TW202319044A - Topical skin agent containing heparinoid and loxoprofen or salt thereof - Google Patents

Abstract

The present invention addresses the problem of providing a topical skin agent containing a heparinoid and another active ingredient, wherein the storage stability of the heparinoid is improved. According to the present invention, there is provided a topical skin agent containing a heparinoid and loxoprofen or a salt thereof.

Description

External preparations for skin containing heparan-like substances and loxoprofen or its salts

The present invention relates to skin external preparations containing heparanoid substances. More specifically, the present invention relates to an external skin preparation for improving the storage stability of a heparin-like substance in a liquid or semi-solid composition containing a heparin-like substance by containing loxoprofen or a salt thereof .

Heparin-like substances are polysulfated mucopolysaccharides such as polysulfated chondroitin extracted from the lungs of healthy edible animals, mainly cattle, which contain tracheal cartilage. It is a sulfate ester of mucopolysaccharides, and it is called by this name because it has a structure similar to that of heparin, which has a structure in which uronic acid and glucosamine interact with each other for 1,4 linkages. Heparan-like substances are known to have a moisturizing effect, an anti-inflammatory effect, a blood circulation promoting effect, and the like. The efficacy and effect of external skin preparations blended with heparin-like substances are considered to be thrombophlebitis (including hemorrhoids), pain and inflammatory diseases based on blood circulation disorders (induration and pain after injection), chilblains, hypertrophic scars/ Treatment and prevention of keloids, progressive palmar keratoderma, cortical deficiency, swelling/hematoma/tenosynovitis/myalgia/arthritis after trauma (bruises, sprains, contusions), muscular torticollis (infancy). As dosage forms of external skin preparations containing a heparan-like substance, creams, ointments, lotions, and sprays are sold.

When a heparin-like substance is blended together with other active ingredients in a composition for external use, the storage stability of each active ingredient or the maintenance of the quality of the composition becomes a problem. For example, in Patent Document 1, it has been disclosed that by blending lidocaine (Lidocaine) and amino alcohol or pyrrolidone carboxylate in a composition for external use on the skin containing a heparan-like substance, the heparan-like substance can be increased. Stability of heparin substances, lidocaine and vitamin A palmitate. In addition, Patent Document 2 discloses that the stability of the heparan-like substance and vitamin B6 can be improved by setting the pH value to 4 or higher in a composition for external use on the skin containing a heparan-like substance and vitamin B6.

However, based on the various effects of heparanoid substances, further development of skin external preparation compositions has been expected. [Prior Art Literature] [Patent Document]

[Patent Document 1] Japanese Patent Laid-Open No. 2004-307491 [Patent Document 2] WO2020/138403

[Problem to be Solved by the Invention]

Therefore, when developing an external skin preparation containing a heparanoid substance, the inventors of the present invention examined the storage stability of the heparanoid substance, and found that when the heparanoid substance was dissolved in purified water, and when the heparanoid substance was When dissolved in purified water together with surfactants or thickeners, the stability is significantly reduced.

That is, an object of the present invention is to provide an external preparation for skin in which a heparanoid substance is stably blended. [Means to solve the problem]

Then, as a result of repeated studies by the inventors in order to solve the above-mentioned problems, it was found that by mixing loxoprofen or its salt into a liquid or semi-solid composition containing a heparinoid, the heparinoid The stability of matter just promotes, then completes the present invention.

That is, according to the present invention, the following inventions are provided. (1) An external preparation for skin containing a heparanoid substance, and loxoprofen or a salt thereof. (2) The external preparation for skin as described in (1), wherein the content of the heparinoid in the external preparation for skin is 0.1 to 10% by mass. (3) The external preparation for skin as described in (1) or (2), wherein the content of the loxoprofen or its salt in the external preparation for skin is 0.1 to 15% by mass. (4) The external preparation for skin according to any one of (1) to (3), which further contains alcohol. (5) The external preparation for skin as described in (4) whose content of the said alcohol in an external preparation for skin is 0.1-70.0 mass %. (6) The external preparation for skin according to (4) or (5), wherein the aforementioned alcohols are lower alcohols. (7) The external preparation for skin according to (4) or (5), wherein the aforementioned alcohols are polyhydric alcohols. (8) The external preparation for skin according to (4) or (5), wherein the alcohols include lower alcohols and polyhydric alcohols. (9) The external preparation for skin as described in any one of (1) to (8), which further contains component (A), and the aforementioned component (A) is selected from the following components (A-1) to (A- 11) More than one of the groups formed, (A-1) tocopherols; (A-2) terpenes; (A-3) glycyrrhizic acid; (A-4) crude drugs; (A-5) tranexamic acids; (A-6) vanilloids; (A-7) Nicotinic acids; (A-8) Chlorpheniramines; (A-9) Diphenhydramine (Diphenhydramine); (A-10) pyrrolidones; (A-11) Inorganic salts. (10) The external skin preparation as described in any one of (1) to (9), wherein the mass ratio of the heparan-like substance to loxoprofen or its salt (heparan-like substance/loxoprofen or its salt) ) is 0.01~100. (11) The skin external preparation according to any one of (1) to (10), wherein the content of loxoprofen or its salt is 0.6% by mass or more based on the total amount of the skin external preparation, and the heparinoid and The mass ratio of loxoprofen or its salt (heparin-like substance/loxoprofen or its salt) is 0.01-10. (12) The external preparation for skin as described in any one of (1) to (11), wherein the dosage form is liquid for external use, ointment, cream, spray, gel, patch or solid for external use agent. (13) The external preparation for skin according to any one of (1) to (11), wherein the dosage form is a liquid preparation for external use. (14) The external preparation for skin according to any one of (1) to (13), which is capable of suppressing a decrease in the content of the heparinoid caused by at least one of a surfactant and a thickener. (15) A stabilizer of a heparan-like substance-containing external preparation for skin, comprising loxoprofen or a salt thereof. (16) The stabilizer for an external skin preparation as described in (15), which is capable of suppressing a decrease in the content of the heparinoid caused by at least one of a surfactant and a thickener. [Invention effect]

According to the external preparation for skin of the present invention, by blending the heparan-like substance and loxoprofen or its salt, the stability of the heparan-like substance is improved, thereby improving the storage stability, and even after preservation, the heparan-like substance can be effectively exerted. Pharmacodynamics of the heparin substance.

The external preparation for skin (hereinafter, sometimes referred to as external preparation) of the present invention contains a heparanoid substance, and loxoprofen or a salt thereof.

The heparin-like substance in the present invention is a substance called mucopolysaccharide polysulfate or heparinoid (heparinoid). Known medicines such as effects, blood circulation promoting effects, etc. Among the heparinoid substances, for example, heparin; polysulfuric chondroitin such as chondroitin sulfate D, chondroitin sulfate E, and the like are included. The source of the heparin-like substance used in the present invention is not particularly limited, and examples thereof include those obtained by polysulfating mucopolysaccharides, those obtained from edible animal tissues (such as those contained in cattle or pigs, etc.) Tracheal cartilage of the lungs) extracted from those obtained. As the heparin-like substance, a heparin-like substance listed in Japanese Pharmacopoeia Non-drug Standards 2002 is preferable.

Heparanoids also need to be in the form of physiologically acceptable salts obtained by salt-forming reactions using alkali metal hydroxides or carbonates such as sodium and potassium, or amines. The proportion (%) of the organic sulfate group of the heparin-like substance in the present invention is not particularly limited, for example, from the viewpoint of improving anti-inflammatory and analgesic effects and reducing skin irritation, etc., it is preferably 20-40% (mass %), Most preferably, it is 25 to 38% (mass %). In addition, the amount of the organic sulfuric acid group was measured by the method described in the item of "heparan-like substances" in Japanese Pharmacopoeia Foreign Medicine Standards 2002. In addition, the average molecular weight of the heparin-like substances in the present invention is not particularly limited. For example, in terms of weight average molecular weight, it is preferably 1,000-1,000,000 Mw, and particularly preferably 5,000-100,000 Mw.

