WO2019240290A1

WO2019240290A1 - Topical composition

Info

Publication number: WO2019240290A1
Application number: PCT/JP2019/023782
Authority: WO
Inventors: 安藤　達也; 翔太井上
Original assignee: ロート製薬株式会社
Priority date: 2018-06-16
Filing date: 2019-06-15
Publication date: 2019-12-19
Also published as: JP2024023937A; JPWO2019240290A1

Abstract

A topical composition containing: (A) adapalene and/or a salt thereof; and (B) at least one component selected from the group consisting of ceramides, cholesterols, amino acids, pyrrolidonecarboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof, the topical composition having excellent dispersibility of the adapalene and/or salt thereof. The topical composition can also contain (C) a polyhydric alcohol, (D) an emulsifier, and/or (E) a hydrocarbon base.

Description

Composition for external use

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

Adapalene is a derivative of naphthalene carboxylic acid and is used as an active ingredient in a therapeutic agent for external use of acne vulgaris. Acne vulgaris occurs as a comedone due to increased sebum secretion in the follicular sebaceous gland and obstruction of the hair follicle due to increased keratinization, and then develops into a skin rash with inflammation. Adapalene suppresses the formation of comedones by controlling the keratinization of the epidermis and improving clogging of pores.
As an external preparation containing adapalene as an active ingredient, deferrin gel 0.1% (trade name) (Galderma Co., Ltd.) is known. Deferin gel 0.1% contains propylene glycol, methyl paraoxybenzoate, carboxyvinyl polymer, polyoxyethylene (20) polyoxypropylene (20) glycol, sodium edetate hydrate, 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. In addition, when a component is aggregated in an 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.

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

The present inventor has conducted research to solve the above problems, and (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, and (A) adapalene and / or a salt-containing composition for external use, By adding at least one component selected from the group consisting of lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof, the dispersibility of adapalene and / or salts thereof in the composition is improved. I found it.

This invention is completed based on the said knowledge, and provides the dispersibility improvement method of the following external composition and adapalene and / or its salt.
Item 1. (A) selected from the group consisting of adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof. An external composition containing at least one component.
Item 2. Item 2. The composition for external use according to Item 1, comprising 0.001 to 1% by weight of component (A).
Item 3. Item 3. The composition for external use according to Item 1 or 2, which contains 0.0001 to 20% by weight of component (B).
Item 4. Item 4. The composition for external use according to any one of Items 1 to 3, further comprising (C) a polyhydric alcohol.
Item 5. Item 5. The 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 6. The composition for external use according to any one of Items 1 to 5, further comprising (D) an emulsifier.
Item 7. (D) The external use 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 ether, and polyoxyethylene sorbitan fatty acid esters. Composition.
Item 8. Item 8. The composition for external use according to any one of Items 1 to 7, further comprising (E) a hydrocarbon base.
Item 9. Item 9. The composition for external use according to any one of Items 1 to 8, wherein the dosage form of the composition is a liquid, suspension, emulsion, cream, gel, lotion, spray, or aerosol.
Item 10. (A) An external composition containing adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof 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:

In general, adapalene and / or a salt thereof has extremely poor dispersibility in an external composition, but the external composition of the present invention further includes ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, lactic acid and the like. By including a component selected from the group consisting of salts, ureas, mucopolysaccharides and salts thereof, adapalene and / or salts thereof have good dispersibility and dispersion maintenance. These components are moisturizing factors originally present in the skin and are blended in cosmetics and the like as moisturizing agents. It is surprising that such moisturizing ingredients improve the dispersibility of adapalene and / or its salts.

Since the composition for external use of the present invention has good dispersibility of adapalene and / or its salt, the amount of adapalene and / or its salt applied becomes uniform when the composition for external use is applied. Furthermore, during the production of the preparation, the adapalene and / or salt thereof is highly dispersible and uniform, so that the preparation can be easily produced. In addition, components having poor dispersibility in the composition for external use generally undergo agglomeration when the composition is applied and dried, but the composition of the present invention contains adapalene in a dried state after application. Aggregation of the salt / salt is also effectively suppressed.
The composition for external use of the present invention contains factors such as ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids, lactic acid and salts thereof, ureas, mucopolysaccharides and salts thereof, or related substances originally present in the skin. Thus, dispersibility of adapalene and / or a salt thereof is improved. Therefore, in order to improve dispersibility, it is not necessary to add a component that does not need to be contained for the skin.

Hereinafter, the present invention will be described in detail.
The composition of the present invention comprises (A) adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and An external composition comprising at least one component selected from the group consisting of salts.

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

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, based on the total amount of the composition. 1% by weight or more is even more preferable. Moreover, 1 weight% or less is preferable, 0.3 weight% or less is more preferable, and 0.15 weight% or less is still more preferable. 0.1% by weight is most preferred. Within this range, appropriate pharmacological activity of adapalene and / or a salt thereof can be obtained, and dispersibility of adapalene and / or a salt thereof is sufficient.
The content of adapalene and / or a salt thereof is 0.001 to 1% by weight, 0.001 to 0.3% by weight, 0.001 to 0.15% by weight, or 0.001% with respect to the total amount of the composition. 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. 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 include sphingosine, phytosphingosine, ceramide with fatty acid amide-bonded to sphingosine, glycosphingolipid with saccharide bound to ceramide (typically cerebroside), and sphingolin with ceramide bound to phosphate and base. Synthetic ceramides (N- (hexadecyloxyhydroxypropyl) -N-hydroxyethylhexadecanamide, hexadecyloxyPG hydroxetylhexadecanamide) having structures similar to lipids (typically sphingomyelin) and ceramide , Cetyl PG hydroxyethyl palmitamide, etc.), human-type ceramide obtained by fermentation with yeast, etc. (eg, ceramide 2, ceramide 3, fermented ceramide), animal-derived ceramide extracted from animal spinal cord or brain, rice, soybean Corn, small Plant-derived ceramides extracted from such, like any of ceramide 1-10.
Of these, synthetic ceramides are preferable in that the dispersibility improvement effect of adapalene is good, and N- (hexadecyloxyhydroxypropyl) -N-hydroxyethylhexadecanamide is more preferable.
Ceramides can be used singly or in combination of two or more.

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 more preferably 0.01% by weight, based on the total amount of the composition. The above is particularly preferable. Moreover, 5 weight% or less is preferable, 1 weight% or less is more preferable, 0.5 weight% or less is still more preferable, 0.25 weight% or less is especially preferable. Within this range, appropriate physiological activity of ceramides can be obtained, and 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, 0.0005 to 0.25% by weight with respect to 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 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.

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

Cholesterols Cholesterols include animal sterols such as cholesterol, cholestanol, lanosterol, ceregrosterol, dehydrocholesterol, cobrostanol; phytosterol, sitosterol, stigmasterol, campesterol, ergosterol, fucostosterol, spinner Plant sterols such as sterols; microorganism-derived sterols such as ergosterol, mycostolol, and timosterol; these cholesterols and fatty acids (for example, fatty acids having 10 to 18 carbon atoms such as lauric acid, Ester with myristic acid, palmitic acid, stearic acid, hydroxystearic acid, oleic acid, isostearic acid, etc.), the hydrogen atom of the hydroxyl group of these cholesterols, carbon number Alkyl ether derivatives substituted with an alkyl group of 1-10, alkyl esters substituted with an acyl group having 1 to 10 carbon atoms, such as cholesterol derivatives, such as glycosides substituted with sugar residues and the like.
Among them, animal sterols and derivatives thereof are preferable, cholesterol and derivatives thereof are more preferable, and cholesterol is even more preferable in that the dispersibility improvement effect of adapalene and / or a salt thereof is good.
Cholesterols can be used singly 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. Moreover, 5 weight% or less is preferable, 2 weight% or less is more preferable, 1 weight% or less is further more preferable, and 0.9 weight% or less is especially preferable. If it is this range, the suitable physiological activity or pharmacological activity of cholesterol will be obtained, and the dispersibility of adapalene and / or its salt will be enough.
The cholesterol content is 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. 0.05-5% by weight, 0.05-2% by weight, 0.05-1% by weight, 0.05-0.9% by weight, 0.1-5% by weight, 0.1-2% by weight, 0.1-1 wt%, 0.1-0.9 wt%, 0.2-5 wt%, 0.2-2 wt%, 0.2-1 wt%, 0.2-0.9 wt% %.

