Liquid composition comprising heparinoid, glycyrrhizinic acid, polyalcohol and surfactant

Abstract

To provide a liquid composition comprising a heparinoid and glycyrrhizinic acid with reduced viscosity without forming insoluble matter, and skin external preparations comprising the liquid composition.SOLUTION: Provided is a liquid composition comprising at least one selected from the group consisting of heparinoids and salts thereof, at least one selected from the group consisting of glycyrrhizinic acid and salts thereof, a polyalcohol, a surfactant having polyoxyethylene structure and water, where the pH of the composition is 6.0 or less.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a liquid composition containing a heparinoid, glycyrrhizic acid, a polyhydric alcohol, and a surfactant, and to a skin external preparation containing the liquid composition. More specifically, the present invention relates to a liquid composition containing a heparinoid and glycyrrhizic acid, which has a reduced viscosity without producing insoluble matter. [Background technology]

[0002] Heparinoids are polysulfated mucopolysaccharides such as chondroitin polysulfate extracted from the lungs, including tracheal cartilage, of healthy animals, mainly cattle. They are called heparinoids because they have a structure similar to that of heparin, which is a sulfate ester of mucopolysaccharides with alternating 1,4 bonds between uronic acid and glucosamine. Heparinoids are known to have moisturizing, anti-inflammatory, and blood circulation promoting effects. The efficacy of skin preparations containing heparinoids is said to be the treatment and prevention of thrombophlebitis (including hemorrhoids), pain and inflammatory diseases due to blood circulation disorders (induration and pain after injection), frostbite, hypertrophic scars and keloids, progressive keratoderma tylodes palmaris, cortical deficiency, swelling, hematoma, tendonitis, muscle pain, arthritis after trauma (bruises, sprains, contusions), and muscular torticollis (infancy). Heparinoid-containing topical skin preparations are available in the form of creams, soft ointments, lotions, and sprays.

[0003] When a heparinoid is mixed with other active ingredients in a composition for external use, the storage stability of each active ingredient and the maintenance of the quality of the composition become issues. For example, Patent Document 1 discloses that in a composition for external use containing a heparinoid, the stability of the heparinoid, lidocaine and vitamin A palmitate can be improved by mixing lidocaine with an amino alcohol or by mixing pyrrolidone carboxylate. In addition, Patent Document 2 discloses that in a composition for external use containing a heparinoid and vitamin B6, the stability of the heparinoid and vitamin B6 can be improved by adjusting the pH to 4 or higher.

[0004] However, based on the diverse actions of heparinoids, the development of further skin topical compositions is anticipated. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2004-307491 [Patent Document 2] WO2020 / 138403 Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, when developing a liquid composition containing a heparinoid and glycyrrhizinic acid, the inventors investigated the viscosity of the liquid composition and found that at pH 4.5, depending on the formulation, insoluble matter may be produced, causing the liquid to become cloudy, and that differences in viscosity may also occur.

[0007] In other words, the present invention aims to provide a liquid composition containing a heparin-like substance and glycyrrhizinic acid, which has a reduced viscosity without producing insoluble matter, and an external skin preparation containing the liquid composition. [Means for solving the problem]

[0008] As a result of extensive research into solving the above problems, the inventors discovered that by adding a surfactant having a polyoxyethylene structure to a liquid composition containing a heparin-like substance and glycyrrhizinic acid, it is possible to provide a liquid composition having a reduced viscosity without producing insoluble matter, and thus completed the present invention.