In addition, the external preparation for skin of the present invention may contain analogues of heparan-like substances as optional components. As analogues of heparanoid substances there may be, for example, other acidic mucopolysaccharides. Examples of acidic mucopolysaccharides that are analogs of heparinoids include chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, chondroitin sulfate K and other chondroitin sulfates, heparin, heparan sulfate, keratan sulfate, etc. That is, in the external preparation for skin of the present invention, together with the heparan-like substance, the above-mentioned acidic mucopolysaccharide, which is an analog of the heparan-like substance, may be further added as needed within the range not impairing the effect of the present invention. The analogues of these heparinoids may also be in the form of pharmaceutically acceptable salts and/or solvates. Examples of pharmaceutically acceptable salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, and the like. In addition, examples of the solvate include hydrates.

On the other hand, loxoprofen, which belongs to propionic acid-based nonsteroidal antipyretic analgesic and anti-inflammatory agents (NSAIDs), has antipyretic/analgesic/anti-inflammatory effects based on the inhibitory effect of prostaglandin production similarly to other NSAIDs. It is also known that loxoprofen has the following characteristics: it is a prodrug, and after oral administration, it is absorbed by the digestive tract in the form of an unaltered body with weak gastric mucosal irritation, and becomes an active body in vivo, so compared with Active body less gastric mucosal disturbance. In addition, it is known that loxoprofen is also converted into trans-OH body (active body) by ketone reductase in the skin. In recent years, loxoprofen is also used as an external anti-inflammatory analgesic, and has been marketed as poultice, Patches and gels are available clinically.

In the present invention, "loxoprofen or its salt" includes loxoprofen or its salt, and their hydrates. The salt of loxoprofen is preferably a pharmacologically acceptable salt, more preferably loxoprofen sodium or loxoprofen sodium hydrate (sometimes expressed as loxoprofen sodium dihydrate ), preferably loxoprofen sodium hydrate. In addition, in this specification, when referring to loxoprofen, it is considered to include loxoprofen or its salt, and the hydrates thereof.

Loxoprofen in the present invention is recorded in the 17th revised Japanese Pharmacopoeia in the form of loxoprofen sodium hydrate.

The external preparation for skin of the present invention may further contain alcohols. The so-called alcohols in the present invention refer to lower alcohols and polyhydric alcohols. The so-called lower alcohols in the present invention are aliphatic alcohols with 1 to 4 carbons used in external preparations as solubilizers, bases, preservatives, solvents, dissolution aids, etc., for example, selected from methanol , ethanol (also known as ethyl alcohol), propanol, isopropanol (also known as isopropyl alcohol) and butyl alcohol, etc. 1 or more of the group consisting of, preferably ethanol. Those with an ethanol content of 99.5% or more by volume are also called absolute ethanol.

The so-called polyhydric alcohol in the present invention refers to alcohols with two or more hydroxyl groups in the molecule used in external preparations, such as propylene glycol , 1,3-butanediol, macrogol (also known as polyethylene glycol), glycerin, D-sorbitol, dipropylene glycol, which are recorded in the pharmaceutical additives Code of Affairs 2021. In addition, the molecular weight of polyethylene glycol is not particularly limited, for example, it may be 200 to 20,000 in terms of number average molecular weight. In addition, the molecular weight of the alcohols in the present invention is not particularly limited. For example, it may be 400 or less, preferably less than 400, more preferably 300 or less, further preferably 250 or less, particularly preferably 200 or less. Below 100.

In addition, the content of the heparin-like substance 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, based on the total amount of the external preparation. In addition, when the dosage form of the external preparation is an adhesive agent (poultice, adhesive patch), the content of the heparinoid substance is not particularly limited, and it is preferably 0.1 to 100% relative to the total amount of paste in the adhesive agent. 10% by mass, more preferably 0.1-0.5% by mass.

In the case where the preparation outside the present invention contains alcohol, the ratio of the content of the heparanoid substance to the mass of the alcohol (mass ratio of the heparanoid substance/alcohol) is not particularly limited, preferably 1.0×10 ^-3 ~100, more preferably It is 1.4×10 ^-3 ~10, more preferably 2.0×10 ^-3 ~5.0. When the preparation outside the present invention contains lower alcohol, the ratio of the content of the heparanoid substance to the mass of the lower alcohol (mass ratio of the heparanoid substance/lower alcohol) is not particularly limited, but is preferably 1.0×10 ^-3 ~100 , more preferably 1.4×10 ^-3 ~10, even more preferably 2.0×10 ^-3 ~5.0. When an agent other than the present invention contains a polyol, the ratio of the content of the heparan-like substance to the mass of the polyol (mass ratio of the heparan-like substance/polyol) is not particularly limited, but is preferably 1.0×10 ^-3 ~100 , more preferably 1.4×10 ^-3 ~10, even more preferably 2.0×10 ^-3 ~5.0.

In addition, the content of loxoprofen or its salt (such as loxoprofen sodium hydrate) in the external preparation of the present invention is not particularly limited, preferably 0.1 to 15% by mass relative to the total amount of the external preparation, More preferably, it is 0.5-10 mass %. In addition, when the dosage form of the external preparation is an adhesive agent (poultice, patch), the content of loxoprofen or its salt (such as loxoprofen sodium hydrate) is not particularly limited, and it is preferably It is 0.1-15 mass % with respect to the whole amount of paste of an adhesive agent, More preferably, it is 0.5-10 mass %.

In the case where the preparation outside the present invention contains alcohol, the ratio of the content of loxoprofen or its salt to the mass of alcohol (loxoprofen or its salt/alcohol mass ratio) is not particularly limited, but is preferably 1.0× 10 ^-3 ~150, more preferably 1.4×10 ^-3 ~100, even more preferably 2.0×10 ^-3 ~35. In the case where the preparation outside the present invention contains a lower alcohol, the ratio of the content of loxoprofen or its salt to the mass ratio of the lower alcohol (loxoprofen or its salt/lower alcohol mass ratio) is not particularly limited, preferably 1.0×10 ^-3 ~150, more preferably 1.4×10 ^-3 ~100, even more preferably 2.0×10 ^-3 ~20. In the case where the preparation outside the present invention contains a polyhydric alcohol, the ratio of the content of loxoprofen or its salt to the mass of the polyhydric alcohol (loxoprofen or its salt/polyhydric alcohol mass ratio) is not particularly limited, preferably It is 1.0×10 ^-3 ~150, more preferably 1.4×10 ^-3 ~100, even more preferably 2.0×10 ^-3 ~35.

The mass ratio of the heparin-like substance and loxoprofen or its salt in the external preparation of the present invention is not particularly limited, and the heparin-like substance/loxoprofen or its salt (HP/Lox mass ratio) can be 0.01～100, Preferably it is 0.01-10. In addition, in the external preparation of the present invention, from the viewpoint of improving the stability of the heparan-like substance, it is more preferable that the content of loxoprofen or its salt is 0.6% by mass or more relative to the total amount of the external preparation, and The heparan-like substance/loxoprofen or its salt (HP/Lox mass ratio) is 0.01-10.

In addition, the content range of the alcohol in the external preparation of the present invention is not particularly limited, and can be selected according to the dosage form, preferably 0.1-70.0% by mass relative to the total amount of the external preparation. In addition, when the dosage form of the external preparation is a patch (poultice, patch), the content of alcohol is not particularly limited, but it is preferably 0.1 to 70.0% by mass relative to the total amount of paste in the patch. %. In addition, the content range of the lower alcohol in the external preparation of the present invention is not particularly limited, and can be selected according to the dosage form, preferably 0.1-70.0% by mass relative to the total amount of the external preparation, more preferably 0.1-50.0% by mass %.

For example, when the external agent of the present invention is an external liquid/gel, the range of the content of the lower alcohol is not particularly limited, for example, relative to the total amount of the external liquid/gel, preferably It is 10.0-70.0 mass %, More preferably, it is 10.0-60.0 mass %. For example, when the agent outside the present invention is a poultice, the range of the content of the lower alcohol is, for example, preferably 0.1 to 50% by mass, more preferably 0.1% by mass, relative to the total amount of the poultice. %~30% by mass. For example, when the agent outside the present invention is a patch agent, there may be a case where a lower alcohol is contained and a case where a lower alcohol is not contained. The range of the content of the case where a lower alcohol is contained is, for example, relative to the total amount of the paste of the patch agent For , it is preferably 0.1 to 10% by mass, more preferably 0.1% to 5% by mass.

