WO2019131648A1 - Composition for external application - Google Patents

Composition for external application Download PDF

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Publication number
WO2019131648A1
WO2019131648A1 PCT/JP2018/047604 JP2018047604W WO2019131648A1 WO 2019131648 A1 WO2019131648 A1 WO 2019131648A1 JP 2018047604 W JP2018047604 W JP 2018047604W WO 2019131648 A1 WO2019131648 A1 WO 2019131648A1
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WIPO (PCT)
Prior art keywords
composition
nicotinic acid
loxoprofen
present
external use
Prior art date
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PCT/JP2018/047604
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French (fr)
Japanese (ja)
Inventor
岡本　浩明
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小林製薬株式会社
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Publication of WO2019131648A1 publication Critical patent/WO2019131648A1/en

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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

Definitions

  • the present invention relates to a composition for external use.
  • tocopherols for example, tocopherol acetate
  • ester derivatives of nicotinic acid for example, nicotinic acid benzyl ester
  • the present inventor has found a problem that when the composition for external use contains at least tocopherols and an ester derivative of nicotinic acid as active ingredients and these are mixed with a solvent containing a lower alcohol and water, clouding occurs.
  • An object of the present invention is to provide an external composition containing tocopherols, a nicotinic acid ester derivative, an alcohol having 1 to 4 carbon atoms, and water, in which white turbidity is suppressed.
  • the inventors of the present invention have conducted intensive studies to solve the above problems, and have found that loxoprofen and / or a pharmaceutical thereof are useful in compositions containing tocopherols, nicotinic acid ester derivatives, alcohols having 1 to 4 carbon atoms, and water. It was found that the white turbidity is suppressed by containing an acceptable salt.
  • the present invention has been completed by further investigation based on such findings, and includes the following aspects.
  • composition for external use (I-1) Loxoprofen and / or its pharmaceutically acceptable salt, Tocopherols, Nicotinic acid ester derivatives, An external composition comprising an alcohol having 1 to 4 carbon atoms and water.
  • I-2) The external composition as described in (I-1), wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
  • II-3) The external composition as described in (I-1) or (I-2), wherein the tocopherols are tocopherol acetate.
  • I-5) The external composition as described in any one of (I-1) to (I-4), which is used for analgesic use.
  • I-6) The composition for external use according to any one of (I-1) to (I-5), which is a liquid agent.
  • (II-3) The method according to (II-1) or (II-2), wherein the tocopherols are tocopherol acetate.
  • (II-4) The method according to any one of (II-1) to (II-3), wherein the nicotinic acid ester derivative is nicotinic acid benzyl ester.
  • (II-5) The method according to any one of (II-1) to (II-4), wherein the composition is a solution.
  • composition for external use and preparation method thereof is Loxoprofen and / or its pharmaceutically acceptable salt, Tocopherols, Nicotinic acid ester derivatives, It contains an alcohol having 1 to 4 carbon atoms, as well as water.
  • loxoprofen Loxoprofen and its pharmaceutically acceptable salt (loxoprofen)
  • the topical composition of the present invention contains loxoprofen and / or a pharmaceutically acceptable salt thereof (herein, these may be collectively referred to as "loxoprofen").
  • Loxoprofen (2- [4- (2-oxocyclopentylmethyl) phenyl] propionic acid) is a non-steroidal non-steroidal antipyretic analgesic / antiinflammatory agent (NSAID) having antipyretic, analgesic and anti-inflammatory activity.
  • NSAID non-steroidal non-steroidal antipyretic analgesic / antiinflammatory agent
  • the composition for external use of the present invention has a suppressed white turbidity.
  • salts thereof in addition to loxoprofen itself, pharmaceutically acceptable salts thereof can also be used.
  • Such salts also include solvates of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol and the like. These are known compounds and can be produced by known methods, and commercially available ones can also be used.
  • loxoprofen or a pharmaceutically acceptable salt thereof is preferably loxoprofen sodium hydrate.
  • composition for external use of the present invention may contain one kind alone or plural kinds in combination as loxoprofen or a pharmaceutically acceptable salt thereof.
  • the content of loxoprofen can be appropriately set in consideration of the effects of the present invention and the antipyretic, analgesic and anti-inflammatory actions, and is not particularly limited.
  • the content of loxoprofen can be, for example, 0.1 to 20% by mass in terms of loxoprofen sodium anhydride in total based on the whole composition for external use of the present invention.
  • the content of loxoprofen is preferably 0.2% by mass or more, more preferably 0 mass% or more in terms of loxaprofen sodium anhydride in total amount with respect to the whole composition for external use of the present invention. 0.5 mass% or more, More preferably, it is 1 mass% or more.
  • the content of loxoprofen is preferably 15 mass in total in terms of loxoprofen sodium anhydride in total with respect to the whole composition for external use of the present invention % Or less, more preferably 10% by mass or less, still more preferably 5% by mass or less.
  • the proportion of loxoprofen can also be set in consideration of the proportion to the total of tocopherols and nicotinic acid ester derivative contained in the composition for external use.
  • the ratio of loxoprofen is usually set in the range of 0.2 to 30 parts by mass with respect to 1 part by mass in total of the tocopherols and the nicotinic acid ester derivative contained in the composition for external use.
  • the amount is preferably 0.5 to 25 parts by mass, more preferably 1 to 20 parts by mass, and still more preferably 5 to 20 parts by mass.
  • composition for external use of the present invention contains tocopherols as a blood circulation promoting component.
  • the tocopherols are not particularly limited, and can be widely used including derivatives.
  • the type of tocopherol itself may be any of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol and ⁇ -tocopherol, with ⁇ -tocopherol being preferred.
  • the derivative of tocopherol is not particularly limited as far as it is pharmaceutically acceptable, and examples thereof include esters with carboxylic acids such as acetic acid, nicotinic acid and succinic acid, and diesters with phosphoric acid.
  • esters with carboxylic acids such as acetic acid, nicotinic acid and succinic acid, and diesters with phosphoric acid.
  • diesters with phosphoric acid preferably an ester with a carboxylic acid, more preferably tocopherol acetate (tocopherol acetate) is mentioned.
  • composition for external use of the present invention may contain tocopherols singly or in combination of two or more.
  • the content of tocopherols in the present invention can be appropriately set in consideration of the effects of the present invention and the blood circulation promoting action, and is not particularly limited.
  • the content of tocopherols can be, for example, 0.01 to 0.5% by mass in total with respect to the whole composition for external use of the present invention.
  • the content of tocopherols is 0.01% by mass or more in total based on the entire composition, a sufficient blood circulation promoting effect can be obtained.
  • the content of tocopherols is preferably 0.05% by mass or more in total based on the entire composition.
  • the white turbidity is remarkably suppressed.
