WO2023277075A1 - Topical skin agent containing heparinoid and loxoprofen or salt thereof - Google Patents

Topical skin agent containing heparinoid and loxoprofen or salt thereof Download PDF

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Publication number
WO2023277075A1
WO2023277075A1 PCT/JP2022/025996 JP2022025996W WO2023277075A1 WO 2023277075 A1 WO2023277075 A1 WO 2023277075A1 JP 2022025996 W JP2022025996 W JP 2022025996W WO 2023277075 A1 WO2023277075 A1 WO 2023277075A1
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Prior art keywords
skin
loxoprofen
external
salt
external preparation
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PCT/JP2022/025996
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French (fr)
Japanese (ja)
Inventor
日加里 大塚
史織 佐藤
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第一三共ヘルスケア株式会社
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Priority to JP2023532025A priority Critical patent/JPWO2023277075A1/ja
Priority to CN202280046283.6A priority patent/CN117715646A/en
Publication of WO2023277075A1 publication Critical patent/WO2023277075A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to an external preparation for skin containing a heparinoid. More specifically, the present invention relates to an external preparation for skin in which the storage stability of a heparinoid in a liquid or semi-solid composition containing a heparinoid is improved by incorporating loxoprofen or a salt thereof.
  • Heparin analogues are polysulfated mucopolysaccharides such as chondroitin polysulfate extracted from lungs containing tracheal cartilage of healthy edible animals, mainly bovines. It is a sulfate ester of a mucopolysaccharide, and is so named because it has a structure similar to heparin, in which uronic acid and glucosamine are alternately 1,4-linked. Heparin-like substances are known to have moisturizing action, anti-inflammatory action, blood circulation promoting action and the like.
  • Indications for topical skin preparations containing heparinoids include thrombophlebitis (including hemorrhoids), pain and inflammatory diseases due to blood circulation disorders (induration and pain after injection), chilblains, hypertrophic scars and keloids. Treatment and prevention, progressive keratoderma palmar, cortical deficiency, post-traumatic (bruise, sprain, contusion) swelling, hematoma, tendonitis, muscle pain, arthritis, muscular torticollis (infancy). Creams, soft ointments, lotions, and sprays are commercially available as dosage forms of external preparations for skin containing heparinoids.
  • Patent Document 1 describes the stability of a heparin analogue, lidocaine, and vitamin A palmitate by blending lidocaine and an amino alcohol or by blending pyrrolidone carboxylate in an external skin composition containing a heparin analogue. can be improved.
  • Patent Document 2 discloses that in an external skin composition containing a heparin analogue and vitamin B6, the stability of the heparin analogue and vitamin B6 can be improved by adjusting the pH to 4 or higher.
  • the present inventors investigated the storage stability of the heparinoid.
  • the inventors have found a problem that the stability is remarkably lowered when dissolved in purified water together with a surfactant or a thickener.
  • an object of the present invention is to provide an external preparation for skin in which a heparinoid is stably blended.
  • the present inventors have made intensive studies in order to solve the above problems, and as a result, obtained a heparin analogue by adding loxoprofen or a salt thereof to a liquid or semi-solid composition containing a heparin analogue.
  • the inventors have found that the stability of is improved, and have completed the present invention.
  • a skin external preparation containing a heparinoid and loxoprofen or a salt thereof (2) The external preparation for skin according to (1), wherein the content of the heparinoid in the external preparation for skin is 0.1 to 10% by mass. (3) The topical skin preparation according to (1) or (2), wherein the content of loxoprofen or a salt thereof in the topical skin preparation is 0.1 to 15% by mass. (4) The external preparation for skin according to any one of (1) to (3), further containing an alcohol. (5) The topical skin preparation according to (4), wherein the alcohol content in the topical skin preparation is 0.1 to 70.0% by mass.
  • the external preparation for skin according to (4) or (5), wherein the alcohol is a lower alcohol.
  • the external preparation for skin according to (4) or (5), wherein the alcohol is a polyhydric alcohol.
  • the external preparation for skin according to (4) or (5), wherein the alcohols include lower alcohols and polyhydric alcohols.
  • component (A) is one or more selected from the group consisting of the following components (A-1) to (A-11), (1) to (8) )
  • the skin external preparation according to any one of (A-1) tocopherols; (A-2) terpenes; (A-3) glycyrrhizic acids; (A-4) crude drugs; (A-5) tranexamic acids; (A-6) vanilloids; (A-7) nicotinic acids; (A-8) chlorpheniramines; (A-9) diphenhydramines; (A-10) pyrrolidones; (A-11) an inorganic salt; (10) The external skin application according to any one of (1) to (9), wherein the mass ratio of the heparin analogue to loxoprofen or its salt (heparin analogue/loxoprofen or its salt) is 0.01 to 100.
  • the content of loxoprofen or its salt relative to the total amount of the external skin preparation is 0.6% by mass or more, and the mass ratio of the heparin analogue to loxoprofen or its salt (heparin analogue/loxoprofen or its salt) is The skin external preparation according to any one of (1) to (10), which is 0.01 to 10.
  • the stability of the heparin analogue is improved by blending the heparin analogue with loxoprofen or a salt thereof.
  • the medicinal effect can be effectively exhibited.
  • the skin external preparation (hereinafter also referred to as external preparation) of the present invention contains a heparinoid and loxoprofen or a salt thereof.
  • the heparin-like substance in the present invention is a substance also called mucopolysaccharide polysulfate ester or heparinoid, which is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is said to have moisturizing, anti-inflammatory, and blood circulation promoting effects. It is a known known drug.
  • Heparin-like substances include, for example, heparin; chondroitin polysulfates such as chondroitin sulfate D and chondroitin sulfate E;
  • the origin of the heparin-like substance used in the present invention is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides, tissues of edible animals (e.g., tracheal cartilage of bovine, porcine, etc.). (including lungs), and the like.
  • heparin-like substance heparin-like substances listed in the Japanese Non-Pharmacopoeia Pharmaceutical Standards 2002 are preferable.
  • the heparin-like substance may be in the form of a physiologically acceptable salt obtained by a salt-forming reaction using hydroxides or carbonates of alkali metals such as sodium and potassium, or amines, if necessary.
  • the ratio (%) of organic sulfate groups in the heparin analogue in the present invention is not particularly limited, but is preferably 20 to 40% (% by mass) from the viewpoint of improving the anti-inflammatory analgesic effect and reducing skin irritation. 25-38% (mass %) is particularly preferred.
  • the amount of the organic sulfate group is measured by the method described in the Japanese Non-Pharmacopoeia Pharmaceutical Standards 2002, "Heparin-like Substances" section.
  • the average molecular weight of the heparin analogue in the present invention is not particularly limited.
  • the external preparation for skin of the present invention may also contain an analogue of a heparinoid as an optional component.
  • Analogues of heparinoids may be, for example, other acidic mucopolysaccharides.
  • 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, chondroitin sulfate K, and heparin.
  • heparin analogue of the heparinoid may be added together with the heparinoid, as long as the effect of the present invention is not impaired.
  • These heparin analogues may optionally be in the form of pharmaceutically acceptable salts and/or solvates.
  • 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. Moreover, a hydrate is mentioned as a solvate.
  • loxoprofen a propionic acid-based non-steroidal antipyretic, analgesic, anti-inflammatory drug (NSAIDs)
  • NSAIDs anti-inflammatory drug
  • Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosa-irritating effect after oral administration and becomes an active form in the body. It is Loxoprofen is also known to be converted to trans-OH form (active form) by ketone reductase in the skin.
  • loxoprofen has been used as an external anti-inflammatory analgesic in poultices, tapes and gels. It is commercially available and clinically available.
  • loxoprofen or a salt thereof includes loxoprofen or a salt thereof and hydrates thereof.
  • the salt of loxoprofen is preferably a pharmacologically acceptable salt, more preferably loxoprofen sodium or loxoprofen sodium hydrate (also referred to as loxoprofen sodium dihydrate), still more preferably loxoprofen. Sodium hydrate.
  • loxoprofen includes loxoprofen, salts thereof, and hydrates thereof.
  • the loxoprofen in the present invention is listed in the 17th revision of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.
  • the skin external preparation of the present invention may further contain alcohols.
  • Alcohols in the present invention refer to lower alcohols and polyhydric alcohols.
  • the term "lower alcohol” as used in the present invention refers to aliphatic alcohols having 1 to 4 carbon atoms which are used in external preparations such as solubilizers, bases, preservatives, solvents, solubilizers, etc. Examples include methanol, One or more selected from the group consisting of ethanol (also referred to as ethyl alcohol), propanol, isopropanol (also referred to as isopropyl alcohol), and butyl alcohol, preferably ethanol. Those with an ethanol content of 99.5% by volume or more are also called anhydrous ethanol.
  • the polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used in external preparations such as solubilizers, bases, wetting agents, thickening agents, solvents, and dissolution aids.
  • the molecular weight of macrogol is not particularly limited, but may be, for example, 200 to 20,000 in number average molecular weight.
  • the molecular weight of the alcohol in the present invention is not particularly limited. It is preferably 200 or less, particularly preferably 100 or less.
  • the content of the heparin-like substance in the topical preparation of the present invention is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.1 to 10% by mass, based on the total amount of the topical preparation. It is 0.5% by mass. Even when the dosage form of the external preparation is a patch (plast, tape), the content of the heparin-like substance is not particularly limited, but it is preferably 0.00% of the total amount of the paste of the patch. It is 1 to 10% by mass, more preferably 0.1 to 0.5% by mass.
  • the ratio of the content of the heparinoid to the mass of alcohol is not particularly limited, but is preferably 1.0 ⁇ 10 ⁇ 3 to 100, more preferably 1.4 ⁇ 10 ⁇ 3 to 10, still more preferably 2.0 ⁇ 10 ⁇ 3 to 5.0.
  • the ratio of the content of the heparinoid to the weight of the lower alcohol is not particularly limited, but is preferably 1.0. ⁇ 10 ⁇ 3 to 100, more preferably 1.4 ⁇ 10 ⁇ 3 to 10, still more preferably 2.0 ⁇ 10 ⁇ 3 to 5.0.
  • the ratio of the content of the heparin analogue to the mass of the polyhydric alcohol is not particularly limited, but preferably It is 1.0 ⁇ 10 ⁇ 3 to 100, more preferably 1.4 ⁇ 10 ⁇ 3 to 10, still more preferably 2.0 ⁇ 10 ⁇ 3 to 5.0.
  • the content of loxoprofen or a salt thereof (eg, loxoprofen sodium hydrate) in the topical preparation of the present invention is not particularly limited, but is preferably 0.1 to 15% by mass relative to the total amount of the topical preparation. Yes, more preferably 0.5 to 10% by mass.
  • the content of loxoprofen or a salt thereof is not particularly limited even when the dosage form of the external preparation is a patch (plast, tape), it is preferably a patch. 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, based on the total amount of the plaster.
  • the ratio of the content of loxoprofen or its salt to the mass of alcohol is not particularly limited, but is preferably 1.0 ⁇ . 10 ⁇ 3 to 150, more preferably 1.4 ⁇ 10 ⁇ 3 to 100, still more preferably 2.0 ⁇ 10 ⁇ 3 to 35.
  • the ratio of the content of loxoprofen or a salt thereof to the weight of the lower alcohol is not particularly limited, but is preferably 1 0 ⁇ 10 ⁇ 3 to 150, more preferably 1.4 ⁇ 10 ⁇ 3 to 100, still more preferably 2.0 ⁇ 10 ⁇ 3 to 20.
  • the ratio of the content of loxoprofen or a salt thereof to the mass of the polyhydric alcohol is not particularly limited, It is preferably 1.0 ⁇ 10 ⁇ 3 to 150, more preferably 1.4 ⁇ 10 ⁇ 3 to 100, still more preferably 2.0 ⁇ 10 ⁇ 3 to 35.
  • the mass ratio of the heparin analogue to loxoprofen or its salt in the external preparation of the present invention is not particularly limited, but the heparin analogue/loxoprofen or its salt (HP/Lox mass ratio) may be 0.01 to 100. , 0.01 to 10.
  • the content of loxoprofen or a salt thereof is 0.6% by mass or more relative to the total amount of the external preparation, and the heparin analogue / Loxoprofen or a salt thereof (HP/Lox mass ratio) is more preferably 0.01-10.
  • the range of alcohol content in the topical preparation of the present invention is not particularly limited, but may be selected according to the dosage form, and is preferably 0.1 to 70.0% by mass relative to the total amount of the topical preparation. may be Even when the dosage form of the external preparation is a patch (plast, tape), the alcohol content is not particularly limited, but is preferably from 0.1 to 0.1 to the total amount of the paste of the patch. 70.0% by mass.
  • the range of the lower alcohol content in the topical preparation of the present invention is not particularly limited, but may be selected according to the dosage form, preferably 0.1 to 70.0 mass relative to the total amount of the topical preparation. %, more preferably 0.1 to 50.0% by mass.
  • the topical preparation of the present invention is a topical liquid or gel
  • the range of the amount of lower alcohol to be added is not particularly limited, but is preferably 10% with respect to the total amount of the topical liquid or gel. 0 to 70.0% by mass, more preferably 10.0 to 60.0% by mass.
  • the content of the lower alcohol is preferably in the range of 0.1 to 50% by mass with respect to the total amount of the paste of the poultice, More preferably, it is 0.1% to 30% by mass.
  • the external preparation of the present invention is a tape, it may or may not contain a lower alcohol. , preferably 0.1 to 10% by mass, more preferably 0.1% to 5% by mass.
  • the content range of the polyhydric alcohol in the topical preparation of the present invention is not particularly limited, but may be selected according to the dosage form, preferably 0.1 to 70% by mass based on the total amount of the topical preparation. Yes, more preferably 0.1 to 20% by mass, more preferably 0.5 to 20% by mass, still more preferably 1.0 to 15% by mass.
  • the topical preparation of the present invention is a topical liquid or gel
  • the range of the content of the polyhydric alcohol to be added is not particularly limited. It is 0.5 to 20% by mass, more preferably 1.0 to 15% by mass.
  • the range of content of the polyhydric alcohol to be added is not particularly limited. 70% by mass, more preferably 3 to 60% by mass.
  • the external preparation of the present invention is a tape, it may or may not contain a polyhydric alcohol. It is preferably 0.1 to 15% by mass, more preferably 0.1% to 10% by mass, based on the total amount of the body.
  • 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.
  • drugs and pharmaceutical additives that are commonly used in pain-relieving and anti-inflammatory topical skin preparations other than the above ingredients can be added.
  • the external preparation for skin of the present invention may further contain a component (A), wherein the component (A) is one or more selected from the group consisting of the following components (A-1) to (A-11).
  • the component (A) is one or more selected from the group consisting of the following components (A-1) to (A-11).
  • Tocopherols include tocopherol, tocotrienol and derivatives thereof (e.g., esterified derivatives such as acetates, succinates, nicotinates, etc.) and salts thereof (e.g., calcium salts, magnesium salts, etc.) alkaline earth metal salts, etc.).
  • the tocopherol may be ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol or ⁇ -tocopherol, but ⁇ -tocopherol is preferred.
  • the tocotrienol may be ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol or ⁇ -tocotrienol, but ⁇ -tocotrienol is preferred.
  • tocopherols tocopherol acetate is particularly preferred.
  • the content of the tocopherols in the external preparation for skin is not particularly limited, but is generally 0.01 to 10% by weight, and 0.03 to 4% by weight, based on the total weight of the external preparation for skin. % by mass is more preferred, and 0.05 to 2% by mass is particularly preferred.
  • Terpenes mean a generic term (terpenoid) including terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and the structure thereof is particularly limited. Instead, monoterpene, sesquiterpene, derivatives thereof, and the like are included. Also, it may be cyclic or chain.
  • terpenes examples include isoborneol, iron, ocimene, carveol, carbotanacetone, carbomentone, carvone, carene, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, and cineol.
  • cymene sylvestrene, thymol, isotjol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocane, pinol, piperitenone, ferrandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, Perillaldehyde, borneol, myrcene, menthol, menthone, yonol, yonone, linalool, limonene and the like.
  • essential oils containing terpenes may be used.
  • essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaput oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, sun Ginger oil, Perilla oil, Citriodora oil, Citronella oil, Ginger oil, Shozuku oil, Camphor oil, Gingergrass oil, Spearmint oil, Peppermint oil, Geranium oil, Daifennel oil, Clove oil, Turpentine oil, Spruce oil, Neroli oil , basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, penyroyal oil, henoposi oil, bergamot oil, boad rose oil, pepper oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime
  • Terpenes preferably include l-menthol, dl-camphor, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1, 2-diol, p-menthane-3,8-diol, isopulegol, thymol, peppermint oil, eucalyptus oil and the like can be used.
  • the content of terpenes in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 6%, based on the total weight of the external skin preparation. % by mass is more preferred, and 0.1 to 4% by mass is particularly preferred.
  • Glycyrrhizic acids include, for example, glycyrrhizic acid or its salts and glycyrrhetinic acid or its salts.
  • salts include alkali metal salts such as potassium salts and sodium salts; ammonium salts and the like.
  • licorice licorice containing glycyrrhizic acid or an extract thereof may be used.
  • the content of glycyrrhizic acids in the external skin preparation when glycyrrhizic acids are used is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 4%, based on the total weight of the external skin preparation. % by mass is more preferred, and 0.1 to 3% by mass is particularly preferred.
  • Herbal medicines include, for example, licorice, arnica tincture, red-clawed mandarin orange, ashenyak, inyukaku, fennel, turmeric, corytal, Scutellaria japonicum, Chinese Peppermint, Phellodendron bark, Phellodendron japonicum, Japanese coptis, onji, zedoary, valerian, chamomile, caronin, bellflower , Kyonin, Chinese wolfberry, Kukoyo, Keigai, Keihi, Ketsumeishi, Gentiana, Gennoshoko, Kouka, Koubushi, Goou, Garbage, Saishin, Sanshishi, Sansho, Shion, Jikoppi, Shikon, Peony, Musk, Shajin, Shazenshi, Shazenso, Paint (Including Yutan (bear bile)), Ginger, Jiryu, Shini, Horse chestnut, Sekisan, Senega, Cnidium, Zenko, Assembly,
  • the content of the crude drugs in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by mass, and 0.05 to 4%, based on the total mass of the external skin preparation. % by mass is more preferred, and 0.1 to 3% by mass is particularly preferred.
  • Tranexamic acids may include, for example, tranexamic acid or salts thereof, tranexamic acid derivatives or salts thereof.
  • Salts of tranexamic acid are 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; basic amino acid salts such as arginine, histidine and ornithine; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine and stearylamine. It may also be a tranexamic acid derivative or a salt thereof, and specific examples thereof include ester derivatives such as tranexamic acid cetyl ester; and amide derivatives such as tranexamic acid methylamide.
  • the content of the tranexamic acids in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 4%, based on the total weight of the external skin preparation. % by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
  • Vanilloids is a generic term for compounds containing a vanillyl group. Vanilloids in the present invention are not particularly limited as long as they are compounds containing a vanillyl group. acid (VMA), vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol), and the like. In addition, the vanilloids in the present invention may contain natural products containing compounds containing a vanillyl group, derivatives of compounds containing a vanillyl group, and synthetic compounds in which a functional group is added to the vanillyl group. good. As the vanilloids in the present invention, capsicums containing a compound containing a vanillyl group may be used, or may be included as part of the vanilloids.
  • peppers for example, peppers (fruits of Capsicum annuum Linne (Solanaceae) listed in the Japanese Pharmacopoeia 17th Edition can be preferably used.
  • the form of the pepper can be adjusted as necessary, and it can be cut or crushed into small pieces, small pieces, or pulverized into powder. can be used as Moreover, you may use the thing (pepper extract, capsicum tincture, etc.) which performed some extraction process on capsicum.
  • the extract of hot pepper may be processed by heating, drying, crushing, etc., in addition to the extraction process.
  • capsaicinoids which are the main components of peppers, may be used as the peppers.
  • pepper extract, hot pepper tincture, nonylic acid vanillylamide, or capsaicin can be preferably used as hot peppers.
  • the content of the vanilloids in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by mass, and 0.05 to 4%, based on the total mass of the external skin preparation. % by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
  • the content of the peppers in the external skin preparation is not particularly limited, but it is generally 0.01 to 10% by weight with respect to the total weight of the external skin preparation, and 0.05% by weight. ⁇ 4% by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
  • Nicotinic acids include nicotinic acid, derivatives thereof, and salts thereof. Nicotinic acid derivatives include, for example, nicotinic acid esters (specifically methyl nicotinic acid, ⁇ -butoxyethyl nicotinic acid, benzyl nicotinic acid, inositol hexanicotinate, hepronicate, etc.), nicotinic acid amide, and nicotinic acid. amide adenine dinucleotide, nicotinic acid amide adenine dinucleotide phosphate, etc.). Nicotinic acid esters are preferably monoesters of nicotinic acid. Nicotinic acid benzyl ester is preferred as the nicotinic acid.
  • the content of nicotinic acids in the external preparation for skin is not particularly limited, but is generally 0.01 to 10% by weight, and 0.015 to 4%, based on the total weight of the external preparation for skin. % by mass is more preferred, and 0.02 to 2% by mass is particularly preferred.
  • Chlorpheniramines include chlorpheniramines and salts thereof.
  • the salts of chlorpheniramine specifically include organic acid salts such as maleates and fumarates; inorganic acid salts such as hydrochlorides and sulfates; and various salts such as metal salts.
  • Chlorpheniramine is preferably chlorpheniramine maleate,
  • the content of chlorpheniramines in the external skin preparation when using chlorpheniramines is not particularly limited, but is generally 0.01 to 10% by weight relative to the total weight of the external skin preparation. 0.05 to 4% by weight is more preferred, and 0.1 to 2% by weight is particularly preferred.
  • Diphenhydramines include, for example, diphenhydramine or a salt thereof.
  • Salts of diphenhydramine include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. salt.
  • diphenhydramines diphenhydramine or diphenhydramine hydrochloride is preferred.
  • the content of diphenhydramines in the external preparation for skin is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 4%, based on the total weight of the external preparation for skin. % by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
  • Pyrrolidones include dl-pyrrolidone carboxylic acid or salts thereof, for example, sodium pyrrolidone carboxylate is preferred.
  • the content of the pyrrolidones in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by weight, and 0.1 to 10% by weight, based on the total weight of the external skin preparation. % by mass is more preferred, and 1 to 10% by mass is particularly preferred.
  • Inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium or the like, and ammonium salts.