Furthermore, the content range of the polyhydric alcohol in the external preparation of the present invention is not particularly limited, and can be selected according to the dosage form, preferably 0.1-70% by mass relative to the total amount of the external preparation, more preferably 0.1-20% by mass. % by mass, more preferably 0.5 to 20% by mass, even more preferably 1.0 to 15% by mass. For example, when the external agent of the present invention is an external liquid/gel, the range of the content of the polyhydric alcohol is not particularly limited, for example, relative to the total amount of the external liquid/gel, preferably 0.5 to 20% by mass, more preferably 1.0 to 15% by mass.

For example, when the agent used outside the present invention is a poultice, the range of the content of the polyhydric alcohol is not particularly limited, for example, it is preferably 0.1 to 70% by mass relative to the total amount of the poultice. , more preferably 3 to 60% by mass. For example, when the agent used outside the present invention is a patch, there are cases where polyols are contained and cases where polyols are not contained, and the range of content in the case of containing polyols is, for example, relative to the total amount of paste of the patch For , it is preferably 0.1 to 15% by mass, more preferably 0.1% to 10% by mass.

In addition, the pH range of the external preparation for skin is not particularly limited, but is preferably 5.0 to 7.5, more preferably 6.0 to 7.5.

In the external skin preparation of the present invention, drugs or pharmaceutical additives generally used in external skin preparations for analgesic and anti-inflammation other than the above-mentioned components may be added.

In the external preparation for skin of the present invention, component (A) may be further contained, and the aforementioned component (A) may contain at least one selected from the group consisting of the following components (A-1) to (A-11) . (A-1) tocopherols; (A-2) terpenes; (A-3) glycyrrhizic acid; (A-4) crude drugs; (A-5) tranexamic acids; (A-6) vanilloids; (A-7) Nicotinic acids; (A-8) Chlorpheniramines; (A-9) Diphenhydramine; (A-10) pyrrolidones; (A-11) Inorganic salts.

Examples of tocopherols (A-1) include tocopherol, tocotrienol, 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.). Any of α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol may be used as the tocopherol, and α-tocopherol is preferred. In addition, the tocotrienol may be any of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, preferably α-tocotrienol phenol. As the tocopherols, particularly preferred is tocopheryl acetate.

The content of tocopherols in the external skin preparation in the case of using tocopherols is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.03 to 4% by mass based on the mass of the total amount of the external skin preparation , especially preferably 0.05~2% by mass.

The so-called (A-2) terpenes are meant to include terpene hydrocarbons. In addition, the general term for terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc. (terpene ( terpenoid)), its structure is not particularly limited, and examples thereof include monoterpenes, sesquiterpenes, and derivatives thereof. In addition, it may be a ring type or a chain type. Examples of terpenes include isoborneol, irone, ocimene, carveol, carvotanacetone, carvomenthone, carvone, carene, carone, and camphene. Camphor, geraniol, sabinene, galalin, cyclocitral, citral, citronellal, citronellic acid, citronellol, eucalyptol, cymene, sylvestrene , Thymol, isothujol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinamol (pinocampheol), pinole, piperitenone, phellandrene, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, perillaldehyde, borneol, myrcene, menthol , Menthone, Ionol, Ionone, Linalool, Limonene, etc.

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, perfume tree oil, chamomile oil, melaleuca oil, caraway oil, cubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, peppermint oil, perilla oil, lemon eucalyptus oil, citronella oil, ginger oil, cardamom oil, camphor oil, ginger grass oil, spearmint oil, peppermint oil, geranium oil, anise Oil, Clove Oil, Turpentine Oil, Spruce Oil, Neroli Oil, Basil Oil, Peppermint Oil, Palmarosa Oil, Allspice Oil, Orange Leaf Oil, Bay Oil, Peppermint Oil, Catmint Oil, Bergamot Oil, Rose Wood oil, linoleum oil, marjoram oil, tangerine oil, lemon balm oil, eucalyptus oil, lime oil, lavender oil, agarwood oil, lemon oil, lemongrass oil, rose oil, rosemary oil, Roman chamomile oil, etc. , these can be used alone or in combination of two or more.

As terpenes, l-menthol, dl-camphor, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), 3-(l-menthoxy)-2 -Methylpropane-1,2-diol, p-mentha-3,8-diol, isopulegol, thymol, peppermint oil, eucalyptus oil, and the like.

The content of terpenes in the external skin preparation in the case of using terpenes is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 6% by mass, based on the mass of the total amount of the external skin preparation. , especially preferably 0.1 to 4% by mass.

As (A-3) glycyrrhizic acid, glycyrrhizic acid or its salt, glycyrrhetinic acid or its salt is mentioned, for example. Examples of salts include alkali metal salts such as potassium salts and sodium salts; ammonium salts; and the like. In addition, as the glycyrrhizic acid, licorice containing glycyrrhizic acid or its extract can also be used.

The content of glycyrrhizic acid in the external skin preparation in the case of using glycyrrhizic acid is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass based on the mass of the total amount of the external skin preparation. Preferably, it is 0.1 to 3% by mass.

(A-4) Herbal medicines include, for example, licorice, arnica tincture, wild sycamore, axilia, epimedium, fennel, turmeric, corydalis, scutellaria baicalensis, sealwort, phellodendron, cherry bark, coptis, polygala , curcuma, valerian, chamomile, coriander seed, platycodon, almond, medlar, wolfberry leaf, nepeta, cinnamon, cassia seed, gentian, safflower, Cyperus radix, bezoar, schisandra, asarum, gardenia , Zanthoxylum bungeanum, aster, Digupi, purple root, peony, musk, sand ginseng, plantain seed, plantain, animal gall (including bear gall), ginger, earthworm, magnolia, horse chestnut, stone Garlic, Polygala, Chuanxiong, Peucedanum, Dangyao, Atractylodes, Morus Alba, Perilla, Garlic, Bamboo Ginseng, Tangerine Peel, Angelica, Ipecaac, Nantianshi, Ginseng, Fritillaria, Ophiopogon, Pinellia, Pansum Herbal medicines such as safflower, anti-nasal, Angelica dahurica, Atractylodes macrocephala, Poria cocos, Moutan bark, bayberry bark, velvet antler, and their extracts (extracts, tinctures, dry extracts, etc.). In addition, licorice can be used as glycyrrhizic acid or crude drug, or it can be used while taking into account the roles of both glycyrrhizic acid and crude drug.

The content of the crude drug in the external skin preparation in the case of using the crude drug is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass based on the mass of the total amount of the external skin preparation. Preferably, it is 0.1 to 3% by mass.

(A-5) Tranexamic acids may include, for example, tranexamic acid or a salt thereof, a tranexamic acid derivative or a salt thereof. The salt of tranexamic acid is not particularly limited, but 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; lysine, spermine, etc. Acid, histidine, ornithine and other basic amino acid salts; ammonium, monoethanolamine, diethanolamine, triethanolamine, stearylamine and other organic amine salts. In addition, tranexamic acid derivatives or salts thereof may be used. Specifically, ester derivatives such as cetyl tranexamic acid and amide derivatives such as methyl tranexamic acid may be exemplified.

The content of tranexamic acid in the external skin preparation in the case of using tranexamic acid is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, based on the mass of the total amount of the external skin preparation , particularly preferably 0.1 to 2% by mass.

(A-6) Vanilloids are a general term for compounds containing a vanillyl group. The vanilloids in the present invention are not particularly limited as long as they contain a vanillyl group. Examples include vanillin, vanillic acid, Capsaicin, vanillyl mandelic acid (VMA), vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol) and the like. In addition, the vanilloids in the present invention may include natural products including compounds containing vanillyl groups, derivatives of compounds having vanillyl groups, or synthetic compounds obtained by further imparting functional groups to vanillyl groups. In addition, as the vanilloids in the present invention, capsicums containing a compound containing a vanillyl group may be used, and may be included as a part of the vanilloids. As peppers, for example, peppers (Capsicum annuum Linne (Solanaceae) fruit) listed in the 17th revised Japanese Pharmacopoeia, etc. can be used suitably. It can be seen that the chili pepper needs to be adjusted in shape. It can be cut or broken into small pieces, small pieces, or pulverized into powder. For example, "pepper powder" obtained by making chili pepper into powder can also be used as "pepper" in the present invention. In addition, those obtained by subjecting capsicum to some extraction treatment (capsicum extract, capsicum tincture, etc.) can also be used. In addition, the extract of capsicum may be subjected to processing such as heating, drying, and pulverization in addition to extraction. In addition, as capsicum, capsaicin, which is a main component of capsicum, can also be used. As the capsaicinoid, capsaicin and nonanoic acid vanillyl amide are preferable. As capsicum, capsicum extract, capsicum tincture, nonanoic acid vanillyl amide, or capsaicin can be preferably used.

