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 an external composition containing adapalene and / or a salt thereof.

Background Art

[0002] Adapalene is a derivative of naphthalene carboxylic acid and is used as an active ingredient in topical therapeutic agents for acne vulgaris (pimples). Acne vulgaris occurs as pimples due to increased sebum secretion in the pilosebaceous system and blockage of hair follicles due to hyperkeratosis, and then progresses to a rash accompanied by inflammation. Adapalene suppresses the formation of pimples by controlling epidermal keratinization and improving clogged pores. Differin Gel 0.1% (trade name) (Galderma) is known as a topical agent containing adapalene as an active ingredient. Differin Gel 0.1% contains propylene glycol, methyl paraben, carboxyvinyl polymer, polyoxyethylene (20) polyoxypropylene (20) glycol, sodium edetate hydrate, and sodium hydroxide as additives (Non-Patent Document 1). Here, in the development of topical agents, if the dispersibility of components in the topical agent is poor, it is difficult to apply the components uniformly. In addition, when the components aggregate in the topical agent, the contact area between the components and the skin becomes small, and thus there is a problem that it is difficult to obtain the desired medicinal effect. In addition, it is known that when an external composition containing adapalene is applied to the skin, the skin is generally prone to dryness, which may cause discomfort, erythema, and itching (Non-Patent Document 1).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The inventor has found that the dispersibility of adapalene and / or its salt in a topical composition is extremely poor. Therefore, an object of the present invention is to provide a topical composition containing adapalene and / or its salt, which has good dispersibility of adapalene and / or its salt. Another object of the present invention is to provide a topical composition containing adapalene and / or its salt, which has good dispersibility of adapalene and / or its salt and suppresses skin dryness.

Means for Solving the Problems

[0005] The inventor has conducted extensive research to solve the above problems and has found that by adding (B) an anti-inflammatory component and / or an antibacterial component to a topical composition containing (A) adapalene and / or its salt, the dispersibility of adapalene and / or its salt in the composition is improved. In addition, it has been found that by adding (B) an anti-inflammatory component to a topical composition containing (A) adapalene and / or its salt, skin dryness when the topical composition is applied to the skin is reduced.

[0006] The present invention has been completed based on the above findings, and provides the following topical composition, a method for improving the dispersibility of adapalene and / or its salt, and a method for reducing skin dryness of a topical composition. Item 1. A topical composition containing (A) adapalene and / or its salt and (B) an anti-inflammatory component and / or an antibacterial component. Item 2. The topical composition according to Item 1, containing 0.001 to 1% by weight of component (A). Item 3. The topical composition according to Item 1 or 2, containing 0.01 to 5% by weight of component (B). Item 4. The topical composition according to any one of Items 1 to 3, further containing (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 propylene glycol, dipropylene glycol, glycerin, 1,3-butylene glycol, and polyethylene glycol. Item 6. The topical composition according to any one of Items 1 to 5, further containing (D) an emulsifier. Item 7. (D) The external composition according to Item 6, wherein 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. Item 8. The external composition according to any one of Items 1 to 7, further containing (E) a hydrocarbon base. Item 9. The external composition according to any one of Items 1 to 8, wherein the dosage form of the composition is a solution, a suspension, an emulsion, a cream, an ointment, a gel, or a 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 external composition containing (A) adapalene and / or a salt thereof. Item 11. A method for suppressing skin dryness of an external composition, comprising adding (B) an anti-inflammatory component to an external composition containing (A) adapalene and / or a salt thereof.

Advantages of the Invention

[0007] Adapalene and / or a salt thereof generally has extremely poor dispersibility in an external composition. However, the external composition of the present invention contains an anti-inflammatory component and / or an antibacterial component, so that the dispersibility and dispersion maintenance property of adapalene and / or a salt thereof are good. Therefore, the application amount of adapalene and / or a salt thereof becomes uniform when the external composition is applied. Further, during the production of the preparation, since the dispersibility of adapalene and / or a salt thereof is high and the uniformity is maintained, the production of the preparation is easy. In addition, components having poor dispersibility in the external composition generally show significant aggregation during the application and drying of the composition. However, in the composition of the present invention, the aggregation of adapalene and / or a salt thereof in the dried state after application is effectively suppressed.

[0008] Further, when the external composition of the present invention contains an anti-inflammatory component, the feeling of skin dryness when applied to the skin is suppressed, reduced, or alleviated. Therefore, the discomfort, erythema, itching, etc. associated with skin dryness are also alleviated. It is surprising that the anti-inflammatory component improves the dispersibility of adapalene and / or a salt thereof and suppresses skin dryness caused by adapalene and / or a salt thereof.

[0009] The external composition of the present invention contains an anti-inflammatory component and / or an antibacterial component that are widely used as components of the external composition, thereby improving the dispersibility of adapalene and / or its salt. Further, by containing an anti-inflammatory component that is widely used as a component of the external composition, the feeling of dry skin is suppressed. Therefore, in order to improve the dispersibility, it is not necessary to add components that are not necessary to be contained for the skin, and at the same time, it can be made into a preparation that can exhibit an anti-inflammatory effect and / or an antibacterial effect.

