External preparation for skin, containing heparin analogue and at least one substance selected from loxoprofen, salts thereof, and hydrates thereof

Abstract

The present invention addresses the problem of providing an external preparation for skin having improved stability in an external preparation for skin containing a heparin analogue and at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof. The present invention provides an external preparation for the skin, which contains a heparin analogue and at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, and which has excellent stability.

Description

Technical Field

[0001] The present invention relates to a skin external preparation containing a heparin analog and at least one member selected from loxoprofen, its salts, and hydrates thereof. More specifically, the present invention relates to a skin external preparation that improves the solubility and stability of the heparin analog and at least one member selected from loxoprofen, its salts, and hydrates thereof in a solvent in a liquid or semisolid composition containing the heparin analog and at least one member selected from loxoprofen, its salts, and hydrates thereof. Background Art

[0002] Heparin analogs are polysulfated mucopolysaccharides, such as polysulfated chondroitin, extracted from the lungs of healthy livestock, primarily cattle, containing tracheal cartilage. They are named so because they are sulfate esters of mucopolysaccharides and have a structure similar to heparin, which consists of alternating 1,4-linked uronic acid and glucosamine. Heparin analogs are known to have moisturizing, anti-inflammatory, and blood circulation promoting properties. Skin topical preparations containing heparin analogs are used to treat and prevent thrombophlebitis (including hemorrhoids), pain and inflammatory conditions caused by impaired circulation (such as post-injection induration and pain), frostbite, hypertrophic scars / keloids, progressive palmar keratoderma, sebum deficiency, swelling / hematoma / tenosynovitis / myalgia / arthritis following trauma (falls, sprains, and contusions), and muscular torticollis (infants). Skin topical preparations containing heparin analogs are commercially available in creams, ointments, lotions, and sprays.

[0003] When a heparin analog is formulated with other active ingredients in a composition for external use, there are issues with the storage stability of the various active ingredients and the maintenance of the quality of the composition. For example, Patent Document 1 discloses that the stability of the heparin analog, lidocaine, and vitamin A palmitate can be improved by formulating lidocaine and an amino alcohol or a pyrrolidone carboxylate in a composition for external use on the skin containing a heparin analog. Furthermore, Patent Document 2 discloses that the stability of the heparin analog and vitamin B6 can be improved by adjusting the pH of the composition to 4 or higher.

[0004] Loxoprofen as propionic acid system nonsteroidal antipyretic analgesic anti-inflammatory agent (NSAID) has the antipyretic / analgesic / anti-inflammatory effect based on the inhibitory effect to prostaglandin biosynthesis similarly with other NSAID.It should be noted that, also known loxoprofen is to be absorbed from the digestive tract, become the prodrug of active body in vivo with the state of the prototype medicine of gastric mucosa irritation weak after oral administration, therefore has the feature (for example, with reference to non-patent literature 1) that gastric mucosa damage ratio active body is few.In recent years, loxoprofen also has cataplasm, plaster, gel and liquid agent commercially available and provides clinical (for example, with reference to non-patent literature 2) as external anti-inflammatory analgesic.In addition, even if known loxoprofen is also converted into trans-OH body (active body) (for example, with reference to patent literature 3) because of ketoreductase in skin.

[0005] However, a skin external preparation containing a heparin analog and at least one selected from loxoprofen, a salt thereof and a hydrate thereof has not been known.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: Japanese Patent Application Laid-Open No. 2004-307491,

[0009] Patent Document 2: WO2020 / 138403,

[0010] Patent Document 3: Japanese Patent Application Laid-Open No. 2008-074873.

[0011] Non-patent literature

[0012] Non-patent literature 1: Pharmacology and Therapy Vol.16No.2 1988p.611-619,

[0013] Non-patent document 2: JAPIC Prescription Drug Collection 2013, Maruzen 2012. Summary of the Invention

[0014] Problems to be solved by the invention

[0015] Therefore, when developing a skin external preparation containing a heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof, the present inventors studied the solubility of the heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof in solvents. As a result, they discovered the following problem: when preparing a composition containing a heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof, white turbidity occurs, and the solubility of the heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof in solvents is reduced.

[0016] That is, an object of the present invention is to provide a skin external preparation comprising a heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof, wherein the heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof have excellent solubility in a solvent and, accordingly, excellent stability.

[0017] Means of solving problems

[0018] Therefore, the present inventors have conducted intensive studies to solve the above-mentioned problems and have found that by including a solubility regulator in a composition of a heparin analogue and at least one selected from loxoprofen, its salts and hydrates thereof, the solubility and stability of the at least one selected from loxoprofen, its salts and hydrates thereof in a solvent can be improved, thereby completing the present invention.

[0019] That is, according to the present invention, the following inventions are provided.

[0020] (1) A skin external preparation comprising:

[0021] Heparin analogs,

[0022] At least one selected from loxoprofen, its salts and hydrates thereof,

[0023] lower alcohols, and

[0024] solubility regulators;

[0025] The content of the lower alcohol in the entire external skin preparation is 49% by mass or less.

[0026] (2) The external skin preparation according to (1), wherein the solubility regulator comprises at least one of dicarboxylic acids, tertiary amines, and six-membered ring-containing compounds.

[0027] (3) The external skin preparation according to (1) or (2), wherein the solubility regulator comprises at least one compound represented by the following formula (1) and a salt thereof:

[0028] [Chemical Formula 1]

[0029]

[0030] In the formula, X represents a single bond or an oxygen atom, Y represents a methine or a nitrogen atom, and R 1 represents a hydrogen atom or a halogen atom, R 2 represents a hydrogen atom or a halogen atom, R 3 represents a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 3 carbon atoms, R 4 It represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent.

[0031] (4) The external skin preparation according to any one of (1) to (3), wherein the solubility regulator comprises at least one of diphenhydramines, chlorpheniramines, malic acid, maleic acid, fumaric acid, and succinic acid.

[0032] (5) The external skin preparation according to any one of (1) to (4), wherein the lower alcohol is one or more selected from methanol, ethanol, propanol, isopropanol, and butanol.

[0033] (6) The external skin preparation according to any one of (1) to (5), further comprising an oil-soluble component.

[0034] (7) The external skin preparation according to any one of (1) to (6), wherein the content of the heparin analog in the external skin preparation is 0.1 to 10% by mass.

[0035] (8) The external skin preparation according to any one of (1) to (7), wherein the content of at least one selected from loxoprofen, its salts, and hydrates thereof in the external skin preparation is 0.1 to 15% by mass.

[0036] (9) The external skin preparation according to any one of (1) to (8), wherein the content of the lower alcohol in the external skin preparation is 0.1 to 45% by mass.

[0037] (10) The external skin preparation according to any one of (1) to (9), further comprising an alcohol other than a lower alcohol.

[0038] (11) The external skin preparation according to (10), wherein the alcohol other than the lower alcohol contains at least one of a polyol and a higher alcohol.

[0039] (12) The external skin preparation according to any one of (1) to (11), further comprising water.

[0040] (13) The skin external preparation according to any one of (1) to (12), further comprising a component (A), wherein the component (A) is one or more selected from the following components (A-1) to (A-9):

[0041] (A-1) Tocopherols,

[0042] (A-2) terpenes,

[0043] (A-3) Glycyrrhizic acid,

[0044] (A-4) Herbal medicines,

[0045] (A-5) Tranexamic acid,

[0046] (A-6) Vanilloids,

[0047] (A-7) Nicotinic acid,

[0048] (A-8) Pyrrolidones,

[0049] (A-9) Inorganic salt.

[0050] (14) The external preparation for skin according to any one of (1) to (13), wherein the mass ratio of the heparin analog to at least one selected from loxoprofen, its salts and hydrates thereof (heparin analog / at least one selected from loxoprofen, its salts and hydrates thereof) is 0.01 to 100.

[0051] (15) The external skin preparation according to any one of (1) to (14), wherein the dosage form is an external liquid, ointment, cream, spray, gel, patch, or external solid preparation.

[0052] (16) The external preparation for skin according to any one of (1) to (15), wherein the dosage form is a liquid preparation for external use.

[0053] Effects of the Invention

[0054] According to the skin external preparation of the present invention, in the composition containing a heparin analogue and at least one selected from loxoprofen, its salts and hydrates thereof, the solubility of the heparin analogue and at least one selected from loxoprofen, its salts and hydrates thereof in a solvent is excellent, thereby improving the stability as a skin external preparation. DETAILED DESCRIPTION

[0055] The skin external preparation of the present invention (hereinafter sometimes referred to as an external preparation) comprises a heparin analog, at least one selected from loxoprofen, its salts and hydrates thereof, a lower alcohol and a solubility regulator, wherein the content of the lower alcohol in the entire skin external preparation is 49% by mass or less.

[0056] The heparin analogues in the present invention are substances also known as mucopolysaccharide polysulfate or heparinoids, which are polysulfated mucopolysaccharides such as polysulfated chondroitin, and are known agents with moisturizing, anti-inflammatory, and blood circulation promoting effects. Heparin analogues include, for example, heparin, polysulfated chondroitin sulfate D, chondroitin sulfate E, etc. There are no particular restrictions on the source of the heparin analogues used in the present invention, and for example, substances obtained by polysulfating mucopolysaccharides, substances extracted from the tissues of edible livestock (such as the lungs containing tracheal cartilage of cattle or pigs, etc.) can be cited. As heparin analogues, the heparin analogues listed in the Japanese Pharmacopoeia Extra-drug Specifications 2002 are preferred.