[0009] That is, according to the present invention, the following inventions are provided. (1) at least one selected from the group consisting of heparinoids and salts thereof; At least one selected from the group consisting of glycyrrhizinic acid and salts thereof; A polyhydric alcohol; A surfactant having a polyoxyethylene structure, and water, and having a pH of 6.0 or less; liquid composition. (2) The liquid composition according to (1), having a viscosity of 20.0 mPa·s or less as measured at 200 rpm using a Brookfield type viscometer. (3) The liquid composition according to (1), having a viscosity of 50.0 mPa·s or less as measured at a rotation speed of 10 rpm using a Brookfield viscometer. (4) The liquid composition according to (1), further comprising a compound having a quaternary ammonium group. (5) The liquid composition according to (1), which contains only water as a solvent. (6) The liquid composition according to any one of (1) to (5), wherein the content of the heparinoid and its salt is 0.1 to 1.0% by mass relative to the total mass of the liquid composition. (7) The liquid composition according to any one of (1) to (5), wherein the content of glycyrrhizinic acid and a salt thereof is 0.1 to 5.0% by mass based on the total mass of the liquid composition. (8) The liquid composition according to any one of (1) to (5), wherein the content of the polyhydric alcohol is 1 to 15% by mass based on the total mass of the liquid composition. (9) The liquid composition according to any one of (1) to (5), wherein the content of the surfactant having a polyoxyethylene structure is 0.5 to 10% by mass based on the total mass of the liquid composition. (10) The liquid composition according to any one of (1) to (5), wherein the ratio of the content of the surfactant having a polyoxyethylene structure to the total content of the heparinoid and its salt, glycyrrhizinic acid and its salt, and polyhydric alcohol is 0.1 to 3. (11) The liquid composition according to (4), wherein the compound having a quaternary ammonium group is at least one selected from the group consisting of benzethonium, benzalkonium, cetylpyridinium, and salts thereof. (12) The liquid composition according to any one of (1) to (5), which is an external preparation for skin. (13) A skin external preparation comprising the liquid composition according to any one of (1) to (5). (14) The topical skin preparation according to (13), which is a liquid, cream, gel, ointment, spray, foam, or patch. Effect of the Invention

[0010] According to the present invention, it is possible to provide a liquid composition having a reduced viscosity without producing insoluble matters. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The liquid composition of the present invention comprises: At least one selected from the group consisting of heparinoids and salts thereof; At least one selected from the group consisting of glycyrrhizinic acid and salts thereof; A polyhydric alcohol; A surfactant having a polyoxyethylene structure, It contains water and has a pH of 6.0 or less.

[0012] The viscosity of the liquid composition of the present invention, as measured using a Brookfield viscometer at a rotation speed of 200 rpm, is preferably 20.0 mPa s or less, more preferably 15.0 mPa s or less, even more preferably 10.0 mPa s or less, and particularly preferably 8.0 mPa s or less. The viscosity of the liquid composition of the present invention, measured using a Brookfield viscometer at a rotation speed of 10 rpm, is preferably 50.0 mPa·s or less, more preferably 20.0 mPa·s or less, preferably 10.0 mPa·s or less, and preferably 5.0 mPa·s or less. The viscosity in the present invention is measured at room temperature (20 to 25° C.) using a Brookfield B-type viscometer (DV3T) under the conditions of spindle: Lv-1, rotation speed: 200 rpm or 10 rpm, and measurement time: 3 minutes.

[0013] Brookfield viscometer means a Brookfield viscometer. A B-type viscometer is a type of rotational viscometer in which a spindle rotor is immersed in liquid and rotated by a motor to measure flow resistance. In a B-type viscometer, the rotation of the motor in the viscometer body is transmitted to the rotor via a spring. The rotor, immersed in the measurement liquid, is subjected to a viscosity friction torque on its outer periphery, and the rotor rotates steadily while this torque and the force of the spring are in equilibrium. The magnitude of the torque is expressed as the deviation angle of a pointer fixed to the rotor shaft, and is proportional to the value read on a scale plate directly connected to the motor shaft. Absolute viscosity can be calculated from this indicated value and a conversion multiplier. In the present invention, the spindle used is an LV-1, which is a standard LV type spindle.

[0014] The heparinoid in the present invention is a substance also called mucopolysaccharide polysulfate or heparinoid, which is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have moisturizing, anti-inflammatory, and blood circulation promoting effects. Examples of heparinoids include heparin; chondroitin polysulfates such as chondroitin sulfate D and chondroitin sulfate E. The origin of the heparinoid used in the present invention is not particularly limited, and examples thereof include those obtained by polysulfating mucopolysaccharides and those extracted from the tissues of edible animals (e.g., lungs containing tracheal cartilage of cows, pigs, etc.). As the heparinoid, heparinoids listed in the Japanese Pharmacopoeia Non-Drug Standards 2002 are preferred.