  • alkaline earth metals such as magnesium or calcium
  • salts of alkali metals such as sodium or the like
  • ammonium salts for example, sodium chloride, potassium chloride and ammonium chloride are preferred.
  • the content of the inorganic salt in the external preparation for skin when an inorganic salt is used is not particularly limited, but is generally 0.01 to 10% by weight, 0.1 to 10% by weight, based on the total weight of the external preparation for skin. % by mass is more preferred, and 1 to 10% by mass is particularly preferred.
  • drugs for component (A) include anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid, diphenhydramine or its salts, antihistamines such as chlorpheniramine maleate, tocopherol acetate, and benzyl nicotinate.
  • anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid
  • diphenhydramine or its salts antihistamines such as chlorpheniramine maleate, tocopherol acetate, and benzyl nicotinate.
  • blood circulation improving ingredients l-menthol, dl-camphor, d-camphor, nonanoic acid vanillylamide (nonylic acid vanillylamide), capsicum extract, capsicum tincture, capsaicin, peppermint oil, eucalyptus oil, menthoxypropanediol (3-(menthoxy) -1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1,2-diol and other local stimulating ingredients, herbal medicine ingredients such as arnica tincture, bactericidal ingredients such as isopropylmethylphenol, and dl- Wetting agents such as pyrrolidone carboxylic acid or salts thereof, inorganic salts such as sodium chloride, and the like can be mentioned, and these component (A) can be blended within a range that does not impair the effects of the present invention.
  • compositions other than the above ingredients are added as necessary for the purpose of, for example, further improving the stability of the content over time and the feeling of use.
  • the external preparation for skin of the present invention may contain other optional ingredients.
  • the external preparation for skin of the present invention preferably does not contain N-methylpyrrolidone (N-methyl-2-pyrrolidone).
  • moistening agent for example, hyaluronic acid, sodium dl-pyrrolidonecarboxylate or a salt thereof (eg, sodium dl-pyrrolidonecarboxylate) can be used.
  • moisturizing agents include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol.
  • thickening agents examples include hypromellose, hydroxypropylcellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, carboxymethylcellulose sodium (carmellose sodium ), methyl cellulose, carrageenan, locust bean gum, propylene glycol alginate and the like can be used.
  • adhesives examples include acrylic acid/octyl acrylate copolymer, acrylic acid ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution, and 2-ethylhexyl acrylate/methacrylic acid 2.
  • tackifying resin examples include rosin, hydrogenated rosin glycerin ester, ester gum, maleic acid resin, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and the like.
  • cross-linking agents examples include dry aluminum hydroxide gel, magnesium aluminum hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosartite, and dihydroxyaluminum aminoacetate.
  • fillers include alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, silica (silicon dioxide ) etc. can be used.
  • Fats and oils include, for example, hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petroleum jelly, and gelling hydrocarbons; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol and lauryl.
  • Higher alcohols such as 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; carnauba wax, whale wax, Waxes such as shellac, jojoba oil, beeswax, bleached beeswax, montan wax, lanolin, refined lanolin and reduced lanolin; silicone oils and the like can be used.
  • softening agents include petroleum oils such as paraffinic process oils, naphthenic process oils and aromatic process oils; squalane; squalene; cottonseed oil, palm oil, coconut oil, almond oil, rapeseed oil, olive oil, camellia oil.
  • antiseptics examples include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, and benzoin.
  • Benzyl acid, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid and the like can be used.
  • Percutaneous absorption enhancers include, for example, alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactic acid esters, acetic acid esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, Propylene carbide, Azone, derivatives thereof, or the like can be used.
  • stabilizers include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (eg, dibenzoylmethane derivatives).
  • solubilizing agents include benzyl alcohol; pyrothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols; , dioctyl adipate, di(2-heptylundecyl) adipate, diisopropyl sebacate, diethyl sebacate and other polybasic acids; polyethylene glycol (PEG), polyalkylene glycols such as polybutylene glycol; polyethylene glycol monostearate, etc. oxyalkylene fatty acid esters and the like can be used.
  • PEG polyethylene glycol
  • polyalkylene glycols such as polybutylene glycol
  • polyethylene glycol monostearate etc.
  • oxyalkylene fatty acid esters and the like can be used.
  • pH adjusters include, for example, hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), phosphorus An acid or the like can be used.
  • Antioxidants include, for example, ascorbic acid, ascorbic palmitic acid, sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, acetic acid Tocopherol, dI- ⁇ tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soybean lecithin, pentaerythryltetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl ) propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate and the like can be used.
  • Cooling agents include, for example, l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, thymol and the like.
  • a nonionic surfactant or an ionic surfactant may be used.
  • nonionic surfactants include propylene glycol mono fatty acid ester, ethylene glycol mono fatty acid ester, glycerin mono fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methylglucoside fatty acid ester, alkyl polyglucoside.
  • polyhydric alcohol fatty acid ester or polyhydric alcohol alkyl ether such as polyethylene glycol fatty acid ester; polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl Polyoxyethylene ethers such as ethers; Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene monofatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80 , polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc.
  • Nonionic surfactants such as oxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, ether ester such as polyoxyethylene polyoxypropylene glycol; sodium lauryl sulfate, cetyl Ionic surfactants such as sodium sulfate; higher alcohols such as octyldodecanol;
  • polyoxyethylene alkyl ethers in the present invention include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether and the like.
  • polyoxyethylene polyoxypropylene alkyl ether in the present invention examples include polyoxyethylene polyoxypropylene cetyl ether.
  • polyoxyethylene polyoxypropylene alkyl ether in the present invention examples include polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyethylene glycol monooleate.
  • the nonionic surfactant in the present invention is listed in the Pharmaceutical Excipients Encyclopedia 2021.
  • ionic surfactants examples include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, dioctyl sodium sulfosuccinate, benzalkonium chloride, chloride cationic surfactants such as benzethonium;
  • the ionic surfactant used in the present invention is listed in the Japanese Pharmacopoeia 2021, 17th edition of the Japanese Pharmacopoeia.
  • the emulsifier in the present invention for example, any of the various surfactants and higher alcohols listed above may be used arbitrarily.
  • Other optional ingredients in the present invention include, for example, crude drugs such as tranexamic acid and licorice.
  • the external preparation for skin containing the heparin analogue of the present invention and loxoprofen or a salt thereof may further contain at least one of tranexamic acid and licorice.
  • Specific dosage forms of the external preparation for skin of the present invention include, for example, liquids for external use, ointments, creams, sprays (external aerosols, pump sprays), gels, patches (tape, poultice). , or a solid preparation for external use, etc., and can be produced by appropriately using additives and bases suitable for each dosage form according to the usual methods described in the 17th revision of the Japanese Pharmacopoeia.
  • a liquid preparation for external use is particularly preferable as the dosage form of the external preparation for skin in the present invention.
  • the concentration of loxoprofen or its salt may vary depending on the amount of plaster.
  • the amount of the paste may be appropriately adjusted so as to obtain the concentration of the salt (for example, loxoprofen sodium).
  • the formulation of the external preparation for skin of the present invention is accommodated, for example, in a container/package made of glass, or a container/package made of metal such as aluminum, or a container/package made of olefinic resin such as polyethylene or polypropylene. and can be sealed.
  • Containers and packaging containing environmentally friendly raw materials such as recycled plastics and biomass raw materials may also be used. Any material that prevents deterioration of topical skin preparations due to factors, elements, and environmental changes from the outside of the drug container and packaging, such as heat and light, and appropriately maintains the quality of topical skin preparations.
  • the drug may be a pharmaceutical product in which the formulation/composition of the external preparation for skin is contained in an appropriate container/package.
  • the stability of the heparinoid can be improved by blending the heparinoid with loxoprofen or a salt thereof.
  • the storage stability of the external preparation for skin can be enhanced, and the efficacy of the heparinoid can be effectively exhibited even after storage.
  • the external preparation for skin of the present invention it is possible to suppress a decrease in the content of heparin analogues (caused by the surfactant, the thickener, etc.) due to at least one of the surfactant and the thickener.
  • the present invention may be used as a stabilizer for external skin preparations containing heparinoids containing loxoprofen or a salt thereof.
  • the loxoprofen or its salt may be used as a heparinoid-like substance stabilizer in a skin preparation for external use containing a heparinoid-like substance.
  • polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 from Nikko Chemicals Co., Ltd., hydroxypropyl methylcellulose from Shin-Etsu Chemical Co., Ltd., hydrochloric acid and sodium hydroxide from Kanto Kagaku Co., Ltd. ) were used.
  • the resulting formulation was dispensed into transparent glass vials with a barrel diameter of 30 mm and sealed tightly.
  • a transparent glass vial Mighty Vial (transparent, No. 6) manufactured by Maruem Co., Ltd. was used.
  • the dispensed specimens 1 to 8 were stored at 40° C. and 75% relative humidity at 50° C. and 60° C. for one month.
  • the content of heparin analogues in the composition was determined based on the Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients 2002 Heparin analogue confirmation test (1) and the determination method of dextran sodium sulfate enteric coated tablets. Measured by the following method, and the residual rate (%) of the heparinoid was calculated based on the following formula.
  • the undiluted sample solution was obtained by diluting the sample specimen to be measured for the residual rate with water so that the concentration of the heparin analogous substance was 6 ⁇ 10 ⁇ 3 mg/mL.
  • the sample stock solution may optionally be prepared using salts as appropriate.
  • -Preparation of standard stock solution for creating a calibration curve A heparin analogue for quantification was diluted with water to prepare a standard stock solution for creating a calibration curve with concentrations of heparin analogues in a range including the concentration of the heparin analogue in the sample stock solution.
  • salts may optionally be used to prepare a standard stock solution for preparation of the calibration curve as appropriate.
  • ⁇ Preparation of sample solution, etc., and measurement of residual rate (%) of heparin-like substances Accurately weigh 5 mL each of the sample undiluted solution, standard undiluted solution, and water, and add 0.1 mol/L citric acid and 0.2 mol/L phosphoric acid. Accurately add 5 mL of toluidine blue O solution (1 ⁇ 50000) prepared with disodium hydrogen (19:1) mixture and shake well. was prepared. For each of the sample solution, standard solution, and blank solution, water was used as a control, and the test was performed immediately after solution preparation by the UV -visible absorbance measurement method.
  • a standard curve (regression line) is prepared using a value (A B ⁇ A S ) obtained by subtracting the absorbance A S obtained from a standard solution having the concentration of each heparin analogue from the absorbance A B obtained from the blank solution. It was created. Based on the absorbance AT obtained from the sample solution and the calibration curve, the proportion (%) of the heparin analogous substance in the specimen was calculated. At this time, the absorbance AB obtained from the blank solution showed 1.0 or more, and the correlation coefficient obtained from the calibration curve showed -0.99 or less, confirming that the conditions were suitable for absorbance measurement. , conducted an experiment.
  • the absorbance was measured using a UV-2700 spectrophotometer manufactured by Shimadzu Corporation.
  • ⁇ Method for calculating the residual rate (%) of the heparinoid in the sample Residual rate (%) of the heparinoid Percentage (%) of the heparinoid after storage / Percentage of the initial heparinoid ( %) ⁇ 100
  • the ratio to the initial heparin analogue content is the component content measured immediately after preparation of the composition for external use for skin or within one month of a stable sample (stored at 5°C) after refrigeration. . By such a procedure, the residual rate (%) of heparin analogues was calculated for various specimens as well.
  • Test Results Table 1 shows the results of samples 1 to 8.
  • Test Example 2 Examination of storage stability of heparinoids (2) Based on the results of Test Example 1, a study was conducted on components that further improve the storage stability of the heparinoid.
  • (1) Preparation of test materials and specimens Mix and dissolve the ingredients listed in each specimen in Table 2 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid to 2 times solution or sodium hydroxide was diluted 10 times (pH adjuster) to adjust the pH to 6.5 to obtain liquid preparations of samples 9 to 15.
  • the heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC.
  • absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Kagaku Co., Ltd., propylene glycol from Maruishi Pharmaceutical Co., Ltd., macro Goal 400 is manufactured by NOF Corporation, concentrated glycerin is manufactured by Kosakai Pharmaceutical Co., Ltd., D-sorbitol liquid is manufactured by Bussan Food Science Co., Ltd., and hydrochloric acid and sodium hydroxide are manufactured by Kanto Kagaku. Co., Ltd. products were used respectively.
  • Test Results Table 2 shows the results of samples 9 to 15.
  • specimens 9 and 10 in which 5% or 40% absolute ethanol was added to the formulation containing the heparin analogue and loxoprofen sodium hydrate, significantly suppressed the decrease in the content of the heparin analogue, and the storage stability was improved. It was found to be extremely superior to In addition, specimen 11 containing 1,3-butylene glycol, specimen 12 containing propylene glycol, specimen 13 containing macrogol 400, and concentrated glycerin were added to a preparation containing a heparinoid and loxoprofen sodium hydrate. Sample 14 containing sorbitol and sample 15 containing sorbitol were remarkably inhibited from lowering the content of heparin analogues, demonstrating excellent storage stability.
  • Test Example 4 Investigation of storage stability of heparin analogues (4) Mix and dissolve the components listed in each sample in Table 17 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid twice or sodium hydroxide solution diluted ten times (pH Adjusting agent) to adjust the pH to 6.5 to obtain a liquid formulation of each sample, in the same manner as in Test Example 1, when stored at 60 ° C. for 1 month Preservation of heparin analogues Stability was considered.
  • the heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC.
  • Test Example 5 Examination of storage stability of heparinoids (5) Mix and dissolve the components listed in each sample in Tables 18 to 21 below, add purified water so that the total amount is 100 g, and then either a solution diluted with hydrochloric acid twice or a solution diluted with sodium hydroxide 10 times. In the same manner as in Test Example 1, except that the pH was adjusted to 6.5 at , and the liquid formulation of each sample was obtained. investigated.
  • the heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. Absolute ethanol is from Imazu Pharmaceutical Co., Ltd.
  • Polyoxyethylene hydrogenated castor oil 60 and Polysorbate 80 are from Nikko Chemicals Co., Ltd. Tocopherol acetate is from Mitsubishi Chemical Foods Co., Ltd. 1-menthol is from Suzuki Minka Co., Ltd., dl-camphor is from Nissei Bailis Co., Ltd., thymol is from Fuji Film Wako Pure Chemical Co., Ltd., peppermint oil is manufactured by Ogi Pharmaceutical Co., Ltd., eucalyptus oil is manufactured by Nippon Terpene Chemical Co., Ltd., 3-(menthoxy)-1,2-propanediol and 3-(l-menthoxy)-2-methylpropane -1,2-diol is from Takasago Perfumery Co., Ltd., tranexamic acid is from Kyowa Pharma Chemical Co., Ltd., dried licorice extract is from Alps Pharmaceutical Co., Ltd., and dipotassium glycyrrhizinate.
  • loxoprofen sodium hydrate was blended, and further tocopherol acetate, l-menthol, dl-camphor, thymol, peppermint oil, eucalyptus oil, 3-(l-menthoxy)propane-1,2 -diol, 3-l-menthoxy-2-methylpropane-1,2-diol, tranexamic acid, dried licorice extract (licorice extract), dipotassium glycyrrhizinate, capsicum tincture, arnica tincture, benzyl nicotinate ester, chlorpheniramine malein
  • preparations containing at least one of acid salts, nonanoic acid vanillylamide, capsaicin, sodium chloride, diphenhydramine, and diphenhydramine hydrochloride reduction in the content of heparin analogues is suppressed and storage stability is extremely excellent. became clear.
  • Test Example 7 Examination of storage stability of heparinoids (7) Mix and dissolve the components listed in each sample in Table 23 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid twice or sodium hydroxide 10 times diluted solution (pH Heparin-like substance when stored at 60 ° C. for 1 month in the same manner as in Test Example 1, except that the pH was adjusted to 6.5 or 8.0 with an adjuster) to obtain a liquid formulation of each sample.
  • the heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Chemical Co., Ltd., hydrochloric acid and sodium hydroxide from Kanto Chemical Co., Ltd. were used respectively. The results are shown in Table 23.
  • the heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Kagaku Co., Ltd., l-menthol from Suzuki Minka Co., Ltd.
  • Polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 are manufactured by Nikko Chemicals Co., Ltd. Hydroxypropyl methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd.
  • Tocopherol acetate is manufactured by Mitsubishi Chemical Foods Co., Ltd. , hydrochloric acid, phosphoric acid and sodium hydroxide manufactured by Kanto Kagaku Co., Ltd. were used.
  • the resulting formulation was dispensed into transparent glass vials with a barrel diameter of 30 mm and sealed tightly.
  • a transparent glass vial Mighty Vial (transparent, No. 6) manufactured by Maruem Co., Ltd. was used.
  • the dispensed samples were stored at 60°C for one month.
  • the amount of loxoprofen sodium in the samples before and after storage was quantified by liquid chromatography, and the residual rate of loxoprofen sodium was calculated. The results are shown in Tables 26 and 27.
  • the external preparation for skin containing a heparin analogue and loxoprofen or a salt thereof according to the present invention has excellent storage stability and is extremely useful.

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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

ヘパリン類似物質、および、ロキソプロフェン又はその塩を含有する皮膚外用剤Skin external preparation containing heparinoid and loxoprofen or its salt
　本発明は、ヘパリン類似物質を含有する皮膚外用剤に関する。より詳しくは、本発明は、ヘパリン類似物質を含有する液状又は半固形状の組成物におけるヘパリン類似物質の保存安定性をロキソプロフェン又はその塩を含有させることによって向上させた皮膚外用剤に関する。 The present invention relates to an external preparation for skin containing a heparinoid. More specifically, the present invention relates to an external preparation for skin in which the storage stability of a heparinoid in a liquid or semi-solid composition containing a heparinoid is improved by incorporating loxoprofen or a salt thereof.
　ヘパリン類似物質は、健康な食用獣、主としてウシの気管軟骨を含む肺臓から抽出したコンドロイチン多硫酸等の多硫酸化ムコ多糖である。ムコ多糖類の硫酸エステルで、ウロン酸とグルコサミンが交互に１，４結合した構造を有するヘパリンに似た構造を持つためこのような名称で呼ばれている。ヘパリン類似物質は、保湿作用、抗炎症作用、血行促進作用等を有することが知られている。ヘパリン類似物質を配合した皮膚外用剤の効能効果は、血栓性静脈炎（痔核を含む）、血行障害に基づく疼痛と炎症性疾患（注射後の硬結及び疼痛）、凍瘡、肥厚性瘢痕・ケロイドの治療と予防、進行性指掌角皮症、皮質欠乏症、外傷（打撲、捻挫、挫傷）後の腫脹・血腫・腱鞘炎・筋肉痛・関節炎、筋性斜頸（乳児期）とされている。ヘパリン類似物質含有皮膚外用剤の剤形としては、クリーム、ソフト軟膏、ローション、スプレーが販売されている。 Heparin analogues are polysulfated mucopolysaccharides such as chondroitin polysulfate extracted from lungs containing tracheal cartilage of healthy edible animals, mainly bovines. It is a sulfate ester of a mucopolysaccharide, and is so named because it has a structure similar to heparin, in which uronic acid and glucosamine are alternately 1,4-linked. Heparin-like substances are known to have moisturizing action, anti-inflammatory action, blood circulation promoting action and the like. Indications for topical skin preparations containing heparinoids include thrombophlebitis (including hemorrhoids), pain and inflammatory diseases due to blood circulation disorders (induration and pain after injection), chilblains, hypertrophic scars and keloids. Treatment and prevention, progressive keratoderma palmar, cortical deficiency, post-traumatic (bruise, sprain, contusion) swelling, hematoma, tendonitis, muscle pain, arthritis, muscular torticollis (infancy). Creams, soft ointments, lotions, and sprays are commercially available as dosage forms of external preparations for skin containing heparinoids.
　へパリン類似物質を他の有効成分とともに外用組成物に配合する場合、それぞれの有効成分の保存安定性や組成物としての品質の維持が課題となる。例えば、特許文献１には、ヘパリン類似物質を含有する皮膚外用組成物において、リドカインとアミノアルコールとを配合するまたはピロリドンカルボン酸塩を配合することでヘパリン類似物質、リドカイン及びビタミンＡパルミテートの安定性を向上させ得ることが開示されている。また、特許文献２には、ヘパリン類似物質とビタミンＢ6とを含有する皮膚外用組成物において、ｐＨを４以上とすることでヘパリン類似物質とビタミンＢ６の安定性を向上させ得ることが開示されている。 When a heparin-like substance is combined with other active ingredients into a composition for external use, maintaining the storage stability of each active ingredient and the quality of the composition is an issue. For example, Patent Document 1 describes the stability of a heparin analogue, lidocaine, and vitamin A palmitate by blending lidocaine and an amino alcohol or by blending pyrrolidone carboxylate in an external skin composition containing a heparin analogue. can be improved. In addition, Patent Document 2 discloses that in an external skin composition containing a heparin analogue and vitamin B6, the stability of the heparin analogue and vitamin B6 can be improved by adjusting the pH to 4 or higher. there is
　しかしながら、ヘパリン類似物質の多様な作用に基づいて更なる皮膚外用剤組成物の開発が期待されている。 However, further development of external skin preparation compositions is expected based on the various actions of heparinoids.
特開２００４－３０７４９１JP 2004-307491 ＷＯ２０２０／１３８４０３WO2020/138403
　そこで、ヘパリン類似物質を含有する皮膚外用剤を開発するにあたり、ヘパリン類似物質の保存安定性について本発明者らが検討したところ、ヘパリン類似物質を精製水に溶解させた場合、およびヘパリン類似物質を界面活性剤又は増粘剤と共に精製水に溶解させた場合に、その安定性が著しく低下するという課題を見出した。 Therefore, in developing an external preparation for skin containing a heparinoid, the present inventors investigated the storage stability of the heparinoid. The inventors have found a problem that the stability is remarkably lowered when dissolved in purified water together with a surfactant or a thickener.
　すなわち、本発明は、ヘパリン類似物質が安定に配合された皮膚外用剤を提供することを目的とする。 That is, an object of the present invention is to provide an external preparation for skin in which a heparinoid is stably blended.
　そこで、本発明者らは、上記問題点を解決する為に鋭意検討を重ねた結果、ヘパリン類似物質を含有する液状又は半固形状の組成物にロキソプロフェン又はその塩を配合することによりヘパリン類似物質の安定性が向上することを見出し、本発明を完成するに至った。 Therefore, the present inventors have made intensive studies in order to solve the above problems, and as a result, obtained a heparin analogue by adding loxoprofen or a salt thereof to a liquid or semi-solid composition containing a heparin analogue. The inventors have found that the stability of is improved, and have completed the present invention.