[0057] The heparin analogue may be in the form of a physiologically acceptable salt obtained by a salt-forming reaction using a hydroxide or carbonate of an alkali metal such as sodium or potassium, or an amine, as needed.

[0058] The ratio (%) of the organic sulfate group in the heparin analogue of the present invention is not particularly limited. For example, from the perspectives of enhancing anti-inflammatory and analgesic effects and reducing skin irritation, it is preferably 20 to 40% (mass %), and particularly preferably 25 to 38% (mass %). The amount of organic sulfate groups is measured by the method described in the "Heparin Analogues" section of the Japanese Pharmacopoeia Extracellular Drug Standards 2002.

[0059] The average molecular weight of the heparin analog in the present invention is not particularly limited, but is preferably 1,000 to 1,000,000, and particularly preferably 5,000 to 100,000, in terms of weight average molecular weight (MW).

[0060] Furthermore, the external skin preparation of the present invention may contain an analog of a heparin analog as an optional component. Examples of the analog of a heparin analog include other acidic mucopolysaccharides.

[0061] Examples of the acidic mucopolysaccharide analogs of heparin analogs include chondroitin sulfates such as chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, and chondroitin sulfate K; heparin, heparan sulfate, and keratan sulfate.

[0062] That is, the external preparation for skin of the present invention may further contain an acidic mucopolysaccharide as an analog of the above-mentioned heparin analog as needed, together with the heparin analog, within a range that does not impair the effects of the present invention.

[0063] These heparin analogs may be in the form of pharmaceutically acceptable salts and / or solvates as appropriate. Pharmaceutically acceptable salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium salts and calcium salts.

[0064] In addition, examples of solvates include hydrates.

[0065] On the other hand, loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic and anti-inflammatory agent (NSAID), has an antipyretic / analgesic / anti-inflammatory effect based on the inhibitory effect on prostaglandin biosynthesis in the same manner as other NSAIDs. It is also known that loxoprofen is a prodrug that is absorbed from the digestive tract and becomes an active form in vivo after oral administration in the state of a prototype drug with a weak gastric mucosal irritation effect, and therefore has the feature that the gastric mucosal damage ratio active form is less. In addition, even if it is known that loxoprofen is converted into a trans-OH body (active form) due to ketoreductase in the skin, in recent years, loxoprofen is also commercially available as a topical anti-inflammatory analgesic in the form of a patch, a plaster and a gel, and is supplied to the clinic.

[0066] In the present invention, "at least one selected from loxoprofen, its salt and their hydrates" refers to a substance comprising loxoprofen or its salt and their hydrates. As the salt of loxoprofen, a pharmacologically acceptable salt is preferred, more preferably loxoprofen sodium or loxoprofen sodium hydrate (sometimes also expressed as loxoprofen sodium dihydrate), further preferably loxoprofen sodium hydrate. It should be noted that, in this specification, when loxoprofen is mentioned, loxoprofen or its salt and their hydrates are included.

[0067] Loxoprofen in the present invention is included in the 18th edition of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.

[0068] The external preparation for skin of the present invention contains a lower alcohol, and the content of the lower alcohol in the entire external preparation for skin is 49% by mass or less.

[0069] When the content of the lower alcohol in the entire external skin preparation of the present invention is 49% by mass or less, the solubility of the heparin analog and at least one selected from loxoprofen, its salts and hydrates thereof is good, and the external skin preparation is stable even at low temperatures.

[0070] Furthermore, in the external skin preparation of the present invention, the content of the lower alcohol in the entire external skin preparation is preferably 0.1% by mass or more and 49% by mass or less from the viewpoint of solubilization of oil-soluble components in the external skin preparation.

[0071] The term "lower alcohol" as used herein refers to aliphatic alcohols having 1 to 4 carbon atoms used in external preparations for applications such as solubilizers, bases, preservatives, solvents, and cosolvents. Examples include one or more alcohols selected from methanol, ethanol (also known as ethyl alcohol), propanol, isopropanol (also known as isopropyl alcohol), and butanol, with ethanol being preferred. Ethanol containing 99.5% or more of an ethanol content by volume is also referred to as anhydrous ethanol.

[0072] As the lower alcohol in the present invention, ethanol is preferably used, for example. Furthermore, in the present invention, ethanol may be used as the first lower alcohol, and one or more alcohols other than ethanol (e.g., the alcohols listed above) may be used in combination with ethanol. If the ethanol content in the overall skin preparation of the present invention is 49% by mass or less, the solubility of the heparin analog and at least one selected from loxoprofen, its salts, and hydrates thereof is improved, and the skin preparation is stable even at low temperatures.

[0073] Furthermore, in the external skin preparation of the present invention, the ethanol content in the entire external skin preparation is preferably 0.1% by mass or more and 49% by mass or less from the viewpoint of solubilization of oil-soluble components in the external skin preparation.

[0074] In the external skin preparation of the present invention, the appropriate range of the ethanol content can be selected depending on the type and dosage form of the solubility regulator and other dissolved substances.

[0075] When the skin external preparation of the present invention is a liquid preparation, there are no particular limitations. For example, the ethanol content is preferably from 0.1% by mass to 49% by mass, more preferably from 10% by mass to 49% by mass, further preferably from 14% by mass to 49% by mass, and may be from 16% by mass to 45% by mass.

[0076] When the skin external preparation of the present invention is a gel, there are no particular limitations. For example, the ethanol content is preferably from 0.1% by mass to 49% by mass, more preferably from 5% by mass to 45% by mass, further preferably from 10% by mass to 35% by mass, and particularly preferably from 10% by mass to 30% by mass.

[0077] When the skin external preparation of the present invention is a patch, there is no particular limitation. For example, the ethanol content is preferably 0.1% by mass or more and 49% by mass or less, more preferably 0.2% by mass or more and 20% by mass or less, further preferably 0.5% by mass or more and 15% by mass or less, and particularly preferably 1% by mass or more and 12% by mass or less.

[0078] In the present invention, ethanol is preferably contained so that the content of ethanol as a compound is 49% by mass or less.

[0079] The ethanol in the present invention can be commercially available ethanol, for example, ethanol listed in the 18th edition of the Japanese Pharmacopoeia (ethanol having an ethanol content of 95.1 to 96.9% by volume) or anhydrous ethanol (ethanol having an ethanol content of 99.5% by volume or more). Anhydrous ethanol is preferably used in the present invention.

[0080] The external preparation for skin of the present invention may further contain alcohols other than lower alcohols.

[0081] Alcohols other than lower alcohols in the present invention include, for example, polyols and higher alcohols.

[0082] That is, the external preparation for skin of the present invention may contain at least one of a polyhydric alcohol and a higher alcohol as an alcohol other than a lower alcohol.

[0083] The polyols in the present invention refer to alcohols with two or more hydroxyl groups in the molecule and are used in external preparations for purposes such as solubilizers, bases, wetting agents, thickeners, solvents, and cosolvents. Examples include propylene glycol, 1,3-butylene glycol, polyethylene glycol (also known as polyethylene glycol), glycerol, D-sorbitol, and dipropylene glycol, which are included in the Dictionary of Pharmaceutical Additives 2021. It should be noted that the molecular weight of polyethylene glycol is not particularly limited and can, for example, be 200 to 20,000 in terms of number average molecular weight.

[0084] The higher alcohol in the present invention is not particularly limited, and examples thereof include higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, hexyldecanol, isostearyl alcohol, and octyldodecanol.

[0085] The molecular weight of the alcohols (eg, lower alcohols, polyols, higher alcohols) in the present invention is not particularly limited, and may be, for example, 450 or less.

[0086] The solubility modifier in the present invention is a substance that modifies the solubility of at least one of a heparin analog and loxoprofen, its salts, and hydrates thereof in a solvent (e.g., a mixed solvent of water and an alcohol such as a lower alcohol). For example, the solubility modifier of the present invention can improve the solubility of at least one of a heparin analog and loxoprofen, its salts, and hydrates thereof in a solvent (e.g., a mixed solvent of water and an alcohol such as a lower alcohol). Furthermore, by using the solubility modifier of the present invention, the solubility of at least one of a heparin analog and loxoprofen, its salts, and hydrates thereof in a solvent (e.g., a mixed solvent of water and an alcohol such as a lower alcohol) can be modulated, thereby improving the stability of the composition for external use on skin, for example, by preventing white turbidity, thereby ensuring appearance stability, and by preventing solute precipitation, thereby ensuring storage stability.

[0087] As the solubility modifier in the present invention, for example, at least one selected from dicarboxylic acids, tertiary amines, and six-membered ring-containing compounds is preferred.

[0088] The dicarboxylic acid in the present invention may be any of dicarboxylic acid itself, a compound containing dicarboxylic acid, and a compound containing a dicarboxylic acid structure.