The ratio of the content of cholesterol to the content of adapalene and / or a salt thereof is preferably 0.1 parts by weight or more, more preferably 0.5 parts by weight or more with respect to 1 part by weight of adapalene and / or a salt thereof. 1 part by weight or more is even more preferable, and 2 parts by weight or more is particularly preferable. Further, it is preferably 50 parts by weight or less, more preferably 20 parts by weight or less, still more preferably 10 parts by weight or less, and particularly preferably 9 parts by weight or less. If it is this range, the suitable physiological activity or pharmacological activity of cholesterol will be obtained, and the dispersibility of adapalene and / or its salt will be enough.
The ratio of the content of cholesterol to the content of adapalene and / or a salt thereof is 0.1 to 50 parts by weight, 0.1 to 20 parts by weight, or 0 with respect to 1 part by weight of adapalene and / or a salt thereof. .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, 1-20 parts by weight, 1-10 parts by weight, 1-9 parts by weight, 2-50 parts by weight, 2-20 parts by weight, 2-10 parts by weight, and 2-9 parts by weight.

Amino acids As amino acids, 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; medium containing sulfur such as cysteine and methionine Neutral amino acids having an amide group such as asparagine and glutamine; neutral amino acids having an imino group such as proline; neutral amino acids having an aromatic ring such as phenylalanine, tyrosine and tryptophan Amino acids); acidic amino acids such as aspartic acid and glutamic acid; and basic amino acids such as arginine, lysine and histidine. Examples of amino acids not included in the protein include ornithine, citrulline, γ-aminobutyric acid, creatine, sarcosine, hydroxylysine, hydroxyproline, desmosine, O-phosphoserine, cystine and the like.
Among these, basic amino acids are preferable and arginine is more preferable in that the dispersibility improvement effect of adapalene and / or a salt thereof is good. Also preferred are glycine, alanine, proline, serine, lysine, glutamic acid, and threonine.
An amino acid can be used individually by 1 type or in combination of 2 or more types.

The content of the amino acid 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 more preferably 0.1% by weight or more based on the total amount of the composition. Is particularly preferred. Moreover, 5 weight% or less is preferable, 1 weight% or less is more preferable, 0.5 weight% or less is further more preferable, and 0.4 weight% or less is especially preferable. Moreover, it can also be 0.3 weight% or less or 0.2 weight% or less. If it is this range, the suitable physiological activity of an amino acid will be acquired, and the dispersibility of adapalene and / or its salt will be enough.
The amino acid content 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 wt%, 0.005 to 0.2 wt%, 0.01 to 5 wt%, 0.01 to 1 wt%, 0.01 to 0.5 wt%, 0.01 -0.4 wt%, 0.01-0.3 wt%, 0.01-0.2 wt%, 0.05-5 wt%, 0.05-1 wt%, 0.05-0.5 Wt%, 0.05 to 0.4 wt%, 0.05 to 0.3 wt%, 0.05 to 0.2 wt%, 0.1 to 5 wt%, 0.1 to 1 wt%, 0 0.1-0.5 wt%, 0.1-0.4 wt%, 0.1-0.3 wt%, 0.1-0.2 wt%.

The ratio of the content of amino acid to the content of adapalene and / or its salt is preferably 0.05 parts by weight or more, more preferably 0.1 parts by weight or more, with respect to 1 part by weight of adapalene 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, it is preferably 50 parts by weight or less, more preferably 10 parts by weight or less, still more preferably 5 parts by weight or less, and particularly preferably 4 parts by weight or less. Further, it can be 3 parts by weight or less, or 2 parts by weight or less. If it is this range, the suitable physiological activity of an amino acid will be acquired, and the dispersibility of adapalene and / or its salt will be enough.
The ratio of the content of the amino acid to the content of adapalene and / or a salt thereof is 0.05 to 50 parts by weight, 0.05 to 10 parts by weight, 0.1 part by weight with respect to 1 part by weight of adapalene and / or a salt thereof. 05-5 parts by weight, 0.05-4 parts by weight, 0.05-3 parts by weight, 0.05-2 parts by weight, 0.1-50 parts by weight, 0.1-10 parts by weight, 0.1-0.1 parts by weight 5 parts by weight, 0.1-4 parts by weight, 0.1-3 parts by weight, 0.1-2 parts by weight, 0.5-50 parts by weight, 0.5-10 parts by weight, 0.5-5 parts by weight Parts, 0.5-4 parts by weight, 0.5-3 parts by weight, 0.5-2 parts by weight, 1-50 parts by weight, 1-10 parts by weight, 1-5 parts by weight, 1-4 parts by weight, Examples are 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 a pharmaceutically or physiologically acceptable salt, and a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine) Salts, organic amine salts such as pyrrolidine salts, tripyridine salts and picoline salts), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts and potassium salts, alkaline earth salts such as calcium salts and magnesium salts) Metal salts such as metal salts, zinc salts and aluminum salts). Of these, salts with inorganic bases are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred.
When the composition of the present invention contains a salt of pyrrolidone carboxylic acid, it may be formulated as a salt of pyrrolidone carboxylic acid, and as a result of separately blending pyrrolidone carboxylic acid and an organic or inorganic base. It may be a salt.
Among these, pyrrolidone carboxylic acid is preferable in that the effect of improving dispersibility of adapalene and / or a salt thereof is good.
Pyrrolidone carboxylic acid and its salt can be used individually by 1 type or in combination of 2 or more types.

The content of pyrrolidonecarboxylic acid and / or a salt thereof is preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and still more preferably 0.01% by weight or more based on the total amount of the composition. 0.05 wt% or more is particularly preferable, and 0.1 wt% or more is most preferable. Moreover, 10 weight% or less is preferable, 5 weight% or less is more preferable, 2 weight% or less is further more preferable, 1 weight% or less is especially preferable, 0.9 weight% or less is more preferable. Within this range, appropriate physiological activity of pyrrolidone carboxylic acid and / or salt thereof can be obtained, and dispersibility of adapalene and / or salt thereof is sufficient.
The content of pyrrolidone carboxylic acid and / or salt thereof is 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 0.001% with respect to the total amount of the composition. 1 wt%, 0.001 to 0.9 wt%, 0.005 to 10 wt%, 0.005 to 5 wt%, 0.005 to 2 wt%, 0.005 to 1 wt%, 0.005 to 0.9 wt%, 0.01 to 10 wt%, 0.01 to 5 wt%, 0.01 to 2 wt%, 0.01 to 1 wt%, 0.01 to 0.9 wt%, 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 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 pyrrolidonecarboxylic acid and / or its salt to the content of adapalene and / or its salt is preferably 0.01 parts by weight or more with respect to 1 part by weight of adapalene and / or its salt, More preferred is more than 0.1 parts by weight, even more preferred is more than 0.5 parts by weight, and most preferred is more than 1 part by weight. Also, it is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, still more preferably 20 parts by weight or less, particularly preferably 10 parts by weight or less, and most preferably 9 parts by weight or less. Within this range, appropriate physiological activity of pyrrolidone carboxylic acid and / or salt thereof can be obtained, and dispersibility of adapalene and / or salt thereof is sufficient.
The ratio of the content of pyrrolidone carboxylic acid and / or salt thereof to the content of adapalene and / or salt thereof is 0.01 to 100 parts by weight, 0.01 parts by weight with respect to 1 part by weight of adapalene and / or salt thereof. -50 parts by weight, 0.01-20 parts by weight, 0.01-10 parts by weight, 0.01-9 parts by weight, 0.05-100 parts by weight, 0.05-50 parts by weight, 0.05-20 Parts by weight, 0.05-10 parts by weight, 0.05-9 parts by weight, 0.1-100 parts by weight, 0.1-50 parts by weight, 0.1-20 parts by weight, 0.1-10 parts by weight 0.1-9 parts by weight, 0.5-100 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 -100 parts by weight, 1-50 parts by weight, 1-20 parts by weight, 1-10 parts by weight, 1-9 parts by weight.