Mode for Carrying Out the Invention

[0010] Hereinafter, the present invention will be described in detail. The composition of the present invention is an external composition containing (A) adapalene and / or its salt, 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, such as 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 and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as zinc salt and aluminum salt, etc.). When the composition of the present invention contains a salt of adapalene, it may be a compounded one as a salt of adapalene, or it may be a salt formed in the composition as a result of separately compounding adapalene and an organic or inorganic base. Among adapalene and its salts, adapalene and salts of adapalene with 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, still 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. Also, it is 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 most preferred. Within this range, appropriate pharmacological activity of adapalene and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.

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

[0014] The salt of the anti-inflammatory component may be any pharmaceutically or physiologically acceptable salt, and examples thereof include salts with organic bases (such as organic amine salts like methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, 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, metal salts such as zinc salt and aluminum salt).

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

[0016] In addition, steroid anti-inflammatory components such as prednisolone, hydrocortisone, cortisone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, difluprednate, mometasone, diflucortolone, fluocinide, fluocinonide, clobetasol, beclomethasone, deprodone, alclometasone, flumethasone, amcinonide, clobetasone, diflorasone, and derivatives (especially esters) thereof can also be used. Examples of the above-mentioned steroid derivatives include prednisolone esters such as prednisolone valerate acetate (PVA), prednisolone succinate, prednisolone acetate, and prednisolone phosphate; betamethasone propionate, betamethasone valerate, dexamethasone valerate, dexamethasone propionate, dexamethasone acetate, dexamethasone phosphate, dexamethasone metasulfobenzoate, dexamethasone cypionate, and dexamethasone palmitate; hydrocortisone esters such as hydrocortisone butyrate (especially hydrocortisone-17-butyrate), 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, fluocortolone pivalate, clobetasone propionate, clobetasone butyrate, and diflorasone acetate.

[0017] Among them, the anti-inflammatory component is preferably a non-steroidal anti-inflammatory component, more preferably allantoin, glycyrrhizic acid and its derivatives, glycyrrhetinic acid and its derivatives, propionic acid-based anti-inflammatory agents, mucopolysaccharides, and their salts, and even more preferably allantoin, glycyrrhizic acid, glycyrrhetinic acid, ibuprofen piconol, and their salts, and heparin-like substances. The anti-inflammatory component can be used alone or in combination of two or more.

[0018] Content of anti-inflammatory component The content of the anti-inflammatory component 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 4% by weight or less, even more preferably 3% by weight or less. Within this range, appropriate physiological or pharmacological activities of the anti-inflammatory component can be obtained, and the dispersibility of adapalene and / or its salt is sufficient, resulting in a topical composition that is less likely to dry the skin.

[0019] The ratio of the content of the anti-inflammatory component to the content of adapalene and / or its salt is preferably 0.1 part by weight or more, more preferably 0.5 part 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 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, appropriate physiological or pharmacological activities of the anti-inflammatory component can be obtained, and the dispersibility of adapalene and / or its salt is sufficient, and the skin-drying property 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% by weight or more, more preferably 0.05% by weight or more, even more preferably 0.1% by weight or more, and particularly preferably 0.15% 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 0.5% by weight or less. Within this range, appropriate physiological or pharmacological activities of allantoin and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient, resulting in a topical composition that is less likely to dry 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 part by weight or more, more preferably 0.5 part by weight or more, even more preferably 1 part by weight or more, and particularly preferably 1.5 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 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, appropriate physiological or pharmacological activities of allantoin and / or its salt can be obtained, the dispersibility of adapalene and / or its salt is sufficient, and the skin dryness of the topical composition is sufficiently suppressed.

[0022] (Glycyrrhizic acid, its derivatives, and / or their salts) When the anti-inflammatory component is glycyrrhizic acid, its derivatives, and / or their salts (particularly dipotassium glycyrrhizinate), 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, particularly preferably 0.2% by weight or more, and most preferably 0.4% 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 0.5% by weight or less. Within this range, appropriate physiological or pharmacological activities of glycyrrhizic acid, its derivatives, and / or their salts (particularly dipotassium glycyrrhizinate) can be obtained, the dispersibility of adapalene and / or its salt is sufficient, and a topical composition that is less likely to dry the skin is obtained.

[0023] The ratio of the content of glycyrrhizic acid, its derivatives, and / or their salts (particularly dipotassium glycyrrhizinate) to the content of adapalene and / or its salts is preferably 0.1 part by weight or more, more preferably 0.5 part 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, particularly preferably 5 parts by weight or less. Within this range, appropriate physiological or pharmacological activities of glycyrrhizic 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 skin dryness of the topical composition is 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, 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, particularly preferably 0.2% by weight or more, and most preferably 0.25% 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, particularly preferably 0.5% by weight or less, and most preferably 0.35% by weight or less. Within this range, appropriate physiological or pharmacological activities of glycyrrhetinic acid, its derivatives, and / or their salts can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the topical composition is less likely to dry 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 part by weight or more, more preferably 0.5 part by weight or more, even more preferably 1 part by weight or more, and particularly preferably 2 parts by weight or more, based on 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 most particularly preferably 3.5 parts by mass or less. Within this range, appropriate physiological or pharmacological activities 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 is sufficiently suppressed.

[0026] (Mucopolysaccharides) When the anti-inflammatory component is a mucopolysaccharide (particularly, a heparin-like substance), 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, particularly preferably 0.2% by weight or more, and most preferably 0.25% 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, particularly preferably 0.5% by weight or less, and most preferably 0.4% by weight or less. Within this range, appropriate physiological or pharmacological activities of the mucopolysaccharide (particularly, a heparin-like substance) can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the topical composition is less likely to dry the skin.

