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, hexadecyloxy-PG hydroxyethylhexadecanamide, cetyl-PG hydroxyethylpalmitamide, etc.), human-type ceramides obtained by fermentation with yeast or the like (e.g., ceramide 2, ceramide 3, fermented ceramide), animal-derived ceramides extracted from the spinal cord or brain of an animal, plant-derived ceramides extracted from rice, soybean, corn, wheat, etc., and any of ceramides 1 to 10. Among these, synthetic ceramides are preferred because of their excellent effect of improving the dispersibility of adapalene, and N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide is more preferred. The ceramides can be used alone or in combination of two or more.

[0013] The content of ceramides is preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, even more preferably 0.005% by weight or more, and particularly preferably 0.01% by weight or more, based on the total amount of the composition. Also, the content is preferably 5% by weight or less, more preferably 1% by weight or less, even more preferably 0.5% by weight or less, and particularly preferably 0.25% by weight or less. Within this range, the appropriate physiological activity of the ceramides can be obtained, and the dispersibility of adapalene and / or its salts is sufficient. The content of ceramides may be 0.0005 to 5 wt%, 0.0005 to 1 wt%, 0.0005 to 0.5 wt%, 0.0005 to 0.25 wt%, 0.001 to 5 wt%, 0.001 to 1 wt%, 0.001 to 0.5 wt%, 0.001 to 0.25 wt%, 0.005 to 5 wt%, 0.005 to 1 wt%, 0.005 to 0.5 wt%, 0.005 to 0.25 wt%, 0.01 to 5 wt%, 0.01 to 1 wt%, 0.01 to 0.5 wt%, or 0.01 to 0.25 wt%, relative to the total amount of the composition.

[0014] The ratio of the content of ceramides to the content of adapalene and / or its salt is preferably 0.005 parts by weight or more, more preferably 0.01 parts by weight or more, even more preferably 0.05 parts by weight or more, and particularly preferably 0.1 parts by weight or more, per 1 part by weight of adapalene and / or its salt. Also, it is preferably 50 parts by weight or less, more preferably 10 parts by weight or less, even more preferably 5 parts by weight or less, and more preferably 2.5 parts by weight or less. Within this range, the appropriate physiological activity of the ceramides can be obtained, and the dispersibility of adapalene and / or its salt is sufficient. The ratio of the content of ceramides relative to the content of adapalene and / or a salt thereof can be 0.005 to 50 parts by weight, 0.005 to 10 parts by weight, 0.005 to 5 parts by weight, 0.005 to 2.5 parts by weight, 0.01 to 50 parts by weight, 0.01 to 10 parts by weight, 0.01 to 5 parts by weight, 0.01 to 2.5 parts by weight, 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0.05 to 5 parts by weight, 0.05 to 2.5 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, or 0.1 to 2.5 parts by weight, per 1 part by weight of adapalene and / or a salt thereof.

[0015] Cholesterols Examples of cholesterols include animal sterols such as cholesterol, cholestanol, lanosterol, selegurosterol, dehydrocholesterol, and cobrostanol; plant sterols such as phytosterol, sitosterol, stigmasterol, campesterol, ergosterol, fucosterol, and spinasterol; sterols derived from microorganisms such as ergosterol, mycosterol, and zymosterol; esters of these cholesterols with fatty acids (e.g., fatty acids having 10 to 18 carbon atoms, specifically, lauric acid, myristic acid, palmitic acid, stearic acid, hydroxystearic acid, oleic acid, and isostearic acid); and cholesterol derivatives such as alkyl ether derivatives in which the hydrogen atom of the hydroxyl group of these cholesterols is substituted with an alkyl group having 1 to 10 carbon atoms, alkyl esters in which the hydrogen atom of the hydroxyl group of these cholesterols is substituted with an acyl group having 1 to 10 carbon atoms, and glycosides in which the hydrogen atom is substituted with a sugar residue. Among these, animal sterols and derivatives thereof are preferred, cholesterol and derivatives thereof are more preferred, and cholesterol is even more preferred, in that they have a good effect of improving the dispersibility of adapalene and / or its salts. The cholesterols can be used singly or in combination of two or more.

[0016] The content of cholesterols is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, even more preferably 0.1% by weight or more, and particularly preferably 0.2% by weight or more, based on the total amount of the composition. Also, it is preferably 5% by weight or less, more preferably 2% by weight or less, even more preferably 1% by weight or less, and particularly preferably 0.9% by weight or less. Within this range, the appropriate physiological or pharmacological activity of cholesterols can be obtained, and adapalene and / or its salts can be sufficiently dispersed. Examples of the content of cholesterols relative to the total amount of the composition include 0.01 to 5 wt%, 0.01 to 2 wt%, 0.01 to 1 wt%, 0.01 to 0.9 wt%, 0.05 to 5 wt%, 0.05 to 2 wt%, 0.05 to 1 wt%, 0.05 to 0.9 wt%, 0.1 to 5 wt%, 0.1 to 2 wt%, 0.1 to 1 wt%, 0.1 to 0.9 wt%, 0.2 to 5 wt%, 0.2 to 2 wt%, 0.2 to 1 wt%, and 0.2 to 0.9 wt%.

[0017] The ratio of the content of cholesterols to the content of adapalene and / or its salt is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more, even more preferably 1 part by weight or more, and particularly preferably 2 parts by weight or more, per 1 part by weight of adapalene and / or its salt. Also, it is preferably 50 parts by weight or less, more preferably 20 parts by weight or less, even more preferably 10 parts by weight or less, and particularly preferably 9 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of the cholesterols can be obtained, and the dispersibility of adapalene and / or its salt is sufficient. The ratio of the cholesterol content to the adapalene and / or salt thereof content may be 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 9 parts by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 to 50 parts by weight, 1 to 20 parts by weight, 1 to 10 parts by weight, 1 to 9 parts by weight, 2 to 50 parts by weight, 2 to 20 parts by weight, 2 to 10 parts by weight, or 2 to 9 parts by weight, per 1 part by weight of adapalene and / or a salt thereof.

[0018] Amino acids Examples of amino acids include neutral amino acids with alkyl chains such as glycine, alanine, valine, leucine, and isoleucine; neutral amino acids with hydroxy groups such as serine and threonine; neutral amino acids containing sulfur such as cysteine ​​and methionine; neutral amino acids with amide groups such as asparagine and glutamine; neutral amino acids with imino groups such as proline; neutral amino acids with aromatic rings such as phenylalanine, tyrosine, and tryptophan (all of these neutral amino acids); acidic amino acids such as aspartic acid and glutamic acid; and basic amino acids such as arginine, lysine, and histidine. Furthermore, amino acids not found in proteins include ornithine, citrulline, γ-aminobutyric acid, creatine, sarcosine, hydroxylysine, hydroxyproline, desmosine, O-phosphoserine, and cystine. Among these, basic amino acids are preferred, and arginine is more preferred, as they have a good effect of improving the dispersibility of adapalene and / or its salts. Glycine, alanine, proline, serine, lysine, glutamic acid, and threonine are also preferred. The amino acids can be used singly or in combination of two or more.

[0019] The content of the amino acid is preferably 0.005% by weight or more, more preferably 0.01% by weight or more, even more preferably 0.05% by weight or more, and particularly preferably 0.1% by weight or more, based on the total amount of the composition. It is also preferably 5% by weight or less, more preferably 1% by weight or less, even more preferably 0.5% by weight or less, and particularly preferably 0.4% by weight or less. It can also be 0.3% by weight or less, or 0.2% by weight or less. Within this range, the appropriate physiological activity of the amino acid can be obtained, and adapalene and / or its salt can be sufficiently dispersed. The content of the amino acid is 0.005 to 5 wt%, 0.005 to 1 wt%, 0.005 to 0.5 wt%, 0.005 to 0.4 wt%, 0.005 to 0.3 wt%, 0.005 to 0.2 wt%, 0.01 to 5 wt%, 0.01 to 1 wt%, 0.01 to 0.5 wt%, 0.01 to 0.4 wt%, 0.01 to 0.3 wt%, based on the total amount of the composition. Examples of the amount include 0.01 to 0.2% by weight, 0.05 to 5% by weight, 0.05 to 1% by weight, 0.05 to 0.5% by weight, 0.05 to 0.4% by weight, 0.05 to 0.3% by weight, 0.05 to 0.2% by weight, 0.1 to 5% by weight, 0.1 to 1% by weight, 0.1 to 0.5% by weight, 0.1 to 0.4% by weight, 0.1 to 0.3% by weight, and 0.1 to 0.2% by weight.