Lactic acid and its salt The salt of lactic acid may be a pharmaceutically or physiologically acceptable salt, and a salt with an organic base (methylamine salt, triethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt) , Organic amine salts such as tripyridine salts and picoline salts), salts with inorganic bases (ammonium salts; alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, Zinc salts, metal salts such as aluminum salts, etc.). Of these, salts with inorganic bases are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred.
When the composition of the present invention contains a salt of lactic acid, it may be formulated as a salt of lactic acid, and as a result of separately blending lactic acid and an organic or inorganic base, it became a salt in the composition. It may be a thing.
Among these, lactic acid and sodium lactate are preferable in that the dispersibility improvement effect of adapalene and / or a salt thereof is good.
Lactic acid and its salt can be used individually by 1 type or in combination of 2 or more types.

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, based on the total amount of the composition. 1% by weight or more is particularly preferable. Moreover, 10 weight% or less is preferable, 5 weight% or less is more preferable, 3 weight% or less is further more preferable, and 1 weight% or less is especially preferable. Within this range, appropriate physiological activity or pharmacological activity of lactic acid and / or a salt thereof can be obtained, and dispersibility of adapalene and / or a salt thereof is sufficient.
The content of lactic acid and / or a salt thereof is 0.005 to 10% by weight, 0.005 to 5% by weight, 0.005 to 3% by weight, 0.005 to 1% by weight with respect to 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 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 salt thereof to the content of adapalene and / or salt thereof is preferably 0.05 parts by weight or more, and 0.1 part by weight with respect to 1 part by weight of adapalene and / or salt thereof. 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, it is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, still more preferably 30 parts by weight or less, and particularly preferably 10 parts by weight or less. Within this range, appropriate physiological activity or pharmacological activity of lactic 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 lactic acid and / or salt thereof to the content of adapalene and / or salt thereof is 0.05 to 100 parts by weight, 0.05 to 50 parts per 1 part by weight of adapalene and / or salt thereof. Parts by weight, 0.05-30 parts by weight, 0.05-10 parts by weight, 0.1-100 parts by weight, 0.1-50 parts by weight, 0.1-30 parts by weight, 0.1-10 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 1 to 10 parts by weight.

Examples of urea ureas include alkylureas having 1 to 4 carbon atoms such as methylurea and ethylurea, as well as urea; hydroxyethylurea, dihydroxyethylurea, bis (hydroxyethyl) urea, hydroxypropylurea And hydroxyalkylurea having a hydroxyalkyl group having 1 to 10 carbon atoms such as dihydroxypropylurea, bis (hydroxypropyl) urea, hydroxybutylurea, dihydroxybutylurea, and bis (hydroxybutyl) urea.
Of these, urea is preferred because it has a good dispersibility improvement effect for adapalene and / or its salts.
Ureas can be used singly or in combination of two or more.

The urea content 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. Moreover, 10 weight% or less is preferable, 5 weight% or less is more preferable, 2 weight% or less is further more preferable, 1 weight% or less is especially preferable, and 0.9 weight% or less is the most preferable. If it is this range, the appropriate physiological activity or pharmacological activity of urea will be acquired, and the dispersibility of adapalene and / or its salt will be enough.
The urea content is 0.001 to 10% by weight, 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 1% by weight, and 0.001% by weight based on the total amount of the composition. 001 to 0.9 wt%, 0.005 to 10 wt%, 0.005 to 5 wt%, 0.005 to 2 wt%, 0.005 to 1 wt%, 0.005 to 0.9 wt%, 0.01 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, 0.05-5 wt%, 0.05-2 wt%, 0.05-1 wt%, 0.05-0.9 wt%, 0.1-10 wt%, 0.1-5 wt%, 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 urea to the content of adapalene and / or a salt thereof is preferably 0.01 parts by weight or more, more preferably 0.05 parts by weight or more with respect to 1 part by weight of adapalene and / or a salt thereof. 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. Also, it is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, still more preferably 20 parts by weight or less, particularly preferably 10 parts by weight or less, and most preferably 9 parts by weight or less. If it is this range, the appropriate physiological activity or pharmacological activity of urea will be acquired, and the dispersibility of adapalene and / or its salt will be enough.
The ratio of the urea content to the content of adapalene and / or its salt is 0.01 to 100 parts by weight, 0.01 to 50 parts by weight, 0 parts by weight with respect to 1 part by weight of adapalene and / or its salt. .01-20 parts by weight, 0.01-10 parts by weight, 0.01-9 parts by weight, 0.05-100 parts by weight, 0.05-50 parts by weight, 0.05-20 parts by weight, 0.05 -10 parts by weight, 0.05-9 parts by weight, 0.1-100 parts by weight, 0.1-50 parts by weight, 0.1-20 parts by weight, 0.1-10 parts by weight, 0.1-9 Parts by weight, 0.5-100 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, 1-100 parts by weight, 1 -50 parts by weight, 1-20 parts by weight, 1-10 parts by weight, 1-9 parts by weight.

Mucopolysaccharides and salts thereof Mucopolysaccharides are polysaccharides composed of amino sugars such as galactosamine or glucosamine and uronic acids or galactoses such as glucuronic acid and iduronic acid.
Examples of mucopolysaccharides include hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin.
The salt of mucopolysaccharide may be a pharmaceutically or physiologically acceptable salt, such as 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 picoline salt), salt with inorganic base (ammonium salt; alkali metal salt such as sodium salt and potassium salt, alkaline earth metal salt such as calcium salt and magnesium salt, zinc salt And metal salts such as aluminum salts). Of these, salts with inorganic bases are preferred, alkali metal salts are more preferred, and sodium salts are even more preferred.
When the composition of the present invention contains a salt of mucopolysaccharide, it may be formulated as a salt of mucopolysaccharide. As a result of separately blending mucopolysaccharide and an organic or inorganic base, the composition It may be a salt.
Of these, hyaluronic acid or a salt thereof (particularly a sodium salt) is preferable in that it has a good dispersibility improvement effect for adapalene and / or a salt thereof. Hyaluronic acid can be a natural product extracted from, for example, a chicken crown, 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. You can also.
Mucopolysaccharides and salts thereof can be used singly 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, based on the total amount of the composition. 0.05% by weight or more is particularly preferable. Moreover, 5 weight% or less is preferable, 2 weight% or less is more preferable, 1 weight% or less is further more preferable, and 0.9 weight% or less is especially preferable. Moreover, 0.5 weight% or less, 0.2 weight% or less, 0.15 weight% or less, or 0.1 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 content of the mucopolysaccharide and its salt is 0.001 to 5% by weight, 0.001 to 2% by weight, 0.001 to 1% by weight, 0.001 to 0. 0% with respect to the total amount of the composition. 9 wt%, 0.001 to 0.5 wt%, 0.001 to 0.2 wt%, 0.001 to 0.15 wt%, 0.001 to 0.1 wt%, 0.005 to 5 wt% %, 0.005 to 2% by weight, 0.005 to 1% by weight, 0.005 to 0.9% by weight, 0.005 to 0.5% by weight, 0.005 to 0.2% by weight, 0. 005 to 0.15 wt%, 0.005 to 0.1 wt%, 0.01 to 5 wt%, 0.01 to 2 wt%, 0.01 to 1 wt%, 0.01 to 0.9 wt% %, 0.01 to 0.5% by weight, 0.01 to 0.2% by weight, 0.01 to 0.15% by weight, 0.01 to 0.1% by weight, 0.05 to 5% by weight, 0.05 2%, 0.05-1%, 0.05-0.9%, 0.05-0.5%, 0.05-0.2%, 0.05-0.15% %, 0.05 to 0.1% by weight.