[0015] The heparinoid 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, if necessary. The proportion (%) of organic sulfate groups in the heparinoid of the present invention is not particularly limited, but is preferably 20 to 40% (mass%), particularly preferably 25 to 38% (mass%), from the viewpoints of improving the anti-inflammatory and analgesic effect and reducing skin irritation, etc. The amount of organic sulfate groups is measured by the method described in the section on "heparinoids" in the Japanese Pharmacopoeia Extra Pharmaceutical Standards 2002. The average molecular weight of the heparinoid in the present invention is not particularly limited, but is preferably, for example, 1,000 to 1,000,000, and particularly preferably 5,000 to 100,000, in weight average molecular weight (MW).

[0016] The liquid composition of the present invention may also contain an analogue of a heparinoid as an optional component. The analogue of a heparinoid may be, for example, another acidic mucopolysaccharide. Examples of acidic mucopolysaccharides as analogs of heparin-like substances 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. That is, in the liquid composition of the present invention, in addition to the heparinoid, an acidic mucopolysaccharide as an analogue of the heparinoid may be further added, if necessary, within a range that does not impair the effects of the present invention. These heparinoid analogs may be in the form of pharma- ceutically acceptable salts and / or solvates, such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., magnesium salt, calcium salt, etc.). Additionally, solvates include hydrates.

[0017] As glycyrrhizinic acid and its salts in the present invention, dipotassium glycyrrhizinate, trisodium glycyrrhizinate, disodium glycyrrhizinate, diammonium glycyrrhizinate, monoammonium glycyrrhizinate, etc. As glycyrrhizinic acid and its salts in the present invention, dipotassium glycyrrhizinate listed in the 18th Edition of the Japanese Pharmacopoeia can be mentioned.

[0018] The polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used in skin external preparations for purposes such as solubilizers, bases, moisturizers, thickeners, solvents, and dissolution aids, and is, for example, propylene glycol, 1,3-butylene glycol, macrogol (also called polyethylene glycol), glycerin, D-sorbitol, and dipropylene glycol, which are listed in the Pharmaceutical Additives Encyclopedia 2021. The molecular weight of macrogol is not particularly limited, and may be, for example, 200 to 20,000 in number average molecular weight. In addition, the molecular weight of the alcohols in the present invention is not particularly limited, but may be, for example, 400 or less, preferably less than 400, more preferably 300 or less, even more preferably 250 or less, particularly preferably 200 or less, and may be 100 or less.

[0019] The surfactant having a polyoxyethylene structure in the present invention is not particularly limited as long as it has a polyoxyethylene structure, but the surfactant is preferably at least one selected from the group consisting of polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester.

[0020] The surfactant is more preferably at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene hydrogenated castor oil, and polysorbate 80 (polyoxyethylene sorbitan oleate).

[0021] More preferably, the surfactant is at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene (20) polyoxypropylene (4) cetyl ether, polyoxyethylene (20) polyoxypropylene (8) cetyl ether, polyoxyethylene hydrogenated castor oil 60, and polysorbate 80 (polyoxyethylene sorbitan oleate).

[0022] The liquid composition of the present invention comprises water. The range of the water content is not particularly limited, but may be selected depending on the dosage form, and is preferably 20 to 99 mass% relative to the total amount of the liquid composition, more preferably 25 to 98 mass%, and even more preferably 30 to 98 mass%.

[0023] The liquid composition of the present invention may be a composition containing only water as a solvent, or a composition containing water and a solvent other than water as a solvent.

[0024] The pH range of the liquid composition of the present invention is 6.0 or less, preferably 4.0 to 6.0, and more preferably 4.0 to 5.5.

[0025] The liquid composition of the present invention preferably comprises a compound having a quaternary ammonium group. The compound having a quaternary ammonium group may be at least one selected from the group consisting of benzethonium, benzalkonium, cetylpyridinium and their salts.The compound having a quaternary ammonium group that can be used in the present invention may, for example, be "benzethonium chloride", "benzalkonium chloride" and "cetylpyridinium chloride" listed in the 18th revised Japanese Pharmacopoeia.

[0026] The liquid composition of the present invention may contain a lower alcohol other than the polyhydric alcohol. The lower alcohol in the present invention refers to an aliphatic alcohol having 1 to 4 carbon atoms that is used in external skin preparations for purposes such as a solubilizer, base, preservative, solvent, and dissolution aid, and is, for example, one or more selected from the group consisting of methanol, ethanol (also called ethyl alcohol), propanol, isopropanol (also called isopropyl alcohol), and butyl alcohol, and is preferably ethanol.

