JP6847656B2 - Topical composition - Google Patents
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- Publication number
- JP6847656B2 JP6847656B2 JP2016254186A JP2016254186A JP6847656B2 JP 6847656 B2 JP6847656 B2 JP 6847656B2 JP 2016254186 A JP2016254186 A JP 2016254186A JP 2016254186 A JP2016254186 A JP 2016254186A JP 6847656 B2 JP6847656 B2 JP 6847656B2
- Authority
- JP
- Japan
- Prior art keywords
- composition
- mass
- present
- loxoprofen
- external composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 claims description 14
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Images
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- 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
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- 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
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- 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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
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Description
本発明は外用組成物に関する。 The present invention relates to an external composition.
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、ロキソプロフェン及びその薬学的に許容される塩（本明細書において、これらを総称して「ロキソプロフェン類」ということがある。）は、その他のＮＳＡＩＤと同様、プロスタグランジン生合成の抑制作用に基づく解熱、鎮痛及び消炎作用を有する。 Loxoprofen, which is a propionic acid-based non-steroidal antipyretic analgesic and anti-inflammatory drug (NSAID), and pharmaceutically acceptable salts thereof (in the present specification, these may be collectively referred to as "loxoprofen") are other substances. Similar to NSAIDs, it has antipyretic, analgesic and anti-inflammatory effects based on the inhibitory effect on prostaglandin biosynthesis.
ロキソプロフェン類を、解熱、鎮痛及び／又は消炎作用の有効成分として配合した外用剤が種々開発されている（特許文献１）。また、同じくＮＳＡＩＤであるジクロフェナク類を、さらに温感成分と組み合わせて配合した外用剤も種々提案されている（特許文献２）。 Various external preparations containing loxoprofen as an active ingredient for antipyretic, analgesic and / or anti-inflammatory action have been developed (Patent Document 1). Further, various external preparations in which diclofenacs, which are also NSAIDs, are further combined with a warming component have been proposed (Patent Document 2).
例えば、特許文献１には、ジクロフェナク類に、温感成分としてカプサイシノイド等を組み合わせた外用組成物が記載されている。 For example, Patent Document 1 describes an external composition in which diclofenacs are combined with capsaicinoids and the like as a warming component.
本発明者は、ロキソプロフェン類に、温感成分としてカプサイシノイド等を組み合わせ、溶媒として炭素数１〜４のアルコール（本明細書において、これらを総称して「低級アルコール」ということがある。）を用いた外用組成物においては、経時的に褐変していくという傾向があることを見出した。本発明は、かかる経時的な褐変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 combines loxoprofen with capsaicinoid and the like as a warming component, and uses alcohol having 1 to 4 carbon atoms as a solvent (these are collectively referred to as "lower alcohol" in the present specification). It was found that the external composition had a tendency to turn brown over time. An object of the present invention is to provide an external composition in which such browning over time 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、低級アルコールを組成物全体に対して５５質量％以上含まれるよう配合することにより、経時的な褐変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 present inventor has conducted diligent studies in order to solve the above problems, and found that by blending a lower alcohol so as to contain 55% by mass or more with respect to the entire composition, browning over time is suppressed. I found it. The present invention has been completed by further studying based on such findings, and includes the following aspects.
（Ｉ）外用組成物
（I-1） ロキソプロフェン又はその薬学的に許容される塩と、カプサイシノイドと、炭素数１〜４のアルコールとを含有する組成物であって、該アルコールを、組成物全体に対して５５質量％以上含有する、外用組成物。
（I-2） 前記カプサイシノイドが、ノナン酸バニリルアミドである、（I-1）に記載の外用組成物。
（I-3） さらに、ニコチン酸のエステル誘導体を含有する、（I-1）又は（I-2）に記載の外用組成物。
（I-4） 鎮痛用途で用いられる、（I-1）〜（I-3）のいずれか一項に記載の外用組成物。
（I-5） 液剤である、（I-1）〜（I-4）のいずれか一項に記載の外用組成物。
(I) Topical composition (I-1) A composition containing loxoprofen or a pharmaceutically acceptable salt thereof, a capsaicinoid, and an alcohol having 1 to 4 carbon atoms, wherein the alcohol is used as a whole. An external composition containing 55% by mass or more based on the amount of the composition.
