JP7299766B2 - external composition - Google Patents

Description

The present invention relates to topical compositions comprising adapalene and/or salts thereof.

Adapalene is a derivative of naphthalenecarboxylic acid, and is used as an active ingredient in external therapeutic agents for acne vulgaris (acne). Acne vulgaris develops as comedones due to increased sebum secretion from the pilosebaceous gland system and blockage of hair follicles due to hyperkeratinization, and then progresses to eruptions accompanied by inflammation. Adapalene reduces the formation of comedones by controlling keratinization of the epidermis and improving pore clogging.
Deferin Gel 0.1% (trade name) (Galderma Co., Ltd.) is known as an external preparation containing adapalene as an active ingredient. Deferin Gel 0.1% contains propylene glycol, methyl paraoxybenzoate, carboxyvinyl polymer, polyoxyethylene (20) polyoxypropylene (20) glycol, sodium edetate hydrate, and sodium hydroxide as additives ( Non-Patent Document 1).
Here, in the development of an external preparation, if the dispersibility of a component in the external preparation is poor, it is difficult to evenly apply the component. In addition, when an ingredient aggregates in an external preparation, the area of contact between the ingredient and the skin becomes small, which makes it difficult to obtain the desired efficacy.
In addition, it is known that when an external composition containing adapalene is applied to the skin, the skin tends to dry out, which tends to cause discomfort, erythema, and itching (Non-Patent Document 1).

Deferin Gel 0.1% package insert

The inventors have found that adapalene and/or its salts are extremely poorly dispersible in topical compositions. Accordingly, an object of the present invention is to provide an external composition containing adapalene and/or a salt thereof, in which adapalene and/or a salt thereof have good dispersibility. Another object of the present invention is to provide an external composition containing adapalene and/or a salt thereof, in which adapalene and/or a salt thereof has good dispersibility and skin dryness is suppressed. and

The present inventors have conducted research to solve the above problems, and (A) an external composition containing adapalene and / or a salt thereof, (B) by adding an anti-inflammatory component and / or an antibacterial component, It has been found that the dispersibility of adapalene and/or its salts in the composition is improved. In addition, it was found that adding (B) an anti-inflammatory component to (A) an external composition containing adapalene and/or a salt thereof reduces skin dryness when the external composition is applied to the skin.

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 salts thereof, and method for reducing skin dryness of the topical composition.
Section 1. An external composition comprising (A) adapalene and/or a salt thereof and (B) an anti-inflammatory component and/or an antibacterial component.
Section 2. Item 2. The composition for external use according to Item 1, containing 0.001 to 1% by weight of component (A).
Item 3. Item 3. The composition for external use according to Item 1 or 2, containing 0.01 to 5% by weight of component (B).
Section 4. Item 4. The composition for external use according to any one of Items 1 to 3, further comprising (C) a polyhydric alcohol.
Item 5. 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. Item 6. The composition for external use according to any one of Items 1 to 5, further comprising (D) an emulsifier.
Item 7. Item 6. External use according to Item 6, wherein (D) the emulsifier is at least one selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters. Composition.
Item 8. Item 8. The composition for external use according to any one of Items 1 to 7, further comprising (E) a hydrocarbon base.
Item 9. Item 9. The composition for external use according to any one of Items 1 to 8, wherein the dosage form of the composition is liquid, suspension, emulsion, cream, ointment, gel, or lotion.
Item 10. (A) 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 adapalene and/or a salt thereof.
Item 11. (A) A method for suppressing skin dryness of an external composition, comprising adding (B) an anti-inflammatory component to an external composition containing adapalene and/or a salt thereof.

Adapalene and/or salts thereof generally have very poor dispersibility in external compositions. good dispersibility and dispersion maintenance. Therefore, the applied amount of adapalene and/or its salt becomes uniform when applying the composition for external use. Furthermore, since adapalene and/or its salt are highly dispersible and uniform even during the production of the formulation, the production of the formulation is easy. In addition, components with poor dispersibility in topical compositions generally aggregate significantly when the composition is applied and dried. Or aggregation of its salt is also effectively suppressed.

In addition, when the composition for external use of the present invention contains an anti-inflammatory component, dryness of the skin is suppressed, reduced, or alleviated when applied to the skin. Therefore, the discomfort, erythema, and itching associated with dry skin are alleviated.
It is surprising that the anti-inflammatory ingredient improves the dispersibility of adapalene and/or its salts and also inhibits skin dryness caused by adapalene and/or its salts.

The topical composition of the present invention contains an anti-inflammatory component and/or an antibacterial component that are commonly used as components of topical compositions, thereby improving the dispersibility of adapalene and/or salts thereof. Skin dryness is suppressed by containing an anti-inflammatory ingredient that is widely used as a component of. Therefore, in order to improve dispersibility, it is not necessary to add ingredients that are not necessary for the skin, and at the same time, it is possible to produce a formulation that can exhibit anti-inflammatory and/or antibacterial effects.

The present invention will be described in detail below.
The composition of the present invention is an external composition comprising (A) adapalene and/or a salt thereof and (B) an anti-inflammatory component and/or an antimicrobial component.

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

The content of adapalene and/or a salt thereof 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 0.001% by weight or more, based on the total amount of the composition. 1% by weight or more is even more preferred. 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, adequate pharmacological activity of adapalene and/or salts thereof can be obtained, and adapalene and/or salts thereof have sufficient dispersibility.

Anti-inflammatory ingredients Anti-inflammatory ingredients include allantoin; glycyrrhizic acid, glycyrrhizic acid derivatives (methyl glycyrrhizinate, stearyl glycyrrhizinate, etc.), glycyrrhetic acid, glycyrrhetic acid derivatives (stearyl glycyrrhetinate, glycyrrhetinate, glycyrrhetinate monoglucuronide, etc.); acetaminophen; epsilon-aminocaproic acid; berberine; azulene; bromelain; zinc; fenamic acid anti-inflammatory ingredients such as mefenamic acid, flufenamic acid, tolfenamic acid; arylacetic acid anti-inflammatory ingredients such as acemethacin, indomethacin, indomethacin farnesyl, edotorac, diclofenac, sulindac, nabutomene, fenbufen, progglutetacin, mofezolac; propionic acids such as aminoprofen, ibuprofen, oxaprozin, ketoprofen, zaltoprofen, tiaprofenic acid, naproxen, flurbiprofen, zaltoprofen, ibuprofen piconol, flurbiprofen axetil, fenoprofen, pranoprofen, loxoprofen anti-inflammatory ingredients; oxicam anti-inflammatory ingredients such as ampiroxicam, tenoxicam, piroxicam, meloxicam and lornoxicam; heparinoids, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, mucopolysaccharides such as heparin, etc. and salts thereof.
These are non-steroidal anti-inflammatory ingredients.