[0020] The ratio of the amino acid content to the adapalene and / or its salt content is preferably 0.05 parts by weight or more, more preferably 0.1 parts by weight or more, even more preferably 0.5 parts by weight or more, and particularly preferably 1 part by weight or more, per 1 part by weight of adapalene and / or its salt. Also, it is preferably 50 parts by weight or less, more preferably 10 parts by weight or less, even more preferably 5 parts by weight or less, and particularly preferably 4 parts by weight or less. It can also be 3 parts by weight or less, or 2 parts by weight or less. Within this range, the appropriate physiological activity of the amino acid can be obtained, and the dispersibility of adapalene and / or its salt is sufficient. The ratio of the amino acid content to the adapalene and / or salt thereof content may be 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0.05 to 5 parts by weight, 0.05 to 4 parts by weight, 0.05 to 3 parts by weight, 0.05 to 2 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, 0.1 to 5 parts by weight, 0.1 to 4 parts by weight, 0.1 to 3 parts by weight, 0.1 to 2 parts by weight, 0.5 to 50 parts by weight, 0.5 to 10 parts by weight, 0.5 to 5 parts by weight, 0.5 to 4 parts by weight, 0.5 to 3 parts by weight, 0.5 to 2 parts by weight, 1 to 50 parts by weight, 1 to 10 parts by weight, 1 to 5 parts by weight, 1 to 4 parts by weight, 1 to 3 parts by weight, or 1 to 2 parts by weight, per 1 part by weight of adapalene and / or a salt thereof.

[0021] Pyrrolidonecarboxylic acid and its salts The salt of pyrrolidonecarboxylic acid may be any pharmaceutically or physiologically acceptable salt, and examples thereof include salts with organic bases (organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, and picoline salt), and salts with inorganic bases (ammonium salt; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and metal salts such as zinc salt and aluminum salt). Among these, salts with inorganic bases are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred. When the composition of the present invention contains a salt of pyrrolidone carboxylic acid, it may be formulated as a salt of pyrrolidone carboxylic acid, or may be a salt formed in the composition as a result of separately formulating pyrrolidone carboxylic acid and an organic or inorganic base. Among these, pyrrolidonecarboxylic acid is preferred because it has a good effect of improving the dispersibility of adapalene and / or a salt thereof. The pyrrolidonecarboxylic acid and its salts can be used singly or in combination of two or more.

[0022] The content of pyrrolidone carboxylic acid and / or its salt is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, even more preferably 0.01% by weight or more, particularly preferably 0.05% by weight or more, and most preferably 0.1% by weight or more, based on the total amount of the composition. It is also preferably 10% by weight or less, more preferably 5% by weight or less, even more preferably 2% by weight or less, particularly preferably 1% by weight or less, and more preferably 0.9% by weight or less. Within this range, the appropriate physiological activity of pyrrolidone carboxylic acid and / or its salt can be obtained, and adapalene and / or its salt can be sufficiently dispersed. The content of pyrrolidone carboxylic acid and / or a salt thereof is 0.001 to 10 wt%, 0.001 to 5 wt%, 0.001 to 2 wt%, 0.001 to 1 wt%, 0.001 to 0.9 wt%, 0.005 to 10 wt%, 0.005 to 5 wt%, 0.005 to 2 wt%, 0.005 to 1 wt%, 0.005 to 0.9 wt%, 0.0 Examples of the amount include 1 to 10% by weight, 0.01 to 5% by weight, 0.01 to 2% by weight, 0.01 to 1% by weight, 0.01 to 0.9% by weight, 0.05 to 10% by weight, 0.05 to 5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.1 to 10% by weight, 0.1 to 5% by weight, 0.1 to 2% by weight, 0.1 to 1% by weight, and 0.1 to 0.9% by weight.

[0023] The ratio of the content of pyrrolidone carboxylic acid and / or its salt to the content of adapalene and / or its salt is preferably 0.01 parts by weight or more, more preferably 0.05 parts by weight or more, even more preferably 0.1 parts by weight or more, particularly preferably 0.5 parts by weight or more, and most preferably 1 part by weight or more, per 1 part by weight of adapalene and / or its salt. Also, it is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, even more preferably 20 parts by weight or less, particularly preferably 10 parts by weight or less, and most preferably 9 parts by weight or less. Within this range, the appropriate physiological activity of pyrrolidone carboxylic acid and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient. The ratio of the content of pyrrolidone carboxylic acid and / or a salt thereof to the content of adapalene and / or a salt thereof is 0.01 to 100 parts by weight, 0.01 to 50 parts by weight, 0.01 to 20 parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 20 parts by weight, 0. Examples of the amount of the hydroxybenzoate include 0.05 to 10 parts by weight, 0.05 to 9 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 9 parts by weight, 0.5 to 100 parts by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 to 100 parts by weight, 1 to 50 parts by weight, 1 to 20 parts by weight, 1 to 10 parts by weight, and 1 to 9 parts by weight.

[0024] Lactic acid and its salts The salt of lactic acid may be any pharmaceutically or physiologically acceptable salt, and examples thereof include salts with organic bases (organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, and picoline salt), and salts with inorganic bases (ammonium salt; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and metal salts such as zinc salt and aluminum salt). Among these, salts with inorganic bases are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred. When the composition of the present invention contains a salt of lactic acid, it may be formulated as a salt of lactic acid, or it may be a salt formed in the composition as a result of formulating lactic acid and an organic or inorganic base separately. Among these, lactic acid and sodium lactate are preferred because they have a good effect of improving the dispersibility of adapalene and / or a salt thereof. Lactic acid and salts thereof can be used singly or in combination of two or more.

[0025] The content of lactic acid and / or its salts is preferably 0.005% by weight or more, more preferably 0.01% by weight or more, even more preferably 0.05% by weight or more, and particularly preferably 0.1% by weight or more, based on the total amount of the composition. It is also preferably 10% by weight or less, more preferably 5% by weight or less, even more preferably 3% by weight or less, and particularly preferably 1% by weight or less. Within this range, the appropriate physiological or pharmacological activity of lactic acid and / or its salts can be obtained, and the dispersibility of adapalene and / or its salts is sufficient. The content of lactic acid and / or a salt thereof, relative to the total amount of the composition, can be 0.005 to 10 wt%, 0.005 to 5 wt%, 0.005 to 3 wt%, 0.005 to 1 wt%, 0.01 to 10 wt%, 0.01 to 5 wt%, 0.01 to 3 wt%, 0.01 to 1 wt%, 0.05 to 10 wt%, 0.05 to 5 wt%, 0.05 to 3 wt%, 0.05 to 1 wt%, 0.1 to 10 wt%, 0.1 to 5 wt%, 0.1 to 3 wt%, or 0.1 to 1 wt%.

[0026] The ratio of the content of lactic acid and / or its salt to the content of adapalene and / or its salt is preferably 0.05 parts by weight or more, more preferably 0.1 parts by weight or more, even more preferably 0.5 parts by weight or more, and particularly preferably 1 part by weight or more, per 1 part by weight of adapalene and / or its salt. Also, the ratio is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, even more preferably 30 parts by weight or less, and particularly preferably 10 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of lactic acid and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient. The ratio of the content of lactic acid and / or a salt thereof to the content of adapalene and / or a salt thereof can be 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 30 parts by weight, 0.05 to 10 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 30 parts by weight, 0.1 to 10 parts by weight, 0.5 to 100 parts by weight, 0.5 to 50 parts by weight, 0.5 to 30 parts by weight, 0.5 to 10 parts by weight, 1 to 100 parts by weight, 1 to 50 parts by weight, 1 to 30 parts by weight, or 1 to 10 parts by weight, per 1 part by weight of adapalene and / or a salt thereof.

[0027] Urea Examples of ureas include urea, as well as alkyl ureas having an alkyl group having 1 to 4 carbon atoms, such as methyl urea and ethyl urea; and hydroxyalkyl ureas having a hydroxyalkyl group having 1 to 10 carbon atoms, such as hydroxyethyl urea, dihydroxyethyl urea, bis(hydroxyethyl) urea, hydroxypropyl urea, dihydroxypropyl urea, bis(hydroxypropyl) urea, hydroxybutyl urea, dihydroxybutyl urea, and bis(hydroxybutyl) urea. Among these, urea is preferred because it has a good effect of improving the dispersibility of adapalene and / or a salt thereof. The ureas can be used alone or in combination of two or more.

[0028] The content of the ureas is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, even more preferably 0.01% by weight or more, particularly preferably 0.05% by weight or more, and most preferably 0.1% by weight or more, based on the total amount of the composition. Also, the content is preferably 10% by weight or less, more preferably 5% by weight or less, even more preferably 2% by weight or less, particularly preferably 1% by weight or less, and most preferably 0.9% by weight or less. Within this range, the appropriate physiological or pharmacological activity of the ureas can be obtained, and the dispersibility of adapalene and / or its salts is sufficient. The content of ureas relative to the total amount of the composition is 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 1% by weight, 0.001 to 0.9% by weight, 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 2% by weight, 0.005 to 1% by weight, 0.005 to 0.9% by weight, or 0.01 to 10% by weight. , 0.01 to 5% by weight, 0.01 to 2% by weight, 0.01 to 1% by weight, 0.01 to 0.9% by weight, 0.05 to 10% by weight, 0.05 to 5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.1 to 10% by weight, 0.1 to 5% by weight, 0.1 to 2% by weight, 0.1 to 1% by weight, and 0.1 to 0.9% by weight.