(I-2) The external composition according to (I-1), wherein the capsaicinoid is nonanoic acid vanillylamide.
(I-3) The external composition according to (I-1) or (I-2), which further contains an ester derivative of nicotinic acid.
(I-4) The external composition according to any one of (I-1) to (I-3), which is used for analgesic use.
(I-5) The external composition according to any one of (I-1) to (I-4), which is a liquid preparation.
（II）ロキソプロフェン類及びカプサイシノイドを含有する組成物の経時的褐変の抑制方法
（II-1） ロキソプロフェン又はその薬学的に許容される塩と、カプサイシノイドと、炭素数１〜４のアルコールとを含有する組成物の経時的褐変を抑制する方法であって、該アルコールの組成物全体に対する含有割合を５５質量％以上にする工程を含む方法。
（II-2） 前記カプサイシノイドが、ノナン酸バニリルアミドである、（II-1）に記載の方法。
（II-3） 前記組成物が、さらに、ニコチン酸のエステル誘導体を含有する、（II-1）又は（II-2）に記載の方法。
（II-4） 前記組成物が、液剤である、（II-1）〜（II-3）のいずれか一項に記載の方法。
(II) Method for suppressing browning over time of a composition containing loxoprofen and capsaicinoid (II-1) Loxoprofen or a pharmaceutically acceptable salt thereof, capsaicinoid, and an alcohol having 1 to 4 carbon atoms are contained. A method for suppressing browning of the composition over time, which comprises a step of increasing the content ratio of the alcohol to the entire composition to 55% by mass or more.
(II-2) The method according to (II-1), wherein the capsaicinoid is nonanoic acid vanillylamide.
(II-3) The method according to (II-1) or (II-2), wherein the composition further contains an ester derivative of nicotinic acid.
(II-4) The method according to any one of (II-1) to (II-3), wherein the composition is a liquid preparation.
本発明によれば、ロキソプロフェン又はその薬学的に許容される塩と、カプサイシノイドと、炭素数１〜４のアルコールとを含有する組成物であって、経時的褐変が抑制された組成物を提供できる。 According to the present invention, it is possible to provide a composition containing loxoprofen or a pharmaceutically acceptable salt thereof, a capsaicinoid, and an alcohol having 1 to 4 carbon atoms, in which browning over time 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、ロキソプロフェン又はその薬学的に許容される塩（ロキソプロフェン類）と、カプサイシノイドと、炭素数１〜４のアルコールとを含有する組成物であって、該アルコールを、組成物全体に対して５５質量％以上含有する。
1. 1. External Composition and Method for Preparing the External Composition The external composition of the present invention is a composition containing loxoprofen or a pharmaceutically acceptable salt thereof (loxoprofen), capsaicinoid, and an alcohol having 1 to 4 carbon atoms. , The alcohol is contained in an amount of 55% by mass or more based on the total composition.
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、ロキソプロフェン類を、解熱、鎮痛及び消炎作用からなる群より選択される少なくとも一種の作用の有効成分として含有する。
1.1. Loxoprofen and its pharmaceutically acceptable salts (loxoprofen)
The external composition of the present invention contains loxoprofen as an active ingredient of at least one action selected from the group consisting of antipyretic, analgesic and anti-inflammatory actions.
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 propionic acid-based nonsteroidal antipyretic analgesic and anti-inflammatory drug (NSAID) having antipyretic, analgesic and anti-inflammatory effects.
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 addition to loxoprofen itself, pharmaceutically acceptable salts thereof can also be used in the present invention. Such salts also include loxoprofen or a pharmaceutically acceptable salt thereof and a solvate of water, alcohol or the like. These are known compounds and can be produced by known methods or commercially available compounds.
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 sodium hydrate is preferable as loxoprofen or a pharmaceutically acceptable salt thereof.
ロキソプロフェン類の含有量は、効能上有効量であればよく特に制限されない。含有量は、本発明の外用組成物全体に対して、ロキソプロフェンナトリウム無水物換算で、例えば、０．１〜１０質量％、好ましくは０．５〜５質量％、さらに好ましくは０．５〜３質量％とすることができる。 The content of loxoprofen is not particularly limited as long as it is an effective amount in terms of efficacy. The content is, for example, 0.1 to 10% by mass, preferably 0.5 to 5% by mass, and more preferably 0.5 to 3 in terms of loxoprofen sodium anhydride with respect to the entire external composition of the present invention. It can be mass%.
