JP2021038217A - External composition for skin, method for controlling skin permeability of antiinflammatory component or antibacterial component, and method for reducing skin irritation of antiinflammatory component or antibacterial component - Google Patents

Abstract

To provide a technique that can control skin permeability of active ingredients of therapeutic pharmaceuticals such as antiinflammatory components or antibacterial components, and to provide an external composition for skin that can control skin permeability of the active ingredients.SOLUTION: An external composition for skin contains (A) a C3-10 dicarboxylate with carboxyl groups at both terminals, and (B) at least one component selected from the group consisting of antiinflammatory components (b1) and antibacterial components (b2).SELECTED DRAWING: None

Description

The present invention relates to a method for controlling the skin permeability of an external composition for skin, an anti-inflammatory component or an antibacterial component, and a method for reducing skin irritation caused by the anti-inflammatory component or the antibacterial component.

Antibacterial agents and anti-inflammatory agents are blended and used in external preparations for skin as active ingredients of pharmaceuticals and quasi-drugs for the treatment of skin diseases and improvement of various skin symptoms.

By the way, it has been reported that side effects due to the active ingredient of a therapeutic drug for skin diseases may occur in some patients and / or users, and steroid contact allergy, non-steroid contact allergy, antifungal agent contact allergy. , Antibacterial contact allergy, allergic contact dermatitis, etc. (see Non-Patent Document 1).

It is also known that in atopic dermatitis (AD) patients, the incidence of contact dermatitis with respect to local drugs is relatively higher than in non-AD patients. (See Non-Patent Document 2). Therefore, if it becomes possible to control the penetration of the active ingredient into the skin, it is possible to reduce side effects such as dermatitis and skin irritation while maintaining the action and effect of the external composition. A technique for controlling the permeability of anti-inflammatory agents has been strongly desired.

Poisoning Research, Vol. 12, No. 3, Page. 275-282, 1999 Environmental Dermatology, Vol. 7, No. 3, Page 137-143, 2000

The present invention has been made in view of such a situation, and an object of the present invention is to provide a technique capable of controlling the penetration of an active ingredient of a therapeutic drug such as an anti-inflammatory ingredient and an antibacterial ingredient into the skin. Another object of the present invention is to provide a composition for external use on the skin, which can control the permeability of the active ingredient into the skin.

As a result of diligent research to solve the above problems, the present inventors have found that a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends is contained in the external composition for skin. It has been found that it is possible to control the penetration of active ingredients of therapeutic drugs such as anti-inflammatory ingredients and antibacterial ingredients into the skin. That is, the gist of the present invention is as follows.

[1] At least selected from the group consisting of (A) a dicarboxylic acid having 3 to 10 carbon atoms and having a carboxyl group at both ends, and (B) an anti-inflammatory component (b1) and an antibacterial component (b2). An external composition for skin containing one component.
[2] The composition for external use on the skin according to [1], wherein the (A) dicarboxylic acid has 4 to 9 carbon atoms.
[3] The composition for external use on the skin according to [1] or [2], wherein the anti-inflammatory component is a non-steroidal anti-inflammatory and analgesic component.
[4] The composition for external use on the skin according to any one of [1] to [3], wherein the antibacterial component (b2) is isopropylmethylphenol.
[5] The composition for external use on the skin according to any one of [1] to [4], wherein the component (B) contains an anti-inflammatory component (b1) and an antibacterial component (b2).
[6] The composition for external use on the skin according to any one of [1] to [5], wherein the (A) dicarboxylic acid is at least one selected from the group consisting of adipic acid, azelaic acid, tartaric acid, and succinic acid. Stuff.
[7] The (B) anti-inflammatory component (b1) and antibacterial component (B1) in the preparation, which comprises (A) a dicarboxylic acid having 3 to 10 carbon atoms and having a carboxyl group at both ends. A method for controlling the skin permeability of at least one component selected from the group consisting of b2).
[8] The (B) anti-inflammatory component (b1) and antibacterial component (B1) in the preparation, which comprises (A) a dicarboxylic acid having 3 to 10 carbon atoms and having a carboxyl group at both ends. A method for reducing skin irritation caused by at least one component selected from the group consisting of b2).

According to the external composition for skin of the present invention, (A) has 3 to 10 carbon atoms and contains a dicarboxylic acid having a carboxyl group at both ends, so that (B) an anti-inflammatory component and an antibacterial component It is possible to effectively control the deeper penetration of the skin layer of at least one component selected from the group. Therefore, according to the present invention, an external composition for skin capable of reducing dermatitis and skin irritation caused by the penetration of an active ingredient such as the above component (B) into the deeper part of the skin layer is designed. can do. In addition, by controlling the permeability, the active ingredient can be stored in the layer of the skin where the action and effect should be exerted, and the action can be exerted more effectively.