  • the content of tocopherols is preferably 0.3% by mass or less in total based on the entire composition.
  • composition for external use of the present invention contains a nicotinic acid ester derivative as a blood circulation promoting component.
  • the nicotinic acid ester derivative is not particularly limited as long as it is pharmaceutically acceptable, and can be widely used.
  • nicotinic acid benzyl ester, nicotinic acid ⁇ -butoxyethyl ester, nicotinic acid methyl ester and the like can be mentioned.
  • These nicotinic acid ester derivatives may be used alone or in combination of two or more.
  • nicotinic acid ester derivatives nicotinic acid benzyl ester is preferred.
  • the content of the nicotinic acid ester derivative in the present invention can be appropriately set in view of the effects of the present invention and the blood circulation promoting action, and is not particularly limited.
  • the content of the nicotinic acid ester derivative can be, for example, 0.005 to 0.1% by mass in total with respect to the whole composition for external use of the present invention.
  • the content of the nicotinic acid ester derivative is 0.005% by mass or more in total based on the whole composition, a sufficient blood circulation promoting effect can be obtained.
  • the content of the nicotinic acid ester derivative being 0.1% by mass or less in total based on the whole composition, the white turbidity is remarkably suppressed.
  • it is preferable that the content of the nicotinic acid ester derivative is 0.05% by mass or less in total based on the entire composition.
  • Alcohol having 1 to 4 carbon atoms (lower alcohol)
  • the lower alcohol is not particularly limited, and can be widely used as long as it functions as an effective base for the above components.
  • lower alcohols include methanol, ethanol, propyl alcohol and isopropyl alcohol, with ethanol being preferred.
  • the composition for external use of the present invention preferably contains 40 to 90% by mass of a lower alcohol based on the whole composition.
  • the composition for external use of the present invention contains ethanol as the lower alcohol, it is preferably 50% by mass or more, more preferably 50 to 90% by mass, still more preferably 60 to 90% by mass, and more preferably ethanol. More preferably, it contains 65 to 80% by mass.
  • the composition for external use of the present invention contains isopropanol as the lower alcohol, the content of isopropanol is preferably 40% by mass or more, more preferably 40 to 90% by mass, still more preferably 50 to 90% by mass, still more preferably 50 to 80% by mass is included.
  • composition for external use of the present invention other blood circulation promoting components can be blended in addition to the above components as long as the effects of the present invention are not impaired.
  • another blood circulation promoting component for example, capsaicinoid and the like can be mentioned.
  • N-acylanililamide can be used as capsaicinoid.
  • the acyl group in the N-acylanilylamide may be linear or branched. Further, the carbon number of the acyl group in the N-acylanilylamide is not particularly limited, and may be, for example, 5 to 15, preferably 6 to 11, and the like.
  • N-acylanilylamide examples include nonanoic acid vanillylamide, and capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin.
  • the capsaicinoid may be a purified product, but a mixture containing other components besides capsaicinoid may be used.
  • a mixture containing capsaicinoid include capsicum extracts such as capsicum extract (capsicum extract), capsicum tincture and capsicum powder.
  • the pepper extract is not particularly limited and can be widely used.
  • the red pepper extract a single type of red pepper extract may be used, or a plurality of red pepper extracts may be used in combination.
  • an alcoholic extract of chili pepper can be used as a chili pepper extract.
  • an alcohol extract of red pepper for example, an ethanol extract of red pepper can be used.
  • capsaicinoids one capsaicinoid may be used alone, or two or more may be used in combination.
  • pepper extract and / or nonanoic acid vanillylamide is preferable from the viewpoint that the effect of suppressing white turbidity in the composition is more easily obtained.
  • a refreshing agent in the composition for external use of the present invention, can be blended in addition to the above components as long as the effects of the present invention are not impaired.
  • These cooling agents may be used alone or in any combination of two or more.
  • the refreshing agent contained in the composition for external use of the present invention is preferably l-menthol, d-menthol, dl-menthol, d-borneol, dl-borneol, mentan, peppermint oil (peppermint) and coolmint, More preferably, it is menthol, particularly preferably l-menthol.
  • a drug efficacy aid may be blended as long as the effects of the present invention are not impaired.
  • Such drug adjuvants include anti-inflammatory agents and skin protecting agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, chlorphene maleate And antihistamines such as lamin; and herbal medicines such as arnica tincture, oat extract, Sanshish extract, horseradish extract, rhodox extract, veradonna extract, sweet potato extract, sikon extract, sansho extract and the like.
  • skin protecting agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and pharmaceutically acceptable
  • additives used in common external composition for external use such as active ingredients, pH adjusters, preservatives, preservatives, antioxidants, stabilizers etc. which can be used in combination
  • An agent can be suitably blended.
  • composition for external use of the present invention is not particularly limited in its form, but is preferably a liquid (including lotion, spray, aerosol and emulsion).
  • composition for external use of the present invention can be prepared according to a conventional method, depending on such a formulation form.
  • loxoprofenes, tocopherols, nicotinic acid ester derivatives and, if necessary, other components are mixed and dissolved with a general-purpose base used for external preparation as described below, including lower alcohols and water.
  • a general-purpose base used for external preparation including lower alcohols and water.
  • it may be dispersed and adjusted to a desired pH.
  • the pH is not limited as long as it has no adverse effect on the skin, and is usually adjusted to 3.5 to 8.5, preferably 4 to 8, and more preferably 4 to 7.5.
  • loxoprofen, tocopherols, nicotinic acid ester derivative and, if necessary, other components are mainly composed of lower alcohol and water. It can be prepared by mixing with a base.
  • the base may contain at least one selected from glycols, water and an emulsifier.
  • the glycols are not particularly limited, and examples thereof include glycerin, propylene glycol, 1,3-butylene glycol, octanediol, ethylene glycol, polyethylene glycol, D-sorbitol and the like. Glycerin, propylene glycol and 1,3-butylene glycol are preferred.
  • the glycols may be used alone or in combination of two or more.
  • the emulsifier is not particularly limited, and examples thereof include nonionic surfactants such as sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyl stearate, lauromacrogol and the like.
  • An emulsifier may be used individually by 1 type, and may be used in combination of multiple types.
  • composition for external use of the present invention is preferably prepared as an external preparation in a form of application, and can be topically administered topically.
  • the dose of the composition for external use of the present invention depends on the degree of the condition to be treated, but the total daily application of the active ingredients loxoprofen, tocopherols and nicotinic acid ester derivative contained therein It is desirable that the dose be 100 mg or less.
  • the composition for external use of the present invention is preferably a pharmaceutical composition.
