External composition

Abstract

To provide an external composition containing adapalene and / or a salt thereof, with excellent dispersibility of the adapalene and / or a salt thereof; or provide an external composition containing adapalene and / or a salt thereof, with excellent dispersibility of the adapalene and / or a salt thereof, whereby skin dry is prevented.SOLUTION: An external composition contains (A) adapalene and / or a salt thereof, and (B) an antiinflammatory component and / or antibacterial component. The external composition may further contain (C) a polyhydric alcohol, (D) an emulsifier, and / or (E) a hydrocarbon base agent.SELECTED DRAWING: None

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 between the ingredients and the skin becomes small, making it difficult to achieve the desired medicinal effect. It is also known that when a topical composition containing adapalene is applied to the skin, the skin generally tends to dry out, which can easily cause discomfort, erythema, and itching (Non-Patent Document 1). [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 its salts in topical compositions is extremely poor. Therefore, an object of the present invention is to provide a topical composition containing adapalene and / or its salts, which has good dispersibility of adapalene and / or its salts. Another object of the present invention is to provide a topical composition containing adapalene and / or its salts, which has good dispersibility of adapalene and / or its salts and suppresses dry skin. [Means for solving the problem]

[0005] The present inventors have conducted extensive research to solve the above problems and have found that adding (B) an anti-inflammatory component and / or an antibacterial component to a topical composition containing (A) adapalene and / or a salt thereof improves the dispersibility of adapalene and / or a salt thereof in the composition. They have also found that adding (B) an anti-inflammatory component to a topical composition containing (A) adapalene and / or a salt thereof reduces skin dryness when the topical composition is applied to the skin.

[0006] The present invention was completed based on the above findings, and provides the following topical composition, method for improving the dispersibility of adapalene and / or a salt thereof, and method for reducing dry skin caused by a topical composition. Item 1. A composition for external use containing (A) adapalene and / or a salt thereof and (B) an anti-inflammatory component and / or an antibacterial component. 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 0.01 to 5% 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 for external use according to Item 4, wherein component (C) is at least one selected from the group consisting of propylene glycol, 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, ointment, gel, or lotion. Item 10. A method for improving the dispersibility of adapalene and / or a salt thereof, comprising adding (B) an anti-inflammatory component and / or an antibacterial component to an externally applied composition containing (A) adapalene and / or a salt thereof. Item 11. A method for suppressing dry skin caused by an externally applied composition, comprising adding (B) an anti-inflammatory component to an externally applied composition containing (A) adapalene and / or a salt thereof. [Effects of the Invention]

[0007] Adapalene and / or its salts generally have very poor dispersibility in topical compositions. However, the topical composition of the present invention contains an anti-inflammatory component and / or an antibacterial component, which allows adapalene and / or its salts to be dispersed and maintained in a uniform amount during application. Furthermore, the high dispersibility and uniformity of adapalene and / or its salts are maintained during preparation, facilitating 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 inhibits aggregation of adapalene and / or its salts in the dried state after application.

[0008] Furthermore, when the topical composition of the present invention contains an anti-inflammatory component, the dry skin sensation caused when applied to the skin is suppressed, reduced, or alleviated, thereby alleviating discomfort, erythema, itching, and other symptoms associated with dry skin. It is surprising that the anti-inflammatory component improves the dispersibility of adapalene and / or a salt thereof and also suppresses dry skin caused by adapalene and / or a salt thereof.

[0009] The topical composition of the present invention contains an anti-inflammatory and / or antibacterial component commonly used in topical compositions, thereby improving the dispersibility of adapalene and / or its salt, and also suppressing the dry skin sensation caused by the inclusion of an anti-inflammatory component commonly used in topical compositions. Therefore, in order to improve dispersibility, it is not necessary to add components that are not necessary for the skin, and a formulation can be obtained that can simultaneously exert anti-inflammatory and / or antibacterial effects. DETAILED DESCRIPTION OF THE INVENTION

[0010] 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) an anti-inflammatory component and / or an antibacterial component.