[0029] The ratio of the content of ureas to the content of adapalene and / or its salts is preferably 0.01 parts by weight or more, more preferably 0.05 parts by weight or more, even more preferably 0.1 parts by weight or more, particularly preferably 0.5 parts by weight or more, and most preferably 1 part by weight or more, per 1 part by weight of adapalene and / or its salts. Also, it is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, even more preferably 20 parts by weight or less, particularly preferably 10 parts by weight or less, and most preferably 9 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of the ureas can be obtained, and the dispersibility of adapalene and / or its salts is sufficient. The ratio of the content of ureas to the content of adapalene and / or a salt thereof is 0.01 to 100 parts by weight, 0.01 to 50 parts by weight, 0.01 to 20 parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 20 parts by weight, or 0.05 to 10 parts by weight per part by weight of adapalene and / or a salt thereof. , 0.05 to 9 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 9 parts by weight, 0.5 to 100 parts by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 to 100 parts by weight, 1 to 50 parts by weight, 1 to 20 parts by weight, 1 to 10 parts by weight, and 1 to 9 parts by weight are examples.

[0030] Mucopolysaccharides and their salts Mucopolysaccharides are polysaccharides composed of amino sugars such as galactosamine or glucosamine and uronic acids such as glucuronic acid and iduronic acid or galactose. Examples of mucopolysaccharides include hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin. The salt of the mucopolysaccharide may be any pharmaceutically or physiologically acceptable salt, and examples thereof include salts with organic bases (organic amine salts such as methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, and picoline salt), and salts with inorganic bases (ammonium salt; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and metal salts such as zinc salt and aluminum salt). Of these, salts with inorganic bases are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred. When the composition of the present invention contains a salt of a mucopolysaccharide, it may be formulated as a salt of the mucopolysaccharide, or it may be a salt that is formed in the composition as a result of separately formulating the mucopolysaccharide and an organic or inorganic base. Among them, hyaluronic acid or its salt (particularly sodium salt) is preferred because it has a good effect of improving the dispersibility of adapalene and / or its salt.Hyaluronic acid can be used as the natural product extracted from, for example, cockscomb, or can be used as the low molecular weight hyaluronic acid (for example, average molecular weight of 100,000 or less) that is obtained by decomposing natural product with acid, alkali or enzyme. The mucopolysaccharides and salts thereof can be used singly or in combination of two or more.

[0031] The content of mucopolysaccharides and salts thereof is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, even more preferably 0.01% by weight or more, and particularly preferably 0.05% by weight or more, based on the total amount of the composition. It is also preferably 5% by weight or less, more preferably 2% by weight or less, even more preferably 1% by weight or less, and particularly preferably 0.9% by weight or less. It is also preferably 0.5% by weight or less, 0.2% by weight or less, 0.15% by weight or less, or 0.1% by weight or less. Within this range, the appropriate physiological activity of the mucopolysaccharides and salts thereof can be obtained, and adapalene and / or its salts can be sufficiently dispersed. The content of mucopolysaccharides and salts thereof relative to the total amount of the composition is 0.001 to 5 wt%, 0.001 to 2 wt%, 0.001 to 1 wt%, 0.001 to 0.9 wt%, 0.001 to 0.5 wt%, 0.001 to 0.2 wt%, 0.001 to 0.15 wt%, 0.001 to 0.1 wt%, 0.005 to 5 wt%, 0.005 to 2 wt%, 0.005 to 1 wt%, 0.005 to 0.9 wt%, 0.005 to 0.5 wt%, 0.005 to 0.2 wt%, 0.005 to 0. Examples of the preferred ranges of the present invention include 0.005 to 0.15% by weight, 0.005 to 0.1% by weight, 0.01 to 5% by weight, 0.01 to 2% by weight, 0.01 to 1% by weight, 0.01 to 0.9% by weight, 0.01 to 0.5% by weight, 0.01 to 0.2% by weight, 0.01 to 0.15% by weight, 0.01 to 0.1% by weight, 0.05 to 5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.05 to 0.5% by weight, 0.05 to 0.2% by weight, 0.05 to 0.15% by weight, and 0.05 to 0.1% by weight.

[0032] The ratio of the content of mucopolysaccharides and their salts to the content of adapalene and / or its salts is preferably 0.01 parts by weight or more, more preferably 0.05 parts by weight or more, even more preferably 0.1 parts by weight or more, and particularly preferably 0.5 parts by weight or more, per 1 part by weight of adapalene and / or its salt. It is also preferably 50 parts by weight or less, more preferably 20 parts by weight or less, even more preferably 10 parts by weight or less, and particularly preferably 9 parts by weight or less. It is also preferably 5 parts by weight or less, 2 parts by weight or less, or 1.5 parts by weight or less. It may also be 1 part by weight or less. Within this range, the appropriate physiological activity of the mucopolysaccharides and their salts can be obtained, and the dispersibility of adapalene and / or its salts is sufficient. The ratio of the content of mucopolysaccharides and their salts to the content of adapalene and / or its salts is 0.01 to 50 parts by weight, 0.01 to 20 parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.01 to 5 parts by weight, 0.01 to 2 parts by weight, 0.01 to 1.5 parts by weight, 0.01 to 1 part by weight, 0.05 to 50 parts by weight, 0.05 to 20 parts by weight, 0.05 to 10 parts by weight, 0.05 to 9 parts by weight, 0.05 0.1 to 5 parts by weight, 0.05 to 2 parts by weight, 0.05 to 1.5 parts by weight, 0.05 to 1 part by weight, 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 9 parts by weight, 0.1 to 5 parts by weight, 0.1 to 2 parts by weight, 0.1 to 1.5 parts by weight, 0.1 to 1 part by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 0.5 to 5 parts by weight, 0.5 to 2 parts by weight, 0.5 to 1.5 parts by weight, and 0.5 to 1 part by weight are examples.

[0033] (B) Content of ingredients The content of component (B) is preferably 0.0001 wt% or more, more preferably 0.0005 wt% or more, even more preferably 0.001 wt% or more, particularly preferably 0.005 wt% or more, and most preferably 0.01 wt% or more, based on the total amount of the composition. Also, the content is preferably 20 wt% or less, more preferably 10 wt% or less, even more preferably 5 wt% or less, particularly preferably 1 wt% or less, and most preferably 0.9 wt% or less. Within this range, the appropriate physiological or pharmacological activity of component (B) can be obtained, and adapalene and / or its salts can be sufficiently dispersed. The content of component (B) relative to the total amount of the composition is 0.0001 to 20% by weight, 0.0001 to 10% by weight, 0.0001 to 5% by weight, 0.0001 to 1% by weight, 0.0001 to 0.9% by weight, 0.0005 to 20% by weight, 0.0005 to 10% by weight, 0.0005 to 5% by weight, 0.0005 to 1% by weight, 0.0005 to 0.9% by weight, 0.001 to 20% by weight, Examples of the content include 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 1% by weight, 0.001 to 0.9% by weight, 0.005 to 20% by weight, 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 1% by weight, 0.005 to 0.9% by weight, 0.01 to 20% by weight, 0.01 to 10% by weight, 0.01 to 5% by weight, 0.01 to 1% by weight, and 0.01 to 0.9% by weight.

[0034] The ratio of the content of component (B) to the content of adapalene and / or its salt is preferably 0.001 parts by weight or more, more preferably 0.005 parts by weight or more, even more preferably 0.01 parts by weight or more, particularly preferably 0.05 parts by weight or more, and most preferably 0.1 parts by weight or more, per part by weight of adapalene and / or its salt. Also, the ratio is preferably 200 parts by weight or less, more preferably 100 parts by weight or less, even more preferably 50 parts by weight or less, particularly preferably 10 parts by weight or less, and most preferably 9 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of component (B) can be obtained, and the dispersibility of adapalene and / or its salt is sufficient. The ratio of the content of component (B) relative to the content of adapalene and / or a salt thereof is 0.001 to 200 parts by weight, 0.001 to 100 parts by weight, 0.001 to 50 parts by weight, 0.001 to 10 parts by weight, 0.001 to 9 parts by weight, 0.005 to 200 parts by weight, 0.005 to 100 parts by weight, 0.005 to 50 parts by weight, 0.005 to 10 parts by weight, 0.00 Examples of the preferred ranges include 5 to 9 parts by weight, 0.01 to 200 parts by weight, 0.01 to 100 parts by weight, 0.01 to 50 parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.05 to 200 parts by weight, 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0.05 to 9 parts by weight, 0.1 to 200 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, and 0.1 to 9 parts by weight.

[0035] Polyhydric alcohol The topical composition of the present invention may contain (C) a polyhydric alcohol, which further improves the dispersibility of adapalene and / or a salt thereof. Polyhydric alcohols include ethylene glycol, propylene glycol, 1,3-propanediol (trimethylene glycol), butylene glycol (1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol), 1,4-butanediol (tetramethylene glycol), 3-methyl-1,3-butanediol, 2-butene-1,4-diol, 1,5-pentanediol (pentamethylene glycol), 1,2-pentanediol, isoprene glycol (isopentyl diol), hexylene glycol, dipropylene glycol, polyethylene glycol (polyethylene glycol), Examples of suitable alcohols include dihydric alcohols such as polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, polyethylene glycol 35000, etc.), and polypropylene glycols (polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000, etc.); trihydric alcohols such as glycerin and trimethylolpropane; diglycerin, polyglycerin, etc. Among these, dihydric alcohols and trihydric alcohols are preferred, and dipropylene glycol, butylene glycol (particularly 1,3-butylene glycol), polyethylene glycol, and glycerin are more preferred. The polyhydric alcohols can be used alone or in combination of two or more.