  • the composition for external use which is the pharmaceutical composition of the present invention, is an external anti-inflammatory and analgesic agent, such as shoulder pain associated with stiff neck, arthralgia, back pain, myalgia, tendonitis (hand and wrist pain), elbow pain (tennis elbow, etc.)
  • the present invention can be suitably used for analgesia for pains such as bruising, bruises, fractures and neuralgia.
  • the method of the present invention comprises tocopherols, nicotinic acid ester derivative, alcohol having 1 to 4 carbon atoms, and water
  • a method of suppressing white turbidity in a composition containing Including loxoprofen and / or a pharmaceutically acceptable salt thereof in the composition is a method of suppressing white turbidity in a composition containing Including loxoprofen and / or a pharmaceutically acceptable salt thereof in the composition.
  • the external composition of the present invention is as described above.
  • the process of including loxoprofen in the composition is not particularly limited, and the above-mentioned 1.
  • it can be carried out by mixing the respective components.
  • the order of mixing of the components is not particularly limited.
  • the composition serving as a starting material is preferably loxoprofen in an amount of less than 0.5% by mass, preferably less than 0.3% by mass, in terms of sodium loxoprofen.
  • it comprises less than 0.1% by weight, more preferably less than 0.05% by weight, even more preferably less than 0.01% by weight, and most preferably less than 0.001% by weight.
  • the unit represents the mass (g) (i.e. mass%) per 100 g of the composition.
  • Example 4 when ethanol is contained as the lower alcohol, the result is "almost absent" (slightly clouded) as in Example 3, but the cloudiness is clearly reduced compared to Comparative Example 2. From the results of Example 4, it was found that the white turbidity suppressing effect was enhanced depending on the content of loxoprofen sodium hydrate.

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Abstract

[Problem] To provide a composition which contains a tocopherol compound, a nicotinic acid ester derivative, an alcohol having 1-4 carbon atoms and water, and which is suppressed in white turbidity. [Solution] A composition for external application, which contains loxoprofen and/or a pharmaceutically acceptable salt thereof, a tocopherol compound, a nicotinic acid ester derivative, an alcohol having 1-4 carbon atoms, and water.

Description

外用組成物Composition for external use
　本発明は外用組成物に関する。 The present invention relates to a composition for external use.
　従来、肩こり等に適用される外用組成物においては、トコフェロール類（例えば、トコフェロール酢酸エステル）及びニコチン酸のエステル誘導体（例えば、ニコチン酸ベンジルエステル）等が血行促進成分として使用されている。 In the past, tocopherols (for example, tocopherol acetate) and ester derivatives of nicotinic acid (for example, nicotinic acid benzyl ester) and the like have been used as blood circulation promoting components in compositions for external use applied to shoulder stiffness and the like.
特開２０１１－０７４０３２号公報JP, 2011-074032, A
　本発明者は、外用組成物において、トコフェロール類とニコチン酸のエステル誘導体とを有効成分として少なくとも配合し、これらを低級アルコールと水とを含む溶媒と混合すると、白濁が生じるという課題を見出した。本発明は、トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する外用組成物であって、白濁が抑制された外用組成物を提供することを課題とする。 The present inventor has found a problem that when the composition for external use contains at least tocopherols and an ester derivative of nicotinic acid as active ingredients and these are mixed with a solvent containing a lower alcohol and water, clouding occurs. An object of the present invention is to provide an external composition containing tocopherols, a nicotinic acid ester derivative, an alcohol having 1 to 4 carbon atoms, and water, in which white turbidity is suppressed.
　本発明者は、上記課題を解決すべく、鋭意検討を行ったところ、トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する組成物において、ロキソプロフェン及び／又はその薬学的に許容される塩を含有させることにより、白濁が抑制されることを見出した。本発明はかかる知見に基づいてさらに検討を加えることにより完成したものであり、以下の態様を含む。 The inventors of the present invention have conducted intensive studies to solve the above problems, and have found that loxoprofen and / or a pharmaceutical thereof are useful in compositions containing tocopherols, nicotinic acid ester derivatives, alcohols having 1 to 4 carbon atoms, and water. It was found that the white turbidity is suppressed by containing an acceptable salt. The present invention has been completed by further investigation based on such findings, and includes the following aspects.
　（Ｉ）外用組成物
（I-1）
　ロキソプロフェン及び／又はその薬学的に許容される塩、
　トコフェロール類、
　ニコチン酸エステル誘導体、
　炭素数１～４のアルコール、並びに
　水
を含有する、外用組成物。
（I-2）
　前記ロキソプロフェンの薬学的に許容される塩が、ロキソプロフェンナトリウム水和物である、（I-1）に記載の外用組成物。
（I-3）
　前記トコフェロール類が、酢酸トコフェロールである、（I-1）又は（I-2）に記載の外用組成物。
（I-4）
　前記ニコチン酸エステル誘導体が、ニコチン酸ベンジルエステルである、（I-1）～（I-3）のいずれか一項に記載の外用組成物。
（I-5）
　鎮痛用途で用いられる、（I-1）～（I-4）のいずれか一項に記載の外用組成物。
（I-6）　液剤である、（I-1）～（I-5）のいずれか一項に記載の外用組成物。 (I) Composition for external use (I-1)
Loxoprofen and / or its pharmaceutically acceptable salt,
Tocopherols,
Nicotinic acid ester derivatives,
An external composition comprising an alcohol having 1 to 4 carbon atoms and water.
(I-2)
The external composition as described in (I-1), wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
(I-3)
The external composition as described in (I-1) or (I-2), wherein the tocopherols are tocopherol acetate.
(I-4)
The external composition according to any one of (I-1) to (I-3), wherein the nicotinic acid ester derivative is nicotinic acid benzyl ester.
(I-5)
The external composition as described in any one of (I-1) to (I-4), which is used for analgesic use.
(I-6) The composition for external use according to any one of (I-1) to (I-5), which is a liquid agent.
　（II）トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する組成物における白濁の抑制方法
（II-1）
　トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する組成物における白濁を抑制する方法であって、
　ロキソプロフェン及び／又はその薬学的に許容される塩を該組成物に含ませる工程を含む方法。
（II-2）
　前記ロキソプロフェンの薬学的に許容される塩が、ロキソプロフェンナトリウム水和物である、（II-1）に記載の方法。
（II-3）
　前記トコフェロール類が、酢酸トコフェロールである、（II-1）又は（II-2）に記載の方法。
（II-4）
　前記ニコチン酸エステル誘導体が、ニコチン酸ベンジルエステルである、（II-1）～（II-3）のいずれか一項に記載の方法。
（II-5）
　前記組成物が、液剤である、（II-1）～（II-4）のいずれか一項に記載の方法。 (II) Method for suppressing white turbidity in a composition containing tocopherols, nicotinic acid ester derivative, alcohol having 1 to 4 carbon atoms and water (II-1)
A method for suppressing white turbidity in a composition containing tocopherols, nicotinic acid ester derivative, alcohol having 1 to 4 carbon atoms, and water,
Including loxoprofen and / or a pharmaceutically acceptable salt thereof in the composition.
