JPWO2019240290A1 - Topical composition - Google Patents

Abstract

Selected from the group consisting of (A) adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salt, lactic acid and its salt, ureas, and mucopolysaccharide and its salt. The external composition containing at least one component has good dispersibility of adapalene and / or a salt thereof. The external composition can further contain (C) a polyhydric alcohol, (D) an emulsifier, and / or (E) a hydrocarbon base.

Description

The present invention relates to an external composition containing adapalene and / or a salt thereof.

Adapalene is a derivative of naphthalenecarboxylic acid and is used as an active ingredient of an external therapeutic agent for acne vulgaris. Acne vulgaris develops as comedones due to increased sebum secretion of the sebaceous gland system and obstruction of hair follicles due to increased keratinization, and then develops into an inflamed eruption. Adapalene suppresses the formation of comedones by controlling the keratinization of the epidermis and improving the clogging of pores.
Deferingel 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 the component in the external preparation is poor, it is difficult to uniformly apply the component. Further, when the component aggregates in the external preparation, the contact area of the component with the skin becomes small, so that there is a problem that it is difficult to obtain the desired medicinal effect.

Deferingel 0.1% Package insert

The present inventor has found that the dispersibility of adapalene and / or a salt thereof in an external composition is extremely poor. Therefore, it is an object of the present invention to provide an external composition containing adapalene and / or a salt thereof, which has good dispersibility of adapalene and / or a salt thereof.

The present inventor has conducted repeated studies to solve the above problems, and added (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and salts thereof to an external composition containing (A) adapalene and / or a salt thereof. By adding at least one component selected from the group consisting of lactic acid and its salt, ureas, and mucopolysaccharide and its salt, the dispersibility of adapalene and / or its salt in the composition is improved. I found it.

The present invention has been completed based on the above findings, and provides the following external composition and a method for improving the dispersibility of adapalene and / or a salt thereof.
Item 1. Selected from the group consisting of (A) adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salt, lactic acid and its salt, ureas, and mucopolysaccharide and its salt. An external composition containing at least one component.
Item 2. Item 2. The external composition according to Item 1, which contains 0.001 to 1% by weight of the component (A).
Item 3. Item 2. The external composition according to Item 1 or 2, which contains 0.0001 to 20% by weight of the component (B).
Item 4. Item 2. The external composition according to any one of Items 1 to 3, further containing (C) a polyhydric alcohol.
Item 5. Item 4. The external composition according to Item 4, wherein the component (C) is at least one selected from the group consisting of dipropylene glycol, glycerin, 1,3-butylene glycol, and polyethylene glycol.
Item 6. Item 2. The external composition according to any one of Items 1 to 5, further containing (D) an emulsifier.
Item 7. Item 2. The external application 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. Composition.
Item 8. Item 2. The external composition according to any one of Items 1 to 7, further containing (E) a hydrocarbon base.
Item 9. Item 2. The external composition according to any one of Items 1 to 8, wherein the dosage form of the composition is a liquid agent, a suspension agent, an emulsion, a cream agent, a gel agent, a lotion agent, a spray agent, or an aerosol agent.
Item 10. (A) An external composition containing adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salt, lactic acid and its salt, ureas, and mucopolysaccharide and its salt. A method for improving dispersibility of adapalene and / or a salt thereof in an external composition, which comprises at least one component selected from the group consisting of.

Adapalene and / or a salt thereof generally has extremely poor dispersibility in an external composition, but the external composition of the present invention further comprises ceramides, cholesterols, amino acids, pyrrolidone carboxylic acid and its salt, lactic acid and By containing the salt, ureas, and a component selected from the group consisting of mucopolysaccharide and its salt, the dispersibility and dispersion retention of adapalene and / or its salt are good. These ingredients are moisturizing factors originally present in the skin and are blended in cosmetics and the like as moisturizers. It is surprising that such moisturizing ingredients improve the dispersibility of adapalene and / or salts thereof.

Since the external composition of the present invention has good dispersibility of adapalene and / or a salt thereof, the amount of adapalene and / or a salt thereof applied becomes uniform when the external composition is applied. Further, even during the production of the pharmaceutical product, the dispersibility of adapalene and / or a salt thereof is high and the uniformity is maintained, so that the pharmaceutical product can be easily produced. In addition, components with poor dispersibility in the external composition generally undergo remarkable aggregation when the composition is applied and dried, but the composition of the present invention contains adapalene and adapalene in a dry state after application. / Or the aggregation of its salts is also effectively suppressed.
The external composition of the present invention contains factors originally present in the skin such as ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acids, lactic acid and salts thereof, ureas, mucopolysaccharides and salts thereof, or related substances thereof. As a result, the dispersibility of adapalene and / or its salt is improved. Therefore, in order to improve the dispersibility, it is not necessary to add components that do not need to be contained for the skin.

Hereinafter, the present invention will be described in detail.
The compositions of the present invention include (A) adapalene and / or salts thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof. It is an external composition containing at least one component selected from the group consisting of salts.

Adaparene and its salts The adaparene salt may be any pharmaceutically or physiologically acceptable salt, and is a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt). , Tripyridine salt, organic amine salt such as picolin salt, etc.), salt with inorganic base (ammonium salt; alkali metal salt such as sodium salt, potassium salt, calcium salt, alkaline earth metal salt such as magnesium salt, Zinc salts, metal salts such as aluminum salts, etc.). When the composition of the present invention contains a salt of adapalene, it may be blended as a salt of adapalene, and as a result of separately blending adapalene and an organic or inorganic base, it becomes a salt in the composition. It may be a thing.
As the adapalene and its salt, among them, adapalene and a salt of adapalene and an inorganic base are preferable, and adapalene is more preferable.

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, more preferably 0.05% by weight or more, and 0. 1% by weight or more is even more preferable. Further, 1% by weight or less is preferable, 0.3% by weight or less is more preferable, and 0.15% by weight or less is even more preferable. Most preferably 0.1% by weight. Within this range, appropriate pharmacological activity of adapalene and / or a salt thereof can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The contents of adaparene and / or a salt thereof were 0.001 to 1% by weight, 0.001 to 0.3% by weight, 0.001 to 0.15% by weight, 0. 01 to 1% by weight, 0.01 to 0.3% by weight, 0.01 to 0.15% by weight, 0.05 to 1% by weight, 0.05 to 0.3% by weight, 0.05 to 0% by weight. Examples thereof include 15% by weight, 0.1 to 1% by weight, 0.1 to 0.3% by weight, and 0.1 to 0.15% by weight.

Ceramides Examples of ceramides include sphingosin, phytosphingocin, ceramide in which fatty acid is amide-bonded to sphingosin, sphingoglycolipid (typically, celebroside) in which sugar is bonded to ceramide, and sphingoline in which phosphoric acid and base are bonded to ceramide. Lipid (typically sphingomyelin), synthetic ceramide having a structure similar to ceramide (N- (hexadecyloxyhydroxypropyl) -N-hydroxyethylhexadecanamide, hexadecyloxy PG hydroxetylhexadecanamide , Cetyl PG hydroxyethyl palmitamide, etc.), human ceramide obtained by fermentation with yeast (for example, ceramide 2, ceramide 3, fermented ceramide), animal-derived ceramide extracted from animal spinal cord and brain, rice, soybean , Ceramides derived from plants extracted from corn, wheat and the like, any one of ceramides 1 to 10 and the like.
Among them, synthetic ceramide is preferable because the effect of improving the dispersibility of adapalene is good, and N- (hexadecyloxyhydroxypropyl) -N-hydroxyethylhexadecanamide is more preferable.
One type of ceramide may be used alone, or two or more types may be used in combination.

The content of ceramides is preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, still more preferably 0.005% by weight or more, and 0.01% by weight, based on the total amount of the composition. The above is particularly preferable. Further, 5% by weight or less is preferable, 1% by weight or less is more preferable, 0.5% by weight or less is even more preferable, and 0.25% by weight or less is particularly preferable. Within this range, appropriate physiological activity of ceramides can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The content of ceramides is 0.0005 to 5% by weight, 0.0005 to 1% by weight, 0.0005 to 0.5% by weight, and 0.0005 to 0.25% by weight based on the total amount of the composition. %, 0.001 to 5% by weight, 0.001 to 1% by weight, 0.001 to 0.5% by weight, 0.001 to 0.25% by weight, 0.005 to 5% by weight, 0.005 to 5% by weight. 1% by weight, 0.005 to 0.5% by weight, 0.005 to 0.25% by weight, 0.01 to 5% by weight, 0.01 to 1% by weight, 0.01 to 0.5% by weight, 0.01 to 0.25% by weight is mentioned.

The ratio of the content of ceramides to the content of adaparene and / or its salt is preferably 0.005 parts by weight or more, more preferably 0.01 parts by weight or more, based on 1 part by weight of adaparene and / or its salt. , 0.05 parts by weight or more is even more preferable, and 0.1 parts by weight or more is particularly preferable. Further, 50 parts by weight or less is preferable, 10 parts by weight or less is more preferable, 5 parts by weight or less is even more preferable, and 2.5 parts by weight or less is more preferable. Within this range, appropriate physiological activity of ceramides can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of ceramides to the content of adaparene and / or its salt is 0.005 to 50 parts by weight, 0.005 to 10 parts by weight, 0 with respect to 1 part by weight of adaparene and / or its salt. .005-5 parts by weight, 0.005-2.5 parts by weight, 0.01-50 parts by weight, 0.01-10 parts by weight, 0.01-5 parts by weight, 0.01-2.5 parts by weight , 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0.05 to 5 parts by weight, 0.05 to 2.5 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight , 0.1 to 5 parts by weight and 0.1 to 2.5 parts by weight.