[0036] Preferred combinations of polyhydric alcohols include a combination of dipropylene glycol and 1,3-butylene glycol, a combination of dipropylene glycol and polyethylene glycol, a combination of dipropylene glycol and glycerin, a combination of 1,3-butylene glycol and polyethylene glycol, a combination of 1,3-butylene glycol and glycerin, a combination of polyethylene glycol and glycerin; a combination of dipropylene glycol, 1,3-butylene glycol and polyethylene glycol, a combination of dipropylene glycol, 1,3-butylene glycol and glycerin, a combination of dipropylene glycol, polyethylene glycol and glycerin, a combination of 1,3-butylene glycol, polyethylene glycol and glycerin; a combination of dipropylene glycol, 1,3-butylene glycol, polyethylene glycol and glycerin, and the like.

[0037] The content of the polyhydric alcohol is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, even more preferably 0.1% by weight or more, and particularly preferably 1% by weight or more, based on the total amount of the composition. Also, the content is preferably 90% by weight or less, more preferably 60% by weight or less, even more preferably 30% by weight or less, and particularly preferably 15% by weight or less. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved, and a topical composition that is less likely to dry out the skin can be obtained. The content of the polyhydric alcohol, relative to the total amount of the composition, may be 0.001 to 90 wt%, 0.001 to 60 wt%, 0.001 to 30 wt%, 0.001 to 15 wt%, 0.01 to 90 wt%, 0.01 to 60 wt%, 0.01 to 30 wt%, 0.01 to 15 wt%, 0.1 to 90 wt%, 0.1 to 60 wt%, 0.1 to 30 wt%, 0.1 to 15 wt%, 1 to 90 wt%, 1 to 60 wt%, 1 to 30 wt%, or 1 to 15 wt%.

[0038] The ratio of the content of polyhydric alcohol to the content of adapalene and / or its salt is preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more, even more preferably 1 part by weight or more, and particularly preferably 10 parts by weight or more, per 1 part by weight of adapalene and / or its salt. Also, it is preferably 900 parts by weight or less, more preferably 600 parts by weight or less, even more preferably 300 parts by weight or less, and particularly preferably 150 parts by weight or less. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved, and a topical composition that is less likely to dry out the skin can be obtained. The ratio of the content of polyhydric alcohol to the content of adapalene and / or a salt thereof may be 0.01 to 900 parts by weight, 0.01 to 600 parts by weight, 0.01 to 300 parts by weight, 0.01 to 150 parts by weight, 0.1 to 900 parts by weight, 0.1 to 600 parts by weight, 0.1 to 300 parts by weight, 0.1 to 150 parts by weight, 1 to 900 parts by weight, 1 to 600 parts by weight, 1 to 300 parts by weight, 1 to 150 parts by weight, 10 to 900 parts by weight, 10 to 600 parts by weight, 10 to 300 parts by weight, or 10 to 150 parts by weight, per 1 part by weight of adapalene and / or a salt thereof.

[0039] emulsifier The topical composition of the present invention may contain (D) an emulsifier, which further improves the dispersibility of adapalene and / or a salt thereof. Examples of emulsifiers include sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-5 ... Hydrogenated castor oil derivatives such as castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 (HCO-80); castor oil derivatives such as polyoxyethylene castor oil; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate. Polyoxyethylene sorbitan fatty acid esters such as bitan; polyoxyethylene monoglyceryl cocoate; glycerin alkyl ethers; alkyl glucosides; polyoxyalkylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether; amines such as stearylamine and oleylamine; silicone surfactants such as polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone; natural surfactants such as phospholipids such as lecithin, surfactin, and saponin; fatty acid amidoamines such as stearic acid diethylaminoethylamide and stearic acid diethylaminopropylamide; alkylamines such as trilaurylamine, dimethylstearylamine, and di-2-ethylhexylamine; betaine-based amphoteric surfactants such as stearic acid dimethylaminopropylamide and laurylhydroxysulfobetaine;Examples include polyoxyethylene polyoxypropylene glycol (such as poloxamer 124); polyglycerin fatty acid esters; glycerin fatty acid esters; polyethylene glycol fatty acid esters; Among these, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and polyglycerin fatty acid esters are preferred, and sorbitan stearate (sorbitan monostearate), sorbitan oleate (sorbitan monooleate), polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether, polyoxyethylene(20) sorbitan monolaurate (polysorbate 20), polyoxyethylene(20) sorbitan monostearate (polysorbate 60), and polyoxyethylene(20) sorbitan monooleate (polysorbate 80) are more preferred. The emulsifiers can be used alone or in combination of two or more.

[0040] The content of the emulsifier is preferably 0.05% by weight or more, more preferably 0.1% by weight or more, even more preferably 0.5% by weight or more, and particularly preferably 1% by weight or more, based on the total weight of the composition. Also, the content is preferably 10% by weight or less, more preferably 8% by weight or less, even more preferably 6% by weight or less, and particularly preferably 4% by weight or less. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved. The content of the emulsifier, relative to the total amount of the composition, can be 0.05 to 10 wt%, 0.05 to 8 wt%, 0.05 to 6 wt%, 0.05 to 4 wt%, 0.1 to 10 wt%, 0.1 to 8 wt%, 0.1 to 6 wt%, 0.1 to 4 wt%, 0.5 to 10 wt%, 0.5 to 8 wt%, 0.5 to 6 wt%, 0.5 to 4 wt%, 1 to 10 wt%, 1 to 8 wt%, 1 to 6 wt%, or 1 to 4 wt%.

[0041] The ratio of the content of the emulsifier to the content of adapalene and / or its salt is preferably 0.5 parts by weight or more, more preferably 1 part by weight or more, even more preferably 5 parts by weight or more, and particularly preferably 10 parts by weight or more, relative to 1 part by weight of adapalene. Also, it is preferably 100 parts by weight or less, more preferably 80 parts by weight or less, even more preferably 60 parts by weight or less, and particularly preferably 40 parts by weight or less. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved. The ratio of the content of the emulsifier to the content of adapalene and / or a salt thereof may be 0.5 to 100 parts by weight, 0.5 to 80 parts by weight, 0.5 to 60 parts by weight, 0.5 to 40 parts by weight, 1 to 100 parts by weight, 1 to 80 parts by weight, 1 to 60 parts by weight, 1 to 40 parts by weight, 5 to 100 parts by weight, 5 to 80 parts by weight, 5 to 60 parts by weight, 5 to 40 parts by weight, 10 to 100 parts by weight, 10 to 80 parts by weight, 10 to 60 parts by weight, or 10 to 40 parts by weight, per 1 part by weight of adapalene.

[0042] Hydrocarbon base The topical composition of the present invention may contain (E) a hydrocarbon base, which further improves the dispersibility of adapalene and / or a salt thereof. Examples of hydrocarbon bases include petrolatum (white petrolatum, yellow petrolatum), gelling hydrocarbons (such as Plastibase), ozokerite, ceresin, microcrystalline wax, squalene, squalane, α-olefin oligomer, paraffin, liquid paraffin, and light liquid paraffin. Among these, hydrocarbon bases that are solid at room temperature (25°C) such as petrolatum (white petrolatum, yellow petrolatum), gelling hydrocarbons (Plastibase, etc.), ozokerite, ceresin, and microcrystalline wax are preferred, with petrolatum, ozokerite, ceresin, and microcrystalline wax being more preferred, and petrolatum being even more preferred. Hydrocarbon bases that are liquid at room temperature (25°C) such as squalene, squalane, α-olefin oligomer, paraffin, liquid paraffin, and light liquid paraffin are also preferred. The hydrocarbon base may be used alone or in combination of two or more.

[0043] The content of the hydrocarbon base is preferably 0.000001 wt% or more, more preferably 0.00001 wt% or more, even more preferably 0.0001 wt% or more, and particularly preferably 0.001 wt% or more, based on the total amount of the composition. It can also be 0.01 wt% or more, 0.1 wt% or more, or 1 wt% or more. It is preferably 50 wt% or less, more preferably 30 wt% or less, even more preferably 20 wt% or less, and particularly preferably 10 wt% or less. It is also preferably 1 wt% or less, 0.1 wt% or less, or 0.01 wt% or less. Within these ranges, the dispersibility of adapalene and / or its salt is sufficiently improved, and a topical composition that is less likely to dry out the skin can be obtained. The content of the hydrocarbon base agent is, relative to the total amount of the composition, 0.000001 to 50% by weight, 0.000001 to 30% by weight, 0.000001 to 20% by weight, 0.000001 to 10% by weight, 0.000001 to 1% by weight, 0.000001 to 0.1% by weight, 0.000001 to 0.01% by weight, 0.00001 to 50% by weight, 0.00001~30% by weight, 0.00001~20% by weight, 0.00001~10% by weight, 0.00001~1% by weight, 0.00001~0 .1% by weight, 0.00001~0.01% by weight, 0.0001~50% by weight, 0.0001~30% by weight, 0.0001~20% by weight, 0.0001~10% by weight Amount%, 0.0001~1wt%, 0.0001~0.1wt%, 0.0001~0.01wt%, 0.001~50wt%, 0.001~30wt%, 0. 001~20wt%, 0.001~10wt%, 0.001~1wt%, 0.001~0.1wt%, 0.001~0.01wt%, 0.01~50wt%, Examples of the amount include 0.01 to 30% by weight, 0.01 to 20% by weight, 0.01 to 10% by weight, 0.01 to 1% by weight, 0.01 to 0.1% by weight, 0.1 to 50% by weight, 0.1 to 30% by weight, 0.1 to 20% by weight, 0.1 to 10% by weight, 0.1 to 1% by weight, 1 to 50% by weight, 1 to 30% by weight, 1 to 20% by weight, and 1 to 10% by weight.