[0027] The ratio of the content of mucopolysaccharides (especially heparin - like substances) to the content of adapalene and / or its salts is preferably 0.1 part by weight or more, more preferably 0.5 part by weight or more, even more preferably 1 part by weight or more, particularly preferably 2 part by weight or more, and most preferably 2.5 part by weight or more, based on 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 most preferably 4 parts by weight or less. Within this range, appropriate physiological or pharmacological activities of the mucopolysaccharides (especially heparin - like substances) can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the skin dryness of the topical composition is sufficiently suppressed.

[0028] (Propionic acid-based anti-inflammatory agents) When the anti - inflammatory component is a propionic acid - based anti - inflammatory agent (especially 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 amount of the composition. Also, it 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, appropriate pharmacological activities of the propionic acid - based anti - inflammatory agent (especially ibuprofen piconol) can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the topical composition is less likely to dry the skin.

[0029] The ratio of the content of the propionic acid - based anti - inflammatory agent (especially ibuprofen piconol) to the content of adapalene and / or its salts 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, based on 1 part by weight of adapalene and / or its salts. Also, it 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, appropriate pharmacological activities of the propionic acid - based anti - inflammatory agent (especially ibuprofen piconol) can be obtained, the dispersibility of adapalene and / or its salts is sufficient, and the skin dryness of the topical composition is sufficiently suppressed.

[0030] Antibacterial component The antibacterial component (B) used in the external composition of the present invention refers to any component known in the art that can exhibit a bactericidal or bacteriostatic effect and suppress the growth of various bacteria (gram-positive bacteria, gram-negative bacteria, fungi, etc.). Examples of antibacterial components include phenolic synthetic bactericides (isopropylmethylphenol, triclosan, salicylic acid, paraoxybenzoic acid (paraben), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), cresol, etc.), oil-soluble antibacterial components such as triclocarban; quaternary ammonium salt type antibacterial components (benzalkonium chloride (also referred to as benzalkonium chloride), benzethonium chloride (also referred to as benzethonium chloride), cetyltrimethylammonium chloride (also referred to as cetyltrimethylammonium chloride), cetyltrimethylammonium bromide (also referred to as cetyltrimethylammonium bromide), decalinium chloride (also referred to as decalinium chloride), etc.), cationic antibacterial components such as chlorhexidine, lysozyme, and their salts (for example, hydrochloride, acetate, gluconate); water-soluble antibacterial components such as acrinol, gluconic acid, alkyldiaminoglycine, and their salts (for example, hydrochloride); iodine-based antibacterial components such as povidone iodine, potassium iodide, iodine; cresol, photosensitizer No. 101, photosensitizer No. 201, phenoxyethanol, 1,2-pentanediol, piroctone olamine, halocarban, benzoyl peroxide, alkyl diaminethyl glycine hydrochloride, cetylpyridinium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, aminoglycoside antibiotics (such as clindamycin). Among these, oil-soluble antibacterial components are preferred as the antibacterial component, phenolic synthetic bactericides are more preferred, and isopropylmethylphenol is even more preferred. The antibacterial component can be used alone or in combination of two or more.

[0031] Content of antibacterial component The content of the antibacterial component 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 amount of the composition. Also, it is 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, appropriate physiological or pharmacological activities of the antibacterial component can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.

[0032] The ratio of the content of the antibacterial component to the content of adapalene and / or its salt is preferably 0.1 part by weight or more, more preferably 0.5 part 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, appropriate physiological or pharmacological activities of the antibacterial component can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.

[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 amount of the composition. Also, it is 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, appropriate physiological or pharmacological activities of isopropylmethylphenol and / or its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.

[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 part by weight or more, more preferably 0.5 part by weight or more, even more preferably 1 part by weight or more, and particularly preferably 3 part by weight or more with respect to 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, appropriate physiological activity 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 external composition of the present invention can contain (C) polyhydric alcohol, whereby the dispersibility of adapalene and / or its salt is further improved, and the external composition becomes less likely to dry the skin. Examples of the polyhydric alcohol include dihydric alcohols such as 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 (isopentyldiol), hexylene glycol, dipropylene glycol, polyethylene glycol (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), polypropylene glycol (such as polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000); trihydric alcohols such as glycerin, trimethylolpropane; and diglycerin, polyglycerin. Among them, dihydric alcohols and trihydric alcohols are preferred, propylene glycol, dipropylene glycol, butylene glycol (especially 1,3-butylene glycol), polyethylene glycol, and glycerin are more preferred, and dipropylene glycol, butylene glycol (especially 1,3-butylene glycol), polyethylene glycol, and glycerin are even more preferred. The polyhydric alcohol can be used alone or in combination of two or more.

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

[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, it 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 it becomes an external composition that is less likely to dry the skin further.

[0038] The ratio of the content of the polyhydric alcohol to the content of adapalene and / or its salt is preferably 0.01 part by weight or more, more preferably 0.1 part by weight or more, even more preferably 1 part by weight or more, and particularly preferably 10 parts by weight or more with respect to 1 part by weight of adapalene and / or its salt. Further, 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 topical composition is less likely to further dry the skin.

