External composition, and method of stabilizing heparin analog in external composition

Abstract

To improve the stability of a heparin analog in an external composition containing the heparin analog.SOLUTION: An external composition contains (A) a heparin analog, and (B) at least one amino acid component selected from the group consisting of tranexamic acid and a salt thereof, acylamino acid, a derivative thereof and a salt thereof, arginine, a derivative thereof and a salt thereof, lysine, a derivative thereof and a salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a topical composition and a method for stabilizing a heparinoid in a topical composition. [Background technology]

[0002] Heparinoids are a type of mucopolysaccharide that have excellent moisturizing, anti-inflammatory, and blood circulation promoting effects, as well as other pharmacological effects (such as the treatment and prevention of atopic dermatitis, hypertrophic scars, and keloids, and care after trauma (bruises, sprains, and contusions)). Therefore, they are widely used as active ingredients in external preparations. To effectively utilize the diverse efficacies of heparinoids, various preparations containing heparinoids have been developed (see Patent Documents 1 and 2). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Application Laid-Open No. 2015-232032 [Patent Document 2] Japanese Patent Application Publication No. 2017-178798 Summary of the Invention [Problem to be solved by the invention]

[0004] Under these circumstances, the present inventors encountered the problem of insufficient stability of the active ingredient, heparinoid, when developing a topical composition containing a heparinoid. This problem was a new one that the present inventors discovered for the first time. Therefore, an object of the present invention is to improve the stability of the heparinoid in a topical composition containing a heparinoid. [Means for solving the problem]

[0005] As a result of intensive research to solve the above-mentioned problems, the inventors have discovered that the stability of heparin-like substances in topical compositions can be improved by adding one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives and their salts, arginine, its derivatives and their salts, and lysine, its derivatives and their salts.

[0006] That is, the gist of the present invention is as follows.

[0007] [1] A composition for external use comprising (A) a heparinoid and (B) one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives and their salts, arginine, its derivatives and their salts, and lysine, its derivatives and their salts. [2] (B) The topical composition according to [1], wherein the acylamino acid, its derivative, and salts thereof in the amino acid component are N-capryloylglycine, N-decanoyl-L-proline, N-stearoyl-L-glutamic acid, N-lauroylglutamic acid, lauroylaspartic acid, lauroyl-ε-lysine, N-lauroyl-L-glutamic acid di(phytosteryl / octyldodecyl)ester, and salts thereof. [3] (B) The topical composition according to [1] or [2], wherein the amino acid component is one or more amino acid components selected from the group consisting of tranexamic acid, sodium N-stearoyl-L-glutamate, L-arginine, and L-lysine. [4] A topical composition described in any one of [1] to [3], having a pH of 6 or higher. [5] The topical composition described in any one of [1] to [4], further containing one or more ingredients selected from the group consisting of (C) a preservative, (D) a thickener, (E) water, and (F) an active ingredient. [6] A method for stabilizing a heparin-like substance in an external composition, characterized by combining (A) a heparin-like substance and (B) one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives and their salts, arginine, its derivatives and their salts, and lysine, its derivatives and their salts. [Effects of the Invention]

[0008] According to the present invention, the stability of a topical composition containing a heparinoid can be improved by adding one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives and their salts, arginine, its derivatives and their salts, and lysine, its derivatives and their salts. Furthermore, the combination of these components in a topical composition containing a heparinoid also provides the unexpected effect of smoothing the skin. Furthermore, despite containing a heparinoid, a type of mucopolysaccharide that causes stickiness, stringiness, and poor penetration, the topical composition of the present invention provides a smooth feel (smoothness) without stickiness or stickiness, and also provides the unexpected effect of blending well with the skin. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention will be described in detail below. The terms used in this specification are to be interpreted in the sense commonly used in the art unless otherwise specified.

[0010] <External composition> The topical composition of the present invention is characterized by containing (A) a heparinoid and (B) one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives, and their salts, arginine, its derivatives, and their salts, and lysine, its derivatives, and their salts (hereinafter simply referred to as "(B) amino acid component"). In a topical composition containing a heparinoid, the inclusion of the (B) amino acid component improves the stability of the heparinoid in the topical composition. In addition to the essential components of (A) a heparinoid and (B) amino acid component, the topical composition of the present invention may contain additional components such as (C) a preservative, (D) a thickener, (E) water, and (F) an active ingredient. Furthermore, the topical composition may contain a base / carrier component and other optional components within the scope of the present invention, provided that the effects of the present invention are not impaired. The essential components (A) and (B), the additional components (C) to (F), the base / carrier component, and other optional components are described in detail below. In addition, when the compounds specifically exemplified as each component overlap, it is sufficient that they are included as either component.