[0044] The ratio of the hydrocarbon base content to the adapalene and / or its salt content is preferably 0.00001 parts by weight or more, more preferably 0.0001 parts by weight or more, even more preferably 0.001 parts by weight or more, and particularly preferably 0.01 parts by weight or more, per 1 part by weight of adapalene and / or its salt. It can also be 0.1 parts by weight or more, 1 part by weight or more, or 10 parts by weight or more. It is preferably 500 parts by weight or less, more preferably 300 parts by weight or less, even more preferably 200 parts by weight or less, and particularly preferably 100 parts by weight or less. It is also preferably 10 parts by weight or less, 1 part by weight or less, or 0.1 parts by weight or less. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved, and a topical composition that is less likely to dry out the skin can be obtained. The ratio of the content of the hydrocarbon base to the content of adapalene and / or a salt thereof is 0.00001 to 500 parts by weight, 0.00001 to 300 parts by weight, 0.00001 to 200 parts by weight, 0.00001 to 100 parts by weight, 0.00001 to 10 parts by weight, 0.00001 to 1 part by weight, or 0.00001 to 1 part by weight, per 1 part by weight of adapalene and / or a salt thereof. Parts by weight, 0.00001~0.1 parts by weight, 0.0001~500 parts by weight, 0.0001~300 parts by weight, 0.0001~200 parts by weight, 0.0001~100 parts by weight parts, 0.0001~10 parts by weight, 0.0001~1 parts by weight, 0.0001~0.1 parts by weight, 0.001~500 parts by weight, 0.001~300 parts by weight, 0.001~ 200 parts by weight, 0.001~100 parts by weight, 0.001~10 parts by weight, 0.001~1 parts by weight, 0.001~0.1 parts by weight, 0.01~500 parts by weight, 0.01 ~300 parts by weight, 0.01~200 parts by weight, 0.01~100 parts by weight, 0.01~10 parts by weight, 0.01~1 parts by weight, 0.01~0.1 parts by weight, 0.1~500 parts by weight parts by weight, 0.1 to 300 parts by weight, 0.1 to 200 parts by weight, 0.1 to 100 parts by weight, 0.1 to 10 parts by weight, 0.1 to 1 part by weight, 1 to 500 parts by weight, 1 to 300 parts by weight, 1 to 200 parts by weight, 1 to 100 parts by weight, 1 to 10 parts by weight, 10 to 500 parts by weight, 10 to 300 parts by weight, 10 to 200 parts by weight, and 10 to 100 parts by weight.

[0045] Other ingredients The topical composition of the present invention can be prepared as a pharmaceutical, quasi-drug, or cosmetic composition for topical use by mixing component (A), component (B), and the other components blended as needed with bases or carriers, additives, other physiologically or pharmacologically active ingredients, etc., used in pharmaceuticals, quasi-drugs, or cosmetics. In particular, it can be a pharmaceutical composition (topical composition).

[0046] Examples of additives include antioxidants, thickeners, antiseptics or preservatives, pH adjusters, stabilizers, chelating agents, ultraviolet absorbers or ultraviolet scattering agents, irritation reducers, colorants, refreshing agents, and fragrances. The additives may be used alone or in combination of two or more. The additives can be used within a range that does not impair the effects of the present invention.

[0047] Examples of antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, p-hydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivatives (ascorbic acid stearate, ascorbic acid palmitate, ascorbyl dipalmitate, ascorbic acid monophosphate, ascorbic acid diphosphate, ascorbic acid triphosphate, ascorbic acid sulfate, etc.), tocopherol, tocopherol derivatives (tocopherol acetate, tocopherol succinate, tocopherol calcium succinate, etc.), erythorbic acid, L-cysteine ​​hydrochloride, lycopene, glutathione, propyl gallate, tannic acid, epigallocatechin, anthocyanin, hydroxytyrosol, norhydroguaiaretenic acid, caffeic acid, and enzymes (catalase, superoxide dismutase, glutathione peroxidase, elastase, etc.).

[0048] Examples of thickeners include guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, acrylate / alkyl methacrylate copolymer, bentonite, alginic acid, macrogol, and cellulose-based thickeners (such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose).

[0049] Examples of antiseptics or preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzyl parahydroxybenzoate, methyl parahydroxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and its salts, chlorhexidine gluconate, alkanediols, and glycerin fatty acid esters.

[0050] Examples of pH adjusters include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), and organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

[0051] Stabilizers include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.

[0052] Chelating agents include EDTA disodium salt and EDTA calcium disodium salt.

[0053] Irritation reducers include licorice extract and sodium alginate.

[0054] Examples of ultraviolet absorbers or ultraviolet scattering agents include 2-ethylhexyl paramethoxycinnamate, 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid hexyl ester, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, t-butylmethoxydibenzoylmethane, ethylhexyl dibenzylidene dioxoimidazolidine propylonate, ethoxyhexyl triazoline, paraaminobenzoic acid and its derivatives, octyl paradimethylaminobenzoate, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide, and zinc oxide.

[0055] Examples of coloring agents include the pigments listed in the Legal Coloring Material Handbook (edited by the Japan Cosmetic Industry Association (2004)).

[0056] Examples of the cooling agent include terpenes such as menthol, camphor, borneol, geraniol, cineole, anethole, limonene, and eugenol (which may be in the d-, l-, or dl-form); and essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil, rose oil, and turpentine. Examples of the fragrance include various essential oils such as herbal essential oils such as lavender oil, rosemary oil, clary sage oil, thyme oil, bergamot oil, and eucalyptus oil, citrus essential oils such as orange oil, lemon oil, and grapefruit oil, and blended fragrances.

[0057] Examples of other physiologically active or pharmacologically active ingredients (physiologically active or pharmacologically active ingredients other than component (A) and component (B)) include anti-inflammatory agents, disinfectants or antibacterial agents, keratin softening or keratin dissolving agents other than urea, antipruritics, moisturizing ingredients other than component (B) and polyhydric alcohols, local anesthetics, vitamins, peptides or derivatives thereof, blood circulation promoting ingredients, cell activating ingredients, anti-aging ingredients, astringent ingredients, proteins, plant extracts, seaweed extracts, antifungal agents, and whitening ingredients. The other physiologically or pharmacologically active ingredients can be used singly or in combination of two or more. Furthermore, other physiologically or pharmacologically active ingredients can be used within the range that does not impair the effects of the present invention.

[0058] Anti-inflammatory agents include allantoin, glycyrrhizinic acid, methyl glycyrrhizinate, stearyl glycyrrhizinate, glycyrrhetinic acid, stearyl glycyrrhetinate, acetaminophen, epsilon-aminocaproic acid, berberine, azulene, bromelain, and zinc; plant extracts such as licorice extract, sage extract, and rosemary extract; enzyme-based anti-inflammatory agents such as lysozyme, serrapeptase, and semi-alkaline proteinase; fenamic acid-based anti-inflammatory agents such as mefenamic acid, flufenamic acid, and tolfenamic acid; acemetacin, indomethacin, indomethacin farnesyl, edotolac, and dimethicone. Examples of nonsteroidal anti-inflammatory drugs include arylacetic acid anti-inflammatory drugs such as clofenac, sulindac, nabutomene, fenbufen, proglumetacin, and mofezolac; propionic acid anti-inflammatory drugs such as aminoprofen, ibuprofen, oxaprozin, ketoprofen, zaltoprofen, tiaprofenic acid, naproxen, flurbiprofen, zaltoprofen, ibuprofen piconol, flurbiprofen axetil, fenoprofen, pranoprofen, and loxoprofen; and oxicam anti-inflammatory drugs such as ampiroxicam, tenoxicam, piroxicam, meloxicam, and lornoxicam. These are nonsteroidal anti-inflammatory drugs. Also useful are steroidal anti-inflammatory agents such as prednisolone, hydrocortisone, cortisone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, difluprednade, mometasone, diflucortolone, fluoniside, fluocinonide, clobetasol, beclomethasone, deprodone, alclometasone, flumethasone, amcinonide, clobetasone, diflorasone, and derivatives thereof (especially esters). Derivatives of the above steroids include prednisolone esters such as prednisolone valerate acetate (PVA), prednisolone succinate, prednisolone acetate, and prednisolone phosphate; dexamethasone esters such as betamethasone propionate, betamethasone valerate, dexamethasone valerate, dexamethasone propionate, dexamethasone acetate, dexamethasone phosphate, dexamethasone metasulfobenzoate, dexamethasone cipesilate, and dexamethasone palmitate; hydrocortisone butyrate (particularly hydrocortisone-17-butyrate); Examples of hydrocortisone esters include hydrocortisone acetate, hydrocortisone succinate, hydrocortisone butyrate, hydrocortisone butyrate propionate, and hydrocortisone phosphate; mometasone furoate, diflucortolone valerate, clobetasol propionate, beclomethasone propionate, beclomethasone dipropionate, clobetasone butyrate, deprodone propionate, alclometasone propionate, flumethasone pivalate, clobetasone propionate, clobetasone butyrate, and diflorasone acetate.