Cholesterols Cholesterols include animal sterols such as cholesterol, cholestanol, lanosterol, selegrosterol, dehydrocholesterol, cobrostanol; phytosterols, citosterols, stigmasterols, campesterols, ergosterols, fucosterols, spinna. Plant sterols such as sterols; microbial-derived sterols such as ergosterols, mycosterols, thymosterols; these cholesterols and fatty acids (eg, fatty acids with 10-18 carbon atoms, specifically lauric acid, Esterates with myristic acid, palmitic acid, stearic acid, hydroxystearic acid, oleic acid, isostearic acid, etc.), alkyl ether derivatives in which the hydrogen atom of the hydroxyl group of these cholesterols is replaced with an alkyl group having 1 to 10 carbon atoms, Examples thereof include alkyl esters substituted with acyl groups having 1 to 10 carbon atoms, cholesterol derivatives such as glycosyl substituted with sugar residues, and the like.
Among them, animal sterols and derivatives thereof are preferable, cholesterol and its derivatives are more preferable, and cholesterol is even more preferable, in that the effect of improving the dispersibility of adapalene and / or a salt thereof is good.
Cholesterols can be used alone or in combination of two or more.

The content of cholesterol is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, still more preferably 0.1% by weight or more, and 0.2% by weight, based on the total amount of the composition. The above is particularly preferable. Further, 5% by weight or less is preferable, 2% by weight or less is more preferable, 1% by weight or less is even more preferable, and 0.9% by weight or less is particularly preferable. Within this range, appropriate physiological or pharmacological activity of cholesterol can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The content of cholesterol was 0.01 to 5% by weight, 0.01 to 2% by weight, 0.01 to 1% by weight, 0.01 to 0.9% by weight, based on the total amount of the composition. 0.05 to 5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.1 to 5% by weight, 0.1 to 2% by weight, 0.1 to 1% by weight, 0.1 to 0.9% by weight, 0.2 to 5% by weight, 0.2 to 2% by weight, 0.2 to 1% by weight, 0.2 to 0.9% by weight %.

The ratio of the content of cholesterol to the content of adaparene and / or its salt is preferably 0.1 part by weight or more, more preferably 0.5 part by weight or more, based on 1 part by weight of adaparene and / or its salt. 1, 1 part by weight or more is even more preferable, and 2 parts by weight or more is particularly preferable. Further, 50 parts by weight or less is preferable, 20 parts by weight or less is more preferable, 10 parts by weight or less is even more preferable, and 9 parts by weight or less is particularly preferable. Within this range, appropriate physiological or pharmacological activity of cholesterol can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of cholesterol to the content of adaparene and / or its salt is 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0 with respect to 1 part by weight of adaparene and / or its salt. .1-10 parts by weight, 0.1-9 parts by weight, 0.5-50 parts by weight, 0.5-20 parts by weight, 0.5-10 parts by weight, 0.5-9 parts by weight, 1-50 parts by weight Examples thereof include parts by weight, 1 to 20 parts by weight, 1 to 10 parts by weight, 1 to 9 parts by weight, 2 to 50 parts by weight, 2 to 20 parts by weight, 2 to 10 parts by weight, and 2 to 9 parts by weight.

Amino acids Examples of amino acids include neutral amino acids having an alkyl chain such as glycine, alanine, valine, leucine and isoleucine; neutral amino acids having a hydroxy group such as serine and threonine; and containing sulfur such as cysteine and methionine. Sexual amino acids; Neutral amino acids with amide groups such as asparagine and glutamine; Neutral amino acids with imino groups such as proline; Neutral amino acids with aromatic rings such as phenylalanine, tyrosine and tryptophan (above, neutral) Amino acids); acidic amino acids such as aspartic acid and glutamic acid; basic amino acids such as arginine, lysine and histidine. Examples of amino acids not contained in proteins include ornithine, citrulline, γ-aminobutyric acid, creatine, sarcosine, hydroxylysine, hydroxyproline, desmosine, O-phosphoserine, and cystine.
Among them, basic amino acids are preferable, and arginine is more preferable, because the effect of improving the dispersibility of adapalene and / or a salt thereof is good. Also preferred are glycine, alanine, proline, serine, lysine, glutamic acid and threonine.
Amino acids may be used alone or in combination of two or more.

The amino acid content is preferably 0.005% by weight or more, more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more, and 0.1% by weight or more, based on the total amount of the composition. Is particularly preferable. Further, 5% by weight or less is preferable, 1% by weight or less is more preferable, 0.5% by weight or less is even more preferable, and 0.4% by weight or less is particularly preferable. Further, it may be 0.3% by weight or less, or 0.2% by weight or less. Within this range, appropriate physiological activity of the amino acid can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The content of amino acids is 0.005 to 5% by weight, 0.005 to 1% by weight, 0.005 to 0.5% by weight, and 0.005 to 0.4% by weight based on the total amount of the composition. , 0.005 to 0.3% by weight, 0.005 to 0.2% by weight, 0.01 to 5% by weight, 0.01 to 1% by weight, 0.01 to 0.5% by weight, 0.01 ~ 0.4% by weight, 0.01 to 0.3% by weight, 0.01 to 0.2% by weight, 0.05 to 5% by weight, 0.05 to 1% by weight, 0.05 to 0.5% by weight %%, 0.05-0.4% by weight, 0.05-0.3% by weight, 0.05-0.2% by weight, 0.1-5% by weight, 0.1-1% by weight, 0 .1 to 0.5% by weight, 0.1 to 0.4% by weight, 0.1 to 0.3% by weight, 0.1 to 0.2% by weight.

The ratio of the content of amino acids to the content of adaparene and / or its salt is preferably 0.05 parts by weight or more, more preferably 0.1 parts by weight or more, based on 1 part by weight of adaparene and / or its salt. 0.5 parts by weight or more is even more preferable, and 1 part by weight or more is particularly preferable. Further, 50 parts by weight or less is preferable, 10 parts by weight or less is more preferable, 5 parts by weight or less is even more preferable, and 4 parts by weight or less is particularly preferable. It can also be 3 parts by weight or less, or 2 parts by weight or less. Within this range, appropriate physiological activity of the amino acid can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of amino acid to the content of adaparene and / or its salt was 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0. 05 to 5 parts by weight, 0.05 to 4 parts by weight, 0.05 to 3 parts by weight, 0.05 to 2 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, 0.1 to 0 parts 5 parts by weight, 0.1 to 4 parts by weight, 0.1 to 3 parts by weight, 0.1 to 2 parts by weight, 0.5 to 50 parts by weight, 0.5 to 10 parts by weight, 0.5 to 5 parts by weight Parts, 0.5 to 4 parts by weight, 0.5 to 3 parts by weight, 0.5 to 2 parts by weight, 1 to 50 parts by weight, 1 to 10 parts by weight, 1 to 5 parts by weight, 1 to 4 parts by weight, Examples thereof include 1 to 3 parts by weight and 1 to 2 parts by weight.

Pyrrolidone carboxylic acid and its salt The salt of pyrrolidone carboxylic acid may be any pharmaceutically or physiologically acceptable salt, and is a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholin salt, piperazine). Salts, pyrrolidine salts, tripyridine salts, organic amine salts such as picolin salts), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts and potassium salts, alkaline soils such as calcium salts and magnesium salts) Metal salts, zinc salts, metal salts such as aluminum salts, etc.). Among them, salts with inorganic bases are preferable, alkali metal salts are more preferable, and sodium salts are even more preferable.
When the composition of the present invention contains a salt of pyrrolidone carboxylic acid, it may be blended as a salt of pyrrolidone carboxylic acid, and as a result of separately blending pyrrolidone carboxylic acid and an organic or inorganic base, the composition It may be salted inside.
Of these, pyrrolidone carboxylic acid is preferable because it has a good effect of improving the dispersibility of adapalene and / or a salt thereof.
Pyrrolidone carboxylic acid and a salt thereof can be used alone or in combination of two or more.

The content of pyrrolidone carboxylic acid and / or a salt thereof is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, based on the total amount of the composition. , 0.05% by weight or more is particularly preferable, and 0.1% by weight or more is most preferable. Further, 10% by weight or less is preferable, 5% by weight or less is more preferable, 2% by weight or less is further preferable, 1% by weight or less is particularly preferable, and 0.9% by weight or less is more preferable. Within this range, appropriate physiological activity of pyrrolidone carboxylic acid and / or a salt thereof can be obtained, and dispersibility of adapalene and / or a salt thereof is sufficient.
The content of pyrrolidone carboxylic acid and / or a salt thereof is 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 2% by weight based on the total amount of the composition. 1% by weight, 0.001 to 0.9% by weight, 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 2% by weight, 0.005 to 1% by weight, 0.005 to 5% by weight 0.9% by weight, 0.01 to 10% by weight, 0.01 to 5% by weight, 0.01 to 2% by weight, 0.01 to 1% by weight, 0.01 to 0.9% by weight, 0. 05 to 10% by weight, 0.05 to 5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.1 to 10% by weight, 0. Examples thereof include 1 to 5% by weight, 0.1 to 2% by weight, 0.1 to 1% by weight, and 0.1 to 0.9% by weight.