[0039] Emulsifier The topical composition of the present invention can contain (D) an emulsifier, whereby the dispersibility of adapalene and / or its salt is further improved. As emulsifiers, there are sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, diglycerol sorbitan penta-2-ethylhexanoate, and diglycerol sorbitan tetra-2-ethylhexanoate; propylene glycol fatty acid esters such as propylene glycol monostearate; hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 (HCO-80), etc.); castor oil derivatives such as polyoxyethylene castor oil; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate; polyoxyethylene glyceryl monopalmitate; glycerin alkyl ether; alkyl glucoside; 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; phospholipids such as lecithin, natural surfactants such as surfactin and saponin; fatty acid amide amines such as diethylaminoethyl stearate amide and diethylaminopropyl stearate amide; alkylamines such as trilaurylamine, dimethylstearylamine, and di-2-ethylhexylamine;and dimethylaminopropylamide stearate, and betaine amphoteric surfactants such as lauryl hydroxysulfobetaine, polyoxyethylene polyoxypropylene glycol (such as poloxamer 124), polyglycerol fatty acid esters, glycerol fatty acid esters, polyethylene glycol fatty acid esters, and the like. Among them, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ether, polyoxyethylene sorbitan fatty acid esters, and polyglycerol 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), polyoxyethylene (20) sorbitan monooleate (polysorbate 80) are more preferred. The emulsifier 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 amount of the composition. Also, 10% by weight or less is preferred, 8% by weight or less is more preferred, 6% by weight or less is even more preferred, and 4% by weight or less is particularly preferred. 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 with respect 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 external composition of the present invention can contain (E) a hydrocarbon base, whereby the dispersibility of adapalene and / or its salt is further improved, and it becomes an external composition that is more difficult to dry the skin. Examples of the hydrocarbon base include petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (such as plastibase), ozokerite, ceresin, microcrystalline wax, squalene, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light liquid paraffin. Among them, hydrocarbon bases that are solid at normal temperature (25°C) such as petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (such as plastibase), ozokerite, ceresin, and microcrystalline wax are preferred, petrolatum, ozokerite, ceresin, and microcrystalline wax are more preferred, and petrolatum is even more preferred. Also, hydrocarbon bases that are liquid at normal temperature (25°C) such as squalene, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light liquid paraffin are also preferred. The hydrocarbon base can be used alone or in combination of two or more.

[0043] The content of the hydrocarbon base is preferably 0.000001% by weight or more, more preferably 0.00001% by weight or more, even more preferably 0.0001% by weight or more, and particularly preferably 0.001% by weight or more, based on the total amount of the composition. Also, 0.1% by weight or more, or 1% by weight or more is also preferable. Further, 50% by weight or less is preferable, 30% by weight or less is more preferable, 20% by weight or less is even more preferable, and 10% by weight or less is particularly preferable. Also, 1% by weight or less, 0.1% by weight or less, or 0.01% by weight or less is also preferable. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved, and it becomes an external composition that is less likely to further dry the skin.

[0044] The ratio of the content of the hydrocarbon base to the content of adapalene and / or its salt is preferably 0.00001 part by weight or more, more preferably 0.0001 part by weight or more, even more preferably 0.001 part by weight or more, and particularly preferably 0.01 part by weight or more, based on 1 part by weight of adapalene and / or its salt. Also, 500 parts by weight or less is preferable, 300 parts by weight or less is more preferable, 200 parts by weight or less is even more preferable, and 100 parts by weight or less is particularly preferable. Also, 10 parts by weight or less, 1 part by weight or less, or 0.1 part by weight or less is also preferable. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved, and it becomes an external composition that is less likely to further dry the skin.

[0045] Other components The external composition of the present invention can be prepared by mixing the component (A), the component (B), and the above-mentioned components that are blended as necessary, with a base or carrier, an additive, and other physiologically active or pharmacologically active components used in pharmaceuticals, quasi-drugs, or cosmetics as necessary, to form an external composition of a pharmaceutical, a quasi-drug, or a cosmetic. In particular, it can be a pharmaceutical composition (pharmaceutical external composition).

[0046] Examples of the additive include an antioxidant, a thickener, an antiseptic or preservative, a pH adjuster, a stabilizer, a chelating agent, an ultraviolet absorber or ultraviolet scattering agent, a pungency reducer, a coloring agent, a cooling agent, a fragrance, and the like. The additives can be used singly or in combination of two or more kinds. Also, the additives can be used as long as the effects of the present invention are not impaired.

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

[0048] Examples of the thickener include guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, acrylic acid methacrylic acid alkyl copolymer, bentonite, alginic acid, macrogol, and cellulose-based thickeners (such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose, etc.).

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

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

[0051] Examples of stabilizers include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.

[0052] Examples of chelating agents include EDTA disodium salt and EDTA calcium disodium salt.

[0053] Examples of irritation reducers include licorice extract and sodium alginate.

[0054] Examples of ultraviolet absorbers or ultraviolet scattering agents include 2-ethylhexyl p-methoxycinnamate, hexyl 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoate, 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, t-butylmethoxydibenzoylmethane, ethylhexyl dibenzylidene dioxoimidazolidine propionate, etocrylene, p-aminobenzoic acid and its derivatives, octyl p-dimethylaminobenzoate, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide, and zinc oxide.

[0055] Examples of the coloring agent include dyes described in the Legal Dye 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 (these may be any of the d-form, l-form, or dl-form); essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, star anise oil, perilla oil, cinnamon oil, rose oil, and turpentine oil. Examples of the fragrance include various essential oils such as herb-based essential oils like lavender oil, rosemary oil, clary sage oil, thyme oil, bergamot oil, and eucalyptus oil, and citrus-based essential oils like orange oil, lemon oil, and grapefruit oil, as well as compound fragrances.

