Topical skin preparations

Abstract

To provide an external preparation for skin which can maintain an α gel structure of a coating film containing an active ingredient for a long period of time and can inhibit the permeation of irritating substances such as allergens and bacteria into the skin for a long period of time.SOLUTION: There is provided an α gel external preparation for skin which comprises the following components (A) to (D), wherein the mass ratio (C) / (A) of the component (C) to the component (A) is 0.4 or more and 40 or less. (A) an amino acid or its salt, (B) a medicinal component selected from a non-steroidal anti-inflammatory agent, a steroidal anti-inflammatory agent, a bactericide, an antibacterial or antifungal agent, an antiviral agent, an immunosuppressive agent, a local anesthetic and an antipruritic agent, (C) an ionic surfactant (excluding that having an amino acid as a counter ion) and (D) water.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a topical skin preparation.

Background Art

[0002] As factors of inflammatory skin diseases, particularly atopic dermatitis, an excessive reaction of the living body to an antigen (allergen), that is, an immunological abnormality and an abnormality of the skin barrier function are known. In normal skin, in the stratum corneum, natural moisturizing factors such as sebum, amino acids, and urea, and intercellular lipids of keratinocytes such as ceramides and fatty acids keep the water content of the skin constant. In contrast, in atopic dermatitis, these factors in the stratum corneum decrease, the stratum corneum undergoes structural abnormalities, and it is known that the skin barrier function is reduced or destroyed. Therefore, water evaporation from the inside of the skin is enhanced, the water content of the stratum corneum also decreases, and allergens from the outside of the skin easily penetrate.

[0003] In addition to atopic dermatitis, for improving skin symptoms that are easily affected by environmental allergens, bacteria, etc., such as suppurative diseases, it is required to structurally stabilize an α-gel preparation containing an active ingredient on the skin for a long time and reduce the contact and penetration of irritating substances such as allergens and bacteria to the skin.

[0004] Patent Document 1 discloses that a topical skin preparation containing a higher alcohol, two or more specific nonionic surfactants, a phospholipid or a specific anionic surfactant, a specific medicinal ingredient, and water forms a dry film having a uniform lamellar structure on the skin, stably holds the medicinal ingredient, and can suppress the penetration of allergens. In addition, Patent Document 2 describes a topical composition containing a heparin-like substance and a specific amino acid component, Patent Document 3 describes a topical skin composition in which ceramide and amino acid are blended in a certain quantitative ratio, and Patent Document 4 describes an emulsified composition containing pyrrolidone carboxylic acid and ufemamate.

Prior Art Documents

Patent Documents

[0005] [Patent Document 1] Japanese Patent Publication No. 2021-6521 [Patent Document 2] Japanese Patent Publication No. 2021-59524 [Patent Document 3] Japanese Patent Publication No. 2008-308462 [Patent Document 4] Japanese Patent Publication No. 2021-91609 [Overview of the project] [Problems that the invention aims to solve]

[0006] However, while the technology described in Patent Document 1 can suppress the penetration of irritants such as allergens and bacteria into the skin by a dried α-gel structure film, it has been found that there is room for improvement in stabilizing the α-gel structure on the skin for a long period of time and maintaining the effect of suppressing the penetration of irritants for a long period of time. Furthermore, Patent Documents 2 to 4 do not describe how to stabilize the α-gel structure film over time.

[0007] Therefore, the present invention relates to an α-gel skin topical preparation composition that can maintain the α-gel structure of a coating film containing an active ingredient for a long period of time, thereby suppressing the penetration of irritating substances to the skin, such as allergens and bacteria, for a long period of time. [Means for solving the problem]

[0008] The inventors have found that by using an amino acid together with an ionic surfactant, or by using an ionic surfactant with an amino acid as a counterion, the structure of the α-gel containing the active ingredient can be maintained for a long time in the dried film after application to the skin. Furthermore, they have found that this can quickly reduce the level of itchiness in diseased skin, improve transepidermal water loss (TEWL) and ceramide levels to healthy levels, and also improve skin pigmentation.

[0009] The present invention provides an α-gel topical skin preparation composition containing the following components (A), (B), (C), and (D), wherein the mass ratio of component (C) to component (A), (C) / (A), is 0.4 or more and 40 or less. (A) Amino acids or their salts (B) Pharmacologically active ingredients selected from nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritics. (C) Ionic surfactants (excluding those with amino acids as counterions) (D) Water

[0010] Furthermore, the present invention provides an α-gel topical skin preparation composition containing the following components (B), (Ca), and (D). (B) Pharmacologically active ingredients selected from nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritics. (Ca) Ionic surfactant with amino acids as counterions (D) Water [Effects of the Invention]

[0011] The topical skin preparation composition of the present invention can maintain the α-gel structure of the coating film containing the active ingredient for a long period of time, thereby suppressing the penetration of irritants such as allergens and bacteria into the skin for an extended period. [Modes for carrying out the invention]