The ratio of the content of pyrrolidone carboxylic acid and / or its salt to the content of adaparene and / or its salt is preferably 0.01 part by weight or more, preferably 0.05 parts by weight or more, based on 1 part by weight of adaparene and / or its salt. By weight or more is more preferable, 0.1 parts by weight or more is even more preferable, 0.5 parts by weight or more is particularly preferable, and 1 part by weight or more is most preferable. Further, 100 parts by weight or less is preferable, 50 parts by weight or less is more preferable, 20 parts by weight or less is even more preferable, 10 parts by weight or less is particularly preferable, and 9 parts by weight or less is most preferable. Within this range, appropriate physiological activity of pyrrolidone carboxylic acid and / or a salt thereof can be obtained, and dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of pyrrolidone carboxylic acid and / or its salt to the content of adaparene and / or its salt is 0.01 to 100 parts by weight, 0.01 with respect to 1 part by weight of adaparene and / or its salt. ~ 50 parts by weight, 0.01 to 20 parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 20 parts Parts by weight, 0.05 to 10 parts by weight, 0.05 to 9 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight , 0.1 to 9 parts by weight, 0.5 to 100 parts by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 Examples thereof include ~ 100 parts by weight, 1 to 50 parts by weight, 1 to 20 parts by weight, 1 to 10 parts by weight, and 1 to 9 parts by weight.

Lactic acid and salts thereof The lactic acid salt may be any pharmaceutically or physiologically acceptable salt, and is a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt). , Tripyridine salt, organic amine salt such as picolin salt, etc.), salt with inorganic base (ammonium salt; alkali metal salt such as sodium salt, potassium salt, calcium salt, alkaline earth metal salt such as magnesium salt, Zinc salts, metal salts such as aluminum salts, etc.). Among them, salts with inorganic bases are preferable, alkali metal salts are more preferable, and sodium salts are even more preferable.
When the composition of the present invention contains a salt of lactic acid, it may be blended as a salt of lactic acid, and as a result of blending lactic acid and an organic or inorganic base separately, it becomes a salt in the composition. It may be a thing.
Of these, lactic acid and sodium lactate are preferable because they have a good effect of improving the dispersibility of adapalene and / or a salt thereof.
Lactic acid and its salts can be used alone or in combination of two or more.

The content of lactic acid and / or a salt thereof is preferably 0.005% by weight or more, more preferably 0.01% by weight or more, still more preferably 0.05% by weight or more, and 0. .1% by weight or more is particularly preferable. Further, 10% by weight or less is preferable, 5% by weight or less is more preferable, 3% by weight or less is even more preferable, and 1% by weight or less is particularly preferable. Within this range, appropriate physiological or pharmacological activity of lactic acid and / or a salt thereof can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The contents of lactic acid and / or a salt thereof are 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 3% by weight, and 0.005 to 1% by weight based on the total amount of the composition. %, 0.01 to 10% by weight, 0.01 to 5% by weight, 0.01 to 3% by weight, 0.01 to 1% by weight, 0.05 to 10% by weight, 0.05 to 5% by weight, Examples thereof include 0.05 to 3% by weight, 0.05 to 1% by weight, 0.1 to 10% by weight, 0.1 to 5% by weight, 0.1 to 3% by weight, and 0.1 to 1% by weight. ..

The ratio of the content of lactic acid and / or its salt to the content of adaparene and / or its salt is preferably 0.05 parts by weight or more, preferably 0.1 parts by weight, based on 1 part by weight of adaparene and / or its salt. The above is more preferable, 0.5 parts by weight or more is even more preferable, and 1 part by weight or more is particularly preferable. Further, 100 parts by weight or less is preferable, 50 parts by weight or less is more preferable, 30 parts by weight or less is even more preferable, and 10 parts by weight or less is particularly preferable. Within this range, appropriate physiological or pharmacological activity of lactic acid and / or a salt thereof can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of lactic acid and / or its salt to the content of adaparene and / or its salt is 0.05 to 100 parts by weight and 0.05 to 50 parts by weight with respect to 1 part by weight of adaparene and / or its salt. Parts by weight, 0.05 to 30 parts by weight, 0.05 to 10 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 30 parts by weight, 0.1 to 10 parts by weight , 0.5 to 100 parts by weight, 0.5 to 50 parts by weight, 0.5 to 30 parts by weight, 0.5 to 10 parts by weight, 1 to 100 parts by weight, 1 to 50 parts by weight, 1 to 30 parts by weight Examples include 1 to 10 parts by weight.

Ureas Examples of ureas include ureas, methyl ureas, alkyl ureas having an alkyl group having 1 to 4 carbon atoms such as ethyl urea; hydroxyethyl urea, dihydroxyethyl urea, bis (hydroxyethyl) urea, and hydroxypropyl urea. , Dihydroxypropyl urea, bis (hydroxypropyl) urea, hydroxybutyl urea, dihydroxybutyl urea, bis (hydroxybutyl) urea and the like, hydroxyalkyl urea having a hydroxyalkyl group having 1 to 10 carbon atoms.
Of these, urea is preferable because it has a good effect of improving the dispersibility of adapalene and / or a salt thereof.
As the ureas, one type can be used alone, or two or more types can be used in combination.

The content of ureas is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, and 0.05% by weight, based on the total amount of the composition. The above is particularly preferable, and 0.1% by weight or more is most preferable. Further, 10% by weight or less is preferable, 5% by weight or less is more preferable, 2% by weight or less is even more preferable, 1% by weight or less is particularly preferable, and 0.9% by weight or less is most preferable. Within this range, appropriate physiological or pharmacological activity of ureas can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The contents of ureas were 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 1% by weight, 0. 001 to 0.9% by weight, 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 2% by weight, 0.005 to 1% by weight, 0.005 to 0.9% by weight, 0.01-10% by weight, 0.01-5% by weight, 0.01-2% by weight, 0.01-1% by weight, 0.01-0.9% by weight, 0.05-10% by weight, 0.05 to 5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.1 to 10% by weight, 0.1 to 5% by weight, Examples thereof include 0.1 to 2% by weight, 0.1 to 1% by weight, and 0.1 to 0.9% by weight.

The ratio of the content of ureas to the content of adaparene and / or its salt is preferably 0.01 part by weight or more, more preferably 0.05 part by weight or more, based on 1 part by weight of adaparene and / or its salt. , 0.1 part by weight or more is even more preferable, 0.5 part by weight or more is particularly preferable, and 1 part by weight or more is most preferable. Further, 100 parts by weight or less is preferable, 50 parts by weight or less is more preferable, 20 parts by weight or less is even more preferable, 10 parts by weight or less is particularly preferable, and 9 parts by weight or less is most preferable. Within this range, appropriate physiological or pharmacological activity of ureas can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of ureas to the content of adaparene and / or its salt is 0.01 to 100 parts by weight, 0.01 to 50 parts by weight, 0 with respect to 1 part by weight of adaparene and / or its salt. 0.01 to 20 parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 20 parts by weight, 0.05 10 parts by weight, 0.05 to 9 parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 9 parts Parts by weight, 0.5 to 100 parts by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight, 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 1 to 100 parts by weight, 1 Examples thereof include ~ 50 parts by weight, 1 to 20 parts by weight, 1 to 10 parts by weight, and 1 to 9 parts by weight.

Mucopolysaccharides and salts thereof Mucopolysaccharides are polysaccharides composed of amino sugars such as galactosamine or glucosamine and uronic acid or galactose such as glucuronic acid and iduronic acid.
Examples of mucopolysaccharides include hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin.
The mucopolysaccharide salt may be any pharmaceutically or physiologically acceptable salt, and is a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholin salt, piperazine salt, pyrrolidine salt, tripyridine). Salts, organic amine salts such as picolin salts), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts and potassium salts, calcium salts, alkaline earth metal salts such as magnesium salts, zinc salts , Metal salts such as aluminum salts). Among them, salts with inorganic bases are preferable, alkali metal salts are more preferable, and sodium salts are even more preferable.
When the composition of the present invention contains a salt of mucopolysaccharide, it may be blended as a salt of mucopolysaccharide, and as a result of blending mucopolysaccharide and an organic or inorganic base separately, the composition It may be salted inside.
Of these, hyaluronic acid or a salt thereof (particularly a sodium salt) is preferable because it has a good effect of improving the dispersibility of adapalene and / or a salt thereof. As the hyaluronic acid, for example, a natural product extracted from a chicken comb or the like can be used, or a low molecular weight (for example, an average molecular weight of 100,000 or less) hyaluronic acid obtained by decomposing a natural product with an acid, an alkali, or an enzyme is used. You can also.
The mucopolysaccharide and its salt can be used alone or in combination of two or more.