[0089] The dicarboxylic acid in the present invention is not particularly limited as long as it is any of dicarboxylic acid itself, a compound containing dicarboxylic acid, and a compound containing a dicarboxylic acid structure. For example, malic acid, maleic acid, fumaric acid, succinic acid, chlorpheniramine maleate, and salts thereof are preferred.

[0090] When dicarboxylic acids are used, the content of the dicarboxylic acid in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 8% by mass, and particularly preferably 0.1 to 5% by mass, based on the total mass of the external skin preparation.

[0091] The tertiary amines in the present invention may be any of a tertiary amine itself, a compound containing a tertiary amine, and a compound containing a tertiary amine structure.

[0092] As the compound containing a tertiary amine structure, a compound having a tertiary amine at a terminal of the compound is preferred.

[0093] When tertiary amines are used, the content of the tertiary amines in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 8% by mass, and particularly preferably 0.1 to 5% by mass, based on the total mass of the external skin preparation.

[0094] The six-membered ring-containing compound in the present invention is not particularly limited, and examples thereof include compounds having an aryl group (aromatic hydrocarbon group) or an aromatic heterocyclic group (for example, a pyridyl group).

[0095] When a six-membered ring-containing compound is used, the content of the six-membered ring-containing compound in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 8% by mass, and particularly preferably 0.1 to 5% by mass, based on the total mass of the external skin preparation.

[0096] As the dicarboxylic acids, tertiary amines and six-membered ring-containing compounds in the present invention, it is preferable to use a compound represented by the following formula (1) or a salt thereof.

[0097] [Chemical Formula 2]

[0098]

[0099] In the formula, X represents a single bond or an oxygen atom, Y represents a methine or a nitrogen atom, and R 1 represents a hydrogen atom or a halogen atom, R 2 represents a hydrogen atom or a halogen atom, R 3 represents a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 3 carbon atoms, R 4 It represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent.

[0100] In R 1 and R 2 In the example of the halogen atom, there are fluorine atom, chlorine atom, bromine atom, iodine atom, etc., preferably chlorine atom. 1 and R 2 The substitution position on the phenyl group is not particularly limited, but substitution at the 4-position is preferred.

[0101] In R 3 In the example, the alkyl group is preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Specifically, methyl, ethyl, n-propyl, and isopropyl can be mentioned, and methyl is preferred. 3 , preferably a hydrogen atom or a methyl group.

[0102] In R 4 In the cyclic amino group which may have a substituent, the cyclic amino group refers to a 5- to 7-membered alicyclic group having at least one, preferably one or two, nitrogen atoms as ring-constituting atoms. Specific examples of the cyclic amino group include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, and homopiperazinyl. Among them, piperidinyl, piperazinyl, and homopiperazinyl are preferred, and piperidinyl and piperazinyl are more preferred.

[0103] Specific examples of substituents in the cyclic amino group that may have a substituent include alkyl groups that may be substituted with one or more groups selected from alkylbenzoyl, 1,3-dihydro-2H-benzimidazol-2-one-1-yl, carboxyalkoxy, carboxyl, carboxyalkylphenyl, and hydroxyl groups. Among them, alkyl, carboxyalkoxyalkyl, and carboxyalkylphenyl(hydroxy)alkyl groups are preferred. Examples of substituents include methyl, 3-(4-tert-butylbenzoyl)propyl, 3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl, 2-(carboxymethoxy)ethyl, 4-[4-(2-carboxypropane-2-yl)phenyl]-4-hydroxybutyl, and 3-carboxypropyl.

[0104] In R 4 Among them, as the cyclic amino group which may have a substituent, 1-methylpiperidin-4-yl, 4-methylhomopiperazin-1-yl, 1-[3-(4-tert-butylbenzoyl)propyl]piperidin-4-yl, 4-[3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl]piperazin-1-yl, 4-[2-(carboxymethoxy)ethyl]piperazin-1-yl, 1-{4-[4-(2-carboxypropane-2-yl)phenyl]-4-hydroxybutyl}piperidin-4-yl, and 1-(3-carboxypropyl)piperidin-4-yl are preferred.

[0105] In R 4In the aminoalkyl group which may have a substituent, the aminoalkyl group means an alkyl group substituted by an amino group, a monoalkylamino group, a dialkylamino group or a cyclic amino group (the so-called "cyclic amino group" herein is synonymous with the "cyclic amino group" in the "cyclic amino group which may have a substituent"). Among them, an alkyl group substituted by a dialkylamino group or a cyclic amino group is preferred. It should be noted that as the cyclic amino group, a pyrrolidinyl group is preferred. Specific examples of such aminoalkyl groups include 2-(dimethylamino)ethyl, 2-(pyrrolidin-2-yl)ethyl, 2-[(isopropyl)(methyl)amino]ethyl, and the like. In addition, examples of the "substituent" in the aminoalkyl group which may have a substituent include a hydroxyl group, a phenyl group, an alkyl group, and the like.

[0106] In R 4 Among them, as the aminoalkyl group which may have a substituent, 2-(dimethylamino)ethyl, 2-(1-methylpyrrolidin-2-yl)ethyl, and 2-[(methyl)(1-phenyl-1-hydroxypropan-2-yl)amino]ethyl are preferred.

[0107] In R 4 In the alkyl group, alkylbenzoyl group, carboxyalkylphenyl group, aminoalkyl group, monoalkylamino group, and dialkylamino group, the alkyl portion is preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, and the like.

[0108] In R 4 In the carboxyalkoxy group, the alkoxy moiety is preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy.

[0109] As salts of the compound represented by formula (1), inorganic acid salts or organic acid salts (such as hydrochloride, maleate, fumarate, diphenyl disulfonate, teoclate, salicylate, tannate, benzenesulfonate, phosphate, etc.) of the compound represented by formula (1) can be listed. In addition, when there is chiral carbon in the chemical structure of the compound represented by formula (1), there are various optical isomers, and any optical isomer can be used. As an optical isomer, it can be a single optical isomer or a mixture of optical isomers. In addition, the compound represented by formula (1) or its salt can also be a solvate. As a solvate, solvates with water or alcohol can be listed.

[0110] Specific examples of the compound represented by formula (1) or its salt include ebastine or its salt; oxatomide or its salt; carbinoxamine or its salt such as carbinoxamine diphenyl disulfonate and carbinoxamine maleate; clemastine or its salt such as clemastine fumarate; chlorpheniramine or its salt such as d-chlorpheniramine maleate and dl-chlorpheniramine maleate; diphenylterol or its salt such as diphenylterol hydrochloride and diphenylterol phosphate; diphenylpyrrol or its salt such as diphenylpyrrol hydrochloride and diphenylpyrrol teoclate; diphenhydramine or its salt such as diphenhydramine hydrochloride, diphenhydramine salicylate and diphenhydramine tannate; cetirizine or its salt such as cetirizine hydrochloride; fexofenadine or its salt; bepotastine or its salt such as bepotastine besylate; perchlorcyclizine or its salt such as perchlorcyclizine hydrochloride. It should be noted that any one of these may be used alone or in combination of two or more.

[0111] As the solubility regulator in the present invention, it is preferred that at least one of chlorpheniramine and diphenhydramine is contained, for example.

[0112] As the chlorpheniramine used in the present invention, for example, at least one of chlorpheniramine and its salts can be listed. As the salt of chlorpheniramine, specifically, organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; various salts such as metal salts can be listed. As the chlorpheniramine, chlorpheniramine maleate is preferred.

[0113] When chlorpheniramine is used, the content of chlorpheniramine in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 8% by mass, and particularly preferably 0.1 to 5% by mass, based on the total mass of the external skin preparation.

[0114] Examples of diphenhydramines used in the present invention include at least one of diphenhydramine and its salts. Examples of diphenhydramine salts include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. Preferred diphenhydramines include diphenhydramine or diphenhydramine hydrochloride.

[0115] When diphenhydramines are used, the content of diphenhydramines in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the external skin preparation.

[0116] Furthermore, as the solubility regulator that satisfies any of the conditions of dicarboxylic acids, tertiary amines, and six-membered ring-containing compounds in the present invention, chlorpheniramine maleate is preferred.

[0117] The content of the heparin analog in the external preparation of the present invention is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.1 to 0.5% by mass, relative to the total amount of the external preparation. It should be noted that even when the external preparation is in the form of a patch (pox, plaster), the content of the heparin analog is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.1 to 0.5% by mass, relative to the total amount of the patch.

[0118] The ratio of the heparin analogue content to the alcohol mass (heparin analogue / alcohol mass ratio) in the external preparation of the present invention is not particularly limited, but is preferably 1.0×10 -3 ~100, more preferably 1.4×10 -3 ~10, more preferably 2.0×10 -3 ~5.0.

[0119] In the external preparation of the present invention, the ratio of the heparin analog content to the mass of the lower alcohol (heparin analog / lower alcohol mass ratio) is not particularly limited as long as it is within a range that does not impair the effects of the present invention, but is preferably 1.0×10 -3 ~100, more preferably 1.4×10 -3 ~10, more preferably 2.0×10 -3 ~5.0.