(II-2)
The method according to (II-1), wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
(II-3)
The method according to (II-1) or (II-2), wherein the tocopherols are tocopherol acetate.
(II-4)
The method according to any one of (II-1) to (II-3), wherein the nicotinic acid ester derivative is nicotinic acid benzyl ester.
(II-5)
The method according to any one of (II-1) to (II-4), wherein the composition is a solution.
　本発明によれば、トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する外用組成物であって、白濁が抑制された外用組成物を提供できる。 According to the present invention, it is possible to provide an external composition containing tocopherols, a nicotinic acid ester derivative, an alcohol having 1 to 4 carbon atoms, and water, in which white turbidity is suppressed.
１．外用組成物及びその調製方法
　本発明の外用組成物は、
　ロキソプロフェン及び／又はその薬学的に許容される塩、
　トコフェロール類、
　ニコチン酸エステル誘導体、
　炭素数１～４のアルコール、並びに
　水
を含有する。 1. Composition for external use and preparation method thereof The composition for external use of the present invention is
Loxoprofen and / or its pharmaceutically acceptable salt,
Tocopherols,
Nicotinic acid ester derivatives,
It contains an alcohol having 1 to 4 carbon atoms, as well as water.
１．１．ロキソプロフェン及びその薬学的に許容される塩（ロキソプロフェン類）
　本発明の外用組成物は、ロキソプロフェン及び／又はその薬学的に許容される塩（本明細書において、これらを「ロキソプロフェン類」と総称することがある）を含有する。 1.1. Loxoprofen and its pharmaceutically acceptable salt (loxoprofen)
The topical composition of the present invention contains loxoprofen and / or a pharmaceutically acceptable salt thereof (herein, these may be collectively referred to as "loxoprofen").
　ロキソプロフェン（２－［４－（２－オキソシクロペンチルメチル）フェニル］プロピオン酸）は、解熱、鎮痛及び消炎作用を有するプロピオン酸系非ステロイド性解熱鎮痛消炎剤（ＮＳＡＩＤ）である。 Loxoprofen (2- [4- (2-oxocyclopentylmethyl) phenyl] propionic acid) is a non-steroidal non-steroidal antipyretic analgesic / antiinflammatory agent (NSAID) having antipyretic, analgesic and anti-inflammatory activity.
　ロキソプロフェン類を含有していることにより、本発明の外用組成物は、白濁が抑制されたものとなる。 By containing the loxoprofen, the composition for external use of the present invention has a suppressed white turbidity.
　本発明ではロキソプロフェンそのものの他、その薬学的に許容される塩も使用することができる。かかる塩には、ロキソプロフェン又はその薬学上許容される塩と、水又はアルコール等との溶媒和物も含まれる。これらは公知の化合物であり、公知の方法により製造できるほか、市販のものを用いることもできる。 In the present invention, in addition to loxoprofen itself, pharmaceutically acceptable salts thereof can also be used. Such salts also include solvates of loxoprofen or a pharmaceutically acceptable salt thereof with water, alcohol and the like. These are known compounds and can be produced by known methods, and commercially available ones can also be used.
　本発明において、ロキソプロフェン又はその薬学的に許容される塩としては、ロキソプロフェンナトリウム水和物が好ましい。 In the present invention, loxoprofen or a pharmaceutically acceptable salt thereof is preferably loxoprofen sodium hydrate.
　本発明の外用組成物は、ロキソプロフェン又はその薬学的に許容される塩としては、１種を単独で含んでいてもよいし、複数種を組み合わせて含んでいてもよい。 The composition for external use of the present invention may contain one kind alone or plural kinds in combination as loxoprofen or a pharmaceutically acceptable salt thereof.
　ロキソプロフェン類の含有量は、本発明の効果と、解熱、鎮痛及び消炎作用とを考慮して適宜設定することができ、特に制限されない。ロキソプロフェン類の含有量は、本発明の外用組成物全体に対して総量で、ロキソプロフェンナトリウム無水物換算で、例えば、０．１～２０質量％とすることができる。白濁の抑制効果の観点では、ロキソプロフェン類の含有量は、本発明の外用組成物全体に対して総量で、ロキソプロフェンナトリウム無水物換算で、好ましくは０．２質量％以上であり、より好ましくは０．５質量％以上であり、さらに好ましくは１質量％以上である。また、十分な解熱、鎮痛及び消炎作用が得られる最小量という観点では、ロキソプロフェン類の含有量は、本発明の外用組成物全体に対して総量で、ロキソプロフェンナトリウム無水物換算で、好ましくは１５質量％以下、より好ましくは１０質量％以下、さらに好ましくは５質量％以下である。 The content of loxoprofen can be appropriately set in consideration of the effects of the present invention and the antipyretic, analgesic and anti-inflammatory actions, and is not particularly limited. The content of loxoprofen can be, for example, 0.1 to 20% by mass in terms of loxoprofen sodium anhydride in total based on the whole composition for external use of the present invention. From the viewpoint of the effect of suppressing white turbidity, the content of loxoprofen is preferably 0.2% by mass or more, more preferably 0 mass% or more in terms of loxaprofen sodium anhydride in total amount with respect to the whole composition for external use of the present invention. 0.5 mass% or more, More preferably, it is 1 mass% or more. In addition, in view of the minimum amount of sufficient antipyretic, analgesic and anti-inflammatory activity, the content of loxoprofen is preferably 15 mass in total in terms of loxoprofen sodium anhydride in total with respect to the whole composition for external use of the present invention % Or less, more preferably 10% by mass or less, still more preferably 5% by mass or less.
　なお、ロキソプロフェン類の割合は、外用組成物中に含まれるトコフェロール類とニコチン酸エステル誘導体との合計に対する割合を考慮して設定することもできる。具体的には、外用組成物中に含まれるトコフェロール類とニコチン酸エステル誘導体との合計１質量部に対して、ロキソプロフェン類の割合が通常０．２～３０質量部の範囲になるように設定され、好ましくは０．５～２５質量部、さらに好ましくは１～２０質量部、さらにより好ましくは５～２０質量部である。 The proportion of loxoprofen can also be set in consideration of the proportion to the total of tocopherols and nicotinic acid ester derivative contained in the composition for external use. Specifically, the ratio of loxoprofen is usually set in the range of 0.2 to 30 parts by mass with respect to 1 part by mass in total of the tocopherols and the nicotinic acid ester derivative contained in the composition for external use. The amount is preferably 0.5 to 25 parts by mass, more preferably 1 to 20 parts by mass, and still more preferably 5 to 20 parts by mass.
