JP2019206496A - External pharmaceutical composition - Google Patents
External pharmaceutical composition Download PDFInfo
- Publication number
- JP2019206496A JP2019206496A JP2018103075A JP2018103075A JP2019206496A JP 2019206496 A JP2019206496 A JP 2019206496A JP 2018103075 A JP2018103075 A JP 2018103075A JP 2018103075 A JP2018103075 A JP 2018103075A JP 2019206496 A JP2019206496 A JP 2019206496A
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- loxoprofen
- salt
- external pharmaceutical
- external
- 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.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 70
- 229960002373 loxoprofen Drugs 0.000 claims abstract description 61
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 230000035699 permeability Effects 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000007788 liquid Substances 0.000 claims abstract description 22
- 239000003921 oil Substances 0.000 claims abstract description 18
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims abstract description 16
- DGSZGZSCHSQXFV-UHFFFAOYSA-N 2,3-bis(2-ethylhexanoyloxy)propyl 2-ethylhexanoate Chemical compound CCCCC(CC)C(=O)OCC(OC(=O)C(CC)CCCC)COC(=O)C(CC)CCCC DGSZGZSCHSQXFV-UHFFFAOYSA-N 0.000 claims abstract description 7
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 claims abstract description 6
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims abstract description 6
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- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims abstract 5
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- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 59
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Landscapes
- Medicinal Preparation (AREA)
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Abstract
Description
本発明は、ロキソプロフェン及び／又はその塩の経皮浸透性が向上された外用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for external use with improved transdermal permeability of loxoprofen and / or a salt thereof.
ロキソプロフェンナトリウムに代表されるロキソプロフェン類（ロキソプロフェン及び／又はその塩）は、優れた鎮痛・消炎作用を有する薬剤として知られており、外用医薬組成物としても使用されている。ロキソプロフェン類を水系基剤中に含む外用医薬組成物は、水系基剤からの放出性が低いために経皮浸透性に問題がある。このような問題を解決するための方法として、特許文献１には、基剤成分としてゴム系エラストマーを含ませる技術が記載されている。 Loxoprofen typified by loxoprofen sodium (loxoprofen and / or a salt thereof) is known as a drug having an excellent analgesic / anti-inflammatory action, and is also used as an external pharmaceutical composition. An external pharmaceutical composition containing loxoprofen in an aqueous base has a problem in percutaneous permeability because of its low release from the aqueous base. As a method for solving such a problem, Patent Document 1 describes a technique of including a rubber-based elastomer as a base component.
しかしながら、特許文献１に記載の技術は、実質的に水を含まない構成を必須とするものであり、その製剤形態は、支持体、軟膏層及び剥離ライナーからなる貼付剤に特化しているために、液剤やゲル剤等の塗布用の製剤形態には対応することができない。液剤やゲル剤等の塗布用の製剤形態とするには水系基剤が不可避であり、そうすると、ロキソプロフェン類の放出性は低下することとなる。つまり、ロキソプロフェン類を含む外用医薬組成物において、水系基剤を含むことと、ロキソプロフェン類の経皮浸透性を向上させることとは依然として両立しない課題があった。 However, the technique described in Patent Document 1 requires a structure that does not substantially contain water, and the preparation form is specialized for a patch comprising a support, an ointment layer, and a release liner. Furthermore, it cannot respond to the formulation form for application, such as a liquid agent or a gel agent. An aqueous base is unavoidable in order to obtain a preparation form for application such as a liquid or a gel, and the release of loxoprofen will be reduced. That is, in an external pharmaceutical composition containing loxoprofen, there is still a problem that the inclusion of an aqueous base and the improvement of transdermal permeability of loxoprofen are still incompatible.
そこで本発明は、水を含みながらも、ロキソプロフェン及び／又はその塩の経皮浸透性に優れた外用医薬組成物を提供することを目的とする。 Accordingly, an object of the present invention is to provide an external pharmaceutical composition excellent in transdermal permeability of loxoprofen and / or a salt thereof while containing water.
本発明者は鋭意検討の結果、ロキソプロフェン及び／又はその塩を水中に含む外用医薬組成物において、液状油を共存させることによって、ロキソプロフェン及び／又はその塩の経皮浸透性が向上することを見出した。本発明は、この知見に基づいてさらに検討を重ねることにより完成したものである。 As a result of intensive studies, the present inventor has found that percutaneous permeability of loxoprofen and / or a salt thereof is improved by coexisting a liquid oil in an external pharmaceutical composition containing loxoprofen and / or a salt thereof in water. It was. The present invention has been completed by further studies based on this finding.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． （Ａ）ロキソプロフェン及び／又はその塩、（Ｂ）トコフェロール酢酸エステル、（Ｃ）液状油、及び（Ｄ）水を含む、外用医薬組成物。
項２． 前記（Ｃ）成分がエステル油である、項１に記載の外用医薬組成物。
項３． 前記（Ｃ）成分が、ミリスチン酸イソプロピル、トリエチルヘキサノイン、アジピン酸ジイソプロピルからなる群より選択される、項１又は２に記載の外用医薬組成物。
項４． 一価低級アルコールをさらに含む、項１〜３のいずれか一項に記載の外用医薬組成物。
項５． 前記（Ｃ）成分が、０．１〜２０重量％含まれる、項１〜４のいずれかに記載の外用組成物。
項６． 前記（Ｃ）成分が、前記（Ａ）成分１重量部当たり０．１〜２０重量部含まれる、項１〜５のいずれかに記載の外用組成物。
項７． 外用医薬組成物中で、（Ａ）ロキソプロフェン及び／又はその塩と、（Ｂ）トコフェロール酢酸エステルと、（Ｄ）水とともに、（Ｃ）液状油を共存させる、外用医薬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の経皮浸透性を向上する方法。
That is, this invention provides the invention of the aspect hung up below.