The content of vanilloids in the external skin preparation in the case of using vanilloids is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass, based on the mass of the total amount of the external skin preparation. % by mass, preferably 0.1 to 2% by mass. In addition, the content of capsicum in the skin external preparation in the case of using capsicum is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.05 to 4% by mass based on the mass of the total amount of the skin external preparation , particularly preferably 0.1 to 2% by mass.

Examples of (A-7) niacin acids include niacin, derivatives thereof, and salts thereof. Examples of derivatives of nicotinic acid include nicotinic acid esters (specifically, methyl nicotinate, β-butoxyethyl nicotinate, benzyl nicotinate, inositol hexanicotinate) , hepronicate, etc.), nicotinamide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, etc.) and the like. The nicotinic acid ester is preferably a monoester of nicotinic acid. As the nicotinic acid, benzyl nicotinate is preferable.

The content of niacin in the external skin preparation in the case of using niacin is not particularly limited, but is generally 0.01 to 10% by mass, more preferably 0.015 to 4% by mass, based on the mass of the total amount of the external skin preparation. , especially preferably 0.02~2% by mass.

Examples of (A-8) chlorpheniramines include chlorpheniramines and salts thereof. Specific examples of the salt of chlorpheniramine include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate; and various salts such as metal salts. Chlorpheniramine maleate is preferred as the chlorpheniramine.

The content of chlorpheniramines in the external skin preparation in the case of using chlorpheniramines is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.05% with respect to the mass of the total amount of the external skin preparation. ~4% by mass, particularly preferably 0.1~2% by mass.

Examples of (A-9) diphenhydramines include diphenhydramine or a salt thereof. Salts of diphenhydramine include hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyl disulfonate, tannin Acid addition salts such as lauryl sulfate, lauryl sulfate, sulfate, etc. As diphenhydramine, diphenhydramine or diphenhydramine hydrochloride is preferable.

The content of diphenhydramine in the external skin preparation in the case of using diphenhydramine is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.05% with respect to the mass of the total amount of the external skin preparation. ~4% by mass, particularly preferably 0.1~2% by mass.

Examples of the (A-10) pyrrolidones include dl-pyrrolidone carboxylic acid or a salt thereof, preferably sodium pyrrolidone carboxylate, for example. The content of pyrrolidones in the external skin preparation in the case of using pyrrolidones is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.1 to 10% by mass, based on the mass of the total amount of the external skin preparation. % by mass, preferably 1 to 10% by mass.

(A-11) Inorganic salts include salts of alkaline earth metals such as magnesium and calcium, salts of alkali metals such as sodium or the like, or ammonium salts, and are preferably sodium chloride, potassium chloride, or ammonium chloride.

In the case of using an inorganic salt, the content of the inorganic salt in the skin external preparation is not particularly limited, but it is generally 0.01 to 10% by mass, more preferably 0.1 to 10% by mass, based on the mass of the total amount of the skin external preparation. Preferably, it is 1 to 10% by mass.

As the drug involved in component (A), preferably anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid, antihistamines such as diphenhydramine or its salt, chlorpheniramine maleate, fertility Blood circulation improving ingredients such as phenol acetate, benzyl nicotinate, l-menthol, dl-camphor, d-camphor, nonylic acid vanillylamide, pepper extract, pepper tincture, capsaicin, Peppermint oil, eucalyptus oil, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1,2-diol, etc. Topical Stimulating ingredients, herbal ingredients such as arnica flower tincture, bactericidal ingredients such as isopropylmethylphenol, humectants such as dl-pyrrolidone carboxylic acid or its salt, inorganic salts such as sodium chloride, etc., these ingredients (A) It can be blended in the range which does not impair the effect of this invention.

Pharmaceutical additives other than the above-mentioned ingredients are added as needed for the purpose of further improving the stability of the content over time or the feeling of use, etc., such as humectants, humectants, viscous agents, adhesives, and adhesion-imparting resins. , crosslinking agent, filler, oil, softener, preservative, percutaneous absorption accelerator, stabilizer, dissolution aid, pH regulator, antioxidant, cooling agent, surfactant, emulsifier, etc. Moreover, the external preparation for skin of this invention may contain other arbitrary components. In addition, it is preferable that the external preparation for skin of the present invention does not contain N-methylpyrrolidone (N-methyl-2-pyrrolidone).

As a humectant, for example, hyaluronic acid, sodium dl-pyrrolidone carboxylate or a salt thereof (for example, sodium dl-pyrrolidone carboxylate) or the like can be used. As a humectant, for example, sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propylene glycol, 1,4-butylene, Polyols such as diols. As thickeners (thickeners/gelling agents), for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, alginic acid Sodium, carboxyvinyl polymer, carboxymethylcellulose, carmellose sodium, methylcellulose, carrageenan, locust bean gum, propylene glycol alginate, and the like.

As adhesives, for example, acrylic acid/octyl acrylate copolymer, acrylate/vinyl acetate copolymer, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution, 2-ethylhexyl acrylate/formyl 2-ethylhexyl acrylate/lauryl 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 silk 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, butyl acrylate/ethyl acrylate/3-hydroxypropyl methacrylate/2-methacrylate Acrylic adhesives such as hydroxyethyl ester/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 Polymer (SIS), Styrene/Butadiene/Styrene Block Copolymer (SBS), Polyisoprene, Polyisobutylene (PIB), Chloroprene Rubber, Polybutene, Natural Rubber Latex, SBR Synthetic Synthetic rubber-based adhesives such as latex; polysiloxane-based adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane; in addition, 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, acacia gum, etc., and those obtained by cross-linking these with metal salts such as aluminum, zinc, magnesium, and calcium, etc.

As the tack-imparting resin, for example, rosin, hydrogenated rosin glyceride, ester gum, maleic acid resin, maleated rosin glyceride, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin and the like can be used. As the crosslinking agent, for example, dry aluminum hydroxide gel, aluminum magnesium hydroxide, magnesium aluminum silicate, magnesium aluminum metasilicate, synthetic hydrotalcite (hydrosartite), dihydroxyaluminum aminoacetate, etc. can be used. As fillers it is possible to use, for example, aluminum oxide, 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. As fats and oils, hydrocarbons such as squalane, paraffin, mobile paraffin, light mobile paraffin, petrolatum, gelled hydrocarbons, etc.; fatty acid esters such as isopropyl myristate and octyldodecyl myristate can be used ; Behenyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol and other higher alcohols; behenic acid, lauric acid, myristic acid, stearic acid, isostearyl fatty acid, oleic acid and other higher fatty acids; carnauba wax, spermaceti, shellac, jojoba oil, beeswax, white beeswax, montan wax, lanolin, refined lanolin, reduced lanolin and other waxes; silicone oil, etc. .

As softeners, petroleum-based oils such as paraffin-based processing oils, naphthenic-based processing oils, and aromatic-based processing oils; squalane; squalene; cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, etc. Vegetable oils such as seed oil, olive oil, camellia oil, castor oil, tall oil and peanut oil; silicone oil; dibasic acid esters such as dibutyl phthalate and dioctyl phthalate; polybutene and liquid liquid rubber such as isoprene rubber; liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate and diisopropyl sebacate; diethylene glycol; Ethylene glycol; diol salicylate; propylene glycol; dipropylene glycol; triacetin; triethyl citrate; Crotamiton; glycerin, etc.