Hereinafter, the present invention will be described in detail. Unless otherwise specified, the terms used in the present specification are interpreted in the meanings commonly used in the art.

<Skin external composition>
The external composition for skin of the present invention comprises (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends (also simply referred to as "(A) dicarboxylic acid" in the present specification), and (B) Contains at least one component (also simply referred to as "(B) component" in the present specification) selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2). Since the external composition for skin of the present invention contains (A) dicarboxylic acid, the permeability of the component (B) to the deeper part of the skin layer can be effectively controlled. Therefore, according to the present invention, it is possible to reduce or suppress dermatitis and skin irritation caused by the penetration of an active ingredient such as the component (B) into a deeper part of the skin layer. In addition, by controlling the permeability, the active ingredient can be stored in the layer of the skin where the action and effect should be exerted, and the action can be exerted more effectively.

In addition to the (A) dicarboxylic acid and the (B) component, the external composition for skin of the present invention may contain other components as long as the effects of the present invention are not impaired. The (A) dicarboxylic acid, the (B) component, and other components will be described below.

[(A) Dicarboxylic acid]
The (A) dicarboxylic acid contained in the external composition for skin of the present invention is a compound having 3 to 10 carbon atoms and having carboxyl groups at both ends. Specific examples thereof include malonic acid, succinic acid, tartaric acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid. Of these, dicarboxylic acids having 4 to 9 carbon atoms are preferable, and adipic acid and azelaic acid are preferable, from the viewpoint of being excellent in the effect of controlling the penetration of the component (B) described later into the deep skin layer, particularly the effect of suppressing the penetration. It is more preferably an acid, and even more preferably adipic acid. As the component (A), the above-mentioned component may be contained alone or two or more kinds may be contained together.

The content of (A) dicarboxylic acid in the external composition for skin of the present invention is 0.001% by weight to 10% by weight, preferably 0.005% by weight to 5% by weight, preferably 0.01% by weight. It is more preferably% to 1% by weight, and further preferably 0.05% by weight to 0.5% by weight. By containing (A) dicarboxylic acid in the above numerical range, the external composition for skin of the present invention can effectively suppress the penetration of the component (B) described later into the deep part of the skin layer.

[(B) component]
The component (B) contained in the external composition for skin of the present invention is at least one component selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2). These ingredients, which are used as active ingredients in therapeutic agents for skin diseases, may penetrate not only near the surface of the skin but also deeper into the dermis of the skin layer when used in topical skin compositions. It may cause side effects such as dermatitis and skin irritation. The external composition for skin of the present invention contains the above-mentioned (A) dicarboxylic acid together with these active ingredients to control the penetration of the active ingredient into the skin and maintain the action and effect, while maintaining dermatitis. It is possible to reduce or suppress side effects such as skin irritation and skin irritation. In addition, by controlling the permeability, the active ingredient can be stored in the layer of the skin where the action and effect should be exerted, and the action can be exerted more effectively. Furthermore, by containing (A) dicarboxylic acid, it is possible not only to effectively control the penetration of the component (B) into the deeper part of the skin layer, but also to improve the stability of the component (B). It was also found that an unexpected effect could be obtained.

The anti-inflammatory component (b1) is not particularly limited as long as it is a component that has an effect of suppressing inflammation. The anti-inflammatory component is classified into a steroidal anti-inflammatory component (SAIDs) and a non-steroidal anti-inflammatory component (NSAIDs). , Non-steroidal anti-inflammatory component (non-steroidal anti-inflammatory and analgesic component) is preferable.

In the present invention, examples of the non-steroidal anti-inflammatory drug include ibuprofen, ibuprofen piconol (IPPN), naproxen, flurbiprofen, flurbiprofen axetyl, ketoprofen, phenoprofen calcium, thiaprofen, oxaprodin, and plano. Profen, loxoprofen sodium, aluminoprofen, zartprofen, sazapyrin, sodium salicylate, aspirin, aspirin dialuminate, diflurbiprofen, indomethacin, sprofen, ufenamate, dimethylisopropylazulene, bufexamac, fervinac, diclofenac, tolmethine sodium, clinolyl, fenbufen Naproxen, Progourmet Tacin, Indomethacin Farnesyl, Acemetasin, Maleic Acid Progourmet Tacin, Amphenac Sodium, Mofezorak, Etodorak, Mephenamic Acid, Aluminum Mephenumate, Torphenamic Acid, Floctafenin, Ketophenylbutazone, Oxyphenbutazone, Pyroxycam, Tenoxycam , Ampyroxycam, Napageln Ointment, Epilyzole, Thiaramid Hydrochloride, Tinolysine Hydrochloride, Emorphazone, Sulpyrine, Migrenine, Salidone, Cedes G, Amypyro-N, Sorbone, Pyrinic Sensitives, Acetaminophen, Phenacetin, Dimethothiazine Mesylate, Simetride Combination, Examples thereof include non-pyrine sensitizers, allantin and its derivatives, glycyrrhetinic acid and its derivatives, glycyrrhizinic acid and its derivatives, salicylic acid derivatives, aminocaproic acid, azulene and its derivatives, zinc oxide, tocopherol acetate and the like.