Item 1. An external pharmaceutical composition comprising (A) loxoprofen and / or a salt thereof, (B) tocopherol acetate, (C) liquid oil, and (D) water.
Item 2. Item 2. The external pharmaceutical composition according to Item 1, wherein the component (C) is an ester oil.
Item 3. Item 3. The external pharmaceutical composition according to Item 1 or 2, wherein the component (C) is selected from the group consisting of isopropyl myristate, triethylhexanoin, and diisopropyl adipate.
Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, further comprising a monovalent lower alcohol.
Item 5. Item 5. The external composition according to any one of Items 1 to 4, wherein the component (C) is contained in an amount of 0.1 to 20% by weight.
Item 6. Item 6. The external composition according to any one of Items 1 to 5, wherein the component (C) is contained in an amount of 0.1 to 20 parts by weight per part by weight of the component (A).
Item 7. In an external pharmaceutical composition, (A) loxoprofen and / or a salt thereof, (B) tocopherol acetate, (D) water, and (C) a liquid oil coexist in the external pharmaceutical composition. A method for improving the transdermal permeability of the pharmaceutically acceptable salt.
本発明によれば、水を含みながらも、ロキソプロフェン及び／又はその塩の経皮浸透性に優れた外用医薬組成物が提供される。 ADVANTAGE OF THE INVENTION According to this invention, the external pharmaceutical composition excellent in the percutaneous permeability of a loxoprofen and / or its salt is provided, including water.
１．外用医薬組成物
本発明の外用医薬組成物は、（Ａ）ロキソプロフェン及び／又はその塩（以下、「（Ａ）成分」と表記することもある）、（Ｂ）トコフェロール酢酸エステル（以下、「（Ｂ）成分」と表記することもある）、（Ｃ）液状油（以下、「（Ｃ）成分」と表記することもある）、及び（Ｄ）水（以下、「（Ｄ）成分」と表記することもある）を含有することを特徴とする。以下、本発明の外用医薬組成物について詳述する。
1. Pharmaceutical composition for external use The pharmaceutical composition for external use of the present invention comprises (A) loxoprofen and / or a salt thereof (hereinafter sometimes referred to as “component (A)”), (B) tocopherol acetate (hereinafter referred to as “( B) component ”), (C) liquid oil (hereinafter also referred to as“ (C) component ”), and (D) water (hereinafter referred to as“ (D) component ”). In some cases). Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.
（Ａ）ロキソプロフェン及び／又はその塩
本発明の外用医薬組成物は、（Ａ）成分としてロキソプロフェン及び／又はその塩を含有する。ロキソプロフェン及び／又はその塩は、非ステロイド性消炎鎮痛剤（ＮＳＡＩＤ）の一種として公知の成分である。ロキソプロフェンは、２−［パラ−（２−オキソシクロペンチルメチル）フェニル］プロピオン酸である。ロキソプロフェンの塩としては、ロキソプロフェンの薬学上許容される塩であれば特に制限されず、例えばナトリウム塩、カリウム塩等のアルカリ金属塩、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、ロキソプロフェンの塩は、水和物であってもよい。
(A) Loxoprofen and / or salt thereof The external pharmaceutical composition of the present invention contains loxoprofen and / or a salt thereof as the component (A). Loxoprofen and / or a salt thereof is a known component as a kind of non-steroidal anti-inflammatory analgesic (NSAID). Loxoprofen is 2- [para- (2-oxocyclopentylmethyl) phenyl] propionic acid. The loxoprofen salt is not particularly limited as long as it is a pharmaceutically acceptable salt of loxoprofen, and examples thereof include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. The loxoprofen salt may be a hydrate.
本発明の外用医薬組成物において、（Ａ）成分として、ロキソプロフェン及び／又はその塩の中から１種を選択して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。（Ａ）成分の中でも、好ましくはロキソプロフェンの塩、より好ましくはロキソプロフェンナトリウム、さらに好ましくはロキソプロフェンナトリウム水和物が挙げられる。 In the pharmaceutical composition for external use of the present invention, as component (A), one may be selected from loxoprofen and / or a salt thereof and used alone, or two or more may be used in combination. . Among the components (A), a salt of loxoprofen is preferable, more preferably loxoprofen sodium, and still more preferably loxoprofen sodium hydrate.