[0011] [(A) Heparinoid] Heparinoids are polysulfated mucopolysaccharides such as chondroitin polysulfate, and are known drugs known to have moisturizing, anti-inflammatory, and blood circulation promoting effects.

[0012] The content of the heparinoid in the topical composition of the present invention is 0.005% to 5% by mass, preferably 0.01% to 3% by mass, more preferably 0.05% to 1% by mass, even more preferably 0.1% to 0.5% by mass, and particularly preferably 0.1% to 0.3% by mass, based on the total amount of the composition. By keeping the content of the heparinoid in the topical composition of the present invention within the above range, the physiological effects of the heparinoid, such as moisturizing effect and blood circulation promoting effect, can be exerted, and the composition can be made to have sufficiently suppressed inflammation induction.

[0013] [(B) Amino acid components] The topical composition of the present invention contains (B) one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives and their salts, arginine, its derivatives and their salts, and lysine, its derivatives and their salts.

[0014] Here, the "salt" is a pharmaceutically acceptable salt. It is not particularly limited as long as it exhibits the effects of the present invention, and examples thereof include salts with organic bases (e.g., salts with tertiary amines such as trimethylamine salt, triethylamine salt, monoethanolamine salt, triethanolamine salt, and pyridine salt; basic ammonium salts such as arginine and lysine), or salts with inorganic bases (e.g., inorganic acid salts such as hydrochloride, sulfate, and phosphate; ammonium salt; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; or zinc salt and aluminum salt). Among these, preferred salts are triethanolamine salt, hydrochloride, sodium salt, potassium salt, magnesium salt, and zinc salt, and more preferred salts are hydrochloride, sodium salt, and potassium salt.

[0015] Furthermore, the above-mentioned "derivative" refers to a compound in which some of the functional groups of an acylamino acid have been chemically modified, or a compound in which a protecting group has been added to some of the functional groups, within the scope that does not impair the effects of the present invention, and also refers to isomers.

[0016] (Tranexamic acid and its salts) Preferred examples of tranexamic acid and salts thereof include tranexamic acid, tranexamic acid hydrochloride, tranexamic acid calcium, and tranexamic acid dimers; tranexamic acid amides such as tranexamic acid methylamide hydrochloride; tranexamic acid hydroquinone esters; tranexamic acid gentisate esters; and tranexamic acid cetyl hydrochloride, with tranexamic acid, tranexamic acid hydrochloride, and tranexamic acid cetyl hydrochloride being more preferred, and tranexamic acid being even more preferred.

[0017] (Acylamino acids, their derivatives and their salts) The amino acid in the acylamino acid may be neutral, acidic, or basic, and may be in any of the L-, D-, or DL-forms. Examples include glutamic acid, aspartic acid, glycine, proline, alanine, threonine, methylalanine, sarcosine, lysine, arginine, methylalanine, taurine, and methyltaurine, with glutamic acid, aspartic acid, glycine, proline, alanine, lysine, and arginine being preferred, glutamic acid, glycine, proline, alanine, lysine, and arginine being more preferred, glutamic acid, aspartic acid, glycine, proline, alanine, and lysine being even more preferred, and glutamic acid and glycine being particularly preferred.

[0018] In the acylamino acid, the number of carbon atoms of the fatty acid constituting the acyl group is preferably 2 to 32, more preferably 8 to 22, and even more preferably 8 to 18. The hydrocarbon may be saturated or unsaturated, may be branched or cyclic, or may be a mixed fatty acid. Specific examples include caproic acid, caprylic acid, decanoic acid, lauric acid, myristic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, behenic acid, coconut oil fatty acid, castor oil fatty acid, olive oil fatty acid, and palm oil fatty acid. Among these, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, behenic acid, coconut oil fatty acid, and olive oil fatty acid are preferred, caprylic acid, coconut oil fatty acid, lauric acid, palmitic acid, and stearic acid are more preferred, and caprylic acid, lauric acid, and stearic acid are even more preferred.

[0019] The acylamino acid derivative is preferably a sterol ester, and examples of the acylamino acid sterol ester include dihexyldecyl N-lauroyl-L-glutamate, dioctyldodecyl N-lauroyl-L-glutamate, di(phytosteryl / octyldodecyl) N-lauroyl-L-glutamate, di(cholesteryl / octyldodecyl) N-lauroyl-L-glutamate, di(cholesteryl / behenyl / octyldodecyl) N-lauroyl-L-glutamate, and di(phytosteryl / behenyl / octyldodecyl) N-lauroyl-L-glutamate. Of these, dioctyldodecyl N-lauroyl-L-glutamate and di(phytosteryl / octyldodecyl) N-lauroyl-L-glutamate are more preferred, and di(phytosteryl / octyldodecyl) N-lauroyl-L-glutamate is even more preferred.