Salts of the above anti-inflammatory components may be pharmaceutically or physiologically acceptable salts, and salts with organic bases (methylamine salts, triethylamine salts, triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, organic amine salts such as tripyridine salts and picoline salts), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, zinc salts, metal salts such as aluminum salts, etc.).

Specifically, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, indomethacin hydrochloride, diclofenac sodium salt, bromfenac acid sodium salt, berberine sulfate, berberine hydrochloride, berberine tannate, azulene sulfonate sodium salt, zinc sulfate , zinc lactate, lysozyme hydrochloride, progestacin 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 ingredient that is a salt, it may be formulated as a salt, and as a result of separately blending the acid compound and the organic or inorganic base, the salt and It may be something that has changed.

In addition, prednisolone, hydrocortisone, cortisone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, difluprednate, mometasone, diflucortolone, fluoniside, fluocinonide, clobetasol, beclomethasone, deprodone, alclomethasone, flumethasone, amcinonide, clobetasone, diflorazone, and these Steroidal anti-inflammatory ingredients such as derivatives (especially esters) of can also be used.
Derivatives of the above steroids include prednisolone esters such as prednisolone valerate acetate (PVA), prednisolone succinate, prednisolone acetate, prednisolone phosphate, betamethasone propionate, betamethasone valerate, dexamethasone valerate, Dexamethasone esters such as dexamethasone propionate, dexamethasone acetate, dexamethasone phosphate, dexamethasone metasulfobenzoate, dexamethasone cipesylate, dexamethasone palmitate, hydrocortisone butyrate (especially hydrocortisone-17-butyrate), Hydrocortisone esters such as hydrocortisone acetate, hydrocortisone succinate, hydrocortisone butyrate, hydrocortisone butyrate propionate, hydrocortisone phosphate, mometasone furoate, diflucortolone valerate, clobetasol propionate, beclomethasone propionate acid ester, beclomethasone dipropionate, clobetasone butyrate, deprodone propionate, alclomethasone propionate, flumethasone pivalate, clobetasone propionate, clobetasone butyrate, diflorazone acetate, etc. mentioned.

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 salts thereof, Allantoin, glycyrrhizic acid, glycyrrhetinic acid, ibuprofenpiconol and salts thereof, and heparin analogues are even more preferred.
Anti-inflammatory components can be used singly or in combination of two or more.

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, and even more preferably 0.1% by weight or more, relative to the total amount of the composition. Preferably, 0.2% by weight or more is particularly preferable. Also, it is preferably 5% by weight or less, more preferably 4% by weight or less, and even more preferably 3% by weight or less. Within this range, an appropriate physiological activity or pharmacological activity of the anti-inflammatory component can be obtained, and adapalene and/or its salt have sufficient dispersibility, resulting in an external composition that does not easily dry the skin.

The ratio of the content of the anti-inflammatory component to the content of adapalene and/or a salt thereof is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more, with respect to 1 part by weight of adapalene and/or a salt thereof. Preferably, 1 part by weight or more is even more preferred, and 2 parts by weight or more is particularly preferred. 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, the appropriate physiological or pharmacological activity of the anti-inflammatory component is obtained, the dispersibility of adapalene and/or a salt thereof is sufficient, and the skin dryness of the composition for external use is sufficiently suppressed. .

(Allantoin and/or its salt)
When the anti-inflammatory component is allantoin and/or a salt thereof, the content thereof is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, and 0.1% by weight, based on the total amount of the composition. % or more is even more preferred, and 0.15 wt % or more is particularly preferred. 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 activity of allantoin and/or its salt is obtained, and adapalene and/or its salt have sufficient dispersibility, resulting in an external composition that does not easily dry the skin.

The ratio of the content of allantoin and/or a salt thereof to the content of adapalene and/or a salt thereof is preferably 0.1 parts by weight or more, preferably 0.5 parts by weight, per 1 part by weight of adapalene and/or a salt thereof. The above is more preferable, 1 part by weight or more is even more preferable, and 1.5 parts by weight or more is particularly preferable. 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 activity of allantoin and/or a salt thereof can be obtained, adapalene and/or a salt thereof has sufficient dispersibility, and the composition for external use has sufficient skin dryness. Suppressed.

(Glycyrrhizic acid, derivatives thereof, and/or salts thereof)
When the anti-inflammatory ingredient is glycyrrhizic acid, derivatives thereof, and/or salts thereof (especially dipotassium glycyrrhizinate), the content thereof is preferably 0.01% by weight or more relative to the total amount of the composition. , 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. 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, glycyrrhizic acid, derivatives thereof, and/or salts thereof (especially dipotassium glycyrrhizinate) can be obtained with appropriate physiological or pharmacological activity, and adapalene and/or salts thereof can be dispersed. This results in an external composition that is sufficient and does not dry out the skin easily.

The ratio of the content of glycyrrhizic acid, derivatives thereof, and/or salts thereof (especially dipotassium glycyrrhizinate) to the content of adapalene and/or salts thereof is based on 1 part by weight of adapalene and/or salts thereof. , 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. 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, glycyrrhizic acid, derivatives thereof, and/or salts thereof (especially dipotassium glycyrrhizinate) can be obtained with appropriate physiological or pharmacological activity, and adapalene and/or salts thereof can be dispersed. It is sufficient, and the skin dryness of the composition for external use is sufficiently suppressed.

(Glycyrrhetinic acid, derivatives thereof, and/or salts thereof)
When the anti-inflammatory component is glycyrrhetinic acid, derivatives thereof, and/or salts thereof, the content thereof is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, relative to the total amount of the composition. Preferably, 0.1 wt% or more is even more preferred, 0.2 wt% or more is particularly preferred, and 0.25 wt% or more is most preferred. 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 activity of glycyrrhetinic acid, derivatives thereof, and/or salts thereof can be obtained, adapalene and/or salts thereof have sufficient dispersibility, and the skin is dried. It becomes a difficult topical composition.

The ratio of the content of glycyrrhetic acid, derivatives thereof, and/or salts thereof to the content of adapalene and/or salts thereof is preferably 0.1 parts by weight or more per 1 part by weight of adapalene and/or salts thereof. , 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. 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 salts thereof can be obtained, and the dispersibility of adapalene and/or salts thereof is sufficient, and the composition for external use Skin dryness is sufficiently suppressed.

(mucopolysaccharides)
When the anti-inflammatory component is a mucopolysaccharide (especially a heparin analogue), the content thereof is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, based on the total amount of the composition. 0.1 wt% or more is even more preferred, 0.2 wt% or more is particularly preferred, and 0.25 wt% or more is most preferred. 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 activity of the mucopolysaccharide (in particular, heparin analogues) can be obtained, adapalene and/or salts thereof have sufficient dispersibility, and the external application is less likely to dry the skin. It becomes a composition.