The ratio of the content of mucopolysaccharide and its salt to the content of adapalene and / or its salt is preferably 0.01 parts by weight or more, and 0.05 parts by weight with respect to 1 part by weight of adapalene 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, it is preferably 50 parts by weight or less, more preferably 20 parts by weight or less, still more preferably 10 parts by weight or less, and particularly preferably 9 parts by weight or less. Also preferably 5 parts by weight or less, 2 parts by weight or less, or 1.5 parts by weight or less. 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 adapalene and / or its salt is 0.01 to 50 parts by weight, 0.01 to 20 with respect to 1 part by weight of adapalene and / or its salt. Parts by weight, 0.01-10 parts by weight, 0.01-9 parts by weight, 0.01-5 parts by weight, 0.01-2 parts by weight, 0.01-1.5 parts by weight, 0.01-1 Parts by weight, 0.05-50 parts by weight, 0.05-20 parts by weight, 0.05-10 parts by weight, 0.05-9 parts by weight, 0.05-5 parts by weight, 0.05-2 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 Examples include 5 to 10 parts by weight, 0.5 to 9 parts by weight, 0.5 to 5 parts by weight, 0.5 to 2 parts by weight, 0.5 to 1.5 parts by weight, and 0.5 to 1 part by weight. .

Component (B) Content The component (B) content 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 preferred, and 0.01% by weight or more is most preferred. Moreover, 20 weight% or less is preferable, 10 weight% or less is more preferable, 5 weight% or less is further more preferable, 1 weight% or less is especially preferable, and 0.9 weight% or less is the most preferable. If it is this range, the appropriate physiological activity or pharmacological activity of (B) component will be acquired, and the dispersibility of adapalene and / or its salt 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 wt%, 0.0005 to 20 wt%, 0.0005 to 10 wt%, 0.0005 to 5 wt%, 0.0005 to 1 wt%, 0.0005 to 0.9 wt% %, 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 adapalene and / or its salt is preferably 0.001 part by weight or more, and 0.005 part by weight or more with respect to 1 part by weight of adapalene and / or its salt. More preferred is 0.01 part by weight or more, still more preferred is 0.05 part by weight or more, and most preferred is 0.1 part by weight or more. Also, it is preferably 200 parts by weight or less, more preferably 100 parts by weight or less, still more preferably 50 parts by weight or less, particularly preferably 10 parts by weight or less, and most preferably 9 parts by weight or less. If it is this range, the appropriate physiological activity or pharmacological activity of (B) component will be acquired, and the dispersibility of adapalene and / or its salt will be enough.
The ratio of the content of component (B) to the content of adapalene and / or salt thereof is 0.001 to 200 parts by weight, 0.001 to 100 parts by weight with respect to 1 part by weight of adapalene 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 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, 0.05-200 parts by weight, 0.05-100 parts by weight, 0.05-50 parts by weight, 0.05-10 parts by weight, 0.05-9 parts by weight, 0.1-200 parts by weight Parts by weight, 0.1 to 100 parts by weight, 0.1 to 50 parts by weight, 0.1 to 10 parts by weight Parts, and 0.1 to 9 parts by weight.

Polyhydric alcohol The composition for external use of this invention can contain (C) polyhydric alcohol, and, thereby, the dispersibility of adapalene and / or its salt further improves.
Examples of the polyhydric alcohol include ethylene glycol, propylene glycol, 1,3-propanediol (trimethylene glycol), butylene glycol (1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol), 1 , 4-butanediol (tetramethylene glycol), 3-methyl-1,3-butanediol, 2-butene-1,4-diol, 1,5-pentanediol (pentamethylene glycol), 1,2-pentanediol , Isoprene glycol (isopentyldiol), hexylene glycol, dipropylene glycol, polyethylene glycol (polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene Dihydric alcohols such as lenglycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, polyethylene glycol 35000), polypropylene glycol (polypropylene glycol 700, polypropylene glycol 1000, polypropylene glycol 2000, etc.); glycerin, Trivalent alcohol such as trimethylolpropane; diglycerin, polyglycerin and the like.
Among 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.
A polyhydric alcohol can be used individually by 1 type or in combination of 2 or more types.

Preferred combinations of polyhydric alcohols include a combination of dipropylene glycol and 1,3-butylene glycol, a combination of dipropylene glycol and polyethylene glycol, a combination of dipropylene glycol and glycerin, and 1,3-butylene glycol and polyethylene. Combination of glycol, combination of 1,3-butylene glycol and glycerin, combination of polyethylene glycol and glycerin; combination of dipropylene glycol, 1,3-butylene glycol and polyethylene glycol, dipropylene glycol and 1,3- Combinations of butylene glycol and glycerin, combinations of dipropylene glycol, polyethylene glycol and glycerin, 1,3-butylene glycol and polyethylene The combination of ethylene glycol and glycerol; a combination of dipropylene glycol and 1,3-butylene glycol and polyethylene glycol and glycerin.

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 more preferably 1% by weight or more based on the total amount of the composition. Is particularly preferred. Moreover, 90 weight% or less is preferable, 60 weight% or less is more preferable, 30 weight% or less is still more preferable, 15 weight% or less is especially preferable. If it is this range, the dispersibility of adapalene and / or its salt can fully improve, and it can be set as the composition for external use which makes it hard to dry skin further.
The polyhydric alcohol content 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. .01-90 wt%, 0.01-60 wt%, 0.01-30 wt%, 0.01-15 wt%, 0.1-90 wt%, 0.1-60 wt%, 0.1 -30 wt%, 0.1-15 wt%, 1-90 wt%, 1-60 wt%, 1-30 wt%, 1-15 wt%.