[0020] As the acylamino acid derivative, commercially available products may be used, such as Eldew CL-301 and Eldew CL-202 (both manufactured by Ajinomoto Co., Inc.), Estemoll CHS (manufactured by Nisshin Oillio Co., Ltd.), Eldew PS-203, Eldew PS-304, Eldew PS-306, and Eldew APS-307 (all manufactured by Ajinomoto Co., Inc.), PLANDOOL-LG1, PLANDOOL-LG2, and PLANDOOL-LG3 (all manufactured by Nippon Fine Chemicals Co., Ltd.), AMITER LG-2000, and AMITER LG-1600 (all manufactured by Nippon Emulsion Co., Ltd.).

[0021] The acylamino acid or a salt thereof is preferably N-capryloylglycine, N-decanoyl-L-proline, N-stearoyl-L-glutamic acid, N-lauroylglutamic acid, lauroylaspartic acid, lauroyl-ε-lysine, or a salt thereof; more preferably N-capryloylglycine, N-decanoyl-L-proline, N-stearoyl-L-glutamic acid, N-lauroylglutamic acid, lauroylaspartic acid, lauroyl-ε-lysine, or a salt thereof; even more preferably N-capryloylglycine, N-decanoyl-L-proline, sodium N-stearoyl-L-glutamate, sodium N-lauroylglutamate, sodium lauroylaspartate, or lauroyl-ε-lysine; and particularly preferably N-capryloylglycine or sodium N-stearoyl-L-glutamate.

[0022] Commercially available acylamino acids or salts thereof may be used, such as Amisoft HS-11P, Amihope (registered trademark) LL (manufactured by Ajinomoto Co., Inc.), Aminosurfact ALMS-P1, Aminoformer FLMS-P1 (manufactured by Asahi Kasei Finechem Co., Ltd.), and LIPACIDE C8G (manufactured by SEPPIC SA).

[0023] (Arginine, its derivatives and their salts) Arginine, its derivatives and salts thereof refer to L-arginine or D-arginine, or derivatives thereof, or salts of L-arginine or D-arginine, or salts of derivatives of L-arginine or D-arginine, and any of these may be used.

[0024] The arginine derivative is not particularly limited, but examples thereof include ester derivatives in which the hydrogen atom in arginine is substituted with an alkyl group, an alkenyl group, an aryl group, or the like; ester derivatives in which the hydrogen atom of a hydroxyl group is substituted with an acyl group, and ether derivatives in which the hydrogen atom of an amino group is substituted with an acyl group; amide derivatives in which the hydrogen atom of an amino group is substituted with an acyl group, and amine derivatives in which the hydrogen atom of an amino group is substituted with an alkyl group, an alkenyl group, an aryl group, or the like.

[0025] In the present invention, as arginine, its derivatives, and salts thereof, L-arginine, its derivatives, or its salts are preferred.

[0026] (Lysine, its derivatives and their salts) Lysine, its derivatives and salts thereof refer to L-lysine or D-lysine or derivatives thereof, salts of L-lysine or D-lysine, and salts of derivatives of L-lysine or D-lysine, and any of these may be used.

[0027] The lysine derivative is not particularly limited, and examples thereof include ester derivatives in which a hydrogen atom in lysine is substituted with an alkyl group, an alkenyl group, an aryl group, or the like; ester derivatives in which a hydrogen atom of a hydroxyl group is substituted with an acyl group, and ether derivatives in which a hydrogen atom of an amino group is substituted with an acyl group; amide derivatives in which a hydrogen atom of an amino group is substituted with an acyl group, and amine derivatives in which a hydrogen atom of an amino group is substituted with an alkyl group, an alkenyl group, an aryl group, or the like.

[0028] In the present invention, preferred examples of lysine, its derivatives and salts thereof include acyl lysines such as lauroyl-ε-lysine, palmitoyl-ε-lysine and caproyl-ε-lysine, and lysine hydrochloride.