[0120] When the external preparation of the present invention contains a polyol, the ratio of the heparin analog content to the mass of the polyol (heparin analog / polyol mass ratio) is not particularly limited as long as it is within a range that does not impair the effects of the present invention, but is preferably 1.0×10 -3 ~100, more preferably 1.4×10 -3 ~10, more preferably 2.0×10 -3 ~5.0.

[0121] In addition, the content of at least one selected from loxoprofen, its salts and hydrates thereof (e.g., loxoprofen sodium hydrate) in the external preparation of the present invention is not particularly limited, and is preferably 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, relative to the total amount of the external preparation. It should be noted that, even when the dosage form of the external preparation is a patch (pox, plaster), the content of at least one selected from loxoprofen, its salts and hydrates thereof (e.g., loxoprofen sodium hydrate) is not particularly limited, and is preferably 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, relative to the total amount of the paste of the patch.

[0122] In the external preparation of the present invention, the ratio of the content of at least one selected from loxoprofen, its salts and hydrates thereof to the mass of the alcohol (the mass ratio of at least one selected from loxoprofen, its salts and hydrates thereof / alcohol) is not particularly limited, but is preferably 1.0×10 -3 ~150, more preferably 1.4×10 -3 ~100, more preferably 2.0×10 -3 ~35.

[0123] In the external preparation of the present invention, the ratio of the content of at least one selected from loxoprofen, its salts and hydrates thereof to the mass of the lower alcohol (mass ratio of at least one selected from loxoprofen, its salts and hydrates thereof / lower alcohol) is not particularly limited as long as it is within a range that does not impair the effects of the present invention, but is preferably 1.0×10 -3 ~150, more preferably 1.4×10 -3 ~100, more preferably 2.0×10 -3 ~20.

[0124] When the external preparation of the present invention contains a polyol, the ratio of the content of at least one selected from loxoprofen, its salts, and hydrates thereof to the mass of the polyol (at least one selected from loxoprofen, its salts, and hydrates thereof / mass ratio of the polyol) is not particularly limited as long as it is within a range that does not impair the effects of the present invention, but is preferably 1.0×10 -3 ~150, more preferably 1.4×10 -3 ~100, more preferably 2.0×10 -3 ~35.

[0125] The mass ratio of the heparin analogue to at least one selected from loxoprofen, its salts and hydrates thereof in the external preparation of the present invention is not particularly limited. The mass ratio of heparin analogue to at least one selected from loxoprofen, its salts and hydrates thereof (HP / Lox mass ratio) can be 0.01 to 100, preferably 0.01 to 10.

[0126] Furthermore, in the external preparation of the present invention, from the viewpoint of improving the stability of the heparin analog, it is more preferred that the content of at least one selected from loxoprofen, its salts and hydrates thereof is 0.6% by mass or more relative to the total amount of the external preparation, and the heparin analog / at least one selected from loxoprofen, its salts and hydrates thereof (HP / Lox mass ratio) is 0.01 to 10.

[0127] The external preparation for skin of the present invention preferably contains ethanol, and the content of ethanol in the entire external preparation for skin is preferably 45% by mass or less.

[0128] When the ethanol content in the entire external skin preparation of the present invention is 45% by mass or less, the solubility of the heparin analog and at least one selected from loxoprofen, its salts, and hydrates thereof is good, and the external skin preparation is stable even at low temperatures.

[0129] Furthermore, in the skin preparation of the present invention, from the perspective of dissolving the oil-soluble components in the skin preparation, the ethanol content of the skin preparation as a whole is more preferably from 0.1% by mass to 45% by mass, further preferably from 1% by mass to 43% by mass, and may also be from 1% by mass to 41% by mass. The content of the solubility modifier and ethanol can be adjusted according to the target content of the oil-soluble components, etc. in the skin preparation.

[0130] The pH range of the external preparation for skin is not particularly limited, but may be 1.5 to 9.0, preferably 1.5 to 4.5, or preferably 6.0 to 9.0.

[0131] For example, when dicarboxylic acids are mainly used as solubility modifiers, the pH may be preferably set to 1.5 to 4.5. When tertiary amines are mainly used as solubility modifiers, the pH may be preferably set to 6.0 to 9.0.

[0132] The pH of the external preparation for skin of the present invention can be appropriately selected depending on the solubility regulator used, and can be appropriately adjusted to a pH suitable for the external preparation for skin after preparing a composition containing the solubility regulator, and is not particularly limited.

[0133] The external preparation for skin of the present invention may contain drugs or drug additives other than the above-mentioned components that are generally used in external preparations for skin for analgesia and anti-inflammatory purposes.

[0134] The external skin preparation of the present invention may further contain a component (A), and the component (A) may contain one or more selected from the following components (A-1) to (A-9).

[0135] (A-1) Tocopherols,

[0136] (A-2) terpenes,

[0137] (A-3) Glycyrrhizic acid,

[0138] (A-4) Herbal medicines,

[0139] (A-5) Tranexamic acid,

[0140] (A-6) Vanilloids,

[0141] (A-7) Nicotinic acid,

[0142] (A-8) Pyrrolidones,

[0143] (A-9) Inorganic salt.

[0144] As (A-1) tocopherols, tocopherol, tocotrienol and derivatives thereof (for example, esterified derivatives such as acetate, succinate, nicotinate, etc.) and salts thereof (for example, alkaline earth metal salts such as calcium salts and magnesium salts, etc.) can be listed. As tocopherol, it can be any one of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, preferably α-tocopherol. In addition, as tocotrienol, it can be any one of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, preferably α-tocotrienol. As tocopherols, tocopherol acetate is particularly preferred.

[0145] The oil-soluble component in the present invention is not particularly limited, and (A-1) tocopherols (oil-soluble substances among tocopherols) can be used as the oil-soluble component in the present invention.

[0146] When tocopherols are used, the content of the tocopherols in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.03 to 4% by mass, and particularly preferably 0.05 to 2% by mass, based on the total mass of the external skin preparation.

[0147] (A-2) Terpenes are a general term (terpenoids) that includes terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, and the like in addition to terpene hydrocarbons. Terpene structures are not particularly limited, and examples thereof include monoterpenes, sesquiterpenes, and derivatives thereof. Terpenes may be cyclic or chain-type. Examples of terpenes include isoborneol, irone, ocimene, carveol, carvone, carvone, carvone, carene, carene, camphene, camphor, geraniol, sabinene, safranal, cyclized citral, citral, citronellal, citronellal, citronellal, citronellol, cineole, cymene, abutilon, thymol, thujone, thujone, terpineol, terpinene, terpinolene, tricyclic terpenes, nerol, pinene, pinelinol, pinene, piperonene, phellandrene, phellandrene, fenchene, fenchol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol, menthone, ionol, ionone, linalool, and limonene.

[0148] As terpenes, essential oils containing terpenes can also be used. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, melaleuca oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, pepper oil, perilla oil, lemon eucalyptus oil, citronella oil, ginger oil, cardamom oil, camphor oil, gingergrass oil, spearmint oil, peppermint oil, geranium oil, anise oil, clove oil, and turpentine oil. , orange peel oil, neroli oil, basil oil, mint oil, palmarosa oil, allspice oil, orange leaf oil, bay leaf oil, peppermint oil, nepeta oil, bergamot oil, rosewood oil, camphor oil, marjoram oil, tangerine oil, lemon balm oil, eucalyptus oil, white lime oil, lavender oil, agarwood oil, lemon oil, lemongrass oil, rose oil, rosemary oil, golden chrysanthemum oil, etc., they can be used alone or in combination of two or more.

[0149] Preferred terpenes include l-menthol, dl-camphor, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1,2-diol, p-menthane-3,8-diol, isopulegol, thymol, peppermint oil, and eucalyptus oil.

[0150] The oil-soluble component in the present invention is not particularly limited, and (A-2) terpenes (oil-soluble substances among terpenes) can be used as the oil-soluble component in the present invention.

[0151] When terpenes are used, the content of the terpenes in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 6% by mass, and particularly preferably 0.1 to 4% by mass, based on the total mass of the external skin preparation.

[0152] Examples of the glycyrrhizic acid derivative (A-3) include glycyrrhizic acid or its salts, and glycyrrhetinic acid or its salts. Examples of the salt include alkali metal salts such as potassium salts and sodium salts, and ammonium salts. Furthermore, glycyrrhizic acid derivatives may be glycyrrhiza uralensis (licorice) or an extract thereof containing glycyrrhizic acid derivatives.

[0153] The oil-soluble component in the present invention is not particularly limited, and (A-3) glycyrrhizic acid derivatives (oil-soluble substances among glycyrrhizic acid derivatives) can be used as the oil-soluble component in the present invention.

[0154] When glycyrrhizic acid is used, the content of glycyrrhizic acid in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 3% by mass, based on the total mass of the external skin preparation.