１．２．トコフェロール類
　本発明の外用組成物は、血行促進成分としてトコフェロール類を含有する。 1.2. Tocopherols The composition for external use of the present invention contains tocopherols as a blood circulation promoting component.
　トコフェロール類としては、特に限定されず、誘導体を含めて幅広く使用できる。トコフェロール自体の種類としては、α－トコフェロール、β－トコフェロール、γ－トコフェロール及び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。 The tocopherols are not particularly limited, and can be widely used including derivatives. The type of tocopherol itself may be any of α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol, with α-tocopherol being preferred.
　トコフェロールの誘導体としては、薬学的に許容されることを限度として特に制限されないが、例えば、酢酸、ニコチン酸、コハク酸等のカルボン酸とのエステル体、リン酸とのジエステル体等が挙げられる。これらのトコフェロールの誘導体の中でも、好ましくはカルボン酸とのエステル体、更に好ましくは酢酸トコフェロール（トコフェロール酢酸エステル）が挙げられる。 The derivative of tocopherol is not particularly limited as far as it is pharmaceutically acceptable, and examples thereof include esters with carboxylic acids such as acetic acid, nicotinic acid and succinic acid, and diesters with phosphoric acid. Among these derivatives of tocopherol, preferably an ester with a carboxylic acid, more preferably tocopherol acetate (tocopherol acetate) is mentioned.
　本発明の外用組成物は、トコフェロール類を１種単独で含んでいてもよいし、複数種を組み合わせて含んでいてもよい。 The composition for external use of the present invention may contain tocopherols singly or in combination of two or more.
　本発明におけるトコフェロール類の含有量は、本発明の効果と血行促進作用とを考慮して適宜設定することができ、特に制限されない。トコフェロール類の含有量は、本発明の外用組成物全体に対して総量で、例えば０．０１～０．５質量％とすることができる。トコフェロール類の含有量が組成物全体に対して総量で０．０１質量％以上であることにより十分な血行促進効果が得られる。この観点では、トコフェロール類の含有量が組成物全体に対して総量で０．０５質量％以上であることが好ましい。また、トコフェロール類の含有量が組成物全体に対して総量で０．５質量％以下であることにより、白濁が顕著に抑制される。この観点では、トコフェロール類の含有量が組成物全体に対して総量で０．３質量％以下であることが好ましい。 The content of tocopherols in the present invention can be appropriately set in consideration of the effects of the present invention and the blood circulation promoting action, and is not particularly limited. The content of tocopherols can be, for example, 0.01 to 0.5% by mass in total with respect to the whole composition for external use of the present invention. When the content of tocopherols is 0.01% by mass or more in total based on the entire composition, a sufficient blood circulation promoting effect can be obtained. In this respect, the content of tocopherols is preferably 0.05% by mass or more in total based on the entire composition. In addition, when the content of tocopherols is 0.5% by mass or less in total based on the entire composition, the white turbidity is remarkably suppressed. In this respect, the content of tocopherols is preferably 0.3% by mass or less in total based on the entire composition.
１．３．ニコチン酸エステル誘導体
　本発明の外用組成物は、血行促進成分としてニコチン酸エステル誘導体を含有する。 1.3. Nicotinic Acid Ester Derivative The composition for external use of the present invention contains a nicotinic acid ester derivative as a blood circulation promoting component.
　ニコチン酸エステル誘導体としては、薬学的に許容されることを限度として特に制限されず、幅広く使用できる。例えば、ニコチン酸ベンジルエステル、ニコチン酸β－ブトキシエチルエステル及びニコチン酸メチルエステル等が挙げられる。これらのニコチン酸エステル誘導体は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。ニコチン酸エステル誘導体の中でも、ニコチン酸ベンジルエステルが好ましい。 The nicotinic acid ester derivative is not particularly limited as long as it is pharmaceutically acceptable, and can be widely used. For example, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid methyl ester and the like can be mentioned. These nicotinic acid ester derivatives may be used alone or in combination of two or more. Among the nicotinic acid ester derivatives, nicotinic acid benzyl ester is preferred.
　本発明におけるニコチン酸エステル誘導体の含有量は、本発明の効果と血行促進作用の点で適宜設定することができ、特に制限されない。ニコチン酸エステル誘導体の含有量は、本発明の外用組成物全体に対して総量で、例えば０．００５～０．１質量％とすることができる。ニコチン酸エステル誘導体の含有量が組成物全体に対して総量で０．００５質量％以上であることにより、十分な血行促進効果が得られる。ニコチン酸エステル誘導体の含有量が組成物全体に対して総量で０．１質量％以下であることにより、白濁が顕著に抑制される。この観点では、ニコチン酸エステル誘導体の含有量が組成物全体に対して総量で０．０５質量％以下であれば好ましい。 The content of the nicotinic acid ester derivative in the present invention can be appropriately set in view of the effects of the present invention and the blood circulation promoting action, and is not particularly limited. The content of the nicotinic acid ester derivative can be, for example, 0.005 to 0.1% by mass in total with respect to the whole composition for external use of the present invention. When the content of the nicotinic acid ester derivative is 0.005% by mass or more in total based on the whole composition, a sufficient blood circulation promoting effect can be obtained. By the content of the nicotinic acid ester derivative being 0.1% by mass or less in total based on the whole composition, the white turbidity is remarkably suppressed. In this respect, it is preferable that the content of the nicotinic acid ester derivative is 0.05% by mass or less in total based on the entire composition.
１．４．炭素数１～４のアルコール（低級アルコール）
　低級アルコールは、特に限定されず、上記の成分に対して有効な基剤として機能するものであれば幅広く使用できる。 1.4. Alcohol having 1 to 4 carbon atoms (lower alcohol)
The lower alcohol is not particularly limited, and can be widely used as long as it functions as an effective base for the above components.
　低級アルコールとしては、具体的には、例えば、メタノール、エタノール、プロピルアルコール及びイソプロピルアルコール等を挙げることができ、エタノールが好ましい。 Specific examples of lower alcohols include methanol, ethanol, propyl alcohol and isopropyl alcohol, with ethanol being preferred.