[0029] The amino acid component (B) in the topical composition of the present invention is preferably at least one selected from the group consisting of tranexamic acid, tranexamic acid hydrochloride, tranexamic acid cetyl hydrochloride, N-capryloylglycine, N-decanoyl-L-proline, N-stearoyl-L-glutamic acid, N-lauroylglutamic acid, lauroylaspartic acid, lauroyl-ε-lysine, dioctyldodecyl N-lauroyl-L-glutamate, di(phytosteryl / octyldodecyl) N-lauroyl-L-glutamate, arginine, lysine, or salts thereof, and is preferably at least one selected from the group consisting of tranexamic acid, N-capryloylglycine, N-decanoyl-L-proline, N-stearoyl-L-glutamic acid, N-lauroylglutamic acid

[0049] More preferred are one or more selected from the group consisting of tranexamic acid, N-capryloylglycine, sodium N-stearoyl-L-glutamate, sodium N-lauroyl-L-glutamate, di(phytosteryl / octyldodecyl) N-lauroyl-L-glutamate, L-arginine, and lysine hydrochloride, even more preferred are one or more selected from the group consisting of tranexamic acid, N-capryloylglycine, sodium N-stearoyl-L-glutamate, sodium N-lauroyl-L-glutamate, di(phytosteryl / octyldodecyl) N-lauroyl-L-glutamate, L-arginine, and lysine hydrochloride, and particularly preferred are one or more selected from the group consisting of tranexamic acid, N-capryloylglycine, and sodium N-stearoyl-L-glutamate.

[0030] The content of the (B) amino acid component in the topical composition of the present invention, when the (B) amino acid component is tranexamic acid, is typically 0.01% to 10% by mass, preferably 0.1% to 5% by mass, more preferably 0.5% to 3% by mass, and even more preferably 1% to 2% by mass, based on the total weight of the composition. Furthermore, when the (B) amino acid component in the topical composition of the present invention is an acylamino acid, a derivative thereof, or a salt thereof, arginine, a derivative thereof, or a salt thereof, or lysine, a derivative thereof, or a salt thereof, the content of the (B) amino acid component in the topical composition of the present invention is typically 0.01% to 10% by mass, preferably 0.01% to 5% by mass, more preferably 0.1% to 3% by mass, and even more preferably 0.5% to 2% by mass, based on the total weight of the composition. By ensuring that the content of the (B) amino acid component in the topical composition of the present invention falls within the above range, the stability of the heparinoid can be effectively improved.

[0031] [(C) Preservatives] In order to impart preservative properties to the topical composition of the present invention, the composition may contain one or more preservatives (C) selected from the group consisting of alkanediols, caprylhydroxamic acid, ethylhexylglycerin, iodopropynyl butylcarbamate, sorbic acid and its salts, chlorobutanol, benzoic acid and its salts, and parabens.

[0032] From the viewpoint of significantly achieving the effects of the present invention, the alkanediol in (C) the preservative preferably has 3 or 5 to 10 carbon atoms, more preferably 3 or 5 to 8 carbon atoms, and even more preferably 3 or 5 to 6 carbon atoms. For example, 1,3-propanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, and 1,2-decanediol are preferred, 1,3-propanediol, 1,2-pentanediol, 1,2-hexanediol, and 1,2-octanediol are more preferred, 1,3-propanediol, 1,2-pentanediol, and 1,2-hexanediol are even more preferred, and 1,2-pentanediol is particularly preferred.

[0033] As the (C) preservative, from the viewpoint of significantly exhibiting the effects of the present invention, it is preferable that the preservative is one or more selected from the group consisting of alkanediols having 5 to 10 carbon atoms (preferably 5 to 8, more preferably 5 to 6), propanediol, caprylhydroxamic acid, ethylhexylglycerin, iodopropynyl butylcarbamate, sorbic acid and its salts, chlorobutanol, benzoic acid and its salts, and parabens, and it is more preferable that the preservative is one or more selected from the group consisting of 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 1,2-decanediol, 1,3-propanediol, caprylhydroxamic acid, ethylhexylglycerin, iodopropynyl butylcarbamate, potassium sorbate, chlorobutanol, sodium benzoate, propylparaben, and methylparaben. More preferred are one or more selected from the group consisting of 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 1,3-propanediol, caprylhydroxamic acid, ethylhexylglycerin, iodopropynyl butylcarbamate, potassium sorbate, chlorobutanol, sodium benzoate, propylparaben, and methylparaben, even more preferred are one or more selected from the group consisting of 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol, 1,3-propanediol, caprylhydroxamic acid, potassium sorbate, chlorobutanol, and sodium benzoate, and particularly preferred are one or more selected from the group consisting of 1,2-pentanediol, 1,2-hexanediol, 1,3-propanediol, and caprylhydroxamic acid.

[0034] (C) The preservative may be a commercially available product, and is not particularly limited. Examples thereof include Zemea Select Propanediol, HYDROLITE-5, HYDROLITE-5 Green (all manufactured by Symrise), KMO-6 (manufactured by Osaka Organic Chemical Industry Co., Ltd.), Microcare Emollient PTGJ, Microcare Emollient HXD (both manufactured by THOR), Diol PD, Diol PD-V (both manufactured by Kokyu Alcohol Kogyo Co., Ltd.), Zeeastat, Spectrastat E, G (both manufactured by INOLEX), GLYCASIL, GLYCASIL 2000, GLYCASIL L, GLYCASIL S (all manufactured by Lonza), and Chloretone (manufactured by Sekisui Medical Co., Ltd.).