[0155] Examples of the (A-4) herbal medicines include licorice, arnica tincture, wild sycamore, ashwagandha, epimedium, fennel, turmeric, corydalis, scutellaria, polygonatum, phellodendron, cherry bark, coptis root, polygala, zedoaria, valerian, matricaria, trichosanthes, platycodon, apricot, wolfberry, wolfberry leaf, schizonepeta, cinnamon bark, cassia seed, gentian, geranium, safflower, cyperus, bezoar, schisandra, asarum, gardenia, zanthoxylum bungeanum, aster, lycopodiella, purple root, peony, musk, Crude drugs such as Adenophora, Plantago, Plantago, animal gall (including bear gall), ginger, earthworm, magnolia, horse chestnut, Lycoris, Polygala tenuifolia, Chuanxiong, Peucedanum chinense, Chinese angelica, Atractylodes macrocephala, Morus alba bark, Perilla leaf, garlic, Panax japonicus, Tangerine peel, Angelica sinensis, Ipecac, Nandina domestica, Panax ginseng, Fritillaria cirrhosa, Ophiopogon japonicus, Pinellia ternata, Crocus sativus, Radix Angelicae Dahuricae, Atractylodes macrocephala, Poria, Paeonia suffruticosa bark, Myrica rubra bark, and deer antler, and their extracts (extracts, tinctures, dried extracts, etc.). It should be noted that licorice can be used as a glycyrrhizic acid group or a crude drug, or it can be used to take into account the effects of both glycyrrhizic acid groups and crude drugs.

[0156] The oil-soluble component in the present invention is not particularly limited, and (A-4) crude drugs (oil-soluble substances among crude drugs) can be used as the oil-soluble component in the present invention.

[0157] When using herbal medicines, the content of the herbal medicines in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 3% by mass, based on the total mass of the external skin preparation.

[0158] (A-5) The tranexamic acid compound may include, for example, at least one selected from tranexamic acid and its salts, and at least one selected from tranexamic acid derivatives and its salts.

[0159] The salt of tranexamic acid is not particularly limited. Specific examples include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; metal salts such as aluminum, iron, and zinc; basic amino acid salts such as lysine, arginine, histidine, and ornithine; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine, and stearylamine. Furthermore, it may be at least one selected from tranexamic acid derivatives and salts thereof. Specific examples include ester derivatives such as tranexamic acid cetyl ester and amide derivatives such as tranexamic acid carboxamide.

[0160] When tranexamic acid is used, the content of tranexamic acid in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the external skin preparation.

[0161] (A-6) Vanilloids is a general term for compounds containing a vanillyl group. Vanilloids in the present invention are not particularly limited as long as they are compounds containing a vanillyl group. Examples thereof include vanillin, vanillic acid, capsaicin, vanillylmandelic acid (VMA), and vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol).

[0162] Furthermore, the vanilloids in the present invention may include natural substances containing compounds containing vanillyl, derivatives of compounds containing vanillyl, and synthetic compounds obtained by further adding a functional group to vanillyl.

[0163] Furthermore, as the vanilloids in the present invention, capsicum containing a compound containing vanillyl can also be used, and can also be included as a part of the vanilloids.

[0164] As peppers, for example, peppers (the fruit of Capsicum annuum Linne (Solanaceae)) included in the 18th edition of the Japanese Pharmacopoeia can be preferably used. The shape of peppers can be adjusted as needed, and can be cut or broken into small pieces or small pieces, or crushed into powder. For example, "pepper powder" obtained by powdering peppers can also be used as the "pepper" of the present invention. In addition, substances obtained by subjecting peppers to certain extraction treatments (pepper extracts, pepper tinctures, etc.) can also be used. It should be noted that, in addition to the extraction treatment, pepper extracts can also be subjected to processing such as heating, drying, and crushing. In addition, as peppers, capsaicinoids, which are the main components of peppers, can also be used. As capsaicinoids, capsaicin and nonanoic acid vanillamide are preferred. As peppers, pepper extracts, pepper tinctures, nonanoic acid vanillamide or capsaicin can be preferably used.

[0165] The oil-soluble component in the present invention is not particularly limited, and (A-6) vanilloids (oil-soluble substances among vanilloids) can be used as the oil-soluble component in the present invention.

[0166] When vanilloids are used, the content of vanilloids in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, based on the total mass of the external skin preparation.

[0167] When capsicum is used, the content of capsicum in the skin external preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, and particularly preferably 0.1 to 2% by mass, relative to the total mass of the skin external preparation.

[0168] Examples of (A-7) nicotinic acid derivatives include nicotinic acid and its derivatives and salts thereof. Examples of nicotinic acid derivatives include nicotinic acid esters (specifically, nicotinic acid methyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid benzyl ester, inositol hexanicotinate, decanoic acid ester, etc.), nicotinamide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, etc. Nicotinic acid esters are preferably monoesters of nicotinic acid. Nicotinic acid benzyl ester is preferred as a nicotinic acid derivative.

[0169] The oil-soluble component in the present invention is not particularly limited, and (A-7) nicotinic acids (oil-soluble substances among nicotinic acids) can be used as the oil-soluble component in the present invention.

[0170] When niacin is used, the content of niacin in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.015 to 4% by mass, and particularly preferably 0.02 to 2% by mass, based on the total mass of the external skin preparation.

[0171] (A-8) Pyrrolidones include dl-pyrrolidonecarboxylic acid or a salt thereof, and sodium pyrrolidonecarboxylate is preferred, for example.

[0172] When pyrrolidones are used, the content of the pyrrolidones in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the external skin preparation.

[0173] (A-9) Inorganic salts include salts of alkaline earth metals such as magnesium and calcium, salts of alkali metals such as sodium, and ammonium salts. For example, sodium chloride, potassium chloride, and ammonium chloride are preferred.

[0174] When an inorganic salt is used, the content of the inorganic salt in the external skin preparation is not particularly limited, but is usually 0.01 to 10% by mass, more preferably 0.1 to 10% by mass, and particularly preferably 1 to 10% by mass, based on the total mass of the external skin preparation.

[0175] Preferred examples of the drug involved in component (A) include anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid, blood circulation improving ingredients such as tocopherol acetate and benzyl nicotinate, local irritants such as l-menthol, dl-camphor, d-camphor, nonanoic acid vanillamide (nonanoic acid vanillamide), capsicum extract, capsicum tincture, capsaicin, mint oil, eucalyptus oil, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), and 3-(l-menthoxy)-2-methylpropane-1,2-diol, herbal medicinal ingredients such as arnica montana tincture, bactericidal ingredients such as isopropylmethylphenol, wetting agents such as dl-pyrrolidonecarboxylic acid or its salts, and inorganic salts such as sodium chloride. These components (A) can be added within a range that does not impair the effects of the present invention.

[0176] In the present invention, an oil-soluble component may also be contained.

[0177] The oil-soluble component in the present invention is not particularly limited, and may include, for example, at least one oil-soluble substance selected from the group consisting of (A-1) tocopherols, (A-2) terpenes, (A-3) glycyrrhizic acids, (A-4) crude drugs, (A-6) vanilloids, and (A-7) nicotinic acids, as described above.

[0178] In the present invention, even when the external skin preparation contains an oil-soluble component, the inclusion of a solubility regulator can stabilize a composition comprising a heparin analog, at least one selected from loxoprofen, its salts, and hydrates thereof, and a lower alcohol. Furthermore, in the present invention, since the composition comprising a heparin analog and at least one selected from loxoprofen, its salts, and hydrates thereof can achieve both stability and the presence of a large amount of lower alcohol, the content of the oil-soluble component can be increased while maintaining the stability of the external skin preparation.

[0179] The external preparation for skin of the present invention may further contain water.

[0180] Pharmaceutical additives other than the above-mentioned ingredients are added as needed, for example, to further improve the stability of the content over time or the feeling of use, and examples thereof include wetting agents, moisturizing agents, thickening agents, adhesives, tackifying resins, cross-linking agents, fillers, oils and fats, softeners, preservatives, percutaneous absorption accelerators, stabilizers, solubilizers, pH regulators, antioxidants, cooling agents, surfactants, emulsifiers, etc. In addition, the skin preparation for external use of the present invention may also contain other arbitrary ingredients. It should be noted that the skin preparation for external use of the present invention preferably does not contain N-methylpyrrolidone (N-methyl-2-pyrrolidone).

[0181] As the wetting agent, for example, hyaluronic acid, sodium dl-pyrrolidonecarboxylate or a salt thereof (for example, sodium dl-pyrrolidonecarboxylate) and the like can be used.

[0182] As the moisturizing agent, for example, polyols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, polyethylene glycol, 1,3-propylene glycol, and 1,4-butylene glycol can be used.

[0183] As thickeners (viscosifiers / gelling agents), for example, hydroxypropylmethylcellulose, hydroxypropyl cellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, sodium carboxymethylcellulose (sodium carboxymethylcellulose), methylcellulose, carrageenan, locust bean gum, propylene glycol alginate, etc. can be used.