１．２．カプサイシノイド
本発明の外用組成物は、カプサイシノイドを、温感作用の有効成分として含有する。
1.2. Capsaicinoid The external composition of the present invention contains capsaicinoid as an active ingredient of a warming effect.
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。Ｎ−アシルワニリルアミドは、血行促進剤として公知の化合物である。 As the capsaicinoid, N-acylvanylylamide can be used. N-acylvanylylamide is a compound known as a blood circulation promoter.
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-acylvanillylamide may be linear or branched. The carbon number of the acyl group in the N-acylvanillylamide is not particularly limited, and may be, for example, 5 to 15, preferably 6 to 11, or 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 the N-acylvanillylamide 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, as the capsaicinoid, a refined product may be used, or a mixture containing other components other than the capsaicinoid may be used. Specific examples of the mixture containing such capsaicinoids include capsicum extracts, capsicum tinctures, and capsicum powders.
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。カプサイシノイドの中でも、エタノールと組み合わせることで経時的褐変の抑制効果をより発揮させやすいという観点から、ノナン酸バニリルアミドが好ましい。 In the present invention, as the capsaicinoid, one kind of capsaicinoid may be used alone, or two or more kinds may be used in combination. Among the capsaicinoids, nonanoic acid vanillylamide is preferable from the viewpoint that it is easier to exert the effect of suppressing browning over time when combined with ethanol.
本発明におけるカプサイシノイドの含有量は、効能上有効量であればよく特に制限されない。含有量は、本発明の外用組成物全体に対して、例えば０．００２〜０．２質量％とすることができ、経時的褐変の抑制効果の観点で、好ましくは０．００３〜０．０５質量％、さらに好ましくは０．０１〜０．０１５質量％とすることができる。 The content of capsaicinoid in the present invention is not particularly limited as long as it is an effective amount in terms of efficacy. The content can be, for example, 0.002 to 0.2% by mass with respect to the entire external composition of the present invention, and is preferably 0.003 to 0.05 from the viewpoint of the effect of suppressing browning over time. It can be mass%, more preferably 0.01 to 0.015 mass%.
なお、カプサイノシドの割合は、外用組成物中に含まれるロキソプロフェン類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ロキソプロフェン類１質量部に対して、カプサイノシドの割合が通常０．００２〜０．２質量部の範囲になるように設定され、好ましくは０．００３〜０．０５質量部、さらに好ましくは０．０１〜０．０１５質量部である。 The ratio of capsinoside can also be set in consideration of the ratio to loxoprofen contained in the external composition. Specifically, the ratio of capsinoside to 1 part by mass of loxoprofen contained in the external composition is usually set to be in the range of 0.002 to 0.2 parts by mass, preferably 0.003 to 0.2 parts by mass. It is 0.05 parts by mass, more preferably 0.01 to 0.015 parts by mass.
１．３．ニコチン酸のエステル誘導体
本発明の外用組成物は、さらに、温感作用の有効成分として、ニコチン酸のエステル誘導体を含有することができる。本発明によれば、ニコチン酸のエステル誘導体を含有させても、さらなる褐変を生じさせることなく、優れた性状を有する外用組成物を得ることができる。
1.3. Ester derivative of nicotinic acid The external composition of the present invention can further contain an ester derivative of nicotinic acid as an active ingredient of a warming effect. According to the present invention, even if an ester derivative of nicotinic acid is contained, an external composition having excellent properties can be obtained without causing further browning.
好ましい態様においては、本発明の外用組成物は、さらにニコチン酸のエステル誘導体を含有することにより、経時的褐変の抑制効果がより高められている。 In a preferred embodiment, the external composition of the present invention further contains an ester derivative of nicotinic acid, so that the effect of suppressing browning over time is further enhanced.
ニコチン酸の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のエステル誘導体は、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。ニコチン酸の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 ester derivative of nicotinic acid 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, the nicotinic acid benzyl ester is preferable.