[0027] The content of heparin-like substances and their salts in the liquid composition of the present invention is not particularly limited, but is preferably 0.1 to 10 mass% relative to the total amount of the liquid composition, more preferably 0.1 to 1.0 mass%, and even more preferably 0.1 to 0.5 mass%.

[0028] When the liquid composition of the present invention contains a compound having a quaternary ammonium group, the content of the compound having a quaternary ammonium group in the liquid composition is not particularly limited, but is preferably 0.05 to 10 mass %, more preferably 0.05 to 1.0 mass %, and even more preferably 0.05 to 0.7 mass %, relative to the total amount of the liquid composition.

[0029] The content of glycyrrhizinic acid and its salts in the liquid composition of the present invention is not particularly limited, but is preferably 0.05 to 10 mass % relative to the total amount of the liquid composition, more preferably 0.1 to 5.0 mass %, and even more preferably 0.1 to 0.7 mass %.

[0030] The range of the polyhydric alcohol content in the liquid composition of the present invention is not particularly limited, but may be selected depending on the dosage form, and is preferably 0.1 to 70 mass% relative to the total amount of the liquid composition, more preferably 0.1 to 20 mass%, more preferably 0.5 to 20 mass%, and even more preferably 1 to 15 mass%.

[0031] The content of the surfactant having a polyoxyethylene structure in the liquid composition of the present invention is not particularly limited, but is preferably 0.5 to 10.0 mass % relative to the total amount of the liquid composition, more preferably 1.0 to 10.0 mass %, and even more preferably 1.0 to 5.0 mass %.

[0032] In the liquid composition of the present invention, the ratio of the content of the surfactant having a polyoxyethylene structure to the total content of the heparinoid and its salts, glycyrrhizinic acid and its salts, and polyhydric alcohol is not particularly limited, but is preferably 0.1 to 3, preferably 0.2 to 2, and preferably 0.3 to 1.0.

[0033] In the liquid composition of the present invention, the ratio of the content of the heparinoid to the mass of the polyhydric alcohol (heparinoid / polyhydric alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 -3 ~100, more preferably 1.4 × 10 -3 ~10, and more preferably 2.0 × 10 -3 ~5.0.

[0034] When the liquid composition of the present invention contains a lower alcohol, the ratio of the content of the heparinoid to the mass of the lower alcohol (heparinoid / lower alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 -3 ~100, more preferably 1.4 × 10 -3 ~10, and more preferably 1.4 × 10 -3 ~5.0.

[0035] The liquid composition of the present invention can be used as an external preparation for the skin as it is. Alternatively, the liquid composition of the present invention may be used to produce an external preparation for skin. That is, according to the present invention, there is provided an external preparation for skin comprising the liquid composition of the present invention.

[0036] The skin external preparation of the present invention may contain drugs and pharmaceutical additives other than the above-mentioned ingredients that are commonly used in analgesic and anti-inflammatory skin external preparations.

[0037] Examples of drugs (active ingredients) other than the above-mentioned ingredients include salicylic acid, sulfur, ibuprofen piconol, dipotassium glycyrrhizinate, glycyrrhetinic acid, allantoin, d-camphor, homosulfamine, tocopherol acetate, ethanol, isopropylmethylphenol, chlorhexygluconate, sulfazine, zinc oxide, pyridoxine hydrochloride, pyridoxine dipalmitate, vitamin A oil, chlorpheniramine maleate, diphenhydramine, and resorcinol.

[0038] Pharmaceutical additives are added as necessary for the purpose of, for example, further improving the stability of content over time and the feeling of use, and examples thereof include wetting agents, moisturizing agents, thickening agents, adhesives, tackifying resins, crosslinking agents, fillers, oils and fats, softeners, preservatives, percutaneous absorption promoters, stabilizers, solubilizing agents, pH regulators, antioxidants, refreshing agents, emulsifiers, etc. Furthermore, the topical skin preparation of the present invention may contain other optional components.