[0011] Adapalene and its salts The salt of adapalene 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). 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 salts thereof, adapalene and salts of adapalene and inorganic bases are preferred, and adapalene is more preferred.

[0012] The content of adapalene and / or its salt is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, even 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.

[0013] anti-inflammatory ingredients Anti-inflammatory ingredients include allantoin; glycyrrhizinic acid, glycyrrhizinic acid derivatives (methyl glycyrrhizinate, stearyl glycyrrhizinate, etc.), glycyrrhetinic acid, glycyrrhetinic acid derivatives (stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinic acid monoglucuronide, etc.); acetaminophen; epsilon-aminocaproic acid; berberine; azulene; bromelain; zinc; plant extracts such as licorice extract, sage extract, and rosemary extract; enzyme-based anti-inflammatory ingredients such as lysozyme, serrapeptase, and semi-alkaline proteinase; fenamic acid-based anti-inflammatory ingredients such as mefenamic acid, flufenamic acid, and tolfenamic acid; acemetacin, indomethacin, indomethacin farnesyl, edotolac, and diclofenac. arylacetic acid-based anti-inflammatory ingredients such as sulindac, nabutomene, fenbufen, proglumetacin, and mofezolac; propionic acid-based anti-inflammatory ingredients such as aminoprofen, ibuprofen, oxaprozin, ketoprofen, zaltoprofen, tiaprofenic acid, naproxen, flurbiprofen, zaltoprofen, ibuprofen piconol, flurbiprofen axetil, fenoprofen, pranoprofen, and loxoprofen; oxicam-based anti-inflammatory ingredients such as ampiroxicam, tenoxicam, piroxicam, meloxicam, and lornoxicam; mucopolysaccharides such as heparinoids, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin; and salts thereof. These are non-steroidal anti-inflammatory ingredients.

[0014] The salt of the anti-inflammatory component 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).

[0015] Specific examples include dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, indomethacin hydrochloride, diclofenac sodium salt, bromfenac sodium salt, berberine sulfate, berberine hydrochloride, berberine tannate, azulene sulfonate sodium salt, zinc sulfate, zinc lactate, lysozyme hydrochloride, proglumetacin maleate, fenoprofen calcium salt, loxoprofen sodium salt, sodium hyaluronate, and sodium chondroitin sulfate. When the composition of the present invention contains an anti-inflammatory ingredient that is a salt, it may be formulated as a salt, or it may be a salt that is formed in the composition as a result of separately formulating an acid compound and an organic or inorganic base.

[0016] Also useful are steroidal anti-inflammatory ingredients 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.

[0017] Among the anti-inflammatory components, non-steroidal anti-inflammatory components are preferred, with allantoin, glycyrrhizinic acid and its derivatives, glycyrrhetinic acid and its derivatives, propionic acid-based anti-inflammatory agents, mucopolysaccharides, and salts thereof being more preferred, and allantoin, glycyrrhizinic acid, glycyrrhetinic acid, ibuprofen piconol, and salts thereof, and heparinoids being even more preferred. The anti-inflammatory ingredients can be used alone or in combination of two or more.

[0018] Anti-inflammatory ingredient content The content of the anti-inflammatory component is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, even more preferably 0.1 wt% or more, and particularly preferably 0.2 wt% or more, based on the total amount of the composition. Also, the content is preferably 5 wt% or less, more preferably 4 wt% or less, and even more preferably 3 wt% or less. Within this range, the anti-inflammatory component exhibits appropriate physiological or pharmacological activity, while the dispersibility of adapalene and / or its salt is sufficient, resulting in a topical composition that is less likely to dry out the skin.

[0019] The ratio of the content of the anti-inflammatory ingredient 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, the ratio is preferably 500 parts by weight or less, more preferably 100 parts by weight or less, even more preferably 50 parts by weight or less, and particularly preferably 30 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of the anti-inflammatory ingredient is obtained, the dispersibility of adapalene and / or its salt is sufficient, and the skin dryness of the topical composition is sufficiently suppressed.