As preservatives, for example, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, isopropyl p-hydroxybenzoate, butyl p-hydroxybenzoate, isobutyl p-hydroxybenzoate , benzyl p-hydroxybenzoate, sodium benzoate, benzoic acid, benzyl benzoate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, amine ethyl ethyl sulfonic acid etc. As the transdermal absorption enhancer, for example, fatty acid esters such as alcohols, fatty acids, and diisopropyl adipate, fatty acid ethers, lactate esters, acetates, terpene compounds, pyrrolidone derivatives, organic acids, Organic acid esters, essential oils, hydrocarbons, carbonized propylene, azone or its derivatives, etc. As a stabilizer, for example, oxybenzone (oxybenzone), dibutylhydroxytoluene (BHT), sodium ethylenediaminetetraacetate, UV absorbers (for example, dibenzylmethane derivatives) and the like can be used.

As dissolution aids, for example, benzyl alcohol; pyrrothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols can be used ; Diethyl adipate, isopropyl adipate, diisopropyl adipate, diisobutyl adipate, dioctyl adipate, bis(2-heptylundecane adipate) base) esters, diisopropyl sebacate, diethyl sebacate and other polyacids; polyethylene glycol (PEG), polytetramethylene glycol and other polyalkylene glycols; polyethylene glycol monostearate, etc. Oxyalkylene fatty acid esters, etc. As the pH adjuster, for example, hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (such as triethanolamine, diisopropanolamine, etc.), phosphoric acid wait. As antioxidants, for example, ascorbic acid, ascorbyl palmitate, sodium bisulfite, dry sodium sulfite, sodium metabisulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, acetic acid tocopheryl Phenol, dl-α-tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylated hydroxyanisole, butylated hydroxyanisole, soybean lecithin, neopentylthritol tetra[3-(3 ,5-di-tert-butyl-4-hydroxyphenyl) propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate, etc. As a cooling agent, l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, thymol etc. are mentioned, for example.

As the surfactant, a nonionic surfactant may be used, and an ionic surfactant may also be used.

Examples of nonionic surfactants include propylene glycol monofatty acid esters, ethylene glycol monofatty acid esters, glycerol monofatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, Polyol fatty acid esters or polyol alkyl ethers such as methyl glucoside fatty acid esters, alkyl polyglucosides, and polyethylene glycol fatty acid esters; polyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, Polyoxyethylene phytosterols, polyoxyethylene phytostanols, polyoxyethylene polyoxypropylene alkyl ethers and other polyoxyethylene ethers; polyoxyethylene monofatty acid esters, polyethylene glycol difatty acid esters, polyoxyethylene Glycerin fatty acid ester, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc. polyoxyethylene sorbitan fatty acid ester , Polyoxyethylene sorbitan fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened castor oil Non-ionic surfactants such as polyoxyethylene hardened castor oil such as castor oil 60, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, polyoxyethylene polyoxypropylene glycol and other ether esters ; Ionic surfactants such as sodium lauryl sulfate and sodium cetyl sulfate; higher alcohols such as octyldodecanol, etc. Polyoxyethylene alkyl ethers in the present invention include, for example, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether. wait.

Examples of the polyoxyethylene polyoxypropylene alkyl ether in the present invention include polyoxyethylene polyoxypropylene cetyl ether and the like. The polyoxyethylene polyoxypropylene alkyl ether in the present invention includes, for example, polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol monooleate, and the like.

The nonionic surfactant in the present invention is listed in the Code of Pharmaceutical Additives 2021.

Examples of ionic surfactants include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, dioctyl sodium sulfosuccinate, chlorine Cationic surfactants such as benzalkonium chloride and benzethonium chloride.

The ionic surfactant in the present invention is listed in the Code of Pharmaceutical Additives 2021, the 17th revised Japanese Pharmacopoeia. As the emulsifier in the present invention, for example, those listed in the above-mentioned various surfactants, the above-mentioned higher alcohols, etc. can also be used arbitrarily. Examples of other arbitrary components in the present invention include herbal medicines such as tranexamic acid and licorice. Specifically, at least one of tranexamic acid and licorice may be further included in the external skin preparation containing a heparan-like substance and loxoprofen or a salt thereof of the present invention.

Specific dosage forms of the external preparation for skin of the present invention include, for example, liquids for external use, ointments, creams, sprays (aerosols for external use, pump sprays), gels, patches (patch preparations) , poultices) or solid preparations for external use, etc., can be manufactured in accordance with the usual methods described in the 17th revised Japanese Pharmacopoeia, etc., using additives or bases suitable for each dosage form. As a dosage form of the external preparation for skin in the present invention, a liquid preparation for external use is particularly preferable. In the present invention, in the case of making an adhesive agent such as a poultice or a plaster, the concentration of loxoprofen or its salt (such as loxoprofen sodium) may vary depending on the amount of the paste, What is necessary is just to adjust the paste amount etc. suitably so that the density|concentration of loxoprofen or its salt (for example, loxoprofen sodium) may become suitable.

In addition, the preparation of the external skin preparation of the present invention can be housed in, for example, glass containers/packages, or metal containers/packages such as aluminum, or containers/packages made of olefin-based resins such as polyethylene and polypropylene, and add seal. In addition, for containers/packages, containers/packages containing environmentally friendly raw materials/materials such as recycled plastics or biomass raw materials can also be used, and laminated structure materials or gas barrier materials can also be used to prevent high-temperature environments, etc. Any material, etc. that degrades external skin preparations due to external factors/elements/environmental changes such as heat and light from pharmaceutical containers/packages and appropriately maintains the quality of skin external preparations. In one embodiment of the present invention, a preparation/composition of an external preparation for skin can also be prepared as a pharmaceutical in which a suitable container/package is accommodated. According to the external preparation for skin of the present invention, the stability of the heparan-like substance can be improved by blending the heparan-like substance and loxoprofen or a salt thereof. Thereby, the storage stability of the external preparation for skin can be improved, and the medicinal effect of the heparan-like substance can be effectively exhibited even after storage. Furthermore, according to the external preparation for skin of the present invention, it is possible to suppress the decrease in the content of heparin-like substances caused by at least one of the surfactant and the thickener (caused by the surfactant or the thickener).

As an embodiment, the present invention can also be used as a stabilizer for an external skin preparation containing a heparan-like substance, which contains loxoprofen or a salt thereof. Specifically, loxoprofen or a salt thereof may also be used as a stabilizer for heparinoid substances in skin external preparations containing heparanoid substances. In addition, in the above-mentioned one embodiment, it is possible to suppress the decrease in the content of the heparanoid substance caused by at least one of the surfactant and the thickener.

Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited at all by these Examples. [Example]

(Test example 1) Examination of storage stability of heparinoid substance (1) (1) Preparation of test materials and specimens Mix/dissolve the components described in each sample in Table 1 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 times. The solution (pH adjuster) was adjusted so that the pH value became 6.5, and the solutions of samples 1 to 8 were obtained. In addition, each of the heparinoids used was made by Api Co., Ltd. (the ratio of the organic sulfate group to the whole heparinoids was 35.2% (mass %)), and the loxoprofen sodium hydrate was used by KOLON LIFE Manufactured by SCIENCE, INC., polyoxyethylene hardened castor oil 60 and polysorbate 80 are manufactured by Nikko Chemicals Co., Ltd., hydroxypropyl methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd., hydrochloric acid and Sodium hydroxide was manufactured by Kanto Chemical Co., Ltd.

The obtained preparation was dispensed into transparent glass vials with a diameter of 30 mm, and tightly fastened. As the transparent glass vial, Mighty Vial (transparent, No. 6) manufactured by Maruemu Co., Ltd. was used. Store the dispensed samples 1-8 at 40°C with a relative humidity of 75%, 50°C, and 60°C for 1 month. For the samples before storage and after storage, heparinoid substances were measured by the following method based on the Japanese Pharmacopoeia Non-drug Component Specifications 2002 Heparinoid Substance Confirmation Test (1) and Dextran Sodium Sulfate Enteric-Coated Tablet Quantitative Method Based on the content in the composition, the remaining rate (%) of the heparinoid substance was calculated based on the following formula.