本発明の外用医薬組成物における（Ａ）成分の含有量は、外用医薬組成物に備えさせるべき薬効等に応じて適宜設定すればよいが、例えば０．１〜１０重量％、好ましくは０．５〜３重量％が挙げられる。また、水系基剤中にロキソプロフェン及び／又はその塩を含む外用医薬組成物は本来ロキソプロフェン及び／又はその塩の経皮浸透性が低いが、本発明の外用医薬組成物ではロキソプロフェン及び／又はその塩の経皮浸透性が向上しているため、外用医薬組成物中のロキソプロフェン及び／又はその塩の含有量が従来と同様の量であっても、また、比較的低含有量であっても、効果的にロキソプロフェン及び／又はその塩を経皮浸透させることができる。 The content of the component (A) in the external pharmaceutical composition of the present invention may be appropriately set according to the drug efficacy to be provided in the external pharmaceutical composition, for example, 0.1 to 10% by weight, preferably 0. 5 to 3 weight% is mentioned. Further, an external pharmaceutical composition containing loxoprofen and / or a salt thereof in an aqueous base inherently has low percutaneous permeability of loxoprofen and / or a salt thereof. However, in the external pharmaceutical composition of the present invention, loxoprofen and / or a salt thereof is used. Therefore, even if the content of loxoprofen and / or a salt thereof in the external pharmaceutical composition is the same amount as before, or a relatively low content, Loxoprofen and / or a salt thereof can be effectively permeated through the skin.
（Ｂ）トコフェロール酢酸エステル
本発明の外用医薬組成物は、（Ｂ）成分としてトコフェロール酢酸エステルを含有する。トコフェロール酢酸エステルは、血行促進成分として公知の成分であり、具体的には酢酸ｄ−α−トコフェロール、酢酸ｌ−α−トコフェロール、酢酸ｄｌ−α−トコフェロールが挙げられる。
(B) Tocopherol acetate The external pharmaceutical composition of the present invention contains tocopherol acetate as the component (B). Tocopherol acetate is a known component as a blood circulation promoting component, and specifically includes d-α-tocopherol acetate, l-α-tocopherol acetate, and dl-α-tocopherol acetate.
本発明の外用医薬組成物における（Ｂ）成分の含有量は、外用医薬組成物に備えさせるべき薬効等に応じて適宜設定すればよいが、例えば０．０１〜１重量％、好ましくは０．０３〜０．５重量％、更に好ましくは０．０５〜０．３重量％が挙げられる。 The content of the component (B) in the external pharmaceutical composition of the present invention may be appropriately set according to the drug efficacy to be provided in the external pharmaceutical composition, for example, 0.01 to 1% by weight, preferably 0. 03-0.5 weight%, More preferably, 0.05-0.3 weight% is mentioned.
（Ｃ）液状油
本発明の外用医薬組成物は、（Ｃ）成分として液状油を含有する。水系基剤中にロキソプロフェン及び／又はその塩を含む外用医薬組成物は本来ロキソプロフェン及び／又はその塩の経皮浸透性が低いが、本発明の外用医薬組成物では（Ｃ）成分を共存させることによって、ロキソプロフェン及び／又はその塩の経皮浸透性を向上させることができる。
(C) Liquid oil The external pharmaceutical composition of this invention contains liquid oil as (C) component. An external pharmaceutical composition containing loxoprofen and / or a salt thereof in an aqueous base inherently has low percutaneous permeability of loxoprofen and / or a salt thereof, but the external pharmaceutical composition of the present invention must contain component (C). Can improve the transdermal permeability of loxoprofen and / or a salt thereof.
液状油とは、２５℃において液状の形態を保つ油である。本発明で使用される液状油としては、化粧料や外用医薬品等に通常用いられるものであればよく、例えば、アボガド油、ツバキ油、マカデミアナッツ油、オリーブ油、ホホバ油等の植物油；オレイン酸、ステアリン酸等の脂肪酸；エチルヘキサン酸セチル、パルミチン酸エチルヘキシル、ミリスチン酸オクチルドデシル、ジエチルヘキサン酸ネオペンチルグリコール、トリエチルヘキサノイン（トリ２−エチルへキサン酸グリセリル）、アジピン酸ジイソプロピル、オレイン酸オクチルドデシル、ミリスチン酸イソプロピル、トリイソステアリン酸グリセリル、ジパラメトキシケイヒ酸−モノエチルへキサン酸グリセリル等のエステル油；ジメチルポリシロキサン、メチルハイドロジエンポリシロキサン、メチルフェニルポリシロキサン、オクタメチルシクロテトラシロキサン等のシリコン油；流動パラフィン、スクワレン、スクワラン等の液状炭化水素油等が挙げられる。 Liquid oil is oil that maintains a liquid form at 25 ° C. The liquid oil used in the present invention is not particularly limited as long as it is usually used in cosmetics, external medicines and the like. For example, vegetable oils such as avocado oil, camellia oil, macadamia nut oil, olive oil, jojoba oil; oleic acid, stearin Fatty acids such as acids; cetyl ethylhexanoate, ethylhexyl palmitate, octyldodecyl myristate, neopentyl glycol diethylhexanoate, triethylhexanoin (glyceryl tri-2-ethylhexanoate), diisopropyl adipate, octyldodecyl oleate, myristine Ester oils such as isopropyl acid, glyceryl triisostearate, diparamethoxycinnamic acid-glyceryl monoethylhexanoate; dimethylpolysiloxane, methylhydropolysiloxane, methylphenylpolysiloxane, o Silicone oils such as motor-tetramethyl cyclotetrasiloxane; liquid paraffin, squalene, include liquid hydrocarbon oils such as squalane.