[0039] As the wetting agent, for example, hyaluronic acid, sodium dl-pyrrolidone carboxylate or a salt thereof (eg, sodium dl-pyrrolidone carboxylate), etc. can be used. As the moisturizing agent, for example, polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol can be used. Examples of thickening agents (thickening agents / gelling agents) that can be used include hypromellose, hydroxypropyl cellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose (carmellose sodium), methyl cellulose, carrageenan, locust bean gum, and propylene glycol alginate.

[0040] Examples of the adhesive include acrylic acid / octyl acrylate copolymer, acrylic acid ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone 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 acid silk fibroin copolymer resin, starch acrylate 300, starch acrylate 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 / ethyl acrylate / 2-hydroxyethyl methacrylate / diacetone acrylamide copolymer, butyl acrylate / 2-ethylhexyl acrylate / methacryl ... acrylic adhesives such as 2-hydroxyethyl acrylate-diacetone acrylamide copolymer, isononyl acrylate-2-hydroxyethyl methacrylate-diacetone acrylamide copolymer, 2-ethylhexyl acrylate-2-hydroxyethyl methacrylate-diacetone acrylamide copolymer, butyl acrylate-ethyl acrylate-3-hydroxypropyl methacrylate-2-hydroxyethyl methacrylate-diacetone acrylamide copolymer, and 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 (PIB), chloroprene rubber, polybutene, natural rubber latex, and SBR synthetic latex;In addition to silicone-based adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane, polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide-sodium acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, sodium carboxymethylcellulose, alginic acid, sodium alginate, gelatin, guar gum, tragacanth gum, gum arabic, and the like, as well as those crosslinked with metal salts such as aluminum, zinc, magnesium, and calcium can be used.

[0041] Examples of tackifying resins that can be used include rosin, hydrogenated rosin glycerin ester, ester gum, maleic acid resin, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, and aliphatic hydrocarbon resin.

[0042] As the crosslinking agent, for example, dried aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosaltite, dihydroxyaluminum aminoacetate, etc. can be used. Examples of the filler that can be used include alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, and silica (silicon dioxide).

[0043] Examples of fats and oils that can be used include hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petrolatum, medium-chain fatty acid triglycerides, and gelled hydrocarbons; 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, and oleyl alcohol; 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; and silicone oils.

[0044] Examples of softeners that can be used include petroleum-based oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil; 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; glycerin, and the like.

[0045] Examples of preservatives that can be used include 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, and aminoethylsulfonic acid. Examples of the percutaneous absorption enhancer that can be used include alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactate esters, acetate esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, propylene carbonate, azone or derivatives thereof, and the like. As the stabilizer, for example, oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, UV absorbers (for example, dibenzoylmethane derivatives), dimethylpolysiloxane, etc. can be used.

[0046] Examples of solubilizing agents that can be used include benzyl alcohol; pyrrothiodecane; 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-heptylundecyl) adipate, diisopropyl sebacate, and diethyl sebacate; polyalkylene glycols such as polyethylene glycol (PEG) and polybutylene glycol; and oxyalkylene fatty acid esters such as polyethylene glycol monostearate. Examples of pH adjusters that can be used include hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, sodium citrate hydrate, trisodium citrate dihydrate, sodium hydrogen phosphate hydrate, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), phosphoric acid, and the like. Examples of antioxidants that can be used include ascorbic acid, ascorbic acid palmitate, sodium bisulfite, dried sodium sulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, tocopherol acetate, dI-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soybean lecithin, pentaerythritol-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate], 2-mercaptobenzimidazole, benzotriazole, and propyl gallate. Examples of the cooling agent include l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, and thymol.

[0047] As the emulsifier in the present invention, for example, any of the above-mentioned various surfactants, the above-mentioned higher alcohols, cetostearyl alcohol, and glycerin monostearate may be used.

[0048] Other optional components in the present invention may include, for example, nonsteroidal anti-inflammatory drugs (NSAIDs). As the NSAIDs, those other than diclofenac and / or its salts and felbinac may be used. More specifically, the skin external preparation of the present invention may further include an NSAID, for example, loxoprofen or its salts.