　本発明の外用組成物は、低級アルコールを、組成物全体に対して、好ましくは４０～９０質量％含有する。具体的には、本発明の外用組成物は、低級アルコールとしてエタノールを含む場合、エタノールを、好ましくは５０質量％以上、より好ましくは５０～９０質量％、さらに好ましくは６０～９０質量％、さらにより好ましくは６５～８０質量％含む。また、本発明の外用組成物は、低級アルコールとしてイソプロパノールを含む場合、イソプロパノールを、好ましくは４０質量％以上、より好ましくは４０～９０質量％、さらに好ましくは５０～９０質量％、さらにより好ましくは５０～８０質量％含む。 The composition for external use of the present invention preferably contains 40 to 90% by mass of a lower alcohol based on the whole composition. Specifically, when the composition for external use of the present invention contains ethanol as the lower alcohol, it is preferably 50% by mass or more, more preferably 50 to 90% by mass, still more preferably 60 to 90% by mass, and more preferably ethanol. More preferably, it contains 65 to 80% by mass. In addition, when the composition for external use of the present invention contains isopropanol as the lower alcohol, the content of isopropanol is preferably 40% by mass or more, more preferably 40 to 90% by mass, still more preferably 50 to 90% by mass, still more preferably 50 to 80% by mass is included.
１．５．その他の成分
　本発明の外用組成物には、本発明の効果を妨げない限り、上記成分の他に、別の血行促進成分を配合することもできる。
　別の血行促進成分としては、例えば、カプサイシノイド等が挙げられる。 1.5. Other Components In the composition for external use of the present invention, other blood circulation promoting components can be blended in addition to the above components as long as the effects of the present invention are not impaired.
As another blood circulation promoting component, for example, capsaicinoid and the like can be mentioned.
　カプサイシノイドとしては、Ｎ－アシルワニリルアミドを使用できる。 As capsaicinoid, N-acylanililamide can be used.
　Ｎ－アシルワニリルアミドにおけるアシル基は、直鎖状又は分岐状のいずれであってもよい。また、Ｎ－アシルワニリルアミドにおけるアシル基の炭素数については、特に制限されず、例えば５～１５、好ましくは６～１１等とすることができる。 The acyl group in the N-acylanilylamide may be linear or branched. Further, the carbon number of the acyl group in the N-acylanilylamide is not particularly limited, and may be, for example, 5 to 15, preferably 6 to 11, and the like.
　Ｎ－アシルワニリルアミドとして、具体的には、ノナン酸バニリルアミド並びに；カプサイシン、ジヒドロカプサイシン、ノルジヒドロカプサイシン、ホモカプサイシン及びホモジヒドロカプサイシン等のカプサイシン類等が挙げられる。 Specific examples of N-acylanilylamide include nonanoic acid vanillylamide, and capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin.
　本発明において、カプサイシノイドは、精製品を使用してもよいが、カプサイシノイド以外に他の成分が含まれている混合物を使用してもよい。このようなカプサイシノイドを含む混合物としては、具体的には、トウガラシ抽出物（トウガラシエキス）、トウガラシチンキ及びトウガラシ末等のトウガラシ類が挙げられる。 In the present invention, the capsaicinoid may be a purified product, but a mixture containing other components besides capsaicinoid may be used. Specific examples of such a mixture containing capsaicinoid include capsicum extracts such as capsicum extract (capsicum extract), capsicum tincture and capsicum powder.
　トウガラシ抽出物としては、特に限定されず、幅広く使用できる。トウガラシ抽出物として、単独種のトウガラシ抽出物を使用してもよいし、複数種のトウガラシ抽出物を組み合わせて使用してもよい。例えば、トウガラシ抽出物として、トウガラシのアルコール抽出物を使用できる。トウガラシのアルコール抽出物としては、例えば、トウガラシのエタノール抽出物を使用できる。 The pepper extract is not particularly limited and can be widely used. As the red pepper extract, a single type of red pepper extract may be used, or a plurality of red pepper extracts may be used in combination. For example, as a chili pepper extract, an alcoholic extract of chili pepper can be used. As an alcohol extract of red pepper, for example, an ethanol extract of red pepper can be used.
　本発明において、カプサイシノイドとしては、１種のカプサイシノイドを単独で使用してもよく、また、２種以上を組み合わせて使用してもよい。 In the present invention, as capsaicinoids, one capsaicinoid may be used alone, or two or more may be used in combination.
　カプサイシノイドの中でも、組成物における白濁の抑制効果がより得られやすいという観点から、トウガラシ抽出物及び／又はノナン酸バニリルアミドが好ましい。 Among the capsaicinoids, pepper extract and / or nonanoic acid vanillylamide is preferable from the viewpoint that the effect of suppressing white turbidity in the composition is more easily obtained.
　本発明の外用組成物には、本発明の効果を妨げない限り、上記成分の他に、清涼化剤を配合することもできる。 In the composition for external use of the present invention, a refreshing agent can be blended in addition to the above components as long as the effects of the present invention are not impaired.
　かかる清涼化剤としては、ｌ－メントール、ｄ－メントール、ｄｌ－メントール、ｄ－カンフル、ｄｌ－カンフル、ｄ－ボルネオール、ｄｌ－ボルネオール、メンタン、乳酸メンチル、ゲラニオール、ユーカリ油、テルペン油、ベルガモット油、ウイキョウ油、ハッカ油（ペパーミント）、ローズ油及びクールミント等が挙げられる。これらの清涼化剤は、１種単独で使用しても、また２種以上を任意に組み合わせて使用してもよい。 As such a refreshing agent, l-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, mentan, menthyl lactate, geraniol, eucalyptus oil, terpene oil, bergamot oil , Fennel oil, peppermint oil (peppermint), rose oil and coolmint. These cooling agents may be used alone or in any combination of two or more.
　本発明の外用組成物に含まれる清涼化剤は、好ましくは、ｌ－メントール、ｄ－メントール、ｄｌ－メントール、ｄ－ボルネオール、ｄｌ－ボルネオール、メンタン、ハッカ油（ペパーミント）及びクールミントであり、より好ましくはメントールであり、特に好ましくはｌ－メントールである。 The refreshing agent contained in the composition for external use of the present invention is preferably l-menthol, d-menthol, dl-menthol, d-borneol, dl-borneol, mentan, peppermint oil (peppermint) and coolmint, More preferably, it is menthol, particularly preferably l-menthol.
　本発明の外用組成物には、本発明の効果を妨げない限り、上記成分の他に、薬効補助剤を配合することもできる。 In the composition for external use of the present invention, other than the above-mentioned components, a drug efficacy aid may be blended as long as the effects of the present invention are not impaired.
　かかる薬効補助剤としては、グリチルレチン酸、グリチルリチン酸二カリウム、グリチルリチン酸アンモニウム、グリチルリチン酸ステアリル等の抗炎症剤や皮膚保護剤；ジフェニルイミダゾール、ジフェンヒドラミン及びその薬学的に許容される塩、マレイン酸クロルフェニラミン等の抗ヒスタミン剤；アルニカチンキ、オウバクエキス、サンシシエキス、セイヨウトチノキエキス、ロートエキス、ベラドンナエキス、トウキエキス、シコンエキス、サンショウエキス等の生薬等が挙げられる。 Such drug adjuvants include anti-inflammatory agents and skin protecting agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, chlorphene maleate And antihistamines such as lamin; and herbal medicines such as arnica tincture, oat extract, Sanshish extract, horseradish extract, rhodox extract, veradonna extract, sweet potato extract, sikon extract, sansho extract and the like.