[0184] As the binder, for example, in addition to acrylic acid / octyl acrylate copolymer, acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinyl pyrrolidone copolymer solution, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate copolymer solution, ethyl acrylate / methyl methacrylate copolymer dispersion, methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution, methacrylic acid / n-butyl acrylate copolymer, acrylic fibroin copolymer resin, acrylic starch 300, acrylic starch 1000 , Butyl acrylate / 2-ethylhexyl methacrylate / diacetone acrylamide copolymer, Butyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, Butyl acrylate / ethyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, Butyl acrylate / 2-ethylhexyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, Isononyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, Acrylates Acrylic adhesives such as butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / ethyl acrylate / 3-hydroxypropyl methacrylate / diacetone acrylamide copolymer; cis-isoprene rubber, styrene isoprene rubber, cis-polyisoprene rubber, high-cis-polyisoprene rubber, styrene butadiene rubber (SBR), styrene / isoprene / styrene block copolymer (SIS), styrene / butadiene / styrene block copolymer (SBS), polyisoprene, polyisobutylene ( In addition to synthetic rubber adhesives such as PIB), chloroprene rubber, polybutene, natural rubber latex, and SBR synthetic latex; silicone adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane; in addition to polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide / sodium acrylate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxymethyl cellulose, sodium carboxymethyl cellulose, alginic acid, sodium alginate, gelatin, guar gum, tragacanth gum, and gum arabic, adhesives obtained by cross-linking them with metal salts such as aluminum, zinc, magnesium, and calcium can also be used.

[0185] As the tackifying resin, for example, rosin, hydrogenated rosin glycerol ester, ester gum, maleic acid resin, maleated rosin glycerol ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin and the like can be used.

[0186] As the cross-linking agent, for example, dried aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminum silicate, magnesium aluminum metasilicate, synthetic hydrotalcite, dihydroxyaluminum aminoacetate, etc. can be used.

[0187] As fillers, for example, alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, silicon oxide (silicon dioxide), etc. can be used.

[0188] As oils and fats, for example, hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, vaseline, and gelled hydrocarbons can be used; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; higher alcohols such as behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, hexyldecanol, isostearyl alcohol, and octyldodecanol; higher fatty acids such as behenic acid, lauric acid, myristic acid, stearic acid, isostearic acid, and oleic acid; waxes such as carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, refined lanolin, and reduced lanolin; silicone oil, etc.

[0189] As softeners, for example, petroleum oils such as paraffinic process oils, cycloparaffinic process oils and aromatic process oils; squalane; squalene; vegetable oils such as cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil, castor oil, tall oil and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; liquid rubbers such as polybutene and liquid isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; crotamiton; glycerol, etc.

[0190] As the preservative, for example, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethanesulfonic acid, etc. can be used.

[0191] Examples of percutaneous absorption enhancers include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactic acid esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, carbonized propylene, azones, and derivatives thereof.

[0192] As the stabilizer, for example, oxybenzone, butylhydroxytoluene (BHT), sodium edetate, a UV absorber (for example, a dibenzoylmethane derivative), etc. can be used.

[0193] As solubilizing agents, for example, benzyl alcohol; pyrrolothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols; polybasic acids such as diethyl adipate, isopropyl adipate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, di(2-heptylundecy) adipate, diisopropyl sebacate, and diethyl sebacate; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; oxyalkylene fatty acid esters such as polyethylene glycol monostearate, etc.

[0194] Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (eg, triethanolamine, diisopropanolamine), and phosphoric acid.

[0195] As the antioxidant, for example, ascorbic acid, ascorbyl palmitate, sodium bisulfite, dried sodium sulfite, sodium metabisulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopheryl acetate, dl-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylated hydroxyanisole, butylated hydroxyanisole, soy lecithin, pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate, etc. can be used.

[0196] Examples of the cooling agent include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

[0197] As the surfactant, either a nonionic surfactant or an ionic surfactant can be used.

[0198] Examples of the nonionic surfactant include polyol fatty acid esters or polyol alkyl ethers such as propylene glycol monofatty acid esters, ethylene glycol monofatty acid esters, glycerol monofatty acid esters, polyglycerol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methyl glucoside fatty acid esters, alkyl polyglucosides, and polyethylene glycol fatty acid esters; polyoxyethylene ethers such as polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene phytosterols, polyoxyethylene phytostanols, and polyoxyethylene polyoxypropylene alkyl ethers; polyoxyethylene monofatty acid esters, polyethylene glycol difatty acid esters, polyoxyethylene glycerol fatty acid esters, polysorbate 20, and polysorbate 4 Nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan ester (such as polyoxyethylene sorbitan ester 60, polyoxyethylene sorbitan ester 65, and polyoxyethylene sorbitan ester 80), polyoxyethylene methyl glucoside fatty acid esters, polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polyoxyethylene vegetable oils, polyoxyethylene alkyl ether fatty acid esters, and ether esters of polyoxyethylene polyoxypropylene glycol; ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; and higher alcohols such as octyldodecanol. Examples of the polyoxyethylene alkyl ethers in the present invention include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether.

[0199] Examples of the polyoxyethylene polyoxypropylene alkyl ether in the present invention include polyoxyethylene polyoxypropylene cetyl ether.

[0200] Examples of the polyoxyethylene-polyoxypropylene alkyl ethers in the present invention include polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyethylene glycol monooleate.

[0201] The nonionic surfactant in the present invention is included in the Pharmaceutical Additive Dictionary 2021.

[0202] Examples of the ionic surfactant include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, and sodium dioctylsulfosuccinate; and cationic surfactants such as benzalkonium chloride and benzethonium chloride.

[0203] The ionic surfactants in the present invention are included in the Dictionary of Pharmaceutical Additives 2021, the 18th edition of the Japanese Pharmacopoeia.

[0204] As the emulsifier in the present invention, for example, any of the above-mentioned various surfactants and higher alcohols can be used.

[0205] Examples of other optional components in the present invention include herbal medicines such as tranexamic acid and licorice.

[0206] Specifically, the external skin preparation of the present invention containing a heparin analog and at least one selected from loxoprofen, a salt thereof, and a hydrate thereof may further contain at least one of tranexamic acid and licorice.

[0207] As the concrete dosage form of the skin external preparation of the present invention, for example, external liquid, ointment, emulsifiable paste, spray (external aerosol, pump spray), gel, patch (patch, cataplasma) or external solid etc. can be listed, the additive or matrix suitable for each dosage form can be suitably used, according to the common method described in the 18th edition Japanese Pharmacopoeia etc., manufacture.As the dosage form of the skin external preparation in the present invention, external liquid is particularly preferred.In the present invention, when making the patch such as cataplasma or plaster, the concentration of at least one (such as loxoprofen sodium) selected from loxoprofen, its salt and their hydrate sometimes changes according to paste amount, as long as regulate suitable paste amount, make at least one (such as loxoprofen sodium) selected from loxoprofen, its salt and their hydrate be suitable concentration.

[0208] In addition, the preparation of the skin external preparation of the present invention can be contained in a glass container / package, or a metal container / package such as aluminum, or a container / package made of an olefin resin such as polyethylene or polypropylene, and sealed, and can be further contained in a moisture-proof bag containing a metal such as aluminum. In addition, the container / package can also use a container / package made of environmentally friendly raw materials / materials such as recycled plastics or biomass raw materials. If necessary, a laminated structure material or a gas barrier material can be used, and any material that prevents the skin external preparation from deteriorating due to factors / elements / environmental changes such as heat or light from outside the container / package of the drug in a high temperature environment and appropriately maintains the quality of the skin external preparation can also be used. In one embodiment of the present invention, a drug can also be prepared by containing the preparation / composition of the skin external preparation in an appropriate container / package.

[0209] According to the present invention, by including a solubility regulator (e.g., at least one of diphenhydramine and chlorpheniramine) in a composition comprising a heparin analog and at least one selected from loxoprofen, its salts, and hydrates thereof, a skin preparation for external use can be obtained that improves the solubility and stability of the at least one selected from loxoprofen, its salts, and hydrates thereof in a solvent. This increases the content of alcohols (e.g., ethanol) in the skin preparation for external use, and concomitantly increases the solubility of other soluble components, such as oil-soluble components, thereby increasing the selection of oil-soluble components.

[0210] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0211] Example

[0212] (Test Example 1) Study on the Solubility of a Composition Containing a Heparin Analog and at least one Selected from Loxoprofen, Its Salts, and Hydrates thereof (1)

[0213] (1) Preparation of test materials and specimens

[0214] The components listed in the following Table 1 were mixed and dissolved to obtain liquid preparations of the following samples.

[0215] The heparin analog used was a product manufactured by API Co., Ltd. (a product having an organic sulfate group ratio of 35.2% (mass%) relative to the total heparin analog), loxoprofen sodium hydrate used was a product manufactured by KOLON LIFE SCIENCE, INC., and anhydrous ethanol used was a product manufactured by Imazu Pharmaceutical Industry Co., Ltd.

[0216] (2) Test method

[0217] The obtained preparation was dispensed into clear glass vials with a body diameter of 30 mm and tightly stoppered. Mighty Vial (transparent, No. 6) manufactured by Maruemu Corporation was used as the clear glass vial. The dispensed sample was stored at 5°C for 1 week.

[0218] The appearance of the samples at room temperature was observed before storage and after storage at 5°C for one week. Samples with clear appearance and no precipitate were rated as 0, while those with unclear appearance or precipitate were rated as ×.