The content of the mucopolysaccharide and its salt is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, still more preferably 0.01% by weight or more, and 0. 0.05% by weight or more is particularly preferable. Further, 5% by weight or less is preferable, 2% by weight or less is more preferable, 1% by weight or less is even more preferable, and 0.9% by weight or less is particularly preferable. Further, 0.5% by weight or less, 0.2% by weight or less, 0.15% by weight or less, or 0.1% by weight or less is also preferable. Within this range, appropriate physiological activity of the mucopolysaccharide and its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.
The contents of mucopolysaccharide and its salt were 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 1% by weight, and 0.001 to 0% by weight based on the total amount of the composition. 9% by weight, 0.001 to 0.5% by weight, 0.001 to 0.2% by weight, 0.001 to 0.15% by weight, 0.001 to 0.1% by weight, 0.005 to 5% by weight %, 0.005-2% by weight, 0.005-1% by weight, 0.005-0.9% by weight, 0.005-0.5% by weight, 0.005-0.2% by weight, 0. 005 to 0.15% by weight, 0.005 to 0.1% by weight, 0.01 to 5% by weight, 0.01 to 2% by weight, 0.01 to 1% by weight, 0.01 to 0.9% by weight %, 0.01-0.5% by weight, 0.01-0.2% by weight, 0.01-0.15% by weight, 0.01-0.1% by weight, 0.05-5% by weight, 0.05 to 2% by weight, 0.05 to 1% by weight, 0.05 to 0.9% by weight, 0.05 to 0.5% by weight, 0.05 to 0.2% by weight, 0.05 to 0% by weight Examples thereof include 0.15% by weight and 0.05 to 0.1% by weight.

The ratio of the content of mucopolysaccharide and its salt to the content of adaparene and / or its salt is preferably 0.01 part by weight or more, preferably 0.05 part by weight, based on 1 part by weight of adaparene and / or its salt. The above is more preferable, 0.1 part by weight or more is even more preferable, and 0.5 part by weight or more is particularly preferable. Further, 50 parts by weight or less is preferable, 20 parts by weight or less is more preferable, 10 parts by weight or less is even more preferable, and 9 parts by weight or less is particularly preferable. Further, 5 parts by weight or less, 2 parts by weight or less, or 1.5 parts by weight or less is also preferable. Further, it may be 1 part by weight or less. Within this range, appropriate physiological activity of the mucopolysaccharide and its salt can be obtained, and the dispersibility of adapalene and / or its salt is sufficient.
The ratio of the content of mucopolysaccharide and its salt to the content of adaparene and / or its salt is 0.01 to 50 parts by weight and 0.01 to 20 parts by weight with respect to 1 part by weight of adaparene and / or its salt. Parts by weight, 0.01 to 10 parts by weight, 0.01 to 9 parts by weight, 0.01 to 5 parts by weight, 0.01 to 2 parts by weight, 0.01 to 1.5 parts by weight, 0.01 to 1 part Parts by weight, 0.05 to 50 parts by weight, 0.05 to 20 parts by weight, 0.05 to 10 parts by weight, 0.05 to 9 parts by weight, 0.05 to 5 parts by weight, 0.05 to 2 parts by weight , 0.05 to 1.5 parts by weight, 0.05 to 1 part by weight, 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, 0.1 to 10 parts by weight, 0.1 to 9 parts by weight , 0.1 to 5 parts by weight, 0.1 to 2 parts by weight, 0.1 to 1.5 parts by weight, 0.1 to 1 part by weight, 0.5 to 50 parts by weight, 0.5 to 20 parts by weight , 0.5 to 10 parts by weight, 0.5 to 9 parts by weight, 0.5 to 5 parts by weight, 0.5 to 2 parts by weight, 0.5 to 1.5 parts by weight, 0.5 to 1 part by weight Can be mentioned.

Content of component (B) The content of component (B) is preferably 0.0001% by weight or more, more preferably 0.0005% by weight or more, and 0.001% by weight or more, based on the total amount of the composition. Even more preferably, 0.005% by weight or more is particularly preferable, and 0.01% by weight or more is most preferable. Further, 20% by weight or less is preferable, 10% by weight or less is more preferable, 5% by weight or less is even more preferable, 1% by weight or less is particularly preferable, and 0.9% by weight or less is most preferable. Within this range, appropriate physiological activity or pharmacological activity of the component (B) can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The content of the component (B) is 0.0001 to 20% by weight, 0.0001 to 10% by weight, 0.0001 to 5% by weight, 0.0001 to 1% by weight, based on the total amount of the composition. 0.0001 to 0.9% by weight, 0.0005 to 20% by weight, 0.0005 to 10% by weight, 0.0005 to 5% by weight, 0.0005 to 1% by weight, 0.0005 to 0.9% by weight %, 0.001 to 20% by weight, 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 1% by weight, 0.001 to 0.9% by weight, 0.005 to 20% by weight. %, 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 1% by weight, 0.005 to 0.9% by weight, 0.01 to 20% by weight, 0.01 to 10% by weight. %, 0.01 to 5% by weight, 0.01 to 1% by weight, and 0.01 to 0.9% by weight.

The ratio of the content of the component (B) to the content of adaparene and / or its salt is preferably 0.001 part by weight or more, preferably 0.005 part by weight or more, based on 1 part by weight of adaparene and / or its salt. More preferably, 0.01 parts by weight or more is even more preferable, 0.05 parts by weight or more is particularly preferable, and 0.1 parts by weight or more is most preferable. Further, 200 parts by weight or less is preferable, 100 parts by weight or less is more preferable, 50 parts by weight or less is even more preferable, 10 parts by weight or less is particularly preferable, and 9 parts by weight or less is most preferable. Within this range, appropriate physiological activity or pharmacological activity of the component (B) can be obtained, and the dispersibility of adapalene and / or a salt thereof is sufficient.
The ratio of the content of the component (B) to the content of adaparene and / or its salt is 0.001 to 200 parts by weight and 0.001 to 100 parts by weight with respect to 1 part by weight of adaparene and / or its salt. , 0.001 to 50 parts by weight, 0.001 to 10 parts by weight, 0.001 to 9 parts by weight, 0.005 to 200 parts by weight, 0.005 to 100 parts by weight, 0.005 to 50 parts by weight, 0 .005 to 10 parts by weight, 0.005 to 9 parts by weight, 0.01 to 200 parts by weight, 0.01 to 100 parts by weight, 0.01 to 50 parts by weight, 0.01 to 10 parts by weight, 0.01 ~ 9 parts by weight, 0.05 to 200 parts by weight, 0.05 to 100 parts by weight, 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0.05 to 9 parts by weight, 0.1 to 200 parts Examples thereof include parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight, and 0.1 to 9 parts by weight.

Polyvalent Alcohol The external composition of the present invention may contain (C) polyvalent alcohol, which further improves the dispersibility of adapalene and / or a salt thereof.
Examples of polyhydric alcohols include ethylene glycol, propylene glycol, 1,3-propanediol (trimethylethylene glycol), butylene glycol (1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol), and 1 , 4-Butandiol (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 Divalent alcohols such as 6000, polyethylene glycol 20000, polyethylene glycol 35000), polypropylene glycols (polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000, etc.); trivalent alcohols such as glycerin, trimethylolpropane; diglycerin, polyglycerin And so on.
Of these, dihydric alcohols and trihydric alcohols are preferable, and dipropylene glycol, butylene glycol (particularly 1,3-butylene glycol), polyethylene glycol and glycerin are more preferable.
The polyhydric alcohol may be used alone or in combination of two or more.

Preferred combinations of polyhydric alcohols include dipropylene glycol and 1,3-butylene glycol, dipropylene glycol and polyethylene glycol, dipropylene glycol and glycerin, and 1,3-butylene glycol and polyethylene. Combination with glycol, combination with 1,3-butylene glycol and glycerin, combination with polyethylene glycol and glycerin; combination with dipropylene glycol and 1,3-butylene glycol and polyethylene glycol, combination with 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 The combination with and the like can be mentioned.

The content of the polyhydric alcohol is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, still more preferably 0.1% by weight or more, and 1% by weight or more, based on the total amount of the composition. Is particularly preferable. Further, 90% by weight or less is preferable, 60% by weight or less is more preferable, 30% by weight or less is even more preferable, and 15% by weight or less is particularly preferable. Within this range, the dispersibility of adapalene and / or a salt thereof is sufficiently improved, and an external composition that is more difficult to dry the skin can be obtained.
The content of the polyhydric alcohol is 0.001 to 90% by weight, 0.001 to 60% by weight, 0.001 to 30% by weight, 0.001 to 15% by weight, 0, based on the total amount of the composition. 0.01 to 90% by weight, 0.01 to 60% by weight, 0.01 to 30% by weight, 0.01 to 15% by weight, 0.1 to 90% by weight, 0.1 to 60% by weight, 0.1 -30% by weight, 0.1 to 15% by weight, 1 to 90% by weight, 1 to 60% by weight, 1 to 30% by weight, 1 to 15% by weight.