The ratio of the content of mucopolysaccharides (in particular, heparin analogues) to the content of adapalene and/or salts thereof is preferably 0.1 parts by weight or more per 1 part by weight of adapalene and/or salts thereof. 0.5 parts by weight or more is more preferred, 1 part by weight or more is even more preferred, 2 parts by weight or more is particularly preferred, and 2.5 parts by weight is most preferred. 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 activity of the mucopolysaccharide (in particular, heparin analogues) can be obtained, adapalene and/or salts thereof have sufficient dispersibility, and skin dryness of the composition for external use is achieved. sex is sufficiently suppressed.

(propionic acid-based anti-inflammatory agent)
When the anti-inflammatory component is a propionic acid-based anti-inflammatory agent (especially ibuprofen piconol), the content thereof is preferably 1% by weight or more, more preferably 2% by weight or more, based on the total amount of the composition. .5 wt% or more is even more preferred. 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, the appropriate pharmacological activity of the propionic acid-based anti-inflammatory agent (especially ibuprofen piconol) can be obtained, the dispersibility of adapalene and/or its salt is sufficient, and the external application is less likely to dry the skin. It becomes a composition.

The ratio of the content of the propionic acid-based anti-inflammatory agent (especially ibuprofen piconol) to the content of adapalene and/or its salt is preferably 10 parts by weight or more per 1 part by weight of adapalene and/or its salt, More preferably 20 parts by weight or more, and even more preferably 25 parts by weight or more. 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, the appropriate pharmacological activity of the propionic acid-based anti-inflammatory agent (especially ibuprofen piconol) can be obtained, the dispersibility of adapalene and/or its salt is sufficient, and the skin dryness of the external composition can be obtained. sex is sufficiently suppressed.

Antibacterial component The antibacterial component (B) used in the composition for external use of the present invention exerts a bactericidal or bacteriostatic action and can suppress the growth of various bacteria (Gram-positive bacteria, Gram-negative bacteria, fungi, etc.). Refers to any ingredient known in the art.
Antibacterial ingredients include phenol-based synthetic fungicides (isopropylmethylphenol, triclosan, salicylic acid, paraoxybenzoic acid (paraben), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl parahydroxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate). etc.), cresol, etc.), oil-soluble antibacterial ingredients such as triclocarban; trimethylammonium (also referred to as cetyltrimethylammonium chloride), cetyltrimethylammonium bromide (also referred to as cetyltrimethylammonium bromide), dequalinium chloride, (also referred to as dequalinium chloride), etc.), chlorhexidine, lysozyme, and salts thereof (e.g., cationic antibacterial ingredients such as hydrochloride, acetate, gluconate); water-soluble antibacterial ingredients such as acrinol, gluconic acid, alkyldiaminoglycine, and salts thereof (e.g., hydrochloride); povidone iodine, potassium iodide, iodine Iodine-based antibacterial ingredients such as 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, aminoglycoside antibiotics (such as clindamycin).
Among them, the antibacterial component is preferably an oil-soluble antibacterial component, more preferably a phenol-based synthetic fungicide, and even more preferably isopropylmethylphenol.
The antibacterial component can be used singly or in combination of two or more.

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, and even more preferably 0.1% by weight or more, relative to the total amount of the composition. 0.3% by weight or more is particularly preferred. 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, the appropriate physiological or pharmacological activity of the antibacterial component can be obtained, and the dispersibility of adapalene and/or its salt is sufficient.

The ratio of the content of the antibacterial component to the content of adapalene and/or a salt thereof is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more, relative to 1 part by weight of adapalene and/or a salt thereof. , 1 part by weight or more is even more preferred, and 3 parts by weight or more is particularly preferred. 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 the antibacterial component can be obtained, and the dispersibility of adapalene and/or its salt is sufficient.

(Isopropylmethylphenol and/or its salt)
When the antibacterial component is isopropylmethylphenol and/or its salt, the content thereof is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, more preferably 0.1% by weight, based on the total amount of the composition. % by weight or more is even more preferred, and 0.3% by weight or more is particularly preferred. 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, isopropylmethylphenol and/or its salt can have appropriate physiological or pharmacological activity, and adapalene and/or its salt have sufficient dispersibility.

The ratio of the content of isopropylmethylphenol and/or a salt thereof to the content of adapalene and/or a salt thereof is preferably 0.1 parts by weight or more, preferably 0.5, per 1 part by weight of adapalene and/or a salt thereof. It is more preferably at least 1 part by weight, even more preferably at least 1 part by weight, and particularly preferably at least 3 parts by weight. 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, isopropylmethylphenol and/or its salt can have appropriate physiological or pharmacological activity, and adapalene and/or its salt have sufficient dispersibility.

Polyhydric alcohol The composition for external use of the present invention can contain (C) a polyhydric alcohol, thereby further improving the dispersibility of adapalene and/or a salt thereof and making the composition for external use less likely to dry the skin. becomes.
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 (isopentyldiol), hexylene glycol, dipropylene glycol, polyethylene glycol (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.), dihydric alcohols such as polypropylene glycol (polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000, etc.); trihydric alcohols such as glycerin and trimethylolpropane; diglycerin, polyglycerin etc.
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 and butylene glycol (especially 1,3-butylene glycol), polyethylene glycol and glycerin are more preferred.
A polyhydric alcohol can be used individually by 1 type or in combination of 2 or more types.

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, and a combination of 1,3-butylene glycol and polyethylene. combination with glycol, combination of 1,3-butylene glycol and glycerin, combination of polyethylene glycol and glycerin; combination of dipropylene glycol, 1,3-butylene glycol and polyethylene glycol, combination of dipropylene glycol and 1,3- Combination of butylene glycol and glycerin, combination of dipropylene glycol, polyethylene glycol and glycerin, combination of 1,3-butylene glycol, polyethylene glycol and glycerin; dipropylene glycol, 1,3-butylene glycol, polyethylene glycol and glycerin and a combination of.

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 1% by weight or more, relative to the total amount of the composition. is particularly preferred. 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 a salt thereof is sufficiently improved, and the composition for external use is even less likely to dry the skin.

The ratio of the polyhydric alcohol content 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, relative to 1 part by weight of adapalene and/or its salt. Preferably, 1 part by weight or more is even more preferred, and 10 parts by weight or more is particularly preferred. 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 a salt thereof is sufficiently improved, and the composition for external use is even less likely to dry the skin.