[0020] (Allantoin and / or its salts) When the anti-inflammatory component is allantoin and / or its salt, its content is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, even more preferably 0.1 wt% or more, and particularly preferably 0.15 wt% or more, based on the total amount of the composition. Also, it is preferably 5 wt% or less, more preferably 2 wt% or less, even more preferably 1 wt% or less, and particularly preferably 0.5 wt% or less. Within this range, allantoin and / or its salt can achieve the appropriate physiological or pharmacological activity, and adapalene and / or its salt can be sufficiently dispersed, resulting in a topical composition that is less likely to dry out the skin.

[0021] The ratio of the content of allantoin and / or its salt 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, particularly preferably 1.5 parts by weight or more, relative to 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, particularly preferably 5 parts by weight or less.Within this range, allantoin and / or its salt can obtain the appropriate physiological activity or pharmacological activity, and the dispersibility of adapalene and / or its salt is sufficient, and the skin dryness of the external use composition can be sufficiently suppressed.

[0022] (Glycyrrhizic acid, its derivatives, and / or their salts) When the anti-inflammatory component is glycyrrhizinic acid, its derivatives, and / or their salts (particularly, dipotassium glycyrrhizinate), the content thereof is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, even more preferably 0.1 wt% or more, particularly preferably 0.2 wt% or more, and most preferably 0.4 wt% or more, based on the total amount of the composition. Also, the content is preferably 5 wt% or less, more preferably 2 wt% or less, even more preferably 1 wt% or less, and particularly preferably 0.5 wt% or less. Within this range, the appropriate physiological or pharmacological activity of glycyrrhizinic acid, its derivatives, and / or their salts (particularly, dipotassium glycyrrhizinate) can be obtained, and the dispersibility of adapalene and / or its salts is sufficient, resulting in a topical composition that is less likely to dry out the skin.

[0023] The ratio of the content of glycyrrhizinic acid, its derivatives, and / or their salts (particularly, dipotassium glycyrrhizinate) to the content of adapalene and / or its salts 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, particularly preferably 2 parts by weight or more, and most preferably 4 parts by weight or more, per 1 part by weight of adapalene and / or its salts. 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 5 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of glycyrrhizinic acid, its derivatives, and / or their salts (particularly, dipotassium glycyrrhizinate) can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the dryness of the topical composition on the skin can be sufficiently suppressed.

[0024] (Glycyrrhetinic acid, its derivatives, and / or their salts) When the anti-inflammatory component is glycyrrhetinic acid, its derivatives, and / or their salts, the content thereof is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, even more preferably 0.1 wt% or more, particularly preferably 0.2 wt% or more, and most preferably 0.25 wt% or more, based on the total amount of the composition. Also, the content is preferably 5 wt% or less, more preferably 2 wt% or less, even more preferably 1 wt% or less, particularly preferably 0.5 wt% or less, and most preferably 0.35 wt% or less. Within this range, the appropriate physiological or pharmacological activity of glycyrrhetinic acid, its derivatives, and / or their salts can be obtained, and the dispersibility of adapalene and / or its salts is sufficient, resulting in a topical composition that is less likely to dry out the skin.

[0025] The ratio of the content of glycyrrhetinic acid, its derivatives, and / or their salts to the content of adapalene and / or its salts 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 salts. 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, particularly preferably 5 parts by weight or less, and particularly preferably 3.5 parts by weight or less. Within this range, appropriate physiological or pharmacological activity of glycyrrhetinic acid, its derivatives, and / or their salts can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the skin dryness of the topical composition can be sufficiently suppressed.