Of these, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetyl, ketoprofen, fenoprofen calcium, thiaprofen, from the viewpoint that the penetration control effect of (A) dicarboxylic acid can be easily obtained. Propionic acid-based anti-inflammatory agents such as oxaprozin, planoprofen, sodium loxoprofen, alminoprofen, and zaltprofen are preferred, with ibuprofen piconol being more preferred.

The content of the anti-inflammatory component (b1) in the external composition for skin of the present invention is 0.01% by weight to 10% by weight, preferably 0.05% by weight to 8% by weight, preferably 0.1. It is more preferably from% to 5% by weight, even more preferably from 0.2% to 3% by weight. When the external composition for skin contains the anti-inflammatory component (b1) in the above numerical range, it may penetrate deeper into the dermis of the skin layer and cause various side effects. As a result, the permeation of the component (b1) is controlled, and side effects can be reduced or suppressed.

The antibacterial component (b2) is not particularly limited as long as it has an effect of suppressing the growth of various bacteria and a bactericidal effect, and for example, isopropylmethylphenol (IPMP), salicylic acid, benzoic acid, amorolphin, chlorhexidine, and the like. And these salts, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, povidone iodine, potassium iodide, iodine, triclosan, triclosan, photosensitizer 101, photosensitizer 201, phenoxyethanol, Examples thereof include alkyldiaminoglycine hydrochloride.

Of these, as the component (b2), isopropylmethylphenol and salts thereof are preferable from the viewpoint that the penetration control effect of (A) dicarboxylic acid can be easily obtained, and isopropylmethylphenol, salicylic acid, and benzoic acid are more preferable. Isopropylmethylphenol is more preferred.

The content of the component (b2) in the external composition for skin of the present invention is 0.005% by weight to 10% by weight, preferably 0.01% by weight to 8% by weight, preferably 0.05% by weight. It is more preferably ~ 5% by weight, further preferably 0.1% by weight to 3% by weight, and particularly preferably 0.3% by weight to 1% by weight. When the composition for external use on the skin contains the antibacterial component (b2) component in the above numerical range, it may penetrate deeper into the dermis of the skin layer and cause various side effects. As a result, the permeation of the component (b2) is controlled, and side effects can be reduced or suppressed.

From the viewpoint that the permeation control effect of the component (A) is remarkable, the external composition for skin of the present invention preferably contains at least the component (b1) as the component (B), and the component (b1) and the component (b2). It is more preferable to include both. Compared with the case where either (b1) or (b2) is contained alone as the component (B), when both components are contained, the effect of controlling the penetration of (A) dicarboxylic acid into the skin is more remarkable. This was a result that the present inventor did not anticipate at all.

The content of the component (B) as a whole in the external composition for skin of the present invention is 0.005% by weight to 20% by weight, preferably 0.01% by weight to 15% by weight, preferably 0.05. It is more preferably 10% by weight to 10% by weight, further preferably 0.1% by weight to 8% by weight, particularly preferably 0.5% by weight to 6% by weight, and 1% by weight to 5% by weight. It is particularly more preferably by weight%, and most preferably 2.0% by weight to 4.0% by weight. When the external composition for skin contains the component (B) in the above numerical range, it may penetrate deeper into the dermis of the skin layer and cause various side effects. The permeation of the component (B) is remarkably controlled, and side effects can be reduced or suppressed. In addition, the permeation of the component (B) is controlled and stored in the upper part of the skin layer, so that the effect can be more effectively exerted.

In the external composition for skin of the present invention, the ratio of the content of (A) dicarboxylic acid to (B) component is 0.0001 parts by weight to 10 parts by weight of (A) dicarboxylic acid with respect to 1 part by weight of (B) component. It is a part by weight, preferably 0.001 part by weight to 5 parts by weight, more preferably 0.005 part by weight to 1 part by weight, and 0.01 part by weight to 0.5 part by weight. Is more preferable, and 0.025 parts by weight to 0.1 parts by weight is particularly preferable. When the external composition for skin of the present invention contains (A) dicarboxylic acid and (B) component in the above ratio, the component (B) penetrates deeper into the dermis of the skin layer and causes various side effects. Can be effectively suppressed.

In the external composition for skin of the present invention, the ratio of the content of (A) dicarboxylic acid to (b1) component is 0.0002 parts by weight to 5 parts by weight of (A) dicarboxylic acid with respect to 1 part by weight of (b1) component. It is a part by weight, preferably 0.001 part by weight to 4 parts by weight, more preferably 0.002 part by weight to 2 parts by weight, and further preferably 0.01 part by weight to 2 parts by weight. More preferred. When the external composition for skin of the present invention contains (A) dicarboxylic acid and (b1) component in the above ratio, the component (b1) penetrates deeper into the dermis of the skin layer and causes various side effects. Can be effectively suppressed.