[0035] When the preservative (C) in the topical composition of the present invention is an alkanediol, the content of the preservative (C) is typically 0.001% to 20% by mass, preferably 0.01% to 15% by mass, more preferably 0.05% to 10% by mass, even more preferably 0.1% to 5% by mass, and particularly preferably 0.5% to 3% by mass, based on the total weight of the composition. When the preservative (C) is other than an alkanediol, the content of the preservative (C) in the topical composition of the present invention is typically 0.001% to 10% by mass, preferably 0.005% to 5% by mass, more preferably 0.01% to 3% by mass, even more preferably 0.05% to 3% by mass, and particularly preferably 0.05% to 1% by mass, based on the total weight of the composition. By setting the content of (C) preservative in the topical composition of the present invention within the above range, the composition can be imparted with a preservative effect without impairing the effect of the invention of effectively improving the stability of heparin-like substances.

[0036] [(D) Thickener] A thickener (D) may be blended in order to impart an appropriate viscosity to the topical composition of the present invention and to stabilize the formulation. Examples of the thickener (D) include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, and carboxyvinyl polymers; cellulose thickeners such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydrophobized hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxyethylcellulose or salts thereof; guar gum, sclerotium gum, tamarind gum, xanthan gum, gellan gum, dextran, pectin, pullulan, gelatin, and locust gum. Examples of suitable polyacrylates include strawberry gum, carrageenan, fucogel, agar, acrylates / alkyl methacrylate copolymer, sodium polyacrylate, bentonite, dextrin fatty acid ester, dimethyl distearyl ammonium hectorite, sodium alginate, propylene glycol alginate, polyethylene glycol, macrogol, hydrophobically modified polyurethane, polyacrylic acid amide, (sodium acrylate / sodium acryloyldimethyl taurate) copolymer, (hydroxyethyl acrylate / sodium acryloyldimethyl taurate) copolymer, and (ammonium acryloyldimethyl taurate / vinylpyrrolidone) copolymer.Among these, xanthan gum, fucogel, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydrophobized hydroxypropyl methylcellulose, carboxyvinyl polymer, acrylate / alkyl methacrylate copolymer, dimethyl distearyl ammonium hectorite, hydrophobically modified polyurethane, polyacrylic acid amide, (sodium acrylate / sodium acryloyldimethyl taurate) copolymer, (hydroxyethyl acrylate / sodium acryloyldimethyl taurate) copolymer, or (ammonium acryloyldimethyl taurate / vinyl pyrrolidone) copolymer is preferred, and xanthan gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydrophobized hydroxypropyl methylcellulose, carboxyvinyl polymer, alkyl acrylate / methacrylate copolymer is preferred. More preferred are alkyl acrylate copolymer, dimethyl distearyl ammonium hectorite, (PEG-240 / decyltetradeceth-20 / HDI) copolymer, polyacrylic acid amide, (sodium acrylate / sodium acryloyldimethyl taurate) copolymer, (hydroxyethyl acrylate / sodium acryloyldimethyl taurate) copolymer, or (ammonium acryloyldimethyl taurate / vinylpyrrolidone) copolymer, and even more preferred are acrylic acid alkyl methacrylate copolymer, (PEG-240 / decyltetradeceth-20 / HDI) copolymer, polyacrylic acid amide, (sodium acrylate / sodium acryloyldimethyl taurate) copolymer, (hydroxyethyl acrylate / sodium acryloyldimethyl taurate) copolymer, or (ammonium acryloyldimethyl taurate / vinylpyrrolidone) copolymer.

[0037] The content of the thickener (D) in the topical composition of the present invention is typically 0.001% by mass to 10% by mass, preferably 0.005% by mass to 5% by mass, more preferably 0.01% by mass to 3% by mass, and even more preferably 0.05% by mass to 2% by mass, relative to the total amount of the composition.

[0038] [(E)Wed] The topical composition of the present invention may contain (E) water. The content of (E) water in the topical composition of the present invention is preferably 40% by mass or more, more preferably 50% by mass or more, even more preferably 55% by mass or more, and particularly preferably 60% by mass or more, based on the total amount of the composition. It is also preferably 98% by mass or less, more preferably 95% by mass or less, even more preferably 93% by mass or less, and particularly preferably 90% by mass or less. By setting the content of (E) water in the above range, the topical composition of the present invention can achieve even better effects.