これらの液状油の中でも、ロキソプロフェン及び／又はその塩の経皮浸透性をより良好に向上させる観点から、好ましくはエステル油が挙げられ、より好ましくは、トリエチルヘキサノイン、アジピン酸ジイソプロピル、ミリスチン酸イソプロピルが挙げられ、特に好ましくは、トリエチルヘキサノイン、ミリスチン酸イソプロピルが挙げられる。 Among these liquid oils, ester oil is preferable from the viewpoint of improving the transdermal permeability of loxoprofen and / or a salt thereof, more preferably triethylhexanoin, diisopropyl adipate, isopropyl myristate. Particularly preferred are triethylhexanoin and isopropyl myristate.
これらの液状油は、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。 These liquid oils may be used individually by 1 type, and may be used in combination of 2 or more type.
本発明の外用医薬組成物における（Ｃ）成分の含有量については、使用する（Ａ）成分の種類や含有量等に応じて適宜設定すればよいが、例えば０．１〜２０重量％が挙げられる。ロキソプロフェン及び／又はその塩の経皮浸透性をより良好に向上させる観点から、本発明の外用医薬組成物における（Ｃ）成分の含有量としては、好ましくは０．５〜１５重量％、更に好ましくは１〜１０重量％が挙げられる。 What is necessary is just to set suitably about content of (C) component in the external pharmaceutical composition of this invention according to the kind, content, etc. of (A) component to be used, for example, 0.1-20 weight% is mentioned. It is done. From the viewpoint of improving the transdermal permeability of loxoprofen and / or a salt thereof better, the content of component (C) in the external pharmaceutical composition of the present invention is preferably 0.5 to 15% by weight, more preferably Is 1 to 10% by weight.
また、本発明の医薬組成物において、（Ａ）成分と（Ｃ）成分との比率については、前述する各含有量に応じて定まるが、ロキソプロフェン及び／又はその塩の経皮浸透性をより良好に向上させる観点から、（Ａ）成分１重量部当たり（Ｃ）成分の含有量が０．１〜２０重量部、好ましくは１〜１５重量部、より好ましくは２〜１０重量部、特に好ましくは３．５〜７重量部が挙げられる。 In the pharmaceutical composition of the present invention, the ratio of the component (A) to the component (C) is determined according to each content described above, but the transdermal permeability of loxoprofen and / or its salt is better. From the viewpoint of improving the content of the component (C), the content of the component (C) is 0.1 to 20 parts by weight, preferably 1 to 15 parts by weight, more preferably 2 to 10 parts by weight, and particularly preferably 3.5-7 weight part is mentioned.
（Ｄ）水
本発明の外用医薬組成物は、（Ｄ）成分として水を含有する。水としては特に制限されず、精製水、蒸留水、イオン交換水、超純水、滅菌水などが挙げられ、好ましくは精製水が挙げられる。本発明の外用医薬組成物における（Ｄ）成分の含有量については、製剤形態に応じて適宜設定すればよいが、例えば５〜５０重量％が挙げられる。水系基剤中にロキソプロフェン及び／又はその塩を含む外用医薬組成物は本来ロキソプロフェン及び／又はその塩の経皮浸透性が低いが、本発明の外用医薬組成物ではロキソプロフェン及び／又はその塩の経皮浸透性が向上しているため、このように水を比較的多く含む場合であっても、ロキソプロフェン及び／又はその塩の経皮浸透性を効果的に向上させることができる。このような本発明の効果を鑑みれば、本発明の外用医薬組成物における（Ｄ）成分の含有量として、好ましくは１０〜４０重量％、より好ましくは１５〜３０重量％が挙げられる。
(D) pharmaceutical composition for external application of the water present invention contains water as component (D). It does not restrict | limit especially as water, Purified water, distilled water, ion-exchange water, ultrapure water, sterilized water, etc. are mentioned, Preferably purified water is mentioned. The content of the component (D) in the external pharmaceutical composition of the present invention may be appropriately set according to the formulation form, and examples thereof include 5 to 50% by weight. An external pharmaceutical composition containing loxoprofen and / or a salt thereof in an aqueous base is inherently low in percutaneous permeability of loxoprofen and / or a salt thereof. Since the skin permeability is improved, the percutaneous permeability of loxoprofen and / or a salt thereof can be effectively improved even when a relatively large amount of water is contained. In view of such effects of the present invention, the content of the component (D) in the external pharmaceutical composition of the present invention is preferably 10 to 40% by weight, more preferably 15 to 30% by weight.