<Calculation method of remaining rate (%) of heparinoid substance> ・Preparation of sample stock solution Dilute the sample sample for measurement of the remaining rate with water so that the concentration of heparinoid substance becomes 6×10 ^-3 mg/mL, The obtained product was used as a sample stock solution. In addition, depending on the dosage form, it is also possible to prepare a sample stock solution using arbitrarily appropriate salts.・Preparation of standard stock solution for calibration curve The heparinoid substance for quantification is diluted with water, and the standard stock solution for calibration curve preparation with the concentration of the heparinoid substance in the range including the concentration of the heparinoid substance in the sample stock solution is prepared. In addition, depending on the dosage form, it is also possible to prepare a standard stock solution for calibration curve preparation using salt arbitrarily as appropriate.・Preparation of sample solutions, etc. and determination of the residual rate (%) of heparin-like substances Accurately weigh 5 mL each of sample stock solution, standard stock solution, and water, and add 0.1 mol/L citric acid, 0.2 mol/L dihydrogen phosphate Sodium (19:1) mixed solution adjusted toluidine blue O solution (1→50000) 5mL and fully shaken to mix, prepare test solution, standard solution, blank solution (solution without heparin-like substances). For each of the sample solution, standard solution and blank solution, water is used as a control, and the test is carried out by the ultraviolet-visible absorbance method immediately after the solution is prepared, and the absorbance _AT (absorbance of the sample solution) and absorbance A _S at a wavelength of 630nm are measured. (the absorbance of the standard solution) and absorbance A _B (the absorbance of the blank solution). A calibration line (regression line) was prepared using the value (A _{B -AS} ) obtained by subtracting the value of the absorbance A _S obtained from the standard solution having the concentration of each heparin substance from the absorbance A _B obtained from the blank solution . The ratio (%) to the blending amount of the heparin-like substance in the sample was calculated from the absorbance A _T and the calibration line obtained from the sample solution. At this time, the absorbance A _B obtained from the blank solution is above 1.0, and the correlation coefficient obtained from the calibration curve is below -0.99, confirming that the conditions are suitable for absorbance measurement, and the experiment is carried out. In addition, absorbance was measured using the Shimadzu Corporation spectrophotometer UV-2700.・Calculation method of residual rate (%) of heparinoid substance in the specimen Residual rate of heparinoid substance (%) = ratio (%) to the heparinoid substance blended amount after storage / relative to initial heparinoid substance Ratio of blending amount of substance (%)×100 In addition, the ratio of the blending amount of heparinoid substance to the initial stage refers to the sample in a stable state immediately after preparation of the skin topical composition or refrigerated storage (5°C Storage) The content of the ingredients measured within 1 month. By this procedure, the calculation of the remaining rate (%) of the heparanoid substance was performed also in various samples.

In addition, for the residual rate of heparinoid substances, the following judgment criteria were set. Based on the judgment criteria, B judgment or above was regarded as good, and in Table 1 and Table 2, it was B judges the above as qualified. From Table 15 onwards, those with a judgment of B or higher under the condition of 60°C are considered to be acceptable. [judgment criteria] A judgment: more than 95% Judgment B: More than 90% and less than 95% Judgment C: more than 80% and less than 90% D judgment: less than 80%

(3) Test results Table 1 shows the results of samples 1 to 8.

※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 1, it is known that the sample 1 obtained by dissolving the heparin-like substance in water, the sample 3 obtained by blending the heparin-like substance and polyoxyethylene hardened castor oil 60, and the sample 3 obtained by blending the heparin-like substance and polysorbate Sample 5 of sugar alcohol ester 80 and sample 7 mixed with heparin-like substances and hydroxypropyl methylcellulose can be seen to reduce the content of heparin-like substances over time under accelerated conditions and severe conditions, and the storage is stable Sex is poor. On the other hand, it was found that, for samples 2, 4, 6, and 8 in which heparinoids and loxoprofen sodium hydrate were mixed, the decrease in the content of heparinoids was suppressed under all storage conditions. Excellent stability.

(Test example 2) Examination of storage stability of heparinoid substance (2) In accordance with the results of Test Example 1, a review was conducted on components that would further improve the storage stability of heparinoids. (1) Preparation of test materials and specimens Mix/dissolve the components described in each sample in Table 2 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 times. The solution (pH adjuster) was adjusted so that the pH value became 6.5, and the solution of specimen 9-15 was obtained. In addition, the heparin-like substance manufactured by Api Co., Ltd., the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC., and the absolute alcohol manufactured by Imazu Pharmaceutical Co., Ltd. were used. 1 , 3-butanediol is made by Kanto Chemical Co., Ltd., propylene glycol is made by Maruishi Pharmaceutical Co., Ltd., macrogol 400 is made by NOF Co., Ltd., and concentrated glycerin is made by Kokai Pharmaceutical Co., Ltd. ), the D-sorbitol solution is made by Product Food Science Co., Ltd., and the hydrochloric acid and sodium hydroxide are made by Kanto Chemical Co., Ltd.

(2) Test method The storage of each of the preparations obtained and the measurement of the content of the heparanoid substance in the composition were carried out in the same manner as in Test Example 1.

(3) Test results Table 2 shows the results of samples 9 to 15.

※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 2, it is known that the content of the heparin-like substances in series 9 and 10 obtained by further blending absolute ethanol 5% or 40% in the preparations blended with heparin-like substances and loxoprofen sodium hydrate Decrease is suppressed remarkably, and storage stability is very excellent. In addition, it was found that the sample 11 obtained by further blending 1,3-butanediol, the sample 12 obtained by blending propylene glycol, Sample 13 obtained by blending polyethylene glycol 400, sample 14 obtained by blending concentrated glycerin, and sample 15 obtained by blending sorbitol also significantly suppressed the decrease in the content of heparin-like substances. Stability is excellent.

From the above test results, it has been found that the content of heparanoids can be suppressed by blending loxoprofen, and the storage stability of heparanoids can be improved. In addition, it has been found that in addition to loxoprofen, further blending of alcohols can suppress the decrease in the content of heparanoid substances, and further improve the storage stability of heparanoid substances.

(preparation example) After stirring/mixing and dissolving the components described in the following Tables 3 to 10, the external preparations for skin of each formulation example were obtained. As a production method, the above-mentioned components and amounts may be used, and the preparations may be carried out in accordance with the items of "liquids for external use", "gels", "poultices", and "patch preparations" in the general regulations of the Japanese Pharmacopoeia. In addition, for example, when the liquid or semi-solid composition is made into a specific dosage form and formulated, as long as it is suitable for the dosage form, it is suitable to store the liquid or semi-solid composition in a container (such as a bottle-shaped container, a tube-shaped container, etc.) container, sheet container, aerosol container, etc.), spreading a liquid or semi-solid composition on a support, forming it, mixing it with a propellant, and storing it in an aerosol can, etc. That's it. In addition, in the case of producing poultices and patches, well-known means such as spreading a liquid or semi-solid composition on a support and shaping it may be used.

In addition, the notes of ※1~※8 described in Table 3~Table 5 correspond to the contents shown below. ※1 Equivalent to loxoprofen sodium 1g (anhydrous conversion) ※2 Equivalent to loxoprofen sodium 2g (anhydrous conversion) ※3 Equivalent to loxoprofen sodium 0.5g (anhydrous conversion) ※4 Equivalent to 0.2g in terms of crude drug ※5 Equivalent to 0.1g in terms of crude drug ※6 Optionally choose one or more kinds as a pH adjuster, and add an appropriate amount ※7 Licorice extract is dry extract of licorice ※8 Equivalent to 2.5g in terms of crude drug

In addition, the notes of ※1~※8 described in Table 6~Table 8 correspond to the contents shown below. ※1 Equivalent to loxoprofen sodium 1g (anhydrous conversion) ※2 Equivalent to loxoprofen sodium 2g (anhydrous conversion) ※3 Equivalent to loxoprofen sodium 0.5g (anhydrous conversion) ※4 Equivalent to 0.2g in terms of crude drug ※5 Equivalent to 0.1g in terms of crude drug ※6 Choose one or more kinds at will, and add an appropriate amount ※7 Licorice extract is dry extract of licorice ※8 Equivalent to 2.5g in terms of crude drug