[0057] Examples of other physiologically active or pharmacologically active components (physiologically active or pharmacologically active components other than component (A) and component (B)) include, for example, antibacterial components, anti-inflammatory components, keratolytic agents or keratoplastic agents, antipruritics, moisturizing components other than polyhydric alcohols, local anesthetics, vitamins, peptides or their derivatives, blood circulation promoting components, cell activating components, anti-aging components, astringent components, amino acids, proteins, plant extracts, seaweed extracts, and whitening components. The other physiologically active or pharmacologically active components can be used alone or in combination of two or more. In addition, the other physiologically active or pharmacologically active components can be used as long as the effects of the present invention are not impaired.

[0058] When component (B) is an anti-inflammatory component in the composition of the present invention, for example, the antibacterial components exemplified as component (B) of the composition of the present invention can also be formulated as other physiologically active or pharmacologically active components. Some of the antibacterial components are also included as preservatives or preservatives.

[0059] In addition, the topical composition of the present invention can exclude preparations for use in the treatment or prevention of acne including drug-resistant acne and P. acnes that is non-responsive / resistant to therapeutic doses of clindamycin, minocycline, tetracycline or erythromycin. Among others, it can exclude preparations for use in the treatment or prevention of acne including drug-resistant acne and P. acnes that is non-responsive / resistant to therapeutic doses of clindamycin, minocycline, tetracycline or erythromycin, and that contain adapalene and an anti-inflammatory agent. Among others, it can exclude preparations for use in the treatment or prevention of acne including drug-resistant acne and P. acnes that is non-responsive / resistant to therapeutic doses of clindamycin, minocycline, tetracycline or erythromycin, and that contain an antibacterial agent, adapalene and an anti-inflammatory agent. Also, the present invention can be made to exclude dual-action rational therapy molecules (excluding adapalene) having two distinct mechanisms of action for the treatment or prevention of bacterial infections. Among others, it can be made to exclude drug carriers or preparations containing a dual-action rational therapy molecule having two distinct mechanisms of action for the treatment or prevention of bacterial infections, adapalene and an anti-inflammatory agent. In particular, for the treatment of bacterial infections caused by both sensitive and resistant Gram-positive and Gram-negative bacteria, it can be made to exclude dual-action rational therapy molecules (excluding adapalene) that cure acne as well as different skin and skin structure infections and additionally prevent the development of resistance. Among others, for the treatment of bacterial infections caused by both sensitive and resistant Gram-positive and Gram-negative bacteria, it can be made to exclude drug carriers or preparations containing a dual-action rational therapy molecule that cures acne as well as different skin and skin structure infections and additionally prevents the development of resistance, adapalene and an anti-inflammatory agent. In addition, the present invention can be a quinolone antibiotic such as 8-chlorofluoroquinolone, nadifloxacin, besifloxacin, clinafloxacin, flurifloxacin, or ozexnoxacin, especially one that does not contain 8-chlorofluoroquinolone. By not containing a quinolone antibiotic, especially 8-chlorofluoroquinolone, the composition does not cause photosensitivity due to the quinolone antibiotic, and denaturation of the composition due to photo-degradation of the quinolone antibiotic is avoided. Further, by not containing a quinolone antibiotic, especially 8-chlorofluoroquinolone, the effects of the present invention are more significantly exhibited.

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

[0061] Examples of the keratolytic agent or keratoplastic agent include urea and its derivatives (alkylureas having an alkyl group with 1 to 4 carbon atoms such as methylurea and ethylurea; hydroxyalkylureas having a hydroxyalkyl group with 1 to 10 carbon atoms such as hydroxyethylurea, dihydroxyethylurea, bis(hydroxyethyl)urea, hydroxypropylurea, dihydroxypropylurea, bis(hydroxypropyl)urea, hydroxybutylurea, dihydroxybutylurea, bis(hydroxybutyl)urea, etc.), salicylic acid and its derivatives (such as methyl salicylate and acetylsalicylic acid), glycolic acid, fruit acid, phytic acid, lactic acid, lactate, sulfur, ethyl alcohol, isopropyl alcohol, propanol, butanol, benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyl dodecanol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurate, lanolin, fatty acid dialkylolamide, sulfur, resorcin, sodium hydroxide, potassium hydroxide, etc.

[0062] Examples of antipruritics include ethanolamine antihistamines such as diphenhydramine, bromodiphenhydramine, clemastine, chlorphenoxamine, diphenylpyraline, doxylamine, orphenadrine, phenyltoloxamine; propylamine antihistamines such as chlorpheniramine, dimethindene, terfenadine; ethylenediamine antihistamines such as mepyramine, metapyrilene, tripelennamine; phenothiazine antihistamines such as alimemazine, hydroxyethylpromethazine, isothipendyl, mequitazine, oxomemazine, promethazine; piperazine antihistamines such as buclizine, cetirizine, homochlorcyclizine, cyclizine, hydroxyzine, levocetirizine, meclizine, oxatomide; antihistamines such as ketotifen, olopatadine, fexofenadine, loratadine, terfenadine, antazoline, azatadine, bamipine, cyproheptadine, deptropine, ebastine, emedastine, epinastine, mebhydroline, mizolastine, pimecrolimus, pyrrobutamine, kifendazole, rupatadine, triprolidine, acrivastine, astemizole, azelastine, bilastine, desloratadine, and salts thereof. In addition, components that are not antihistamines, such as crothiamine, ichthyol, moktal, thymol, are also included.