[0012] [Component (A): Amino acid or its salt] The amino acids can be acidic, neutral, or basic. They can also be D-forms, L-forms, or mixtures of D and L-forms, with the L-form being preferred. Examples of acidic amino acids include glutamic acid, aspartic acid, and pyrrolidone carboxylic acid. Examples of neutral amino acids include glycine, alanine, phenylalanine, leucine, isoleucine, cysteine, methionine, tyrosine, valine, threonine, serine, proline, tryptophan, asparagine, and glutamine. Examples of basic amino acids include lysine, arginine, and histidine. Among these amino acids, those with bulkier side chains are more effective in maintaining a long-lasting inhibitory effect on irritant penetration on the skin. Specifically, arginine, lysine, glutamic acid, pyrrolidone carboxylic acid, alanine, and glycine are preferred, with arginine, lysine, glutamic acid, and pyrrolidone carboxylic acid being more preferred. Examples of salts of these amino acids include sodium salts, potassium salts, hydrochloride salts, and phosphate salts. Component (A) can be used individually or in combination of two or more components.

[0013] The content of component (A) in the topical skin preparation composition of the present invention is preferably 0.005% by mass or more, more preferably 0.01% by mass or more, even more preferably 0.015% by mass or more, and even more preferably 0.02% by mass or more, from the viewpoint of maintaining an effect of suppressing the penetration of irritants on the skin for a long period of time, and from the viewpoint of forming a good emulsified state, it is preferably 1.2% by mass or less, more preferably 1.0% by mass or less, even more preferably 0.5% by mass or less, and even more preferably 0.2% by mass or less.

[0014] [Ingredient (B): A medicinal ingredient selected from nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritics] Examples of nonsteroidal anti-inflammatory drugs include ufenamate, ibuprofen piconol, glycol salicylate, actarit, adapalene, acemetacin, ampiroxicam, amfenac, ibuprofen, indomethacin, etodolac, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, tiaprofenic acid, tenoxicam, delgocitinib, naproxen, piroxicam, felbinac, pranoprofen, flurbiprofen, mefenamic acid, medicoxib, meloxicam, mofezolac, refecoxib, loxoprofen, lobenzarit, lornoxicam, and their salts.

[0015] Steroidal anti-inflammatory agents include clobetasol propionate, diflorasone acetate, mometasone furoate, betamethasone butyrate propionate, fluocinonide, betamethasone dipropionate, difluprednate, amcinonide, diflucortolone valerate, hydrocortisone butyrate propionate, deprodone propionate, dexamethasone propionate, dexamethasone valerate, betamethasone valerate, and Bec Examples include lometasone propionate, fluocinolone acetonide, prednisolone valerate acetate, triamcinolone acetonide, alclometasone propionate, clobetasone butyrate, hydrocortisone butyrate, prednisolone, dexamethasone acetate, hydrocortisone acetate, hydrocortisone valerate, dexamethasone metasulfobenzoate sodium, prednisolone valerate, dexamethasone, and hydrocortisone.

[0016] Examples of disinfectants include chlorhexidine gluconate, sodium copper chlorophyllin, isopropylmethylphenol, cetylpyridinium chloride hydrate, benzethonium chloride, benzalkonium chloride, resorcinol, zinc oxide, sulfur, salicylic acid, acrinol hydrate, chlorhexidine gluconate, homosulfamine, homosulfamine hydrochloride, povidone-iodine, iodine / potassium iodide, mercurochrome, hydrogen peroxide, cresol, iodoform, thymol, chlorhexidine hydrochloride, and trichlorocarbanilide.

[0017] Antibacterial or antifungal agents include undecylenic acid, zinc undecylenate, phenyl-11-iodo-10-undecinoate, exalamide, clotrimazole, econazole nitrate, thioconazole, zinc diethyldithiocarbamate, cyclopiroxolamine, siccanicin, tricomycin, pyrrolnitrin, thianthol, 2,4,6-tribromphenylcaproate, trimethylcetylammonium pentachlorophenate, tolcyclate, tolnaftate, haloprozine, hibiscus bark, berberine benzoate, decalinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate solution, decalinium acetate, hinokitiol, rebrucin, benzoyl peroxide, and nadifloxane. Examples include levofloxan, clindamycin phosphate, benzoic acid, chlorobutanol, acetic acid, phenol, iodine tincture, diphenylpyraline hydrochloride, diphenhydramine salicylate, diphenylimidazole, chlorpheniramine maleate, chloramphenicol, oxytetracycline hydrochloride, dibucaine hydrochloride, procaine hydrochloride, lidocaine hydrochloride, aldioxa, diethyl phthalate, chlorohydroxyaluminum, sulfonamides, polymyxin B sulfate, colistin sulfate, bacitracin, fradiomycin sulfate, miconazole nitrate, gentamicin sulfate, pentamidine isethionate, silver sulfadiazine, oxiconazole nitrate, sulconazole nitrate, bifonazole, neticonazole hydrochloride, lanoconazole, tenafine hydrochloride, amorolfine hydrochloride, terbinafine hydrochloride, and butenafine hydrochloride.

[0018] Examples of antiviral agents include acyclovir, adenine arabinoside, penciclovir, ganciclovir, vidarabine, famciclovir, valaciclovir, amenamevir, and pharmaceutically acceptable salts thereof.

[0019] Examples of immunosuppressive agents include cyclosporine, tacrolimus, and paclitaxel.

[0020] Examples of local anesthetics include lidocaine, mepivacaine, bupivacaine, ropivacaine, levobupivacaine, dibucaine, dibucaine hydrochloride, ethyl aminobenzoate, and the like.

[0021] Examples of antipruritics include antihistamines such as diphenhydramine and / or its salts, chlorpheniramine and / or its salts, and the like, and other examples include chlorotrimeton.

[0022] Generally, when the active ingredient is oil-soluble, after application to the skin, the solid fat in the formulation dissolves into this oil-soluble active ingredient over time, causing the emulsion structure to collapse, and it becomes even more difficult to maintain the α-gel structure for a long time, resulting in the problem that the inhibitory effect on the permeation of irritants cannot be maintained for a long time. However, according to the present invention, even when an oil-soluble active ingredient is used, the α-gel structure can be maintained for a long time, and the inhibitory effect on the permeation of irritants can also be maintained for a long time. Therefore, the present invention is particularly useful when the active ingredient of component (B) is oil-soluble.

[0023] These active ingredients can be used alone or in combination of two or more. The preferred content of component (B) in the skin external preparation composition of the present invention differs depending on whether component (B) is an active ingredient other than a steroid anti-inflammatory agent or a steroid anti-inflammatory agent.

[0024] When component (B) is a pharmacoactive ingredient other than a steroidal anti-inflammatory agent, the content of the steroidal anti-inflammatory agent in the topical skin preparation composition of the present invention is preferably 0.1% by mass or more, more preferably 0.3% by mass or more, and even more preferably 0.5% by mass or more, from the viewpoint of the efficacy of the drug, and preferably 8.0% by mass or less, more preferably 5.0% by mass or less, and even more preferably 3.0% by mass or less, from the viewpoint of maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time.

[0025] When component (B) is a steroidal anti-inflammatory agent, the content of the steroidal anti-inflammatory agent in the topical skin preparation composition of the present invention is preferably 0.01% by mass or more, more preferably 0.025% by mass or more, and even more preferably 0.05% by mass or more, from the viewpoint of the efficacy of the drug, and preferably 0.8% by mass or less, more preferably 0.5% by mass or less, and even more preferably 0.3% by mass or less, from the viewpoint of maintaining the effect of suppressing the penetration of irritants on the skin for a long period of time and suppressing drug aggregation in the α-gel.

[0026] [Ingredient (C): Ionic surfactant (excluding those with amino acids as counterions)] As the ionic surfactant of component (C), any of anionic surfactants, cationic surfactants, or amphoteric surfactants can be used. Among these, anionic surfactants and cationic surfactants are preferred, and cationic surfactants are more preferred, from the viewpoint of maintaining the effect of suppressing the penetration of irritants on the skin for a long period of time.

[0027] Examples of anionic surfactants include carboxylate types such as N-acyl amino acids, fatty acids, alkyl ether carboxylic acids, polyoxyethylene alkyl ether carboxylic acids, acyl lactic acid, N-acyl methylalanine, N-acyl sarcosine, diacyl amino acids and their salts; sulfonate types such as alkanesulfonic acids, α-olefin sulfonic acids, α-sulfo fatty acid methyl esters, acyl isethionic acid, alkyl sulfosuccinic acid, N-acyl methyl taurine and their salts; sulfate types such as alkyl sulfates, polyoxyethylene alkyl sulfates, alkyl ether sulfates, polyoxyethylene alkyl ether sulfates, fatty acid alkanolamide sulfates and their salts; and phosphate types such as alkyl phosphates, polyoxyethylene alkyl ether phosphates and their salts.

[0028] As anionic surfactants, from the viewpoint of maintaining an effect of suppressing the penetration of irritants on the skin for a long period of time, it is preferable to include one or more selected from N-acyl amino acids, alkyl ether carboxylic acids, diacyl glutamate lysine, alkyl sulfosuccinic acid, N-acylmethyl taurine, alkyl sulfate esters, polyoxyethylene alkyl sulfate esters, alkyl phosphate esters, polyoxyethylene alkyl ether phosphate and salts thereof, and from the viewpoint of maintaining an effect of suppressing the penetration of irritants on the skin for a long period of time, it is preferable to include one or more selected from N-acyl amino acids, alkyl ether carboxylic acids, diacyl glutamate lysine, alkyl sulfosuccinic acid, N-acylmethyl taurine, alkyl sulfate esters, polyoxyethylene alkyl sulfate esters, polyoxyethylene alkyl ether It is more preferable to include one or more selected from acyl acid and its salts, even more preferable to include one or more selected from N-acyl amino acids, alkyl ether carboxylic acids, diacyl glutamate lysine, alkyl sulfosuccinic acid, N-acylmethyl taurine, polyoxyethylene alkyl sulfate esters, polyoxyethylene alkyl ether phosphate and its salts, even more preferable to include one or more selected from N-acyl amino acids, diacyl glutamate lysine, N-acylmethyl taurine, polyoxyethylene alkyl ether phosphate and its salts, and even more preferable to include one or more selected from N-acyl amino acids, N-acylmethyl taurine and its salts.

[0029] Examples of N-acylmethyltaurines and their salts include N-myristoyl-N-methyltaurine, N-lauroyl-N-methyltaurine, N-stearoyl-N-methyltaurine, and their salts. Examples of N-acylamino acids and their salts include N-lauroyl-L-glutamic acid, N-stearoyl-L-glutamic acid, N-myristoyl-L-glutamic acid, N-palm fatty acid glutamic acid, and other N-acylglutamic acids and their salts. Examples of fatty acids and their salts include lauric acid, palmitic acid, stearic acid, and other fatty acids with 12 to 24 carbon atoms and their salts. Examples of alkyl ether carboxylic acids and their salts include polyoxyethylene lauryl ether acetate and its salts. Examples of diacylglutamic acid lysine and its salts include dilauroylglutamic acid lysine and its salts. Examples of alkyl sulfosuccinic acid and its salts include di-2-ethylhexyl sulfosuccinic acid and its salts. Examples of alkyl sulfate esters and their salts include lauryl sulfate and its salts. Examples of polyoxyethylene alkyl sulfate esters and their salts include polyoxyethylene lauryl sulfate and its salts. Examples of alkyl phosphate and its salts include monomyristyl phosphate, monostearyl phosphate, di(C12-15)pareth-8-phosphate and their salts. Examples of polyoxyethylene alkyl ether phosphate and its salts include polyoxyethylene oleyl ether phosphate, polyoxyethylene cetyl ether phosphate, polyoxyethylene stearyl ether phosphate and their salts.

[0030] Examples of salt structures constituting these anionic surfactant salts include alkali metal salts such as sodium salts and potassium salts; and alkanolamine salts such as triethanolamine salts. These anionic surfactants can be used individually or in combination of two or more.

[0031] Cationic surfactants include sphingosine salts, aliphatic amine salts, quaternary ammonium salts, acylarginine ester salts, alkylamidoamines and their salts, and benzalkonium chloride. From the viewpoint of maintaining moisturizing effects and inhibiting the penetration of irritants on the skin for a long period of time, it is preferable to include one or more selected from sphingosine salts, monoC12-24 alkyltrimethylammonium salts, diC12-24 alkyldimethylammonium salts, diacylethylhydroxyethylmonium methosulfate, acylarginine ester salts, alkylamidoamine salts, and benzalkonium chloride, and it is more preferable to include one or more selected from distearyldimethylammonium chloride, behenamidopropyldimethylamine lactate, acylarginine ethyl ester salts, and benzalkonium chloride.

[0032] Examples of mono-C12-24 alkyltrimethylammonium salts include lauryltrimethylammonium chloride, stearyltrimethylammonium chloride, and behenyltrimethylammonium chloride. Examples of di-C12-24 alkyldimethylammonium salts include dilauryldimethylammonium chloride, distearyldimethylammonium chloride, and dibehenyldimethylammonium chloride. Examples of diacylethylhydroxyethylmonium methosulfate include dicocoylethylhydroxyethylmonium methosulfate. Examples of alkylamidoamine salts include N-(3-(dimethylamino)propyl)docosanamide (also known as behenamidopropyldimethylamine) and its salts. One or more of these cationic surfactants can be used.

[0033] Among the cationic surfactants used in the present invention, sphingosine salts are composed of sphingosine compounds and acidic substances. As sphingosine compounds, naturally derived sphingosine compounds or synthetic products having the same structure, and their derivatives (hereinafter referred to as natural-type sphingosine) or pseudo-type sphingosine compounds having a sphingosine structure (hereinafter referred to as pseudo-type sphingosine) are preferred.

[0034] Examples of natural sphingosine include natural sphingosine, dihydrosphingosine, phytosphingosine, sphingadienine, dehydrosphingosine, dehydrophytosphingosine, and their N-alkyl forms (e.g., N-methyl forms). These sphingosines may be the optically active natural form (D(+) form), the optically active unnatural form (L(-) form), or a mixture of natural and unnatural forms. The relative stereochemistry of the above compounds may be that of the natural form, or other unnatural forms, or a mixture thereof. Furthermore, PHYTOSPHINGOSINE (INCI name; 8th Edition) and those represented by the following formula are preferred.

[0035] [ka]

[0036] These can be either natural extracts or synthetic compounds, and commercially available products can be used. Examples of commercially available natural sphingosine include D-Sphingosine (4-Sphingenine) (SIGMA-ALDRICH), DS-phytosphingosine (DOOSAN), and phytosphingosine (Cosmofarm).

[0037] Specific examples of pseudo-sphingosine include the following pseudo-sphingosine(i) to (iv), and 1-(2-hydroxyethylamino)-3-isostearyloxy-2-propanol.

[0038] [ka]

[0039] As for sphingosine compounds, natural sphingosine, phytosphingosine, and pseudo-sphingosine are preferred, pseudo-sphingosine is more preferred, and pseudo-sphingosine(ii) and 1-(2-hydroxyethylamino)-3-isostearyloxy-2-propanol are even more preferred.

[0040] Examples of acidic substances that constitute salts with these natural sphingosine, phytosphingosine, and pseudo-sphingosine include inorganic acids such as phosphoric acid and hydrochloric acid; monocarboxylic acids such as acetic acid; dicarboxylic acids such as succinic acid; and oxycarboxylic acids such as citric acid, lactic acid, and malic acid. Among these, succinate and lactate salts of natural sphingosine, phytosphingosine, or pseudo-sphingosine (pseudo-sphingosine(II), 1-(2-hydroxyethylamino)-3-isostearyloxy-2-propanol) are preferred.

[0041] Among these cationic surfactants, benzalkonium chloride and phytosphingosine are preferred from the viewpoint of maintaining an effect of suppressing the penetration of irritants on the skin for a long period of time.

[0042] Examples of amphoteric surfactants include phospholipids, alkyldimethylamine oxides, alkylcarboxybetaines, alkylsulfobetaines, amide amino acid salts, and alkylamidopropyl betaines. Among these, alkylamidopropyl betaines, soybean phospholipids, and hydrogenated soybean phospholipids are preferred, with hydrogenated soybean phospholipids being even more preferred, from the viewpoint of maintaining an effect of suppressing the penetration of irritants on the skin for a long period of time.

[0043] The content of component (C) in the topical skin preparation composition of the present invention is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, and even more preferably 0.3% by mass or more, from the viewpoint of improving the storage stability of the emulsified state and maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time. Furthermore, from the viewpoint of smoothness during application and maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time, it is preferably 1.0% by mass or less, more preferably 0.8% by mass or less, and even more preferably 0.6% by mass or less.

[0044] The mass ratio (C) / (A) of component (C) to component (A) is 0.4 or higher, preferably 1.0 or higher, more preferably 2.0 or higher, and even more preferably 5.0 or higher, from the viewpoint of forming a good emulsified state, and from the viewpoint of maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time, it is 40 or lower, preferably 30 or lower, more preferably 25 or lower, and even more preferably 17 or lower.

[0045] Furthermore, the mass ratio of the sum of components (A) and (C) to component (B), [(A)+(C)] / (B), differs depending on whether component (B) is a steroid anti-inflammatory drug or a steroid anti-inflammatory drug. When component (B) is a pharmacoactive ingredient other than a steroidal anti-inflammatory agent, the mass ratio [(A)+(C)] / (B) is preferably 0.05 or higher, more preferably 0.14 or higher, and even more preferably 0.3 or higher, from the viewpoint of forming a good emulsified state and maintaining an effect of inhibiting the penetration of irritants on the skin for a long period of time. Furthermore, from the viewpoint of the efficacy of the drug and smoothness during application, it is preferably 3.0 or lower, more preferably 2.0 or lower, and even more preferably 1.0 or lower. When component (B) is a steroidal anti-inflammatory agent, the mass ratio [(A)+(C)] / (B) is preferably 0.8 or higher, more preferably 1.4 or higher, and even more preferably 2.5 or higher, from the viewpoint of suppressing drug aggregation in the α-gel and maintaining the effect of suppressing the penetration of irritants on the skin for a long period of time. Furthermore, from the viewpoint of the drug's effect and smoothness during application, it is preferably 20 or lower, more preferably 15 or lower, and even more preferably 10 or lower.

[0046] [Component (Ca): Ionic surfactant with amino acids as counterions] Instead of using components (A) and (C) in combination, an ionic surfactant with an amino acid as the counterion can be used as component (Ca). As component (Ca), an amino acid salt of the ionic surfactant listed as component (C) above can be used. Examples of counterions for anionic surfactants include basic amino acid salts such as L-arginine salt, L-histidine salt, and L-lysine salt, while examples of counterions for cationic surfactants include acidic amino acids such as glutamic acid, aspartic acid, and pyrrolidone carboxylic acid.

[0047] Specific examples of component (Ca) include phytosphingosine derivatives such as phytosphingosine salt, cocoyl arginine ethyl glutamate, lauroyl arginine isopropyl glutamate, cocoyl arginine ethylpyrrolidone carboxylate, cocoyl arginine isopropylpyrrolidone carboxylate, cocoyl arginine isobutylpyrrolidone carboxylate, and lauroyl arginine ethylpyrrolidone carboxylate, as well as acidic amino acid salts of acylarginine esters.

[0048] When the topical skin preparation composition of the present invention contains component (Ca), its content is preferably 0.1% by mass or more, more preferably 0.2% by mass or more, and even more preferably 0.3% by mass or more, from the viewpoint of improving the storage stability of the emulsified state and maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time. Furthermore, from the viewpoint of smoothness during application and maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time, it is preferably 1.0% by mass or less, more preferably 0.8% by mass or less, and even more preferably 0.6% by mass or less.

[0049] Furthermore, the mass ratio (Ca) / (B) of component (B) differs depending on whether component (B) is a steroid anti-inflammatory drug or a steroid anti-inflammatory drug. When component (B) is a pharmacoactive ingredient other than a steroid anti-inflammatory agent, the mass ratio (Ca) / (B) is preferably 0.05 or higher, more preferably 0.14 or higher, and even more preferably 0.3 or higher, from the viewpoint of forming a good emulsified state and maintaining an effect of inhibiting the penetration of irritants on the skin for a long period of time. Furthermore, from the viewpoint of the efficacy of the drug and smoothness during application, it is preferably 3.0 or lower, more preferably 2.0 or lower, and even more preferably 1.0 or lower. When component (B) is a steroidal anti-inflammatory agent, the mass ratio (Ca) / (B) is preferably 0.8 or higher, more preferably 1.4 or higher, and even more preferably 2.5 or higher, from the viewpoint of suppressing drug aggregation in the α-gel and maintaining the effect of suppressing the penetration of irritants on the skin for a long period of time. Furthermore, from the viewpoint of the drug's effectiveness and smoothness during application, it is preferably 20 or lower, more preferably 15 or lower, and even more preferably 10 or lower.

[0050] [Component (D): Water] The topical skin preparation composition of the present invention contains water, component (D), as a medium. From the viewpoint of smoothness during application, the content of component (D) in the topical skin preparation composition of the present invention is preferably 50% by mass or more, more preferably 55% by mass or more, more preferably 60% by mass or more, even more preferably 65% ​​by mass or more, and even more preferably 70% by mass or more. Furthermore, from the viewpoint of maintaining the effect of inhibiting the penetration of irritants on the skin for a long period of time, it is preferably 95% by mass or less, more preferably 90% by mass or less, even more preferably 87% by mass or less, and even more preferably 85% by mass or less.

[0051] [Ingredient (E): Higher alcohol] The topical skin preparation composition of the present invention may further contain a higher alcohol as component (E) in order to form a good α-gel structure. Examples of higher alcohols include aliphatic alcohols having 14 to 20 carbon atoms, with linear aliphatic alcohols being preferred, and saturated aliphatic alcohols being preferred. Specific examples include myristyl alcohol, cetyl alcohol, stearyl alcohol, and arachidyl alcohol.

[0052] Component (E) can be used individually or in combination of two or more, but from the viewpoint of storage stability of the emulsified state, it is preferable to use a combination of two or more compounds with different numbers of carbon atoms. Furthermore, from the same viewpoint, the mass ratio (e1) / (e2) of component (E) from (e2) long-chain (18 or more carbon atoms to 20 or less carbon atoms) aliphatic alcohol to (e1) short-chain (14 or more carbon atoms to less than 18 carbon atoms) aliphatic alcohol is preferably 0.1 or more, more preferably 0.6 or more, even more preferably 1.0 or more, and also preferably 7.0 or less, more preferably 5.0 or less, and even more preferably 3.0 or less.

[0053] The content of component (E) in the topical skin preparation composition of the present invention is preferably 0.3% by mass or more, more preferably 0.5% by mass or more, and even more preferably 0.8% by mass or more, from the viewpoint of maintaining an effect of suppressing the penetration of irritants on the skin for a long period of time, and from the viewpoint of smoothness during application, it is preferably 4.0% by mass or less, more preferably 3.0% by mass or less, and even more preferably 2.0% by mass or less.

[0054] [Ingredient (F): Nonionic surfactant] The topical skin preparation composition of the present invention may further contain a nonionic surfactant as component (F) in order to maintain an effect of inhibiting the penetration of irritants on the skin for a long period of time. Examples of nonionic surfactants include polyhydric alcohol fatty acid ester type nonionic surfactants, preferably sucrose fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, monofatty acid sorbitan, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene fatty acid esters, and polyoxyethylene hydrogenated castor oil.

[0055] Component (F) can be used alone or in combination of two or more, but it is preferable to use it in combination of two or more. As for the combination of two or more polyhydric alcohol fatty acid esters, from the viewpoint of maintaining the effect of suppressing the penetration of irritants on the skin for a long period of time, a combination of one or more polyhydric alcohol fatty acid esters having (f1) an HLB of 3 to 7, more preferably 4 to 6, and one or more polyhydric alcohol fatty acid esters having (f2) an HLB of 11 to 16, more preferably 13 to 15, is preferred. Also from the same viewpoint, the mass ratio (f1) / (f2) is preferably 0.25 or more, more preferably 0.4 or more, even more preferably 0.6 or more, and also preferably 4.0 or less, more preferably 2.0 or less, and even more preferably 1.0 or less.

[0056] The content of component (F) in the skin topical preparation composition of the present invention is preferably 0.3% by mass or more, more preferably 0.5% by mass or more, and even more preferably 1.0% by mass or more, from the viewpoint of storage stability in the emulsified state, and preferably 5.0% by mass or less, more preferably 4.0% by mass or less, and even more preferably 3.0% by mass or less, from the viewpoint of smoothness when applied.

[0057] In the topical skin preparation composition of the present invention, the mass ratio (E) / (F) of component (E) to component (F) is preferably 0.3 or higher, more preferably 0.35 or higher, and even more preferably 0.4 or higher, from the viewpoint of maintaining the effect of suppressing the penetration of irritants on the skin for a long period of time, and from the viewpoint of smoothness during application, it is preferably 3.0 or lower, more preferably 2.5 or lower, even more preferably 2.0 or lower, and even more preferably 0.8 or lower.

[0058] [Ingredient (G): Ceramides] The topical skin preparation composition of the present invention may further contain ceramides as component (G) in order to further improve the skin's barrier function.

[0059] Ceramides include one or more selected from natural ceramides and pseudo-ceramides. Specific examples of natural ceramides include ceramides Type 1-7, which are amidated sphingosine, dihydrosphingosine, phytosphingosine, or sphingadienine, and also include their N-alkyl forms (e.g., N-methyl forms). Specific examples of pseudo-ceramides include (N-hexadecyloxyhydroxypropyl)-N-hydroxyhexadecanamide, (N-hexadecyloxyhydroxypropyl)-N-hydroxydecanamide, and N-[2-(2,3-dihydroxypropyloxy)-3-hexadecyloxypropyl]-N-3-methoxypropyltetradecaneamide. Component (G) can be used individually or in combination of two or more.

[0060] The content of component (G) in the topical skin preparation composition of the present invention is preferably 1.0% by mass or more, more preferably 1.5% by mass or more, and even more preferably 2.0% by mass or more, from the viewpoint of further improving the barrier function of the skin, and preferably 6.0% by mass or less, more preferably 5.0% by mass or less, and even more preferably 4.0% by mass or less, from the viewpoint of smoothness during application.

[0061] [Iss] The pH of the topical skin preparation composition of the present invention is preferably 7.5 or less, more preferably 7.0 or less, and even more preferably 6.5 or less, from the viewpoint of adjusting to the pH environment of normal skin and improving the stability of component (B). Furthermore, from the viewpoint of reducing skin irritation, the pH is preferably 3.5 or higher, more preferably 3.8 or higher, and even more preferably 4.0 or higher.

[0062] [Other ingredients] The skin topical preparation composition of the present invention may appropriately contain hydrocarbon oils, ether oils, ester oils, silicone oils, fluorinated oils, waxes, cholesterol derivatives, phytosterol derivatives, dipentaerythritol fatty acid esters, triglycerides, lanolin, lanosterol derivatives, oils other than higher alcohols such as petrolatum, polyhydric alcohols such as glycerin and propylene glycol, thickeners, moisturizers, humectants, colorants, preservatives, texture enhancers, powders, fragrances, whitening agents, antiperspirants, UV absorbers, antioxidants, and the like.

[0063] The α-gel topical skin preparation composition of the present invention contains components (A) to (C), or components (B) and (Ca), in predetermined proportions in water, thereby forming an α-gel structure even in the state of the composition before application. When applied to the skin, a stable dry film of the α-gel structure can be formed on the skin surface as the water evaporates. The α-gel structure can be confirmed by wide-angle X-ray diffraction, polarizing microscope, etc. [Examples]

[0064] Examples 1-29, Comparative Examples 1-4 Topical skin preparations were prepared according to the formulations shown in Tables 1-4, and each evaluation was performed according to the following methods and criteria.

[0065] [Method for evaluating the α-gel ratio in bulk] For each topical preparation, the intensity of the sharp diffraction peak characteristic of α-gel, appearing around the Bragg angle of 21.5°, was measured by wide-angle X-ray diffraction. The peak intensity of each topical preparation is expressed as a percentage, with the peak intensity of the topical preparation without component (B) in Example 1 set to 1.

[0066] [Method for evaluating the sustained effect of inhibiting the permeation of irritants] Each topical agent is placed on a membrane filter with a pore size of 5.0 μm at a concentration of 4 mg / cm³. 2Membrane filters were prepared by coating the membrane and drying it at 32°C and 30% humidity. One membrane filter was dried for 1 hour, and the other for 6 hours. Next, 1 μL of a dye aqueous solution (Fast Green FCF, 1 mg / mL) was dropped onto the dried membrane. After standing for 1 hour at 32°C and 30% humidity, the amount of dye permeation was measured using a densitometer. Permeability was expressed as a percentage of dye permeation with the uncoated membrane being set to 1, and the average of 3 to 4 measurements was used. Topical agents that showed low dye permeation with the 1-hour dried membrane filter and also low dye permeation with the 6-hour dried membrane filter were evaluated as having high sustained inhibition of irritant permeation.

[0067] [Method for evaluating the storage stability of emulsified products] The condition of each topical preparation (either creaming or aggregation) after storage at 50°C and -5°C for one month was evaluated visually according to the following criteria, and a score of C or higher was considered acceptable. A: No change B: The state changed slightly, but it was in a good emulsified state. C: The state has clearly changed, but no separation or gelation has occurred. D: Partial separation or gelation E: The whole thing separates or gels.

[0068] [Method for evaluating skin application (tightness)] Ten expert panelists conducted sensory evaluations of the feeling of tightness when each topical agent was applied. This shows the number of people who rated it as "no feeling of tightness (good)."

[0069] [Table 1]

[0070] [Table 2]

[0071] [Table 3]

[0072] [Table 4]

[0073] The following are examples of formulations for the topical skin preparation of the present invention.

[0074] Prescription Example 1: Anti-inflammatory and antipruritic topical cream (mass%) Pretnisolone 0.25 Phytosphingosine 0.15 Glutamic acid 0.09 Cetanol 0.9 Glycerin fatty acid ester 0.5 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 2.5 Ethyl [(methacryloyloxy)ethyl]dimethylammonium ethyl sulfate, N,N-dimethylacrylamide, polyethylene glycol dimethacrylate copolymer / polyethylene glycol mixture 0.15 Glycerin 20 Dimethylpolysiloxane 2 Polyethylene glycol 4 Phenoxyethanol 0.4 Purified water remaining amount

[0075] Prescription Example 2: Antipruritic topical cream (mass%) Diphenhydramine 1 Hydrogenated soybean phospholipid 0.2 N-acyl-L-sodium glutamate 0.2 Sodium pyrrolidone carboxylate 0.02 Stearyl alcohol 0.9 Glyceryl monostearate 0.5 Polyoxyethylene (20) sorbitan monostearate 0.8 Sorbitan monostearate 0.5 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 2.5 Hydrophobized hydroxypropyl methylcellulose 0.15 Glycerin 14 Dipropylene glycol 4 Squalane 1 Dimethylpolysiloxane 3 Succinic acid 0.02 Methyl parahydroxybenzoate 0.2 Heparin-like substance 0.3 Purified water remaining amount

[0076] Prescription Example 3: Antiviral Topical Cream (mass%) Acyclovir 5 N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate 0.4 Monosodium glutamate 0.02 Cetanol 0.9 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 3 Polyoxyethylene (20) sorbitan monostearate 1 Sorbitan monostearate 0.8 Dimethylpolysiloxane 3 Phenoxyethanol 0.4 Glycerin 20 Purified water remaining amount

[0077] Prescription Example 4: Antifungal Topical Cream (mass%) Miconazole nitrate 1 N-cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate 0.2 Hydrogenated soybean phospholipid 0.2 Arginine 0.02 Cetanol 3 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 2 Polyoxyethylene (20) sorbitan monostearate 1.2 Sorbitan monostearate 0.5 Light liquid paraffin 3 Methyl parahydroxybenzoate 0.3 Glycerin 20 Purified water remaining amount

[0078] Prescription Example 5: Antibacterial Topical Cream (mass%) Clindamycin phosphate 1 Hydrogenated soybean phospholipid 0.4 Monosodium glutamate 0.025 Stearyl alcohol 0.8 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 3 Polyoxyethylene (20) sorbitan monostearate 1.2 Sorbitan monostearate 0.6 Dimethylpolysiloxane 3 Phenoxyethanol 0.5 Glycerin 20 Purified water remaining amount

[0079] Prescription Example 6: Immunosuppressant Topical Cream (mass%) Tacrolimus 0.1 Hydrogenated soybean phospholipid 1 Sodium pyrrolidonecarboxylate 0.05 Stearyl alcohol 0.8 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 1.5 Polyoxyethylene (20) sorbitan monostearate 1.8 Sorbitan monostearate 1.2 Light liquid paraffin 3 Methyl parahydroxybenzoate 0.25 Glycerin 20 Purified water remaining amount

[0080] Prescription Example 7: Anti-inflammatory topical cream (mass%) Delgocitinib 0.25 Hydrogenated soybean phospholipid 0.5 Glycine 0.05 Cetyl alcohol 1 N-(Hexadecyloxyhydroxypropyl)-N-hydroxyethylhexadecanamide 2.5 Polyoxyethylene (20) sorbitan monostearate 0.9 Sorbitan monostearate 0.6 Squalane 3 Phenoxyethanol 0.45 Glycerin 10 Dipropylene glycol 10 Purified water remaining amount

Claims

1. The following components (A), (B), (C), and (D) It contains, The mass ratio of component (C) to component (A), (C) / (A), is 0.4 or more and 40 or less. The mass ratio of the sum of components (A) and (C) to component (B) [(A) + (C)] / (B) is between 0.8 and 20. Alpha gel skin topical preparation composition. (A) Amino acids or their salts (B) Medicinal components selected from steroid anti-inflammatory drugs (C) Ionic surfactants (excluding those with amino acids as counterions) (D) Water

2. The following components (A), (B), (C), and (D) It contains, The mass ratio of component (C) to component (A), (C) / (A), is 0.4 or more and 40 or less. The mass ratio of the sum of components (A) and (C) to component (B) [(A) + (C)] / (B) is between 0.05 and 1.

0. Alpha gel skin topical preparation composition. (A) Amino acids or their salts (B) A medicinal component selected from nonsteroidal anti-inflammatory drugs, antiseptics, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritics. (C) Ionic surfactants (excluding those with amino acids as counterions) (D) Water

3. The topical skin preparation composition according to claim 1 or 2, wherein the content of component (A) is 0.01% by mass or more and 1.2% by mass or less.

4. The topical skin preparation composition according to claim 1 or 2, wherein component (B) is an oil-soluble pharmacoactive ingredient.

5. The topical skin preparation composition according to claim 1 or 2, wherein component (C) is a cationic surfactant.

6. The skin topical preparation composition according to claim 5, wherein the cationic surfactant is benzalkonium chloride or phytosphingosine.

7. The topical skin preparation composition according to claim 1 or 2, further comprising a higher alcohol as component (E).

8. The topical skin preparation composition according to claim 1 or 2, further comprising a nonionic surfactant as component (F).

9. The topical skin composition according to claim 1 or 2, further comprising a higher alcohol as component (E) and a nonionic surfactant as component (F), wherein the mass ratio (E) / (F) of component (E) to component (F) in the topical skin composition is 0.3 or more and 3.0 or less.

10. The topical skin preparation composition according to claim 1 or 2, further comprising ceramides as component (G).

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