In the external composition for skin of the present invention, the ratio of the content of (A) dicarboxylic acid to (b2) component is 0.001 part by weight to 200 parts by weight of (A) dicarboxylic acid with respect to 1 part by weight of (b2) component. It is by weight, preferably 0.005 parts by weight to 100 parts by weight, more preferably 0.01 parts by weight to 20 parts by weight, and further preferably 0.05 parts by weight to 10 parts by weight. It is preferably 0.1 part by weight to 0.5 part by weight, and particularly preferably 0.1 part by weight. When the external composition for skin of the present invention contains (A) dicarboxylic acid and (b2) component in the above ratio, the component (b2) penetrates deeper into the dermis of the skin layer and causes various side effects. Can be effectively suppressed.

[(C) Chelating agent]
The external composition for skin of the present invention preferably further contains (C) a chelating agent. The external composition for skin of the present invention can more effectively control the permeation of the component (B) into the skin by further containing the chelating agent (C).

Examples of the chelating agent (C) include EDTA, hydroxyethanediphosphonic acid, citric acid, and salts thereof. More specifically, EDTA (EDTA-2Na salt, EDTA-4Na salt), hydroxyetane diphosphonic acid, calcium, disodium salt and the like can be mentioned. Of these, EDTA and salts thereof are preferable from the viewpoint of further promoting the effects of the present invention.

The content of the (C) chelating agent in the external composition for skin of the present invention is 0.001% by weight to 1% by weight and 0.005% by weight to 0.5% by weight of the entire external composition for skin. It is preferably 0.01% by weight to 0.1% by weight, more preferably 0.01% by weight. By containing the chelating agent (C) in the above numerical range, the skin penetration of the component (B) can be controlled more effectively.

[(D) Lipid]
The external composition for skin of the present invention preferably further contains (D) lipid. The external composition for skin of the present invention can effectively control the permeation of the component (B) into the skin by further containing the lipid (D).

Examples of the (D) lipid include phospholipids, cholesterol, ceramide and the like. Of these, phospholipids are preferable, and lecithin and hydrogenated lecithin are more preferable, from the viewpoint of further promoting the effects of the present invention.

The content of the (D) lipid in the external composition for skin of the present invention is 0.001% by weight to 8% by weight, preferably 0.01% by weight to 5% by weight, based on the entire external composition for skin. , 0.05% by weight to 3% by weight, and even more preferably 0.1% by weight to 2% by weight. By containing the lipid (D) in the above numerical range, the skin penetration of the component (B) can be controlled more effectively.

The external composition for skin of the present invention contains other optional components, a base or a carrier, additives and the like in addition to the above-mentioned components (A) to (D) as long as the effects of the present invention are not impaired. May be good.

[Arbitrary component]
Optional components contained in the external composition for skin of the present invention include, for example, a whitening component, a turnover accelerator, an anti-glycation component, an antioxidant component, an anti-aging component, an anti-inflammatory agent other than the component (b1), and a refreshing agent. Vitamin, (A) Organic acids other than dicarboxylic acid, moisturizing ingredients, polyhydric alcohols, emulsifiers, scrubbing agents, ultraviolet absorbing components, ultraviolet scattering components, astringent components, peptides or derivatives thereof, amino acids or derivatives thereof, cleaning components, keratin Examples thereof include a softening component, a cell activating component, and a blood circulation promoting action component. In the external composition for skin of the present invention, each of these components may be used alone or in combination of two or more.

Examples of the whitening component include tocopherol, vitamin C and its derivatives, arbutin, kojic acid, placenta extract, ellagic acid, nicotinamide, tranexamic acid and its derivatives, hydroquinone, 4-n-butylresorcinol, and 4-methoxysalicylic acid. Examples thereof include potassium salts, linoleic acid and derivatives thereof.

Examples of the turnover accelerator include vitamins, keratin softening components, cell activating components, blood circulation promoting components, etc., which will be described later.

Examples of the anti-glycation component include plant extracts such as Budreja axilaris leaf extract, evening primrose oil, Amler fruit, fruit juice or extracts thereof, L-arginine, L-lysine, hydrolyzed casein, and hydrolyzable tannin. , Carnosin and the like.

Examples of the antioxidant component include components derived from plants (for example, grapes, glutathione, and comfrey); proanthocyanidins, tocopherols and their derivatives, ascorbic acid and its derivatives, hesperidin and its derivatives, ergothioneine, and sulfite. Examples thereof include sodium bisulfite, erythorbic acid and salts thereof, flavonoids, glutathione and the like.

Examples of the antiaging component include hydrolyzed soy protein, retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-. Examples thereof include methyl-L-serine and mevalonolactone.