[0026] (mucopolysaccharides) When the anti-inflammatory ingredient is a mucopolysaccharide (especially a heparinoid), its content is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, even more preferably 0.1 wt% or more, particularly preferably 0.2 wt% or more, and most preferably 0.25 wt% or more, based on the total amount of the composition. It is also preferably 5 wt% or less, more preferably 2 wt% or less, even more preferably 1 wt% or less, particularly preferably 0.5 wt% or less, and most preferably 0.4 wt% or less. This range ensures that the appropriate physiological or pharmacological activity of the mucopolysaccharide (especially a heparinoid) is obtained, that adapalene and / or its salt is sufficiently dispersible, and that the topical composition is less likely to dry out the skin.

[0027] The ratio of the content of mucopolysaccharides (particularly, heparinoids) to the content of adapalene and / or its salts 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, particularly preferably 2 parts by weight or more, and most preferably 2.5 parts by weight, per part by weight of adapalene and / or its salts. The content 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, particularly preferably 5 parts by weight or less, and most preferably 4 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of the mucopolysaccharides (particularly, heparinoids) can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the dryness of the topical composition on the skin is sufficiently suppressed.

[0028] (Propionic acid-based anti-inflammatory agent) When the anti-inflammatory component is a propionic acid-based anti-inflammatory agent (particularly, ibuprofen piconol), its content is preferably 1% by weight or more, more preferably 2% by weight or more, and even more preferably 2.5% by weight or more, based on the total weight of the composition. Also, its content is preferably 5% by weight or less, more preferably 4% by weight or less, and even more preferably 3.5% by weight or less. Within this range, the appropriate pharmacological activity of the propionic acid-based anti-inflammatory agent (particularly, ibuprofen piconol) is obtained, adapalene and / or its salts are sufficiently dispersible, and the composition for external use is unlikely to dry out the skin.

[0029] The ratio of the content of the propionic acid anti-inflammatory agent (particularly, ibuprofen piconol) to the content of adapalene and / or its salt is preferably 10 parts by weight or more, more preferably 20 parts by weight or more, and even more preferably 25 parts by weight or more, per part by weight of adapalene and / or its salt. Also, the ratio is preferably 50 parts by weight or less, more preferably 40 parts by weight or less, and even more preferably 35 parts by weight or less. Within this range, the appropriate pharmacological activity of the propionic acid anti-inflammatory agent (particularly, ibuprofen piconol) is obtained, the dispersibility of adapalene and / or its salt is sufficient, and the skin dryness of the topical composition is sufficiently suppressed.

[0030] Antibacterial ingredient The antibacterial component (B) used in the topical composition of the present invention refers to any component known in the art that exhibits bactericidal or bacteriostatic action and can suppress the growth of contaminating bacteria (gram-positive bacteria, gram-negative bacteria, fungi, etc.). Antibacterial ingredients include phenolic synthetic disinfectants (isopropylmethylphenol, triclosan, salicylic acid, parahydroxybenzoic acid (paraben), parahydroxybenzoic acid esters (methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, etc.), cresol, etc.), oil-soluble antibacterial ingredients such as triclocarban; quaternary ammonium salt-type antibacterial ingredients (benzalkonium chloride (also called benzalkonium chloride), benzethonium chloride (also called benzethonium chloride), cetyltrimethylammonium chloride (also called cetyltrimethylammonium chloride), cetyltrimethylammonium bromide (also called cetyltrimethylammonium bromide), dequalinium chloride (also called dequalinium chloride), etc.), and chlorhexidine. cationic antibacterial ingredients such as lysozyme and salts thereof (e.g., hydrochloride, acetate, gluconate); water-soluble antibacterial ingredients such as acrinol, gluconic acid, alkyldiaminoglycine and salts thereof (e.g., hydrochloride); iodine-based antibacterial ingredients such as povidone-iodine, potassium iodide, and iodine; cresol, photosensitizer No. 101, photosensitizer No. 201, phenoxyethanol, 1,2-pentanediol, piroctone olamine, halocarban, benzoyl peroxide, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, and aminoglycoside antibiotics (e.g., clindamycin). Of the antibacterial components, oil-soluble antibacterial components are preferred, phenolic synthetic disinfectants are more preferred, and isopropylmethylphenol is even more preferred. The antibacterial component can be used alone or in combination of two or more.