（Ｅ）一価低級アルコール
本発明の外用医薬組成物は、ロキソプロフェン及び／又はその塩の経皮浸透性をより向上させるために、（Ｅ）成分として一価低級アルコールをさらに含んでよい。
(E) Monovalent lower alcohol The pharmaceutical composition for external use of the present invention may further contain a monovalent lower alcohol as the component (E) in order to further improve the transdermal permeability of loxoprofen and / or a salt thereof.
一価低級アルコールとしては、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、エタノール、プロパノール、イソプロパノール、ｎ−ブタノール、ｓｅｃ−ブタノール、ｔｅｒｔ−ブタノール、ペンタノール等の炭素数１〜５の一価アルコールが挙げられる。これらの一価低級アルコールは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。これらの一価低級アルコールの中でも、好ましくはエタノール、イソプロパノールが挙げられ、特に好ましくはエタノールが挙げられる。 The monovalent lower alcohol is not particularly limited as long as it is pharmaceutically acceptable. For example, ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, pentanol, etc. 5 monohydric alcohols. These monovalent lower alcohols may be used alone or in combination of two or more. Among these monovalent lower alcohols, ethanol and isopropanol are preferable, and ethanol is particularly preferable.
本発明の外用医薬組成物において、一価低級アルコールを含有させる場合、その含有量については、ロキソプロフェン及び／又はその塩の経皮浸透性を向上させる観点から、好ましくは４０〜９０重量％、より好ましくは６０〜９０重量％が挙げられる。 In the external pharmaceutical composition of the present invention, when a monohydric lower alcohol is contained, the content thereof is preferably 40 to 90% by weight from the viewpoint of improving the transdermal permeability of loxoprofen and / or a salt thereof. Preferably 60 to 90 weight% is mentioned.
メントール
本発明の外用医薬組成物は、必要に応じて、メントールが含まれていてもよい。メントールを含有させることにより、適用した皮膚に清涼感を付与し、使用感を良好にすることも可能になる。
Menthol The external pharmaceutical composition of the present invention may contain menthol as required. By containing menthol, it is possible to impart a refreshing feeling to the applied skin and improve the feeling of use.
メントールは、ｄ体、ｌ体、ｄｌ体のいずれであってもよいが、好ましくはｌ体が挙げられる。 Menthol may be any of d-form, l-form, and dl-form, and preferably 1-form.
また、本発明の外用医薬組成物は、メントールを含有させるために、メントールを含む精油を使用してもよい。メントールを含む精油は、公知のものから適宜選択して使用することができるが、例えば、ハッカ油、ペパーミント油、スペアミント油等が挙げられる。 Moreover, the external pharmaceutical composition of this invention may use the essential oil containing a menthol in order to contain a menthol. The essential oil containing menthol can be appropriately selected from known ones, and examples thereof include peppermint oil, peppermint oil, spearmint oil, and the like.
本発明の外用医薬組成物におけるメントールの含有量については、特に制限されないが、例えば０．１〜２０重量％、好ましくは１〜１０重量％が挙げられる。 Although there is no restriction | limiting in particular about content of menthol in the external pharmaceutical composition of this invention, For example, 0.1-20 weight%, Preferably 1-10 weight% is mentioned.
カプサイシノイド
本発明の外用医薬組成物は、消炎鎮痛作用を高めるため、及び／又は血行促進のために、カプサイシノイドが含まれていてもよい。カプサイシノイドとは、Ｎ−アシルワニリルアミドであり、血行促進剤として公知の化合物である。カプサイシノイ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、カプサイシノイドにおけるアシル基の炭素数については、特に制限されないが、例えば５〜１５、好ましくは６〜１１が挙げられる。
Capsaicinoid The pharmaceutical composition for external use of the present invention may contain a capsaicinoid for enhancing anti-inflammatory analgesia and / or promoting blood circulation. Capsaicinoid is N-acyl vanillyl amide and is a known compound as a blood circulation promoter. The acyl group in capsaicinoid may be either linear or branched. Moreover, although it does not restrict | limit especially about carbon number of the acyl group in a capsaicinoid, For example, 5-15, Preferably 6-11 is mentioned.
カプサイシノイドとして、具体的には、ノナン酸バニリルアミド；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、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。これらのカプサイシノイドは、１種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。これらのカプサイシノイドの中でも、好ましくはノナン酸バニリルアミドが挙げられる。 Specific examples of capsaicinoids include nonanoic acid vanillylamide; capsaicins such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, and homodihydrocapsaicin. These capsaicinoids may be used individually by 1 type, and may be used in combination of 2 or more type. Among these capsaicinoids, nonanoic acid vanillylamide is preferable.