Examples of the refreshing agent include terpenes such as menthol, camphor, geraniol, etc. (these may be d-form, l-form, or dl-form); eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint. Examples include essential oils such as oil and mint oil.

The vitamins may be either water-soluble vitamins or oil-soluble vitamins. For example, vitamin B6s, pantothenic acids, nicotinic acids, vitamins B1, vitamins B2, biotins folic acids, vitamins B12, etc. Water-soluble vitamin Cs, oil-soluble vitamin Cs, vitamin Ks; vitamin-like acting factors such as ferulic acid can be mentioned.

Examples of organic acids other than the above (A) dicarboxylic acid include gluconic acid, aspartic acid, aminoethylsulfonic acid, citric acid, glutamate, oxalic acid, fumaric acid, propionic acid, malic acid, salicylic acid, glycolic acid, and phytic acid. , Acetic acid, lactic acid, and salts thereof. Examples of the salt include a salt of a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, a salt of an organic acid such as maleic acid or methanesulfonic acid, an alkali metal salt such as sodium or potassium, an alkaline earth metal salt, an ammonium salt and the like. Can be mentioned.

Examples of the moisturizing component include high molecular compounds such as sodium hyaluronate, heparinoid, sodium chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan, and proteoglycan; amino acids such as glycine, aspartic acid, and arginine; sodium lactate, Natural moisturizing factors such as urea and sodium pyrrolidone carboxylate; plant extracts such as chamomile extract, hamamelis extract, cha extract and perilla extract, and polyhydric alcohols such as glycerin can be mentioned.

The polyhydric alcohol preferably has 2 to 10 carbon atoms, and for example, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1 , 3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentandiol, hexanediol, octanediol, decanediol, neopentyl glycol and the like.

Examples of the emulsifier include polyether-based silicones such as polyether-modified silicones and crosslinked polyether-modified silicones; polyoxyethylene curing such as POE (5), POE (7.5), and POE (10) cured castor oil. Casting oil; Dipolyhydroxystearic acid esters: Polyglyceryl-2 dipolyhydroxystearate, high molecular weight lipophilic activators such as PEG30 dipolyhydroxystearate; cetyldimethiconecopolyol and the like.

Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride granules, olive kernel powder, seawater dried product granules, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, and charcoal powder. , Almond shell powder, polyethylene powder, silicic anhydride and the like.

Examples of the ultraviolet absorbing component include ethylhexyl methoxycinnamate, hexyl diethylaminohydroxybenzoyl benzoate, bisethylhexyloxyphenol methoxyphenyltriazine, ethylhexyltriazone, t-butylmethoxydibenzoylmethane, octocrylene, ethylhexyl salicylate, homosalate, and poly. Examples thereof include silicone-15, methylenebisbenzotriazolyltetramethylbutylphenol, octyl dimethoxybenzylidene dioxoimidazolidine propionate, and phenylbenzimidazole sulfonic acid.

Examples of the ultraviolet scattering component include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, iron oxide, zinc oxide, and silicic anhydride. Inorganic compounds coated with inorganic powders such as hydrous silicic acid, aluminum hydroxide, mica and talc, composited with resin powders such as polyamide, polyethylene, polyester, polystyrene and nylon, and silicone oil and aluminum fatty acid Examples thereof include those treated with salt or the like.

Examples of the astringent component include alum, zinc sulfate, aluminum chloride, zinc sulfophenol, tannic acid and the like.

Examples of the peptide or a derivative thereof include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, and the like. Elastin-degrading peptide, conchiolin-degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, Examples thereof include casein-degrading peptides and acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

Examples of the amino acid or a derivative thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, and the like. Examples thereof include cystine, methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosin, creatine and the like.

Examples of the cleaning component include soaps selected from alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate or potassium stearate, alkanolamide salts or amino acid salts; Na cocoyl glutamate, Na cocoyl methyl taurine Amino acid-based surfactants such as; ether sulfate ester salts such as laureth sulfate Na; ether carboxylates such as lauryl ether acetate; sulfosuccinic acid ester salts such as alkyl sulfosuccinate Na; palm oil fatty acid monoethanolamide, palm oil Amino acid alkanolamides such as fatty acid diethanolamide; monoalkyl phosphate esters such as sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate; coconut oil fatty acid amide propyldimethylaminoacetic acid betaine, lauryldimethylaminoacetic acid betaine, 2-alkyl Betain-type amphoteric surfactants such as -N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, lauryl hydroxysulfobetaine and lauroylamide ethyl hydroxyethyl carboxymethyl betaine hydroxypropyl phosphate; amino acids such as sodium lauryl aminopropionate Examples include type amphoteric surfactants.

Examples of the keratin softening component include lactic acid, salicylic acid, glycolic acid, citric acid, malic acid, fruit acid, phytic acid, urea, and sulfur.