The ratio of the content of 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, based on 1 part by weight of adapalene and / or its salt. Preferably, 1 part by weight or more is even more preferable, and 10 parts by weight or more is particularly preferable. Further, 900 parts by weight or less is preferable, 600 parts by weight or less is more preferable, 300 parts by weight or less is even more preferable, and 150 parts by weight or less is particularly preferable. Within this range, the dispersibility of adapalene and / or a salt thereof is sufficiently improved, and an external composition that is more difficult to dry the skin can be obtained.
The ratio of the content of polyhydric alcohol to the content of adaparene and / or its salt was 0.01 to 900 parts by weight, 0.01 to 600 parts by weight, based on 1 part by weight of adaparene and / or its salt. 0.01 to 300 parts by weight, 0.01 to 150 parts by weight, 0.1 to 900 parts by weight, 0.1 to 600 parts by weight, 0.1 to 300 parts by weight, 0.1 to 150 parts by weight, 1 to Examples thereof include 900 parts by weight, 1 to 600 parts by weight, 1 to 300 parts by weight, 1 to 150 parts by weight, 10 to 900 parts by weight, 10 to 600 parts by weight, 10 to 300 parts by weight, and 10 to 150 parts by weight.

Emulsifier The external composition of the present invention can contain (D) an emulsifier, which further improves the dispersibility of adapalene and / or a salt thereof.
Emulsifiers include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, penta-2-ethylhexylate diglycerol sorbitan, and tetra-2-ethylhexylate diglycerol sorbitan. Sorbitane 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 () Hardened bean oil derivatives such as HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 (HCO-80); Oil derivatives; polyoxyethylene monolaurate (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), and isostear. Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan acid; polyoxyethylene monopalm 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 copolymers, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and Silicone surfactants such as PEG-9 polydimethylsiloxyethyl dimethicone; natural surfactants such as phospholipids such as lecithin, surfactin, and saponin; diethylaminoethyl amide stearate, and diethyl aminopropyl amide stearate. Fatty acid amidamines; alkylamines such as trilaurylamine, dimethylstearylamine, and di-2-ethylhexylamine; betaine-based amphoteric surfactants such as dimethylaminopropylamide stearate and laurylhydroxysulfobetaine; polyoxyethylene Polyoxypro Examples thereof include pyrene glycol (poroxumer 124 and the like); polyglycerin fatty acid esters; glycerin fatty acid esters; polyethylene glycol fatty acid esters and the like.
Of these, 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) and sorbitan oleate (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 monolaurate (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), mono Polyoxyethylene (20) sorbitan (polysorbate 80) oleate is more preferable.
The emulsifier may be used alone or in combination of two or more.

The content of the emulsifier is preferably 0.05% by weight or more, more preferably 0.1% by weight or more, still more preferably 0.5% by weight or more, and particularly preferably 1% by weight or more, based on the total amount of the composition. preferable. Further, 10% by weight or less is preferable, 8% by weight or less is more preferable, 6% by weight or less is even more preferable, and 4% by weight or less is particularly preferable. Within this range, the dispersibility of adapalene and / or its salt is sufficiently improved.
The content of the emulsifier is 0.05 to 10% by weight, 0.05 to 8% by weight, 0.05 to 6% by weight, 0.05 to 4% by weight, or 0.1 based on the total amount of the composition. 10% by weight, 0.1 to 8% by weight, 0.1 to 6% by weight, 0.1 to 4% by weight, 0.5 to 10% by weight, 0.5 to 8% by weight, 0.5 to 6% Examples thereof include% by weight, 0.5 to 4% by weight, 1 to 10% by weight, 1 to 8% by weight, 1 to 6% by weight, and 1 to 4% by weight.

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 further more preferably 5 parts by weight or more with respect to 1 part by weight of adapalene. It is preferable, and 10 parts by weight or more is particularly preferable. Further, 100 parts by weight or less is preferable, 80 parts by weight or less is more preferable, 60 parts by weight or less is even more preferable, and 40 parts by weight or less is particularly preferable. 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 adaparene and / or its salt is 0.5 to 100 parts by weight, 0.5 to 80 parts by weight, and 0.5 to 60 parts by weight with respect to 1 part by weight of adaparene. , 0.5-40 parts by weight, 1-100 parts by weight, 1-80 parts by weight, 1-60 parts by weight, 1-40 parts by weight, 5-100 parts by weight, 5-80 parts by weight, 5-60 parts by weight. , 5 to 40 parts by weight, 10 to 100 parts by weight, 10 to 80 parts by weight, 10 to 60 parts by weight, and 10 to 40 parts by weight.

Hydrocarbon Base The external composition of the present invention can contain (E) a hydrocarbon base, which further improves the dispersibility of adapalene and / or a salt thereof.
Hydrocarbon bases include petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (plastibase, etc.), ozokerite, ceresin, microcrystalline wax, squalane, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light fluid. Examples include paraffin.
Among them, petrolatum bases that are solid at room temperature (25 ° C) such as petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (plastibase, etc.), ozokerite, selecin, and microcrystalline wax are preferable, and petrolatum, ozokelite, and selecin are preferable. , Microcrystalline wax is more preferred, and petrolatum is even more preferred. Hydrocarbon bases that are liquid at room temperature (25 ° C.), such as squalene, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light liquid paraffin, are also preferred.
The hydrocarbon base may be used alone or in combination of two or more.

The content of the hydrocarbon base is preferably 0.000001% by weight or more, more preferably 0.00001% by weight or more, still more preferably 0.0001% by weight or more, and 0.001% by weight, based on the total amount of the composition. Weight% or more is particularly preferable. Further, it may be 0.01% by weight or more, 0.1% by weight or more, or 1% by weight or more. 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. Further, 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 a salt thereof is sufficiently improved, and an external composition that is more difficult to dry the skin can be obtained.
The content of the hydrocarbon base is 0.000001 to 50% by weight, 0.000001 to 30% by weight, 0.000001 to 20% by weight, 0.000001 to 10% by weight, based on the total amount of the composition. 0.000001 to 1% by weight, 0.000001 to 0.1% by weight, 0.000001 to 0.01% by weight, 0.00001 to 50% by weight, 0.00001 to 30% by weight, 0.00001 to 20% by weight %, 0.00001 to 10% by weight, 0.00001 to 1% by weight, 0.00001 to 0.1% by weight, 0.00001 to 0.01% by weight, 0.0001 to 50% by weight, 0.0001 to 0%. 30% by weight, 0.0001 to 20% by weight, 0.0001 to 10% by weight, 0.0001 to 1% by weight, 0.0001 to 0.1% by weight, 0.0001 to 0.01% by weight, 0. 001 to 50% by weight, 0.001 to 30% by weight, 0.001 to 20% by weight, 0.001 to 10% by weight, 0.001 to 1% by weight, 0.001 to 0.1% by weight, 0. 001 to 0.01% by weight, 0.01 to 50% by weight, 0.01 to 30% by weight, 0.01 to 20% by weight, 0.01 to 10% by weight, 0.01 to 1% by weight, 0. 01 to 0.1% by weight, 0.1 to 50% by weight, 0.1 to 30% by weight, 0.1 to 20% by weight, 0.1 to 10% by weight, 0.1 to 1% by weight, 1 to Examples thereof include 50% by weight, 1 to 30% by weight, 1 to 20% by weight, and 1 to 10% by weight.

The ratio of the content of the hydrocarbon base to the content of adaparene and / or its salt is preferably 0.00001 parts by weight or more, preferably 0.0001 parts by weight or more, based on 1 part by weight of adaparene and / or its salt. More preferably, 0.001 part by weight or more is even more preferable, and 0.01 part by weight or more is particularly preferable. Further, it may be 0.1 parts by weight or more, 1 part by weight or more, or 10 parts by weight or more. Further, 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. Further, 10 parts by weight or less, 1 part by weight or less, or 0.1 parts by weight or less is also preferable. Within this range, the dispersibility of adapalene and / or a salt thereof is sufficiently improved, and an external composition that is more difficult to dry the skin can be obtained.
The ratio of the content of the hydrocarbon base to the content of adaparene and / or its salt is 0.00001 to 500 parts by weight and 0.00001 to 300 parts by weight with respect to 1 part by weight of adaparene and / or its salt. , 0.00001 to 200 parts by weight, 0.00001 to 100 parts by weight, 0.00001 to 10 parts by weight, 0.00001 to 1 part by weight, 0.00001 to 0.1 parts by weight, 0.0001 to 500 parts by weight. , 0.0001 to 300 parts by weight, 0.0001 to 200 parts by weight, 0.0001 to 100 parts by weight, 0.0001 to 10 parts by weight, 0.0001 to 1 part by weight, 0.0001 to 0.1 parts by weight. , 0.001 to 500 parts by weight, 0.001 to 300 parts by weight, 0.001 to 200 parts by weight, 0.001 to 100 parts by weight, 0.001 to 10 parts by weight, 0.001 to 1 part by weight, 0 .001 to 0.1 parts by weight, 0.01 to 500 parts by weight, 0.01 to 300 parts by weight, 0.01 to 200 parts by weight, 0.01 to 100 parts by weight, 0.01 to 10 parts by weight, 0 0.01 to 1 part by weight, 0.01 to 0.1 parts by weight, 0.1 to 500 parts by weight, 0.1 to 300 parts by weight, 0.1 to 200 parts by weight, 0.1 to 100 parts by weight, 0 1 to 10 parts by weight, 0.1 to 1 part by weight, 1 to 500 parts by weight, 1 to 300 parts by weight, 1 to 200 parts by weight, 1 to 100 parts by weight, 1 to 10 parts by weight, 10 to 500 parts by weight , 10 to 300 parts by weight, 10 to 200 parts by weight, and 10 to 100 parts by weight.