　すなわち、本発明によれば以下の発明が提供される。
（１）　ヘパリン類似物質、および、ロキソプロフェン又はその塩を含有する皮膚外用剤。
（２）　皮膚外用剤における前記ヘパリン類似物質の含有量が、０．１～１０質量％である、（１）に記載の皮膚外用剤。
（３）　皮膚外用剤における前記ロキソプロフェン又はその塩の含有量が、０．１～１５質量％である、（１）または（２）に記載の皮膚外用剤。
（４）　さらにアルコール類を含有する、（１）～（３）の何れか一に記載の皮膚外用剤。
（５）　皮膚外用剤における前記アルコール類の含有量が、０．１～７０．０質量％である、（４）に記載の皮膚外用剤。
（６）　前記アルコール類が低級アルコールである、（４）又は（５）に記載の皮膚外用剤。
（７）　前記アルコール類が多価アルコールである、（４）又は（５）に記載の皮膚外用剤。
（８）　前記アルコール類が低級アルコールおよび多価アルコールを含む、（４）又は（５）に記載の皮膚外用剤。
（９）　さらに成分（Ａ）を含有し、前記成分（Ａ）が、下記成分（Ａ－１）～（Ａ－１１）よりなる群から選ばれる１種以上である、（１）～（８）のいずれか一に記載の皮膚外用剤。
（Ａ－１）トコフェロール類；
（Ａ－２）テルペン類；
（Ａ－３）グリチルリチン酸類；
（Ａ－４）生薬類；
（Ａ－５）トラネキサム酸類；
（Ａ－６）バニロイド類；
（Ａ－７）ニコチン酸類；
（Ａ－８）クロルフェニラミン類；
（Ａ－９）ジフェンヒドラミン類；
（Ａ－１０）ピロリドン類；
（Ａ－１１）無機塩；
（１０）　ヘパリン類似物質とロキソプロフェン又はその塩との質量比（ヘパリン類似物質／ロキソプロフェン又はその塩）が０．０１～１００である、（１）～（９）のいずれか一に記載の皮膚外用剤。
（１１）　皮膚外用剤全量に対するロキソプロフェン又はその塩の含有量が０．６質量％以上であり、かつ、ヘパリン類似物質とロキソプロフェン又はその塩との質量比（ヘパリン類似物質／ロキソプロフェン又はその塩）が０．０１～１０である、（１）～（１０）のいずれか一に記載の皮膚外用剤。
（１２）　剤形が外用液剤、軟膏剤、クリーム剤、スプレー剤、ゲル剤、貼付剤、又は外用固形剤である、（１）～（１１）のいずれか一に記載の皮膚外用剤。
（１３）　剤形が外用液剤である、（１）～（１１）のいずれか一に記載の皮膚外用剤。
（１４）　界面活性剤および増粘剤のうち少なくとも１つによる前記ヘパリン類似物質の含量低下を抑制可能である、（１）～（１３）のいずれか一に記載の皮膚外用剤。
（１５）　ロキソプロフェン又はその塩を含有する、ヘパリン類似物質を含有する皮膚外用剤の安定化剤。
（１６）　界面活性剤および増粘剤のうち少なくとも１つによる前記ヘパリン類似物質の含量低下を抑制可能である、（１５）に記載の皮膚外用剤の安定化剤。 That is, according to the present invention, the following inventions are provided.
(1) A skin external preparation containing a heparinoid and loxoprofen or a salt thereof.
(2) The external preparation for skin according to (1), wherein the content of the heparinoid in the external preparation for skin is 0.1 to 10% by mass.
(3) The topical skin preparation according to (1) or (2), wherein the content of loxoprofen or a salt thereof in the topical skin preparation is 0.1 to 15% by mass.
(4) The external preparation for skin according to any one of (1) to (3), further containing an alcohol.
(5) The topical skin preparation according to (4), wherein the alcohol content in the topical skin preparation is 0.1 to 70.0% by mass.
(6) The external preparation for skin according to (4) or (5), wherein the alcohol is a lower alcohol.
(7) The external preparation for skin according to (4) or (5), wherein the alcohol is a polyhydric alcohol.
(8) The external preparation for skin according to (4) or (5), wherein the alcohols include lower alcohols and polyhydric alcohols.
(9) Further containing a component (A), wherein the component (A) is one or more selected from the group consisting of the following components (A-1) to (A-11), (1) to (8) ) The skin external preparation according to any one of
(A-1) tocopherols;
(A-2) terpenes;
(A-3) glycyrrhizic acids;
(A-4) crude drugs;
(A-5) tranexamic acids;
(A-6) vanilloids;
(A-7) nicotinic acids;
(A-8) chlorpheniramines;
(A-9) diphenhydramines;
(A-10) pyrrolidones;
(A-11) an inorganic salt;
(10) The external skin application according to any one of (1) to (9), wherein the mass ratio of the heparin analogue to loxoprofen or its salt (heparin analogue/loxoprofen or its salt) is 0.01 to 100. agent.
(11) The content of loxoprofen or its salt relative to the total amount of the external skin preparation is 0.6% by mass or more, and the mass ratio of the heparin analogue to loxoprofen or its salt (heparin analogue/loxoprofen or its salt) is The skin external preparation according to any one of (1) to (10), which is 0.01 to 10.
(12) The external preparation for skin according to any one of (1) to (11), which is in the form of a liquid for external use, an ointment, a cream, a spray, a gel, a patch, or a solid preparation for external use.
(13) The external preparation for skin according to any one of (1) to (11), which is in the form of a liquid preparation for external use.
(14) The external preparation for skin according to any one of (1) to (13), which can suppress a decrease in the content of the heparin analogue due to at least one of a surfactant and a thickening agent.
(15) Stabilizers for topical skin preparations containing heparin analogues, containing loxoprofen or a salt thereof.
(16) The stabilizer for the external preparation for skin according to (15), which is capable of suppressing a decrease in the content of the heparin analogue due to at least one of a surfactant and a thickening agent.
　本発明の皮膚外用剤によればヘパリン類似物質とロキソプロフェン又はその塩を配合することによって、ヘパリン類似物質の安定性が向上しているため、保存安定性を高め、保存後でも、ヘパリン類似物質の薬効を効果的に発揮することができる。 According to the external preparation for skin of the present invention, the stability of the heparin analogue is improved by blending the heparin analogue with loxoprofen or a salt thereof. The medicinal effect can be effectively exhibited.
　本発明の皮膚外用剤（以下、外用剤と呼ぶこともある）は、ヘパリン類似物質、および、ロキソプロフェン又はその塩を含有する。 The skin external preparation (hereinafter also referred to as external preparation) of the present invention contains a heparinoid and loxoprofen or a salt thereof.
　本発明におけるヘパリン類似物質は、別名ムコ多糖類多硫酸エステル又はヘパリノイドと呼ばれる物質であり、コンドロイチン多硫酸等の多硫酸化ムコ多糖で、保湿作用、抗炎症作用、血行促進作用等を有することが知られている公知の薬剤である。ヘパリン類似物質には、例えば、ヘパリン；コンドロイチン硫酸Ｄ、コンドロイチン硫酸Ｅのようなコンドロイチン多硫酸などが含まれる。本発明で使用されるヘパリン類似物質の由来については、特に制限されないが、例えば、ムコ多糖類を多硫酸化することにより得られたもの、食用獣の組織（例えば、ウシやブタ等の気管軟骨を含む肺臓）から抽出したもの等が挙げられる。ヘパリン類似物質としては、日本薬局方外医薬品規格２００２に収載されているヘパリン類似物質が好ましい。 The heparin-like substance in the present invention is a substance also called mucopolysaccharide polysulfate ester or heparinoid, which is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is said to have moisturizing, anti-inflammatory, and blood circulation promoting effects. It is a known known drug. Heparin-like substances include, for example, heparin; chondroitin polysulfates such as chondroitin sulfate D and chondroitin sulfate E; The origin of the heparin-like substance used in the present invention is not particularly limited, but examples include those obtained by polysulfating mucopolysaccharides, tissues of edible animals (e.g., tracheal cartilage of bovine, porcine, etc.). (including lungs), and the like. As the heparin-like substance, heparin-like substances listed in the Japanese Non-Pharmacopoeia Pharmaceutical Standards 2002 are preferable.
　ヘパリン類似物質は、必要に応じ、ナトリウム、カリウム等のアルカリ金属の水酸化物若しくは炭酸塩、又はアミン類等を用いる造塩反応により得られる生理学的に許容される塩形態のものでもよい。
　本発明におけるヘパリン類似物質の有機硫酸基の割合（％）は、特に限定されないが、例えば、消炎鎮痛効果の向上及び皮膚刺激の低減などの観点から、２０～４０％（質量％）が好ましく、２５～３８％（質量％）が特に好ましい。なお、有機硫酸基の量は、日本薬局方外医薬品規格２００２中、「ヘパリン類似物質」の項に記載の方法により測定する。
　また、本発明におけるヘパリン類似物質の平均分子量は、特に限定されないが、例えば、重量平均分子量にて、１，０００～１，０００，０００Ｍｗが好ましく、５，０００～１００，０００Ｍｗが特に好ましい。 The heparin-like substance may be in the form of a physiologically acceptable salt obtained by a salt-forming reaction using hydroxides or carbonates of alkali metals such as sodium and potassium, or amines, if necessary.
The ratio (%) of organic sulfate groups in the heparin analogue in the present invention is not particularly limited, but is preferably 20 to 40% (% by mass) from the viewpoint of improving the anti-inflammatory analgesic effect and reducing skin irritation. 25-38% (mass %) is particularly preferred. The amount of the organic sulfate group is measured by the method described in the Japanese Non-Pharmacopoeia Pharmaceutical Standards 2002, "Heparin-like Substances" section.
In addition, the average molecular weight of the heparin analogue in the present invention is not particularly limited.
　また、本発明の皮膚外用剤は、ヘパリン類似物質の類縁体も任意成分として含んでいてもよい。ヘパリン類似物質の類縁体としては、例えば、その他の酸性ムコ多糖であってよい。
　ヘパリン類似物質の類縁体としての酸性ムコ多糖としては、例えば、コンドロイチン硫酸Ａ、コンドロイチン硫酸Ｂ（デルマタン硫酸）、コンドロイチン硫酸Ｃ、コンドロイチン硫酸Ｄ、コンドロイチン硫酸Ｅ、コンドロイチン硫酸Ｋ等のコンドロイチン硫酸類、ヘパリン、ヘパラン硫酸、ケラタン硫酸等が挙げられる。
　すなわち、本発明の皮膚外用剤においては、ヘパリン類似物質と併せて、必要に応じ、本発明の効果を損なわない範囲で、上記ヘパリン類似物質の類縁体としての酸性ムコ多糖をさらに加えてもよい。
　これらヘパリン類似物質の類縁体は、場合によっては製薬上許容される塩及び／又は溶媒和物の形態であってよい。製薬上許容される塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩等が挙げられる。
　また、溶媒和物としては水和物が挙げられる。 In addition, the external preparation for skin of the present invention may also contain an analogue of a heparinoid as an optional component. Analogues of heparinoids may be, for example, other acidic mucopolysaccharides.
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, chondroitin sulfate K, and heparin. , heparan sulfate, keratan sulfate, and the like.
That is, in the skin preparation for external use of the present invention, an acidic mucopolysaccharide as an analogue of the heparinoid may be added together with the heparinoid, as long as the effect of the present invention is not impaired. .
These heparin analogues may optionally be in the form of pharmaceutically acceptable salts and/or solvates. 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.
Moreover, a hydrate is mentioned as a solvate.
　一方、プロピオン酸系非ステロイド性解熱鎮痛消炎剤（ＮＳＡＩＤｓ）であるロキソプロフェンは、他のＮＳＡＩＤｓと同様にプロスタグランジン生合成の抑制作用に基づく解熱・鎮痛・消炎作用を有する。ロキソプロフェンは経口投与後に胃粘膜刺激作用の弱い未変化体のまま消化管から吸収され、体内で活性体となるプロドラッグであるため、活性体よりも胃粘膜障害は少ないという特徴を有することでも知られている。また、ロキソプロフェンは、皮膚においてもケトン還元酵素によってトランス－ＯＨ体（活性体）に変換されることが知られており、近年、ロキソプロフェンは外用消炎鎮痛剤としてもパップ剤、テープ剤及びゲル剤が市販され、臨床に供されている。 On the other hand, loxoprofen, a propionic acid-based non-steroidal antipyretic, analgesic, anti-inflammatory drug (NSAIDs), has antipyretic, analgesic, and anti-inflammatory effects based on the inhibition of prostaglandin biosynthesis, similar to other NSAIDs. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract as an unchanged form with a weak gastric mucosa-irritating effect after oral administration and becomes an active form in the body. It is Loxoprofen is also known to be converted to trans-OH form (active form) by ketone reductase in the skin. In recent years, loxoprofen has been used as an external anti-inflammatory analgesic in poultices, tapes and gels. It is commercially available and clinically available.
　本発明において、「ロキソプロフェン又はその塩」とは、ロキソプロフェン又はその塩、並びにそれらの水和物を含むものである。ロキソプロフェンの塩としては、薬理学的に許容できる塩が好ましく、より好ましくは、ロキソプロフェンナトリウム又はロキソプロフェンナトリウム水和物（ロキソプロフェンナトリウム・２水和物と示すこともある）であり、さらに好ましくは、ロキソプロフェンナトリウム水和物である。なお、本明細書においてロキソプロフェンと言う場合には、ロキソプロフェン又はその塩、並びにそれらの水和物を包含するものとする。 In the present invention, "loxoprofen or a salt thereof" includes loxoprofen or a salt thereof and hydrates thereof. The salt of loxoprofen is preferably a pharmacologically acceptable salt, more preferably loxoprofen sodium or loxoprofen sodium hydrate (also referred to as loxoprofen sodium dihydrate), still more preferably loxoprofen. Sodium hydrate. In the present specification, the term loxoprofen includes loxoprofen, salts thereof, and hydrates thereof.
　本発明におけるロキソプロフェンは、ロキソプロフェンナトリウム水和物として第１７改正日本薬局方に収載されている。 The loxoprofen in the present invention is listed in the 17th revision of the Japanese Pharmacopoeia as loxoprofen sodium hydrate.
　本発明の皮膚外用剤は、さらにアルコール類を含有してもよい。
　本発明におけるアルコール類とは低級アルコールおよび多価アルコールのことを指す。本発明における低級アルコールとは、可溶化剤、基剤、保存剤、溶剤、溶解補助剤等の用途で外用剤に用いられる炭素数１～４個の脂肪族アルコール類であり、例えば、メタノール、エタノール（エチルアルコールとも言う）、プロパノール、イソプロパノール（イソプロピルアルコールとも言う）、およびブチルアルコール等からなる群より選ばれる１種または２種以上であり、好ましくはエタノールである。エタノール含量が９９．５体積％以上のものは無水エタノールとも呼ばれる。 The skin external preparation of the present invention may further contain alcohols.
Alcohols in the present invention refer to lower alcohols and polyhydric alcohols. The term "lower alcohol" as used in the present invention refers to aliphatic alcohols having 1 to 4 carbon atoms which are used in external preparations such as solubilizers, bases, preservatives, solvents, solubilizers, etc. Examples include methanol, One or more selected from the group consisting of ethanol (also referred to as ethyl alcohol), propanol, isopropanol (also referred to as isopropyl alcohol), and butyl alcohol, preferably ethanol. Those with an ethanol content of 99.5% by volume or more are also called anhydrous ethanol.
　本発明における多価アルコールとは、可溶化剤、基剤、湿潤剤、粘稠剤、溶剤、溶解補助剤等の用途で外用剤に用いられる、分子内に水酸基が２個以上あるアルコールであり、例えば、プロピレングリコール、１，３‐ブチレングリコール、マクロゴール（ポリエチレングリコールともいう）、グリセリン、D‐ソルビトール、ジプロピレングリコールであり、医薬品添加物事典２０２１に収載されている。なお、マクロゴールの分子量は特に限定されないが、例えば、数平均分子量で２００～２００００であってもよい。
　また、本発明におけるアルコール類の分子量は、特に限定されないが、例えば、４００以下であってもよく、４００未満であることが好ましく、３００以下であることがより好ましく、２５０以下であることがさらに好ましく、２００以下であることが特に好ましく、１００以下であってもよい。 The polyhydric alcohol in the present invention is an alcohol having two or more hydroxyl groups in the molecule, which is used in external preparations such as solubilizers, bases, wetting agents, thickening agents, solvents, and dissolution aids. , for example, propylene glycol, 1,3-butylene glycol, macrogol (also referred to as polyethylene glycol), glycerin, D-sorbitol, dipropylene glycol, listed in the Japanese Pharmaceutical Excipients Dictionary 2021. The molecular weight of macrogol is not particularly limited, but may be, for example, 200 to 20,000 in number average molecular weight.
In addition, the molecular weight of the alcohol in the present invention is not particularly limited. It is preferably 200 or less, particularly preferably 100 or less.
　また、本発明の外用剤における、ヘパリン類似物質の含有量は、特に限定されないが、好ましくは、外用剤全量に対して、０．１～１０質量％であり、より好ましくは、０．１～０．５質量％である。なお、外用剤の剤形が貼付剤（パップ剤、テープ剤）の場合においても、ヘパリン類似物質の含有量は、特に限定されないが、好ましくは、貼付剤の膏体全量に対して、０．１～１０質量％であり、より好ましくは、０．１～０．５質量％である。 The content of the heparin-like substance in the topical preparation of the present invention is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.1 to 10% by mass, based on the total amount of the topical preparation. It is 0.5% by mass. Even when the dosage form of the external preparation is a patch (plast, tape), the content of the heparin-like substance is not particularly limited, but it is preferably 0.00% of the total amount of the paste of the patch. It is 1 to 10% by mass, more preferably 0.1 to 0.5% by mass.
　本発明の外用剤が、アルコールを含有する場合、アルコールの質量に対する、ヘパリン類似物質の含有量の比（ヘパリン類似物質／アルコール質量比）は、特に限定されないが、好ましくは１．０×１０－３～１００であり、より好ましくは、１．４×１０－３～１０であり、さらに好ましくは２．０×１０－３～５．０である。
　本発明の外用剤が、低級アルコールを含有する場合、低級アルコールの質量に対する、ヘパリン類似物質の含有量の比（ヘパリン類似物質／低級アルコール質量比）は、特に限定されないが、好ましくは１．０×１０－３～１００であり、より好ましくは、１．４×１０－３～１０であり、さらに好ましくは２．０×１０－３～５．０である。
　本発明の外用剤が、多価アルコールを含有する場合、多価アルコールの質量に対する、ヘパリン類似物質の含有量の比（ヘパリン類似物質／多価アルコール質量比）は、特に限定されないが、好ましくは１．０×１０－３～１００であり、より好ましくは、１．４×１０－３～１０であり、さらに好ましくは２．０×１０－３～５．０である。 When the external preparation of the present invention contains alcohol, the ratio of the content of the heparinoid to the mass of alcohol (heparinoid/alcohol mass ratio) is not particularly limited, but is preferably 1.0×10 − 3 to 100, more preferably 1.4×10 −3 to 10, still more preferably 2.0×10 −3 to 5.0.
When the external preparation of the present invention contains a lower alcohol, the ratio of the content of the heparinoid to the weight of the lower alcohol (heparinoid/lower alcohol mass ratio) is not particularly limited, but is preferably 1.0. ×10 −3 to 100, more preferably 1.4×10 −3 to 10, still more preferably 2.0×10 −3 to 5.0.
When the external preparation of the present invention contains a polyhydric alcohol, the ratio of the content of the heparin analogue to the mass of the polyhydric alcohol (heparin analogue/polyhydric alcohol mass ratio) is not particularly limited, but preferably It is 1.0×10 −3 to 100, more preferably 1.4×10 −3 to 10, still more preferably 2.0×10 −3 to 5.0.
　また、本発明の外用剤における、ロキソプロフェン又はその塩（例えば、ロキソプロフェンナトリウム水和物）の含有量は、特に限定されないが、好ましくは、外用剤全量に対して、０．１～１５質量％であり、より好ましくは、０．５～１０質量％である。なお、外用剤の剤形が貼付剤（パップ剤、テープ剤）の場合においても、ロキソプロフェン又はその塩（例えば、ロキソプロフェンナトリウム水和物）の含有量は、特に限定されないが、好ましくは、貼付剤の膏体全量に対して、０．１～１５質量％であり、より好ましくは、０．５～１０質量％である。 The content of loxoprofen or a salt thereof (eg, loxoprofen sodium hydrate) in the topical preparation of the present invention is not particularly limited, but is preferably 0.1 to 15% by mass relative to the total amount of the topical preparation. Yes, more preferably 0.5 to 10% by mass. Although the content of loxoprofen or a salt thereof (for example, loxoprofen sodium hydrate) is not particularly limited even when the dosage form of the external preparation is a patch (plast, tape), it is preferably a patch. 0.1 to 15% by mass, more preferably 0.5 to 10% by mass, based on the total amount of the plaster.
　本発明の外用剤が、アルコールを含有する場合、アルコールの質量に対する、ロキソプロフェン又はその塩の含有量の比（ロキソプロフェン又はその塩／アルコール質量比）は、特に限定されないが、好ましくは１．０×１０－３～１５０であり、より好ましくは、１．４×１０－３～１００であり、さらに好ましくは、２．０×１０－３～３５である。
　本発明の外用剤が、低級アルコールを含有する場合、低級アルコールの質量に対する、ロキソプロフェン又はその塩の含有量の比（ロキソプロフェン又はその塩／低級アルコール質量比）は、特に限定されないが、好ましくは１．０×１０－３～１５０であり、より好ましくは、１．４×１０－３～１００であり、さらに好ましくは、２．０×１０－３～２０である。
　本発明の外用剤が、多価アルコールを含有する場合、多価アルコールの質量に対する、ロキソプロフェン又はその塩の含有量の比（ロキソプロフェン又はその塩／多価アルコール質量比）は、特に限定されないが、好ましくは１．０×１０－３～１５０であり、より好ましくは、１．４×１０－３～１００であり、さらに好ましくは、２．０×１０－３～３５である。 When the external preparation of 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 to 150, more preferably 1.4×10 −3 to 100, still more preferably 2.0×10 −3 to 35.