本発明の外用医薬組成物におけるカプサイシノイドの含有量については、特に制限されないが、例えば０．００２〜０．２重量％、好ましくは０．００３〜０．０５重量％が挙げられる。 The content of capsaicinoid in the external pharmaceutical composition of the present invention is not particularly limited, and for example, 0.002 to 0.2% by weight, preferably 0.003 to 0.05% by weight.
ニコチン酸のエステル誘導体
本発明の外用医薬組成物は、消炎鎮痛作用を高めるため、及び／又は血行促進のために、ニコチン酸のエステル誘導体が含まれていてもよい。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ないが、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、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。これらのニコチン酸のエステル誘導体の中でも、好ましくはニコチン酸ベンジルエステルが挙げられる。
Nicotinic Acid Ester Derivative The pharmaceutical composition for external use of the present invention may contain an nicotinic acid ester derivative for enhancing anti-inflammatory analgesia and / or promoting blood circulation. The ester derivative of nicotinic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, and nicotinic acid methyl ester. These ester derivatives of nicotinic acid may be used alone or in combination of two or more. Among these ester derivatives of nicotinic acid, nicotinic acid benzyl ester is preferable.
本発明の外用医薬組成物におけるニコチン酸のエステル誘導体の含有量については、特に制限されないが、例えば０．００２〜０．２重量％、好ましくは０．００３〜０．０５重量％、更に好ましくは０．００８〜０．０１５重量％が挙げられる。 The content of the ester derivative of nicotinic acid in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.002 to 0.2% by weight, preferably 0.003 to 0.05% by weight, more preferably 0.008-0.015 weight% is mentioned.
その他の成分
本発明の外用医薬組成物には、本発明の効果を妨げない限り、前述する成分の他に、必要に応じて、他の薬理成分を含んでいてもよい。本発明の外用医薬組成物に配合可能な他の薬理成分については、特に制限されないが、例えば、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；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；リドカイン及びその薬学的に許容される塩、ジブカイン及びその薬学的に許容される塩、アミノ安息香酸エチル等の局所麻酔剤；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。
Other components The pharmaceutical composition for external use of the present invention may contain other pharmacological components as needed in addition to the components described above, as long as the effects of the present invention are not hindered. Other pharmacological components that can be blended in the external pharmaceutical composition of the present invention are not particularly limited. For example, anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine And pharmaceutically acceptable salts thereof, antihistamines such as chlorpheniramine maleate; lidocaine and pharmaceutically acceptable salts thereof, dibucaine and pharmaceutically acceptable salts thereof, and local anesthetics such as ethyl aminobenzoate And herbal medicines such as arnica tincture, apricot extract, sushi extract, horse chestnut extract, funnel extract, belladonna extract, toki extract, sicon extract, salamander extract and the like.
更に、本発明の外用医薬組成物は、前述する成分の他に、必要に応じて、外用医薬組成物に通常使用される他の添加剤が含まれていてもよい。このような添加剤としては、例えば、ｐＨ調節剤、界面活性剤、乳化剤、可溶化剤、防腐剤、保存剤、酸化防止剤、安定化剤、キレート剤、増粘剤、香料、着色料等が挙げられる。本発明の外用医薬組成物に配合可能な増粘剤については、特に制限されないが、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、カルボキシビニルポリマー、ヒアルロン酸、キサンタンガム等が挙げられる。 Furthermore, the external pharmaceutical composition of the present invention may contain other additives usually used in the external pharmaceutical composition, if necessary, in addition to the components described above. Examples of such additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, and coloring agents. Is mentioned. Although it does not restrict | limit especially about the thickener which can be mix | blended with the external pharmaceutical composition of this invention, For example, a hydroxypropyl cellulose, a hydroxypropyl methylcellulose, a hydroxyethyl cellulose, a carboxy vinyl polymer, a hyaluronic acid, a xanthan gum etc. are mentioned.
製剤形態
本発明の外用医薬組成物の製剤形態については、経皮適用可能であることを限度として特に制限されず、例えば、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）、フォーム剤、軟膏剤、クリーム剤、ゲル剤、貼付剤等が挙げられる。これらの中でも、好ましくは液剤又はゲル剤が挙げられる。これらの製剤形態への調製は、第十七改正日本薬局方 製剤総則等に記載の公知の方法に従って、製剤形態に応じた添加剤を用いて製剤化することにより行うことができる。
Formulation Form The formulation form of the external pharmaceutical composition of the present invention is not particularly limited as long as it can be applied transdermally. For example, liquids (including lotions, sprays, aerosols, and emulsions), Examples include foams, ointments, creams, gels, patches and the like. Among these, Preferably a liquid agent or a gel agent is mentioned. These preparation forms can be prepared by formulating with additives according to the preparation form in accordance with known methods described in the 17th revised Japanese Pharmacopoeia General Rules for Preparations.