Emulsifier The topical composition of the present invention may contain (D) an emulsifier, which further improves the dispersibility of adapalene and/or its salt.
Emulsifiers include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate. sorbitan fatty acid esters such as; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 ( hydrogenated castor oil derivatives such as HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 (HCO-80); castor oils such as polyoxyethylene castor oil Oil derivatives; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and isostearin. Polyoxyethylene sorbitan fatty acid esters such as acid polyoxyethylene (20) sorbitan; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene polyoxyalkylene alkyl ethers such as oleyl ether, polyoxyethylene behenyl ether; amines such as stearylamine and oleylamine; polyoxyethylene-methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and silicone surfactants such as PEG-9 polydimethylsiloxyethyl dimethicone; natural surfactants such as phospholipids such as lecithin, surfactins, and saponins; fatty acids such as diethylaminoethylamide stearate and diethylaminopropylamide stearate. amidoamines; alkylamines such as trilaurylamine, dimethylstearylamine, and di-2-ethylhexylamine; and betaine amphoteric surfactants such as dimethylaminopropylamide stearate and lauryl hydroxysulfobetaine, polyoxyethylene polyoxypropylene Glycols (poloxamer 124, etc.), polyglycerin fatty acid esters, glycerin 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 polyglycerin fatty acid esters are preferable, 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), mono Polyoxyethylene (20) sorbitan oleate (polysorbate 80) is more preferred.
An emulsifier can be used individually by 1 type or in combination of 2 or more types.

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 1% by weight or more, relative to the total amount of the composition. preferable. Also, it is preferably 10% by weight or less, more preferably 8% by weight or less, even more preferably 6% by weight or less, and particularly preferably 4% by weight or less. Within this range, the dispersibility of adapalene and/or its salt is sufficiently improved.

The ratio of the content of the emulsifier to the content of adapalene and/or a salt thereof is preferably 0.5 parts by weight or more, more preferably 1 part by weight or more, and even more preferably 5 parts by weight or more, relative to 1 part by weight of adapalene. Preferably, 10 parts by weight or more is particularly preferred. 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.

Hydrocarbon base The composition for external use of the present invention can contain (E) a hydrocarbon base, which further improves the dispersibility of adapalene and/or its salt and makes the skin less likely to dry out. It becomes a composition.
Hydrocarbon bases include petrolatum (white petrolatum, yellow petrolatum), gelling hydrocarbons (plastibase, etc.), ozokerite, ceresin, microcrystalline wax, squalene, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light fluid paraffin and the like.
Among them, preferred are hydrocarbon bases that are solid at room temperature (25°C) such as petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (plastibase, etc.), ozokerite, ceresin, and microcrystalline wax. , microcrystalline wax is more preferred, petrolatum is 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.
A hydrocarbon base can be used individually by 1 type or in combination of 2 or more types.

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 0.001% by weight, based on the total amount of the composition. More than % by weight is particularly preferred. Moreover, 0.1% by weight or more, or 1% by weight or more is also preferable. Also, it is preferably 50% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and particularly preferably 10% by weight or less. It is also preferably 1% by weight or less, 0.1% by weight or less, or 0.01% by weight or less. Within this range, the dispersibility of adapalene and/or a salt thereof is sufficiently improved, and the composition for external use is even less likely to dry the skin.

The ratio of the content of the hydrocarbon base to the content of adapalene and/or salts thereof is preferably 0.00001 parts by weight or more, preferably 0.0001 parts by weight or more, relative to 1 part by weight of adapalene and/or salts thereof. More preferably, 0.001 parts by weight or more is even more preferable, and 0.01 parts by weight or more is particularly preferable. Also, it is preferably 500 parts by weight or less, more preferably 300 parts by weight or less, even more preferably 200 parts by weight or less, and particularly preferably 100 parts by weight or less. It is also preferably 10 parts by weight or less, 1 part by weight or less, or 0.1 parts by weight or less. Within this range, the dispersibility of adapalene and/or a salt thereof is sufficiently improved, and the composition for external use is even less likely to dry the skin.

Other Ingredients In the external composition of the present invention, the (A) ingredient, (B) ingredient, and the above-mentioned ingredients blended as necessary are used in pharmaceuticals, quasi-drugs, or cosmetics as needed. It can be mixed with a base or carrier, additives, other physiologically active or pharmacologically active ingredients, etc. to prepare a pharmaceutical composition, a quasi-drug, or a cosmetic composition for external use. In particular, it may be a pharmaceutical composition (external pharmaceutical composition).

Additives include, for example, antioxidants, thickeners, antiseptics or preservatives, pH adjusters, stabilizers, chelating agents, UV absorbers or UV scattering agents, irritation reducing agents, coloring agents, and cooling agents. , fragrances, etc.
An additive can be used individually by 1 type or in combination of 2 or more types.
In addition, additives can be used within a range that does not impair the effects of the present invention.

Antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, p-hydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivatives (ascorbyl stearate, ascorbyl palmitate, ascorbyl dipalmitate, ascorbyl acid monophosphate, ascorbyl diphosphate, ascorbate triphosphate, ascorbate 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, norhydroguaceretenoic acid, caffeic acid, enzymes (catalase, superoxide dismutase, glutathione peroxidase, elastase, etc.) mentioned.

Thickeners include guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl acrylate methacrylate copolymer, bentonite, alginic acid, macrogol, and cellulose-based thickeners (methyl cellulose , ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.).

Antiseptics or preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, parahydroxybenzoic acid. benzyl, methyl p-oxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and its salts, chlorhexidine gluconate, alkanediols, and glycerin fatty acid esters.

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.). ), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.), and the like.

Stabilizers include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole, and the like.

The chelating agent includes EDTA.disodium salt, EDTA.calcium.disodium salt, and the like.

Irritation reducing agents include licorice extract, sodium alginate and the like.

UV absorbers or UV 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, dibenzylidene dioxoimidazolidine ethylhexylpropyronate, ethlhexyltriazoline, para-aminobenzoic acid and its derivatives, para-dimethylamino octyl benzoate, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide, zinc oxide and the like.

Examples of the coloring agent include those listed in the Legal Coloring Handbook (edited by Japan Cosmetic Industry Association (2004)).

Cooling agents include terpenes such as menthol, camphor, borneol, geraniol, cineole, anethole, limonene, and eugenol (these may be d-, l-, or dl-forms); eucalyptus oil, bergamot oil, Essential oils such as peppermint oil, cool mint oil, spearmint oil, fennel oil, peppermint oil, cinnamon oil, rose oil, turpentine oil, and the like.
Fragrances include herbal essential oils such as lavender oil, rosemary oil, clary sage oil, thyme oil, bergamot oil, and eucalyptus oil; various essential oils such as citrus essential oils such as orange oil, lemon oil, and grapefruit oil; is mentioned.

Other physiologically active or pharmacologically active ingredients (physiologically active or pharmacologically active ingredients other than components (A) and (B)) include, for example, antibacterial ingredients, anti-inflammatory ingredients, keratin softeners or keratolytic agents, antipruritic agents, Moisturizing ingredients other than polyhydric alcohols, local anesthetics, vitamins, peptides or their derivatives, blood circulation promoting ingredients, cell activating ingredients, anti-aging ingredients, astringent ingredients, amino acids, proteins, plant extracts, seaweed extracts, whitening ingredients, etc. mentioned.
Other physiologically active or pharmacologically active ingredients can be used singly or in combination of two or more.
In addition, other physiologically active or pharmacologically active ingredients can be used as long as they do not impair the effects of the present invention.