The ratio of the content of polyhydric alcohol to the content of adapalene and / or a salt thereof is preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more with respect to 1 part by weight of adapalene and / or a salt thereof. Preferably, 1 part by weight or more is even more preferable, and 10 parts by weight or more is particularly preferable. Also, 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. If it is this range, the dispersibility of adapalene and / or its salt can fully improve, and it can be set as the composition for external use which makes it hard to dry skin further.
The ratio of the content of the polyhydric alcohol to the content of adapalene and / or a salt thereof is 0.01 to 900 parts by weight, 0.01 to 600 parts by weight with respect to 1 part by weight of adapalene and / or a salt thereof, 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 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 composition for external use of the present invention can contain (D) an emulsifier, whereby dispersibility of adapalene and / or a salt thereof is further improved.
Examples of emulsifiers include sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate Sorbitan fatty acid esters such as propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 ( Hydrogenated castor oil derivatives such as HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 (HCO-80)); Castor oil derivatives such as siethylene castor oil; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene monooleate (20) Polyoxyethylene sorbitan fatty acid esters such as sorbitan (polysorbate 80) and polyoxyethylene (20) sorbitan isostearate; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyethylene lauryl ether, poly Polyoxyalkylene alkyl ethers such as oxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether; Amines, and amines such as oleylamine; silicone surfactants such as polyoxyethylene methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone; lecithin Natural surfactants such as phospholipids, surfactins, and saponins; fatty acid amidoamines such as diethylaminoethylamide stearate and diethylaminopropylamide stearate; trilaurylamine, dimethylstearylamine, and di-2-ethylhexyl Alkylamines such as amines; betaine amphoteric surfactants such as dimethylaminopropylamide stearate and laurylhydroxysulfobetaine; polyoxyethylene polyoxypro Examples include pyrene glycol (such as poloxamer 124); polyglycerin fatty acid esters; glycerin fatty acid esters; polyethylene glycol fatty acid esters.
Among them, sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ether, polyoxyethylene sorbitan fatty acid esters, and polyglycerin fatty acid esters are preferable, sorbitan stearate (sorbitan monostearate), sorbitan oleate ( Sorbitan monooleate), polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene lauryl ether , Polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether, polyoxyethylene monolaurate (20) sorbitan (polysorbate 20) , Monostearate polyoxyethylene (20) sorbitan (Polysorbate 60), monooleate polyoxyethylene (20) sorbitan (Polysorbate 80) is more preferable.
An emulsifier can be used individually by 1 type or in combination of 2 or more types.

The content of the emulsifier is preferably 0.05% by weight or more, more preferably 0.1% by weight or more, still more preferably 0.5% by weight or more, and particularly preferably 1% by weight or more with respect to the total amount of the composition. preferable. Moreover, 10 weight% or less is preferable, 8 weight% or less is more preferable, 6 weight% or less is further more preferable, and 4 weight% or less is especially preferable. If it is this range, the dispersibility of adapalene and / or its salt will fully improve.
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, 0.1% with respect to the total amount of the composition. -10 wt%, 0.1-8 wt%, 0.1-6 wt%, 0.1-4 wt%, 0.5-10 wt%, 0.5-8 wt%, 0.5-6 Weight percent, 0.5 to 4 weight percent, 1 to 10 weight percent, 1 to 8 weight percent, 1 to 6 weight percent, and 1 to 4 weight percent.

The ratio of the content of the emulsifier to the content of adapalene and / or a salt thereof is preferably 0.5 parts by weight or more, more preferably 1 part by weight or more, and even more preferably 5 parts by weight or more with respect to 1 part by weight of adapalene. The amount is preferably 10 parts by weight or more. Further, it is preferably 100 parts by weight or less, more preferably 80 parts by weight or less, still more preferably 60 parts by weight or less, and particularly preferably 40 parts by weight or less. If it is this range, the dispersibility of adapalene and / or its salt will fully improve.
The ratio of the content of the emulsifier to the content of adapalene and / or a salt thereof is 0.5 to 100 parts by weight, 0.5 to 80 parts by weight, 0.5 to 60 parts by weight with respect to 1 part by weight of adapalene. 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 Examples thereof include 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 composition for external use of the present invention can contain (E) a hydrocarbon base, whereby dispersibility of adapalene and / or a salt thereof is further improved.
Hydrocarbon bases include petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (plasty base, etc.), ozokerite, ceresin, microcrystalline wax, squalene, squalane, α-olefin oligomers, paraffin, liquid paraffin, and light fluid Examples include paraffin.
Of these, hydrocarbon bases that are solid at room temperature (25 ° C.) such as petrolatum (white petrolatum, yellow petrolatum), gelled hydrocarbons (plastibase, etc.), ozokerite, ceresin, and microcrystalline wax are preferred. Vaseline, ozokerite, ceresin Microcrystalline wax is more preferable, and petrolatum is even more preferable. Hydrocarbon bases that are liquid at room temperature (25 ° C.) such as squalene, squalane, α-olefin oligomer, paraffin, liquid paraffin, and light liquid paraffin are also preferred.
A hydrocarbon base can be used individually by 1 type or in combination of 2 or more types.

The content of the hydrocarbon base is preferably 0.000001% by weight or more, more preferably 0.00001% by weight or more, still more preferably 0.0001% by weight or more, based on the total amount of the composition, 0.001 A weight percent or more is particularly preferred. Moreover, it can also be 0.01 weight% or more, 0.1 weight% or more, or 1 weight% or more. Moreover, 50 weight% or less is preferable, 30 weight% or less is more preferable, 20 weight% or less is further more preferable, and 10 weight% or less is especially preferable. Moreover, 1 weight% or less, 0.1 weight% or less, or 0.01 weight% or less is also preferable. If it is this range, the dispersibility of adapalene and / or its salt can fully improve, and it can be set as the composition for external use which makes it hard to dry skin further.
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 wt%, 0.000001 to 0.1 wt%, 0.000001 to 0.01 wt%, 0.00001 to 50 wt%, 0.00001 to 30 wt%, 0.00001 to 20 wt% %, 0.00001-10 wt%, 0.00001-1 wt%, 0.00001-0.1 wt%, 0.00001-0.01 wt%, 0.0001-50 wt%, 0.0001- 30 wt%, 0.0001-20 wt%, 0.0001-10 wt%, 0.0001-1 wt%, 0.0001-0.1 wt%, 0.0001-0.01 wt%, 001-5 Wt%, 0.001-30 wt%, 0.001-20 wt%, 0.001-10 wt%, 0.001-1 wt%, 0.001-0.1 wt%, 0.001-0 0.01% by weight, 0.01-50% by weight, 0.01-30% by weight, 0.01-20% by weight, 0.01-10% by weight, 0.01-1% by weight, 0.01-0 0.1% by weight, 0.1-50% by weight, 0.1-30% by weight, 0.1-20% by weight, 0.1-10% by weight, 0.1-1% by weight, 1-50% 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 adapalene and / or its salt is preferably 0.00001 part by weight or more, and 0.0001 part by weight or more with respect to 1 part by weight of adapalene 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. Moreover, it can also be 0.1 weight part or more, 1 weight part or more, or 10 weight part or more. Moreover, 500 weight part or less is preferable, 300 weight part or less is more preferable, 200 weight part or less is still more preferable, 100 weight part or less is especially preferable. Also, 10 parts by weight or less, 1 part by weight or less, or 0.1 part by weight or less is preferable. If it is this range, the dispersibility of adapalene and / or its salt can fully improve, and it can be set as the composition for external use which makes it hard to dry skin further.
The ratio of the content of the hydrocarbon base to the content of adapalene and / or a salt thereof is 0.00001 to 500 parts by weight, 0.00001 to 300 parts by weight with respect to 1 part by weight of adapalene and / or a salt thereof. 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 .01-1 part by weight, 0.01-0.1 part by weight, 0.1-500 part by weight, 0.1-300 part by weight, 0.1-200 part by weight, 0.1-100 part 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 Examples thereof include 10 to 300 parts by weight, 10 to 200 parts by weight, and 10 to 100 parts by weight.

Other components The composition for external use of the present invention uses the component (A), the component (B), and the above-described components blended as necessary for pharmaceuticals, quasi drugs, or cosmetics. The composition can be mixed with a base or carrier, an additive, other physiologically active or pharmacologically active ingredients, and the like, and used as an external composition for pharmaceuticals, quasi drugs, or cosmetics. In particular, it may be a pharmaceutical composition (composition for pharmaceutical use).

Additives include, for example, antioxidants, thickeners, preservatives or preservatives, pH adjusters, stabilizers, chelating agents, UV absorbers or UV scattering agents, irritation reducers, colorants, and cooling agents. And fragrances.
An additive can be used individually by 1 type or in combination of 2 or more types.
Moreover, an additive can be used in the range which does not impair the effect of this invention.

Antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, p-hydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivatives (ascorbic acid stearate, ascorbyl palmitate, ascorbyl dipalmitate, ascorbine, ascorbine Acid monophosphates, ascorbic acid diphosphates, ascorbic acid triphosphates, ascorbic acid sulfates, etc.), tocopherols, tocopherol derivatives (tocopherol acetate, tocopherol succinate, tocopherol calcium succinate, etc.), erythorbic acid, L-cysteine hydrochloride , Lycopene, glutathione, propyl gallate, tannic acid, epigallocatechin, anthocyanin, hydroxytylo Lumpur, nor hydro guar Serre Ten acid, caffeic acid, enzymes (catalase, superoxide dismutase, glutathione peroxidase, elastase, etc.) and the like.

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

Examples of 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 include benzyl, methyl paraoxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and its salts, chlorhexidine gluconate, alkanediol, and glycerin fatty acid ester.

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

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

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

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

Examples of the UV absorber or UV scattering agent include 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, 2,4,6-tris [4- (2 -Ethylhexyloxycarbonyl) anilino] -1,3,5-triazine, t-butylmethoxydibenzoylmethane, dibenzylidenedioxoimidazolidinepropionate ethylhexyl, etorhexyltriazoline, paraaminobenzoic acid and its derivatives, paradimethylamino Examples include octyl benzoate, ethylene glycol salicylate, dihydroxybenzophenone, titanium oxide, and zinc oxide.

Examples of the coloring agent 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, cineol, anethole, limonene, 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, spearmint oil, fennel oil, mint oil, cinnamon oil, rose oil, and turpentine oil.
As perfumes, herbal essential oils such as lavender oil, rosemary oil, clary sage oil, thyme oil, bergamot oil, eucalyptus oil, various essential oils such as citrus essential oils such as orange oil, lemon oil, grapefruit oil, blended perfumes, etc. Is mentioned.

Examples of other physiologically active or pharmacologically active components (physiologically active or pharmacologically active components other than the components (A) and (B)) include, for example, anti-inflammatory agents, bactericides or antibacterial agents, and keratin softeners or keratins other than urea. Melting agent, antipruritic agent, (B) component and moisturizing component other than polyhydric alcohol, local anesthetic, vitamins, peptide or derivative thereof, blood circulation promoting component, cell activation 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 can be used singly or in combination of two or more.
Further, 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 allantoin, glycyrrhizic acid, methyl glycyrrhizinate, stearyl glycyrrhizinate, glycyrrhetinic acid, stearyl glycyrrhetinate, acetaminophen, epsilon-aminocaproic acid, berberine, azulene, bromelain, zinc; licorice extract, sage extract, Plant extracts such as rosemary extract; Enzymatic anti-inflammatory agents such as lysozyme, serrapeptase, semi-alkaline proteinase; Phenamic acid-based anti-inflammatory agents such as mefenamic acid, flufenamic acid, and tolfenamic acid; Arylacetic anti-inflammatory agents such as edtrac, diclofenac, sulindac, nabutome, fenbufen, progouritacin, mofezolac; aminobrofen, eve Propionic acid anti-inflammatory agents such as lofen, oxaprozin, ketoprofen, zaltoprofen, thiaprofenic acid, naproxen, flurbiprofen, zaltoprofen, ibuprofenpiconol, flurbiprofen axetil, fenoprofen, pranoprofen, loxoprofen; Examples thereof include oxicam anti-inflammatory agents such as ampiroxicam, tenoxicam, piroxicam, meloxicam, and lornoxicam. These are non-steroidal anti-inflammatory agents.
Also, prednisolone, hydrocortisone, cortisone, betamethasone, dexamethasone, triamcinolone, triamcinolone acetonide, diflupredonade, mometasone, diflucortron, fluoniside, fluocinonide, clobetasol, beclomethasone, deprodon, alclomethasone, flumezonone, ambetaine Steroidal anti-inflammatory agents such as derivatives thereof (especially esters) can also be used.
Examples of the steroid derivatives include prednisolone valerate acetate (PVA), prednisolone succinate, prednisolone acetate, prednisolone phosphate, etc., prednisolone esters, betamethasone propionate, betamethasone valerate, dexamethasone valerate, Dexamethasone propionate, dexamethasone acetate, dexamethasone phosphate, dexamethasone metasulfobenzoate, dexamethasone cipesylate, dexamethasone ester such as dexamethasone palmitate, hydrocortisone butyrate (particularly hydrocortisone-17-butyrate), Hydrocortisone acetate, hydrocortisone succinate, Hydrocortisone esters such as drocortisone butyrate, hydrocortisone butyrate propionate, hydrocortisone phosphate, mometasone furan carboxylate, diflucortron valerate, clobetasol propionate, beclomethasone propionate, beclomethasone dipropionate Clobetasone butyrate, deprodon propionate, alcromethasone propionate, flumethasone pivalate, clobetasone propionate, clobetasone butyrate, diflorazone acetate and the like.

Antibacterial or antibacterial agents include aminoglycoside antibiotics such as clindamycin, nadifloxacin, besifloxacin, clinadifloxacin, flurifloxacin, quinolone antibiotics such as ozenoxacin, benzoyl peroxide, isopropylmethylphenol, 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 Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinosulfate Emissions, phenethyl alcohol, benzyl alcohol, salicylic acid, cresol, triclosan, and the like biguanide compound. Some bactericides or antibacterials are included as preservatives or preservatives.

In addition, the composition for external use of this invention shall not contain a benzoyl peroxide.
In addition, the composition for external use of the present invention has a P.P. 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 them 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 and may not include formulations containing adapalene and anti-inflammatory agents, among which drug resistant acne and therapeutic doses of clindamycin, minocycline P., non-responsive / resistant to tetracycline or erythromycin. Formulations for use in the treatment or prevention of acne including acne and may not include formulations comprising antibacterial agents, adapalene and anti-inflammatory agents.
The present invention may also not include dual action rational therapy molecules (except adapalene) having two distinct mechanisms of action for the treatment or prevention of bacterial infections, among others bacterial infections It may not include a drug carrier or formulation comprising a dual-acting rational therapeutic molecule with two distinct mechanisms of action for the treatment or prevention of illness, adapalene and an anti-inflammatory agent.
Especially for the treatment of bacterial infections caused by both susceptible and resistant gram-positive and gram-negative bacteria, especially cures acne and different skin and skin structure infections and additionally resists Bacterial infections caused by both sensitive and resistant gram-positive and gram-negative bacteria, which may not include dual action rational therapy molecules (except adapalene) to prevent the occurrence of For the treatment of acne, in particular with dual action rational therapy molecules and adapalene and anti-inflammatory agents to cure acne and different skin and skin structure infections and additionally prevent the development of resistance It may not include the included drug carrier or formulation.
In addition, the present invention may be free of quinolone antibiotics, especially 8-chlorofluoroquinolone, especially besifloxacin or besifloxacin hydrochloride. By not containing quinolone antibiotics, especially 8-chlorofluoroquinolone, the composition does not cause photosensitivity due to quinolone antibiotics, and the composition is not denatured due to photodegradation of quinolone antibiotics. . Further, the effect of the present invention is more remarkably achieved by not containing quinolone antibiotics, especially 8-chlorofluoroquinolone, especially besifloxacin or besifloxacin hydrochloride.

As keratin softener or keratomelting agent other than urea, 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, hexyl decanol, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, triethanolamine, diisopropyl adipate, ethyl laurate, lanolin, fatty acid dialkyrolamide, sulfur, resorcin, sodium hydroxide, potassium hydroxide Etc.