[0063] Examples of moisturizing components other than polyhydric alcohols include ceramides (such as sphingosine, phytosphingosine, ceramide, cerebroside such as glycosphingolipids, sphingomyelin such as sphingophospholipids, N-(hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide, hexadecyloxy PG hydroxyethylhexadecanamide, cetyl PG hydroxyethyl palmitamide such as synthetic ceramides, ceramide 2, ceramide 3, human-type ceramides such as fermented ceramide, animal-derived ceramides, plant-derived ceramides, ceramide 1 to 10, etc.), cholesterols (such as cholesterol, cholestanol, lanosterol, stigmasterol, dehydrocholesterol, zoosterols such as coprostanol; phytosterols such as phytosterol, sitosterol, stigmasterol, campesterol, ergosterol, fucosterol, spinasterol; microbial-derived sterols such as ergosterol, mycosterol, thymosterol; esters of these sterols and fatty acids having 10 to 18 carbon atoms, etc.), amino acids, pyrrolidonecarboxylic acid and its salts, lactic acid and its salts, ureas (such as urea, alkyl ureas having an alkyl group with 1 to 4 carbon atoms, hydroxyalkyl ureas having a hydroxyalkyl group with 1 to 10 carbon atoms, etc.), trehalose, xylitol, saccharides such as sorbitol, high molecular compounds such as keratin, chitin, chitosan, lipids such as phospholipids, plant extracts such as chamomile extract, witch hazel extract, tea extract, aloe extract, etc.).

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

[0065] Examples of vitamins include vitamin E compounds such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, calcium dl-α-tocopherol succinate, ubiquinone derivatives and pharmaceutically or physiologically acceptable salts thereof, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5'-phosphate, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate, ascorbigen-A, ascorbic acid stearate, ascorbic acid palmitate, L-ascorbyl dipalmitate, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, pharnoquinone, γ-oryzanol, dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, cetyl thiamine hydrochloride, thiamine thiocyanate, lauryl thiamine hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate ester monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, pyridoxal 5'-phosphate, pyridoxamine hydrochloride, cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinamide, pantothenic acid, calcium pantothenate, panthenyl alcohol (panthenol), D-pantethine, D-pantethine, coenzyme A, pantothenic acid compounds such as pantothenyl ethyl ether, biotin, biocytin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, eriocitrin, and the like.

[0066] Examples of the peptide or its derivative include keratin hydrolyzate, hydrolyzed keratin, collagen, gelatin, elastin, elastin hydrolyzate, collagen hydrolyzate, hydrolyzed collagen, hydrolyzed silk, etc.

[0067] As the blood circulation promoting component, plant-derived components are preferably exemplified. For example, components derived from parsley, ashitaba, arnica, ginkgo, polygonatum, dutchmans pipe, carrot, gentiana, burdock, rice, Japanese quince, shiitake mushroom, European quince, European spindle tree, cnidium, asparagus, thyme, clove, Chinese chive, angelica, dong quai, yew, carrot, garlic, butcher's broom, grape, button mushroom, paulownia, lemon balm, yuzu, yokukinin, rosemary, rose hip, peach, apricot, walnut, corn, etc. (such as extracts of these plants), and glucosyl hesperidin, etc.

[0068] Examples of the cell activating component include amino acids such as γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, ε-aminocaproic acid, vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, biotin, α-hydroxy acids such as glycolic acid, tannin, flavonoid, saponin, allantoin, photosensitizer No. 301, placenta extract, hinokitiol, cephalanthin, kiwifruit seed extract, etc.

[0069] Examples of the anti-aging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, etc.

[0070] Examples of the astringent component include zinc paraphenolsulfonate, zinc oxide, menthol, and ethanol, etc.

[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, peony extract, snowbell extract, aloe extract, and the like.

[0074] Base or carrier Examples of the base or carrier include an oily base and an aqueous base. As the oily base, in addition to the hydrocarbon base described above, higher alcohols such as cetyl alcohol, 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, whale wax, and beeswax; hardened oil; silicone oils such as 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 alkyl polyether-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, 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 methyl cellulose, cationized guar gum, and acetylated hyaluronic acid; synthetic polymers such as polyvinyl pyrrolidone, carboxyvinyl polymer, and alkyl 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 glyceryl tri(caprylate / caprate); polysaccharides such as dextrin and maltodextrin;Examples of glycol ethers include 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.; In addition to water and buffer solutions, examples of the aqueous base include lower alcohols such as ethanol and isopropanol. Polyhydric alcohols also function as an aqueous base. The base or carrier can be used alone or in combination of two or more.

[0075] When the external composition of the present invention contains water, the content 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 amount of the composition. Also, it can 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 external composition of the present invention can also be one that does not contain water.

[0076] The external composition of the present invention can be one that does not contain polyoxyethylene alkyl ether, stearyl alcohol, or a liquid oily component (for example, a liquid oily base such as a liquid hydrocarbon base). In particular, the external composition of the present invention can exclude an external composition containing adapalene, polyoxyethylene alkyl ether, stearyl alcohol, a liquid oily component (for example, a liquid oily base such as a liquid hydrocarbon base), a moisturizing component, and water. The external composition of the present invention can be one that does not contain mequinol (also referred to as 4 - methoxyphenol or 4 - hydroxyanisole).