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

It should be noted that the topical composition of the present invention is useful for drug-resistant acne and therapeutic doses of clindamycin, minocycline, tetracycline, or erythromycin for non-responsive/resistant P. Formulations for use in treating or preventing acne, including acne, may not include drug-resistant acne and P unresponsive/resistant to therapeutic doses of clindamycin, minocycline, tetracycline or erythromycin, among others. . Formulations for use in treating or preventing acne, including acne, which may not include formulations containing adapalene and anti-inflammatory agents, including drug-resistant acne and therapeutic doses of clindamycin, minocycline, among others. , tetracycline- or erythromycin-nonresponsive/resistant P. Formulations for use in treating or preventing acne, including acne, which may not include formulations comprising antibacterial agents, adapalene, and anti-inflammatory agents.
Also, the present invention may not encompass dual-acting rational therapeutic molecules (other than adapalene) that have two distinct mechanisms of action for the treatment or prevention of bacterial infections, including, among others, bacterial infections. Drug carriers or formulations comprising a dual-acting rational therapeutic molecule with two distinct mechanisms of action for the treatment or prevention of disease, adapalene, and an anti-inflammatory agent may not be included.
Especially for the treatment of bacterial infections caused by Gram-positive and Gram-negative bacteria, both susceptible and resistant, especially acne and different skin and structure infections, additionally resistant dual-acting rational therapeutic molecules (other than adapalene) to prevent the occurrence of bacterial infections caused by, among other things, Gram-positive and Gram-negative bacteria, both susceptible and resistant Adapalene and an anti-inflammatory agent with a dual action rational therapy molecule to cure acne and different skin infections and skin structure infections and additionally prevent the development of resistance for the treatment of acne. It may not include drug carriers or formulations containing.
The present invention can also be free of quinolone antibiotics such as 8-chlorofluoroquinolone, nadifloxacin, besifloxacin, clinadifloxacin, flulifloxacin, ozenoxacin, among others 8-chlorofluoroquinolone. . By not containing quinolone antibiotics, especially 8-chlorofluoroquinolone, the composition does not cause photosensitivity due to quinolone antibiotics, and denaturation of the composition due to photodegradation of quinolone antibiotics is avoided. . Moreover, the effects of the present invention are more remarkably exhibited by not containing quinolone antibiotics, especially 8-chlorofluoroquinolone.

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

As a keratin softening agent or keratolytic agent, urea and its derivatives (alkyl urea having an alkyl group having 1 to 4 carbon atoms such as methyl urea and ethyl urea; hydroxyethyl urea, dihydroxyethyl urea, bis(hydroxyethyl) urea , hydroxypropyl urea, dihydroxypropyl urea, bis (hydroxypropyl) urea, hydroxybutyl urea, dihydroxybutyl urea, hydroxyalkyl urea having a hydroxyalkyl group having 1 to 10 carbon atoms such as bis (hydroxybutyl) urea), salicylic acid and its Derivatives (methyl salicylate, acetylsalicylic acid, etc.), glycolic acid, fruit acid, phytic acid, lactic acid, lactate, sulfur, ethyl alcohol, isopropyl alcohol, propanol, butanol, benzyl alcohol, phenylethyl alcohol, propylene carbonate, hexyldodecanol, Dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurylate, lanolin, fatty acid dialkylolamide, sulfur, resorcinol, sodium hydroxide, potassium hydroxide and the like.

Antipruritic agents include ethanolamine antihistamines such as diphenhydramine, bromodiphenhydramine, clemastine, chlorphenoxamine, diphenylpyraline, doxylamine, orphenadrine, and phenyltoxamine, and propylamine antihistamines such as chlorpheniramine, dimethindene, and talastine. ethylenediamine antihistamines such as , mepyramine, metapyrylene, tripelennamine, alimemazine, hydroxyethylpromethazine, isothipendyl, phenothiazine antihistamines such as mequitazine, oxomemazine, promethazine, buclizine, cetirizine, homochlorcyclidine, cyclizine, hydroxyzine, levocetirizine, meclizine , piperazine antihistamines such as oxatomide, ketotifen, olopatadine, fexofenadine, loratadine, terfenadine, antazoline, azatadine, vamipine, cyproheptadine, deptropine, ebastine, emedastine, epinastine, mebhydroline, mizolastine, pimethixene, pyrobutamine, kifenadine, rupatadine, triplo Antihistamines such as lysine, acrivastine, astemizole, azelastine, bilastine, desloratadine, and salts thereof.
Also included are non-antihistamine ingredients such as crotamiton, octamol, moktar, thymol.

Moisturizing ingredients other than polyhydric alcohols include ceramides (glycosphingolipids such as phingosine, phytosphingosine, ceramide, cerebroside, sphingophospholipids such as sphingomyelin, N-(hexadecyloxyhydroxypropyl)-N-hydroxy Synthetic ceramides such as ethylhexadecanamide, hexadecyloxy PG hydroxyethylhexadecanamide, cetyl PG hydroxyethylpalmitamide, human ceramides such as ceramide 2, ceramide 3, fermented ceramides, animal-derived ceramides, plants derived ceramides, ceramides 1-10, etc.), cholesterols (cholesterol, cholestanol, lanosterol, selegrosterol, dehydrocholesterol, animal sterols such as cobrostanol; phytosterol, sitosterol, stigmasterol, campesterol, ergo plant sterols such as sterol, fucosterol, and spinasterol; microorganism-derived sterols such as ergosterol, mycosterol, and timosterol; esters of these sterols with fatty acids having 10 to 18 carbon atoms, etc.), amino acids , pyrrolidone carboxylic acid and its salts, lactic acid and its salts, ureas (urea, alkyl urea having an alkyl group having 1 to 4 carbon atoms, hydroxyalkyl urea having a hydroxyalkyl group having 1 to 10 carbon atoms, etc.), trehalose, sugars such as xylitol and sorbitol; polymer compounds such as keratin, chitin and chitosan; lipids such as phospholipid;

Local anesthetics include local anesthetics having amine and amide structures such as lidocaine, dibucaine, mepivacaine, bupivacaine, ropivacaine, levobupivacaine, oxethazaine, and salts thereof, cocaine, procaine, chloroprocaine, tetracaine, and Examples include local anesthetics having an amine structure and an ester structure such as salts thereof, ethyl aminobenzoate having an ester structure, oxypolyethoxide decane, and the like.