[0219] (3) Test results

[0220] The results of each sample are shown in Table 1.

[0221] [Table 1]

[0222]

[0223] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0224] According to the results in Table 1, the composition containing a heparin analog and loxoprofen sodium hydrate exhibited a colorless and clear appearance both immediately after production and after one week at 5°C when the ethanol concentration in the entire composition was 36.5% by mass or less and the "ethanol / water" ratio was 0.588 or less.

[0225] (Test Example 2) Study on the Solubility and Stability of Heparin Analogs

[0226] Based on the results of Test Example 1, components capable of dissolving loxoprofen sodium hydrate and heparin analogs in a water / ethanol solvent having a higher ethanol concentration were studied.

[0227] (1) Preparation of test materials and specimens

[0228] The components listed in the following Table 2 were mixed and dissolved to obtain liquid preparations of the following samples.

[0229] The test materials used were the same as those in Test Example 1, except that diphenhydramine hydrochloride and chlorpheniramine maleate were manufactured by Kongon Chemical Co., Ltd., DL-malic acid was manufactured by Junsei Chemical Co., Ltd., and maleic acid was manufactured by Fujifilm Wako Pure Chemical Corporation.

[0230] (2) Test method

[0231] The storage and appearance confirmation of each obtained preparation were carried out in the same manner as in Test Example 1.

[0232] (3) Test results

[0233] The results of samples 8 to 89 are shown in Tables 2 to 10.

[0234] [Table 2]

[0235]

[0236] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0237] [Table 3]

[0238]

[0239] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0240] [Table 4]

[0241]

[0242] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0243] [Table 5]

[0244]

[0245] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0246] [Table 6]

[0247]

[0248] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0249] [Table 7]

[0250]

[0251] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0252] [Table 8]

[0253]

[0254] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0255] [Table 9]

[0256]

[0257] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0258] [Table 10]

[0259]

[0260] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0261] According to the results in Tables 2 to 7, in the composition comprising a heparin analogue and loxoprofen sodium hydrate, when a diphenhydramine or chlorpheniramine was contained, even when the ethanol concentration in the entire composition was 41% by mass or 45% by mass, respectively, the composition did not become cloudy or precipitate, and the solute was dissolved, thereby achieving a stable state.

[0262] Furthermore, according to the results in Tables 8 to 10, in the composition comprising a heparin analogue and loxoprofen sodium hydrate, when DL-malic acid or maleic acid was contained, even when the ethanol concentration in the entire composition was 38% by mass or 40% by mass, respectively, the composition did not become cloudy or precipitate, and the solute was dissolved, thereby achieving a stable state.

[0263] By containing any one of diphenhydramines, chlorpheniramines, DL-malic acid, and maleic acid, the "ethanol / water" ratio at which the composition containing the heparin analog and loxoprofen sodium hydrate reaches a stable state increases.

[0264] (Test Example 3) Study on the Solubility and Stability of Heparin Analogs

[0265] Following the results of Test Example 2, the solubility of loxoprofen and heparin analogs in formulations containing oil-soluble components that require a certain ethanol concentration for dissolution was examined.

[0266] (1) Preparation of test materials and specimens

[0267] The components listed in the following Table 11 were mixed and dissolved to obtain liquid preparations of the following samples.

[0268] The test materials used were the same as those in Test Example 2, except that l-menthol manufactured by Suzuki Menthol Co., Ltd. was used.

[0269] (2) Test method

[0270] The storage and appearance confirmation of each obtained preparation were carried out in the same manner as in Test Example 1.

[0271] (3) Test results

[0272] The results of samples 90 and 91 are shown in Table 11.

[0273] [Table 11]

[0274]

[0275]

[0276] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0277] According to the above test results, in a composition comprising a heparin analog and loxoprofen sodium hydrate, the ethanol content in the entire composition can be increased by incorporating a dicarboxylic acid or a tertiary amine.

[0278] It was found that even in a composition having an increased ethanol concentration by containing a dicarboxylic acid or a tertiary amine, a skin external preparation can be obtained in which a heparin analogue and loxoprofen sodium hydrate are dissolved, and an oil-soluble component such as l-menthol, which requires a certain ethanol concentration for dissolution, is stably dissolved.

[0279] (Preparation Example)

[0280] The components listed in Tables 12 to 17 below were stirred, mixed, and dissolved to obtain the external skin preparations of the respective preparation examples.

[0281] As a manufacturing method, the above ingredients and amounts can be taken and manufactured according to the Japanese Pharmacopoeia General Rules for Preparations, "Liquids for External Use", "Gels", and "Paticles".

[0282] It should be noted that, for example, when formulating a liquid or semisolid composition into a specific dosage form, it is sufficient to appropriately apply means known for each dosage form, such as storing the liquid or semisolid composition in a container (e.g., a bottle container, a tubular container, a sheet container, a spray container, etc.), stretching the liquid or semisolid composition on a support to form it, mixing it with a propellant, and storing it in an aerosol can.

[0283] Furthermore, when producing a patch, a known method such as stretching a liquid or semisolid composition on a support to form the patch may be applied.

[0284] [Table 12] <Liquid agent>

[0285]

[0286]

[0287] [Table 13]

[0288] <Liquid>

[0289]

[0290]

[0291] Note that the notes ※1 to ※6 in Tables 12 and 13 correspond to the following.

[0292] ※1Equivalent to 1g of loxoprofen sodium (converted to anhydrous form) ※2Equivalent to 2g of loxoprofen sodium (converted to anhydrous form) ※3Equivalent to 0.5g of loxoprofen sodium (converted to anhydrous form) ※4Equivalent to 0.2g of the original drug

[0293] ※5 is equivalent to 0.1g of the original medicine

[0294] ※6 Choose one or more and add appropriate amount

[0295] ※7 Licorice extract is dried licorice extract

[0296] ※8 is equivalent to 2.5g of the original medicine

[0297] [Table 14]

[0298] <Gel>

[0299]

[0300]

[0301] [Table 15]

[0302] <Gel>

[0303]

[0304]

[0305]

[0306] Note that the notes ※1 to ※6 in Tables 14 and 15 correspond to the following.

[0307] ※1 is equivalent to 1g of loxoprofen sodium (converted to anhydrous form)

[0308] ※2 is equivalent to 2g of loxoprofen sodium (converted to anhydrous form)

[0309] ※3Equivalent to 0.5g of loxoprofen sodium (converted to anhydrous form)

[0310] ※4Equivalent to 0.2g of original medicinal material

[0311] ※5 is equivalent to 0.1g of the original medicine

[0312] ※6 Choose one or more and add appropriate amount

[0313] ※7 Licorice extract is dried licorice extract

[0314] ※8 is equivalent to 2.5g of the original medicine

[0315] [Table 16]

[0316] <Catch>

[0317]

[0318]

[0319] [Table 17]

[0320] <Catch>

[0321]

[0322]

[0323] Note that the notes ※1 to ※5 in Tables 16 and 17 correspond to the following.

[0324] ※1 is equivalent to 1g of loxoprofen sodium (converted to anhydrous form)

[0325] ※2 is equivalent to 2g of loxoprofen sodium (converted to anhydrous form)

[0326] ※3Equivalent to 0.5g of loxoprofen sodium (converted to anhydrous form)

[0327] ※4Equivalent to 0.2g of original medicinal material

[0328] ※5 is equivalent to 0.1g of the original medicine

[0329] ※6 Licorice extract is dried licorice extract

[0330] ※7 is equivalent to 2.5g of the original medicine

[0331] (Test Example 4) Study on the Solubility of a Composition Containing a Heparin Analog and at least one Selected from Loxoprofen, Its Salts, and Hydrates thereof (2)

[0332] Following the results of Test Example 1, the solubility was confirmed when the ethanol concentration was lower than that of Test Example 1 in which loxoprofen sodium hydrate and a heparin analog were blended.

[0333] (1) Preparation of test materials and specimens

[0334] The components described in the following Table 18 for each sample were mixed and dissolved to obtain liquid preparations of the following samples.

[0335] Note that the test materials used were the same as those in Test Example 1.

[0336] (2) Test method

[0337] The storage and appearance confirmation of each obtained preparation were carried out in the same manner as in Test Example 1.

[0338] (3) Test results

[0339] The results of samples 92 to 94 are shown in Table 18.

[0340] [Table 18]

[0341]

[0342] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0343] According to the results in Table 18, the composition containing the heparin analog and loxoprofen sodium hydrate had a colorless and clear appearance both immediately after production and after one week at 5°C.

[0344] (Test Example 5) Study on the Solubility and Stability of Heparin Analogs

[0345] Based on the results of Experimental Examples 1 and 2, further research was conducted on components that could dissolve loxoprofen sodium hydrate and heparin analogs in water / ethanol solvents with higher ethanol concentrations.

[0346] (1) Preparation of test materials and specimens

[0347] The components described in the following Tables 19 to 25 were mixed and dissolved to obtain liquid preparations of the following samples.

[0348] In addition, the test materials used were the same as those in Tests 1 and 2, except that fumaric acid was a product manufactured by FUJIFILM Wako Pure Chemical Corporation.