[0077] Any of the components contained in the external composition of the present invention may be a hydrate, hemihydrate, or anhydride.

[0078] Dosage form Examples of the dosage form of the external composition of the present invention include solutions, suspensions, emulsions, creams, ointments, gels, liniments, lotions, sprays, aerosols, powders, poultices, and sheet preparations in which a chemical solution is impregnated into a sheet such as a non-woven fabric. Among them, solutions, suspensions, emulsions, creams, ointments, gels, and lotions are preferable, and emulsions, creams, ointments, gels, and lotions are more preferable, in terms of more significantly demonstrating the effects of the present application and reducing the irritation to the skin during application. In the case of a dosage form in an emulsified state such as an emulsion, cream, or emulsion-type ointment, it may be either oil-in-water type or water-in-oil type, but the oil-in-water type is preferable in terms of good usability and good dispersibility of adapalene.

[0079] pH The pH of the external composition of the present invention can be 2 or more, 3 or more, or 4 or more. Further, it can be 8 or less, 7 or less, or 6 or less.

[0080] Method of use The external composition of the present invention can usually be applied to the sites where acne vulgaris of the skin has occurred. The skin includes the scalp. The external composition of the present invention is usually applied to the affected area in an appropriate amount 1 to 3 times a day, particularly once a day.

[0081] Method for improving the dispersibility of adapalene and / or its salts The present invention includes a method for improving the dispersibility of adapalene and / or its salt, in which (B) an anti-inflammatory component and / or an antibacterial component is included in an external composition containing (A) adapalene and / or its salt. The types and contents of each component, the properties of the composition, etc. are as described for the external composition of the present invention.

[0082] Method for suppressing skin dryness The present invention includes a method for suppressing skin dryness of an external composition, which comprises adding (B) an anti-inflammatory component to an external composition containing (A) adapalene and / or a salt thereof. The types and contents of each component, the properties of the composition, etc. are as described for the external composition of the present invention. In this method, "skin dryness" means the property of drying the skin or the property of giving a dry feeling to the skin. Further, in this method, "suppression" can also mean "decrease", "reduction" or "mitigation".

Examples

[0083] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. Test Example 1 (Dispersibility evaluation) Formulations of external compositions having the compositions shown in Table 1 and Table 2 were prepared by a conventional method. The dosage form of each formulation in Table 1 and Table 2 is a lotion. Using these formulations, the dispersibility of adapalene was evaluated. Specifically, after each formulation was stirred to be uniform, 50 μL was dropped onto a slide glass, and particles were observed and photographed using a microscope (product name: VHX-5000; KEYENCE CORPORATION), and only the particle part was extracted by automatic image processing, and the average area (average particle area) of the particles was measured. When adapalene aggregates, the area of each observed particle becomes larger. Therefore, the more uniformly adapalene is dispersed in the composition, the smaller the average particle area becomes.

[0084] Next, according to the following formula (1), the particle area reduction rate (%) compared with the corresponding comparative example was calculated. 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 the corresponding comparative example - Average particle area of the example) / Average particle area of the corresponding comparative example〕×100 ·····(1)

[0085] The results are shown in Table 1 and Table 2.

Table 1

[0086]

Table 2

[0087] As shown in Table 1 and Table 2, by formulating dipotassium glycyrrhizinate, allantoin, heparin-like substance, glycyrrhetinic acid, or ibuprofen piconol in the topical composition containing adapalene, the particle area of adapalene in the composition decreased. It can be seen that the dispersibility of adapalene in the composition was improved by the formulation of component (B).

[0088] Test Example 2 (Dispersion persistence evaluation) A preparation, which is a topical composition having the composition shown in Table 3, was prepared by a conventional method. The dosage form of each preparation in Table 3 is a lotion. Using these preparations, the persistence of the dispersion of adapalene was evaluated. Specifically, 100 mL of each preparation was dispensed into a 100 mL volumetric glass vial and allowed to stand at room temperature in the dark for 2 days. Next, the preparation filled in the above glass vial was sonicated for 5 minutes using an ultrasonic cleaner (model number: US-107, manufacturer: SND Co., Ltd.), then shaken up and down 5 times, and allowed to stand at room temperature in the dark for 10 minutes. Before and after stirring, that is, before and after "sonication using an ultrasonic cleaner, shaking, and standing at room temperature in the dark for 10 minutes", 5 mL of each preparation was sampled from the central part of the height between the liquid surface in the above glass vial and the bottom surface of the glass vial, put into 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 defined as the separation degree. The smaller the increase in turbidity due to stirring, the smaller the separation degree. A small separation degree indicates a high persistence of the dispersion of adapalene in the preparation.

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

[0091] The results are shown in Table 3.

Table 3

[0092] Test Example 3 (Dispersibility evaluation after formulation application) Preparations that were topical compositions with the compositions shown in Table 4 were prepared by a conventional method. The dosage form of each preparation in Table 4 is a lotion. Using these preparations, the dispersibility of adapalene after application was evaluated. Specifically, after each preparation was stirred to uniformity, 50 μL was dropped onto a slide glass and dried at room temperature in the dark for about 18 hours. Then, particles were observed and photographed using a microscope (product name: VHX-5000; KEYENCE Corporation), only the particle part was extracted by automatic image processing, and the average area (average particle area) of the particles was measured.