[0059] Examples of disinfectants or antibacterial agents include aminoglycoside antibiotics such as clindamycin, quinolone antibiotics such as nadifloxacin, besifloxacin, clinadifloxacin, flurifloxacin, and ozenoxacin, benzoyl peroxide, isopropylmethylphenol, phenoxyethanol, dequalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, salicylic acid, cresol, triclosan, and biguanide compounds. Some disinfectants or antibacterial agents are used as antiseptics or preservatives.

[0060] The topical composition of the present invention may be one that does not contain benzoyl peroxide. In addition, the topical compositions of the present invention may not include formulations for use in the treatment or prevention of drug-resistant acne and acne, including P. acnes, that are non-responsive / resistant to therapeutic doses of clindamycin, minocycline, tetracycline, or erythromycin, and particularly may not include formulations for use in the treatment or prevention of drug-resistant acne and acne, including P. acnes, that are non-responsive / resistant to therapeutic doses of clindamycin, minocycline, tetracycline, or erythromycin, that comprise adapalene and an anti-inflammatory agent, and particularly may not include formulations for use in the treatment or prevention of drug-resistant acne and acne, including P. acnes, that are non-responsive / resistant to therapeutic doses of clindamycin, minocycline, tetracycline, or erythromycin, that comprise an antibacterial agent, adapalene, and an anti-inflammatory agent. Furthermore, the present invention may not encompass dual action rational therapy molecules (excluding adapalene) having two distinct mechanisms of action for the treatment or prevention of bacterial infections, and in particular, may not encompass drug carriers or formulations comprising dual action rational therapy molecules having two distinct mechanisms of action for the treatment or prevention of bacterial infections, adapalene, and an anti-inflammatory agent. In particular, it may not include dual-action rational therapy molecules (excluding adapalene) for the treatment of bacterial infections caused by both sensitive and resistant Gram-positive and Gram-negative bacteria, in particular for curing acne and different skin and skin structure infections, and additionally for preventing the development of resistance, and, among others, it may not include drug carriers or formulations comprising a dual-action rational therapy molecule, adapalene, and an anti-inflammatory agent for the treatment of bacterial infections caused by both sensitive and resistant Gram-positive and Gram-negative bacteria, in particular for curing acne and different skin and skin structure infections, and additionally for preventing the development of resistance. Furthermore, the present invention can be one that does not contain a quinolone antibiotic, particularly 8-chlorofluoroquinolone, especially besifloxacin or besifloxacin hydrochloride. By not containing a quinolone antibiotic, especially 8-chlorofluoroquinolone, the composition does not induce photosensitivity due to quinolone antibiotics, and degeneration of the composition due to photodegradation of the quinolone antibiotic is avoided. Furthermore, by not containing a quinolone antibiotic, especially 8-chlorofluoroquinolone, especially besifloxacin or besifloxacin hydrochloride, the effects of the present invention are more pronounced.

[0061] Examples of keratin softening or keratin dissolving agents other than urea include salicylic acid and its derivatives (methyl salicylate, acetylsalicylic acid, etc.), glycolic acid, fruit acids, phytic acid, sulfur, ethyl alcohol, isopropyl alcohol, propanol, butanol, benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyldodecanol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurate, lanolin, fatty acid dialkylolamide, sulfur, resorcinol, sodium hydroxide, and potassium hydroxide.

[0062] Antipruritic agents include ethanolamine antihistamines such as diphenhydramine, bromodiphenhydramine, clemastine, chlorphenoxamine, diphenylpyraline, doxylamine, orphenadrine, and phenyltoloxamine; propylamine antihistamines such as chlorpheniramine, dimethindene, and talastine; ethylenediamine antihistamines such as mepyramine, methapyrilene, and tripelennamine; phenothiazine antihistamines such as alimemazine, hydroxyethylpromethazine, isothipendyl, mequitazine, oxomemazine, and promethazine; buclizine and cetirizine; antihistamines such as piperazine antihistamines such as benzodiazepine, homochlorcyclizine, cyclizine, hydroxyzine, levocetirizine, meclizine, and oxatomide, and antihistamines such as ketotifen, olopatadine, fexofenadine, loratadine, terfenadine, antazoline, azatadine, bamipine, cyproheptadine, deptropine, ebastine, emedastine, epinastine, mebhydroline, mizolastine, pimethixene, pyrobutamine, quifenadine, rupatadine, triprolidine, acrivastine, astemizole, azelastine, bilastine, desloratadine, and salts thereof. Also included are non-antihistamine ingredients such as crotamiton, ichthammol, moctal, and thymol.

[0063] Examples of moisturizing ingredients other than component (B) and polyhydric alcohols include sugars such as trehalose, xylitol, and sorbitol; polymeric compounds such as keratin, chitin, and chitosan; lipids such as phospholipids; and plant extracts such as chamomile extract, witch hazel extract, tea extract, and aloe extract.

[0064] Examples of local anesthetics include local anesthetics having an amine structure or an amide structure such as lidocaine, dibucaine, mepivacaine, bupivacaine, ropivacaine, levobupivacaine, oxethazaine, and salts thereof; local anesthetics having an amine structure or an ester structure such as cocaine, procaine, chloroprocaine, tetracaine, and salts thereof; and local anesthetics having an ester structure such as ethyl aminobenzoate and oxypolyethoxydodecane.

[0065] Vitamins include vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate, ubiquinone derivatives and pharmaceutically or physiologically acceptable salts thereof, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, and nicotine. Benzyl Nicotinate, Methyl Nicotinate, β-Butoxyethyl Nicotinate, 1-(4-Methylphenyl)ethyl Nicotinate, Ascorbigen-A, Ascorbyl Stearate, Ascorbyl Palmitate, L-Ascorbyl Dipalmitate, Methylhesperidin, Ergocalciferol, Cholecalciferol, Phylloquinone, Farnoquinone, γ-Oryzanol, Dibenzoylthiamine, Dibenzoylthiamine Hydrochloride, Thiamine Hydrochloride, Thiamine Cetyl Hydrochloride, Thiamine Thiocyanate, Thiamine Lauryl Hydrochloride, Thiamine Thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, pyridoxal 5'-phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinic acid Examples of pantothenic acids include lactic acid amide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantethesain, D-pantethine, coenzyme A, pantothenyl ethyl ether, etc., biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, and eriocitrin.

[0066] Examples of peptides or derivatives thereof include keratin-decomposed peptides, hydrolyzed keratin, collagen, gelatin, elastin, elastin-decomposed peptides, collagen-decomposed peptides, hydrolyzed collagen, and hydrolyzed silk.

[0067] Preferred examples of blood circulation-promoting ingredients include plant-derived ingredients, such as ingredients derived from ginseng, angelica tree, arnica, ginkgo, emmeisou, Dutch oak, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, European hawthorn, European juniper, cnidium rhizome, Swertia japonica, thyme, clove, tangerine peel, angelica acutiloba, peach kernel, spruce, carrot, garlic, butcher's broom, grape, peony, horse chestnut, melissa, yuzu, coix seed, rosemary, rosehip, peach, apricot, walnut, corn, etc. (e.g., extracts of these plants), and glucosyl hesperidin.

[0068] Cell-activating ingredients include amino acids other than component (B) such as gamma-aminobutyric acid, gamma-amino-beta-hydroxybutyric acid, and epsilon-aminocaproic acid, vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, and biotin, alpha-hydroxy acids such as glycolic acid, tannins, flavonoids, saponin, allantoin, photosensitizer No. 301, placenta extract, hinokitiol, cepharanthine, and kiwi seed extract.

[0069] Anti-aging ingredients include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

[0070] Astringent ingredients include zinc paraphenolsulfonate, zinc oxide, menthol, and ethanol.

[0071] Plant extracts include mulberry bark, saxifrage, perilla, rice bran, sake lees, white mustard, peony, barley bark, lotus seed, Job's tears seed, Pandanus amaryllifolius Roxb., Arcangelicia flava Merrilli, chamomile, coral grass, rice leaf, apricot fruit, Euonymus chinensis, rose flower, bamboo shoot skin, gentian, carrot, ginseng, red ginseng, loofah, peach, peach kernel, kiwi, sunflower, and Zizyphus Examples of plant extracts include joazeiro, pau d'arco, daylily, hibiscus flower, silverleaf wormwood, cherimoya, mango, Benifuki, Bletilla serrata, Japanese pepper peel or seed coat, safflower flower, Casablanca lily, guava leaf, Houttuynia cordata, Banpeiyu, Aloe fig flower, apple, white asparagus, yerba mate tea, cherry blossom leaf, and ylang ylang leaves.