Examples of the cell activating component include amino acids such as γ-aminobutyric acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins and flavonoids. Examples thereof include saponin and photosensitizer No. 301.

Examples of the blood circulation promoting component include plants (for example, ginseng, Ashitaba, Arnica, Ginkgo, Angelica acutiloba, Angelica acutiloba, Dutch oak, chamomile, Roman chamomile, carrot, gentiana, gobo, rice, sanzashi, shiitake, ginger, ryokuch, and ryokuch. , Senkyu, Senburi, Thyme, Chouji, Chimpi, Angelica acutiloba, Angelica acutiloba, Angelica acutiloba, Angelica acutiloba, Butcher bloom, Grape, Button, Maronie, Melissa, Yuzu, Yokuinin, Ryokucha, Rosemary, Rosehip, Chimpi, Touki, Ingredients derived from (Angelica acutiloba, peach, apricot, walnut, corn, etc.); acetylcholine, ictamol, cantalistinki, gamma oryzanol, cepharanthin, trazoline, tocopherol nicotinate, glucosyl hesperidine and the like.

[Base material or carrier]
Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, vaseline, gelled hydrocarbon (plastibase, etc.), ozokelite, α-olefin oligomer, light liquid paraffin; methylpolysiloxane, cyclic silicone, modified silicone. , Silicone oils such as silicone resins; oils and fats such as palm oil, olive oil, rice bran oil, shea butter; waxes such as jojoba oil, miuro, candelilla wax, lanolin; cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodeca Higher alcohols such as ol, isostearyl alcohol, phytosterol; methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, carrageenan, polyethylene glycol, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononan Examples thereof include esters such as isononyl acid and pentaerythritol tetra2-ethylhexanoic acid; polysaccharides such as dextrin and maltodextrin; lower alcohols such as ethanol; glycol ethers such as diethylene glycol monoethyl ether; and water.

The base or carrier described above may be used alone or in combination of two or more. The amount used thereof is appropriately selected from a range known to those skilled in the art.

[Additive]
The external composition for skin of the present invention includes known additives to be added to pharmaceuticals and quasi-drugs, for example, surfactants, antioxidants, colorants, and pearl luster, as long as the effects of the present invention are not impaired. Additives, pH adjusters, preservatives, thickeners and the like can be added. These additives may be used alone or in combination of two or more.

The surfactant may be any of nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants and the like, and for example, sorbitan monoisostearate and sorbitan monolaurate. , Solbitan monopalmitate, sorbitan monostearate, penta-2-ethylhexylate diglycerol sorbitan, tetra-2-ethylhexylate diglycerol sorbitan and other sorbitan fatty acid esters; propylene glycol fatty acid esters such as propylene glycol monostearate; Hardened polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80, etc. Oil derivatives; polyoxyethylene monolaurate (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), isostearic acid Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan; polyoxyethylene monopalm oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; stearylamine, oleylamine Amins such as: polyoxyethylene / methylpolysiloxane copolymer, silicone-based surfactants such as laurylPEG-9 polydimethylsiloxyethyl dimethicone and PEG-9 polydimethylsiloxyethyl dimethicone.

Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride and the like.

Examples of the colorant include inorganic pigments and natural pigments.

Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), organic bases (triethanolamine, diisopropanol, etc.). Amine, triisopropanolamine, etc.) and the like.

Examples of the preservative include alkanediols such as dehydroacetic acid, sodium dehydroacetate, phenoxyethanol, caprylhydroxamic acid, pentanediol, hexanediol, and octanediol.

Examples of the thickener include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose. Cellulose thickeners, guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, xanthan gum, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, chondroitin sulfate. Examples thereof include sodium, hyaluronic acid, sodium hyaluronate, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer, (acryloyldimethyltaurinammonium / vinylpyrrolidone) copolymer and the like.

[Manufacturing method of external composition for skin]
The method for producing the external composition for skin of the present invention is not particularly limited, and is an essential component (A) dicarboxylic acid, (B) component and other components (optional component, base or carrier) to be blended as necessary. Additives, etc.) can be appropriately selected and blended, and the product can be produced by a conventional method.

[Use of topical skin composition]
The external composition for skin of the present invention may be used as a pharmaceutical product or a quasi-drug having at least one of the therapeutic effects such as anti-inflammatory and antibacterial effects.

[Formulation form]
The formulation form of the external composition for skin of the present invention is not particularly limited, and for example, a liquid preparation, a cream preparation, a gel preparation, a jelly preparation, a sherbet preparation, an aerosol preparation, a foam preparation, a spray preparation, a patch, a stick preparation, and other ointments. , Solid agent and the like. These preparations can be produced according to a conventional method, for example, the method described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations. Further, a dosage form such as W / O, O / W, W / O / W, O / W / O type emulsion can be appropriately selected in consideration of the desired stability, usability and the like. The patch may be, for example, a non-woven fabric sheet, a gel sheet or the like impregnated with a beauty essence composition, a lotion composition, a milky lotion composition or the like.