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

Additives include, for example, antioxidants, thickeners, preservatives or preservatives, pH regulators, stabilizers, chelating agents, UV absorbers or UV scatterers, stimulants, colorants, refreshing agents. , Perfume and the like.
As the additive, one type can be used alone, or two or more types can be used in combination.
Further, the additive can be used as long as the effect of the present invention is not impaired.

Antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, p-hydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivatives (ascorbic acid stearate, ascorbic acid palmitate, ascorbic acid dipalmitate, ascorbic acid). Acid monophosphate ester, ascorbic acid diphosphate ester, ascorbic acid triphosphate ester, ascorbic acid sulfate ester, etc.), tocopherol, tocopherol derivative (tocopherol acetate, tocopherol succinate, tocopherol succinate, etc.), erythorbic acid, L-cysteine hydrochloride , Lycopene, glutathione, propyl carcinate, tannic acid, epigalocatechin, ascorbic acid, hydroxytyrosole, norhydroguaceretenic acid, caffeic acid, enzymes (catalase, superoxide dismutase, glutathione peroxidase, elastase, etc.) Can be mentioned.

Thickeners include guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl methacrylate copolymer, bentonite, alginic acid, macrogol, and cellulosic thickeners (methylcellulose). , Ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, etc.) and the like.

Preservatives or preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid. Examples thereof include benzyl, methyl paraoxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and salts thereof, chlorhexidine gluconate, alcandiol, and glycerin fatty acid ester.

As pH adjusters, inorganic acids (hydrogen, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citrate, sodium citrate, succinate, sodium succinate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.) ), Organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.) and the like.

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

Examples of the chelating agent include EDTA / disodium salt and EDTA / calcium / disodium salt.

Examples of the irritation reducing agent include licorice extract and sodium alginate.

Examples of the ultraviolet absorber or ultraviolet scattering agent include 2-ethylhexyl paramethoxysilicate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, and 2,4,6-tris [4- (2). -Ethylhexyloxycarbonyl) anilino] -1,3,5-triazine, t-butylmethoxydibenzoylmethane, dibenzilidendioxoimidazolidine ethylhexyl propyronate, etruhexyltriazoline, para-aminobenzoic acid and its derivatives, paradimethylamino Examples thereof include octyl benzoate, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide and zinc oxide.

Examples of the colorant include dyes described in the Legal Dye Handbook (edited by the Japan Cosmetic Industry Association (2004)).

As the refreshing agent, terpenes such as menthol, camphor, borneol, geraniol, cineole, anethole, limonene and eugenol (these may be d-form, l-form or dl-form); eucalyptus oil, bergamot oil, Examples include essential oils such as peppermint oil, cool mint oil, spear mint oil, camphor oil, peppermint oil, keihi oil, rose oil, and terpene oil.
As fragrances, various essential oils such as lavender oil, rosemary oil, clarisage oil, thyme oil, bergamot oil, eucalyptus oil and other herbal essential oils, orange oil, lemon oil, grapefruit oil and other citrus essential oils, compounded fragrances, etc. Can be mentioned.

Other bioactive or pharmacologically active ingredients (physiologically active or pharmacologically active ingredients other than (A) and (B)) include, for example, anti-inflammatory agents, bactericidal agents or antibacterial agents, keratin softeners other than urea, or keratin Thawing agent, antipruritic agent, moisturizing component other than (B) component and polyhydric alcohol, local anesthetic, vitamins, peptides or derivatives thereof, blood circulation promoting component, cell activating component, anti-aging component, astringent component, protein, plant Examples include extracts, seaweed extracts, antifungal agents, and whitening ingredients.
Other physiologically active or pharmacologically active ingredients may be used alone or in combination of two or more.
In addition, other physiologically active or pharmacologically active ingredients can be used as long as the effects of the present invention are not impaired.

Anti-inflammatory agents include allantin, glycyrrhizinic acid, methyl glycyrrhizinate, stearyl glycyrrhizinate, glycyrrhetinic acid, stearyl glycyrrhetinate, acetaminophen, epsilon-aminocaproic acid, velverin, azulene, bromeline, zinc; licorice extract, sage extract, Plant extracts such as rosemary extract; enzyme-based anti-inflammatory agents such as lysoteam, therapeptase, semi-alkaline proteinase; phenamic anti-inflammatory agents such as mephenamic acid, flurbiprofen, tolfenamic acid; acemetacin, indomethacin, indomethacin farnesyl , Edtrak, diclofenac, slindak, nabutmen, fenbufen, progourmet tacin, arylacetic acid anti-inflammatory agents such as mofezolac; aminobrophen, ibuprofen, oxaprozin, ketoprofen, zartprofen, thiaprofenic acid, naproxene, flurbiprofen, zartprofen, Propionic anti-inflammatory agents such as ibuprofen piconol, flurbiprofen axetil, phenoprofen, planoprofen, loxoprofen; oxycam anti-inflammatory agents such as ampyroxycam, tenoxycam, pyroxicum, meroxycam, lornoxicum, etc. Can be mentioned. These are non-steroidal anti-inflammatory drugs.
In addition, prednisolone, hydrocortisone, cortisone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, difluprednisolone, mometasone, diflucortron, fluonicid, fluosinonide, clobetasol, betamethasone, deprodone, clobetasol, bechrometasone, deprodone, alcromethasone, flumetasone, amcinonide. Steroidal anti-inflammatory agents such as derivatives of (especially esters) can also be used.
Examples of the steroid derivative include predonizolone esters such as prednisolone valerate acetate (PVA), prednisolone succinate, prednisolone acetate, and prednisolone phosphate, betamethasone propionate, betamethasone valerate, and dexamethasone valerate. Dexametazone esters such as dexamethasone propionate, dexametazone acetate, dexamethasone phosphate, dexamethasone metasulfobenzoic acid ester, dexametazone cypesylate, dexamethasone palmitate, hydrocortisone butyrate (particularly hydrocortisone-17-butyrate), Hydrocortisone acetates such as hydrocortisone acetate, hydrocortisone succinate, hydrocortisone butyrate, hydrocortisone butyrate propionate, hydrocortisone phosphate, mometazone furancarboxylic acid ester, diflucortron valerate, clobetazole propionate, bechrometazone propion Acid ester, beclomethasone dipropionic acid ester, clobetazone butyric acid ester, deprodon propionic acid ester, alcromethazone propionic acid ester, flumethazone pivalic acid ester, clobetazone propionic acid ester, clobetazone butyric acid ester, diflorazone acetate, etc. Can be mentioned.

Bactericides or antibacterial agents include aminoglycoside antibiotics such as clindamycin, quinolone antibiotics such as nadifloxacin, vesifloxacin, clinazifloxacin, furlifloxacin, ozenoxacin, benzoyl peroxide, isopropylmethylphenol, etc. Phenoxyethanol, decalinium chloride, benzalkonium chloride, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, alkyldiaminoethylglycine hydrochloride, cetylpyridinium chloride, sodium benzoate, ethanol, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Examples thereof include sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, salicylic acid, cresol, triclosan, and biguanide compounds. Some fungicides or antibacterial agents are included as preservatives or preservatives.

The external composition of the present invention may not contain benzoyl peroxide.
In addition, the topical compositions of the present invention are non-responsive / resistant to drug-resistant acne and therapeutic doses of clindamycin, minocycline, tetracycline or erythromycin. Formulations for use in the treatment or prevention of acne, including acne, may not be included, among others non-responsive / resistant P to drug-resistant acne and therapeutic doses of clindamycin, minocycline, tetracycline or erythromycin. .. Formulations for use in the treatment or prevention of acne, including acne, which may not include preparations containing adapalene and anti-inflammatory agents, among others drug-resistant acne and therapeutic doses of clindamycin, minocycline. , Tetracycline or erythromycin non-responsive / resistant P. cerevisiae. A preparation for use in the treatment or prevention of acne containing acne, which may not include a preparation containing an antibacterial agent, adapalene and an anti-inflammatory agent.
The invention may also be free of dual-action rational therapeutic molecules (excluding adapalene) having two distinct mechanisms of action for the treatment or prevention of bacterial infections, among which bacterial infections. It may not include drug carriers or formulations containing dual-action rational therapeutic molecules with two distinct mechanisms of action for the treatment or prevention of disease and adapalene and anti-inflammatory agents.
In particular, for the treatment of bacterial infections caused by both Gram-positive and Gram-negative bacteria, both susceptible and resistant, it cures acne and different skin and structural infections, and is additionally resistant. Dual-action rational therapy to prevent the development of acne can be free of molecules (except adapalene), among which bacterial infections caused by both sensitive and resistant Gram-positive and Gram-negative bacteria Dual-action rational therapy molecules and adapalene and anti-inflammatory agents to cure acne and other skin and structural infections, and additionally prevent the development of resistance, for the treatment of acne It may not include drug carriers or formulations that contain.
In addition, the present invention can be free of quinolone antibiotics, especially 8-chlorofluoroquinolones, especially besifloxacin or besifloxacin hydrochloride. 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. .. Further, the effect of the present invention is more remarkably exhibited by not containing a quinolone antibiotic, particularly 8-chlorofluoroquinolone, particularly besifloxacin or besifloxacin hydrochloride.