[0093] When adapalene aggregates during and after drying of the preparation, the observed particle area becomes larger. This test evaluates the ease of aggregation of adapalene in the preparation after application. When the observed particle area is small, it becomes easier to spread adapalene uniformly over the application site when the preparation is applied.

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

[0095] The results are shown in Table 4.

Table 4

[0096] Test Example 4 (Moisturizing evaluation) Formulations of topical compositions having the compositions shown in Table 5 and Table 6 were prepared by a conventional method. The dosage form of each formulation in Table 5 is a lotion, and the dosage form of each formulation in Table 6 is an emulsion. Using these formulations, the moisturizing power or moisturizing performance of each formulation was tested by the following method. The inner forearm of healthy adult subjects (2 persons) was used as the test site. First, before applying the test formulation to the test site, the test site was washed with water, and 15 minutes after washing, the horny layer moisture content was measured using a skin surface horny layer moisture content measuring device (Skicon-200EX; Yayoiken Co., Ltd.), and this was taken as the initial moisture content. Next, 20 μL of the test formulation was applied to the test site, and 60 minutes later, the horny layer moisture content of the test site was measured. The difference obtained by subtracting the initial moisture content from the horny layer moisture content (moisture content after application) 60 minutes later was taken as the change in horny layer moisture content. Furthermore, using the following formula (3), the difference between the change in horny layer moisture content of each example and the change in horny layer moisture content of the corresponding comparative example was calculated.

[0097] The comparative examples corresponding to Examples 5A and 5B are Comparative Example 5, and the comparative examples corresponding to Examples 6A and 6B are Comparative Example 6. Since the change in horny layer moisture content indicates the moisturizing power of the test formulation, the larger the change in horny layer moisture content of each example compared to the change in horny layer moisture content of the corresponding comparative example, the more the moisturizing power was improved by the blending of the anti-inflammatory agent. Difference in change in horny layer moisture content = Change in horny layer moisture content of the example - Change in horny layer moisture content of the corresponding comparative example ·····(3)

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

Table 5

[0099]

Table 6

[0100] Test Example 5 (Dispersibility evaluation) A preparation which is a topical composition having the composition shown in Table 7 was prepared by a conventional method. The dosage form of each preparation in Table 7 is a lotion. Using these preparations, the dispersibility of adapalene was evaluated in the same manner as in Test Example 1. Next, according to the above formula (1), the particle area reduction rate (%) compared with the corresponding comparative example was calculated. The comparative example corresponding to Example 7A is Comparative Example 7.

[0101] The results are shown in Table 7.

Table 7

[0102] Test Example 6 (Dispersibility evaluation) Preparations which are topical compositions having the compositions shown in Table 8 and Table 9 were prepared by a conventional method. The dosage form of each preparation in Table 8 and Table 9 is an emulsion. Using these preparations, the dispersibility of adapalene was evaluated. Specifically, after stirring each preparation to make it uniform, 50 μL was dropped onto a slide glass, and the particles were observed and photographed using a microscope (product name: VHX-5000; KEYENCE CORPORATION). Only the particle part was extracted by automatic image processing, and the average area of the particles (average particle area) was measured.

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

[0104] Next, according to the above formula (1), the particle area reduction rate (%) compared with the corresponding comparative example was calculated. 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

[0107] Formulation example External compositions (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] Since the external composition of the present invention has good dispersibility of adapalene and / or its salt, adapalene can be uniformly applied to the affected area, and since the aggregation of adapalene and / or its salt is suppressed, the desired medicinal effect can be sufficiently obtained. In addition, since the dryness and associated symptoms known as side effects of adapalene and / or its salt are alleviated, it is easy to use.

Claims

1. An external composition containing (A) adapalene and / or a salt thereof, (B) allantoin, and (D) at least one emulsifier selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters, and having a pH of 3 to 7 (however, excluding the cases where besifloxacin hydrochloride is included, nadifloxacin is included, and benzoyl peroxide is included).

2. The external composition according to Claim 1, containing 0.001 to 1% by weight of component (A).

3. The external composition according to Claim 1 or 2, containing 0.01 to 5% by weight of component (B).

4. The external composition according to any one of Claims 1 to 3, further containing (C) a polyhydric alcohol.

5. The external composition according to Claim 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.

6. The external composition according to Claim 4 or 5, containing 0.001 to 30% by weight of component (C).

7. The external composition according to any one of Claims 1 to 6, containing 0.05 to 10% by weight of component (D).

8. The external composition according to any one of Claims 1 to 7, further containing (E) a hydrocarbon base and / or an oily base.

9. The external composition according to any one of Claims 1 to 8, which is a solution, suspension, emulsion, cream, ointment, or lotion.

10. A method for improving the dispersibility of adapalene and / or a salt thereof by adding (B) allantoin to an external composition containing (A) adapalene and / or a salt thereof and (D) at least one emulsifier selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters, and having a pH of 3 to 7 (however, excluding the cases where besifloxacin hydrochloride is included, nadifloxacin is included, and benzoyl peroxide is included).

11. A method for suppressing skin dryness of an external composition, which comprises adding (B) allantoin to an external composition containing (A) adapalene and / or a salt thereof and at least one emulsifier selected from the group consisting of (D) sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ether, and polyoxyethylene sorbitan fatty acid esters, and having a pH of 3 to 7 (however, excluding the cases where besifloxacin hydrochloride is contained, where nadifloxacin is contained, and where benzoyl peroxide is contained).

Images