Antipruritic agents include diphenhydramine, bromodiphenhydramine, clemastine, chlorphenoxamine, diphenylpyraline, doxylamine, orphenadrine, ethanolamine antihistamines such as phenyltoloxamine, propylamine antihistamines such as chlorpheniramine, dimethindene, and tarastine. , Ethylenediamine antihistamines such as mepyramine, metapyrylene, tripelenamine, alimemazine, hydroxyethylpromethazine, isothipentyl, mequitazine, phenothiazine antihistamines such as oxomemazine, promethazine, buclidine, cetirizine, homochlorcyclidine, cyclidine, hydroxyzine, levocetirizine Piperazine antihistamines such as oxatomide Ketotifen, olopatadine, fexofenadine, loratadine, terfenadine, antazoline, azatadine, bamipine, cyproheptadine, deptropine, ebastine, emedastine, epinastine, mebhydroline, mizolastine, pimethixene, pyrobutamine, quifenadine, lupatiazine, luphezine And antihistamines such as desloratadine and salts thereof.
In addition, components that are not antihistamines such as crotamiton, ectamol, moctar, and thymol are also included.

As the moisturizing component other than the component (B) and the polyhydric alcohol, sugars such as trehalose, xylitol and sorbitol, polymer compounds such as keratin, chitin and chitosan, lipids such as phospholipid, chamomile extract, hamamelis extract, Examples include plant extracts such as tea extract and aloe extract.

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

Vitamins include dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate and the like, ubiquinone derivatives and their pharmacologically or physiologically Acceptable salts, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin sodium 5'-phosphate, riboflavin tetranicotinate, nicotinic acid dl-α-tocopherol, nicotinic acid Benzyl, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, ascorbigen-A, ascorbyl stearate, palmitate ascorbate Esters, L-ascorbyl dipalmitate, methyl hesperidin, ergocalciferol, cholecalciferol, phylloquinone, farnoquinone, γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiaminecetyl hydrochloride, thiamine thiocyanate Salt, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine Triphosphate, thiamine triphosphate monophosphate, pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride, Anokobalamin, hydroxocobalamin, deoxyadenosylcobalamin, folic acid, pteroylglutamic acid, nicotinic acid, nicotinic acid amide, pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthecin, D-panthetin, coenzyme A, pantothenic acids such as pantothenyl ethyl ether, biotin, bioticin, ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, carnitine, ferulic acid, α-lipoic acid, Examples include orotic acid, hesperidin, γ-oryzanol, orotic acid, rutin, and eriocitrin.

Examples of peptides or derivatives thereof include keratin-degrading peptides, hydrolyzed keratins, collagen, gelatin, elastin, elastin-degrading peptides, collagen-degrading peptides, 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, Enmezo, Dutch oak, Carrot, Gentian, Burdock, Rice, Hawthorn, Shiitake, Hawthorn, Prunus, Cicada, Assembly, Thyme, Thymus, Chimpi, Toki, Tonin, Spruce, Carrot, Ingredients derived from garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, peach, apricot, walnut, corn, etc. (extracts of these plants), glucosyl hesperidin, etc. Can be mentioned.

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

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

Convergence components include zinc paraphenol sulfonate, zinc oxide, menthol, and ethanol.

Plant extracts include Sakuhakuhi, Yukinoshita, perilla, rice bran, sake lees, white coconut, peonies, purple saplings, lotus seeds, barley seeds, Pandanus amaryllifolius Roxb., Arcangelicia flava (Arcangelicia flava) , Chamomile, coral grass, rice leaf, apricot fruit, catamen giraffe, rose flower, bamboo shoot skin, gentian, carrot, ginseng, red ginseng, loofah, peach, peach seed, kiwi, sunflower, zizyphus joazeiro, pawdarco , Daylily, hibiscus flower, hagoromogusa, cherimoya, mango, red rich, silane, yam pericarp or seed coat, safflower flower, casablanca, guava leaf, dokudami, evening birch, aloe fig flower, apple, white asparagus, Mate tea, cherry leaves, Extracts of plants such as Ran'iran leaf (ylang ylang leaves) and the like.

The seaweed extract includes green algae such as Chlorella vulgaris, Chlorella pyrenoidosa, Chlorella ellipsoidia, Aonori, Aosa, Anaaaosa; , Mozuku, Hirome, Hijiki, Hibamata, Umiuchiwa, Usubaumiuchiwa, Kirebanoumiuchiwa, Akaubami Uchiwa, Konuumiuchiwa, Okinawa Uchiwa, Usuki Uchiwa, Etsuki Umiuchiwa, Hijirimena, Maca Osa , Yatabegusa, Yuikiri, Striped primrose, Tokakanori, Togekininsai, Amakusa Ginsai, Giraffe, Rhinoceros giraffe, Tsunomata, Oobatsunomata, To Catcher mosquitoes or Yahazutsunomata, Ezotsunomata, Togetsunomata, Hirakotoji, Kotojitsunomata, Ibotsunomata, Marubatsunomata, Hirakotoji, Suginori, Shikin'nori, Kainori, Yareusubanori, Kagiusubanori, Sujiusubanori, Haiusubanori, like red algae such as Akamomijinori.

Antifungal agents include terbinafine, naphthifine, butenafine, tolnaphthalate, rylanaphthalate, miconazole, ranoconazole, luliconazole, isconazole, ketoconazole, clotrimazole, neticonazole, sulconazole, bifonazole, oxiconazole, econazole, fluconazole, fluconazole, fluconazole, fluconazole, , Eficonazole, butconazole, fenticonazole, sertaconazole and the like.

Examples of whitening ingredients include tocopherol, ascorbic acid, tranexamic acid, arbutin, 4-alkylresorcinol, 4-methoxysalicylic acid, hydroquinone, kojic acid, salts thereof, or derivatives thereof, placental extract, and extract of buckwheat , Yukinoshita extract, aloe extract and the like.

Examples of the base or carrier base or carrier include an oily base and an aqueous base.
In addition to the above-mentioned hydrocarbon bases, oily bases include higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; vegetable fats such as shea butter, carbana wax, cocoa butter, and candelilla wax Animal oils such as lanolin, orange luffy oil, squalane, horse oil, whale wax, and beeswax; hardened oil; methyl polysiloxane, cross-linked methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked 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 oils such as ricone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose , Cationized guar gum, and natural polymer derivatives such as acetylated hyaluronic acid; synthetic polymers such as polyvinylpyrrolidone, carboxyvinyl polymer, and alkyl methacrylate copolymer; carrageenan, alginic acid, cellulose, guar gum, quince Natural polymers such as seed, dextran, and gellan gum; isopropyl myristate, octyldodecyl myristate, palmitic Esters such as isopropyl acid, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra-2-ethylhexanoate, and tri (caprylic / capric) glyceryl; polysaccharides such as dextrin and maltodextrin; ethylene glycol Monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl Ether and dipropylene glycol monopropyl ether Examples thereof include glycol ethers such as tellurium.
Examples of the aqueous base include lower alcohols such as ethanol and isopropanol in addition to water and buffer solutions. The polyhydric alcohol also functions as an aqueous base.
A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

When the composition for external use of the present invention contains water, the content is 3% by weight or more, 5% by weight or more, 30% by weight or more, 50% by weight or more, 70% by weight or more, or the total amount of the composition It can be 95 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 wt%, 3 to 95 wt%, 3 to 70 wt%, 3 to 50 wt%, 3 to 30 wt%, 5 to 97 wt%, 5 to 95 wt%, 5 ~ 70 wt%, 5-50 wt%, 5-30 wt%, 30-97 wt%, 30-95 wt%, 30-70 wt%, 30-50 wt%, 50-97 wt%, 50-95 And 50 to 70% by weight, 70 to 97% by weight, 70 to 95% by weight, and 95 to 97% by weight.