When the external preparation of the present invention contains a lower alcohol, the ratio of the content of loxoprofen or a salt thereof to the weight of the lower alcohol (mass ratio of loxoprofen or a salt thereof/lower alcohol) is not particularly limited, but is preferably 1 0×10 −3 to 150, more preferably 1.4×10 −3 to 100, still more preferably 2.0×10 −3 to 20.
When the external preparation of the present invention contains a polyhydric alcohol, the ratio of the content of loxoprofen or a salt thereof to the mass of the polyhydric alcohol (mass ratio of loxoprofen or a salt thereof/polyhydric alcohol mass ratio) is not particularly limited, It is preferably 1.0×10 −3 to 150, more preferably 1.4×10 −3 to 100, still more preferably 2.0×10 −3 to 35.
　本発明の外用剤におけるヘパリン類似物質とロキソプロフェン又はその塩との質量比は、特に限定されないが、ヘパリン類似物質／ロキソプロフェン又はその塩（ＨＰ/Ｌｏｘ質量比）が０．０１～１００であってよく、０．０１～１０であることが好ましい。
　また、本発明の外用剤においては、ヘパリン類似物質の安定性向上の観点から、外用剤全量に対してロキソプロフェン又はその塩の含有量が０．６質量％以上であり、かつ、ヘパリン類似物質／ロキソプロフェン又はその塩（ＨＰ/Ｌｏｘ質量比）が０．０１～１０であることがより好ましい。 The mass ratio of the heparin analogue to loxoprofen or its salt in the external preparation of the present invention is not particularly limited, but the heparin analogue/loxoprofen or its salt (HP/Lox mass ratio) may be 0.01 to 100. , 0.01 to 10.
In addition, in the external preparation of the present invention, from the viewpoint of improving the stability of the heparin analogue, the content of loxoprofen or a salt thereof is 0.6% by mass or more relative to the total amount of the external preparation, and the heparin analogue / Loxoprofen or a salt thereof (HP/Lox mass ratio) is more preferably 0.01-10.
　また、本発明の外用剤におけるアルコールの含有量の範囲は、特に限定されないが、 剤形に応じて選択してよく、 好ましくは、外用剤全量に対して、０．１～７０．０質量％であってもよい。なお、外用剤の剤形が貼付剤（パップ剤、テープ剤）の場合においても、アルコールの含有量は、特に限定されないが、好ましくは、貼付剤の膏体全量に対して、０．１～７０．０質量％である。
　また、本発明の外用剤における低級アルコールの含有量の範囲は、特に限定されないが、剤形に応じて選択してよく、好ましくは、外用剤全量に対して、０．１～７０．０質量％であり、より好ましくは、０．１～５０．０質量％である。 In addition, the range of alcohol content in the topical preparation of the present invention is not particularly limited, but may be selected according to the dosage form, and is preferably 0.1 to 70.0% by mass relative to the total amount of the topical preparation. may be Even when the dosage form of the external preparation is a patch (plast, tape), the alcohol content is not particularly limited, but is preferably from 0.1 to 0.1 to the total amount of the paste of the patch. 70.0% by mass.
In addition, the range of the lower alcohol content in the topical preparation of the present invention is not particularly limited, but may be selected according to the dosage form, preferably 0.1 to 70.0 mass relative to the total amount of the topical preparation. %, more preferably 0.1 to 50.0% by mass.
　例えば、本発明の外用剤が外用液剤・ゲル剤の場合には、低級アルコールの添加量含有量の範囲は、例えば、外用液剤・ゲル剤の全量に対して、特に限定されないが、好ましくは１０．０～７０．０質量％であり、より好ましくは、１０．０～６０．０質量％である。
　例えば、本発明の外用剤がパップ剤の場合には、低級アルコールの添加量含有量の範囲は、例えば、パップ剤の膏体全量に対して、好ましくは０．１～５０質量％ であり、より好ましくは０．１％～３０質量％である。
　例えば、本発明の外用剤がテープ剤の場合には、低級アルコールを含有する場合と含有しない場合とがあり、低級アルコールを含有する場合の含有量の範囲は、例えば、テープ剤の膏体全量に対して、好ましくは０．１～1０質量％ であり、より好ましくは０．１％～５質量％である。 For example, when the topical preparation of the present invention is a topical liquid or gel, the range of the amount of lower alcohol to be added is not particularly limited, but is preferably 10% with respect to the total amount of the topical liquid or gel. 0 to 70.0% by mass, more preferably 10.0 to 60.0% by mass.
For example, when the topical preparation of the present invention is a poultice, the content of the lower alcohol is preferably in the range of 0.1 to 50% by mass with respect to the total amount of the paste of the poultice, More preferably, it is 0.1% to 30% by mass.
For example, when the external preparation of the present invention is a tape, it may or may not contain a lower alcohol. , preferably 0.1 to 10% by mass, more preferably 0.1% to 5% by mass.
　さらに、本発明の外用剤における多価アルコールの含有量の範囲は、特に限定されないが、剤形に応じて選択してよく、好ましくは外用剤全量に対して、０．１～７０質量％であり、より好ましくは０．１～２０質量％であり、より好ましくは０．５～２０質量％であり、さらに好ましくは、１．０～１５質量％である。
　例えば、本発明の外用剤が外用液剤・ゲル剤の場合には、多価アルコールの添加量含有量の範囲は、特に限定されないが、例えば、外用液剤・ゲル剤の全量に対して、好ましくは０．５～２０質量％であり、より好ましくは、１．０～１５質量％％である。 Furthermore, the content range of the polyhydric alcohol in the topical preparation of the present invention is not particularly limited, but may be selected according to the dosage form, preferably 0.1 to 70% by mass based on the total amount of the topical preparation. Yes, more preferably 0.1 to 20% by mass, more preferably 0.5 to 20% by mass, still more preferably 1.0 to 15% by mass.
For example, when the topical preparation of the present invention is a topical liquid or gel, the range of the content of the polyhydric alcohol to be added is not particularly limited. It is 0.5 to 20% by mass, more preferably 1.0 to 15% by mass.
　例えば、本発明の外用剤がパップ剤の場合には、多価アルコールの添加量含有量の範囲は、特に限定されないが、例えば、パップ剤の膏体全量に対して、好ましくは０．１～７０質量％ であり、より好ましくは３～６０質量％である。
　例えば、本発明の外用剤がテープ剤の場合には、多価アルコールを含有する場合と含有しない場合とがあり、多価アルコールを含有する場合の含有量の範囲は、例えば、テープ剤の膏体全量に対して、好ましくは０．１～1５質量％ であり、より好ましくは０．１％～１０質量％である。 For example, when the topical preparation of the present invention is a poultice, the range of content of the polyhydric alcohol to be added is not particularly limited. 70% by mass, more preferably 3 to 60% by mass.
For example, when the external preparation of the present invention is a tape, it may or may not contain a polyhydric alcohol. It is preferably 0.1 to 15% by mass, more preferably 0.1% to 10% by mass, based on the total amount of the body.
　また、皮膚外用剤のｐＨの範囲は、特に限定されないが、好ましくは５．０～７．５であり、より好ましくは６．０～７．５である。 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.
　本発明の皮膚外用剤において、上記成分以外の鎮痛消炎用の皮膚外用剤に通常使用される、薬物や医薬品添加物を添加することができる。 In the topical skin preparation of the present invention, drugs and pharmaceutical additives that are commonly used in pain-relieving and anti-inflammatory topical skin preparations other than the above ingredients can be added.
　本発明の皮膚外用剤においては、さらに成分（Ａ）を含んでいてもよく、前記成分（Ａ）が下記成分（Ａ―１）～（Ａ―１１）よりなる群から選ばれる１種以上を含有してよい。
（Ａ－１）トコフェロール類 ；
（Ａ－２）テルペン類； 
（Ａ－３）グリチルリチン酸類 ；
（Ａ－４）生薬類； 
（Ａ－５）トラネキサム酸類； 
（Ａ－６）バニロイド類； 
（Ａ－７）ニコチン酸類； 
（Ａ－８）クロルフェニラミン類 ；
（Ａ－９）ジフェンヒドラミン類 ；
（Ａ－１０）ピロリドン類； 
（Ａ－１１）無機塩 ； The external preparation for skin of the present invention may further contain a component (A), wherein the component (A) is one or more selected from the group consisting of the following components (A-1) to (A-11). may contain.
(A-1) tocopherols;
(A-2) terpenes;
(A-3) glycyrrhizic acids;
(A-4) crude drugs;
(A-5) tranexamic acids;
(A-6) vanilloids;
(A-7) nicotinic acids;
(A-8) chlorpheniramines;
(A-9) diphenhydramines;
(A-10) pyrrolidones;
(A-11) inorganic salt;
（Ａ－１）トコフェロール類としては、トコフェロール、トコトリエノール及びそれらの誘導体（例えば、酢酸エステル、コハク酸エステル、ニコチン酸エステル等のエステル化誘導体など）並びにそれらの塩（例えば、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩など）を挙げることができる。トコフェロールとしては、α－トコフェロール、β－トコフェロール、γ－トコフェロール、δ－トコフェロールのいずれであってもよいが、α－トコフェロールが好ましい。また、トコトリエノールとしては、α－トコトリエノール、β－トコトリエノール、γ－トコトリエノール、δ－トコトリエノールのいずれであってもよいが、α－トコトリエノールが好ましい。トコフェロール類としては、トコフェロール酢酸エステルが特に好ましい。 (A-1) Tocopherols include tocopherol, tocotrienol and derivatives thereof (e.g., esterified derivatives such as acetates, succinates, nicotinates, etc.) and salts thereof (e.g., calcium salts, magnesium salts, etc.) alkaline earth metal salts, etc.). The tocopherol may be α-tocopherol, β-tocopherol, γ-tocopherol or δ-tocopherol, but α-tocopherol is preferred. The tocotrienol may be α-tocotrienol, β-tocotrienol, γ-tocotrienol or δ-tocotrienol, but α-tocotrienol is preferred. Among the tocopherols, tocopherol acetate is particularly preferred.
　トコフェロール類を使用する場合における皮膚外用剤におけるトコフェロール類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０３～４質量％がより好ましく、０．０５～２質量％が特に好ましい。 When tocopherols are used, the content of the tocopherols in the external preparation for skin is not particularly limited, but is generally 0.01 to 10% by weight, and 0.03 to 4% by weight, based on the total weight of the external preparation for skin. % by mass is more preferred, and 0.05 to 2% by mass is particularly preferred.
（Ａ－２）テルペン類とは、テルペン炭化水素のほか、テルペンアルコール、テルペンアルデヒド、テルペンケトン、テルペンオキシド、テルペンラクトンなどを包含する総称（テルペノイド）を意味し、その構造は特に限定されるものではなく、モノテルペン、セスキテルペン又はそれらの誘導体等が挙げられる。また、環式でも鎖式でもよい。テルペン類としては、例えば、イソボルネオール、イロン、オシメン、カルベオール、カルボタナセトン、カルボメントン、カルボン、カレン、カロン、カンフェン、カンフル、ゲラニオール、サビネン、サフラナール、シクロシトラール、シトラール、シトロネラール、シトロネル酸、シトロネロール、シネオール、シメン、シルベストレン、チモール、イソツジョール、ツジョン、テルピネオール、テルピネン、テルピノレン、トリシクレン、ネロール、ピネン、ピノカンフェオール、ピノール、ピペリテノン、フェランドラール、フェランドレン、フェンチェン、フェンチルアルコール、ペリリルアルコール、ペリルアルデヒド、ボルネオール、ミルセン、メントール、メントン、ヨノール、ヨノン、リナロール、リモネン等が挙げられる。 (A-2) Terpenes mean a generic term (terpenoid) including terpene hydrocarbons, terpene alcohols, terpene aldehydes, terpene ketones, terpene oxides, terpene lactones, etc., and the structure thereof is particularly limited. Instead, monoterpene, sesquiterpene, derivatives thereof, and the like are included. Also, it may be cyclic or chain. Examples of terpenes include isoborneol, iron, ocimene, carveol, carbotanacetone, carbomentone, carvone, carene, caron, camphene, camphor, geraniol, sabinene, safranal, cyclocitral, citral, citronellal, citronellic acid, citronellol, and cineol. , cymene, sylvestrene, thymol, isotjol, thujone, terpineol, terpinene, terpinolene, tricyclene, nerol, pinene, pinocane, pinol, piperitenone, ferrandral, phellandrene, fenchene, fenchyl alcohol, perillyl alcohol, Perillaldehyde, borneol, myrcene, menthol, menthone, yonol, yonone, linalool, limonene and the like.
　テルペン類としては、テルペン類を含む精油を用いてもよい。精油としては、例えば、アニス油、イランイラン油、イリス油、ウイキョウ油、オレンジ油、カナンガ油、カミツレ油、カヤプト油、カラウェー油、クベブ油、グレープフルーツ油、ケイヒ油、コリアンダー油、サフラン油、サンショウ油、シソ油、シトリオドラ油、シトロネラ油、ショウキョウ油、ショウズク油、樟脳油、ジンジャーグラス油、スペアミント油、セイヨウハッカ油、ゼラニウム油、ダイウイキョウ油、チョウジ油、テレビン油、トウヒ油、ネロリ油、バジル油、ハッカ油、パルマローザ油、ピメント油、プチグレン油、ベイ油、ペニローヤル油、ヘノポジ油、ベルガモット油、ボアドローズ油、ホウショウ油、マジョラン油、マンダリン油、メリッサ油、ユーカリ油、ライム油、ラベンダー油、リナロエ油、レモン油、レモングラス油、ローズ油、ローズマリー油、ローマカミツレ油等が挙げられ、これらを単独で又は２種以上組み合わせて用いてもよい。 As terpenes, essential oils containing terpenes may be used. Examples of essential oils include anise oil, ylang-ylang oil, iris oil, fennel oil, orange oil, cananga oil, chamomile oil, kayaput oil, caraway oil, kubeb oil, grapefruit oil, cinnamon oil, coriander oil, saffron oil, sun Ginger oil, Perilla oil, Citriodora oil, Citronella oil, Ginger oil, Shozuku oil, Camphor oil, Gingergrass oil, Spearmint oil, Peppermint oil, Geranium oil, Daifennel oil, Clove oil, Turpentine oil, Spruce oil, Neroli oil , basil oil, peppermint oil, palmarosa oil, pimento oil, petitgrain oil, bay oil, penyroyal oil, henoposi oil, bergamot oil, boad rose oil, pepper oil, marjolan oil, mandarin oil, melissa oil, eucalyptus oil, lime oil, lavender oil, linaloe oil, lemon oil, lemongrass oil, rose oil, rosemary oil, Roman chamomile oil, etc., and these may be used alone or in combination of two or more.
　テルペン類としては、好ましくは、ｌ－メントール、ｄｌ―カンフル、メントキシプロパンジオール（３－（メントキシ）－１，２-プロパンジオール）、３－（ｌ－メントキシ）－２－メチルプロパン－１，２－ジオール、p－メンタン－３，８－ジオール、イソプレゴール、チモール、ハッカ油、ユーカリ油などを使用することができる。 Terpenes preferably include l-menthol, dl-camphor, menthoxypropanediol (3-(menthoxy)-1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1, 2-diol, p-menthane-3,8-diol, isopulegol, thymol, peppermint oil, eucalyptus oil and the like can be used.
　テルペン類を使用する場合における皮膚外用剤におけるテルペン類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～６質量％がより好ましく、０．１～４質量％が特に好ましい。 When terpenes are used, the content of terpenes in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 6%, based on the total weight of the external skin preparation. % by mass is more preferred, and 0.1 to 4% by mass is particularly preferred.
（Ａ－３）グリチルリチン酸類としては、例えば、グリチルリチン酸またはその塩、グリチルレチン酸またはその塩を挙げることができる。塩としては、例えば、カリウム塩、ナトリウム塩等のアルカリ金属塩；アンモニウム塩などを挙げることができる。また、グリチルリチン酸類としては、グリチルリチン酸類を含有するカンゾウ（甘草）やその抽出物を用いてもよい。 (A-3) Glycyrrhizic acids include, for example, glycyrrhizic acid or its salts and glycyrrhetinic acid or its salts. Examples of salts include alkali metal salts such as potassium salts and sodium salts; ammonium salts and the like. As the glycyrrhizic acid, licorice (licorice) containing glycyrrhizic acid or an extract thereof may be used.
　グリチルリチン酸類を使用する場合における皮膚外用剤におけるグリチルリチン酸類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～３質量％が特に好ましい。 The content of glycyrrhizic acids in the external skin preparation when glycyrrhizic acids are used is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 4%, based on the total weight of the external skin preparation. % by mass is more preferred, and 0.1 to 3% by mass is particularly preferred.
（Ａ－４）生薬類としては、例えば、カンゾウ、アルニカチンキ、アカメガシワ、アセンヤク、インヨウカク、ウイキョウ、ウコン、エンゴサク、オウゴン、オウセイ、オウバク、オウヒ、オウレン、オンジ、ガジュツ、カノコソウ、カミツレ、カロニン、キキョウ、キョウニン、クコシ、クコヨウ、ケイガイ、ケイヒ、ケツメイシ、ゲンチアナ、ゲンノショウコ、コウカ、コウブシ、ゴオウ、ゴミシ、サイシン、サンシシ、サンショウ、シオン、ジコッピ、シコン、シャクヤク、ジャコウ、シャジン、シャゼンシ、シャゼンソウ、獣胆(ユウタン(熊胆)を含む)、ショウキョウ、ジリュウ、シンイ、セイヨウトチノキ、セキサン、セネガ、センキュウ、ゼンコ、センブリ、ソウジュツ、ソウハクヒ、ソヨウ、タイサン、チクセツニンジン、チンピ、トウキ、トコン、ナンテンジツ、ニンジン、バイモ、バクモンドウ、ハンゲ、バンコウカ、ハンピ、ビャクシ、ビャクジュツ、ブクリョウ、ボタンピ、ヨウバイヒ、ロクジョウ等の生薬及びこれらの抽出物（エキス、チンキ、乾燥エキス等）等が挙げられる。なお、カンゾウは、グリチルリチン酸類として用いてもよく、生薬類としても用いてもよく、グリチルリチン酸類及び生薬類の両方の役割を兼ねて用いてもよい。 (A-4) Herbal medicines include, for example, licorice, arnica tincture, red-clawed mandarin orange, ashenyak, inyukaku, fennel, turmeric, corytal, Scutellaria japonicum, Chinese Peppermint, Phellodendron bark, Phellodendron japonicum, Japanese coptis, onji, zedoary, valerian, chamomile, caronin, bellflower , Kyonin, Chinese wolfberry, Kukoyo, Keigai, Keihi, Ketsumeishi, Gentiana, Gennoshoko, Kouka, Koubushi, Goou, Garbage, Saishin, Sanshishi, Sansho, Shion, Jikoppi, Shikon, Peony, Musk, Shajin, Shazenshi, Shazenso, Beast (Including Yutan (bear bile)), Ginger, Jiryu, Shini, Horse chestnut, Sekisan, Senega, Cnidium, Zenko, Assembly, Sojutsu, Souhakuhi, Soyou, Taisan, Chikuset carrot, Chimp, Toki, Tokon, Nantenjitsu, Crude drugs such as carrot, fritillaria, bakumondou, hange, bankouka, hampi, byakushi, byakujutsu, bukuryo, botanpi, yobahi, and rokujo, and extracts thereof (extracts, tinctures, dried extracts, etc.). Glycyrrhiza may be used as glycyrrhizic acids, as a crude drug, or as both glycyrrhizic acids and crude drugs.
　生薬類を使用する場合における皮膚外用剤における生薬類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～３質量％が特に好ましい。 When crude drugs are used, the content of the crude drugs in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by mass, and 0.05 to 4%, based on the total mass of the external skin preparation. % by mass is more preferred, and 0.1 to 3% by mass is particularly preferred.
（Ａ－５）トラネキサム酸類は、例えば、トラネキサム酸またはその塩、トラネキサム酸誘導体またはその塩を含んでいてもよい。
　トラネキサム酸の塩としては、特に制限はないが、具体的には、ナトリウム、カリウム等のアルカリ金属塩；カルシウム、マグネシウム等のアルカリ土類金属塩；アルミニウム、鉄、亜鉛等の金属塩；リジン、アルギニン、ヒスチジン、オルニチン等の塩基性アミノ酸塩；アンモニウム、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、ステアリルアミン等の有機アミン塩等が挙げられる。また、トラネキサム酸誘導体またはその塩であってもよく、具体的には、トラネキサム酸セチルエステル等のエステル誘導体；トラネキサム酸メチルアミド等のアミド誘導体が例示できる。 (A-5) Tranexamic acids may include, for example, tranexamic acid or salts thereof, tranexamic acid derivatives or salts thereof.
Salts of tranexamic acid are 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; basic amino acid salts such as arginine, histidine and ornithine; and organic amine salts such as ammonium, monoethanolamine, diethanolamine, triethanolamine and stearylamine. It may also be a tranexamic acid derivative or a salt thereof, and specific examples thereof include ester derivatives such as tranexamic acid cetyl ester; and amide derivatives such as tranexamic acid methylamide.
　トラネキサム酸類を使用する場合における皮膚外用剤におけるトラネキサム酸類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～２質量％が特に好ましい。 When tranexamic acids are used, the content of the tranexamic acids in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 4%, based on the total weight of the external skin preparation. % by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
（Ａ－６）バニロイド類は、バニリル基を含む化合物の総称である、本発明におけるバニロイド類としては、バニリル基を含む化合物であれば特に限定されず、例えば、バニリン、バニリン酸、カプサイシン、バニリルマンデル酸（VMA）、バニリルブチルエーテル（４-ブトキシメチル-２-メトキシフェノール）などが挙げられる。
　また、本発明におけるバニロイド類は、バニリル基を含む化合物を含む天然物を含んでいてもよく、バニリル基を有する化合物の誘導体やさらにバニリル基に官能基を付与した合成化合物などを含んでいてもよい。
　また、本発明におけるバニロイド類としては、バニリル基を含む化合物を含有するトウガラシ類を用いてもよく、バニロイド類の一部として含んでいてもよい。
　トウガラシ類としては、例えば、第１７改正日本薬局方に収載のトウガラシ（Capsicum annuum Linne（Solanaceae）の果実）などを好適に用いることができる。トウガラシは必要に応じてその形態を調節することができ、小片、小塊に切断若しくは破砕、又は粉末に粉砕することができ、例えば、トウガラシを粉末とした「トウガラシ末」も本発明の「トウガラシ」として用いることができる。また、トウガラシに何らかの抽出処理を施したもの（トウガラシエキス、トウガラシチンキなど）を用いてもよい。なお、トウガラシの抽出物は、抽出処理に加えて、加熱、乾燥、粉砕等の加工処理を施したものでもよい。さらに、トウガラシ類としては、トウガラシの主成分であるカプサイシノイドを用いてもよい。カプサイシノイドとしては、カプサイシン、ノナン酸バニリルアミドが好ましい。トウガラシ類としては、好ましくは、トウガラシエキス、トウガラシチンキ、ノニル酸バニリルアミド、又はカプサイシンを使用することができる。 (A-6) Vanilloids is a generic term for compounds containing a vanillyl group. Vanilloids in the present invention are not particularly limited as long as they are compounds containing a vanillyl group. acid (VMA), vanillyl butyl ether (4-butoxymethyl-2-methoxyphenol), and the like.