[0039] [(F) Active ingredient] The topical composition of the present invention may further contain (F) an active ingredient to impart medicinal effects, such as one or more selected from the group consisting of glycyrrhizinic acid, glycyrrhetinic acid, and salts thereof; ascorbic acid, its derivatives, and salts thereof; allantoin, l-menthol, nicotinamide, and placenta extract.

[0040] The "salt" is a pharmaceutically acceptable salt, and includes, but is not limited to, salts with organic bases (e.g., tertiary amine salts, ammonium salts, etc.) or salts with inorganic bases (e.g., inorganic acid salts such as hydrochloride, sulfate, phosphate, etc.; alkali metal salts such as sodium salt, potassium salt, dipotassium salt, magnesium salt, zinc salt, etc.). Among these, monoammonium salts, sodium salts, potassium salts, dipotassium salts, magnesium salts, and zinc salts are preferred, monoammonium salts, sodium salts, dipotassium salts, and magnesium salts are more preferred, and dipotassium salts, sodium salts, and magnesium salts are even more preferred.

[0041] (F) Examples of active ingredients include dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, glycyrrhetinic acid, allantoin, l-menthol, ascorbic acid, sodium ascorbate, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, disodium ascorbyl sulfate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbic acid-2-glucoside, disodium isostearyl ascorbyl phosphate, trisodium ascorbyl palmitate phosphate, glyceryl ascorbate, bisglyceryl ascorbate, hexyl 3-glyceryl ascorbate, 3-glyceryl ascorbate, myristyl 3-glyceryl ascorbate, 3-laurylglyceryl ascorbate, potassium (ascorbyl / tocopheryl) phosphate, and maleic acid. Ascorbyl tocopheryl, nicotinamide, and placenta extract are preferred, with dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, allantoin, l-menthol, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbic acid-2-glucoside, and nicotinamide being more preferred, with dipotassium glycyrrhizinate, allantoin, l-menthol, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, 3-O-ethyl ascorbic acid, ascorbic acid-2-glucoside, and nicotinamide being even more preferred, and dipotassium glycyrrhizinate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, 3-O-ethyl ascorbic acid, ascorbic acid-2-glucoside, and nicotinamide being particularly preferred.

[0042] The content of the active ingredient (F) in the topical composition of the present invention is 0.001% by mass to 10% by mass, preferably 0.01% by mass to 8% by mass, more preferably 0.05% by mass to 5% by mass, and even more preferably 0.1% by mass to 5% by mass, based on the total amount of the composition. By setting the content of the active ingredient (F) within the above range, the topical composition of the present invention can impart more preferable medicinal effects in addition to the remarkable effect of improving the stability of the heparinoid in the topical composition of the present invention.

[0043] (Base or carrier) The topical composition of the present invention can be prepared by mixing the essential components and the components described above, etc., with a base or carrier commonly used in pharmaceuticals, quasi-drugs, cosmetics, etc., and, if necessary, additives, in a conventional manner, and emulsifying or solubilizing the mixture as necessary to prepare a composition in a formulation suitable for various uses.

[0044] The topical composition of the present invention may contain optional ingredients, such as known ingredients added to cosmetics, pharmaceuticals, quasi-drugs, etc., within the scope of the present invention, so long as the optional ingredients do not impair the effects of the present invention. These optional ingredients include blood circulation promoters, astringents, UV scattering agents, UV absorbers, surfactants, stabilizers, antioxidants, colorants, pearlescent agents, dispersants, chelating agents, pH adjusters, preservatives, thickeners, irritation reducers, anti-inflammatory ingredients, bactericidal and disinfecting ingredients (antibacterial ingredients), keratin softening ingredients, warming ingredients, hair growth promoting ingredients, moisturizing ingredients, anti-wrinkle agents, anti-glycation ingredients, cell activating ingredients, and whitening ingredients. These optional ingredients may be used alone or in combination of two or more. Note that these optional ingredients exclude the ingredients included in (F) the active ingredient.

[0045] The method for preparing the topical composition of the present invention is not particularly limited, and the topical composition can be prepared by appropriately selecting, blending, and mixing the above-mentioned various components necessary for preparing the topical composition in a conventional manner. The amount and method of application of the topical composition of the present invention are also not particularly limited, and the topical composition can usually be used by applying an appropriate amount to the area, including the affected area, once to several times a day.

[0046] The topical composition of the present invention generally has a pH in the range of 3 to 9, and from the viewpoint of improving the stability of the heparinoid and the preparation itself, the pH is preferably 5 or higher, more preferably 6 or higher, and even more preferably 6 to 9. This pH can be adjusted by using a pH adjuster.