Vitamins include vitamin E such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, ubiquinone derivatives and their pharmacologically or physiologically Acceptable salts, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5′-phosphate sodium, riboflavin tetranicotinate, dl-α-tocopherol nicotinate, nicotinic acid Benzyl, methyl nicotinate, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate, ascorbigen-A, ascorbyl stearate, ascorbate palmitate, L-ascorbyl dipalmitate, methyl hesperidin , ergocalciferol, cholecalciferol, phylloquinone, farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, 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, nicotinamide, pantothenic acid, calcium pantothenate, Pantothenyl alcohol (panthenol), D-pantesaine, D-pantethine, coenzyme A, pantothenic acids such as pantothenyl ethyl ether, biotin, biotycin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, ascorbic acid phosphate Sodium, magnesium ascorbic acid phosphate, carnitine, ferulic acid, α-lipoic acid, orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, eriocitrin and the like.

Peptides or derivatives thereof include keratinolytic peptides, hydrolyzed keratin, collagen, gelatin, elastin, elastinolytic peptides, collagenolytic peptides, hydrolyzed collagen, hydrolyzed silk, and the like.

A plant-derived component is preferably exemplified as the blood circulation-promoting component. For example, Panax ginseng, Angelica keiskei, Arnica, Ginkgo biloba, Tripod, Dutch oak, Carrot, Gentian, Burdock, Rice, Hawthorn, Shiitake mushroom, Hawthorn, Juniper, Cnidium, Japanese juniper, Thyme, Clove, Chimp, Angelica keiskei, Tonin, Spruce, Carrot, Ingredients derived from garlic, butcher bloom, grapes, peonies, horse chestnut, melissa, yuzu, yokuinin, rosemary, rosehip, peach, apricot, walnut, corn (including extracts of these plants), glucosyl hesperidin, etc. mentioned.

Cell activating ingredients include amino acids such as γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, and ε-aminocaproic acid, retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, vitamins such as biotin, and glycol. α-hydroxy acids such as acids, tannin, flavonoids, saponin, allantoin, photosensitizer No. 301, placental extract, hinokitiol, cepharanthine, kiwi seed extract and the like.

Antiaging ingredients include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone and the like.

Astringents include zinc paraphenolsulfonate, zinc oxide, menthol, and ethanol.

Plant extracts include saffron, saxifrage, perilla, rice bran, sake lees, white mustard, peony, violet, lotus seed, pearl barley seed, Pandanus amaryllifolius Roxb., Arcangelicia flava Merrilli. , chamomile, coral grass, rice leaves, apricot fruit, euphorbia, rose flower, bamboo shoot skin, gentian, carrot, panax ginseng, red ginseng, loofah, peach, peach kernel, kiwi, sunflower, Zizyphus joazeiro, Pau d'Arco , day lily, hibiscus flower, red wormwood, cherimoya, mango, red fuki, lilac, Japanese pepper peel or seed coat, safflower flower, casablanca, guava leaf, houttuynia cordata, banpei yuzu, aloe fig flower, apple, white asparagus, Extracts of plants such as mate tea, cherry leaves, ylang ylang leaves and the like.

Seaweed extracts include green algae such as Chlorella vulgaris, Chlorella pyrenoidosa, Chlorella ellipsoidia, sea lettuce, sea lettuce, and sea lettuce; Brown algae such as , Mozuku, Hirome, Hijiki, Hibamata, Sea fan, Blue fan, Kireba no sea fan, Akabau fan, Konami fan, Okinouchiwa, Usuyuki fan, Etsuki sea fan; , Yatabegusa, Yuikiri, Shima Tengusa, Tosaka Nori, Thorny Eucheuma, Amakusa Eucheuma, Eucheuma muricatum, Juniper eucheuma, Tsunomata, Oobatsunomata, Tochaka or Yahazutsunomata, Ezotsunomata, Thorny tsunomata, Hirakotoji, Kotojitsunomata, Wart nomata, Marubatsunomata, Hirakotoji, Su Ginori, Shikinori, Kainori, Yareus Banori red algae such as , Kagiusubanori, Suziusubanori, Hyusubanori, and Akamomijinori.

Whitening ingredients include tocopherol, ascorbic acid, tranexamic acid, arbutin, 4-alkylresorcinol, 4-methoxysalicylic acid, hydroquinone, kojic acid, their salts or their derivatives, placenta extract, and bark extract. , saxifrage extract, and aloe extract.

Bases or Carriers Bases or carriers include oleaginous bases and aqueous bases.
Oily bases include, in addition to the aforementioned hydrocarbon bases, higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; sterols such as cholesterol, phytosterol, and phytosteryl hydroxystearate; shea butter. vegetable fats such as lanolin, orange roughy oil, squalane, horse oil, whale wax, and beeswax; hydrogenated oils; methylpolysiloxanes, crosslinked methylpolysiloxanes , 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 silicones, silicone-alkyl chain co-modified polyglycerin-modified silicones, polyether-modified branched silicones, polyglycerin-modified branched silicones, acrylic silicones, phenyl-modified silicones, and silicone oils such as silicone resin; ethyl cellulose; , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cationic guar gum, and natural polymer derivatives such as acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and alkyl acrylate methacrylate copolymer; carrageenan , alginic acid, cellulose, guar gum, quince seed, dextran, and gellan gum; esters such as slit and tri(caprylic/capric)glyceryl; polysaccharides such as dextrin and maltodextrin; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, Glycol ethers such as 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.
Further, examples of aqueous bases include water, buffers, and lower alcohols such as ethanol and isopropanol. Polyhydric alcohols also function as aqueous bases.
The base or carrier can be used singly or in combination of two or more.

When the composition for external use of the present invention contains water, the content is 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 It can be 95% by weight or more. 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 topical composition of the present invention can also be free of water.

The topical composition of the present invention may be free of polyoxyethylene aralkyl ether, stearyl alcohol, or liquid oleaginous components (eg, liquid oleaginous bases such as liquid hydrocarbon bases). The topical composition of the present invention comprises, inter alia, adapalene, polyoxyethylene aralkyl ether, stearyl alcohol, a liquid oleaginous component (e.g., a liquid oleaginous base such as a liquid hydrocarbon base), a moisturizing component, and water. It may not include topical compositions.
The topical composition of the present invention may be free of mekinol (also referred to as 4-methoxyphenol or 4-hydroxyanisole).

Any component contained in the topical composition of the present invention may be a hydrate, a hemihydrate, or an anhydrate.

Dosage forms The dosage forms of the composition for external use of the present invention include liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, sprays, aerosols, powders, poultices, and non-woven fabrics. and the like, which is obtained by impregnating a sheet such as a sheet with a chemical solution. Among them, liquid formulations, suspensions, emulsions, creams, ointments, gels, and lotions are preferable in that the effects of the present invention are exhibited more remarkably and that irritation to the skin during application is reduced. , creams, ointments, gels and lotions are more preferred.
In the case of emulsified formulations such as emulsions, creams, and emulsion ointments, either oil-in-water type or water-in-oil type may be used. The oil-in-water type is preferred.

pH
The external composition of the present invention can have a pH of 2 or higher, 3 or higher, or 4 or higher. It can also be 8 or less, 7 or less, or 6 or less.