In addition, the vanilloids in the present invention may contain natural products containing compounds containing a vanillyl group, derivatives of compounds containing a vanillyl group, and synthetic compounds in which a functional group is added to the vanillyl group. good.
As the vanilloids in the present invention, capsicums containing a compound containing a vanillyl group may be used, or may be included as part of the vanilloids.
As the peppers, for example, peppers (fruits of Capsicum annuum Linne (Solanaceae)) listed in the Japanese Pharmacopoeia 17th Edition can be preferably used. The form of the pepper can be adjusted as necessary, and it can be cut or crushed into small pieces, small pieces, or pulverized into powder. can be used as Moreover, you may use the thing (pepper extract, capsicum tincture, etc.) which performed some extraction process on capsicum. The extract of hot pepper may be processed by heating, drying, crushing, etc., in addition to the extraction process. Furthermore, capsaicinoids, which are the main components of peppers, may be used as the peppers. As the capsaicinoid, capsaicin and nonanoic acid vanillylamide are preferred. Pepper extract, hot pepper tincture, nonylic acid vanillylamide, or capsaicin can be preferably used as hot peppers.
　バニロイド類を使用する場合における皮膚外用剤におけるバニロイド類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～２質量％ が特に好ましい。
　また、トウガラシ類を使用する場合における皮膚外用剤におけるトウガラシ類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～２質量％が特に好ましい。 When vanilloids are used, the content of the vanilloids in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by mass, and 0.05 to 4%, based on the total mass of the external skin preparation. % by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
In addition, when using peppers, the content of the peppers in the external skin preparation is not particularly limited, but it is generally 0.01 to 10% by weight with respect to the total weight of the external skin preparation, and 0.05% by weight. ~4% by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
（Ａ－７）ニコチン酸類としては、ニコチン酸及びその誘導体並びにそれらの塩を挙げることができる。ニコチン酸の誘導体としては、例えば、ニコチン酸エステル（具体的にはニコチン酸メチルエステル、ニコチン酸β－ブトキシエチルエステル、ニコチン酸ベンジルエステル、イノシトールヘキサニコチネート、ヘプロニカートなど）、ニコチン酸アミド、ニコチン酸アミドアデニンジヌクレオチド、ニコチン酸アミドアデニンジヌクレオチドリン酸など）などが挙げられる。ニコチン酸エステルとしては、ニコチン酸のモノエステルが好ましい。ニコチン酸類としては、ニコチン酸ベンジルエステルが好ましい。 (A-7) Nicotinic acids include nicotinic acid, derivatives thereof, and salts thereof. Nicotinic acid derivatives include, for example, nicotinic acid esters (specifically methyl nicotinic acid, β-butoxyethyl nicotinic acid, benzyl nicotinic acid, inositol hexanicotinate, hepronicate, etc.), nicotinic acid amide, and nicotinic acid. amide adenine dinucleotide, nicotinic acid amide adenine dinucleotide phosphate, etc.). Nicotinic acid esters are preferably monoesters of nicotinic acid. Nicotinic acid benzyl ester is preferred as the nicotinic acid.
　ニコチン酸類を使用する場合における皮膚外用剤におけるニコチン酸類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０１５～４質量％がより好ましく、０．０２～２質量％が特に好ましい。 When nicotinic acids are used, the content of nicotinic acids in the external preparation for skin is not particularly limited, but is generally 0.01 to 10% by weight, and 0.015 to 4%, based on the total weight of the external preparation for skin. % by mass is more preferred, and 0.02 to 2% by mass is particularly preferred.
（Ａ－８）クロルフェニラミン類としては、クロルフェニラミン類およびその塩が挙げられる。クロルフェニラミンの塩としては、具体的には、マレイン酸塩、フマル酸塩等の有機酸塩；塩酸塩、硫酸塩等の無機酸塩；金属塩等の各種塩が挙げられる。クロルフェニラミン類としては、クロルフェニラミンマレイン酸塩が好ましい、 (A-8) Chlorpheniramines include chlorpheniramines and salts thereof. The salts of chlorpheniramine specifically include organic acid salts such as maleates and fumarates; inorganic acid salts such as hydrochlorides and sulfates; and various salts such as metal salts. Chlorpheniramine is preferably chlorpheniramine maleate,
　クロルフェニラミン類を使用する場合における皮膚外用剤におけるクロルフェニラミン類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～２質量％が特に好ましい。 The content of chlorpheniramines in the external skin preparation when using chlorpheniramines is not particularly limited, but is generally 0.01 to 10% by weight relative to the total weight of the external skin preparation. 0.05 to 4% by weight is more preferred, and 0.1 to 2% by weight is particularly preferred.
（Ａ－９）ジフェンヒドラミン類としては、例えば、ジフェンヒドラミンまたはその塩を挙げることができる。ジフェンヒドラミンの塩としては、塩酸塩、クエン酸塩、コハク酸塩、酒石酸塩、フマル酸塩、マレイン酸塩、サリチル酸塩、ジフェニルジスルホン酸塩、タンニン酸塩、ラウリル硫酸塩、硫酸塩等の酸付加塩が挙げられる。ジフェンヒドラミン類としては、ジフェンヒドラミンまたはジフェンヒドラミン塩酸塩が好ましい。 (A-9) Diphenhydramines include, for example, diphenhydramine or a salt thereof. Salts of diphenhydramine include acid addition salts such as hydrochloride, citrate, succinate, tartrate, fumarate, maleate, salicylate, diphenyldisulfonate, tannate, lauryl sulfate, and sulfate. salt. As diphenhydramines, diphenhydramine or diphenhydramine hydrochloride is preferred.
　ジフェンヒドラミン類を使用する場合における皮膚外用剤におけるジフェンヒドラミン類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．０５～４質量％がより好ましく、０．１～２質量％が特に好ましい。 When diphenhydramines are used, the content of diphenhydramines in the external preparation for skin is not particularly limited, but is generally 0.01 to 10% by weight, and 0.05 to 4%, based on the total weight of the external preparation for skin. % by mass is more preferred, and 0.1 to 2% by mass is particularly preferred.
（Ａ－１０）ピロリドン類としては、ｄｌ-ピロリドンカルボン酸またはその塩が挙げられ、例えば、ピロリドンカルボン酸ナトリウムが好ましい。
　ピロリドン類を使用する場合における皮膚外用剤におけるピロリドン類の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．１～１０質量％がより好ましく、１～１０質量％が特に好ましい。 (A-10) Pyrrolidones include dl-pyrrolidone carboxylic acid or salts thereof, for example, sodium pyrrolidone carboxylate is preferred.
When pyrrolidones are used, the content of the pyrrolidones in the external skin preparation is not particularly limited, but is generally 0.01 to 10% by weight, and 0.1 to 10% by weight, based on the total weight of the external skin preparation. % by mass is more preferred, and 1 to 10% by mass is particularly preferred.
（Ａ－１１）無機塩は、マグネシウム又はカルシウム等のアルカリ土類金属の塩、ナトリウム又は等のアルカリ金属の塩、またはアンモニウム塩など挙げられ、例えば、塩化ナトリウム、塩化カリウム、塩化アンモニウムは好ましい。 (A-11) Inorganic salts include salts of alkaline earth metals such as magnesium or calcium, salts of alkali metals such as sodium or the like, and ammonium salts. For example, sodium chloride, potassium chloride and ammonium chloride are preferred.
　無機塩を使用する場合における皮膚外用剤における無機塩の含有量は特に限定されないが、皮膚外用剤全量の質量に対して一般的には０．０１～１０質量％であり、０．１～１０質量％がより好ましく、１～１０質量％が特に好ましい。 The content of the inorganic salt in the external preparation for skin when an inorganic salt is used is not particularly limited, but is generally 0.01 to 10% by weight, 0.1 to 10% by weight, based on the total weight of the external preparation for skin. % by mass is more preferred, and 1 to 10% by mass is particularly preferred.
　成分（Ａ）にかかる薬物としては、好ましくは、例えば、グリチルリチン酸、グリチルレチン酸等の抗炎症剤、ジフェンヒドラミン又はその塩、クロルフェニラミンマレイン酸塩等の抗ヒスタミン剤、トコフェロール酢酸エステル、ニコチン酸ベンジルエステル等の血行改善成分、ｌ－メントール、dl-カンフル、ｄ-カンフル、ノナン酸バニリルアミド（ノニル酸ワニリルアミド）、トウガラシエキス、トウガラシチンキ、カプサイシン、ハッカ油、ユーカリ油、メントキシプロパンジオール （３－（メントキシ）－１，２-プロパンジオール）、３－（ｌ－メントキシ）－２－メチルプロパン－１，２－ジオール等の局所刺激成分、アルニカチンキ等の生薬成分、イソプロピルメチルフェノール等の殺菌成分、ｄｌ-ピロリドンカルボン酸またはその塩等の湿潤剤、塩化ナトリウムなどの無機塩等を挙げることができ、これらの成分（Ａ）は、本発明の効果を損なわない範囲で配合することができる。 Preferred examples of drugs for component (A) include anti-inflammatory agents such as glycyrrhizic acid and glycyrrhetinic acid, diphenhydramine or its salts, antihistamines such as chlorpheniramine maleate, tocopherol acetate, and benzyl nicotinate. blood circulation improving ingredients, l-menthol, dl-camphor, d-camphor, nonanoic acid vanillylamide (nonylic acid vanillylamide), capsicum extract, capsicum tincture, capsaicin, peppermint oil, eucalyptus oil, menthoxypropanediol (3-(menthoxy) -1,2-propanediol), 3-(l-menthoxy)-2-methylpropane-1,2-diol and other local stimulating ingredients, herbal medicine ingredients such as arnica tincture, bactericidal ingredients such as isopropylmethylphenol, and dl- Wetting agents such as pyrrolidone carboxylic acid or salts thereof, inorganic salts such as sodium chloride, and the like can be mentioned, and these component (A) can be blended within a range that does not impair the effects of the present invention.
　上記成分以外の医薬品添加物は、例えば、経時的な含量安定性や使用感の更なる向上等を目的として必要に応じて添加するものであり、例えば、湿潤剤、保湿剤、粘稠剤、粘着剤、粘着付与樹脂、架橋剤、充填剤、油脂類、軟化剤、防腐剤、経皮吸収促進剤、安定化剤、溶解補助剤、ｐＨ調節剤、抗酸化剤、清涼化剤、界面活性剤、乳化剤、等を挙げることができる。また、本発明の皮膚外用剤は、その他、任意の成分を含んでいてもよい。なお、本発明の皮膚外用剤は、好ましくは、Ｎ－メチルピロリドン（Ｎ－メチル－２－ピロリドン）を含まない。 Pharmaceutical additives other than the above ingredients are added as necessary for the purpose of, for example, further improving the stability of the content over time and the feeling of use. Adhesives, tackifying resins, cross-linking agents, fillers, fats and oils, softeners, preservatives, transdermal absorption enhancers, stabilizers, solubilizers, pH adjusters, antioxidants, cooling agents, surfactants agents, emulsifiers, and the like. In addition, the external preparation for skin of the present invention may contain other optional ingredients. The external preparation for skin of the present invention preferably does not contain N-methylpyrrolidone (N-methyl-2-pyrrolidone).
　湿潤剤としては、例えば、ヒアルロン酸、ｄｌ－ピロリドンカルボン酸ナトリウムまたはその塩（例えば、ｄｌ－ピロリドンカルボン酸ナトリウム）等を用いることができる。
　保湿剤としては、例えば、ソルビトール、エチレングリコール、プロピレングリコール、ポリエチレングリコール、流動パラフィン、グリセリン、マクロゴール、１，３－プロパンジオール、１，４－ブタンジオール等の多価アルコールを用いることができる。
　増粘剤（粘稠剤・ゲル化剤）としては、例えば、ヒプロメロース、ヒドロキシプロピルセルロース、キサンタンガム、ゼラチン、ポリビニルアルコール、ポリビニルピロリドン、アルギン酸ナトリウム、カルボキシビニルポリマー、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム（カルメロースナトリウム）、メチルセルロース、カラギーナン、ローカストビーンガム、アルギン酸プロピレングリコール等を用いることができる。 As the moistening agent, for example, hyaluronic acid, sodium dl-pyrrolidonecarboxylate or a salt thereof (eg, sodium dl-pyrrolidonecarboxylate) can be used.
Examples of moisturizing agents that can be used include polyhydric alcohols such as sorbitol, ethylene glycol, propylene glycol, polyethylene glycol, liquid paraffin, glycerin, macrogol, 1,3-propanediol, and 1,4-butanediol.
Examples of thickening agents (viscosifying agents/gelling agents) include hypromellose, hydroxypropylcellulose, xanthan gum, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, carboxyvinyl polymer, carboxymethylcellulose, carboxymethylcellulose sodium (carmellose sodium ), methyl cellulose, carrageenan, locust bean gum, propylene glycol alginate and the like can be used.
　粘着剤としては、例えば、アクリル酸・アクリル酸オクチルエステル共重合体、アクリル酸エステル・酢酸ビニル共重合体、アクリル酸２－エチルヘキシル・ビニルピロリドン共重合体溶液、アクリル酸２－エチルヘキシル・メタクリル酸２－エチルヘキシル・メタクリル酸ドデシル共重合体溶液、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、アクリル酸メチル・アクリル酸２－エチルヘキシル共重合体樹脂エマルジョン、アクリル樹脂アルカノールアミン溶液、メタクリル酸・アクリル酸ｎ－ブチルコポリマー、アクリル酸シルクフィブロイン共重合樹脂、アクリル酸デンプン３００、アクリル酸デンプン１０００、アクリル酸ブチル・メタクリル酸２－エチルヘキシル・ジアセトンアクリルアミド共重合体、アクリル酸ブチル・メタクリル酸２－ヒドロキシエチル・ジアセトンアクリルアミド共重合体、アクリル酸ブチル・アクリル酸エチル・メタクリル酸２－ヒドロキシエチル・ジアセトンアクリルアミド共重合体、アクリル酸ブチル・アクリル酸２－エチルヘキシル・メタクリル酸２－ヒドロキシエチル・ジアセトンアクリルアミド共重合体、アクリル酸イソノニル・メタクリル酸２－ヒドロキシエチル・ジアセトンアクリルアミド共重合体、アクリル酸２－エチルヘキシル・メタクリル酸２－ヒドロキシエチル・ジアセトンアクリルアミド共重合体、アクリル酸ブチル・アクリル酸エチル・メタクリル酸３－ヒドロキシプロピル・メタクリル酸２－ヒドロキシエチル・ジアセトンアクリルアミド共重合体、アクリル酸ブチル・アクリル酸エチル・メタクリル酸３－ヒドロキシプロピル・ジアセトンアクリルアミド共重合体等のアクリル系粘着剤；シスイソプレンゴム、スチレンイソプレンゴム、シスポリイソプレンゴム、ハイシスポリイソプレンゴム、スチレンブタジエンゴム（ＳＢＲ）、スチレン・イソプレン・スチレンブロック共重合体（ＳＩＳ）、スチレン・ブタジエン・スチレンブロック共重合体（ＳＢＳ）、ポリイソプレン、ポリイソブチレン（ＰＩＢ）、クロロプレンゴム、ポリブテン、天然ゴムラテックス、ＳＢＲ合成ラテックス等の合成ゴム系粘着剤；ポリジメチルシロキサン、ポリメチルビニルシロキサン、ポリメチルフェニルシロキサン等のシリコーン系粘着剤の他、ポリアクリル酸、ポリアクリル酸ナトリウム、ポリアクリル酸部分中和物、Ｎ－ビニルアセトアミド・アクリル酸ナトリウム共重合体、ポリビニルアルコール、ポリビニルピロリドン、ヒドロキシメチルセルロース、カルボキシメチルセルロースナトリウム、アルギン酸、アルギン酸ナトリウム、ゼラチン、グァーガム、トラガントガム、アラビアゴム等に加えて、これらをアルミニウム、亜鉛、マグネシウム、カルシウム等の金属塩で架橋したもの等を用いることができる。 Examples of adhesives include acrylic acid/octyl acrylate copolymer, acrylic acid ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/vinylpyrrolidone copolymer solution, and 2-ethylhexyl acrylate/methacrylic acid 2. -Ethylhexyl/dodecyl methacrylate copolymer solution, ethyl acrylate/methyl methacrylate copolymer dispersion, methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution, methacrylic acid/acrylic acid n- Butyl copolymer, silk fibroin acrylate copolymer resin, starch acrylate 300, starch acrylate 1000, butyl acrylate/2-ethylhexyl methacrylate/diacetone acrylamide copolymer, butyl acrylate/2-hydroxyethyl methacrylate/di Acetone Acrylamide Copolymer, Butyl Acrylate/Ethyl Acrylate/2-Hydroxyethyl Methacrylate/Diacetone Acrylamide Copolymer, Butyl Acrylate/2-Ethylhexyl Acrylate/2-Hydroxyethyl Methacrylate/Diacetone Acrylamide Copolymer coalescence, isononyl acrylate/2-hydroxyethyl methacrylate/diacetone acrylamide copolymer, 2-ethylhexyl acrylate/2-hydroxyethyl methacrylate/diacetone acrylamide copolymer, butyl acrylate/ethyl acrylate/methacrylic acid Acrylic adhesives such as 3-hydroxypropyl/2-hydroxyethyl methacrylate/diacetoneacrylamide copolymer, butyl acrylate/ethyl acrylate/3-hydroxypropyl methacrylate/diacetoneacrylamide 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), poly synthetic rubber adhesives such as isoprene, polyisobutylene (PIB), chloroprene rubber, polybutene, natural rubber latex, SBR synthetic latex; silicone adhesives such as polydimethylsiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane; Polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, N-vinylacetamide In addition to sodium acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethyl cellulose, sodium carboxymethyl cellulose, alginic acid, sodium alginate, gelatin, guar gum, tragacanth gum, gum arabic, etc., metals such as aluminum, zinc, magnesium, calcium, etc. A material crosslinked with a salt or the like can be used.
　粘着付与樹脂としては、例えば、ロジン、水素添加ロジングリセリンエステル、エステルガム、マレイン酸レジン、マレイン化ロジングリセリンエステル、テルペン樹脂、石油樹脂、脂環族飽和炭化水素樹脂、脂肪族炭化水素樹脂等を用いることができる。
　架橋剤としては、例えば、乾燥水酸化アルミニウムゲル、水酸化アルミニウムマグネシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、合成ヒドロサルタイト、ジヒドロキシアルミニウムアミノアセテート等を用いることができる。
　充填剤としては、例えば、アルミナ、カオリン、ベントナイト、酸化亜鉛、酸化アルミニウム、酸化チタン、合成ケイ酸アルミニウム、酸化マグネシウム、酸化鉄、ステアリン酸亜鉛、亜鉛酸カルシウム、タルク、炭酸カルシウム、シリカ（二酸化ケイ素）等を用いることができる。
　油脂類としては、例えば、スクワラン、パラフィン、流動パラフィン、軽質流動パラフィン、ワセリン、ゲル化炭化水素等の炭化水素類；ミリスチン酸イソプロピル、ミリスチン酸オクチルドデシル等の脂肪酸エステル類；べへニルアルコール、ラウリルアルコール、ミリスチルアルコール、セチルアルコール、ステアリルアルコール、イソステアリルアルコール、オレイルアルコール等の高級アルコール類；ベヘニン酸、ラウリン酸、ミリスチン酸、ステアリン酸、イソステアリン酸、オレイン酸等の高級脂肪酸；カルナウバロウ、鯨ロウ、セラック、ホホバ油、ミツロウ、サラシミツロウ、モンタンロウ、ラノリン、精製ラノリン、還元ラノリン等のロウ類；シリコーン油等を用いることができる。 Examples of the tackifying resin include rosin, hydrogenated rosin glycerin ester, ester gum, maleic acid resin, maleated rosin glycerin ester, terpene resin, petroleum resin, alicyclic saturated hydrocarbon resin, aliphatic hydrocarbon resin, and the like. can be used.
Examples of cross-linking agents that can be used include dry aluminum hydroxide gel, magnesium aluminum hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrosartite, and dihydroxyaluminum aminoacetate.
Examples of fillers include alumina, kaolin, bentonite, zinc oxide, aluminum oxide, titanium oxide, synthetic aluminum silicate, magnesium oxide, iron oxide, zinc stearate, calcium zincate, talc, calcium carbonate, silica (silicon dioxide ) etc. can be used.
Fats and oils include, for example, hydrocarbons such as squalane, paraffin, liquid paraffin, light liquid paraffin, petroleum jelly, and gelling hydrocarbons; fatty acid esters such as isopropyl myristate and octyldodecyl myristate; behenyl alcohol and lauryl. Higher alcohols such as 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; carnauba wax, whale wax, Waxes such as shellac, jojoba oil, beeswax, bleached beeswax, montan wax, lanolin, refined lanolin and reduced lanolin; silicone oils and the like can be used.