使用態様
本発明の外用医薬組成物は、消炎鎮痛が求められる局所（皮膚）に外用投与することにより使用される。本発明の外用医薬組成物は、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、変形性関節症、関節炎等に対する治療目的で使用することができる。
Mode of Use The external pharmaceutical composition of the present invention is used by externally administering to the topical (skin) where anti-inflammatory analgesia is required. The topical pharmaceutical composition of the present invention is an external anti-inflammatory analgesic, such as shoulder pain associated with stiff shoulders, joint pain, low back pain, muscle pain, tendonitis (hand / wrist pain), elbow pain (tennis elbow, etc.), bruise pain It can be used for the treatment of pain, fracture pain, neuralgia, osteoarthritis, arthritis and the like.
２．ロキソプロフェン及び／又はその薬学的に許容される塩の経皮浸透性を向上する方法
本発明は、（Ａ）ロキソプロフェン及び／又はその塩と、（Ｂ）トコフェロール酢酸エステルと、（Ｄ）水とを含む外用医薬組成物の、ロキソプロフェン及び／又はその塩の経皮浸透性を向上する方法を提供する。具体的には、本発明のロキソプロフェン及び／又はその薬学的に許容される塩の経皮浸透性を向上する方法は、外用医薬組成物中で、（Ａ）ロキソプロフェン及び／又はその塩と、（Ｂ）トコフェロール酢酸エステルと、（Ｄ）水とともに、（Ｃ）液状油を共存させる。本発明のロキソプロフェン及び／又はその薬学的に許容される塩の経皮浸透性を向上する方法において、使用される成分の種類や配合量、外用医薬組成物の製剤形態等については、前記「１．外用医薬組成物」の欄に記載の通りである。
2. Method for improving transdermal permeability of loxoprofen and / or pharmaceutically acceptable salt thereof The present invention comprises (A) loxoprofen and / or a salt thereof, (B) tocopherol acetate, and (D) water. A method for improving the percutaneous permeability of loxoprofen and / or a salt thereof of an external pharmaceutical composition is provided. Specifically, the method for improving the transdermal permeability of loxoprofen and / or a pharmaceutically acceptable salt thereof of the present invention comprises (A) loxoprofen and / or a salt thereof in an external pharmaceutical composition, B) A tocopherol acetate and (D) water are coexisted with (C) liquid oil. In the method for improving the percutaneous permeability of loxoprofen and / or a pharmaceutically acceptable salt thereof of the present invention, the kind and amount of components used, the formulation form of an external pharmaceutical composition, etc. are described in “1. As described in the column of “.External pharmaceutical composition”.
以下に実施例を示して本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.
試験例１
［外用医薬組成物の調製］
表１に示す組成の外用医薬組成物を調製した。具体的には、以下の手順で調製した。まず、エタノールにロキソプロフェンＮａ（ロキソプロフェンナトリウム水和物）を混合し、均一になるまで撹拌した。得られた溶液に、トコフェロール酢酸エステル（酢酸ｄｌ−α−トコフェロール）と、ミリスチン酸イソプロピル、トリエチルヘキサノイン、又はアジピン酸ジイソプロピルを混合し、均一になるまで攪拌し、さらに、ニコチン酸ベンジルエステル、ノナンバニリルアミド、又はｌ−メントールとを混合し、均一になるまで撹拌した。最後に、合計量が１００ｇとなるように精製水を添加し、均一になるまで撹拌した。なお、表１において各成分の量を示す数値の単位は、重量％である。
Test example 1
[Preparation of pharmaceutical composition for external use]
An external pharmaceutical composition having the composition shown in Table 1 was prepared. Specifically, it was prepared by the following procedure. First, loxoprofen Na (loxoprofen sodium hydrate) was mixed with ethanol and stirred until uniform. Tocopherol acetate (dl-α-tocopherol acetate) and isopropyl myristate, triethylhexanoin, or diisopropyl adipate are mixed in the resulting solution and stirred until homogeneous, and further nicotinic acid benzyl ester, nonane Vanillylamide or l-menthol was mixed and stirred until uniform. Finally, purified water was added so that the total amount was 100 g, and stirred until uniform. In Table 1, the unit of the numerical value indicating the amount of each component is% by weight.
［経皮浸透性の評価］
調製した外用医薬組成物を、以下のフランツセル試験に供した。
縦型フランツセル（型式TP-8S、VIDREX社製）をスターラーの上に固定し、ウォーターバスにつないで３２℃程度に保った。ヘアレスマウスから摘出した皮膚（直径約１．５ｃｍ、面積約１．７７ｃｍ2）をフランツセルに角層が上になるように置いた。その上からフランツセルの蓋を止め、金具で固定した。次いで、空気が入らないように、レセプターセルにリン酸緩衝液（PBS）を９．６ｍｌ充填した。調製した外用医薬組成物５６μｌをドナーである上記皮膚の角質層側に塗布した。１時間後、レセプター液を３００μｌ採取し、採取したレセプター液中のロキソプロフェンナトリウムをＨＰＬＣで定量分析した。ロキソプロフェンナトリウムの定量値から、以下の式に基づいて、ロキソプロフェンナトリウムの経皮透過率（％）を求めた。なお、レセプターセル中の累積透過ロキソプロフェン重量とは、採取したレセプター液３００μｌ中のロキソプロフェンナトリウムの定量値を、充填量９．６ｍｌ当たりに換算した量である。
[Evaluation of transdermal permeability]
The prepared external pharmaceutical composition was subjected to the following Franz cell test.