Examples of keratin softeners or keratolytic agents other than urea include salicylic acid and its derivatives (methyl salicylate, acetylsalicylic acid, etc.), glycolic acid, fruit acid, phytic acid, sulfur, ethyl alcohol, isopropyl alcohol, propanol, butanol, benzyl alcohol, Phenylethyl alcohol, propylene carbonate, hexyldodecanol, dimethylsulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyladipate, ethyllaurylate, lanolin, fatty acid dialchirolamide, sulfur, resorcin, sodium hydroxide, potassium hydroxide And so on.

Antihistamines include ethanolamine antihistamines such as diphenhydramine, bromodiphenhydramine, cremastine, chlorphenoxamine, diphenylpyraline, doxylamine, orphenadine, phenyltroxamine, and propylamine antihistamines such as chlorpheniramine, dimethindene, and tarastin. , Ethylenediamine antihistamines such as mepyramine, metapyrylene, tryperenamine, alimemazine, hydroxyethyl promethazine, isothipendil, mekitadine, oxomemazine, phenothiazine antihistamines such as promethazine, buclizine, cetirizine, homochlorcyclidine, cyclidine , Piperazine antihistamines such as oxatomide, ketotiphen, oropatazine, fexofenadine, loratazine, terfenadine, anthazoline, azatazine, bamipin, cyproheptazine, deptropin, evastin, emedastin, epinastine, mebuhydroline Antihistamines such as lysine, acrivastin, astemizole, azerastin, virastine, desloratazine, and salts thereof.
Also included are non-antihistamine components such as crotamiton, ictamol, moctar and thymol.

Examples of the moisturizing component other than the component (B) and the polyhydric alcohol include saccharides such as trehalose, xylitol and sorbitol, high molecular weight compounds such as keratin, chitin and chitosan, lipids such as phospholipids, chamomile extract and hamamelis extract. Examples include plant extracts such as cha extract and aloe extract.

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

Examples of vitamins include vitamin Es such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, ubiquinone derivatives and their pharmaceutical or physiological. Acceptable salts, riboflavin, flavin mononucleotide, flavin adenin dinucleotide, riboflabin butyrate, riboflavin tetrabutyrate, riboflavin 5'-sodium phosphate, riboflavin tetranicotinic acid ester, dl-α-tocopherol nicotinate, nicotinic acid Benzyl, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbate stearate, ascorbate palmitate, dipalmitate L-ascorbyl, methyl hesperidine , Ergocalciferol, Cholecalciferol, Phylloquinone, Farnoquinone, γ-Oryzanol, Dibenzoylthiamine, Dibenzoylthiamine hydrochloride, Thiamine hydrochloride, Thiaminecetyl hydrochloride, Thiaminethiocyanate, Thiaminelauryl hydrochloride, Thiaminenitrate, 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 monophosphate , Pyridoxin hydrochloride, Pyridoxin acetate, Pyridoxal hydrochloride, Pyridoxal 5'-phosphate, Pyridoxamine hydrochloride, Cyanocobalamine, Hydroxocobalamine, Deoxyadenosylcobalamine, Folic acid, Pteroylglutamic acid, Nicotinic acid, Nicotinic acid amide, Pantothenic acid, Calcium pantothenate Pantothenic acids such as pantothenyl alcohol (pantenol), D-pantesin, D-panthetin, coenzyme A, pantothenyl ethyl ether, biotin, biothicin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, ascorbic acid phosphate Examples thereof include sodium, magnesium ascorbic acid phosphate, carnitine, ferulic acid, α-lipoic acid, ollotic acid, hesperidin, γ-orizanol, orotic acid, rutin, eriocitrin and the like.

Examples of the peptide or a derivative thereof include keratin-degrading peptide, hydrolyzed keratin, collagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, and hydrolyzed silk.

As the blood circulation promoting component, a plant-derived component is preferably exemplified. For example, Panax ginseng, Ashitaba, Arnica, Ginkgo, Enmeisou, Dutch oak, Carrot, Gentiana, Gobo, Rice, Sanzashi, Shiitake, Seiyousanzashi, Yuzu, Senkyu, Senburi, Thyme, Chouji, Chinpi, Touki, Tounin, Tohi Ingredients derived from garlic, butcher bloom, grapes, buttons, marronnier, melissa, yuzu, ginseng, rosemary, rosehip, peach, apricot, walnut, corn, etc. (extracts of these plants, etc.), glucosyl hesperidin, etc. Can be mentioned.

The cell activating components include amino acids other than the component (B) such as γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, and ε-aminocaproic acid, retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids, and biotin. Such vitamins, α-hydroxy acids such as glycolic acid, tannins, flavonoids, saponins, allantin, photosensitizer 301, placenta extract, hinokithiol, cepharanthin, kiwi seed extract and the like.

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

Examples of the astringent component include zinc paraphenol sulfonate, zinc oxide, menthol, ethanol and the like.

Plant extracts include Japanese pepper, yukinoshita, pericarp, rice bran, sake lees, white pepper, shakuyaku, purple kib, hass seeds, honeybee seeds, Pandanus amaryllifolius Roxb., Arcangelicia flava (Arcangelicia flava) , Chamomile, coral grass, rice leaf, apricot fruit, catamen giraffe, rose flower, bamboo shoot skin, gentiana, carrot, otane carrot, red ginseng, hechima, peach, peach seed, kiwi, sunflower, zuzyphus joazeiro, paudalco , Sunflower, Hibiscus flower, Hagoromogusa, Cherimoya, Mango, Benitomi, Silane, Japanese pepper peel or seed coat, Benibana flower, Casablanca, Guava leaf, Dokudami, Late white yuzu, Aloe chijiku flower, Apple, White asparagus, Examples include plant extracts such as mate tea, cherry leaves, ylang ylang leaves.

Seaweed extracts include green algae such as chlorella bulgaris, chlorella pyrenoidosa, chlorella ellipsoidia, aonori, aosa, anaaosa; , Mozuku, Hirome, Hijiki, Hibamata, Umiuchiwa, Usubaumiuchiwa, Kirebanoumiuchiwa, Akabaumiuchiwa, Konaumiuchiwa, Okinawauchiwa, Usuyukiuchiwa, Etsukiumiuchiwa, Brown algae; , Yatabegusa, Yuikiri, Shimatengusa, Tosakanori, Togekirinsai, Amaxakirinsai, Kirinsai, Byakushinkirinsai, Tsunomata, Oobatsunomata, Tochaka or Yahazutsunomata, Ezotsunomata, Togetsunomata, Hirakotoji , Kagius banori, Sujius banori, Haius banori, red algae such as red seaweed.

Antifungal agents include terbinafine, naftifine, butenafin, tornafate, lylanafate, miconazole, lanoconazole, luriconazole, isoconazole, ketoconazole, clotrimazole, neticonazole, sulconazole, bihonazole, oxyconazole, econazole, fluconazole, fluconazole, fluconazole, fluconazole. , Eficonazole, butconazole, fenticonazole, sertaconazole and the like.

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

Examples of the base or carrier base or carrier include oil-based bases and aqueous bases.
Oily bases include higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; and vegetable fats such as shea butter, carbanal wax, cacao butter, and candelilla wax, in addition to the above-mentioned hydrocarbon bases. Animal fats and oils such as lanolin, orange raffy oil, squalane, horse oil, whale wax, and beeswax; hardened oil; methylpolysiloxane, crosslinked methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, crosslinked Type alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkyl polyether-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain Silicone oils such as modified polyglycerin modified silicones, polyether modified branched silicones, polyglycerin modified branched silicones, acrylic silicones, phenyl modified silicones, and silicone resins; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cationized guagam, and acetyl. Natural Polymer Derivatives such as Hyaluronic Acid Chemicals; Synthetic Polymers such as Polyvinylpyrrolidone, Carboxyvinyl Polymers, and Alkyl Methacrylate Copolymers of Acrylic Acids; Natural polymers such as isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythlit tetra2-ethylhexanoate, and tri (caprylic / capric acid) glyceryl. Esters; polysaccharides such as dextrin and maltodextrin; 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 A Glycol ethers such as tell can be mentioned.
Examples of the aqueous base include water, a buffer solution, ethanol, and lower alcohols such as isopropanol. The polyhydric alcohol also functions as an aqueous base.
The base or carrier may be used alone or in combination of two or more.

When the external composition of the present invention contains water, the content thereof 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 70% by weight or more, based on the total amount of the composition. It can be 95% by weight or more. Further, 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 water content is 3 to 97% by weight, 3 to 95% by weight, 3 to 70% by weight, 3 to 50% by weight, 3 to 30% by weight, 5 to 97% by weight, 5 to 95% by weight, 5 ~ 70% by weight, 5 to 50% by weight, 5 to 30% by weight, 30 to 97% by weight, 30 to 95% by weight, 30 to 70% by weight, 30 to 50% by weight, 50 to 97% by weight, 50 to 95% by weight. Examples thereof include% by weight, 50 to 70% by weight, 70 to 97% by weight, 70 to 95% by weight, and 95 to 97% by weight.