Method of use The composition for external use of the present invention can usually be applied to a site of acne vulgaris on the skin. The skin includes the scalp.
The composition for external use of the present invention may be applied to the affected area in an appropriate amount usually 1 to 3 times a day, especially once a day.

A method for improving the dispersibility of adapalene and/or a salt thereof The present invention comprises (A) an external composition containing adapalene and/or a salt thereof, and (B) an anti-inflammatory component and/or an antibacterial component. or a method for improving the dispersibility of its salt. The type and content of each component, the properties of the composition, etc. are as described for the topical composition of the present invention.

Method for Suppressing Dry Skin The present invention includes a method for suppressing dry skin of an external composition, comprising (A) incorporating an anti-inflammatory component into (A) an external composition containing adapalene and/or a salt thereof. . The type and content of each component, the properties of the composition, etc. are as described for the topical composition of the present invention. In this method, "skin dryness" means the property of drying the skin or the property of giving the skin a feeling of dryness. Moreover, in this method, "suppression" can also be referred to as "reduction", "reduction" or "mitigation".

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these.
Test Example 1 (dispersibility evaluation)
Formulations of compositions for external use shown in Tables 1 and 2 were prepared by a conventional method. The dosage form of each formulation in Tables 1 and 2 is a lotion.
These formulations were used to evaluate the dispersibility of adapalene. Specifically, after stirring each formulation to make it uniform, 50 μL was dropped onto a slide glass, particles were observed and photographed using a microscope (product name: VHX-5000; Keyence Corporation), and subjected to automatic image processing. Only the grain portion was extracted by using a sieve, and the average area of the grains (average grain area) was measured.
Aggregation of adapalene increases the area of each particle observed. Therefore, the more uniformly the adapalene is dispersed in the composition, the smaller the average particle area.

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

Particle area decrease rate (%)
= [(average particle area of corresponding comparative example-average particle area of example)/average particle area of corresponding comparative example] x 100 (1)

The results are shown in Tables 1 and 2.

As shown in Tables 1 and 2, by adding dipotassium glycyrrhizinate, allantoin, a heparinoid, glycyrrhetinic acid, or ibuprofenpiconol to an external composition containing adapalene, the particle area of adapalene in the composition was reduced to Decreased. It can be seen that the addition of component (B) improved the dispersibility of adapalene in the composition.

Test Example 2 (Dispersion Sustainability Evaluation)
A formulation, which is an external composition having the composition shown in Table 3, was prepared by a conventional method. The dosage form of each formulation in Table 3 is a lotion.
These formulations were used to assess the persistence of dispersion of adapalene. Specifically, 100 mL of each formulation was dispensed into 100 mL capacity glass vials and allowed to stand under light shielding at room temperature for 2 days.
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 5 times, and light-shielded at room temperature. Let stand for 10 minutes below.
Before and after stirring, i.e., ``sonication using an ultrasonic cleaner, shaking, and standing for 10 minutes under light shielding at room temperature'', the center of the height between the liquid surface in the glass vial and the bottom of the glass vial 5 mL of each formulation was sampled from each part, placed in a quartz cell, and absorbance at 600 nm was measured using an ultraviolet-visible spectrophotometer (product name: UV-2600, manufactured by Shimadzu Corporation). Absorbance at 600 nm is an indicator of turbidity.

The value obtained by subtracting the turbidity before stirring from the turbidity after stirring was defined as the degree of separation. If the increase in turbidity due to stirring is small, the degree of separation will be small. A small degree of separation indicates a high persistence of dispersion of adapalene in the formulation.

The degree of separation was determined for each formulation, 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-3C is Comparative Example 3.

Dispersion sustainability improvement rate (%)
= [(Separation degree of corresponding comparative example - Separation degree of each example)/Separation degree of corresponding comparative example] × 100 (2)

表３が示す通り、アダパレンを含む外用組成物に、グリチルリチン酸二カリウム、アラントイン、又はヘパリン類似物質を配合することにより、アダパレンの分散の持続性が改善した。 The results are shown in Table 3.

As shown in Table 3, by adding dipotassium glycyrrhizinate, allantoin, or a heparinoid to the topical composition containing adapalene, the persistence of dispersion of adapalene was improved.

Test Example 3 (Evaluation of dispersibility after application of formulation)
A formulation, which is an external composition having the composition shown in Table 4, was prepared by a conventional method. The dosage form of each formulation in Table 4 is a lotion.
These formulations were used to evaluate the dispersibility of adapalene after application. Specifically, each formulation was stirred and homogenized, and then 50 μL of the formulation was dropped onto a slide glass and dried at room temperature under light shielding for about 18 hours. After that, the particles were observed and photographed using a microscope (product name: VHX-5000; Keyence Corporation), only the particle portion was extracted by automatic image processing, and the average area of the particles (average particle area) was measured. .

Aggregation of adapalene during and after drying of the formulation increases the observed particle area. This test evaluates the susceptibility of adapalene to aggregate in the formulation after application. When the observed particle area is small, it becomes easy to spread adapalene evenly over the application site when the formulation is applied.

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-4C is Comparative Example 4.

表４が示す通り、アダパレンを含む外用組成物に、グリチルリチン酸二カリウム、アラントイン、又はヘパリン類似物質を配合することにより、組成物の塗布、乾燥後の粒子面積が著しく低下した。（Ｂ）成分の配合により、本発明の外用組成物を皮膚に塗布した後にアダパレンが凝集し難くなることが分かる。 The results are shown in Table 4.

As shown in Table 4, the addition of dipotassium glycyrrhizinate, allantoin, or a heparin-like substance to the composition for external use containing adapalene significantly reduced the particle area after application and drying of the composition. It can be seen that the combination of component (B) makes it difficult for adapalene to agglomerate after applying the composition for external use of the present invention to the skin.

Test Example 4 (moisture retention evaluation)
Formulations of compositions for external use shown in Tables 5 and 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 test site was the inner forearm of two healthy adult subjects. First, before applying the test preparation to the test site, the test site was washed with water, and after 15 minutes of washing, the stratum corneum moisture content was measured using a skin surface stratum corneum water content measuring device (Skicon-200EX; Yayoi Co., Ltd.). was measured and taken as the initial moisture content. Next, 20 μL of the test formulation was applied to the test site, and 60 minutes later, the stratum corneum moisture content of the test site was measured. The keratin moisture change was obtained by subtracting the initial moisture content from the keratin moisture content after 60 minutes (moisture content after application). Furthermore, using the following formula (3), the difference between the keratin moisture change amount of each example and the keratin moisture change amount of the corresponding comparative example was calculated.