A vertical Franz cell (model TP-8S, manufactured by VIDREX) was fixed on a stirrer and connected to a water bath and kept at about 32 ° C. The skin (diameter: about 1.5 cm, area: about 1.77 cm 2 ) removed from the hairless mouse was placed on the Franz cell so that the stratum corneum was on top. The top of the Franz cell was stopped from above and fixed with metal fittings. Subsequently, 9.6 ml of phosphate buffer solution (PBS) was filled in the receptor cell so that air could not enter. 56 μl of the prepared external pharmaceutical composition was applied to the stratum corneum side of the skin as a donor. One hour later, 300 μl of the receptor solution was collected, and loxoprofen sodium in the collected receptor solution was quantitatively analyzed by HPLC. From the quantitative value of loxoprofen sodium, percutaneous permeability (%) of loxoprofen sodium was determined based on the following formula. The cumulative permeated loxoprofen weight in the receptor cell is an amount obtained by converting the quantitative value of loxoprofen sodium in 300 μl of the collected receptor solution into a per 9.6 ml filling amount.
ロキソプロフェンナトリウムの透過率（％）に応じて、経皮浸透性の程度を以下の基準で評価した。
◎１０％以上
○１％以上１０％未満
×１％未満
According to the permeation rate (%) of loxoprofen sodium, the degree of percutaneous permeability was evaluated according to the following criteria.
◎ 10% or more ○ 1% or more and less than 10% × <1%
得られた結果を表１に示す。表１から明らかなように、水、ロキソプロフェンナトリウム及びトコフェロール酢酸エステルに加えて液状油を含む場合（実施例１〜９）には、液状油を含まない場合（比較例１）に比べて、ロキソプロフェンナトリウムの経皮浸透量が飛躍的に増加していた。 The obtained results are shown in Table 1. As is apparent from Table 1, when liquid oil is included in addition to water, loxoprofen sodium and tocopherol acetate (Examples 1 to 9), loxoprofen is compared to the case where liquid oil is not included (Comparative Example 1). The percutaneous penetration of sodium has increased dramatically.
Claims (7)
Priority Applications (1)
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| JPH10316564A (en) * | 1997-05-21 | 1998-12-02 | Sekisui Chem Co Ltd | Antipruritic and analgesic medicine for external use |
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| JP2015193540A (en) * | 2013-03-29 | 2015-11-05 | 興和株式会社 | Loxoprofen-containing solid formulation for external use |
| JP2017178877A (en) * | 2016-03-31 | 2017-10-05 | 株式会社東洋新薬 | Skin external preparations |
| JP2018021002A (en) * | 2016-01-29 | 2018-02-08 | 興和株式会社 | Pharmaceutical preparation containing loxoprofen |
| JP2018030861A (en) * | 2015-12-28 | 2018-03-01 | 積水化学工業株式会社 | External preparation and method for producing the same |
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| JPH05271076A (en) * | 1992-03-26 | 1993-10-19 | Taisho Pharmaceut Co Ltd | Anti-inflammatory analgesic external preparation |
| JPH092943A (en) * | 1995-06-21 | 1997-01-07 | Lion Corp | Film-forming type solution for external use |
| JPH10316564A (en) * | 1997-05-21 | 1998-12-02 | Sekisui Chem Co Ltd | Antipruritic and analgesic medicine for external use |
| JP2002128701A (en) * | 2000-10-26 | 2002-05-09 | Sankyo Co Ltd | External antiphologistic and analgesic agent composition |
| JP2012214444A (en) * | 2011-03-25 | 2012-11-08 | Taisho Pharmaceutical Co Ltd | Loxoprofen-containing external preparation |
| JP2015193540A (en) * | 2013-03-29 | 2015-11-05 | 興和株式会社 | Loxoprofen-containing solid formulation for external use |
| JP2015067545A (en) * | 2013-09-26 | 2015-04-13 | 株式会社東洋新薬 | Foam-type external preparation for skin |
| JP2018030861A (en) * | 2015-12-28 | 2018-03-01 | 積水化学工業株式会社 | External preparation and method for producing the same |
| JP2018021002A (en) * | 2016-01-29 | 2018-02-08 | 興和株式会社 | Pharmaceutical preparation containing loxoprofen |
| JP2017178877A (en) * | 2016-03-31 | 2017-10-05 | 株式会社東洋新薬 | Skin external preparations |
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