[0049] Specific examples of the dosage form of the skin external preparation of the present invention include liquids, creams, gels, ointments, sprays (aerosols for external use, pump sprays), foams, and poultices, and each dosage form can be produced by appropriately using additives and bases suitable for the dosage form, according to the usual methods described in the 18th Edition of the Japanese Pharmacopoeia, etc. The dosage form of the skin external preparation of the present invention is preferably a liquid (particularly a liquid for external use).

[0050] The preparation of the topical skin preparation of the present invention can be, for example, stored and sealed in a glass container or package, or a container or package made of a metal such as aluminum, or a container or package made of an olefin resin such as polyethylene or polypropylene, and can further be stored in a moisture-proof bag containing a metal such as aluminum. In addition, the container or package may be a container or package containing environmentally friendly raw materials such as recycled plastics or biomass raw materials, and if necessary, any material that prevents deterioration of the topical skin preparation due to factors, elements, and environmental changes from outside the container or package of the pharmaceutical product, such as laminated materials, gas barrier materials, heat and light in a high-temperature environment, and appropriately maintains the quality of the topical skin preparation may be used. In one embodiment of the present invention, the topical skin preparation may be a pharmaceutical product in which the preparation or composition of the topical skin preparation is stored in a suitable container or package.

[0051] In one embodiment of the present invention, a surfactant having a polyoxyethylene structure may be used as a viscosity reducing agent for a liquid composition containing at least one selected from the group consisting of heparinoids and their salts, and at least one selected from the group consisting of glycyrrhizic acid and its salts. Specifically, a viscosity reducing agent for a liquid composition containing at least one selected from the group consisting of heparinoids and their salts, and at least one selected from the group consisting of glycyrrhizic acid and its salts, which contains a surfactant having a polyoxyethylene structure, is provided.

[0052] The present invention will be described in more detail below by way of examples, but the present invention is not limited to these examples in any way. EXAMPLES

[0053] (Test Example 1) Study of the viscosity of a composition containing a heparinoid, a compound having a quaternary ammonium group (benzethonium chloride), and a polyhydric alcohol Components that reduce the viscosity of compositions containing heparinoids, benzethonium chloride, and polyhydric alcohols were examined.

[0054] (1) Preparation of test materials and specimens The components were mixed and dissolved in the amounts (%) shown for each sample in Table 1 below, and the pH was adjusted to 4.5 or 6.0 using a solution of citric acid diluted 2-fold or a solution of trisodium citrate dihydrate diluted 4-fold (pH adjuster) to obtain liquid preparations for samples 1 to 9. The following reagents were used: Heparinoid (manufactured by API Co., Ltd.) (ratio of organic sulfate groups to the total heparinoid is 35.2% (mass%)) Dipotassium glycyrrhizinate (Maruzen Pharmaceutical Co., Ltd.) Benzethonium chloride (Lonza Co., Ltd.) 1,3-Butylene glycol (Kanto Chemical Co., Ltd.) Polysorbate 80 (NIKKOL TO-10MV, Nikko Chemicals Co., Ltd.) Citric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) Sodium citrate hydrate (Fujifilm Wako Pure Chemical Industries, Ltd.)

[0055] (2) Manufacturing method The obtained formulation was dispensed into 450 mL UM sample bottles SCC manufactured by AS ONE Corporation and sealed. The dispensed samples were left to stand at room temperature for one week, after which the appearance of each sample was confirmed and the viscosity (mPa·s) at room temperature (20-25°C) was measured. A Brookfield B-type viscometer (DV3T) was used for the measurement, and the viscosity was measured under the following conditions: spindle: Lv-1, rotation speed: 200 rpm, measurement time: 3 minutes. If the measurement could not be performed under these conditions, the spindle was changed to Lv-1 and rotation speed: 10 rpm, and the measurement was performed again.

[0056] (3) Test results The results for each sample are shown in Tables 1 and 2.