　本発明の外用組成物には、上記の成分の他、併用可能な活性成分、ｐＨ調節剤、防腐剤、保存剤、酸化防止剤、安定化剤等の通常の外用組成物に使用される添加剤を適宜配合することができる。 In the composition for external use of the present invention, in addition to the above-mentioned components, additives used in common external composition for external use such as active ingredients, pH adjusters, preservatives, preservatives, antioxidants, stabilizers etc. which can be used in combination An agent can be suitably blended.
１．６．形態および製造方法
　本発明の外用組成物は、その形態を特に制限するものではないが、好ましくは液剤（ローション剤、スプレー剤、エアゾール剤、及び乳液剤を含む）である。 1.6. Form and Production Method The composition for external use of the present invention is not particularly limited in its form, but is preferably a liquid (including lotion, spray, aerosol and emulsion).
本発明の外用組成物は、かかる製剤形態に応じて、定法に従って調製することができる。例えば、ロキソプロフェン類、トコフェロール類、ニコチン酸エステル誘導体、並びに必要に応じてその他の成分を、低級アルコール及び水を含む、下記に説明するような外用製剤に用いられる汎用の基剤と混合して溶解又は分散させ、所望のｐＨに調整する方法を挙げることができる。 The composition for external use of the present invention can be prepared according to a conventional method, depending on such a formulation form. For example, loxoprofenes, tocopherols, nicotinic acid ester derivatives and, if necessary, other components, are mixed and dissolved with a general-purpose base used for external preparation as described below, including lower alcohols and water. Alternatively, it may be dispersed and adjusted to a desired pH.
　なお、ｐＨとしては皮膚に悪影響のない範囲であれば制限されず、通常ｐＨ３．５～８．５、好ましくはｐＨ４～８、より好ましくは４～７．５になるように調整される。 The pH is not limited as long as it has no adverse effect on the skin, and is usually adjusted to 3.5 to 8.5, preferably 4 to 8, and more preferably 4 to 7.5.
　例えば、本発明の外用組成物を液剤として調製する場合は、ロキソプロフェン類と、トコフェロール類と、ニコチン酸エステル誘導体と、さらに必要に応じてその他の成分とを、低級アルコール及び水を主成分とする基剤と混合することにより調製できる。基剤には、グリコール類、水及び乳化剤から選択される少なくとも一種を配合することができる。 For example, in the case of preparing the composition for external use of the present invention as a liquid preparation, loxoprofen, tocopherols, nicotinic acid ester derivative and, if necessary, other components are mainly composed of lower alcohol and water. It can be prepared by mixing with a base. The base may contain at least one selected from glycols, water and an emulsifier.
　グリコール類としては、特に限定されず、例えば、グリセリン、プロピレングリコール、１，３－ブチレングリコール、オクタンジオール、エチレングリコール、ポリエチレングリコール、Ｄ－ソルビトール等が挙げられる。グリセリン、プロピレングリコール及び１，３－ブチレングリコールが好ましい。グリコール類は、一種を単独で使用してもよいし、複数種を組み合わせて使用してもよい。 The glycols are not particularly limited, and examples thereof include glycerin, propylene glycol, 1,3-butylene glycol, octanediol, ethylene glycol, polyethylene glycol, D-sorbitol and the like. Glycerin, propylene glycol and 1,3-butylene glycol are preferred. The glycols may be used alone or in combination of two or more.
　乳化剤としては、特に限定されず、例えば、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ステアリン酸ポリオキシル、ラウロマクロゴール等の非イオン性界面活性剤等が挙げられる。乳化剤は、一種を単独で使用してもよいし、複数種を組み合わせて使用してもよい。 The emulsifier is not particularly limited, and examples thereof include nonionic surfactants such as sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyl stearate, lauromacrogol and the like. An emulsifier may be used individually by 1 type, and may be used in combination of multiple types.
　本発明の外用組成物は、好ましくは塗布形態の外用剤として調製され、局所的に外用投与することができる。 The composition for external use of the present invention is preferably prepared as an external preparation in a form of application, and can be topically administered topically.
　本発明の外用組成物の投与量は、治療すべき症状の程度により左右されるが、中に含まれている有効成分であるロキソプロフェン類、トコフェロール類及びニコチン酸エステル誘導体の１日あたりの合計塗布投与量が１００ｍｇ以下となる量であることが望ましい。 The dose of the composition for external use of the present invention depends on the degree of the condition to be treated, but the total daily application of the active ingredients loxoprofen, tocopherols and nicotinic acid ester derivative contained therein It is desirable that the dose be 100 mg or less.
　本発明の外用組成物は、好ましくは医薬組成物である。本発明の医薬組成物である外用組成物は、外用消炎鎮痛剤として、肩こりに伴う肩の痛み、関節痛、腰痛、筋肉痛、腱鞘炎（手・手首の痛み）、肘の痛み（テニス肘等）、打撲痛、ねんざ痛、骨折痛、神経痛等の痛みに対して、鎮痛を目的とする好適に使用することができる。 The composition for external use of the present invention is preferably a pharmaceutical composition. The composition for external use, which is the pharmaceutical composition of the present invention, is an external anti-inflammatory and analgesic agent, such as shoulder pain associated with stiff neck, arthralgia, back pain, myalgia, tendonitis (hand and wrist pain), elbow pain (tennis elbow, etc.) The present invention can be suitably used for analgesia for pains such as bruising, bruises, fractures and neuralgia.
２．トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する組成物における白濁の抑制方法
　本発明の方法は、トコフェロール類、ニコチン酸エステル誘導体、炭素数１～４のアルコール及び水を含有する組成物における白濁を抑制する方法であって、
　ロキソプロフェン及び／又はその薬学的に許容される塩を該組成物に含ませる工程
を含む方法である。 2. Method for suppressing white turbidity in a composition containing tocopherols, nicotinic acid ester derivative, alcohol having 1 to 4 carbon atoms, The method of the present invention comprises tocopherols, nicotinic acid ester derivative, alcohol having 1 to 4 carbon atoms, and water A method of suppressing white turbidity in a composition containing
Including loxoprofen and / or a pharmaceutically acceptable salt thereof in the composition.
　トコフェロール類、ニコチン酸エステル誘導体及びロキソプロフェン類をはじめ、かかる組成物に配合される各成分については、前記１．の本発明の外用組成物についての説明の通りである。 With regard to each component to be incorporated in such a composition, including tocopherols, nicotinic acid ester derivatives and loxoprofen, the above-mentioned 1 .. The external composition of the present invention is as described above.