In addition, the notes of ※1~※7 described in Table 9~Table 11 correspond to the contents shown below. ※1 Equivalent to loxoprofen sodium 1g (anhydrous conversion) ※2 Equivalent to loxoprofen sodium 2g (anhydrous conversion) ※3 Equivalent to loxoprofen sodium 0.5g (anhydrous conversion) ※4 Equivalent to 0.2g in terms of crude drug ※5 Equivalent to 0.1g in terms of crude drug ※6 Licorice extract is dry extract of licorice ※7 Equivalent to 2.5g in terms of crude drug

In addition, the notes of ※1~※7 described in Table 12~Table 14 correspond to the contents shown below. ※1 Equivalent to loxoprofen sodium 5g (anhydrous conversion) ※2 Equivalent to loxoprofen sodium 6g (anhydrous conversion) ※3 Equivalent to loxoprofen sodium 8g (anhydrous conversion) ※4 Equivalent to 0.2g in terms of crude drug ※5 Equivalent to 0.1g in terms of crude drug ※6 Licorice extract is dry extract of licorice ※7 Equivalent to 2.5g in terms of crude drug

(Test Example 3) Examination of the storage stability of heparin-like substances (3) Mix/dissolve the components described in each sample in Table 15 and Table 16 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 The obtained solution (pH adjuster) was adjusted so that the pH value became 6.5, and the solution of each sample was obtained. In the same manner as in Test Example 1, storage at 60°C for one month was examined. The storage stability of heparin-like substances. In addition, the heparin-like substance manufactured by Api Co., Ltd. was used, the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC., and the hydrochloric acid and sodium hydroxide were manufactured by Kanto Chemical Co., Ltd. . The results are shown in Table 15 and Table 16.

In Table 15 and Table 16, ※1 Equivalent to loxoprofen sodium 15g (anhydrous conversion) ※2 Equivalent to loxoprofen sodium 8g (anhydrous conversion) ※3 Equivalent to loxoprofen sodium 2g (anhydrous conversion) ※4 Equivalent to loxoprofen sodium 1g (anhydrous conversion)

From the results in Table 15, when the content of loxoprofen sodium is 1 to 15% by mass, the heparanoid content reduction inhibitory effect can be seen. From the results in Table 16, it can be seen that when the content of the heparanoid substance is 0.15 to 9% by mass, the effect of suppressing the decrease in the content of the heparanoid substance is enhanced, and the storage stability is very excellent.

(Test Example 4) Examination of the storage stability of heparan-like substances (4) Mix/dissolve the components described in each sample in Table 17 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 times. In addition to adjusting the solution (pH adjuster) so that the pH value becomes 6.5, and obtaining the solution of each sample, in the same manner as in Test Example 1, the case of storing at 60°C for one month was examined. Heparin The storage stability of the substance. In addition, the heparin-like substances manufactured by Api Co., Ltd. were used, the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC. was used, the absolute alcohol was manufactured by Imatsu Pharmaceutical Co., Ltd., and Isoprofen sodium hydrate was used by Imazu Pharmaceutical Co., Ltd. For propanol, manufactured by Kokai Pharmaceutical Co., Ltd., for 1,3-butanediol, manufactured by Kanto Chemical Co., Ltd., for propylene glycol, manufactured by Maruishi Pharmaceutical Co., Ltd., and for polyethylene glycol 400, NOF ( Co., Ltd., hydrochloric acid and sodium hydroxide are made by Kanto Chemical Co., Ltd. The results are shown in Table 17.

In Table 17, ※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 17, it can be seen that by combining lower alcohols and polyhydric alcohols, the effect of suppressing the decrease in the content of heparanoid substances is enhanced, and the storage stability is very excellent. In addition, similarly to the case of absolute ethanol, it was found that by using isopropanol, the effect of suppressing the decrease in the content of heparanoid substances is also enhanced, and the storage stability is very excellent.

(Test Example 5) Examination of the storage stability of heparin-like substances (5) Mix/dissolve the components described in each sample in Tables 18 to 21 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 times. The obtained solution was adjusted so that the pH value becomes 6.5, and the solution of each specimen was obtained, and the preservation of the heparin-like substance in the case of storing at 60° C. for one month was examined in the same manner as in Test Example 1. stability. In addition, the heparin-like substances manufactured by Api Co., Ltd. were used, the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC. was used, the absolute alcohol was manufactured by Imatsu Pharmaceutical Co., Ltd., and poly Ethylene oxide hardened castor oil 60 and polysorbate 80 were manufactured by Nikko Chemicals Co., Ltd., tocopherol acetate was manufactured by Mitsubishi Chemical Foods Co., Ltd., and l-menthol was manufactured by Suzuki Mint Co., Ltd. dl-camphor is manufactured by Nissei Bilis Co., Ltd., thymol is manufactured by Fuji Film and Wako Pure Chemicals Co., Ltd., peppermint oil is manufactured by Xiaocheng Pharmaceutical Co., Ltd., and eucalyptus oil is manufactured by Japanese terpene Produced by Chemical Co., Ltd., 3-(menthoxy)-1,2-propanediol and 3-(l-menthoxy)-2-methylpropane-1,2-diol are used by Takasago Fragrance Industry Co., Ltd. ), tranexamic acid made by Kyowa Pharma Chemical Co., Ltd., licorice dry extract made by ALPS Pharmaceutical Co., Ltd., dipotassium glycyrrhizinate made by ALPS Pharmaceutical Co., Ltd., capsicum tincture Arnica flower tincture is made by Japan Powder Pharmaceutical Co., Ltd., benzyl nicotinate is made by Tokyo Chemical Industry Co., Ltd., and chlorpheniramine maleate is made by King Kong Chemical Co., Ltd. Nonanoic acid vanillyl amide is made by Tokyo Chemical Industry Co., Ltd., capsaicin and sodium chloride are made by Nacalai Tesque Co., Ltd., diphenhydramine is made by Tokyo Chemical Industry Co., Ltd., and benzene Hylaramine hydrochloride was produced by King Kong Chemical Co., Ltd., and hydrochloric acid and sodium hydroxide were produced by Kanto Chemical Co., Ltd. The results are shown in Tables 18-21.

In Table 18~Table 21, ※1 Equivalent to loxoprofen sodium 1g (anhydrous conversion) ※2 Equivalent to 2.5g in terms of crude drug ※3 Equivalent to 0.04g in terms of crude drug

From the results of tables 18 to 21, it is known that after blending loxoprofen sodium hydrate, and further blending tocopheryl acetate, l-menthol, dl-camphor, thymol, peppermint oil, eucalyptus oil, 3-(l-menthoxy)propan-1,2-diol, 3-l-menthyloxy-2-methylpropan-1,2-diol, tranexamic acid, dry extract of licorice (licorice extract dipotassium glycyrrhizinate, capsicum tincture, arnica flower tincture, benzyl nicotinate, chlorpheniramine maleate, nonanoic vanillyl amide, capsaicin, sodium chloride, diphenhydramine In the preparation of at least one of diphenhydramine hydrochloride and diphenhydramine hydrochloride, the decrease in the content of the heparanoid substance is suppressed, and the storage stability is very excellent.

(Test example 6) Examination of storage stability of heparan-like substances (6) Mix/dissolve the components described in each sample in Table 22 below, add purified water so that the total amount is 100 g, and then adjust the pH with a solution (pH adjuster) obtained by diluting hydrochloric acid to 2 times The storage stability of the heparin-like substance was examined in the same manner as in Test Example 1, when it was stored at 60° C. for one month, except that the solution of each sample was obtained at 6.5. In addition, the heparin-like substance manufactured by Api Co., Ltd. was used, the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC. was used, and the dl-pyrrolidone carboxylate solution was manufactured by Ajinomoto. Produced by Healthy Supply Co., Ltd., hydrochloric acid is produced by Kanto Chemical Co., Ltd. The results are shown in Table 22.

In Table 22, ※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 22, it can be known that in the preparation blended with loxoprofen sodium hydrate and further blended with dl-pyrrolidone carboxylic acid sodium solution, the reduction of the content of heparinoids is suppressed, and the storage stability is very good excellent.