[0057] [Table 1]

[0058] [Table 2]

[0059] The results in Tables 1 and 2 show that sample 1, which contained only dipotassium glycyrrhizinate, had a viscosity of 104.8 mPa·s at a rotation speed (10 rpm). Sample 2, which contained sample 1 further containing 1,3-butylene glycol, and sample 3, which contained a heparinoid, showed increased viscosities of 203.2 mPa·s and 206.6 mPa·s at a rotation speed (10 rpm). Furthermore, samples 4 and 7, which contained sample 1 further containing 1,3-butylene glycol and a heparinoid, or benzethonium chloride, showed significant increases in viscosity to 429.8 mPa·s and 385.4 mPa·s at a rotation speed (10 rpm). On the other hand, in samples 5, 6, 8, and 9, in which polysorbate 80 was added to sample 4 or 7, the viscosity was significantly reduced to 1.0 mPa·s, 0.6 mPa·s, 1.4 mPa·s, and 0.8 mPa·s at a rotation speed (10 rpm) and to 6.1 mPa·s, 5.9 mPa·s, 5.8 mPa·s, and 6.2 mPa·s at a rotation speed (200 rpm).

[0060] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible without departing from the spirit of the present invention.

[0061] (Formulation example) After dissolving the components shown in the following Tables 3 to 6 by stirring and mixing, the skin topical preparation of each formulation example can be obtained. The preparation can be produced by taking the above-mentioned ingredients and amounts and following the procedures prescribed in the General Provisions for Preparations in the Japanese Pharmacopoeia, Sections on "External Solutions" and "Creams". For example, when a liquid or semi-solid composition is formulated as a specific dosage form, a known means may be applied for each dosage form, such as placing the liquid or semi-solid composition in a container (e.g., a bottle-shaped container, a tube-shaped container, a sheet-shaped container, a spray container, etc.) as appropriate for the dosage form, spreading the liquid or semi-solid composition on a support to form a shape, or mixing with a propellant and then placing it in an aerosol can.

[0062] [Table 3] JPEG2025020502000004.jpg180170

[0063] [Table 4] JPEG2025020502000006.jpg151170

[0064] [Table 5] JPEG2025020502000008.jpg234170JPEG2025020502000009.jpg139170

[0065] [Table 6] JPEG2025020502000011.jpg245170JPEG2025020502000012.jpg156170

[0066] Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Addition, omission, substitution, and other modifications of the configuration are possible without departing from the spirit of the present invention. [Industrial Applicability]

[0067] The liquid composition of the present invention has excellent storage stability and is extremely useful.

Claims

1. At least one selected from the group consisting of heparinoids and salts thereof; At least one selected from the group consisting of glycyrrhizinic acid and salts thereof; A polyhydric alcohol; A surfactant having a polyoxyethylene structure, and water, and having a pH of 6.0 or less; liquid composition.

2. 2. The liquid composition according to claim 1, having a viscosity of 20.0 mPa·s or less as measured using a Brookfield viscometer at a rotation speed of 200 rpm.

3. 2. The liquid composition according to claim 1, having a viscosity of 50.0 mPa·s or less as measured using a Brookfield viscometer at a rotation speed of 10 rpm.

4. The liquid composition according to claim 1 , further comprising a compound having a quaternary ammonium group.

5. 2. The liquid composition of claim 1, comprising only water as a solvent.

6. 6. The liquid composition according to claim 1, wherein the content of the heparinoid and its salt is 0.1 to 1.0% by mass based on the total mass of the liquid composition.

7. The liquid composition according to any one of claims 1 to 5, wherein the content of glycyrrhizinic acid and its salts is 0.1 to 5.0% by mass based on the total mass of the liquid composition.

8. 6. The liquid composition according to claim 1, wherein the content of the polyhydric alcohol is 1 to 15% by mass based on the total mass of the liquid composition.

9. 6. The liquid composition according to claim 1, wherein the content of the surfactant having a polyoxyethylene structure is 0.5 to 10% by mass relative to the total mass of the liquid composition.

10. The liquid composition according to any one of claims 1 to 5, wherein the ratio of the content of the surfactant having a polyoxyethylene structure to the total content of the heparinoid and its salt, glycyrrhizinic acid and its salt, and polyhydric alcohol is 0.1 to 3.

11. The liquid composition according to claim 4, wherein the compound having a quaternary ammonium group is at least one selected from the group consisting of benzethonium, benzalkonium, cetylpyridinium, and salts thereof.

12. The liquid composition according to any one of claims 1 to 5, which is an external preparation for skin.

13. A skin external preparation comprising the liquid composition according to any one of claims 1 to 5.

14. The skin topical preparation according to claim 13, which is a liquid, cream, gel, ointment, spray, foam, or patch.

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