　ロキソプロフェン類を組成物に含ませる工程は、特に限定されず、前記１．の本発明の外用組成物についての説明の通り、各成分を混合することによって行うことができる。成分の混合の順番は特に限定されない。 The process of including loxoprofen in the composition is not particularly limited, and the above-mentioned 1. As described for the composition for external use of the present invention, it can be carried out by mixing the respective components. The order of mixing of the components is not particularly limited.
　ロキソプロフェン類を組成物に含ませる工程において、出発原料となる組成物は、好ましくは、ロキソプロフェン類を、ロキソプロフェンナトリウム無水物換算で、０．５質量％未満、好ましくは０．３質量％未満、より好ましくは０．１質量％未満、さらに好ましくは０．０５質量％未満、さらにより好ましくは０．０１質量％未満、最も好ましくは０．００１質量％未満含む。 In the step of including loxoprofen in the composition, the composition serving as a starting material is preferably loxoprofen in an amount of less than 0.5% by mass, preferably less than 0.3% by mass, in terms of sodium loxoprofen. Preferably it comprises less than 0.1% by weight, more preferably less than 0.05% by weight, even more preferably less than 0.01% by weight, and most preferably less than 0.001% by weight.
　以下、実施例を挙げて本発明を説明するが、本発明はこれらの実施例等に限定されるものではない。なお、表中において単位は組成物１００ｇ当たりの質量（ｇ）（すなわち質量％）を表わす。 Hereinafter, the present invention will be described by way of examples, but the present invention is not limited to these examples and the like. In the table, the unit represents the mass (g) (i.e. mass%) per 100 g of the composition.
　表１（単位は質量％）に記載する通り、各成分を各分量、量り取り、攪拌して溶解させることにより液状組成物を調製した（比較例１及び２、実施例１～４）。 As described in Table 1 (unit:% by mass), each component was weighed, weighed, dissolved and stirred to prepare liquid compositions (Comparative Examples 1 and 2, Examples 1 to 4).
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　得られた各組成物を、ガラス瓶（Ｍ－２２５、柏洋硝子株式会社製）に入れて、白濁の有無を観察した。白濁について、「あり」「ほぼなし」及び「なし」の３段階でそれぞれ評価を行った。 Each composition obtained was placed in a glass bottle (M-225, manufactured by Sanyo Glass Co., Ltd.), and the presence or absence of white turbidity was observed. The white turbidity was evaluated in three stages of "yes", "almost none" and "none".
　表１に示す通り、酢酸トコフェロール及びニコチン酸ベンジルエステルを、イソプロパノール（比較例１）又はエタノール（比較例２）と水とを混合した溶媒に溶解すると白濁するが、そこにロキソプロフェンナトリウム水和物をさらに溶解させると白濁が消失した（実施例１～４）。低級アルコールとしてイソプロパノールを含有する場合、ロキソプロフェンナトリウム水和物を溶解させることで白濁が完全に抑制されることが確認できた（実施例１、２）。また、低級アルコールとして、エタノールを含有する場合には、実施例３のように「ほぼなし」（わずかに白濁あり）との結果であったが、比較例２に比べて白濁が明らかに減少しており、実施例４の結果から、ロキソプロフェンナトリウム水和物の含有量に依存して白濁抑制効果が増強することが分かった。 As shown in Table 1, when tocopherol acetate and nicotinic acid benzyl ester are dissolved in a solvent in which isopropanol (comparative example 1) or ethanol (comparative example 2) and water are mixed, it becomes cloudy, but there is loxoprofen sodium hydrate there Further dissolution made the white turbidity disappear (Examples 1 to 4). When isopropanol was contained as the lower alcohol, it was confirmed that white turbidity was completely suppressed by dissolving loxoprofen sodium hydrate (Examples 1 and 2). In addition, when ethanol is contained as the lower alcohol, the result is "almost absent" (slightly clouded) as in Example 3, but the cloudiness is clearly reduced compared to Comparative Example 2. From the results of Example 4, it was found that the white turbidity suppressing effect was enhanced depending on the content of loxoprofen sodium hydrate.

Claims (6)

  1. 　ロキソプロフェン及び／又はその薬学的に許容される塩、
    　トコフェロール類、
    　ニコチン酸エステル誘導体、
    　炭素数１～４のアルコール、並びに
    　水
    を含有する、外用組成物。     Loxoprofen and / or its pharmaceutically acceptable salt,
    Tocopherols,
    Nicotinic acid ester derivatives,
    An external composition comprising an alcohol having 1 to 4 carbon atoms and water.
  2. 　前記ロキソプロフェンの薬学的に許容される塩が、ロキソプロフェンナトリウム水和物である、請求項１に記載の外用組成物。 The composition for external use according to claim 1, wherein the pharmaceutically acceptable salt of loxoprofen is loxoprofen sodium hydrate.
  3. 　前記トコフェロール類が、酢酸トコフェロールである、請求項１又は２に記載の外用組成物。 The composition for external use according to claim 1 or 2, wherein the tocopherols are tocopherol acetate.
  4. 　前記ニコチン酸エステル誘導体が、ニコチン酸ベンジルエステルである、請求項１～３のいずれか一項に記載の外用組成物。 The composition for external use according to any one of claims 1 to 3, wherein the nicotinic acid ester derivative is nicotinic acid benzyl ester.
  5. 　鎮痛用途で用いられる、請求項１～４のいずれか一項に記載の外用組成物。 The composition for external use according to any one of claims 1 to 4, which is used for analgesic use.
  6. 　液剤である、請求項１～５のいずれか一項に記載の外用組成物。 The composition for external use according to any one of claims 1 to 5, which is a liquid agent.
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WO2014163030A1 (en) * 2013-04-01 2014-10-09 第一三共株式会社 Preparation for treating equine inflammation
JP2016193850A (en) * 2015-03-31 2016-11-17 小林製薬株式会社 External pharmaceutical composition
WO2017111167A1 (en) * 2015-12-25 2017-06-29 興和株式会社 Pharmaceutical preparation containing loxoprofen

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Publication number Priority date Publication date Assignee Title
JP2011074032A (en) * 2009-09-30 2011-04-14 Kobayashi Pharmaceutical Co Ltd Pharmaceutical composition for external use
WO2014163030A1 (en) * 2013-04-01 2014-10-09 第一三共株式会社 Preparation for treating equine inflammation
JP2016193850A (en) * 2015-03-31 2016-11-17 小林製薬株式会社 External pharmaceutical composition
WO2017111167A1 (en) * 2015-12-25 2017-06-29 興和株式会社 Pharmaceutical preparation containing loxoprofen

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