Comparative Example 5 corresponds to Examples 5A and 5B, and Comparative Example 6 corresponds to Examples 6A and 6B. Since the change in keratin water content indicates the moisturizing power of the test preparation, the greater the change in keratin water content in each example compared to the corresponding comparative example, the greater the moisturizing power due to the addition of an anti-inflammatory agent. indicate that

Difference in stratum corneum moisture content = stratum corneum moisture variation in the example - stratum corneum moisture variation in the corresponding comparative example
(3)

Tables 5 and 6 show the results.

表５、表６が示す通り、アダパレンを含む外用組成物に、アラントイン、グリチルリチン酸二カリウム、グリチルレチン酸、又はイブプロフェンピコノールを配合することにより、保湿力が著しく向上した。

As shown in Tables 5 and 6, adding allantoin, dipotassium glycyrrhizinate, glycyrrhetinic acid, or ibuprofenpiconol to the external composition containing adapalene significantly improved the moisturizing power.

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

表７が示す通り、アダパレンを含む外用組成物に、イソプロピルメチルフェノールを配合することにより、組成物中のアダパレンの粒子面積が低下した。（Ｂ）成分の配合により組成物中でのアダパレンの分散性が向上したことが分かる。 The results are shown in Table 7.

As shown in Table 7, the addition of isopropylmethylphenol to the topical composition containing adapalene reduced the particle area of adapalene in the composition. It can be seen that the addition of component (B) improved the dispersibility of adapalene in the composition.

Test Example 6 (dispersibility evaluation)
Formulations of compositions for external use shown in Tables 8 and 9 were prepared by a conventional method. The dosage form of each formulation in Tables 8 and 9 is an emulsion.
These formulations were used to evaluate the dispersibility of adapalene. Specifically, after stirring each formulation to make it uniform, 50 μL was dropped onto a slide glass, particles were observed and photographed using a microscope (product name: VHX-5000; Keyence Corporation), and subjected to automatic image processing. Only the grain portion was extracted by using a sieve, and the average area of the grains (average grain area) was measured.

Aggregation of adapalene increases the area of each particle observed. Therefore, the more uniformly the adapalene is dispersed in the composition, the smaller the average particle area.

Next, the particle area reduction rate (%) compared with the corresponding comparative example was calculated according to the above formula (1). The comparative example corresponding to Examples 8A-8C is Comparative Example 8, and the comparative example corresponding to Examples 9A-9B is Comparative Example 9.

The results are shown in Tables 8 and 9.

表８、９が示す通り、多価アルコールとしてグリセリン及び１，３－ブチレングリコール、又はプロピレングリコールを用いた場合も、アダパレンを含む外用組成物に、グリチルリチン酸、アラントイン、又はヘパリン類似物質を配合することにより、組成物中のアダパレンの粒子面積が低下した。（Ｂ）成分の配合により組成物中でのアダパレンの分散性が向上したことが分かる。

As shown in Tables 8 and 9, even when glycerin and 1,3-butylene glycol or propylene glycol are used as polyhydric alcohols, glycyrrhizic acid, allantoin, or a heparin-like substance is added to the external composition containing adapalene. This reduced the particle area of adapalene in the composition. It can be seen that the addition of component (B) improved the dispersibility of adapalene in the composition.

Formulation Examples External compositions (formulation examples 1 to 70) were prepared according to the formulations described below.

Adapalene and/or salts thereof have good dispersibility in the composition for external use of the present invention, so that adapalene can be uniformly applied to the affected area, and aggregation of adapalene and/or salts thereof is suppressed. The desired medicinal effect can be sufficiently obtained from In addition, dry feeling and accompanying symptoms, which are known side effects of adapalene and/or its salts, are alleviated, so that it is easy to use.

Claims (11)

An external composition containing the following components (A), (B) and (C).
(A) 0.01 to 0.15% by weight of adapalene and/or a salt thereof relative to the total amount of the composition (B) glycyrrhetinic acid, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, glycyrrhizic acid, glycyrrhizic acid At least one selected from the group consisting of methyl, stearyl glycyrrhizinate, salts thereof, ibuprofenpiconol, isopropylmethylphenol, and 0.01 to 5% by weight of heparin analogues relative to the total amount of the composition (C) composition 0.01 to 30% by weight of polyhydric alcohol relative to the total amount of the product The composition for external use according to claim 1, containing 0.01 to 5% by weight of component (B). 3. The composition for external use according to claim 1, 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. The composition for external use according to any one of claims 1 to 3, further comprising (D) an emulsifier. (D) The emulsifier is at least one selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters according to claim 4. External composition. 6. The composition for external use according to any one of claims 1 to 5, further comprising (E) a hydrocarbon base. The component (B) is selected from the group consisting of glycyrrhetinic acid, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, glycyrrhizic acid, methyl glycyrrhizinate, stearyl glycyrrhizinate, salts thereof, ibuprofenpiconol, and heparin-like substances. When at least one anti-inflammatory component is contained, the content of this anti-inflammatory component is 0.1 to 500 parts by weight per 1 part by weight of adapalene and/or a salt thereof, and isopropylmethylphenol is used as component (B). 7. The composition for external use according to any one of claims 1 to 6, wherein the content of isopropylmethylphenol, when included, is 0.1 to 50 parts by weight per 1 part by weight of adapalene and/or a salt thereof. The composition for external use according to any one of claims 1 to 7, which has a pH of 2-8. The composition for external use according to any one of claims 1 to 8, wherein the dosage form of the composition is liquid, suspension, emulsion, cream, ointment, gel, or lotion. (B) glycyrrhetinic acid , stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, glycyrrhizic acid, methyl glycyrrhizinate, and A composition containing at least one selected from the group consisting of stearyl glycyrrhizinate, salts thereof, heparinoids, ibuprofen piconol, and isopropylmethylphenol, and comprising components (A), (B), and (C) The content of (A) adapalene and/or a salt thereof shall be 0.01 to 0.15% by weight relative to the total amount of the product, and when a heparinoid is contained as the component (B), the content of the heparinoid is 0.01 to 5% by weight, and the content of (C) polyhydric alcohol is 0.01 to 30% by weight. (B) glycyrrhetinic acid , stearyl glycyrrhetinate, glyceryl glycyrrhetinate, glycyrrhetinate monoglucuronide, glycyrrhizic acid, methyl glycyrrhizinate, and A composition containing at least one selected from the group consisting of stearyl glycyrrhizinate, salts thereof, heparinoids, ibuprofen piconol, and isopropylmethylphenol, and comprising components (A), (B), and (C) The content of (A) adapalene and/or a salt thereof shall be 0.01 to 0.15% by weight relative to the total amount of the product, and when a heparinoid is contained as the component (B), the content of the heparinoid is 0.01 to 5% by weight, and the content of (C) a polyhydric alcohol is 0.01 to 30% by weight.