　軟化剤としては、例えば、パラフィン系プロセスオイル、ナフテン系プロセスオイル及び芳香族系プロセスオイル等の石油系オイル；スクワラン；スクワレン；綿実油、パーム油、ヤシ油、アーモンド油、ナタネ油、オリーブ油、ツバキ油、ヒマシ油、トール油及びラッカセイ油等の植物系オイル；シリコンオイル；ジブチルフタレート及びジオクチルフタレートなどの二塩基酸エステル；ポリブテン及び液状イソプレンゴム等の液状ゴム；ミリスチン酸イソプロピル、ラウリン酸ヘキシル、セバシン酸ジエチル及びセバシン酸ジイソプロピル等の液状脂肪酸エステル類；ジエチレングリコール；ポリエチレングリコール；サリチル酸グリコール；プロピレングリコール；ジプロピレングリコール；トリアセチン；クエン酸トリエチル；クロタミトン；グリセリン等を用いることができる。 Examples of softening agents include petroleum oils such as paraffinic process oils, naphthenic process oils and aromatic process oils; squalane; squalene; 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; isopropyl myristate, hexyl laurate, sebacic acid Liquid fatty acid esters such as diethyl and diisopropyl sebacate; diethylene glycol; polyethylene glycol; glycol salicylate; propylene glycol;
　防腐剤としては、例えば、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸イソプロピル、パラオキシ安息香酸ブチル、パラオキシ安息香酸イソブチル、パラオキシ安息香酸ベンジル、安息香酸ナトリウム、安息香酸、安息香酸ベンジル、塩化ベンザルコニウム、塩化セチルピリジニウム、塩化ベンゼトニウム、アミノエチルスルホン酸等を用いることができる。
　経皮吸収促進剤としては、例えば、アルコール、脂肪酸、アジピン酸ジイソプロピル等の脂肪酸エステル、脂肪酸エーテル、乳酸エステル、酢酸エステル、テルペン系化合物、ピロリドン誘導体、有機酸、有機酸エステル、精油、炭化水素、炭化プロピレン、エイゾン又はその誘導体等を用いることができる。
　安定化剤としては、例えば、オキシベンゾン、ジブチルヒドロキシトルエン（ＢＨＴ）、エデト酸ナトリウム、ＵＶ吸収剤（例えば、ジベンゾイルメタン誘導体）等を用いることができる。 Examples of antiseptics include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, isopropyl parahydroxybenzoate, butyl parahydroxybenzoate, isobutyl parahydroxybenzoate, benzyl parahydroxybenzoate, sodium benzoate, benzoic acid, and benzoin. Benzyl acid, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, aminoethylsulfonic acid and the like can be used.
Percutaneous absorption enhancers include, for example, alcohols, fatty acids, fatty acid esters such as diisopropyl adipate, fatty acid ethers, lactic acid esters, acetic acid esters, terpene compounds, pyrrolidone derivatives, organic acids, organic acid esters, essential oils, hydrocarbons, Propylene carbide, Azone, derivatives thereof, or the like can be used.
Examples of stabilizers that can be used include oxybenzone, dibutylhydroxytoluene (BHT), sodium edetate, and UV absorbers (eg, dibenzoylmethane derivatives).
　溶解補助剤としては、例えば、ベンジルアルコール；ピロチオデカン；ミリスチン酸イソプロピル；クロタミトン；Ｎ－メチル－２－ピロリドン等のピロリドン類；高級アルコール類；アジピン酸ジエチル、アジピン酸イソプロピル、アジピン酸ジイソプロピル、アジピン酸ジイソブチル、アジピン酸ジオクチル、アジピン酸ジ（２－ヘプチルウンデシル）、セバシン酸ジイソプロピル、セバシン酸ジエチル等の多塩基酸類；ポリエチレングリコール（ＰＥＧ）、ポリブチレングリコール等のポリアルキレングリコール；モノステアリン酸ポリエチレングリコール等のオキシアルキレン脂肪酸エステル等を用いることができる。
　ｐＨ調節剤としては、例えば、塩酸、水酸化ナトリウム、水酸化カリウム、クエン酸、リンゴ酸、酒石酸、グルコン酸、乳酸、有機酸、有機アミン（例えば、トリエタノールアミン、ジイソプロパノールアミンなど）、リン酸等を用いることができる。
　抗酸化剤としては、例えば、アスコルビン酸、パルミチン酸アスコルビン酸、亜硫酸水素ナトリウム、乾燥亜硫酸ナトリウム、ピロ亜硫酸ナトリウム、エデト酸ナトリウム、クエン酸水和物、無水クエン酸、クエン酸、クエン酸ナトリウム、酢酸トコフェロール、ｄＩ－αートコフェロール、ジクロルイソシアヌル酸カリウム、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール、プチルヒドロキシアニソール、大豆レシチン、ペンタエリスリルーテトラキス［３一（３，５－ジーｔ－ブチルー４－ヒドロキシフエニル）プロピオネート］、２－メルカプトベンズイミダゾール、ベンゾトリアゾール、没食子酸プロピル等を用いることができる。
　清涼化剤としては、例えば、ｌ－メントール、カンフル、ｄｌ－カンフル、ハッカ油、ユーカリ油、チモール等を挙げることができる。 Examples of solubilizing agents include benzyl alcohol; pyrothiodecane; isopropyl myristate; crotamiton; pyrrolidones such as N-methyl-2-pyrrolidone; higher alcohols; , dioctyl adipate, di(2-heptylundecyl) adipate, diisopropyl sebacate, diethyl sebacate and other polybasic acids; polyethylene glycol (PEG), polyalkylene glycols such as polybutylene glycol; polyethylene glycol monostearate, etc. oxyalkylene fatty acid esters and the like can be used.
pH adjusters include, for example, hydrochloric acid, sodium hydroxide, potassium hydroxide, citric acid, malic acid, tartaric acid, gluconic acid, lactic acid, organic acids, organic amines (e.g., triethanolamine, diisopropanolamine, etc.), phosphorus An acid or the like can be used.
Antioxidants include, for example, ascorbic acid, ascorbic palmitic acid, sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, sodium edetate, citric acid hydrate, anhydrous citric acid, citric acid, sodium citrate, acetic acid Tocopherol, dI-α tocopherol, potassium dichloroisocyanurate, dibutylhydroxytoluene, butylhydroxyanisole, butylhydroxyanisole, soybean lecithin, pentaerythryltetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl ) propionate], 2-mercaptobenzimidazole, benzotriazole, propyl gallate and the like can be used.
Cooling agents include, for example, l-menthol, camphor, dl-camphor, peppermint oil, eucalyptus oil, thymol and the like.
　界面活性剤としては、非イオン性界面活性剤を用いてもよく、イオン性界面活性剤を用いてもよい。 As the surfactant, a nonionic surfactant or an ionic surfactant may be used.
　非イオン性界面活性剤としては、例えば、プロピレングリコールモノ脂肪酸エステル、エチレングリコールモノ脂肪酸エステル、グリセリンモノ脂肪酸エステル、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ショ糖脂肪酸エステル、メチルグルコシド脂肪酸エステル、アルキルポリグルコシド、ポリエチレングリコール脂肪酸エステル等の多価アルコール脂肪酸エステル又は多価アルコールアルキルエーテル；ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェニルエーテル、ポリオキシエチレンフィトステロール、ポリオキシエチレンフィトスタノール、ポリオキシエチレンポリオキシプロピレンアルキルエーテル等のポリオキシエチレンエーテル；ポリオキシエチレンモノ脂肪酸エステル、ポリエチレングリコールジ脂肪酸エステル、ポリオキシエチレングリセリン脂肪酸エステル、ポリソルベート２０、ポリソルベート４０、ポリソルベート６０、ポリソルベート６５、ポリソルベート８０等のポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンソルビトール脂肪酸エステル、ポリオキシエチレンメチルグルコシド脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油２０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等のポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンヒマシ油、ポリオキシエチレン植物油、ポリオキシエチレンアルキルエーテル脂肪酸エステル、ポリオキシエチレンポリオキシプロピレングリコール等のエーテルエステル等の非イオン性界面活性剤；ラウリル硫酸ナトリウム、セチル硫酸ナトリウムなどのイオン性界面活性剤；オクチルドデカノール等の高級アルコールなどが挙げられる。本発明におけるポリオキシエチレンアルキルエーテルは、例えば、ポリオキシエチレンラウリルエーテル、ポリオキシエチレンセチルエーテル、ポリオキシエチレンステアリルエーテル、ポリオキシエチレンオレイルエーテル、ポリオキシエチレンベヘニルエーテル等を挙げることができる。 Examples of nonionic surfactants include propylene glycol mono fatty acid ester, ethylene glycol mono fatty acid ester, glycerin mono fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, methylglucoside fatty acid ester, alkyl polyglucoside. , polyhydric alcohol fatty acid ester or polyhydric alcohol alkyl ether such as polyethylene glycol fatty acid ester; polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene polyoxypropylene alkyl Polyoxyethylene ethers such as ethers; Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene monofatty acid ester, polyethylene glycol difatty acid ester, polyoxyethylene glycerin fatty acid ester, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80 , polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc. Nonionic surfactants such as oxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, ether ester such as polyoxyethylene polyoxypropylene glycol; sodium lauryl sulfate, cetyl Ionic surfactants such as sodium sulfate; higher alcohols such as octyldodecanol; Examples of polyoxyethylene alkyl ethers in the present invention include polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether and the like.
　本発明におけるポリオキシエチレンポリオキシプロピレンアルキルエーテルは、例えば、ポリオキシエチレンポリオキシプロピレンセチルエーテル等を挙げることができる。
　本発明におけるポリオキシエチレンポリオキシプロピレンアルキルエーテルは、例えば、モノラウリン酸ポリエチレングリコール、モノステアリン酸ポリエチレングリコール、モノオレイン酸ポリエチレングリコール等を挙げることができる。 Examples of the polyoxyethylene polyoxypropylene alkyl ether in the present invention include polyoxyethylene polyoxypropylene cetyl ether.
Examples of the polyoxyethylene polyoxypropylene alkyl ether in the present invention include polyethylene glycol monolaurate, polyethylene glycol monostearate, and polyethylene glycol monooleate.
　本発明における非イオン性界面活性剤は、医薬品添加物事典２０２１に収載されている。 The nonionic surfactant in the present invention is listed in the Pharmaceutical Excipients Encyclopedia 2021.
　イオン性界面活性剤としては、例えば、ステアリン酸ナトリウム、ステアリン酸カリウム、セチル硫酸ナトリウム、ポリオキシエチレンラウリルエーテルリン酸ナトリウム、ジオクチルソジウムスルホサクシネート等のアニオン界面活性剤、塩化ベンザルコニウム、塩化ベンゼトニウム等のカチオン界面活性剤が挙げられる。 Examples of ionic surfactants include anionic surfactants such as sodium stearate, potassium stearate, sodium cetyl sulfate, sodium polyoxyethylene lauryl ether phosphate, dioctyl sodium sulfosuccinate, benzalkonium chloride, chloride cationic surfactants such as benzethonium;
　本発明におけるイオン性界面活性剤は、医薬品添加物事典２０２１、第１７改正日本薬局方に収載されている。
　本発明における乳化剤は、例えば、上記各種界面活性剤、上記高級アルコールなどで挙げたものを任意に用いてもよい。
　本発明におけるその他の任意の成分としては、例えば、トラネキサム酸、カンゾウなどの生薬等が挙げられる。
　具体的に、本発明のヘパリン類似物質、および、ロキソプロフェン又はその塩を含有する皮膚外用剤においては、さらにトラネキサム酸およびカンゾウのうち少なくとも１つを含んでいてもよい。 The ionic surfactant used in the present invention is listed in the Japanese Pharmacopoeia 2021, 17th edition of the Japanese Pharmacopoeia.
As the emulsifier in the present invention, for example, any of the various surfactants and higher alcohols listed above may be used arbitrarily.
Other optional ingredients in the present invention include, for example, crude drugs such as tranexamic acid and licorice.
Specifically, the external preparation for skin containing the heparin analogue of the present invention and loxoprofen or a salt thereof may further contain at least one of tranexamic acid and licorice.
　本発明の皮膚外用剤の具体的な剤形としては、例えば、外用液剤、軟膏剤、クリーム剤、スプレー剤（外用エアゾール剤、ポンプスプレー剤）、ゲル剤、貼付剤（テープ剤、パップ剤）、又は外用固形剤等を挙げることができ、各剤形に適した添加剤や基剤を適宜使用し、第１７改正日本薬局方などに記載される通常の方法に従い、製造することができる。本発明における皮膚外用剤の剤形としては、外用液剤が特に好ましい。本発明において、パップ剤やテープ剤のような貼付剤を作成する場合には、膏体量によってロキソプロフェン又はその塩（例えば、ロキソプロフェンナトリウム）の濃度が変動することがあるが、適切なロキソプロフェン又はその塩（例えば、ロキソプロフェンナトリウム）の濃度となるように適宜膏体量等を調整すればよい。 Specific dosage forms of the external preparation for skin of the present invention include, for example, liquids for external use, ointments, creams, sprays (external aerosols, pump sprays), gels, patches (tape, poultice). , or a solid preparation for external use, etc., and can be produced by appropriately using additives and bases suitable for each dosage form according to the usual methods described in the 17th revision of the Japanese Pharmacopoeia. A liquid preparation for external use is particularly preferable as the dosage form of the external preparation for skin in the present invention. In the present invention, when a patch such as a poultice or a tape is prepared, the concentration of loxoprofen or its salt (for example, loxoprofen sodium) may vary depending on the amount of plaster. The amount of the paste may be appropriately adjusted so as to obtain the concentration of the salt (for example, loxoprofen sodium).
　また、本発明の皮膚外用剤の製剤は、例えば、ガラス製の容器・包装、又は、アルミニウム等の金属製の容器・包装、又は、ポリエチレン、ポリプロピレン等のオレフィン系樹脂製の容器・包装に収容し、密封することができる。また、容器・包装には、再生プラスチックやバイオマス原料など環境に配慮された原料・材料を含む容器・包装を用いてもよく、必要に応じ、ラミネート構造の材料やガスバリア材料、高温環境などの際の熱や光など、医薬品の容器・包装の外部からの因子・要素・環境変化による皮膚外用剤の劣化を防ぎ、適切に皮膚外用剤の品質が保持されるような任意の材料などを用いてもよい本発明の一実施形態においては、適切な容器・包装に皮膚外用剤の製剤・組成物が収容された医薬品としてもよい。
　本発明の皮膚外用剤によれば、ヘパリン類似物質とロキソプロフェン又はその塩を配合することによって、ヘパリン類似物質の安定性を向上させることができる。このことによって、皮膚外用剤の保存安定性を高め、保存後でも、ヘパリン類似物質の薬効を効果的に発揮することができる。
　また、本発明の皮膚外用剤によれば、界面活性剤および増粘剤のうち少なくとも１つによる（界面活性剤や増粘剤等に起因する）ヘパリン類似物質の含量低下を抑制可能である。 In addition, the formulation of the external preparation for skin of the present invention is accommodated, for example, in a container/package made of glass, or a container/package made of metal such as aluminum, or a container/package made of olefinic resin such as polyethylene or polypropylene. and can be sealed. Containers and packaging containing environmentally friendly raw materials such as recycled plastics and biomass raw materials may also be used. Any material that prevents deterioration of topical skin preparations due to factors, elements, and environmental changes from the outside of the drug container and packaging, such as heat and light, and appropriately maintains the quality of topical skin preparations. In one embodiment of the present invention, the drug may be a pharmaceutical product in which the formulation/composition of the external preparation for skin is contained in an appropriate container/package.
According to the external preparation for skin of the present invention, the stability of the heparinoid can be improved by blending the heparinoid with loxoprofen or a salt thereof. As a result, the storage stability of the external preparation for skin can be enhanced, and the efficacy of the heparinoid can be effectively exhibited even after storage.
In addition, according to the external preparation for skin of the present invention, it is possible to suppress a decrease in the content of heparin analogues (caused by the surfactant, the thickener, etc.) due to at least one of the surfactant and the thickener.
　本発明は、一実施形態として、ロキソプロフェン又はその塩を含有する、ヘパリン類似物質を含有する皮膚外用剤の安定化剤として使用してもよい。具体的には、ロキソプロフェン又はその塩を含有する、ヘパリン類似物質を含有する皮膚外用剤におけるヘパリン類似物質の安定化剤として使用してもよい。
　また、上記一実施形態においては、界面活性剤および増粘剤のうち少なくとも１つによる前記ヘパリン類似物質の含量低下を抑制可能である。 In one embodiment, the present invention may be used as a stabilizer for external skin preparations containing heparinoids containing loxoprofen or a salt thereof. Specifically, the loxoprofen or its salt may be used as a heparinoid-like substance stabilizer in a skin preparation for external use containing a heparinoid-like substance.
Further, in the above embodiment, it is possible to suppress a decrease in the content of the heparin analogue due to at least one of the surfactant and the thickening agent.
　以下に、実施例をあげて本発明を更に具体的に説明するが、本発明はこれら実施例に何ら限定されるものではない。 Although the present invention will be described in more detail below with reference to examples, the present invention is not limited to these examples.
（試験例１）ヘパリン類似物質の保存安定性の検討（１）
（１）試験材料及び検体の調製
　以下の表１の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、検体１～８の液剤を得た。
　なお、ヘパリン類似物質はアピ（株）製のもの（ヘパリン類似物質全体に対する有機硫酸基の割合が３５．２％（質量％）のもの）を、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、ポリオキシエチレン硬化ヒマシ油６０およびポリソルベート８０は日光ケミカルズ（株）製のものを、ヒドロキシプロピルメチルセルロースは信越化学工業（株）のものを、塩酸および水酸化ナトリウムは関東化学（株）製のものをそれぞれ使用した。 (Test Example 1) Investigation of storage stability of heparinoids (1)
(1) Preparation of test materials and specimens Mix and dissolve the ingredients listed in each specimen in Table 1 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid to 2 times solution or sodium hydroxide was diluted 10 times (pH adjuster) to adjust the pH to 6.5 to obtain liquid preparations of specimens 1 to 8.
The heparin-like substance was manufactured by API Co., Ltd. (the ratio of organic sulfate groups to the total heparin-like substance was 35.2% (mass%)), and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 from Nikko Chemicals Co., Ltd., hydroxypropyl methylcellulose from Shin-Etsu Chemical Co., Ltd., hydrochloric acid and sodium hydroxide from Kanto Kagaku Co., Ltd. ) were used.
　得られた製剤を胴径３０ｍｍの透明ガラスバイアルに分注し、密栓した。透明ガラスバイアルは（株）マルエム製のマイティバイアル（透明、Ｎｏ．６）を使用した。分注した検体１～８を４０℃相対湿度７５％、５０℃、６０℃にて１箇月間保管した。
　保管前、及び保管後のサンプルについてヘパリン類似物質の組成物中の含有量を日本薬局方外医薬品成分規格２００２ヘパリン類似物質の確認試験（１）及び、デキストラン硫酸ナトリウム腸溶錠の定量法に基づいて規定した、下記方法で測定し、ヘパリン類似物質の残存率（％）を下記式に基づき算出した。 The resulting formulation was dispensed into transparent glass vials with a barrel diameter of 30 mm and sealed tightly. As a transparent glass vial, Mighty Vial (transparent, No. 6) manufactured by Maruem Co., Ltd. was used. The dispensed specimens 1 to 8 were stored at 40° C. and 75% relative humidity at 50° C. and 60° C. for one month.
For samples before and after storage, the content of heparin analogues in the composition was determined based on the Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients 2002 Heparin analogue confirmation test (1) and the determination method of dextran sodium sulfate enteric coated tablets. Measured by the following method, and the residual rate (%) of the heparinoid was calculated based on the following formula.
＜ヘパリン類似物質の残存率（％）の算出方法＞
・試料原液の調製
　残存率測定対象の試料検体をヘパリン類似物質の濃度が６×１０－３ｍｇ／ｍLとなるように水で希釈したものを試料原液とした。なお、剤形によっては、適切になるように、任意で塩を用いて試料原液を調製してもよい。
・検量線作成用標準原液の調製
　定量用ヘパリン類似物質を水で希釈し、試料原液のヘパリン類似物質の濃度を含む範囲のヘパリン類似物質濃度の検量線作成用の標準原液を調製した。なお、剤形によっては、適切になるように、任意で塩を用いて検量線作成用の標準原液を調製してもよい。
・試料溶液等の調製、および、ヘパリン類似物質の残存率（％）の測定
　試料原液、標準原液、水をそれぞれ５ｍＬを正確に量り、０．１ｍｏｌ／Ｌ　クエン酸
・　０．２ｍｏｌ／Ｌ　リン酸水素二ナトリウム（１９：１）混液で調整したトルイジンブルーＯ溶液（１→５００００）５ｍＬを正確に加えてよく振り混ぜ、試料溶液、標準溶液、ブランク溶液（ヘパリン類似物質が含まれていない溶液）を調製した。　
　試料溶液、標準溶液、及びブランク溶液のそれぞれについて、水を対照として、溶液調製後直ちに紫外可視吸光度測定法により試験を行い、波長６３０ｎｍにおける吸光度ＡＴ（試料溶液の吸光度）、吸光度ＡＳ（標準溶液の吸光度）、及び吸光度ＡＢ（ブランク溶液の吸光度）を測定した。
　ブランク溶液から得られた吸光度ＡＢから、各ヘパリン類似物質の濃度を有する標準溶液から得られた吸光度ＡＳの値を引いた値（ＡＢ－ＡＳ）を用いて検量線（回帰直線）を作成した。試料溶液から得られた吸光度ＡＴと検量線から検体中のヘパリン類似物質の配合量に対する割合（％）を算出した。
　このとき、ブランク溶液から得られた吸光度ＡＢは１．０以上を示し、検量線から得られた相関係数は－０．９９以下を示し、吸光度測定において適切な条件であることを確認し、実験を行った。
　なお、吸光度は島津製作所（株）製　分光光度計ＵＶ－２７００を用いて測定した。
・検体中のヘパリン類似物質の残存率（％）の算出方法
　ヘパリン類似物質の残存率（％）＝保存後のヘパリン類似物質配合量に対する割合（％）／初期のヘパリン類似物質配合量に対する割合（％）×１００
　なお、初期のヘパリン類似物質配合量に対する割合とは、皮膚外用組成物を調製した直後に、または、冷蔵保存した安定な状態の試料（５℃保存）を１カ月以内に測定した成分含量である。
　このような手順により、各種検体においてもヘパリン類似物質の残存率（％）の算出を行った。 <Method for calculating residual rate (%) of heparin-like substance>
・Preparation of undiluted sample solution The undiluted sample solution was obtained by diluting the sample specimen to be measured for the residual rate with water so that the concentration of the heparin analogous substance was 6×10 −3 mg/mL. Depending on the dosage form, the sample stock solution may optionally be prepared using salts as appropriate.
-Preparation of standard stock solution for creating a calibration curve A heparin analogue for quantification was diluted with water to prepare a standard stock solution for creating a calibration curve with concentrations of heparin analogues in a range including the concentration of the heparin analogue in the sample stock solution. Depending on the dosage form, salts may optionally be used to prepare a standard stock solution for preparation of the calibration curve as appropriate.