[0349] (2) Test method

[0350] The storage and appearance confirmation of each obtained preparation were carried out in the same manner as in Test Example 1.

[0351] (3) Test results

[0352] The results of samples 95 to 153 are shown in Tables 19 to 25.

[0353] [Table 19]

[0354]

[0355] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0356] [Table 20]

[0357]

[0358]

[0359] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0360] [Table 21]

[0361]

[0362] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0363] [Table 22]

[0364]

[0365]

[0366] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0367] [Table 23]

[0368]

[0369] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0370] [Table 24]

[0371]

[0372]

[0373] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0374] [Table 25]

[0375]

[0376] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0377] The results in Table 19 show that in the composition comprising a heparin analog and loxoprofen sodium hydrate, when fumaric acid was contained, even when the ethanol concentration in the entire composition was 37% by mass, the composition did not become turbid or precipitate, and the solute was dissolved and in a stable state.

[0378] The results in Table 20 show that in the composition comprising a heparin analog and loxoprofen sodium hydrate, when maleic acid was contained, even when the ethanol concentration in the entire composition was 40% by mass, the composition did not become turbid or precipitate, and the solute was dissolved and in a stable state.

[0379] Furthermore, according to the results of Table 21, in the composition containing heparin and loxoprofen sodium hydrate, when a combination of diphenhydramines and maleic acid is contained, even if the ethanol concentration in the entire composition is 41% by mass, the composition does not have white turbidity or precipitation, and the solute is dissolved and becomes stable.

[0380] According to the results in Table 22, in the composition containing heparin analogs and loxoprofen sodium hydrate, when a diphenhydramine and DL-malic acid were contained in combination, even when the ethanol concentration in the entire composition was 40% by mass, the composition did not become turbid or precipitate, and the solute was dissolved, thereby achieving a stable state.

[0381] According to the results in Table 23, in the composition containing a heparin analogue and loxoprofen sodium hydrate, when maleic acid and DL-malic acid were contained in combination, even when the ethanol concentration in the entire composition was 40% by mass, the composition did not become turbid or precipitate, and the solute was dissolved and maintained in a stable state.

[0382] According to the results in Table 24, in the composition containing heparin analogs and loxoprofen sodium hydrate, when chlorpheniramine and diphenhydramine were contained in combination, even if the ethanol concentration in the entire composition was 41% by mass, the composition did not become turbid or precipitate, and the solute was dissolved and became stable.

[0383] According to the results in Table 25, in the composition containing a heparin analog and loxoprofen sodium hydrate, when diphenhydramine and fumaric acid were contained in combination, even when the ethanol concentration in the entire composition was 40% by mass, the composition did not become turbid or precipitate, and the solute was dissolved and maintained in a stable state.

[0384] Furthermore, the "ethanol / water" ratio at which the composition containing the heparin analog and loxoprofen sodium hydrate reaches a stable state is increased by containing any one of diphenhydramines, chlorpheniramines, DL-malic acid, and maleic acid.

[0385] (Test Example 6) Study on the Solubility and Stability of Heparin Analogs

[0386] Based on the results of Test Example 1, the solubility of loxoprofen sodium hydrate and a heparin analogue in a formulation containing loxoprofen sodium hydrate and a heparin analogue depending on the amount of isopropyl alcohol added was examined.

[0387] (1) Preparation of test materials and specimens

[0388] The components listed in the following Table 26 were mixed and dissolved to obtain liquid preparations of the following samples.

[0389] In addition, the test materials used were the same as those in Test Example 1, except that isopropyl alcohol used was a product manufactured by Kosakai Pharmaceutical Co., Ltd.

[0390] (2) Test method

[0391] The storage and appearance confirmation of each obtained preparation were carried out in the same manner as in Test Example 1.

[0392] (3) Test results

[0393] The results of samples 154 to 161 are shown in Table 26.

[0394] [Table 26]

[0395]

[0396] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0397] According to the results in Table 26, in the composition containing a heparin analogue and loxoprofen sodium hydrate, the appearance was colorless and clear both immediately after production and after one week at 5°C when the isopropyl alcohol concentration in the entire composition was 34.5% by mass or less and the "isopropyl alcohol / water" ratio was 0.539 or less.

[0398] (Test Example 7) Study on the Solubility and Stability of Heparin Analogs

[0399] Based on the results of Experimental Example 6, further research was conducted on components that could dissolve loxoprofen sodium hydrate and heparin analogs in a water / isopropanol solvent with a higher isopropanol concentration.

[0400] (1) Preparation of test materials and specimens

[0401] The components described in the following Tables 27 to 30 were mixed and dissolved to obtain liquid preparations of the following samples.

[0402] Note that the test materials used were the same as those in Test Examples 1, 2, 5, and 6.

[0403] (2) Test method

[0404] The storage and appearance confirmation of each obtained preparation were carried out in the same manner as in Test Example 1.

[0405] (3) Test results

[0406] The results of samples 162 to 204 are shown in Tables 27 to 30.

[0407] [Table 27]

[0408]

[0409] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0410] [Table 28]

[0411]

[0412]

[0413] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0414] [Table 29]

[0415]

[0416] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0417] [Table 30]

[0418]

[0419]

[0420] ※Equivalent to 1g of loxoprofen sodium (converted to anhydrous form).

[0421] According to the results in Tables 27 to 30, in the composition comprising a heparin analogue and loxoprofen sodium hydrate, when chlorpheniramines, diphenhydramines, or maleic acid were contained, even if the isopropyl alcohol concentration in the entire composition was 41% by mass, 36% by mass, and 36% by mass, respectively, the composition did not become turbid or precipitate, and the solute was dissolved, thereby achieving a stable state.

[0422] Furthermore, the "isopropyl alcohol / water" ratio at which the composition containing the heparin analog and loxoprofen sodium hydrate reaches a stable state also increases by containing any one of diphenhydramines, chlorpheniramines, and maleic acid.

[0423] While preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto and additions, omissions, substitutions, and other modifications may be made without departing from the spirit of the present invention.

[0424] Industrial applicability

[0425] The external preparation for skin containing a heparin analog and at least one selected from loxoprofen, a salt thereof, and a hydrate thereof of the present invention is excellent in stability and is extremely useful.

Claims

1. A skin external preparation comprising: Heparin analogs, At least one selected from loxoprofen, its salts and hydrates thereof, lower alcohols, and solubility regulators; The content of the lower alcohol in the entire external skin preparation is 49% by mass or less. 2 . The external preparation for skin according to claim 1 , wherein the solubility regulator comprises at least one of dicarboxylic acids, tertiary amines, and six-membered ring-containing compounds.

3. The external preparation for skin according to claim 1, wherein the solubility regulator comprises at least one compound represented by the following formula (1) or a salt thereof: [Chemical Formula 1] In the formula, X represents a single bond or an oxygen atom, Y represents a methine or a nitrogen atom, and R 1 represents a hydrogen atom or a halogen atom, R 2 represents a hydrogen atom or a halogen atom, R 3 represents a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 3 carbon atoms, R 4 It represents a cyclic amino group which may have a substituent or an aminoalkyl group which may have a substituent. 4 . The external preparation for skin according to claim 1 , wherein the solubility regulator comprises at least one of diphenhydramines, chlorpheniramines, malic acid, maleic acid, fumaric acid, and succinic acid. The external preparation for skin according to claim 1 , wherein the lower alcohol is one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, and butanol. The external skin preparation according to any one of claims 1 to 5, further comprising an oil-soluble component. 7 . The external preparation for skin according to claim 1 , wherein the content of the heparin analog in the external preparation for skin is 0.1 to 10% by mass. 8 . The external skin preparation according to claim 1 , wherein the content of at least one member selected from loxoprofen, its salts and hydrates thereof in the external skin preparation is 0.1 to 15% by mass. 9 . The external preparation for skin according to claim 1 , wherein the content of the lower alcohol in the external preparation for skin is 0.1 to 45% by mass. 10 . The external skin preparation according to claim 1 , further comprising an alcohol other than a lower alcohol. The external skin preparation according to claim 10 , wherein the alcohol other than the lower alcohol comprises at least one of a polyol and a higher alcohol. 12 . The external skin preparation according to claim 1 , further comprising water.

13. The external skin preparation according to any one of claims 1 to 5, further comprising a component (A), wherein the component (A) is one or more selected from the following components (A-1) to (A-9): (A-1) Tocopherols, (A-2) terpenes, (A-3) Glycyrrhizic acid, (A-4) Herbal medicines, (A-5) Tranexamic acid, (A-6) Vanilloids, (A-7) Nicotinic acid, (A-8) Pyrrolidones, (A-9) Inorganic salt. The external skin preparation according to any one of claims 1 to 5, wherein the mass ratio of the heparin analogue to at least one selected from loxoprofen, its salts and hydrates thereof (heparin analogue / at least one selected from loxoprofen, its salts and hydrates thereof) is 0.01 to 100.

15. The external skin preparation according to any one of claims 1 to 5, wherein the dosage form is an external liquid, ointment, cream, spray, gel, patch or external solid preparation.

16. The external preparation for skin according to any one of claims 1 to 5, wherein the dosage form is a liquid preparation for external use.

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