The composition for external use of the present invention may be free from polyoxyethylene aralkyl ether, stearyl alcohol, or a liquid oily component (for example, a liquid oily base such as a liquid hydrocarbon base). From the composition for external use of the present invention, in particular, it contains adapalene, polyoxyethylene aralkyl ether, stearyl alcohol, liquid oily component (eg, liquid oily base such as liquid hydrocarbon base), moisturizing component, and water. Compositions can be excluded.
When the composition for external use of the present invention contains at least one selected from the group consisting of macrogol (polyethylene glycol), glycerin, and 1,3-butylene glycol having an average molecular weight of 4000 or less, It can be less than 5% by weight or more than 40% by weight with respect to the total amount of the product.

Any of the components contained in the composition for external use of the present invention can be a hydrate, a hemihydrate, or an anhydride.

The dosage form of the composition for external use of the present invention includes liquids, suspensions, emulsions, creams, ointments, gels, liniments, lotions, sprays, aerosols, powders, poultices, non-woven fabrics For example, a sheet agent in which a chemical solution is impregnated in a sheet such as the above may be used. Among these, the liquid agent, suspension agent, emulsion, cream agent, gel agent, lotion agent, spray agent, aerosol agent are the point that the effect of the present invention is more remarkably exhibited and the irritation to the skin during application is reduced. A liquid agent, a suspension agent, an emulsion, a cream agent, a gel agent, and a lotion agent are more preferable.
In the case of a dosage form in an emulsified state such as an emulsion, cream, emulsion ointment, it may be either an oil-in-water type or a water-in-oil type, but it has a good feeling of use and has good dispersibility of adapalene An oil-in-water type is preferred.

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

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

The present invention relates to a method for improving dispersibility of adapalene and / or a salt thereof . (A) An external composition containing adapalene and / or a salt thereof includes (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts 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 kind and content of each component, the properties of the composition, and the like are as described for the external composition of the present invention.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
Test Example 1 (Dispersibility evaluation)
Preparations that were compositions for external use having the compositions shown in Table 1, Table 2, and Table 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.
Using these preparations, the dispersibility of adapalene was evaluated. Specifically, after each formulation was stirred and homogenized, 50 μL was dropped onto a slide glass, and the particles were observed and photographed using a microscope (product name: VHX-5000; Keyence Corporation). Only the particle 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 adapalene is dispersed in the composition, the smaller the average particle area.

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

Particle area reduction rate (%)
= [(Average particle area of corresponding comparative example−Average particle area of example) / Average particle area of corresponding comparative example] × 100 (1)

The results are shown in Tables 1 to 3.

As shown in Tables 1 to 3, an external composition containing adapalene is added to N- (hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide, cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or By adding sodium hyaluronate, the particle area of adapalene in the composition was reduced, and it was found that the dispersibility of adapalene in the composition was improved by adding the component (B).

Test example 2 (dispersion sustainability evaluation)
Preparations that are compositions for external use having the compositions shown in Tables 4 and 5 were prepared by a conventional method. The dosage form of each formulation of Table 4 and Table 5 is a lotion.
These formulations were used to evaluate the persistence of adapalene dispersion. Specifically, 100 mL of each formulation was dispensed into a 100 mL glass vial and allowed to stand at room temperature for 2 days.
Next, the formulation filled in the glass vial was sonicated for 5 minutes using an ultrasonic cleaner (model number: US-107, manufacturer: SNDI Inc.), then shaken up and down 5 times and shielded from room temperature. Let stand under for 10 minutes.
The center of the height between the liquid level in the glass vial and the bottom of the glass vial before and after stirring, that is, “sonication using an ultrasonic cleaner, shaking, and standing at room temperature for 10 minutes” 200 μL of each preparation was sampled from each part, placed in a 96-well plate (manufactured by FALCON, Tissue Culture Plate), and the absorbance at 600 nm was measured using a plate reader (manufactured by Molecular Devices, 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. When the increase in turbidity by stirring is small, the degree of separation decreases. A low degree of separation indicates a high persistence of adapalene dispersion in the formulation.

The degree of separation was determined for each formulation, and the dispersion persistence improvement rate (%) compared with the corresponding comparative example was calculated according to the following formula (2). The comparative example corresponding to Examples 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 embodiment) / Separation degree of corresponding comparative example] × 100 (2)

The results are shown in Tables 4 and 5.

As Table 4 and Table 5 show, the persistence of the dispersion of adapalene in the preparation was remarkably improved by blending sodium lactate, arginine, pyrrolidone carboxylic acid, or sodium hyaluronate into the external composition containing adapalene. .

Test Example 3 (Dispersibility evaluation after application of formulation)
Preparations that are compositions for external use having the compositions shown in Tables 6 and 7 were prepared by a conventional method. The dosage forms of the preparations in Tables 6 and 7 are lotions. The dispersibility of adapalene after application was evaluated using these preparations. Specifically, after each formulation was stirred and homogenized, 50 μL was dropped on a slide glass and dried for about 18 hours at room temperature under light shielding. Thereafter, 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.

When the adapalene aggregates during and after the preparation is dried, the observed particle area increases. This test evaluates the ease of aggregation of adapalene in the preparation after application. When the observed particle area is small, it is 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 (%) compared with the corresponding comparative example was calculated. As the corresponding comparative example, 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 an external composition containing adapalene, the particle area after application and drying of the composition Decreased significantly. (B) It turns out that adapalene becomes difficult to aggregate after apply | coating the external composition of this invention to skin by the mixing | blending of a component.

Test Example 4 (Dispersibility evaluation)
Preparations that are compositions for external use having the compositions shown in Tables 8 to 11 were prepared by a conventional method. The dosage form of each formulation in Tables 8 to 11 is an emulsion.
Using these preparations, the dispersibility of adapalene was evaluated. Specifically, after each formulation was stirred and homogenized, 50 μL was dropped onto a slide glass, and the particles were observed and photographed using a microscope (product name: VHX-5000; Keyence Corporation). Only the particle 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 adapalene is dispersed in the composition, the smaller the average particle area.

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

The results are shown in Tables 8 to 11.

Each Example formulation shown in Tables 8 to 11 is different from each Example formulation shown in Tables 1 to 3 in that 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. N- (hexadecyloxyhydroxypropyl-N-hydroxyethylhexadecanamide, cholesterol, lactic acid, sodium lactate, arginine, urea, pyrrolidone carboxylic acid, or sodium hyaluronate is added to the external composition containing adapalene. Adapalene particles in the composition Product was reduced. (B) it can be seen that dispersibility of adapalene in the composition by blending the components is improved.

Formulation Examples Compositions for external use (Formulation Examples 1 to 98) were prepared according to the formulation described below.

Since the composition for external use 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. Therefore, the desired medicinal effects can be obtained sufficiently.

Claims

(A) selected from the group consisting of adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof. An external composition containing at least one component.
The external composition according to claim 1, comprising 0.001 to 1% by weight of component (A).
The external composition according to claim 1 or 2, which contains 0.0001 to 20% by weight of component (B).
The external composition according to any one of claims 1 to 3, further comprising (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 composition for external use according to any one of claims 1 to 5, further comprising (D) an emulsifier.
(D) The emulsifier is at least one selected from the group consisting of sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyalkylene alkyl ether, and polyoxyethylene sorbitan fatty acid esters. Composition for external use.
The composition for external use according to any one of claims 1 to 7, further comprising (E) a hydrocarbon base.
The composition for external use according to any one of claims 1 to 8, wherein the dosage form of the composition is a liquid, suspension, emulsion, cream, gel, lotion, spray, or aerosol.
(A) An external composition containing adapalene and / or a salt thereof, and (B) ceramides, cholesterols, amino acids, pyrrolidone carboxylic acids and salts thereof, lactic acid and salts thereof, ureas, and mucopolysaccharides and salts thereof 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: