External preparation for skin

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 an external preparation for skin. [Background technology]

[0002] The causes of inflammatory skin diseases, especially atopic dermatitis, are known to be the body's excessive response to antigens (allergens), i.e., immunological abnormalities and abnormalities in the skin's barrier function. In normal skin, natural moisturizing factors such as sebum, amino acids, and urea, and intercellular lipids such as ceramides and fatty acids in the stratum corneum maintain a constant moisture content in the skin. In contrast, in atopic dermatitis, it is known that these factors in the stratum corneum decrease, causing structural abnormalities in the stratum corneum and reducing or destroying the skin's barrier function. As a result, water evaporation from within the skin increases, the moisture content of the stratum corneum decreases, and allergens from the outside of the skin become more easily invaded.

[0003] In order to improve skin conditions such as atopic dermatitis and suppurative diseases that are susceptible to environmental allergens and bacteria, it is necessary to stabilize the structure of the α-gel formulation containing the active ingredient on the skin for a long period of time and reduce the contact and penetration of skin irritants such as allergens and bacteria.

[0004] Patent Document 1 discloses that a skin topical 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 coating having a uniform lamellar structure on the skin, stably retaining the medicinal ingredient and suppressing the permeation of allergens. In addition, Patent Document 2 discloses a skin topical composition containing a specific amino acid component together with a heparinoid, Patent Document 3 discloses a skin topical composition containing ceramide and amino acid in a fixed ratio, and Patent Document 4 discloses an emulsion composition containing pyrrolidone carboxylic acid and ufenamate. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2021-6521 [Patent Document 2] Patent Publication No. 2021-59524 [Patent Document 3] JP 2008-308462 A [Patent Document 4] Patent Publication No. 2021-91609 Summary of the Invention [Problem to be solved by the invention]

[0006] However, although the technology described in Patent Document 1 can suppress the permeation of irritating substances such as allergens and bacteria into the skin by using a dry coating of the α-gel structure, it was found that there is room for improvement in terms of stabilizing the α-gel structure on the skin for a long period of time and maintaining the effect of suppressing the permeation of irritating substances for a long period of time. Furthermore, Patent Documents 2 to 4 do not disclose anything about stabilizing the coating of the α-gel structure 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 and inhibit the permeation of skin-irritating substances such as allergens and bacteria for a long period of time. [Means for solving the problem]

[0008] The inventors have discovered 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 period of time in the dried coating after application to the skin, and further that this quickly reduces the itching level of diseased skin, improves transepidermal water loss (TEWL) and ceramide levels to healthy levels, and also improves skin pigmentation.

[0009] The present invention provides an α-gel skin topical preparation composition comprising the following components (A), (B), (C), and (D), in which the mass ratio (C) / (A) of component (C) to component (A) is 0.4 or more and 40 or less. (A) Amino acid or its salt (B) A medicinal ingredient selected from nonsteroidal anti-inflammatory agents, steroidal anti-inflammatory agents, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritic agents. (C) Ionic surfactants (excluding those with amino acids as counterions) (D) Water

[0010] Furthermore, the present invention provides an α-gel skin topical preparation composition containing the following components (B), (Ca), and (D). (B) A medicinal ingredient selected from nonsteroidal anti-inflammatory agents, steroidal anti-inflammatory agents, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritic agents. (Ca) Ionic surfactant with amino acid as counterion (D) Water Effect of the Invention

[0011] The skin topical 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 inhibiting the permeation of irritating substances such as allergens and bacteria into the skin for a long period of time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] [Component (A): Amino acid or its salt] The amino acid may be any of acidic amino acids, neutral amino acids, and basic amino acids. In addition, it may be any of D-form, L-form, or a mixture of D-form and L-form, and L-form is preferable. 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, from the viewpoint of maintaining the effect of suppressing the permeation of irritating substances on the skin for a long time, those with bulky amino acid side chains are more effective, and specifically, arginine, lysine, glutamic acid, pyrrolidone carboxylic acid, alanine, and glycine are preferable, and arginine, lysine, glutamic acid, and pyrrolidone carboxylic acid are more preferable. In addition, examples of the salts of these include sodium salts, potassium salts, hydrochlorides, and phosphates. Component (A) can be used either alone or in combination of two or more.

[0013] The content of component (A) in the topical skin composition of the present invention is, from the viewpoint of maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, 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, and from the viewpoint of forming a good emulsified state, 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] [Component (B): a medicinal component selected from nonsteroidal anti-inflammatory agents, steroidal anti-inflammatory agents, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics, and antipruritic agents] Nonsteroidal anti-inflammatory agents 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, lefecoxib, loxoprofen, lobenzarit, lornoxicam, and salts thereof.

[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, dexamethasone propionate, dexamethasone valerate, betamethasone valerate, becquerel. Examples of such agents 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] Bactericides include chlorhexidine gluconate, sodium copper chlorophyllin, isopropyl methylphenol, 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] Examples of antibacterial or antifungal agents include undecylenic acid, zinc undecylenate, phenyl-11-iodo-10-undecynoate, exalamide, clotrimazole, econazole nitrate, tioconazole, zinc diethyldithiocarbamate, ciclopirox olamine, siccanin, trichomycin, pyrrolnitrin, thianthol, 2,4,6-tribromophenylcaproic acid ester, trimethylcetylammonium pentachlorophenate, tolciclate, tolnaftate, haloprogin, Hibiscus bark, berberine benzoate, dequalinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate solution, dequalinium acetate, hinokitiol, rebrucin, benzoyl peroxide, and nadifloxan. , levofloxacin, clindamycin phosphate, benzoic acid, chlorobutanol, acetic acid, phenol, tincture of iodine, diphenylpyraline hydrochloride, diphenhydramine salicylate, diphenylimidazole, chlorpheniramine maleate, chloramphenicol, oxytetracycline hydrochloride, dibucaine hydrochloride, procaine hydrochloride, lidocaine hydrochloride, aldioxa, diethyl phthalate, aluminum chlorhydrate, sulfa drugs, 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, butenafine hydrochloride, etc.

[0018] Antiviral agents include acyclovir, adenine arabinoside, penciclovir, ganciclovir, vidarabine, famciclovir, valacyclovir, amenamevir and pharma- ceutically acceptable salts thereof.

[0019] Immunosuppressants include cyclosporine, tacrolimus, and paclitaxel.

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

[0021] Antipruritic agents include antihistamines such as diphenhydramine and / or its salts, and chlorpheniramine and / or its salts, as well as crotamiton.

[0022] Generally, when the medicinal ingredient is oil-soluble, after application to the skin, the solid fat in the formulation dissolves in the oil-soluble medicinal ingredient over time, causing the emulsion structure to collapse, making it even more difficult to maintain the α-gel structure for a long time, and making it impossible to maintain the irritant permeation inhibitory effect for a long time. However, according to the present invention, even when an oil-soluble medicinal ingredient is used, the α-gel structure can be maintained for a long time, and the irritant permeation inhibitory effect can also be maintained for a long time, making the present invention particularly useful when the medicinal ingredient of component (B) is oil-soluble.

[0023] These medicinal 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 a medicinal ingredient other than a steroidal anti-inflammatory agent or a steroidal anti-inflammatory agent.

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

[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 is 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 inhibitory effect on the skin for a long period of time and inhibiting drug aggregation in the α-gel.

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

[0027] Examples of anionic surfactants include carboxylate-type surfactants such as N-acylamino acids, fatty acids, alkyl ether carboxylic acids, polyoxyethylene alkyl ether carboxylic acids, acyl lactic acids, N-acyl methyl alanines, N-acyl sarcosines, diacyl amino acids, and salts thereof; sulfonate-type surfactants such as alkanesulfonic acids, α-olefin sulfonic acids, α-sulfofatty acid methyl esters, acyl isethionic acids, alkyl sulfosuccinic acids, N-acyl methyl taurines, and salts thereof; sulfate-type surfactants such as alkyl sulfates, polyoxyethylene alkyl sulfates, alkyl ether sulfates, polyoxyethylene alkyl ether sulfates, fatty acid alkanolamide sulfates, and salts thereof; and phosphate-type surfactants such as alkyl phosphates, polyoxyethylene alkyl ether phosphoric acids, and salts thereof.

[0028] From the viewpoint of maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, the anionic surfactant preferably contains one or more selected from N-acyl amino acids, alkyl ether carboxylic acids, diacyl glutamic acid lysine, alkyl sulfosuccinic acids, N-acyl methyl taurines, alkyl sulfates, polyoxyethylene alkyl sulfates, alkyl phosphates, polyoxyethylene alkyl ether phosphates, and salts thereof, and more preferably contains one or more selected from N-acyl amino acids, alkyl ether carboxylic acids, diacyl glutamic acid lysine, alkyl sulfosuccinic acids, N-acyl methyl taurines, alkyl sulfates, polyoxyethylene alkyl sulfates, polyoxyethylene alkyl ether phosphates, and salts thereof. More preferably, the acidic acid ester contains one or more selected from N-acylamino acids, alkyl ether carboxylic acids, diacylglutamic acid lysine, alkylsulfosuccinic acids, N-acylmethyltaurines, polyoxyethylene alkyl sulfates, polyoxyethylene alkyl ether phosphates, and salts thereof, and even more preferably, the acidic acid ester contains one or more selected from N-acylamino acids, diacylglutamic acid lysine, N-acylmethyltaurines, polyoxyethylene alkyl ether phosphates, and salts thereof, and even more preferably, the acidic acid ester contains one or more selected from N-acylamino acids, N-acylmethyltaurines, and salts thereof.

[0029] Examples of N-acyl methyl taurine and its salts include N-myristoyl-N-methyl taurine, N-lauroyl-N-methyl taurine, N-stearoyl-N-methyl taurine, and their salts. Examples of N-acyl amino acids and their salts include N-acyl glutamic acids and their salts, such as N-lauroyl-L-glutamic acid, N-stearoyl-L-glutamic acid, N-myristoyl-L-glutamic acid, and N-palm fatty acid glutamic acid. Examples of fatty acids and their salts include fatty acids having 12 to 24 carbon atoms, such as lauric acid, palmitic acid, and stearic acid, and their salts. Examples of alkyl ether carboxylic acids and their salts include polyoxyethylene lauryl ether acetic acid and its salts. Examples of diacyl glutamic acid lysine and its salts include dilauroyl glutamic 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 their salts. Examples of polyoxyethylene alkyl sulfate esters and their salts include polyoxyethylene lauryl sulfate and its salts. Examples of alkyl phosphoric acid and its salts include monomyristyl phosphoric acid, monostearyl phosphoric acid, di(C12-15) pareth-8-phosphoric acid and their salts. Examples of polyoxyethylene alkyl ether phosphoric acid and its salts include polyoxyethylene oleyl ether phosphoric acid, polyoxyethylene cetyl ether phosphoric acid, polyoxyethylene stearyl ether phosphoric acid and their salts.

[0030] Examples of the salt structure constituting the salt of these anionic surfactants include alkali metal salts such as sodium salts and potassium salts, and alkanolamine salts such as triethanolamine salts. These anionic surfactants can be used alone or in combination of two or more.

[0031] Examples of the cationic surfactant include sphingosine salts, aliphatic amine salts, quaternary ammonium salts, acylarginine ester salts, alkylamidoamines and their salts, and benzalkonium chloride. From the viewpoint of maintaining the moisturizing effect and the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, it is preferable to include one or more selected from sphingosine salts, mono-C12-24 alkyltrimethylammonium salts, di-C12-24 alkyldimethylammonium salts, diacylethylhydroxyethylmonium methosulfate, acylarginine ester salts, alkylamidoamine salts, and benzalkonium chloride, and it is more preferable to include one or more selected from distearyl dimethylammonium chloride, behenamidopropyl dimethylamine lactate, acylarginine ethyl ester salts, and benzalkonium chloride.

[0032] Examples of mono C12-24 alkyl trimethyl ammonium salts include lauryl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, and behenyl trimethyl ammonium chloride. Examples of di C12-24 alkyl dimethyl ammonium salts include dilauryl dimethyl ammonium chloride, distearyl dimethyl ammonium chloride, and dibehenyl dimethyl ammonium chloride. Examples of diacyl ethyl hydroxyethyl monium methosulfate include dicocoyl ethyl hydroxyethyl monium methosulfate. Examples of alkyl amidoamine salts include N-(3-(dimethylamino)propyl) docosanamide (also known as behenamidopropyl dimethylamine) and its salts. One or more of these cationic surfactants can be used.

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

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

[0035] [ka]

[0036] These may be either naturally occurring extracts or synthetic products, and commercially available products can be used. Commercially available natural sphingosines include, for example, D-sphingosine (4-sphingosine) (Sigma-Aldrich), DS-phytosphingosine (DOOSAN), and phytosphingosine (Cosmopharm).

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

[0038] [ka]

[0039] As the sphingosines, 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 form 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] Of these cationic surfactants, benzalkonium chloride and phytosphingosine are preferred from the viewpoint of maintaining the effect of inhibiting the permeation of irritating substances 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 alkylamidopropylbetaines. Among these, from the viewpoint of maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, alkylamidopropylbetaines, soybean phospholipids, and hydrogenated soybean phospholipids are preferred, and hydrogenated soybean phospholipids are even more preferred.

[0043] The content of component (C) in the topical skin 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 viewpoints of improving the storage stability of the emulsified state and maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, and 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, from the viewpoints of smoothness upon application and maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time.

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

[0045] In addition, the mass ratio of the sum of components (A) and (C) to component (B), [(A) + (C)] / (B), differs depending on whether component (B) is an active ingredient other than a steroidal anti-inflammatory agent or a steroidal anti-inflammatory agent. When component (B) is an active ingredient other than a steroidal anti-inflammatory agent, the mass ratio [(A)+(C)] / (B) is preferably 0.05 or more, more preferably 0.14 or more, and even more preferably 0.3 or more, from the viewpoint of forming a good emulsified state and maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, and is preferably 3.0 or less, more preferably 2.0 or less, and even more preferably 1.0 or less, from the viewpoint of the efficacy of the drug and smoothness upon application. When component (B) is a steroidal anti-inflammatory agent, the mass ratio [(A)+(C)] / (B) is preferably 0.8 or more, more preferably 1.4 or more, and even more preferably 2.5 or more, from the viewpoint of suppressing drug aggregation in the α-gel and maintaining the inhibitory effect on the skin permeation of irritating substances for a long period of time; and from the viewpoint of the efficacy of the drug and smoothness upon application, it is preferably 20 or less, more preferably 15 or less, and even more preferably 10 or less.

[0046] [Component (Ca): Ionic surfactant with amino acid as counterion] Instead of using component (A) and component (C) in combination, an ionic surfactant with an amino acid as a counter ion can be used as component (Ca). As component (Ca), the amino acid salt of the ionic surfactant listed as component (C) can be used, and the counter ion of the anionic surfactant can be a basic amino acid salt such as L-arginine salt, L-histidine salt, or L-lysine salt, and the counter ion of the cationic surfactant can be an acidic amino acid such as glutamic acid, aspartic acid, or pyrrolidone carboxylic acid.

[0047] Specific examples of component (Ca) include phytosphingosines such as phytosphingosine glutamate, cocoyl arginine ethyl glutamate, lauroyl arginine isopropyl glutamate, cocoyl arginine ethyl pyrrolidone carboxylate, cocoyl arginine isopropyl pyrrolidone carboxylate, cocoyl arginine isobutyl pyrrolidone carboxylate, and lauroyl arginine ethyl pyrrolidone carboxylate, and acidic amino acid salts of acyl arginine esters.

[0048] When the skin topical preparation composition of the present invention contains the component (Ca), the content thereof 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 viewpoints of improving the storage stability of the emulsified state and maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, and 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, from the viewpoints of smoothness upon application and maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time.

[0049] In addition, the mass ratio (Ca) / (B) of component (Ca) to component (B) differs depending on whether component (B) is an active ingredient other than a steroidal anti-inflammatory drug or a steroidal anti-inflammatory drug. When component (B) is an active ingredient other than a steroidal anti-inflammatory agent, the mass ratio (Ca) / (B) is preferably 0.05 or more, more preferably 0.14 or more, and even more preferably 0.3 or more, from the viewpoint of forming a good emulsified state and maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, and is preferably 3.0 or less, more preferably 2.0 or less, and even more preferably 1.0 or less, from the viewpoint of the efficacy of the drug and smoothness upon application. When component (B) is a steroidal anti-inflammatory agent, the mass ratio (Ca) / (B) is preferably 0.8 or more, more preferably 1.4 or more, and even more preferably 2.5 or more, from the viewpoint of suppressing drug aggregation in the α-gel and maintaining the inhibitory effect on irritant permeation on the skin for a long period of time, and is preferably 20 or less, more preferably 15 or less, and even more preferably 10 or less, from the viewpoint of the efficacy of the drug and smoothness upon application.

[0050] [Component (D): Water] The skin topical preparation composition of the present invention contains water as a medium, which is component (D). The content of component (D) in the skin topical 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 from the viewpoint of smoothness during application, and 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 from the viewpoint of maintaining the effect of suppressing the permeation of irritating substances on the skin for a long period of time.

[0051] [Component (E): Higher alcohol] The skin topical preparation composition of the present invention can 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, of which straight-chain aliphatic alcohols are preferred, and saturated aliphatic alcohols are also preferred. Specific examples include myristyl alcohol, cetyl alcohol, stearyl alcohol, and arachyl alcohol.

[0052] Component (E) may be used alone or in combination of two or more, but from the viewpoint of storage stability in an emulsion state, it is preferable to use a combination of two or more compounds with different carbon numbers. Furthermore, from the same viewpoint, the mass ratio (e1) / (e2) of (e1) short chain (carbon number 14 or more and less than 18) aliphatic alcohol to (e2) long chain (carbon number 18 or more and 20 or less) aliphatic alcohol in component (E) 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, even more preferably 3.0 or less.

[0053] The content of component (E) in the topical skin 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 the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, and 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, from the viewpoint of smoothness during application.

[0054] [Component (F): Nonionic surfactant] The skin topical preparation composition of the present invention can further contain a nonionic surfactant as component (F) in order to maintain the irritant permeation inhibitory effect on the skin for a long period of time. Examples of the nonionic surfactant 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, polyoxyethylene hydrogenated castor oil, etc.

[0055] Component (F) can be used alone or in combination of two or more, but it is preferable to use two or more in combination. As a combination of two or more polyhydric alcohol fatty acid esters, from the viewpoint of maintaining the irritant permeation suppression effect on the skin for a long time, a combination of (f1) one or more polyhydric alcohol fatty acid esters having an HLB of 3 to 7, more preferably 4 to 6, and (f2) one or more polyhydric alcohol fatty acid esters having an HLB of 11 to 16, more preferably 13 to 15, is preferable. 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 preferably 4.0 or less, more preferably 2.0 or less, even more preferably 1.0 or less.

[0056] The content of component (F) in the topical skin 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 is 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 upon application.

[0057] The mass ratio (E) / (F) of component (E) to component (F) in the topical skin composition of the present invention is preferably 0.3 or more, more preferably 0.35 or more, and even more preferably 0.4 or more, from the viewpoint of maintaining the effect of inhibiting the permeation of irritating substances on the skin for a long period of time, and is preferably 3.0 or less, more preferably 2.5 or less, even more preferably 2.0 or less, and even more preferably 0.8 or less, from the viewpoint of smoothness during application.

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

[0059] The ceramides include one or more selected from natural ceramides and pseudo-ceramides. Specific examples of natural ceramides include ceramides Types 1 to 7 in which sphingosine, dihydrosphingosine, phytosphingosine, or sphingadienine is amidated, and further include N-alkylated forms (e.g., N-methylated forms) thereof. Specific examples of pseudo-ceramides include (N-hexadecyloxyhydroxypropyl)-N-hydroxyhexadecanamide, (N-hexadecyloxyhydroxypropyl)-N-hydroxydecaneamide, and N-[2-(2,3-dihydroxypropyloxy)-3-hexadecyloxypropyl]-N-3-methoxypropyltetradecaneamide. The component (G) may be used alone or in combination of two or more.

[0060] The content of component (G) in the topical skin 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 skin's barrier function, and is 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 upon application.

[0061] [pH] The pH of the topical skin 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 the pH environment of the skin to a normal one and improving the stability of component (B), and is preferably 3.5 or more, more preferably 3.8 or more, and even more preferably 4.0 or more, from the viewpoint of reducing skin irritation.

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

[0063] The α-gel skin topical preparation composition of the present invention contains components (A) to (C) or components (B) and (Ca) in water at a specified ratio, so that the composition forms an α-gel structure even before application, but when applied to the skin and the water evaporates, a stable dry coating of the α-gel structure can be formed on the skin surface. The α-gel structure can be confirmed by wide-angle X-ray diffraction, polarizing microscope, etc. EXAMPLES

[0064] Examples 1 to 29, Comparative Examples 1 to 4 External skin preparations were prepared according to the formulations shown in Tables 1 to 4, and each evaluation was carried out according to the following methods and standards.

[0065] [Method for evaluating α-gel ratio in bulk] For each topical preparation, the intensity of the sharp diffraction peak that appears near the Bragg angle of 21.5°, which is characteristic of α-gel, was measured by wide-angle X-ray diffraction. The peak intensity of each topical preparation was expressed as a percentage, assuming that the peak intensity of the topical preparation in Example 1 to which component (B) was not added was 1.

[0066] [Method for evaluating the duration of inhibition of irritant permeation] Each topical agent was applied at 4 mg / cm on a membrane filter with a pore size of 5.0 μm. 2The membrane filter was applied and dried under conditions of 32°C and 30%, and a membrane filter that was dried for 1 hour and a membrane filter that was dried for 6 hours were prepared. Next, 1 μL of a dye solution (Fast Green FCF, 1 mg / mL) was dropped onto the dried membrane. After leaving it for 1 hour under conditions of 32°C and 30%, the amount of dye transmission was measured using a densitometer. The transmittance was expressed as a percentage of the amount of dye transmission when no application was taken as 1, and was expressed as a numerical value obtained by averaging three to four measured values. The topical agent that had a low amount of dye transmission in the membrane filter dried for 1 hour and a low amount of dye transmission in the membrane filter dried for 6 hours was evaluated as having a high durability of suppressing the transmission of irritating substances.

[0067] [Method for evaluating storage stability of emulsion state] After storage at 50°C and -5°C for one month, the state of each topical preparation (either creaming or aggregation) was visually evaluated according to the following criteria, with a grade of C or higher being deemed a pass. A: No change B: Slight change in state, but good emulsification C: The state has clearly changed, but no separation or gelation has occurred. D: Partial separation or gelation E: The whole thing separated or gelled.

[0068] [Method for evaluating application to skin (tightness)] Ten expert panelists performed a sensory evaluation of the sensation of tightness when each topical agent was applied, The number of people who rated it as having no tightness (good) is shown.

[0069] [Table 1]

[0070] [Table 2]

[0071] [Table 3]

[0072] [Table 4]

[0073] Formulation examples of the external skin preparation of the present invention are given below.

[0074] Prescription example 1 Anti-inflammatory and anti-pruritic topical cream (mass%) Prednisolone 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 Distilled water remaining

[0075] Prescription Example 2 Antipruritic cream for external use (mass%) Diphenhydramine 1 Hydrogenated soybean phospholipids 0.2 Sodium N-acyl-L-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 Heparinoid 0.3 Distilled water remaining

[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 Distilled water remaining

[0077] Prescription Example 4 Antifungal topical cream (mass%) Miconazole nitrate 1 N-Cocoyl-L-arginine ethyl ester DL-pyrrolidone carboxylate 0.2 Hydrogenated soybean phospholipids 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 Distilled water remaining

[0078] Prescription Example 5: Antibacterial topical cream (mass%) Clindamycin phosphate 1 Hydrogenated soy phospholipids 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 Distilled water remaining

[0079] Prescription Example 6 Immunosuppressant topical cream (mass%) Tacrolimus 0.1 Hydrogenated soybean phospholipid 1 Sodium pyrrolidone carboxylate 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 Distilled water remaining

[0080] Formulation Example 7 Anti-inflammatory topical cream (mass%) Delgocitinib 0.25 Hydrogenated soybean phospholipids 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 Distilled water remaining

Claims

1. An α-gel topical skin preparation composition containing the following components (A), (B), (C) and (D), wherein the mass ratio (C) / (A) of component (C) to component (A) is 0.4 or more and 40 or less. (A) Amino acid or its salt (B) A medicinal ingredient selected from non-steroidal anti-inflammatory agents, steroidal anti-inflammatory agents, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics and antipruritics (C) An ionic surfactant (excluding those having an amino acid as a counter ion) (D) Water

2. The topical skin preparation composition according to claim 1, wherein component (B) is a medicinal ingredient other than a steroidal anti-inflammatory agent, and the total mass ratio [(A)+(C)] / (B) of component (A) and component (C) to component (B) is 0.05 or more and 3.0 or less.

3. The topical skin preparation composition according to claim 1, wherein component (B) is a steroidal anti-inflammatory agent, and the total mass ratio [(A)+(C)] / (B) of component (A) and component (C) to component (B) is 0.8 or more and 20 or less.

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

5. The topical skin preparation composition according to any one of claims 1 to 4, wherein the content of component (A) is 0.01% by mass or more and 1.2% by mass or less.

6. An α-gel topical skin preparation composition containing the following components (B), (C-a) and (D). (B) A medicinal ingredient selected from non-steroidal anti-inflammatory agents, steroidal anti-inflammatory agents, bactericides, antibacterial or antifungal agents, antiviral agents, immunosuppressants, local anesthetics and antipruritics (C-a) An ionic surfactant having an amino acid as a counter ion (D) Water

7. The topical skin preparation composition according to claim 1 or 6, wherein component (B) is an oil-soluble medicinal ingredient.

8. The topical skin preparation composition according to claim 1 or 6, further containing a higher alcohol as component (E).

9. The topical skin preparation composition according to claim 1 or 6, further containing a nonionic surfactant as component (F).

10. The topical skin preparation composition according to claim 1 or 6, further containing ceramides as component (G).