本発明におけるニコチン酸のエステル誘導体の含有量は、効能上有効量であればよく特に制限されない。含有量は、本発明の外用組成物全体に対して、例えば０．００２〜０．２質量％とすることができ、経時的褐変の抑制効果の観点で、好ましくは０．００３〜０．０５質量％、さらに好ましくは０．００８〜０．０１５質量％とすることができる。 The content of the ester derivative of nicotinic acid in the present invention is not particularly limited as long as it is an effective amount in terms of efficacy. The content can be, for example, 0.002 to 0.2% by mass with respect to the entire external composition of the present invention, and is preferably 0.003 to 0.05 from the viewpoint of the effect of suppressing browning over time. It can be mass%, more preferably 0.008 to 0.015 mass%.
なお、ニコチン酸のエステル誘導体の割合は、外用組成物中に含まれるロキソプロフェン類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ロキソプロフェン類１質量部に対して、ニコチン酸のエステル誘導体の割合が通常０．００２〜０．２質量部の範囲になるように設定され、好ましくは０．００３〜０．０５質量部、さらに好ましくは０．００８〜０．０１５質量部である。 The proportion of the nicotinic acid ester derivative can also be set in consideration of the proportion of loxoprofen contained in the external composition. Specifically, the ratio of the ester derivative of nicotinic acid is usually set to be in the range of 0.002 to 0.2 parts by mass with respect to 1 part by mass of loxoprofen contained in the external composition, preferably. It is 0.003 to 0.05 parts by mass, more preferably 0.008 to 0.015 parts by mass.
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、上記の有効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 with 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 active ingredients.
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 the lower alcohol include methanol, ethanol, propyl alcohol, isopropyl alcohol and the like, and ethanol is preferable.
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５５質量％以上含有する。このことにより、本発明の外用組成物は、経時的褐変が抑制されたものとなる。 The external composition of the present invention contains 55% by mass or more of a lower alcohol with respect to the entire composition. As a result, the external composition of the present invention suppresses browning over time.
本発明の外用組成物は、皮膚刺激を抑制するという観点で、低級アルコールを、組成物全体に対して、９０質量％以下含有することが好ましく、８０質量％以下含有することがより好ましい。 From the viewpoint of suppressing skin irritation, the external composition of the present invention preferably contains a lower alcohol in an amount of 90% by mass or less, more preferably 80% by mass or less, based on the entire composition.
本発明の外用組成物は、経時的褐変の抑制効果の観点で、低級アルコールを、組成物全体に対して、６０質量％以上含有することが好ましい。 The external composition of the present invention preferably contains 60% by mass or more of a lower alcohol with respect to the entire composition from the viewpoint of the effect of suppressing browning over time.
したがって、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、５５〜９０質量％含有していることにより、皮膚刺激を抑えながら、外用組成物の経時的褐変も抑制することができ、この観点で、低級アルコールを組成物全体に対して、６０〜９０質量％含有していることが好ましく、６０〜８０質量％含有していることがより好ましい。 Therefore, the external composition of the present invention contains 55 to 90% by mass of the lower alcohol with respect to the entire composition, thereby suppressing skin irritation and also suppressing browning of the external composition over time. From this viewpoint, the lower alcohol is preferably contained in an amount of 60 to 90% by mass, more preferably 60 to 80% by mass, based on the whole composition.
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、清涼化剤を配合することもできる。
1.5. Other Ingredients In addition to the above ingredients, a cooling agent may be added to the external composition of the present invention 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、ウィキョウ油、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。 Examples of such refreshing agents include l-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, menthol, menthol lactate, geraniol, eucalyptus oil, terpene oil, and bergamot oil. , Camphor oil, peppermint oil (peppermint), rose oil, cool mint and the like. These refreshing agents may be used alone or in 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 cooling agents contained in the external composition of the present invention are preferably l-menthol, d-menthol, dl-menthol, d-borneol, dl-borneol, menthol, peppermint and cool mint. More preferably, it is menthol, and 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 addition to the above-mentioned components, a medicinal aid may be added to the external composition of the present invention 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；酢酸トコフェロール等の血行促進剤；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 medicinal aids include anti-inflammatory agents and skin protectants such as glycyrrhizic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, chlorpheni maleate. Antihistamines such as lamin; blood circulation promoters such as tocopherol acetate; crude drugs such as arnica tincture, pearl oyster extract, sardine extract, sardine extract, funnel extract, veradonna extract, touki extract, shikon extract, and sansho extract can be mentioned.