・Preparation of sample solution, etc., and measurement of residual rate (%) of heparin-like substances Accurately weigh 5 mL each of the sample undiluted solution, standard undiluted solution, and water, and add 0.1 mol/L citric acid and 0.2 mol/L phosphoric acid. Accurately add 5 mL of toluidine blue O solution (1 → 50000) prepared with disodium hydrogen (19:1) mixture and shake well. was prepared.
For each of the sample solution, standard solution, and blank solution, water was used as a control, and the test was performed immediately after solution preparation by the UV -visible absorbance measurement method. solution absorbance), and absorbance A B (blank solution absorbance) were measured.
A standard curve (regression line) is prepared using a value (A B −A S ) obtained by subtracting the absorbance A S obtained from a standard solution having the concentration of each heparin analogue from the absorbance A B obtained from the blank solution. It was created. Based on the absorbance AT obtained from the sample solution and the calibration curve, the proportion (%) of the heparin analogous substance in the specimen was calculated.
At this time, the absorbance AB obtained from the blank solution showed 1.0 or more, and the correlation coefficient obtained from the calibration curve showed -0.99 or less, confirming that the conditions were suitable for absorbance measurement. , conducted an experiment.
The absorbance was measured using a UV-2700 spectrophotometer manufactured by Shimadzu Corporation.
・Method for calculating the residual rate (%) of the heparinoid in the sample Residual rate (%) of the heparinoid = Percentage (%) of the heparinoid after storage / Percentage of the initial heparinoid ( %) × 100
The ratio to the initial heparin analogue content is the component content measured immediately after preparation of the composition for external use for skin or within one month of a stable sample (stored at 5°C) after refrigeration. .
By such a procedure, the residual rate (%) of heparin analogues was calculated for various specimens as well.
　なお、ヘパリン類似物質の残存率について、下記判定基準を設け、判定基準に基づきＢ判定以上が良好であるとして、表１および表２においては、４０℃、５０℃、および６０℃のいずれの条件でもＢ判定以上であったものを合格とした。表１５以降は、６０℃の条件でＢ判定以上であったものを合格とした。
［判定基準］ 
Ａ判定：９５％以上 
Ｂ判定：９０％以上９５％未満
Ｃ判定：８０％以上９０％未満
Ｄ判定：８０％未満 Regarding the residual rate of heparin-like substances, the following criteria are provided, and based on the criteria, B or higher is considered to be good, and in Tables 1 and 2, any condition of 40 ° C., 50 ° C., and 60 ° C. However, those with a grade of B or higher were regarded as acceptable. From Table 15 onwards, those with a grade of B or higher under the condition of 60° C. were regarded as acceptable.
[criterion]
A judgment: 95% or more
B judgment: 90% or more and less than 95% C judgment: 80% or more and less than 90% D judgment: less than 80%
（３）試験結果
　検体１～８の結果を表１に示す。 (3) Test Results Table 1 shows the results of samples 1 to 8.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
※ロキソプロフェンナトリウム1g（無水物換算）に相当する * Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表１の結果から、ヘパリン類似物質を水に溶解させた検体１、ヘパリン類似物質とポリオキシエチレン硬化ヒマシ油６０を配合した検体３、ヘパリン類似物質とポリソルベート８０を配合した検体５、ヘパリン類似物質とヒドロキシプロピルメチルセルロースを配合した検体７は、加速条件および苛酷条件にて経時的なヘパリン類似物質の含量低下が見られ、保存安定性に劣ることが明らかとなった。一方、ヘパリン類似物質とロキソプロフェンナトリウム水和物を配合した検体２、４、６、８では、いずれの保管条件でもヘパリン類似物質の含量低下が抑制され、保存安定性に優れていることが明らかとなった。 From the results in Table 1, sample 1 in which a heparin analogue was dissolved in water, sample 3 in which a heparin analogue was mixed with polyoxyethylene hydrogenated castor oil 60, sample 5 in which a heparin analogue and polysorbate 80 were mixed, and a heparin analogue and hydroxypropyl methylcellulose, the content of heparin analogues decreased over time under accelerated and severe conditions, demonstrating poor storage stability. On the other hand, samples 2, 4, 6, and 8, in which heparinoids and loxoprofen sodium hydrate were mixed, suppressed the decrease in the content of heparinoids under any storage conditions, demonstrating excellent storage stability. became.
（試験例２）ヘパリン類似物質の保存安定性の検討（２）
　試験例１の結果を受けて、ヘパリン類似物質の保存安定性をさらに向上させる成分について、検討した。
（１）試験材料及び検体の調製
　以下の表２の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、検体９～１５の液剤を得た。
　なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、無水エタノールは今津薬品工業（株）製のものを、１，３－ブチレングリコールは関東化学（株）製のものを、プロピレングリコールは丸石製薬（株）製のものを、マクロゴール４００は日油（株）製のものを、濃グリセリンは小堺製薬（株）製のものを、D‐ソルビトール液は物産フードサイエンス（株）製のものを、塩酸および水酸化ナトリウムは関東化学（株）製のものを、それぞれ使用した。 (Test Example 2) Examination of storage stability of heparinoids (2)
Based on the results of Test Example 1, a study was conducted on components that further improve the storage stability of the heparinoid.
(1) Preparation of test materials and specimens Mix and dissolve the ingredients listed in each specimen in Table 2 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid to 2 times solution or sodium hydroxide was diluted 10 times (pH adjuster) to adjust the pH to 6.5 to obtain liquid preparations of samples 9 to 15.
The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Kagaku Co., Ltd., propylene glycol from Maruishi Pharmaceutical Co., Ltd., macro Goal 400 is manufactured by NOF Corporation, concentrated glycerin is manufactured by Kosakai Pharmaceutical Co., Ltd., D-sorbitol liquid is manufactured by Bussan Food Science Co., Ltd., and hydrochloric acid and sodium hydroxide are manufactured by Kanto Kagaku. Co., Ltd. products were used respectively.
（２）試験方法
　得られた各製剤の保管およびヘパリン類似物質の組成物中の含有量の測定を試験例１と同様に行った。 (2) Test method Storage of each preparation obtained and measurement of the content of the heparin analogue in the composition were performed in the same manner as in Test Example 1.
（３）試験結果
　検体９～１５の結果を表２に示す。 (3) Test Results Table 2 shows the results of samples 9 to 15.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
※ロキソプロフェンナトリウム1g（無水物換算）に相当する * Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表２の結果から、ヘパリン類似物質とロキソプロフェンナトリウム水和物を配合した製剤にさらに無水エタノールを５％または４０％配合した検体９、１０はヘパリン類似物質の含量低下が著しく抑制され、保存安定性に非常に優れていることが明らかとなった。また、ヘパリン類似物質とロキソプロフェンナトリウム水和物を配合した製剤に、さらに１，３－ブチレングリコールを配合した検体１１、プロピレングリコールを配合した検体１２、マクロゴール４００を配合した検体１３、濃グリセリンを配合した検体１４、ソルビトールを配合した検体１５についてもヘパリン類似物質の含量低下が著しく抑制され、保存安定性に非常に優れていることが明らかとなった。 From the results in Table 2, specimens 9 and 10, in which 5% or 40% absolute ethanol was added to the formulation containing the heparin analogue and loxoprofen sodium hydrate, significantly suppressed the decrease in the content of the heparin analogue, and the storage stability was improved. It was found to be extremely superior to In addition, specimen 11 containing 1,3-butylene glycol, specimen 12 containing propylene glycol, specimen 13 containing macrogol 400, and concentrated glycerin were added to a preparation containing a heparinoid and loxoprofen sodium hydrate. Sample 14 containing sorbitol and sample 15 containing sorbitol were remarkably inhibited from lowering the content of heparin analogues, demonstrating excellent storage stability.
　以上の試験結果から、ロキソプロフェンを配合することでヘパリン類似物質の含量低下を抑制し、ヘパリン類似物質の保存安定性を向上できることが判明した。また、ロキソプロフェンに加え、さらにアルコール類を配合することでヘパリン類似物質の含量低下を抑制し、よりヘパリン類似物質の保存安定性を向上できることが判明した。 From the above test results, it was found that the addition of loxoprofen suppresses the decrease in the content of heparinoids and improves the storage stability of heparinoids. In addition, it was found that by blending alcohols in addition to loxoprofen, the decrease in the content of heparinoids can be suppressed and the storage stability of heparinoids can be further improved.
（製剤例）
　以下の表３～表１０に記載した成分を攪拌・混合して溶解後、各製剤例の皮膚外用剤を得ることができる。
　製造方法としては、上記成分及び分量を取り、日本薬局方製剤総則「外用液剤」、「ゲル剤」、「パップ剤」、「テープ剤」の項に準じて製造することができる。
　なお、例えば、液状又は半固形状の組成物を具体的な剤形として製剤化する場合においては、剤形に応じて適宜、液状又は半固形状の組成物を容器（例えば、ボトル状容器、チューブ状容器、シート状容器、スプレー剤用容器等）に収容する、液状又は半固形状の組成物を支持体に展延して成形する、噴射剤と混合したうえでエアゾール缶に収容する等、各剤形について公知の手段を適用すればよい。
　また、パップとテープの製造を行う場合にも、液状又は半固形状の組成物を支持体に展延して成形する等、公知の手段を適用すればよい。 (Formulation example)
After dissolving by stirring and mixing the components shown in Tables 3 to 10 below, the external preparation for skin of each formulation example can be obtained.
As for the manufacturing method, the above ingredients and quantities can be taken and manufactured according to the Japanese Pharmacopoeia General Rules for Preparations, "External Liquids,""Gels,""Plasters," and "Tape Preparations."
In addition, for example, when formulating a liquid or semi-solid composition as a specific dosage form, the liquid or semi-solid composition is appropriately placed in a container (e.g., bottle-shaped container, a tube-shaped container, a sheet-shaped container, a spray container, etc.), spreading a liquid or semi-solid composition on a support and molding it, mixing it with a propellant and then storing it in an aerosol can, etc. , a known means may be applied for each dosage form.
In the case of producing cataplasms and tapes, well-known means such as spreading a liquid or semi-solid composition on a support and molding it may be applied.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-I000004
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-I000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-I000006
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-I000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
　なお、表３～表５に記載された※1～※8の注釈は以下に示す内容に対応する。
※1 ロキソプロフェンナトリウム1g（無水物換算）に相当する
※2 ロキソプロフェンナトリウム2g（無水物換算）に相当する
※3 ロキソプロフェンナトリウム0.5g（無水物換算）に相当する
※4 原生薬として0.2g相当
※5 原生薬として0.1g相当
※6 ｐＨ調整剤として任意で１種類以上選択し、適量添加する
※7 カンゾウエキスは、カンゾウ乾燥エキスである
※8 原生薬として2.5g相当 The annotations *1 to *8 in Tables 3 to 5 correspond to the contents shown below.
*1 Equivalent to 1 g of loxoprofen sodium (anhydrous conversion) *2 Equivalent to 2 g of loxoprofen sodium (anhydrous conversion) *3 Equivalent to 0.5 g of loxoprofen sodium (anhydrous conversion) *4 Equivalent to 0.2 g of crude drug *5 Equivalent to 0.1 g as a crude drug *6 Select one or more types of pH adjusters and add an appropriate amount *7 Glycyrrhiza extract is a dried licorice extract *8 Equivalent to 2.5 g as a crude drug
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-I000009
Figure JPOXMLDOC01-appb-I000010
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-I000009
Figure JPOXMLDOC01-appb-I000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-I000012
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-I000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
　なお、表６～表８に記載された※1～※8の注釈は以下に示す内容に対応する。
※1 ロキソプロフェンナトリウム1g（無水物換算）に相当する
※2 ロキソプロフェンナトリウム2g（無水物換算）に相当する
※3 ロキソプロフェンナトリウム0.5g（無水物換算）に相当する
※4 原生薬として0.2g相当
※5 原生薬として0.1g相当
※6 任意で１種類以上選択し、適量添加する
※7 カンゾウエキスは、カンゾウ乾燥エキスである
※8 原生薬として2.5g相当 The annotations *1 to *8 in Tables 6 to 8 correspond to the contents shown below.
*1 Equivalent to 1 g of loxoprofen sodium (anhydrous conversion) *2 Equivalent to 2 g of loxoprofen sodium (anhydrous conversion) *3 Equivalent to 0.5 g of loxoprofen sodium (anhydrous conversion) *4 Equivalent to 0.2 g of crude drug *5 Equivalent to 0.1 g of crude drug *6 Select one or more types and add an appropriate amount *7 Glycyrrhiza extract is dried licorice extract *8 Equivalent to 2.5 g of crude drug
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-I000015
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-I000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-I000017
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-I000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
　なお、表９～表１１に記載された※1～※7の注釈は以下に示す内容に対応する。
※1 ロキソプロフェンナトリウム1g（無水物換算）に相当する
※2 ロキソプロフェンナトリウム2g（無水物換算）に相当する
※3 ロキソプロフェンナトリウム0.5g（無水物換算）に相当する
※4 原生薬として0.2g相当
※5 原生薬として0.1g相当
※6 カンゾウエキスは、カンゾウ乾燥エキスである
※7 原生薬として2.5g相当 The annotations *1 to *7 in Tables 9 to 11 correspond to the contents shown below.
*1 Equivalent to 1 g of loxoprofen sodium (anhydrous conversion) *2 Equivalent to 2 g of loxoprofen sodium (anhydrous conversion) *3 Equivalent to 0.5 g of loxoprofen sodium (anhydrous conversion) *4 Equivalent to 0.2 g of crude drug *5 Equivalent to 0.1g as an original herbal medicine *6 Glycyrrhiza extract is dried licorice extract *7 Equivalent to 2.5g as an original herbal medicine
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-I000020
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-I000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-I000022
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-I000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　なお、表１２～表１４に記載された※1～※7の注釈は以下に示す内容に対応する。
※1 ロキソプロフェンナトリウム5g（無水物換算）に相当する
※2 ロキソプロフェンナトリウム6g（無水物換算）に相当する
※3 ロキソプロフェンナトリウム8g（無水物換算）に相当する
※4原生薬として0.2g相当
※5 原生薬として0.1g相当
※6 カンゾウエキスは、カンゾウ乾燥エキスである
※7 原生薬として2.5g相当 The annotations *1 to *7 in Tables 12 to 14 correspond to the contents shown below.
*1 Equivalent to 5 g of loxoprofen sodium (anhydrous conversion) *2 Equivalent to 6 g of loxoprofen sodium (anhydrous conversion) *3 Equivalent to 8 g of loxoprofen sodium (anhydrous conversion) *4 Equivalent to 0.2 g of crude drug *5 Raw material Equivalent to 0.1g as a crude drug *6 Glycyrrhiza extract is dried licorice extract *7 Equivalent to 2.5g as an original crude drug
（試験例３）ヘパリン類似物質の保存安定性の検討（３）
　以下の表１５及び表１６の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、各検体の液剤を得たこと以外は、試験例１と同様にして、６０℃にて１箇月間保管した場合のヘパリン類似物質の保存安定性を検討した。　なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、塩酸および水酸化ナトリウムは関東化学（株）製のものをそれぞれ使用した。
結果を表１５及び表１６に示す。 (Test Example 3) Investigation of storage stability of heparinoids (3)
After mixing and dissolving the components described in each sample in Tables 15 and 16 below, purified water was added so that the total amount was 100 g, and then a solution obtained by diluting hydrochloric acid twice or sodium hydroxide was diluted 10 times. Heparin-like when stored at 60 ° C. for 1 month in the same manner as in Test Example 1, except that the pH was adjusted to 6.5 with a solution (pH adjuster) to obtain the liquid formulation of each sample. The storage stability of the substance was investigated. The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. The hydrochloric acid and sodium hydroxide used were those manufactured by Kanto Kagaku Co., Ltd., respectively.
The results are shown in Tables 15 and 16.
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
表１５及び表１６において、
※１　ロキソプロフェンナトリウム１５ｇ（無水物換算）に相当する
※２　ロキソプロフェンナトリウム８ｇ（無水物換算）に相当する
※３　ロキソプロフェンナトリウム２ｇ（無水物換算）に相当する
※４　ロキソプロフェンナトリウム１ｇ（無水物換算）に相当する In Tables 15 and 16,
*1 Equivalent to 15 g of loxoprofen sodium (anhydrous conversion) *2 Equivalent to 8 g of loxoprofen sodium (anhydrous conversion) *3 Equivalent to 2 g of loxoprofen sodium (anhydrous conversion) *4 Equivalent to 1 g of loxoprofen sodium (anhydrous conversion) Equivalent to
　表１５の結果から、ロキソプロフェンナトリウム含有量が１～１５質量％である場合において、ヘパリン類似物質の含量低下抑制効果がみられた。
　表１６の結果から、ヘパリン類似物質含有量が０．１５～９質量％である場合において、ヘパリン類似物質の含量低下の抑制効果が向上し、保存安定性に非常に優れていることが明らかとなった。 From the results in Table 15, when the content of loxoprofen sodium was 1 to 15% by mass, an effect of suppressing a decrease in the content of heparin analogues was observed.
From the results in Table 16, it is clear that when the content of the heparinoid is 0.15 to 9% by mass, the effect of suppressing the decrease in the content of the heparinoid is improved, and the storage stability is very excellent. became.
（試験例４）ヘパリン類似物質の保存安定性の検討（４）
　以下の表１７の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、各検体の液剤を得たこと以外は、試験例１と同様にして、６０℃にて１箇月間保管した場合のヘパリン類似物質の保存安定性を検討した。なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、無水エタノールは今津薬品工業（株）製のものを、イソプロパノールは小堺製薬（株）製のものを、１，３－ブチレングリコールは関東化学（株）製のものを、プロピレングリコールは丸石製薬（株）製のものを、マクロゴール４００は日油（株）製のものを、塩酸および水酸化ナトリウムは関東化学（株）製のものをそれぞれ使用した。結果を表１７に示す。 (Test Example 4) Investigation of storage stability of heparin analogues (4)
Mix and dissolve the components listed in each sample in Table 17 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid twice or sodium hydroxide solution diluted ten times (pH Adjusting agent) to adjust the pH to 6.5 to obtain a liquid formulation of each sample, in the same manner as in Test Example 1, when stored at 60 ° C. for 1 month Preservation of heparin analogues Stability was considered. The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., isopropanol from Kosakai Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Kagaku Co., Ltd., propylene glycol was manufactured by Maruishi Pharmaceutical Co., Ltd., Macrogol 400 was manufactured by NOF Corporation, and hydrochloric acid and sodium hydroxide were manufactured by Kanto Kagaku Co., Ltd., respectively. The results are shown in Table 17.
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
表１７において、
※　ロキソプロフェンナトリウム1g（無水物換算）に相当する In Table 17,
* Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表１７の結果から、低級アルコールと多価アルコールとの組み合わせによって、ヘパリン類似物質の含量低下の抑制効果が向上し、保存安定性に非常に優れていることが明らかとなった。また、無水エタノールの場合と同様に、イソプロパノールを用いることによっても、ヘパリン類似物質の含量低下の抑制効果が向上し、保存安定性に非常に優れていることが明らかとなった。 From the results in Table 17, it was clarified that the combination of a lower alcohol and a polyhydric alcohol improved the effect of suppressing the decrease in the content of heparin analogues and was extremely excellent in storage stability. In addition, as in the case of absolute ethanol, isopropanol was also found to improve the effect of suppressing the decrease in the content of heparin analogues and to be extremely excellent in storage stability.
（試験例５）ヘパリン類似物質の保存安定性の検討（５）
　以下の表１８～２１の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液でｐＨを６．５になるよう調節し、各検体の液剤を得たこと以外は、試験例１と同様にして、６０℃にて１箇月間保管した場合のヘパリン類似物質の保存安定性を検討した。なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、無水エタノールは今津薬品工業（株）製のものを、ポリオキシエチレン硬化ヒマシ油６０およびポリソルベート８０は日光ケミカルズ（株）製のものを、トコフェロール酢酸エステルは三菱ケミカルフーズ（株）製のものを、ｌ－メントールは鈴木薄荷（株）製のものを、ｄｌ－カンフルは日精バイリス（株）製のものを、チモールは富士フィルム和光純薬（株）製のものを、ハッカ油は小城製薬（株）製のものを、ユーカリ油は日本テルペン化学（株）製のものを、３－（メントキシ）－１，２-プロパンジオールおよび３－（ｌ－メントキシ）－２－メチルプロパン－１，２－ジオールは高砂香料工業（株）製のものを、トラネキサム酸は協和ファーマケミカル（株）製のものを、カンゾウ乾燥エキスはアルプス薬品工業（株）製のものを、グリチルリチン酸ジカリウムはアルプス薬品工業（株）製のものを、トウガラシチンキおよびアルニカチンキは日本粉末薬品（株）製のものを、ニコチン酸ベンジルエステルは東京化成工業（株）製のものを、クロルフェニラミンマレイン酸塩は金剛化学（株）製のものを、ノナン酸バニリルアミドは東京化成工業（株）製のものを、カプサイシンおよび塩化ナトリウムはナカライテスク（株）製のものを、ジフェンヒドラミンは東京化成工業（株）製のものを、ジフェンヒドラミン塩酸塩は金剛化学（株）製のものを、塩酸および水酸化ナトリウムは関東化学（株）製のものをそれぞれ使用した。結果を表１８～２１に示す。 (Test Example 5) Examination of storage stability of heparinoids (5)
Mix and dissolve the components listed in each sample in Tables 18 to 21 below, add purified water so that the total amount is 100 g, and then either a solution diluted with hydrochloric acid twice or a solution diluted with sodium hydroxide 10 times. In the same manner as in Test Example 1, except that the pH was adjusted to 6.5 at , and the liquid formulation of each sample was obtained. investigated. The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. Absolute ethanol is from Imazu Pharmaceutical Co., Ltd. Polyoxyethylene hydrogenated castor oil 60 and Polysorbate 80 are from Nikko Chemicals Co., Ltd. Tocopherol acetate is from Mitsubishi Chemical Foods Co., Ltd. 1-menthol is from Suzuki Minka Co., Ltd., dl-camphor is from Nissei Bailis Co., Ltd., thymol is from Fuji Film Wako Pure Chemical Co., Ltd., peppermint oil is manufactured by Ogi Pharmaceutical Co., Ltd., eucalyptus oil is manufactured by Nippon Terpene Chemical Co., Ltd., 3-(menthoxy)-1,2-propanediol and 3-(l-menthoxy)-2-methylpropane -1,2-diol is from Takasago Perfumery Co., Ltd., tranexamic acid is from Kyowa Pharma Chemical Co., Ltd., dried licorice extract is from Alps Pharmaceutical Co., Ltd., and dipotassium glycyrrhizinate. is manufactured by Alps Pharmaceutical Industry Co., Ltd., red pepper tincture and arnica tincture are manufactured by Nippon Kobayaku Co., Ltd., benzyl nicotinic acid is manufactured by Tokyo Chemical Industry Co., Ltd., chlorpheniramine maleic acid Salt is from Kongo Chemical Co., Ltd. Nonanoic acid vanillylamide is from Tokyo Chemical Industry Co., Ltd. Capsaicin and sodium chloride are from Nacalai Tesque Co., Ltd. Diphenhydramine is from Tokyo Chemical Industry Co., Ltd. diphenhydramine hydrochloride from Kongo Chemical Co., Ltd., and hydrochloric acid and sodium hydroxide from Kanto Kagaku Co., Ltd. were used. The results are shown in Tables 18-21.