[0047] (Form of formulation) The form of the topical composition of the present invention is not particularly limited as long as it is a formulation suitable for each drug, quasi-drug, cosmetic, etc., and can be, for example, liquid, fluid, or semi-solid. Examples of formulation forms include solutions, suspensions, emulsions, creams, milky lotions, ointments, gels, liniments, lotions, sheets in which nonwoven fabric is impregnated with a drug solution, mists, aerosols, sticks, and foams. These formulations can be manufactured according to conventional methods, such as those described in the General Provisions for Preparations in the 17th Edition of the Japanese Pharmacopoeia.

[0048] The topical composition of the present invention has improved stability of the heparinoid, which has moisturizing, anti-inflammatory, blood circulation-promoting, and other pharmacological effects, compared to conventional products, and is therefore expected to stably exert these effects over a long period of time. Furthermore, it also has unexpected effects in terms of feel, such as improving skin smoothness and leaving it feeling silky smooth. Therefore, it is suitable for a wide range of uses, including cosmetics, quasi-drugs, and pharmaceuticals. For example, it is suitable not only for areas affected by symptoms such as inflammation and rashes, but also for skin with temporary or chronic moisture loss (e.g., dry skin), skin with a weakened barrier function, atopic skin, sensitive skin, hypersensitive skin, and sensitive skin, as well as for use on babies, infants, and children.

[0049] Furthermore, the topical composition of the present invention has a smooth feel when used without any sticky or greasy feeling, and has a high water retention and moisturizing effect that makes the skin smooth. Therefore, even though it is a lotion or skin toner, it can have a moisturizing effect like an emulsion. Furthermore, since it can be spread over a wide area without putting any strain on the skin, it is also highly effective as an all-in-one preparation that can be used in any season or on any part of the body.

[0050] The topical composition of the present invention can be stored and used in a container of a shape and material appropriately selected depending on the purpose and application. Specific examples of containers include spray types (inverted or non-inverted), bottle types, tube types, jar types, dropper types, dispenser types, stick types, pouch bags, and cheer packs.

[0051] Examples of materials for these containers include polyethylene terephthalate, polypropylene, polyethylene (HDPE, LDPE, LLDPE, etc.), ABS resin, ethylene vinyl alcohol resin, polystyrene, glass, and metal (aluminum, etc.). Taking into consideration strength, flexibility, weather resistance, component stability, and the like, these materials can be used as container materials by applying various coating treatments, combining these materials by mixing, or laminating them. Examples of coating materials include polyethylene terephthalate, epoxy resin, and polyamide-imide. Among these, polypropylene, polyethylene (HDPE, LDPE, LLDPE, etc.), ethylene vinyl alcohol resin, and metal (aluminum, etc.) are preferred. Polyamide-imide, polyethylene terephthalate, etc. can be used as the resin for coating the inner surface.

[0052] Furthermore, with sticky or slimy formulations, there may be concerns about the composition sticking to clothing after application. However, the topical composition of the present invention has a pleasant feel when used (smoothness and smoothness on the skin), making it easy to apply using a spray or mist-type container to affected areas or skin that are hard to reach, such as the scalp, back, or waist, or when used by babies, infants, children, or the elderly, and it is expected that concerns about the composition sticking to clothing after application will also be alleviated.

[0053] (application site) The topical skin composition of the present invention can be used on the face or body for skin care purposes, but is not particularly limited thereto. It can also be used on areas prone to sweating or sebum, areas with symptoms such as atopic dermatitis caused by friction with clothing or bedsores, areas with dry skin or a weakened barrier function, etc. It can be used on the scalp, face, neck, chest (including the top of the bust), back, arms, elbows (inside and outside), hands, around the nails, armpits, abdomen, vulva, buttocks, delicate areas, anal area, legs, fingers, toes, and soles, depending on the symptoms.

[0054] (Application) The skin topical composition of the present invention can be used, for example, for babies, infants, children, the elderly, those requiring care, those with weak skin, sensitive skin, hypersensitive skin, dry skin, unstable skin, troubled skin, those with temporarily sensitive skin, atopic skin, and those with heat rash or rashes.