[0031] Antibacterial ingredient content The content of the antibacterial component is preferably 0.01 wt% or more, more preferably 0.05 wt% or more, even more preferably 0.1 wt% or more, and particularly preferably 0.3 wt% or more, based on the total amount of the composition. It is also preferably 5 wt% or less, more preferably 3 wt% or less, even more preferably 2 wt% or less, and preferably 1 wt% or less. Within this range, the antibacterial component can exhibit appropriate physiological or pharmacological activity, while ensuring sufficient dispersibility of adapalene and / or its salt.

[0032] The ratio of the content of the antibacterial component 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 3 parts by weight or more, per 1 part by weight of adapalene and / or its salt. Also, the ratio is preferably 50 parts by weight or less, more preferably 30 parts by weight or less, even more preferably 20 parts by weight or less, and particularly preferably 10 parts by weight or less. Within this range, the antibacterial component can exhibit appropriate physiological or pharmacological activity, and adapalene and / or its salt can be sufficiently dispersed.

[0033] (Isopropylmethylphenol and / or its salts) When the antibacterial component is isopropylmethylphenol and / or its salt, its content 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 0.3% by weight or more, based on the total weight of the composition. It is also preferably 5% by weight or less, more preferably 3% by weight or less, even more preferably 2% by weight or less, and preferably 1% by weight or less. Within this range, the appropriate physiological or pharmacological activity of isopropylmethylphenol and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt can be sufficiently achieved.

[0034] The ratio of the content of isopropylmethylphenol and / or its salt 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 3 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 30 parts by weight or less, even more preferably 20 parts by weight or less, and particularly preferably 10 parts by weight or less. Within this range, the appropriate physiological or pharmacological activity of isopropylmethylphenol and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.

[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 and makes the topical composition less likely to dry out the skin. 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, propylene glycol, dipropylene glycol, butylene glycol (particularly, 1,3-butylene glycol), polyethylene glycol, and glycerin are more preferred, and dipropylene glycol, butylene glycol (particularly, 1,3-butylene glycol), polyethylene glycol, and glycerin are even 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 the composition for external use is less likely to dry out the skin.

[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 the composition for external use is less likely to dry out the skin.

[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-4 hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated 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 Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan isostearate; 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; alkyl amines such as trilaurylamine, dimethylstearylamine, and di-2-ethylhexylamine;and betaine-based amphoteric surfactants such as stearic acid dimethylaminopropylamide and lauryl hydroxysulfobetaine, polyoxyethylene polyoxypropylene glycol (such as poloxamer 124), polyglycerin fatty acid esters, glycerin fatty acid esters, polyethylene glycol fatty acid esters, etc.; 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.

[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.

[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 and makes the topical composition less likely to dry out the skin. 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. Also preferred are hydrocarbon bases that are liquid at room temperature (25°C) such as squalene, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light liquid paraffin. 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. Also preferred is 0.1 wt% or more, or even 1 wt% or more. Also preferred is 50 wt% or less, more preferably 30 wt% or less, even more preferably 20 wt% or less, and particularly preferably 10 wt% or less. Also preferred are 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, resulting in a topical composition that is even less likely to dry out the skin.

[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 is also 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 is obtained.

[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] Other physiologically or pharmacologically active ingredients (physiologically or pharmacologically active ingredients other than component (A) and component (B)) include, for example, antibacterial ingredients, anti-inflammatory ingredients, keratin softening or keratin dissolving agents, antipruritic agents, moisturizing ingredients other than polyhydric alcohols, local anesthetics, vitamins, peptides or derivatives thereof, blood circulation promoting ingredients, cell activating ingredients, anti-aging ingredients, astringent ingredients, amino acids, proteins, plant extracts, seaweed extracts, 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] When component (B) in the composition of the present invention is an anti-inflammatory component, for example, the antibacterial component exemplified as component (B) of the composition of the present invention can be blended as another physiologically or pharmacologically active component. Some antibacterial components are included as antiseptics or preservatives.

[0059] The topical composition 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 free of quinolone antibiotics such as 8-chlorofluoroquinolone, nadifloxacin, besifloxacin, clinadifloxacin, flurifloxacin, and ozenoxacin, especially 8-chlorofluoroquinolone. By not including 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 including a quinolone antibiotic, especially 8-chlorofluoroquinolone, the effects of the present invention are more pronounced.

[0060] When component (B) in the composition of the present invention is a bactericidal component, for example, an anti-inflammatory component exemplified as component (B) of the composition of the present invention can also be blended as another physiologically or pharmacologically active component.

[0061] Examples of keratolytic agents include urea and its derivatives (alkyl ureas having an alkyl group having 1 to 4 carbon atoms, such as methyl urea and ethyl urea; 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), salicylic acid and its derivatives (methyl salicylate), , acetylsalicylic acid, glycolic acid, fruit acids, phytic acid, lactic acid, lactate salts, 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 dialkylolamides, sulfur, resorcinol, sodium hydroxide, potassium hydroxide, etc.

[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] Moisturizing ingredients other than polyhydric alcohols include ceramides (glycosphingolipids such as fingosine, phytosphingosine, ceramide, cerebrosides, sphingophospholipids such as sphingomyelin, synthetic ceramides such as N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, hexadecyloxy PG hydroxyethyl hexadecanamide, cetyl PG hydroxyethyl palmitamide, human-type ceramides such as ceramide 2, ceramide 3, and fermented ceramide, animal-derived ceramides, plant-derived ceramides, ceramides 1 to 10, etc.), cholesterols (animal sterols such as cholesterol, cholestanol, lanosterol, selegurosterol, dehydrocholesterol, and coprostanol; phytosterol, sitosterol), plant sterols such as ergosterol, stigmasterol, campesterol, ergosterol, fucosterol, and spinasterol; microbially derived sterols such as ergosterol, mycosterol, and zymosterol; esters of these sterols with fatty acids having 10 to 18 carbon atoms, and the like), amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas (urea, alkyl ureas having an alkyl group having 1 to 4 carbon atoms, hydroxyalkyl ureas having a hydroxyalkyl group having 1 to 10 carbon atoms, and the like), 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 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, tannin, 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] 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.

[0074] 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; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate; 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; methylpolysiloxane, crosslinked methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, crosslinked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, crosslinked polyether-modified silicone, crosslinked alkylpolyether-modified silicone, silicone / alkyl chain co-modified polyether-modified silicone, silicone / alkyl chain co-modified polyglycerin-modified silicone. silicone oils such as cellulose, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; natural polymer derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cationized guar gum, and acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and alkyl acrylate / methacrylate copolymer; 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.

[0075] When the topical composition of the present invention contains water, the content of water can 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. It can also be 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. The topical composition of the present invention may also be water-free.

[0076] The topical compositions 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 compositions of the present invention may not contain, in particular, topical 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. The topical compositions of the present invention may be free of mequinol (also known as 4-methoxyphenol or 4-hydroxyanisole).

[0077] Any of the ingredients contained in the topical composition of the present invention may be in the form of a hydrate, hemihydrate, or anhydrous.

[0078] Dosage form Dosage forms of the topical composition of the present invention include solutions, 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, solutions, suspensions, emulsions, creams, ointments, gels, and lotions are preferred, with emulsions, creams, ointments, 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.

[0079] 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.

[0080] 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.

[0081] 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) an anti-inflammatory component and / or an antibacterial component to a topical composition containing (A) adapalene and / or a salt thereof. 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.