The external composition of the present invention may be free of polyoxyethylene araquil ether, stearyl alcohol, or a liquid oily component (eg, a liquid oily base such as a liquid hydrocarbon base). From the external compositions of the present invention, in particular, adapalene, polyoxyethylene araquil ether, stearyl alcohol, liquid oily components (eg, liquid oily bases such as liquid hydrocarbon bases), moisturizing components, and water are included. The composition can be excluded.
When the external composition of the present invention contains at least one selected from the group consisting of macrogol (polyethylene glycol) having an average molecular weight of 4000 or less, glycerin, and 1,3-butylene glycol, the content thereof is the composition. It can be less than 5% by weight or more than 40% by weight based on the total amount of the substance.

The components contained in the external composition of the present invention can be hydrates, hemihydrates, or anhydrides.

Dosage Form The dosage form of the external composition of the present invention includes liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, sprays, aerosols, powders, poultices, and non-woven fabrics. Examples thereof include a sheet agent obtained by impregnating a sheet such as, etc. with a chemical solution. Among them, liquids, suspensions, emulsions, creams, gels, lotions, sprays, and aerosols are the ones in which the effects of the present invention are more pronounced and the irritation to the skin at the time of application is reduced. Liquids, suspensions, emulsions, creams, gels and lotions are more preferred.
In the case of an emulsified dosage form such as an emulsion, a cream, or an emulsion ointment, either an oil-in-water type or a water-in-oil type may be used, but it has a good usability and good dispersibility of adaparene. The oil-in-water type is preferable.

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.

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

Method for improving dispersibility of adapalene and / or its salt In the present invention, (A) an external composition containing adapalene and / or a salt thereof, (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acid and a salt thereof, It includes a method for improving the dispersibility of adapalene and / or a salt thereof, which comprises at least one component selected from the group consisting of lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof. The type and content of each component, the properties of the composition, etc. are as described for the external composition of the present invention.

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 (Evaluation of dispersibility)
The preparations which are the external compositions having the compositions shown in Tables 1, 2 and 3 were prepared by a conventional method. The dosage form of each preparation in Table 1 is an emulsion, and the dosage form of each preparation in Tables 2 and 3 is a lotion.
The dispersibility of adapalene was evaluated using these preparations. Specifically, after stirring each preparation to make it uniform, 50 μL is dropped on a slide glass, and the particles are observed and photographed using a microscope (product name VHX-5000; KEYENCE), and the particles are subjected to automatic image processing. Only the particle portion was extracted, and the average area (average particle area) of the particles was measured.
When adapalene aggregates, the observed particle area increases. Therefore, the more uniformly dispersed the adapalene in the composition, the smaller the average particle area.

Then, according to the following formula (1), the particle area reduction rate (%) as compared with the corresponding comparative example was calculated. The comparative example corresponding to Examples 1A to 1B is Comparative Example 1, the Comparative Example corresponding to Examples 2A to 2E is Comparative Example 2, and the Comparative Example corresponding to Example 3A is Comparative Example 3.

Particle area reduction rate (%)
= [(Average particle area of the corresponding Comparative Example-Average particle area of the Example) / Average particle area of the corresponding Comparative Example] × 100 ・ ・ ・ ・ ・ (1)

The results are shown in Tables 1 to 3.

As shown in Tables 1 to 3, N- (hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide, cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or By blending sodium hyaluronate, the particle area of adapalene in the composition was reduced. It can be seen that the blending of the component (B) improved the dispersibility of adapalene in the composition.

Test Example 2 (Dispersion Sustainability Evaluation)
The preparations which are the external compositions having the compositions shown in Tables 4 and 5 were prepared by a conventional method. The dosage form of each of the formulations shown in Tables 4 and 5 is a lotion.
These preparations were used to evaluate the persistence of dispersion of adapalene. Specifically, 100 mL of each preparation was dispensed into a 100 mL volume glass vial and allowed to stand for 2 days in the dark at room temperature.
Next, the formulation filled in the glass vial is sonicated for 5 minutes using an ultrasonic cleaner (model number: US-107, manufacturer: SND Co., Ltd.), and then shaken up and down 5 times to block light at room temperature. It was allowed to stand underneath for 10 minutes.
The center of the height between the liquid level in the glass vial and the bottom surface of the glass vial before and after stirring, that is, "sonication using an ultrasonic cleaner, shaking, and standing for 10 minutes under shading at room temperature". 200 μL of each preparation was sampled from each part, placed in a 96-well plate (FALCON, Tissue Culture Plate), and the absorbance at 600 nm was measured using a plate reader (Molecular Technologies, VERSA max). 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. The low degree of separation indicates that the dispersion of adapalene in the formulation is long-lasting.

The degree of separation was determined for each pharmaceutical product, and the dispersion sustainability improvement rate (%) compared with the corresponding comparative example was calculated according to the following formula (2). The comparative example corresponding to Examples 4A to 4C is Comparative Example 4, and the Comparative Example corresponding to Example 5A is Comparative Example 5.

Dispersion sustainability improvement rate (%)
= [(Separation degree of corresponding Comparative Example-Separation degree of each Example) / Separation degree of Corresponding Comparative Example] × 100 ・ ・ ・ ・ ・ (2)

The results are shown in Tables 4 and 5.

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

Test Example 3 (Evaluation of dispersibility after application of pharmaceutical product)
The preparations which are the external compositions having the compositions shown in Tables 6 and 7 were prepared by a conventional method. The dosage forms of the respective preparations in Tables 6 and 7 are lotions. Using these preparations, the dispersibility of adapalene after application was evaluated. Specifically, after stirring and homogenizing each pharmaceutical product, 50 μL was added dropwise to a slide glass, and the product was dried at room temperature under light shielding for about 18 hours. Then, 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 (average particle area) of the particles was measured.

Aggregation of adapalene during and after drying of the pharmaceutical product increases the observed particle area. This test evaluates the ease of agglutination of adapalene in the pharmaceutical product after application. When the observed particle area is small, it becomes easy to spread adapalene uniformly on the application site when the preparation is applied.

According to the above formula (1), the particle area reduction rate (%) as compared with the corresponding comparative example was calculated. As for the corresponding comparative examples, the comparative example corresponding to Examples 6A to 6E is Comparative Example 6, and the comparative example corresponding to Example 7A is Comparative Example 7.

The results are shown in Tables 6 and 7.

As shown in Tables 6 and 7, by adding lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate to the external composition containing adapalene, the particle area after application and drying of the composition Has decreased significantly. It can be seen that the combination of the component (B) makes it difficult for adapalene to aggregate after the external composition of the present invention is applied to the skin.

Test Example 4 (Evaluation of dispersibility)
The preparations which are the external compositions having the compositions shown in Tables 8 to 11 were prepared by a conventional method. The dosage form of each of the formulations shown in Tables 8 to 11 is an emulsion.
The dispersibility of adapalene was evaluated using these preparations. Specifically, after stirring each preparation to make it uniform, 50 μL is dropped on a slide glass, and the particles are observed and photographed using a microscope (product name VHX-5000; KEYENCE), and the particles are subjected to automatic image processing. Only the particle portion was extracted, and the average area (average particle area) of the particles was measured.

When adapalene aggregates, the observed particle area increases. Therefore, the more uniformly dispersed the adapalene in the composition, the smaller the average particle area.

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

The results are shown in Tables 8 to 11.

Each of the example preparations shown in Tables 8 to 11 is different from each of the example preparations shown in Tables 1 to 3 as N- (hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide, cholesterol, lactic acid, lactic acid. The concentrations of sodium, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate are different, and glycerin, 1,3-butylene glycol, polyethylene glycol, and / or propylene glycol are used as polyhydric alcohols. Also, N- (hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide, cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate is added to the external composition containing adaparene. As a result, the particle area of adaparene in the composition was reduced. It can be seen that the dispersibility of adaparene in the composition was improved by blending the component (B).

Formulation Example An external composition (formulation examples 1 to 98) was prepared according to the formulation described below.

Since the external composition of the present invention has good dispersibility of adapalene and / or a salt thereof, adapalene can be uniformly applied to the affected area, and aggregation of adapalene and / or a salt thereof is suppressed. The desired medicinal effect can be sufficiently obtained.

Claims (10)

Selected from the group consisting of (A) adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salt, lactic acid and its salt, ureas, and mucopolysaccharide and its salt. An external composition containing at least one component. The external composition according to claim 1, which contains 0.001 to 1% by weight of the component (A). The external composition according to claim 1 or 2, which contains 0.0001 to 20% by weight of the component (B). The external composition according to any one of claims 1 to 3, further containing (C) a polyhydric alcohol. The external composition according to claim 4, wherein the component (C) is at least one selected from the group consisting of dipropylene glycol, glycerin, 1,3-butylene glycol, and polyethylene glycol. The external composition according to any one of claims 1 to 5, further containing (D) an emulsifier. The sixth aspect of claim 6, wherein the emulsifier (D) is at least one selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters. External composition. The external composition according to any one of claims 1 to 7, further containing (E) a hydrocarbon base. The external composition according to any one of claims 1 to 8, wherein the dosage form of the composition is a liquid agent, a suspension agent, an emulsion, a cream agent, a gel agent, a lotion agent, a spray agent, or an aerosol agent. (A) An external composition containing adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acid and its salt, lactic acid and its salt, ureas, and mucopolysaccharide and its salt. A method for improving dispersibility of adapalene and / or a salt thereof in an external composition, which comprises at least one component selected from the group consisting of.