[PH]
The pH of the external composition for skin of the present invention is usually pH 3.0 to 8.0, preferably pH 3.5 to 7.5, more preferably pH 4.0 to 6.8, and pH 4 It is even more preferably .5 to 6.5, and particularly preferably pH 5.0 to 6.0. The pH can be adjusted, for example, by using a pH adjuster. However, this does not apply to formulations in which pH measurement is impossible or difficult.

Examples of the administration method or application method of the external composition for skin of the present invention include transdermal administration, and a suitable method may be appropriately selected according to the type of disease and the purpose of use.

Since the external composition for skin of the present invention has an effect of reducing skin irritation by controlling the permeability to the skin, it can also be used for sensitive skin and rough skin. Sensitive skin is a condition in which there is no obvious inflammation or damage to the skin, but because the barrier function of the keratin is reduced, irritation from the external environment (chemical substances, fibers of hair, clothing, etc.) ) Indicates that the skin is in a state where it is easy to feel a tingling sensation or a burning sensation. In sensitive skin, the amount of intercellular lipids between the stratum corneum is lower than that in healthy skin, which disturbs the texture of the skin, lowers the barrier function, lowers the threshold of stimulation, and makes the skin more susceptible to stimulation. It has become. Therefore, the external composition of the present invention can be suitably used for improving the skin quality of sensitive skin. In addition, rough skin includes skin in which the texture of the skin is disturbed, that is, skin in which the barrier function is broken, and sensitive skin in which the barrier function is likely to be broken.

<Method of controlling the skin permeability of component (B)>
The present invention is characterized in that (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends is used, and (B) an anti-inflammatory component (b1) and an antibacterial component in a preparation. It also includes a method of controlling the skin permeability of at least one component selected from the group consisting of (b2). In the external composition for skin containing the component (b1) and / or the component (b2) as an active ingredient, by blending the (A) dicarboxylic acid together, the component (b1) and / or the component (b2) becomes the skin. For the first time, we have found that it is possible to effectively control the penetration deeper into the layer. This new technology has made it possible to reduce or suppress dermatitis and skin irritation that may be caused by the penetration of active ingredients such as the above component (B) into the deeper part of the skin layer. .. The above-mentioned external composition for skin is a preparation that realizes this technique. As a specific description of the (A) dicarboxylic acid, the (B) component, etc. in the method of the present invention, the description in the section of external composition for skin can be applied as it is.

<Method of reducing skin irritation caused by component (B)>
The present invention is characterized in that (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends is used, and (B) an anti-inflammatory component (b1) and an antibacterial component in a preparation. It also includes a method of reducing skin irritation caused by at least one component selected from the group consisting of (b2). In the external composition for skin containing the component (b1) and / or the component (b2) as an active ingredient, by blending the (A) dicarboxylic acid together, as described above, the component (b1) and / or (b2) ) Ingredients can be effectively controlled to penetrate deeper into the skin layer. According to this technique of the present invention, it is possible to reduce or suppress dermatitis and skin irritation that may be caused by the penetration of an active ingredient such as the above-mentioned component (B) into the deeper part of the skin layer. became. Therefore, the present invention is a method for reducing skin irritation caused by the component (B), which comprises using (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends. You can also. As a specific description of the (A) dicarboxylic acid, the (B) component, etc. in the method of the present invention, the description in the section of external composition for skin can be applied as it is.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

<Skin permeability test>
In this test, the permeability of the active ingredient was determined according to the Organization for Economic Co-operation and Development (OECD) guidelines for chemical substance testing, OECD TG428 (Skin Absorption: Invitro Method, April 13, 2004), which is an Invitaro skin absorption test method. The test was conducted according to (adopted on a daily basis) and calculated.

More specifically, each composition is prepared by a conventional method according to the composition shown in Table 1, and the permeability of each component in the composition is measured in an infinitely closed system by Franzcel (PermeGear, static type with jacket-flat jacket). -Clear-9 mm, 5 mL, transmission area 0.64 square cm) was used for measurement. That is, a reservoir solution (0.1% (w / v) polyethylene glycol monooleyl ether (20EO) in PBS) was prepared, the receptor chamber was filled with 5 mL of the reservoir solution, and the mixture was stirred for 30 minutes with Franz cell. A piece of skin (Yucatan Micro Pig, about 700 μm) was sandwiched between the glass donors and fixed. The constant temperature bath was set to 32 ° C., the constant temperature bath and Franz cell were connected, and the reservoir solution was kept at a constant temperature. Twenty-four hours after the start of stirring, Franz cells were decomposed, skin fragments were removed, a reservoir solution was collected, and the content of each component in the reservoir solution was measured by HPLC. The components were detected using an ultraviolet absorptiometer at a wavelength of 280 nm, and the content (rate) was calculated from the calibration line of each component. The permeability suppression rate for each composition was calculated according to the following formula (1). The "corresponding comparative example" in the following formula refers to a comparative example having the same number as that of the example. For example, the comparative example corresponding to the first example is the comparative example 1. The test results are shown in the table. It is shown together with 1.