[0082] How to prevent dry skin The present invention encompasses a method for suppressing dry skin in a topical composition, comprising adding (B) an anti-inflammatory component to (A) a topical composition containing adapalene and / or a salt thereof. 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. In this method, "dry skin" refers to the property of drying the skin or the property of giving the skin a dry feeling. In this method, "suppression" can also be referred to as "reduction," "reduction," or "alleviation." [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 a conventional method, with the compositions shown in Tables 1 and 2. The formulations in Tables 1 and 2 were 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. When adapalene aggregates, the area of ​​each observed particle increases. Thus, the more uniformly adapalene is dispersed in the composition, the smaller the average particle area.

[0084] Next, the particle area reduction rate (%) compared to the corresponding comparative example was calculated according to the following formula (1). The comparative example corresponding to Examples 1A to 1C is Comparative Example 1, and the comparative example corresponding to Examples 2A and 2B is Comparative Example 2. 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 and 2. [Table 1]

[0086] [Table 2]

[0087] As shown in Tables 1 and 2, the particle area of ​​adapalene in a topical composition containing adapalene was reduced by adding dipotassium glycyrrhizinate, allantoin, a heparinoid, glycyrrhetinic acid, or ibuprofen piconol. This shows that the addition of component (B) improved the dispersibility of adapalene in the composition.

[0088] Test Example 2 (Dispersion Sustainability Evaluation) Preparations for topical use, each with the composition shown in Table 3, were prepared by a conventional method. The dosage form of each preparation in Table 3 was a lotion. 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 for 10 minutes at room temperature in the dark," 5 mL 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 quartz cell, and the absorbance at 600 nm was measured using an ultraviolet-visible spectrophotometer (product name: UV-2600, manufactured by Shimadzu Corporation). The absorbance at 600 nm is an index of turbidity.

[0089] The value obtained by subtracting the turbidity before stirring from the turbidity after stirring was taken as the degree of separation. The smaller the increase in turbidity due to stirring, the smaller the degree of separation. A small degree of separation indicates that adapalene remains dispersed in the formulation for a long time.

[0090] The degree of separation was determined for each preparation, and the improvement rate (%) of dispersion sustainability compared to the corresponding comparative example was calculated according to the following formula (2). Comparative example 3 corresponds to Examples 3A to 3C. Dispersion sustainability improvement rate (%) = [(resolution of corresponding comparative example - resolution of each example) / resolution of corresponding comparative example] × 100 (2)

[0091] The results are shown in Table 3. [Table 3] As shown in Table 3, the duration of dispersion of adapalene was improved by adding dipotassium glycyrrhizinate, allantoin, or a heparinoid to a topical composition containing adapalene.

[0092] Test Example 3 (Evaluation of dispersibility after application of formulation) Preparations for topical use, each with the composition shown in Table 4, were prepared by a conventional method. The dosage form of each preparation in Table 4 was a lotion. 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 dried at room temperature in the dark for approximately 18 hours. The particles were then observed and photographed using a microscope (product name: VHX-5000; Keyence Corporation). Automatic image processing was used to extract only the particle portion, and the average particle area (average particle area) was measured.

[0093] 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.

[0094] The particle area reduction rate (%) compared to the corresponding comparative example was calculated according to the above formula (1). Comparative example 4 corresponds to Examples 4A to 4C.

[0095] The results are shown in Table 4. [Table 4] As shown in Table 4, by adding dipotassium glycyrrhizinate, allantoin, or a heparinoid to a topical composition containing adapalene, 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.