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
表１８～表２１において、
※1 ロキソプロフェンナトリウム1g（無水物換算）に相当する
※2 原生薬として2.5g相当
※3 原生薬として0.04g相当 In Tables 18 to 21,
*1 Equivalent to 1 g of loxoprofen sodium (anhydrous equivalent) *2 Equivalent to 2.5 g of crude drug *3 Equivalent to 0.04 g of crude drug
　表１８～２１の結果から、ロキソプロフェンナトリウム水和物を配合し、さらにトコフェロール酢酸エステル、ｌ－メントール、dl-カンフル、チモール、ハッカ油、ユーカリ油、3-(l-メントキシ)プロパン-1,2-ジオール、 3－l－メントキシ―2－メチルプロパン―1,2－ジオール、トラネキサム酸、カンゾウ乾燥エキス（カンゾウエキス）、グリチルリチン酸ジカリウム、トウガラシチンキ、アルニカチンキ、ニコチン酸ベンジルエステル、クロルフェニラミンマレイン酸塩、ノナン酸バニリルアミド、カプサイシン、塩化ナトリウム、ジフェンヒドラミン、およびジフェンヒドラミン塩酸塩のうち少なくとも１種を配合した製剤においては、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。 From the results of Tables 18 to 21, loxoprofen sodium hydrate was blended, and further tocopherol acetate, l-menthol, dl-camphor, thymol, peppermint oil, eucalyptus oil, 3-(l-menthoxy)propane-1,2 -diol, 3-l-menthoxy-2-methylpropane-1,2-diol, tranexamic acid, dried licorice extract (licorice extract), dipotassium glycyrrhizinate, capsicum tincture, arnica tincture, benzyl nicotinate ester, chlorpheniramine malein In preparations containing at least one of acid salts, nonanoic acid vanillylamide, capsaicin, sodium chloride, diphenhydramine, and diphenhydramine hydrochloride, reduction in the content of heparin analogues is suppressed and storage stability is extremely excellent. became clear.
（試験例６）ヘパリン類似物質の保存安定性の検討（６）
　以下の表２２の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、各検体の液剤を得たこと以外は、試験例１と同様にして、６０℃にて１箇月間保管した場合のヘパリン類似物質の保存安定性を検討した。なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、ｄｌ－ピロリドンカルボン酸ナトリウム液は味の素ヘルシーサプライ（株）製のものを、塩酸は関東化学（株）製のものをそれぞれ使用した。結果を表２２に示す。 (Test Example 6) Examination of storage stability of heparinoids (6)
Mix and dissolve the components listed in each sample in Table 22 below, add purified water so that the total amount is 100 g, and then adjust the pH to 6.5 with a solution (pH adjuster) diluted hydrochloric acid twice. The storage stability of the heparinoid when stored at 60° C. for 1 month was examined in the same manner as in Test Example 1, except that a liquid preparation for each sample was obtained. The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. Sodium dl-pyrrolidonecarboxylate solution was from Ajinomoto Healthy Supply Co., Ltd., and hydrochloric acid was from Kanto Kagaku Co., Ltd. The results are shown in Table 22.
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
表２２において、
※　ロキソプロフェンナトリウム1g（無水物換算）に相当する In Table 22,
* Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表２２の結果から、ロキソプロフェンナトリウム水和物を配合し、さらにｄｌ－ピロリドンカルボン酸ナトリウム液を配合した製剤においては、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。 From the results in Table 22, it was found that the preparation containing loxoprofen sodium hydrate and the sodium dl-pyrrolidonecarboxylate solution inhibited the decrease in the content of heparin analogues and exhibited excellent storage stability. became clear.
（試験例７）ヘパリン類似物質の保存安定性の検討（７）
　以下の表２３の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液（ｐＨ調整剤）でｐＨ６．５またはｐＨ８．０になるよう調節し、各検体の液剤を得たこと以外は、試験例１と同様にして、６０℃にて１箇月間保管した場合のヘパリン類似物質の保存安定性を検討した。なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、無水エタノールは今津薬品工業（株）製のものを、１，３－ブチレングリコールは関東化学（株）製のものを、塩酸および水酸化ナトリウムは関東化学（株）製のものをそれぞれ使用した。結果を表２３に示す。 (Test Example 7) Examination of storage stability of heparinoids (7)
Mix and dissolve the components listed in each sample in Table 23 below, add purified water so that the total amount is 100 g, and then dilute hydrochloric acid twice or sodium hydroxide 10 times diluted solution (pH Heparin-like substance when stored at 60 ° C. for 1 month in the same manner as in Test Example 1, except that the pH was adjusted to 6.5 or 8.0 with an adjuster) to obtain a liquid formulation of each sample. We investigated the storage stability of The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Chemical Co., Ltd., hydrochloric acid and sodium hydroxide from Kanto Chemical Co., Ltd. were used respectively. The results are shown in Table 23.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
表２３において、
※　ロキソプロフェンナトリウム1g（無水物換算）に相当する In Table 23,
* Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表２３の結果から、ロキソプロフェンナトリウム水和物を配合したｐＨ６．５～ｐＨ８．０の製剤においては、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。
　表２３の結果から、ロキソプロフェンナトリウム水和物を配合し、さらにエタノールを配合したｐＨ６．５～ｐＨ８．０の製剤においては、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。
　表２３の結果から、ロキソプロフェンナトリウム水和物を配合し、さらに１，３－ブチレングリコールを配合したｐＨ６．５～ｐＨ８．０の製剤においては、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。 From the results in Table 23, it became clear that the preparations containing loxoprofen sodium hydrate at pH 6.5 to pH 8.0 inhibited the decrease in the content of heparin analogues and had excellent storage stability. rice field.
From the results in Table 23, in the preparations of pH 6.5 to pH 8.0 containing loxoprofen sodium hydrate and ethanol, the decrease in the content of heparin analogues was suppressed, and the storage stability was very excellent. It became clear that there was
From the results in Table 23, in the preparations of pH 6.5 to pH 8.0 containing loxoprofen sodium hydrate and further containing 1,3-butylene glycol, the decrease in the content of heparin analogues was suppressed and storage stability was improved. It was found to be extremely superior to
（試験例８）ヘパリン類似物質の保存安定性の検討（８）
　以下の表２４の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、りん酸を２倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、各検体の液剤を得た。また、以下の表２５の各検体に記載された成分を混合・溶解し、各検体のゲル剤を得たこと以外は、試験例１と同様にして、６０℃にて１箇月間保管した場合のヘパリン類似物質の保存安定性を検討した。なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、無水エタノールは今津薬品工業（株）製のものを、１，３－ブチレングリコールは関東化学（株）製のものを、ｌ－メントールは鈴木薄荷（株）製のものを、ポリオキシエチレン硬化ヒマシ油６０およびポリソルベート８０は日光ケミカルズ（株）製のものを、ヒドロキシプロピルメチルセルロースは信越化学工業（株）製のものを、マクロゴール４００は日油（株）製のものを、トリエタノールアミンは富士フィルム和光純薬（株）製のものを、カルボキシビニルポリマーは住友精化（株）製のものを、りん酸は関東化学（株）製のものをそれぞれ使用した。結果を表２４及び表２５に示す。 (Test Example 8) Investigation of storage stability of heparinoids (8)
Mix and dissolve the components listed in each sample in Table 24 below, add purified water so that the total amount is 100 g, and then adjust the pH to 6.5 with a solution (pH adjuster) in which phosphoric acid is diluted twice. A liquid preparation of each test sample was obtained. In addition, when stored at 60 ° C. for 1 month in the same manner as in Test Example 1, except that the components described in each sample in Table 25 below were mixed and dissolved to obtain a gel of each sample. We investigated the storage stability of heparin-like substances in The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Kagaku Co., Ltd., l-menthol from Suzuki Minka Co., Ltd. Polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 are manufactured by Nikko Chemicals Co., Ltd. Hydroxypropyl methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd. Macrogol 400 is manufactured by NOF Corporation. Triethanolamine available from Fujifilm Wako Pure Chemical Industries, Ltd., carboxyvinyl polymer available from Sumitomo Seika Co., Ltd., and phosphoric acid available from Kanto Kagaku Co., Ltd. were used. The results are shown in Tables 24 and 25.
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
表２４及び表２５において、
※　ロキソプロフェンナトリウム1g（無水物換算）に相当する In Tables 24 and 25,
* Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表２４の結果から、ロキソプロフェンナトリウム水和物を配合したローション剤において、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。
　表２５の結果から、ロキソプロフェンナトリウム水和物を配合したゲル剤において、ヘパリン類似物質の含量低下が抑制され、保存安定性に非常に優れていることが明らかとなった。 From the results in Table 24, it was revealed that the lotion formulated with loxoprofen sodium hydrate inhibited a decrease in the content of heparin-like substances and had excellent storage stability.
From the results in Table 25, it was clarified that the gel containing loxoprofen sodium hydrate inhibited the decrease in the content of heparin analogues and was extremely excellent in storage stability.
（試験例９）ロキソプロフェンナトリウムの保存安定性の検討
　以下の表２６の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸を２倍に希釈した溶液または水酸化ナトリウムを１０倍に希釈した溶液（ｐＨ調整剤）でｐＨ６．５またはｐＨ８．０になるよう調節し、各検体の液剤を得た。また、表２７の各検体に記載された成分を混合・溶解し、全量１００ｇとなるよう精製水を添加後、塩酸またはりん酸を２倍に希釈した溶液（ｐＨ調整剤）でｐＨを６．５になるよう調節し、各検体の液剤を得た。なお、ヘパリン類似物質はアピ（株）製のものを、ロキソプロフェンナトリウム水和物はＫＯＬＯＮ　ＬＩＦＥ　ＳＣＩＥＮＣＥ, ＩＮＣ．製のものを、無水エタノールは今津薬品工業（株）製のものを、１，３－ブチレングリコールは関東化学（株）製のものを、ｌ－メントールは鈴木薄荷（株）製のものを、ポリオキシエチレン硬化ヒマシ油６０およびポリソルベート８０は日光ケミカルズ（株）製のものを、ヒドロキシプロピルメチルセルロースは信越化学工業（株）製のものを、トコフェロール酢酸エステルは三菱ケミカルフーズ（株）製のものを、塩酸、りん酸および水酸化ナトリウムは関東化学（株）製のものをそれぞれ使用した。 (Test Example 9) Study of Storage Stability of Loxoprofen Sodium A solution obtained by mixing and dissolving the components listed in each sample in Table 26 below, adding purified water so that the total amount becomes 100 g, and then diluting hydrochloric acid by 2 times. Alternatively, the pH was adjusted to 6.5 or 8.0 with a 10-fold diluted solution (pH adjuster) of sodium hydroxide to obtain a liquid preparation of each sample. In addition, the components described in each sample in Table 27 were mixed and dissolved, and after adding purified water so that the total amount was 100 g, the pH was adjusted to 6.0 with a solution (pH adjuster) in which hydrochloric acid or phosphoric acid was diluted twice. It was adjusted to 5 to obtain a liquid formulation of each sample. The heparin-like substance was manufactured by API Co., Ltd., and the loxoprofen sodium hydrate was manufactured by KOLON LIFE SCIENCE, INC. absolute ethanol from Imazu Pharmaceutical Co., Ltd., 1,3-butylene glycol from Kanto Kagaku Co., Ltd., l-menthol from Suzuki Minka Co., Ltd. Polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 are manufactured by Nikko Chemicals Co., Ltd. Hydroxypropyl methylcellulose is manufactured by Shin-Etsu Chemical Co., Ltd. Tocopherol acetate is manufactured by Mitsubishi Chemical Foods Co., Ltd. , hydrochloric acid, phosphoric acid and sodium hydroxide manufactured by Kanto Kagaku Co., Ltd. were used.
　得られた製剤を胴径３０ｍｍの透明ガラスバイアルに分注し、密栓した。透明ガラスバイアルは（株）マルエム製のマイティバイアル（透明、Ｎｏ．６）を使用した。分注した検体を６０℃にて１箇月間保管した。
　保管前及び保管後のサンプルについて、ロキソプロフェンナトリウムの定量を液体クロマトグラフィーにより行い、ロキソプロフェンナトリウムの残存率を算出した。結果を表２６及び表２７に示す。 The resulting formulation was dispensed into transparent glass vials with a barrel diameter of 30 mm and sealed tightly. As a transparent glass vial, Mighty Vial (transparent, No. 6) manufactured by Maruem Co., Ltd. was used. The dispensed samples were stored at 60°C for one month.
The amount of loxoprofen sodium in the samples before and after storage was quantified by liquid chromatography, and the residual rate of loxoprofen sodium was calculated. The results are shown in Tables 26 and 27.
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
表２６及び表２７において、
※　ロキソプロフェンナトリウム1g（無水物換算）に相当する In Tables 26 and 27,
* Equivalent to 1g of loxoprofen sodium (converted to anhydrous)
　表２６の結果から、ｐＨ６．５～ｐＨ８．０の間でロキソプロフェンナトリウムの保存安定性が優れていることが明らかになった。
　表２７の結果から、製造した３種類の処方においてロキソプロフェンナトリウムの保存安定性が優れていることが明らかになった。 From the results in Table 26, it became clear that loxoprofen sodium has excellent storage stability between pH 6.5 and pH 8.0.
From the results in Table 27, it became clear that loxoprofen sodium has excellent storage stability in the three formulations produced.
　以上、本発明の好ましい実施形態および実施例を説明したが、本発明はこれらに限定されることはない。本発明の趣旨を逸脱しない範囲で、構成の付加、省略、置換、およびその他の変更が可能である。 Although the preferred embodiments and examples of the present invention have been described above, the present invention is not limited to these. Configuration additions, omissions, substitutions, and other changes are possible without departing from the scope of the present invention.
　本発明の、ヘパリン類似物質、および、ロキソプロフェン又はその塩を含有する皮膚外用剤は、保存安定性に優れており、極めて有用である。
  INDUSTRIAL APPLICABILITY The external preparation for skin containing a heparin analogue and loxoprofen or a salt thereof according to the present invention has excellent storage stability and is extremely useful.

Claims (16)

  1. 　ヘパリン類似物質、および、ロキソプロフェン又はその塩を含有する皮膚外用剤。 A skin external preparation containing a heparin-like substance and loxoprofen or its salt.
  2. 　皮膚外用剤における前記ヘパリン類似物質の含有量が、０．１～１０質量％である、請求項１に記載の皮膚外用剤。 The external preparation for skin according to claim 1, wherein the content of the heparinoid in the external preparation for skin is 0.1 to 10% by mass.
  3. 　皮膚外用剤における前記ロキソプロフェン又はその塩の含有量が、０．１～１５質量％である、請求項１または２に記載の皮膚外用剤。 The external skin preparation according to claim 1 or 2, wherein the content of the loxoprofen or its salt in the skin external preparation is 0.1 to 15% by mass.
  4. 　さらにアルコール類を含有する、請求項１または２に記載の皮膚外用剤。 The skin external preparation according to claim 1 or 2, further containing alcohols.
  5. 　皮膚外用剤における前記アルコール類の含有量が、０．１～７０．０質量％である、請求項４に記載の皮膚外用剤。 The external skin preparation according to claim 4, wherein the content of the alcohol in the skin external preparation is 0.1 to 70.0% by mass.
  6. 　前記アルコール類が低級アルコールである、請求項４に記載の皮膚外用剤。 The skin external preparation according to claim 4, wherein the alcohol is a lower alcohol.
  7. 　前記アルコール類が多価アルコールである、請求項４に記載の皮膚外用剤。 The skin external preparation according to claim 4, wherein the alcohol is a polyhydric alcohol.
  8. 　前記アルコール類が低級アルコールおよび多価アルコールを含む、請求項４に記載の皮膚外用剤。 The skin external preparation according to claim 4, wherein the alcohols include lower alcohols and polyhydric alcohols.
  9. 　さらに成分（Ａ）を含有し、前記成分（Ａ）が、下記成分（Ａ－１）～（Ａ－１１）よりなる群から選ばれる１種以上である、請求項１または２に記載の皮膚外用剤。
    （Ａ－１）トコフェロール類；
    （Ａ－２）テルペン類；
    （Ａ－３）グリチルリチン酸類；
    （Ａ－４）生薬類；
    （Ａ－５）トラネキサム酸類；
    （Ａ－６）バニロイド類；
    （Ａ－７）ニコチン酸類；
    （Ａ－８）クロルフェニラミン類；
    （Ａ－９）ジフェンヒドラミン類；
    （Ａ－１０）ピロリドン類；
    （Ａ－１１）無機塩；     The skin according to claim 1 or 2, further comprising component (A), wherein said component (A) is one or more selected from the group consisting of components (A-1) to (A-11) below. External agents.
    (A-1) tocopherols;
    (A-2) terpenes;
    (A-3) glycyrrhizic acids;
    (A-4) crude drugs;
    (A-5) tranexamic acids;
    (A-6) vanilloids;
    (A-7) nicotinic acids;
    (A-8) chlorpheniramines;
    (A-9) diphenhydramines;
    (A-10) pyrrolidones;
    (A-11) an inorganic salt;
  10. 　ヘパリン類似物質とロキソプロフェン又はその塩との質量比（ヘパリン類似物質／ロキソプロフェン又はその塩）が０．０１～１００である、請求項１または２に記載の皮膚外用剤。 The skin external preparation according to claim 1 or 2, wherein the mass ratio of the heparin analogue to loxoprofen or its salt (heparin analogue/loxoprofen or its salt) is 0.01 to 100.
  11. 　皮膚外用剤全量に対するロキソプロフェン又はその塩の含有量が０．６質量％以上であり、かつ、ヘパリン類似物質とロキソプロフェン又はその塩との質量比（ヘパリン類似物質／ロキソプロフェン又はその塩）が０．０１～１０である、請求項１または２に記載の皮膚外用剤。 The content of loxoprofen or its salt relative to the total amount of the external skin preparation is 0.6% by mass or more, and the mass ratio of the heparinoid to loxoprofen or its salt (heparinoid/loxoprofen or its salt) is 0.01. 3. The external preparation for skin according to claim 1 or 2, which is ∼10.
  12. 　剤形が外用液剤、軟膏剤、クリーム剤、スプレー剤、ゲル剤、貼付剤、又は外用固形剤である、請求項１または２に記載の皮膚外用剤。 The skin external preparation according to claim 1 or 2, wherein the dosage form is a liquid for external use, an ointment, a cream, a spray, a gel, a patch, or a solid for external use.
  13. 　剤形が外用液剤である、請求項１または２に記載の皮膚外用剤。 The skin external preparation according to claim 1 or 2, wherein the dosage form is an external liquid preparation.
  14. 　界面活性剤および増粘剤のうち少なくとも１つによる前記ヘパリン類似物質の含量低下を抑制可能である、請求項１または２に記載の皮膚外用剤。 The skin external preparation according to claim 1 or 2, capable of suppressing a decrease in the content of the heparin analogue by at least one of a surfactant and a thickening agent.
  15. 　ロキソプロフェン又はその塩を含有する、ヘパリン類似物質を含有する皮膚外用剤の安定化剤。 A stabilizer for external skin preparations containing heparinoids containing loxoprofen or a salt thereof.
  16. 　界面活性剤および増粘剤のうち少なくとも１つによる前記ヘパリン類似物質の含量低下を抑制可能である、請求項１５に記載の皮膚外用剤の安定化剤。
     
          16. The stabilizer for external preparation for skin according to claim 15, which is capable of suppressing a decrease in the content of the heparin-like substance due to at least one of a surfactant and a thickening agent.
PCT/JP2022/025996 2021-06-30 2022-06-29 Topical skin agent containing heparinoid and loxoprofen or salt thereof WO2023277075A1 (en)

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Publication number Priority date Publication date Assignee Title
JP2000038352A (en) * 1998-07-24 2000-02-08 Lion Corp Composition for external use
JP2012092067A (en) * 2010-10-28 2012-05-17 Kowa Co Nonsteroidal anti-inflammatory analgesic agent for external use
WO2014002599A1 (en) * 2012-06-25 2014-01-03 興和株式会社 Crude-drug-containing pharmaceutical composition
JP2017048163A (en) * 2015-09-04 2017-03-09 小林製薬株式会社 Emulsion composition
JP2017057145A (en) * 2015-09-14 2017-03-23 小林製薬株式会社 External composition
JP2017171643A (en) * 2016-03-25 2017-09-28 小林製薬株式会社 External composition
JP2021059524A (en) * 2019-10-02 2021-04-15 ロート製薬株式会社 External composition, and method of stabilizing heparin analog in external composition
JP2021138683A (en) * 2020-03-04 2021-09-16 大正製薬株式会社 Composition for external use

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000038352A (en) * 1998-07-24 2000-02-08 Lion Corp Composition for external use
JP2012092067A (en) * 2010-10-28 2012-05-17 Kowa Co Nonsteroidal anti-inflammatory analgesic agent for external use
WO2014002599A1 (en) * 2012-06-25 2014-01-03 興和株式会社 Crude-drug-containing pharmaceutical composition
JP2017048163A (en) * 2015-09-04 2017-03-09 小林製薬株式会社 Emulsion composition
JP2017057145A (en) * 2015-09-14 2017-03-23 小林製薬株式会社 External composition
JP2017171643A (en) * 2016-03-25 2017-09-28 小林製薬株式会社 External composition
JP2021059524A (en) * 2019-10-02 2021-04-15 ロート製薬株式会社 External composition, and method of stabilizing heparin analog in external composition
JP2021138683A (en) * 2020-03-04 2021-09-16 大正製薬株式会社 Composition for external use

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