[0072] Seaweed extracts include green algae such as Chlorella vulgaris, Chlorella pyrenoidosa, Chlorella ellipsoidea, green laver, sea lettuce, and sea lettuce; brown algae such as kelp (such as Gagome kelp, Laminaria japonica, Lisilis kelp, Narrow Laminaria japonica, and Mitsuishi kelp), giant kelp, wakame or green wakame, mozuku, unripe seaweed, hijiki, fucus, sea fan, thin-leaved sea fan, red-leaved sea fan, Kona sea fan, Okinawa fan, thin-leaved snow fan, and Etsuki sea fan; and brown algae such as Hijirimen, Makusa, or Examples include red algae such as Agar, Hirakusa, Onikusa, Obakusa, Kataobakusa, Yatabegusa, Yukikiri, Shimatengusa, Tosakanori, Togekirinsai, Amakusa Kirinsai, Eucheuma, Byakushin Kirinsai, Tsunomata, Oobatonomata, Tochaka or Yahazutsunomata, Ezotsunomata, Togetsunomata, Hirakotoji, Kotojitsunomata, Ibotsunomata, Marubatonomata, Hirakotoji, Suginori, Shikinori, Kainori, Yareusubanori, Kagiusubanori, Sujiusubanori, Haiusubanori, and Akamomijinanori.

[0073] Antifungal agents include terbinafine, naftifine, butenafine, tolnaftate, liranaftate, miconazole, lanoconazole, luliconazole, isoconazole, ketoconazole, clotrimazole, neticonazole, sulconazole, bifonazole, oxiconazole, econazole, fluconazole, itraconazole, fosfluconazole, voriconazole, eficonazole, butoconazole, fenticonazole, and sertaconazole.

[0074] Examples of whitening ingredients include tocopherol, ascorbic acid, tranexamic acid, arbutin, 4-alkylresorcinol, 4-methoxysalicylic acid, hydroquinone, kojic acid, salts thereof, or derivatives thereof, placenta extract, Phellodendron bark extract, Saxifraga extract, and aloe extract.

[0075] Base or carrier The base or carrier may be an oily base or an aqueous base. In addition to the hydrocarbon bases mentioned above, oily bases include higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; vegetable fats such as shea butter, carnauba wax, cocoa butter, and candelilla wax; animal fats and oils such as lanolin, orange roughy oil, squalane, horse oil, spermaceti, and beeswax; hydrogenated oils; methyl polysiloxane, crosslinked methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic silicone, alkyl-modified silicone, crosslinked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, crosslinked polyether-modified silicone, crosslinked alkyl polyether-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, ... Silicone oils such as phosphorus-modified branched silicones, acrylic silicones, phenyl-modified silicones, and silicone resins; natural polymer derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cationized guar gum, and acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymers, and alkyl acrylate / methacrylate copolymers; natural polymers such as carrageenan, alginic acid, cellulose, guar gum, quince seed, dextran, and gellan gum; esters such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythrityl tetra-2-ethylhexanoate, and caprylic / capric triglyceride; polysaccharides such as dextrin and maltodextrin;Glycol ethers such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether are included; In addition to water and buffer solutions, the aqueous base may also include lower alcohols such as ethanol and isopropanol. Polyhydric alcohols can also function as aqueous bases. The base or carrier may be used alone or in combination of two or more.

[0076] When the topical composition of the present invention contains water, the content of water may be 3% by weight or more, 5% by weight or more, 30% by weight or more, 50% by weight or more, 70% by weight or more, or 95% by weight or more, based on the total weight of the composition, and 97% by weight or less, 95% by weight or less, 70% by weight or less, 50% by weight or less, 30% by weight or less, or 5% by weight or less. Examples of the water content include 3 to 97% by weight, 3 to 95% by weight, 3 to 70% by weight, 3 to 50% by weight, 3 to 30% by weight, 5 to 97% by weight, 5 to 95% by weight, 5 to 70% by weight, 5 to 50% by weight, 5 to 30% by weight, 30 to 97% by weight, 30 to 95% by weight, 30 to 70% by weight, 30 to 50% by weight, 50 to 97% by weight, 50 to 95% by weight, 50 to 70% by weight, 70 to 97% by weight, 70 to 95% by weight, and 95 to 97% by weight.

[0077] The topical composition of the present invention may not contain polyoxyethylene arachidyl ether, stearyl alcohol, or a liquid oily component (e.g., a liquid oily base such as a liquid hydrocarbon base).The topical composition of the present invention may specifically exclude compositions containing adapalene, polyoxyethylene arachidyl ether, stearyl alcohol, a liquid oily component (e.g., a liquid oily base such as a liquid hydrocarbon base), a moisturizing component, and water. Furthermore, when the topical composition of the present invention contains at least one selected from the group consisting of macrogol (polyethylene glycol) having an average molecular weight of 4000 or less, glycerin, and 1,3-butylene glycol, the content thereof can be less than 5% by weight or more than 40% by weight of the total amount of the composition.

[0078] Any of the ingredients contained in the topical composition of the present invention may be in the form of a hydrate, hemihydrate, or anhydrous.

[0079] Dosage form Dosage forms of the topical composition of the present invention include liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, sprays, aerosols, powders, poultices, and sheets of nonwoven fabric or other materials impregnated with a medicinal solution. Among these, liquids, suspensions, emulsions, creams, gels, lotions, sprays, and aerosols are preferred, with liquids, suspensions, emulsions, creams, gels, and lotions being more preferred, in that they more significantly exhibit the effects of the present invention and reduce irritation to the skin upon application. In the case of an emulsified dosage form such as an emulsion, cream, or emulsion ointment, either an oil-in-water type or a water-in-oil type may be used, but the oil-in-water type is preferred in terms of the good feel when used and the good dispersibility of adapalene.

[0080] pH The pH of the topical composition of the present invention can be 2 or higher, 3 or higher, or 4 or higher, and 8 or lower, 7 or lower, or 6 or lower.

[0081] How to use The topical compositions of the present invention can be applied to areas of the skin affected by acne vulgaris, including the scalp. The topical composition of the present invention may be applied in an appropriate amount to the affected area usually 1 to 3 times a day, particularly once a day.

[0082] Method for improving dispersibility of adapalene and / or its salt The present invention encompasses a method for improving the dispersibility of adapalene and / or a salt thereof, which comprises adding (B) at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas, and mucopolysaccharides and its salts to a topical composition containing adapalene and / or its salt (A). The type and content of each component, the properties of the composition, and the like are as described for the topical composition of the present invention. [Example]

[0083] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Test Example 1 (Dispersibility Evaluation) Preparations for topical use were prepared by conventional methods, with the compositions shown in Tables 1, 2, and 3. The formulations in Table 1 are in the form of emulsions, and the formulations in Tables 2 and 3 are in the form of lotions. The dispersibility of adapalene was evaluated using these formulations. Specifically, after each formulation was stirred to homogenize, 50 μL was dropped onto a glass slide, and the particles were observed and photographed using a microscope (product name VHX-5000; Keyence Corporation). Only the particle portion was extracted using automatic image processing, and the average particle area was measured. The more agglomerated the adapalene, the larger the particle area observed. Thus, the more uniformly the adapalene is dispersed in the composition, the smaller the average particle area.

[0084] Next, the particle area reduction rate (%) compared to the corresponding comparative examples was calculated according to the following formula (1). The comparative example corresponding to Examples 1A to 1B is Comparative Example 1, the comparative example corresponding to Examples 2A to 2E is Comparative Example 2, and the comparative example corresponding to Example 3A is Comparative Example 3. Particle area reduction rate (%) = [(average particle area of ​​corresponding comparative example - average particle area of ​​example) / average particle area of ​​corresponding comparative example] × 100 (1)

[0085] The results are shown in Tables 1 to 3. [Table 1]

[0086] [Table 2]

[0087] [Table 3]

[0088] As shown in Tables 1 to 3, the particle area of ​​adapalene in a topical composition containing adapalene was reduced by adding N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide), cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate. This shows that the addition of component (B) improved the dispersibility of adapalene in the composition.

[0089] Test Example 2 (Dispersion Sustainability Evaluation) Preparations for topical use shown in Tables 4 and 5 were prepared by a conventional method. The preparations in Tables 4 and 5 were in the form of lotions. These formulations were used to evaluate the sustainability of adapalene dispersion. Specifically, 100 mL of each formulation was dispensed into a 100 mL glass vial and left to stand for 2 days at room temperature in the dark. Next, the formulation filled in the glass vial was sonicated for 5 minutes using an ultrasonic cleaner (model number: US-107, manufacturer: SND Co., Ltd.), then shaken up and down five times and allowed to stand for 10 minutes at room temperature in the dark. Before and after stirring, i.e., "sonication using an ultrasonic cleaner, shaking, and leaving to stand at room temperature in the dark for 10 minutes," 200 μL of each formulation was sampled from the center of the height between the liquid surface and the bottom of the glass vial, placed in a 96-well plate (FALCON, Tissue Culture Plate), and the absorbance at 600 nm was measured using a plate reader (Molecular Devices, VERSA max). The absorbance at 600 nm is an index of turbidity.