[0096] Test Example 4 (Evaluation of Moisture Retention) Preparations for topical use with the compositions shown in Tables 5 and 6 were prepared by a conventional method. The preparations in Table 5 were in the form of a lotion, and the preparations in Table 6 were in the form of an emulsion. These preparations were used to test the moisturizing power or moisturizing performance of each preparation by the following method. The test sites were the inner forearms of two healthy adult subjects. First, before applying the test preparation to the test site, the test site was washed with water. 15 minutes after washing, the stratum corneum moisture content was measured using a skin surface stratum corneum moisture content measuring device (Skicon-200EX; Yayoi Co., Ltd.), and this was recorded as the initial moisture content. Next, 20 μL of the test preparation was applied to the test site, and 60 minutes later, the stratum corneum moisture content of the test site was measured. The stratum corneum moisture content after 60 minutes (post-application moisture content) minus the initial moisture content was recorded as the stratum corneum moisture change. Furthermore, the difference between the stratum corneum moisture change of each Example and the stratum corneum moisture change of the corresponding Comparative Example was calculated using the following formula (3):

[0097] The comparative example corresponding to Examples 5A and 5B is Comparative Example 5, and the comparative example corresponding to Examples 6A and 6B is Comparative Example 6. The change in stratum corneum moisture content indicates the moisturizing power of the test preparation, and therefore, the greater the change in stratum corneum moisture content of each Example compared to the corresponding comparative example, the more improved the moisturizing power is due to the incorporation of the anti-inflammatory agent. Difference in stratum corneum moisture change = Change in keratinocyte moisture content of Example - Change in keratinocyte moisture content of corresponding Comparative Example ·····(3)

[0098] The results are shown in Tables 5 and 6. [Table 5]

[0099] [Table 6] As shown in Tables 5 and 6, the moisturizing power was significantly improved by adding allantoin, dipotassium glycyrrhizinate, glycyrrhetinic acid, or ibuprofen piconol to a topical composition containing adapalene.

[0100] Test Example 5 (Dispersibility Evaluation) Preparations for topical use, each with the composition shown in Table 7, were prepared by a conventional method. The dosage form of each preparation in Table 7 was a lotion. Using these preparations, the dispersibility of adapalene was evaluated in the same manner as in Test Example 1. 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 Example 7A is Comparative Example 7.

[0101] The results are shown in Table 7. [Table 7] As shown in Table 7, the particle size of adapalene in the topical composition containing adapalene was reduced by adding isopropylmethylphenol. This indicates that the addition of component (B) improved the dispersibility of adapalene in the composition.

[0102] Test Example 6 (Dispersibility Evaluation) Preparations for external use with the compositions shown in Tables 8 and 9 were prepared by a conventional method. The formulations in Tables 8 and 9 were in the form of emulsions. 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.

[0103] When adapalene aggregates, the area of ​​each observed particle increases. Thus, the more uniformly adapalene is dispersed in the composition, the smaller the average particle area.

[0104] 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 8C is Comparative Example 8, and the comparative example corresponding to Examples 9A to 9B is Comparative Example 9.

[0105] The results are shown in Tables 8 and 9. [Table 8]

[0106] [Table 9] As shown in Tables 8 and 9, even when glycerin and 1,3-butylene glycol or propylene glycol were used as the polyhydric alcohol, the particle area of ​​adapalene in the composition was reduced by adding glycyrrhizinic acid, allantoin, or a heparinoid to the topical composition containing adapalene. This shows that the addition of component (B) improved the dispersibility of adapalene in the composition.

[0107] Formulation example Compositions for external use (Formulation Examples 1 to 70) were prepared according to the formulations described below. [Table 10]

[0108] [Table 11]

[0109] [Table 12]

[0110] [Table 13]

[0111] [Table 14]

[0112] [Table 15]

[0113] [Table 16]

[0114] [Table 17] [Industrial Applicability]

[0115] The topical composition of the present invention has good dispersibility of adapalene and / or its salts, allowing adapalene to be applied uniformly to the affected area, and the aggregation of adapalene and / or its salts is suppressed, thereby fully achieving the desired medicinal effect. Furthermore, the dryness and accompanying symptoms, known side effects of adapalene and / or its salts, are alleviated, making the composition easy to use.

Claims

[Claim 1] A topical composition containing (A) adapalene and / or a salt thereof and (B) an anti-inflammatory component and / or an antibacterial component.

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