(Test Example 7) Examination of the storage stability of heparin-like substances (7) Mix/dissolve the components described in each sample in Table 23 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 times. In addition to adjusting the solution (pH adjuster) so that it becomes pH 6.5 or pH 8.0, and obtaining the solution of each sample, in the same manner as in Test Example 1, storage at 60°C for one month was examined. The storage stability of heparin-like substances. In addition, the heparin-like substance manufactured by Api Co., Ltd., the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC., and the absolute alcohol manufactured by Imazu Pharmaceutical Co., Ltd. were used. 1 , 3-butanediol was manufactured by Kanto Chemical Co., Ltd., and hydrochloric acid and sodium hydroxide were manufactured by Kanto Chemical Co., Ltd. The results are shown in Table 23.

In Table 23, ※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 23, it can be seen that in the preparations of pH 6.5 to pH 8.0 in which loxoprofen sodium hydrate was blended, the decrease in the content of heparanoids was suppressed, and the storage stability was very excellent. From the results in Table 23, it can be seen that in the formulation of pH 6.5 to pH 8.0 obtained by blending loxoprofen sodium hydrate and further blending ethanol, the reduction of the content of heparinoids is suppressed, and the storage stability is very good. excellent. From the results in Table 23, it can be seen that in the preparation of pH6.5～pH8.0 blended with loxoprofen sodium hydrate and further blended with 1,3-butanediol, the reduction of the content of heparanoids is influenced by Inhibition, very excellent storage stability.

(Test Example 8) Examination of the storage stability of heparan-like substances (8) Mix/dissolve the components described in each sample in Table 24 below, add purified water so that the total amount is 100 g, and adjust the pH with a solution obtained by diluting phosphoric acid to 2 times (pH adjuster) It becomes 6.5, and the solution of each sample is obtained. In addition, except for mixing/dissolving the components described in each sample in Table 25 below to obtain a gel of each sample, in the same manner as in Test Example 1, the results of storage at 60°C for one month were examined. The storage stability of heparin substances such as circumstances. In addition, the heparin-like substance manufactured by Api Co., Ltd., the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC., and the absolute alcohol manufactured by Imazu Pharmaceutical Co., Ltd. were used. 1 , 3-butanediol is made by Kanto Chemical Co., Ltd., l-menthol is made by Suzuki Mentha Co., Ltd., and polyoxyethylene hardened castor oil 60 and polysorbate 80 are made by Nikko Chemicals. ), hydroxypropyl methylcellulose made by Shin-Etsu Chemical Co., Ltd., macrogol 400 made by NOF Co., Ltd., and triethanolamine made by Fuji Film Wako Pure Chemical Industries, Ltd. As for the carboxyvinyl polymer, the one manufactured by Sumitomo Seika Co., Ltd. was used, and the one manufactured by Kanto Chemical Co., Ltd. was used for the phosphoric acid. The results are shown in Table 24 and Table 25.

In Table 24 and Table 25, ※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 24, it can be seen that in the lotion blended with loxoprofen sodium hydrate, the decrease in the content of heparanoid substances was suppressed, and the storage stability was very excellent. From the results in Table 25, it can be seen that in the gel prepared by mixing loxoprofen sodium hydrate, the decrease in the content of heparanoid substances was suppressed, and the storage stability was very excellent.

(Test example 9) review of the storage stability of loxoprofen sodium Mix/dissolve the components described in each sample in Table 26 below, add purified water so that the total amount is 100 g, and dilute hydrochloric acid to 2 times or dilute sodium hydroxide to 10 times. The solution (pH adjuster) was adjusted so as to have a pH of 6.5 or pH 8.0 to obtain a solution of each sample. In addition, the components described in each sample in Table 27 were mixed/dissolved, and after adding purified water so that the total amount was 100 g, it was adjusted with a solution obtained by diluting hydrochloric acid or phosphoric acid to 2 times (pH adjuster) so that The pH value was adjusted to 6.5, and liquid preparations of each sample were obtained. In addition, the heparin-like substance manufactured by Api Co., Ltd., the loxoprofen sodium hydrate manufactured by KOLON LIFE SCIENCE, INC., and the absolute alcohol manufactured by Imazu Pharmaceutical Co., Ltd. were used. 1 , 3-butanediol is made by Kanto Chemical Co., Ltd., l-menthol is made by Suzuki Mentha Co., Ltd., and polyoxyethylene hardened castor oil 60 and polysorbate 80 are made by Nikko Chemicals. ), hydroxypropyl methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd., tocopheryl acetate is manufactured by Mitsubishi Chemical Foods Co., Ltd., hydrochloric acid, phosphoric acid and sodium hydroxide are manufactured by Kanto Chemical Co., Ltd. ) maker.

The obtained preparation was dispensed into transparent glass vials with a diameter of 30 mm, and tightly fastened. As the transparent glass vial, Mighty Vial (transparent, No. 6) manufactured by Maruemu Co., Ltd. was used. Store the dispensed samples at 60°C for 1 month. For the samples before storage and after storage, quantification of loxoprofen sodium was carried out by liquid chromatography, and the residual rate of loxoprofen sodium was calculated. The results are shown in Table 26 and Table 27.

In Table 26 and Table 27, ※Equivalent to 1 g of loxoprofen sodium (anhydrous conversion)

From the results in Table 26, it can be seen that loxoprofen sodium has excellent storage stability between pH 6.5 and pH 8.0. From the results in Table 27, it can be seen that loxoprofen sodium has excellent storage stability among the three formulations produced.

As mentioned above, although the preferred embodiment and the Example of this invention were demonstrated, this invention is not limited to these. Additions, omissions, substitutions, and other changes can be made without departing from the scope of the present invention. [Industrial availability]

The skin external preparation containing a heparin-like substance and loxoprofen or a salt thereof of the present invention has excellent storage stability and is extremely useful.

Claims (16)

An external preparation for skin, which contains a heparan-like substance, and loxoprofen or a salt thereof. The skin external preparation according to Claim 1, wherein the content of the aforementioned heparin-like substance in the skin external preparation is 0.1 to 10% by mass. The external preparation for skin according to claim 1 or 2, wherein the content of loxoprofen or a salt thereof in the external preparation for skin is 0.1 to 15% by mass. The skin external preparation according to claim 1 or 2, which further contains alcohols. The skin external preparation according to claim 4, wherein the content of the aforementioned alcohols in the skin external preparation is 0.1 to 70.0% by mass. The skin external preparation according to claim 4, wherein said alcohols are lower alcohols. The skin external preparation according to claim 4, wherein the aforementioned alcohols are polyhydric alcohols. The skin external preparation according to claim 4, wherein said alcohols include lower alcohols and polyhydric alcohols. The skin external preparation according to claim 1 or 2, which further contains component (A), and the aforementioned component (A) is at least one selected from the group consisting of the following components (A-1) to (A-11) , (A-1) tocopherols; (A-2) terpenes; (A-3) glycyrrhizic acid; (A-4) crude drugs; (A-5) tranexamic acids; (A-6) vanilloids; (A-7) Nicotinic acids; (A-8) Chlorpheniramines; (A-9) Diphenhydramine (Diphenhydramine); (A-10) pyrrolidones; (A-11) Inorganic salts. The skin external preparation according to claim 1 or 2, wherein the mass ratio of the heparan-like substance to loxoprofen or its salt (heparan-like substance/loxoprofen or its salt) is 0.01-100. Such as the skin external preparation of claim 1 or 2, wherein, the content of loxoprofen or its salt relative to the total amount of skin external preparation is more than 0.6 mass %, and the mass ratio of heparinoid substance and loxoprofen or its salt ( Heparin-like substance/loxoprofen or its salt) is 0.01~10. The external skin preparation according to claim 1 or 2, wherein the dosage form is liquid for external use, ointment, cream, spray, gel, patch or solid for external use. The skin external preparation according to claim 1 or 2, wherein the dosage form is a liquid preparation for external use. The skin external preparation according to claim 1 or 2, which can suppress the decrease in the content of the aforementioned heparinoids caused by at least one of the surfactant and the thickener. A stabilizer for an external skin preparation containing a heparan-like substance, which contains loxoprofen or a salt thereof. The stabilizer of an external skin preparation according to claim 15, capable of suppressing the decrease in the content of the aforementioned heparinoids caused by at least one of a surfactant and a thickener.