[0055] <Method for stabilizing heparinoids> The present invention also relates to a method for stabilizing a heparinoid in a topical composition, comprising blending (A) a heparinoid and (B) one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, derivatives thereof, and salts thereof, arginine, derivatives thereof, and salts thereof, and lysine, derivatives thereof, and salts thereof. Topical compositions containing heparinoids have the problem of poor heparinoid stability, resulting in a decrease in the residual rate of the heparinoid itself after long-term storage. The inclusion of one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, derivatives thereof, and salts thereof, arginine, derivatives thereof, and salts thereof, and lysine, derivatives thereof, and salts thereof improves the stability of the heparinoid in the topical composition. The specific descriptions of (A) a heparinoid, (B) amino acid components, and topical compositions containing them are the same as those described above in the topical composition section. [Example]

[0056] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0057] [Test 1] Stability test Compositions of Examples 1 to 4 and Comparative Example 1 were prepared by conventional methods according to the formulations shown in Table 1 below. The units of values ​​in each table are mass (%) unless otherwise specified. Each composition was filled into a 30 mL glass bottle and stored in a constant temperature bath at 60°C. After 3 weeks, the test preparation was removed from the constant temperature bath and allowed to fully warm to room temperature, after which the stability of the heparinoid in each composition was evaluated. The content of the heparinoid was measured using HPLC, and the residual rate (%) and inhibition rate (%) were calculated according to the following formula. A residual rate (%) of 95% or more was marked "Good," and a residual rate (%) of less than 95% was marked "Poor," as shown in Table 1. Residual rate (%) = Content after 3W storage at 60°C (mass%) / Amount blended at time of preparation (mass%) Inhibition rate (%) = (residual rate (%) of Example - residual rate (%) of Comparative Example 1) / residual rate (%) of Comparative Example 1

[0058] [Test 2] Usability monitor test Six expert panelists scored the feel of use (skin smoothness, silky feeling) of the compositions of Examples 1 to 4 and Comparative Example 1 on a 5-point scale according to the following criteria, and the values ​​were averaged. An average score of 4 or more was represented by ◎, an average score of 3.0 or more but less than 4.0 by ○, and an average score less than 3.0 by ×. These results are shown in Table 1. In the table, "nd" indicates that no evaluation was performed. Evaluation item: Skin becomes smooth / smooth Evaluation criteria: Feel: Score 5 Somewhat: Score 4 Neutral: score 3 Not much: score 2 No feeling: Score 1

[0059] [Table 1]

[0060] As shown in Table 1, among the topical compositions containing heparinoids, the topical compositions of Examples 1 to 4 containing the amino acid component (B) had higher heparinoid stability than the topical composition of Comparative Example 1, which did not contain the amino acid component (B), with 95% or more of the heparinoid remaining even after three weeks of storage at 60° C. In addition, the results of the monitoring test showed that the topical compositions of Examples 1 to 4 had the effect of smoothing the skin, and the topical compositions of Examples 1, 2, and 4 also had the unexpected effect of providing a smooth feeling.

[0061] The skin-smoothing effect achieved by the topical compositions of the above examples is believed to be due to the formulation's excellent water-retaining and moisturizing properties. The water-retaining and moisturizing properties of this formulation normalized the skin's condition and smoothed it. Furthermore, despite the fact that the topical compositions of the examples contain heparinoids, a mucopolysaccharide that has long been problematic due to poor usability, such as stickiness, stringiness, and poor penetration, they blend well with the skin and have a smooth feel (smoothness), which was a completely unexpected effect. The formulation's smooth and comfortable feel also allows it to be spread over a wide area of ​​the skin without straining it. Thus, the excellent feel of the topical compositions of the examples makes them effective not only for areas affected by symptoms such as inflammation and rash, but also for skin with temporary or chronic moisture loss (e.g., dry skin), skin with a weakened barrier function, atopic skin, sensitive skin, hypersensitive skin, and sensitive skin, as well as for babies, infants, and children.

[0062] Examples of formulations for the topical composition of the present invention are shown below.

[0063] [Table 2-1]

[0064] [Table 2-2]

[0065] Table 3-1

[0066] Table 3-2

[0067] Table 4-1

[0068] Table 4-2

[0069] Table 5-1

[0070] Table 5-2

[0071] Table 6-1

[0072] Table 6-2

[0073] Table 7-1

[0074] Table 7-2

[0075] [Table 8-1]

[0076] [Table 8-2] [Industrial Applicability]

[0077] According to the present invention, the stability of a heparinoid in a topical composition for topical use can be improved by adding one or more amino acid components selected from the group consisting of tranexamic acid and its salts, acylamino acids, their derivatives and their salts, arginine, its derivatives and their salts, and lysine, its derivatives and their salts. Furthermore, the combination of these components in a topical composition for topical use containing a heparinoid provides unexpected effects in terms of skin smoothness and a silky feel.

Claims

[Claim 1] (A) a heparinoid, and (B) one or more amino acid components selected from the group consisting of N-capryloylglycine, N-decanoyl-L-proline, lauroyl aspartic acid, lauroyl-ε-lysine, dioctyldodecyl N-lauroyl-L-glutamate, di(phytosteryl / octyldodecyl N-lauroyl-L-glutamate), lysine, and salts thereof; A topical composition comprising:

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