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 addition to the above-mentioned ingredients, the external composition of the present invention includes additives used in ordinary external compositions such as active ingredients, pH regulators, preservatives, preservatives, antioxidants, stabilizers, etc. that can be used in combination. The agent can be appropriately 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 external composition of the present invention is not particularly limited in its form, but is preferably a liquid agent (including a lotion agent, a spray agent, an aerosol agent, and an emulsion agent).
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、カプサイノシド、または必要に応じてニコチン酸のエステル誘導体を、低級アルコールを含む、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。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 external composition of the present invention can be prepared according to a conventional method according to such a formulation form. For example, loxoprofen, capsinoside, or optionally an ester derivative of nicotinic acid, is mixed with a general purpose base used in topical formulations as described below, including lower alcohols, to dissolve or disperse the desired A method of adjusting the pH can be mentioned. The pH is not limited as long as it does not adversely affect the skin, and is usually adjusted to pH 3.5 to 8.5, preferably pH 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、カプサイノシドと、さらに必要に応じてニコチン酸のエステル誘導体とを、低級アルコール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, when the external composition of the present invention is prepared as a liquid preparation, loxoprofen, capsinoside, and, if necessary, an ester derivative of nicotinic acid are mixed with a base containing a lower alcohol as a main component. Can be prepared. The base may contain at least one selected from glycols, water and emulsifiers.
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, octane diol, ethylene glycol, polyethylene glycol, and D-sorbitol. Glycerin, propylene glycol and 1,3-butylene glycol are preferred. As the glycols, one type may be used alone, or a plurality of types may be used in combination.
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, and lauromacrogol. As the emulsifier, one type may be used alone, or a plurality of types may be used in combination.
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。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の１日あたりの塗布投与量が１００ｍｇ以下となる量であることが望ましい。 The external composition of the present invention is preferably prepared as an external preparation in a coated form, and can be locally administered externally. The dose of the external composition of the present invention depends on the degree of symptoms to be treated, but the daily application dose of loxoprofen, which is an active ingredient contained therein, is 100 mg or less. It is desirable to have.
本発明の外用組成物は、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 external composition of the present invention, as an external anti-inflammatory analgesic, includes shoulder pain associated with stiff shoulders, joint pain, lower back pain, muscle pain, tendonitis (hand / wrist pain), elbow pain (tennis elbow, etc.), bruising pain, etc. It can be suitably used for the purpose of relieving pain such as numbness pain, fracture pain, and nerve pain.
２．ロキソプロフェン類及びカプサイシノイドを含有する組成物の経時的褐変の抑制方法
本発明の方法は、ロキソプロフェン又はその薬学的に許容される塩と、カプサイシノイドと、炭素数１〜４のアルコールとを含有する組成物の経時的褐変を抑制する方法であって、該アルコールの組成物全体に対する含有割合を５５質量％以上にする工程を含む方法である。
2. Method for Suppressing Browning of Composition Containing Loxoprofen and Capsaicinoid with Time The method of the present invention is a composition containing loxoprofen or a pharmaceutically acceptable salt thereof, capsaicinoid, and an alcohol having 1 to 4 carbon atoms. This is a method for suppressing browning over time, which comprises a step of increasing the content ratio of the alcohol to the entire composition to 55% by mass or more.
ロキソプロフェン及びカプサイシノイドをはじめ、かかる組成物に配合される各成分については、前記（Ｉ）の本発明の外用組成物についての説明の通りである。 Each component to be blended in such a composition, including loxoprofen and capsaicinoid, is as described above for the external composition of the present invention in (I).
アルコールの組成物全体に対する含有割合を５５質量％以上にする工程は、特に限定されず、前記（Ｉ）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。混合の順番は特に限定されない。 The step of adjusting the content ratio of the alcohol to 55% by mass or more with respect to the entire composition is not particularly limited, and can be carried out by mixing each component as described in the above-mentioned (I) for the external composition of the present invention. it can. The order of mixing is not particularly limited.