Penetration suppression rate (%) = (permeation amount of 1-Example / permeation amount of corresponding comparative example) × 100
... (1)

As shown in Table 1 above, in the external composition for skin containing the active ingredients isopropylmethylphenol and / or ibuprofen piconol, in the examples containing adipic acid, compared with the comparative examples not containing it. , Isopropylmethylphenol, and ibuprofen piconol were confirmed to suppress the penetration deeper than the dermis. That is, in the external composition for skin of Comparative Examples 1 and 2 not containing adipic acid, when applied to the skin, the active ingredients contained therein permeate the epidermis and dermis and penetrate deeper. On the other hand, it was found that in the external composition for skin of Examples 1 and 2 containing adipic acid, the permeation of the active ingredient into the deep part as described above was significantly suppressed. Interestingly, it was found that in Example 2 containing two kinds of the above active ingredients, the penetration inhibition rate of the active ingredient was remarkably higher than that in Example 1 containing only ibuprofen piconol. Furthermore, it was confirmed that when EDTA as a chelating agent and lecithin as a lipid were contained (Examples 3 and 4), the penetration inhibition rate of the active ingredient was remarkably increased.

In addition, ibprofenpiconol 3% and adipic acid 0.1%, 1,3-butylene glycol, isopropyl palmitate, diethyl sebacate, polyoxyethylene hydrogenated castor oil, ethanol, glycerin, sorbitan stearate, squalane, carboxyvinyl polymer. , Soybean lecithin, cholesterol, sodium edetate, pH adjuster, cream preparation containing preservatives (Example 5, pH 5.6), and the same formulation as Example 5 except that it does not contain 0.1% adipic acid. A cream preparation (Comparative Example 5, pH 5.6) was prepared, filled in a tube container whose innermost layer was made of polyethylene, and stored at 40 ° C. for 2 months under shading. In the cream preparation of Example 5, the stability of ibuprofen piconol tended to be improved as compared with Comparative Example 5. The inclusion of adipic acid not only effectively controls the deeper penetration of ibuprofen piconol into the skin layer, but also has the unpredictable effect of improving the stability of ibuprofen piconol. I understood it.

Examples of formulations (formulation examples) of the external composition for skin of the present invention are shown below. The following can all be prepared by a conventional method. The present invention is not limited to these prescription examples.

According to the external composition for skin of the present invention, (A) has 3 to 10 carbon atoms and contains a dicarboxylic acid having a carboxyl group at both ends, so that (B) an anti-inflammatory component and an antibacterial component It is possible to effectively control the deeper penetration of the skin layer of at least one component selected from the group. Therefore, according to the present invention, an external composition for skin capable of reducing dermatitis and skin irritation caused by the penetration of an active ingredient such as the above component (B) into the deeper part of the skin layer is designed. can do. In addition, by storing the component (B) above the skin layer, it is possible to design a composition for external use on the skin with further improved effectiveness.

Claims (8)

At least one selected from the group consisting of (A) a dicarboxylic acid having 3 to 10 carbon atoms and having a carboxyl group at both ends, and (B) an anti-inflammatory component (b1) and an antibacterial component (b2). An external composition for skin containing an ingredient. (A) The composition for external use on the skin according to claim 1, wherein the dicarboxylic acid has 4 to 9 carbon atoms. The composition for external use on the skin according to claim 1 or 2, wherein the anti-inflammatory component (b1) is a non-steroidal anti-inflammatory and analgesic component. The composition for external use on the skin according to any one of claims 1 to 3, wherein the antibacterial component (b2) is isopropylmethylphenol. The external composition for skin according to any one of claims 1 to 4, wherein the component (B) contains an anti-inflammatory component (b1) and an antibacterial component (b2). The composition for external use on the skin according to any one of claims 1 to 5, wherein the (A) dicarboxylic acid is at least one selected from the group consisting of adipic acid, azelaic acid, tartaric acid, and succinic acid. (A) From (B) anti-inflammatory component (b1) and antibacterial component (b2) in the preparation, which comprises using a dicarboxylic acid having 3 to 10 carbon atoms and having a carboxyl group at both ends. A method for controlling the skin permeability of at least one component selected from the group. (A) From (B) anti-inflammatory component (b1) and antibacterial component (b2) in the preparation, which comprises using a dicarboxylic acid having 3 to 10 carbon atoms and having a carboxyl group at both ends. A method for reducing skin irritation caused by at least one component selected from the group.