[0090] The value obtained by subtracting the turbidity before stirring from the turbidity after stirring was taken as the degree of separation. If the increase in turbidity due to stirring is small, the degree of separation will be small. A small degree of separation indicates that the dispersion of adapalene in the formulation is highly sustained.

[0091] The degree of separation was determined for each formulation, and the improvement rate (%) of dispersion sustainability compared to the corresponding comparative example was calculated according to the following formula (2). The comparative example corresponding to Examples 4A to 4C is Comparative Example 4, and the comparative example corresponding to Example 5A is Comparative Example 5. Dispersion sustainability improvement rate (%) = [(resolution of corresponding comparative example - resolution of each example) / resolution of corresponding comparative example] × 100 (2)

[0092] The results are shown in Tables 4 and 5. [Table 4]

[0093] [Table 5]

[0094] As shown in Tables 4 and 5, by adding sodium lactate, arginine, pyrrolidone carboxylic acid, or sodium hyaluronate to a topical composition containing adapalene, the sustainability of the dispersion of adapalene in the formulation was significantly improved.

[0095] Test Example 3 (Evaluation of dispersibility after application of formulation) The topical compositions shown in Tables 6 and 7 were prepared by a conventional method. The formulations in Tables 6 and 7 were lotions. These formulations were used to evaluate the dispersibility of adapalene after application. Specifically, each formulation was stirred to homogenize, then 50 μL was dropped onto a glass slide and allowed to dry at room temperature in the dark for approximately 18 hours. The particles were then observed and photographed using a microscope (Keyence VHX-5000). Automatic image processing was used to extract only the particle portion, and the average particle area was measured.

[0096] If adapalene aggregates during and after drying of the formulation, the observed particle area will be larger. This test evaluates the tendency of adapalene to aggregate in the formulation after application. If the observed particle area is small, it will be easier to spread adapalene evenly over the application site when the formulation is applied.

[0097] The particle area reduction rate (%) compared to the corresponding comparative example was calculated according to the above formula (1). The corresponding comparative example is Comparative Example 6 for Examples 6A to 6E, and Comparative Example 7 for Example 7A.

[0098] The results are shown in Tables 6 and 7. [Table 6]

[0099] [Table 7]

[0100] As shown in Tables 6 and 7, by adding lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate to an adapalene-containing topical composition, the particle area after application and drying of the composition was significantly reduced. It can be seen that the addition of component (B) makes adapalene less likely to aggregate after the topical composition of the present invention is applied to the skin.

[0101] Test Example 4 (Dispersibility Evaluation) Preparations for external use, which have the compositions shown in Tables 8 to 11, were prepared by a conventional method. The formulations in Tables 8 to 11 were each in the form of an emulsion. The dispersibility of adapalene was evaluated using these formulations. Specifically, after each formulation was stirred to homogenize, 50 μL was dropped onto a glass slide, and the particles were observed and photographed using a microscope (product name VHX-5000; Keyence Corporation). Only the particle portion was extracted using automatic image processing, and the average particle area was measured.

[0102] The more agglomerated the adapalene, the larger the particle area observed. Thus, the more uniformly the adapalene is dispersed in the composition, the smaller the average particle area.

[0103] Next, the particle area reduction rate (%) compared to the corresponding comparative example was calculated according to the above formula (1). The comparative example corresponding to Examples 8A to 8E is Comparative Example 8, the comparative example corresponding to Examples 9A to 9B is Comparative Example 9, the comparative example corresponding to Examples 10A to 10B is Comparative Example 10, and the comparative example corresponding to Examples 11A to 11E is Comparative Example 11.

[0104] The results are shown in Tables 8 to 11. [Table 8]

[0105] [Table 9]

[0106] [Table 10] [Table 11]

[0107] The formulations of the examples shown in Tables 8 to 11 differ from the formulations of the examples shown in Tables 1 to 3 in the concentration of N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide), cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate, and also use glycerin, 1,3-butylene glycol, polyethylene glycol, and / or propylene glycol as the polyhydric alcohol. In these cases, too, by blending N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide), cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate into a topical composition containing adapalene, the particle area of ​​adapalene in the composition was reduced. It can be seen that the blending of component (B) improved the dispersibility of adapalene in the composition.

[0108] Formulation example Compositions for external use (Formulation Examples 1 to 98) were prepared according to the formulations described below. [Table 12]

[0109] [Table 13]

[0110] [Table 14]

[0111] [Table 15]

[0112] [Table 16]

[0113] [Table 17]

[0114] [Table 18]

[0115] [Table 19]

[0116] [Table 20]

[0117] [Table 21] [Industrial Applicability]

[0118] The topical composition of the present invention has good dispersibility of adapalene and / or its salt, allowing adapalene to be applied uniformly to the affected area, and since aggregation of adapalene and / or its salt is suppressed, the desired medicinal effect can be fully obtained.

Claims

1. (A) 0.001 to 1 wt% of adapalene and / or a salt thereof relative to the total amount of the topical composition; (B) 0.0005 to 5 wt% of N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide relative to the total amount of the topical composition and 0.005 to 50 parts by weight per part by weight of the (A) component; 0.01 to 5 wt% of cholesterol relative to the total amount of the topical composition and 0.1 to 50 parts by weight per part by weight of the (A) component; 0.005 to 5 wt% of arginine relative to the total amount of the topical composition and 0.05 to 50 parts by weight per part by weight of the (A) component; A topical composition comprising at least one component selected from the group consisting of 0.001 to 10% by weight of sodium pyrrolidonecarboxylate and 0.01 to 100 parts by weight per part by weight of component (A), 0.005 to 10% by weight of lactic acid or sodium lactate and 0.05 to 100 parts by weight per part by weight of component (A) based on the total weight of the topical composition, 0.001 to 10% by weight of urea and 0.01 to 100 parts by weight per part by weight of component (A), and 0.001 to 5% by weight of sodium hyaluronate and 0.01 to 50 parts by weight per part by weight of component (A), and (C) 0.001 to 15% by weight of a polyhydric alcohol based on the total weight of the topical composition. However, the following cases are excluded. (1) Formula (I) 【Chemistry 1】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a branched or unbranched alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, or a substituted or unsubstituted alicyclic group.] and benzoyl peroxide. (2) When besifloxacin hydrochloride is contained (3) When containing purpurifloxacin (4) When containing dapsone and adapalene (5) Cases containing adapalene and benzoyl peroxide

2. The topical composition according to claim 1, wherein component (C) is at least one selected from the group consisting of dipropylene glycol, glycerin, 1,3-butylene glycol, and polyethylene glycol.

3. The topical composition according to claim 1 or 2, further comprising (D) an emulsifier.

4. The topical composition according to claim 3, wherein (D) the emulsifier is at least one selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters.

5. The topical composition according to any one of claims 1 to 4, further comprising (E) a hydrocarbon base.

6. The composition for external use according to any one of claims 1 to 5, wherein the composition is in the form of a liquid, suspension, emulsion, cream, gel, lotion, spray, or aerosol.

7. A method for improving the dispersibility of adapalene and / or a salt thereof in a topical composition, comprising adding (B) at least one component selected from the group consisting of N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide), cholesterol, arginine, sodium pyrrolidonecarboxylate, lactic acid, sodium lactate, urea, and sodium hyaluronate to a topical composition containing (A) adapalene and / or a salt thereof and (C) a polyhydric alcohol; the concentration of each component after the incorporation of component (B) is, relative to the total amount of the topical composition, 0.001 to 1 wt % for adapalene and / or a salt thereof, 0.001 to 15 wt % for the polyhydric alcohol, 0.0005 to 5 wt % for N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide), 0.01 to 5 wt % for cholesterol, 0.005 to 5 wt % for arginine, 0.001 to 10 wt % for sodium pyrrolidonecarboxylate, 0.005 to 10 wt % for lactic acid or sodium lactate, 0.001 to 10 wt % for urea, and 0.001 to 5 wt % for sodium hyaluronate; The content of each of the components (B) in the topical composition after the incorporation of the components (B) is, relative to 1 part by weight of the component (A), 0.005 to 50 parts by weight if the composition contains N-(hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide), 0.1 to 50 parts by weight if the composition contains cholesterol, 0.05 to 50 parts by weight if the composition contains arginine, 0.01 to 100 parts by weight if the composition contains sodium pyrrolidonecarboxylate, 0.05 to 100 parts by weight if the composition contains lactic acid or sodium lactate, 0.01 to 100 parts by weight if the composition contains urea, and 0.01 to 50 parts by weight if the composition contains sodium hyaluronate. However, this does not include the following cases after the incorporation of component (B): (1) Formula (I) 【Chemistry 2】 [In the formula, R represents a hydrogen atom, a hydroxyl group, a branched or unbranched alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, or a substituted or unsubstituted alicyclic group.] and benzoyl peroxide. (2) When besifloxacin hydrochloride is contained (3) When pulfrilloxacin is included (4) When containing dapsone and adapalene (5) Cases containing adapalene and benzoyl peroxide

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