また本発明の方法において、その効果をより高く発揮できる態様は、組成物に、ロキソプロフェン及びカプサイシノイドに加えて、さらにニコチン酸のエステル誘導体を配合する態様である。 Further, in the method of the present invention, an embodiment in which the effect can be exhibited more highly is an embodiment in which an ester derivative of nicotinic acid is further added to the composition in addition to loxoprofen and capsaicinoid.
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 with reference to examples, but the present invention is not limited to these examples and the like. In the table, the unit represents the mass (g) (that is, mass%) per 100 g of the composition.
表１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（実施例１〜６、比較例１〜４）。 As shown in Table 1, a liquid composition was prepared by weighing each component in an amount, stirring and dissolving the components (Examples 1 to 6 and Comparative Examples 1 to 4).
得られた各組成物を、スクリュー管（マルエム製、Ｎｏ．５、直径２７ｍｍ、高さ５５ｍｍ）に入れ、６０℃で１ヶ月間保管し、性状を観察した。目視にて透明なものを「◎」、褐変傾向の最も強いものを「×」とし、「×〜◎」の４段階（悪い順に「×」、「△」、「○」、「◎」）で評価した。結果を表１に示す。図１に「◎」と「×」それぞれの写真を示す。向かって左側が「◎」（実施例１）、右側が「×」（比較例３）の写真である。 Each of the obtained compositions was placed in a screw tube (manufactured by Maruem, No. 5, diameter 27 mm, height 55 mm) and stored at 60 ° C. for 1 month, and the properties were observed. Visually transparent ones are marked with "◎", those with the strongest browning tendency are marked with "x", and there are four stages of "x to ◎" (in order of worst, "x", "△", "○", "◎"). Evaluated in. The results are shown in Table 1. FIG. 1 shows photographs of “◎” and “×”, respectively. The left side is a photograph of "◎" (Example 1), and the right side is a photograph of "x" (Comparative Example 3).
表１に示す通り、エタノール２０質量％にロキソプロフェンナトリウム水和物、ノナン酸バニリルアミドのいずれか、またはその両方を配合した組成物においては、経時的に褐変傾向が見られた（比較例１〜４）。 As shown in Table 1, in the composition in which 20% by mass of ethanol was mixed with loxoprofen sodium hydrate, / or nonanoic acid vanillylamide, a browning tendency was observed over time (Comparative Examples 1 to 4). ).
一方、エタノールの量を５５質量％以上にした組成物においては、同様に保管しても褐変傾向が見られず透明性の高い性状のままであった（実施例１〜６）。 On the other hand, in the composition in which the amount of ethanol was 55% by mass or more, no browning tendency was observed even when stored in the same manner, and the properties remained highly transparent (Examples 1 to 6).
エタノール含有量が２０質量％である比較例３を基準とし、そこにさらにニコチン酸ベンジルエステルを加えたとしても依然として褐変が観察された（比較例４）。これに対して、比較例３を基準として、そのエタノール含量を５５質量％以上に変化させただけで、褐変を抑制することができた（実施例４〜６）。これらのことから、褐変抑制効果は、エタノール含量を５５質量%以上にすることにより得られるものであることが判る。 Based on Comparative Example 3 in which the ethanol content was 20% by mass, browning was still observed even when the nicotinic acid benzyl ester was further added thereto (Comparative Example 4). On the other hand, based on Comparative Example 3, browning could be suppressed only by changing the ethanol content to 55% by mass or more (Examples 4 to 6). From these facts, it can be seen that the effect of suppressing browning is obtained by increasing the ethanol content to 55% by mass or more.
ニコチン酸ベンジルエステル存在下における褐変抑制効果（実施例４〜６）は、ニコチン酸ベンジルエステル非存在下における褐変抑制効果（実施例１、２）と比べると、より顕著な傾向にあった。このように、エタノール含有量を５５％以上とすることによる褐変抑制効果は、ニコチン酸ベンジルエステル存在下において顕著に向上することが判明した。 The browning-suppressing effect in the presence of the nicotinic acid benzyl ester (Examples 4 to 6) tended to be more remarkable than the browning-suppressing effect in the absence of the nicotinic acid benzyl ester (Examples 1 and 2). As described above, it was found that the effect of suppressing browning by setting the ethanol content to 55% or more is remarkably improved in the presence of the nicotinic acid benzyl ester.
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