JP6632810B2 - Topical pharmaceutical composition - Google Patents
Topical pharmaceutical composition Download PDFInfo
- Publication number
- JP6632810B2 JP6632810B2 JP2015074542A JP2015074542A JP6632810B2 JP 6632810 B2 JP6632810 B2 JP 6632810B2 JP 2015074542 A JP2015074542 A JP 2015074542A JP 2015074542 A JP2015074542 A JP 2015074542A JP 6632810 B2 JP6632810 B2 JP 6632810B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- inflammatory
- diclofenac
- component
- fatty acid
- 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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- 239000012049 topical pharmaceutical composition Substances 0.000 title description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 53
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 44
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 30
- 229960001259 diclofenac Drugs 0.000 claims description 27
- 239000004359 castor oil Substances 0.000 claims description 26
- 235000019438 castor oil Nutrition 0.000 claims description 26
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 24
- 230000001760 anti-analgesic effect Effects 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- -1 sorbitan fatty acid ester Chemical class 0.000 description 70
- 235000014113 dietary fatty acids Nutrition 0.000 description 43
- 239000000194 fatty acid Substances 0.000 description 43
- 229930195729 fatty acid Natural products 0.000 description 43
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 19
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- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 150000004665 fatty acids Chemical class 0.000 description 15
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- 238000012360 testing method Methods 0.000 description 9
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- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 6
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- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 4
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- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
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Description
本発明は、外用医薬組成物に関する。より詳細には、本発明は、優れた消炎鎮痛作用を発揮する外用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for external use. More specifically, the present invention relates to a pharmaceutical composition for external use which exhibits an excellent anti-inflammatory and analgesic action.
現代社会では、ＯＡ機器の普及による長時間の同じ姿勢、過度のストレス、運動不足等によって、肩こり、筋肉痛、関節痛等に悩む人が増えている。従来、このような、肩こり、筋肉や関節の痛み等に対しては、患部で発生している炎症を抑え、症状を改善するために、消炎鎮痛剤を塗布するという対処が行なわれている。 In the modern society, people who suffer from stiff shoulders, muscle pain, joint pain, etc. due to the same posture for a long time, excessive stress, lack of exercise, etc. due to the spread of OA equipment are increasing. Conventionally, for such stiff shoulders, muscle and joint pains and the like, measures have been taken to apply an anti-inflammatory analgesic to suppress inflammation occurring in the affected area and improve symptoms.
従来、消炎鎮痛剤として、ジクロフェナク、フェルビナク、インドメタシン、イブプロフェン等の非ステロイド性抗炎症薬が知られている。これらの非ステロイド性抗炎症薬の中でも、ジクロフェナクは、シクロオキシゲナーゼに対する阻害活性が高く、優れた消炎鎮痛作用を発揮できることが知られており、ジクロフェナクを配合した外用医薬組成物が多く実用化されている。ジクロフェナクは、経口又は直腸投与した場合、副作用として胃腸、腎臓又は肝臓障害が生じる場合があり、特に胃腸については重篤な副作用を呈することもあることから、最近では外用剤としての適用が増えている。しかしながら、ジクロフェナクは、経皮吸収性が低く、経皮適用すると、本来有する消炎鎮痛作用を十分に発揮できないという欠点がある。 Conventionally, non-steroidal anti-inflammatory drugs such as diclofenac, felbinac, indomethacin, ibuprofen and the like have been known as anti-inflammatory analgesics. Among these non-steroidal anti-inflammatory drugs, diclofenac is known to have a high inhibitory activity against cyclooxygenase and to exert an excellent anti-inflammatory and analgesic action, and many external pharmaceutical compositions containing diclofenac have been put to practical use. . Diclofenac, when administered orally or rectally, may cause gastrointestinal, renal or liver damage as a side effect, and in particular, may have serious side effects on the gastrointestinal tract. I have. However, diclofenac has a drawback that transdermal absorbability is low and, when applied transdermally, the anti-inflammatory and analgesic effects inherent to diclofenac cannot be sufficiently exhibited.
これまでに、ジクロフェナクの経皮吸収性を向上させたり、その薬効を向上させたりする製剤技術の検討が種々為されている。例えば、特許文献１には、外用医薬組成物中で、ジクロフェナク又はその薬学的に許容される塩を０．５〜１．５重量％、清涼化剤を５〜１５重量％の割合で含有させることにより、鎮痛効果が向上することが開示されている。 Until now, various studies have been made on formulation techniques for improving the transdermal absorbability of diclofenac and improving its drug efficacy. For example, Patent Document 1 discloses that a topical pharmaceutical composition contains diclofenac or a pharmaceutically acceptable salt thereof in a proportion of 0.5 to 1.5% by weight and a cooling agent in a proportion of 5 to 15% by weight. It is disclosed that the analgesic effect is thereby improved.
しかしながら、肩こり、筋肉痛、関節痛等に悩む人の増加に伴って、より優れた消炎鎮痛作用を発揮できる外用剤への要望が高まっており、ジクロフェナクの消炎鎮痛作用をより一層向上させる製剤技術の開発への期待は高くなっている。 However, with the increase in the number of people suffering from stiff shoulders, muscle pain, joint pain, etc., there has been a growing demand for external preparations capable of exhibiting better anti-inflammatory and analgesic effects, and formulation technology for further improving the anti-inflammatory and analgesic effects of diclofenac. Expectations for the development of are increasing.
本発明は、ジクロフェナク及び／又はその薬学的に許容される塩を含む外用医薬組成物において、ジクロフェナク及び／又はその薬学的に許容される塩の消炎作用を向上させる製剤技術を提供することを目的とする。 An object of the present invention is to provide, in an external pharmaceutical composition containing diclofenac and / or a pharmaceutically acceptable salt thereof, a formulation technique for improving the anti-inflammatory effect of diclofenac and / or a pharmaceutically acceptable salt thereof. And
本発明者は、前記課題を解決すべく鋭意検討を行ったところ、外用医薬組成物において、ジクロフェナク及び／又はその薬学的に許容される塩と共に、セルロース系水溶性高分子化合物と、非イオン性界面活性剤とを併用すると、消炎作用が格段に向上し、消炎鎮痛作用を飛躍的に向上させ得ることを見出した。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 The present inventors have made intensive studies to solve the above-mentioned problems, and found that in a topical pharmaceutical composition, together with diclofenac and / or a pharmaceutically acceptable salt thereof, a cellulose-based water-soluble polymer compound and a nonionic It has been found that when used in combination with a surfactant, the anti-inflammatory effect is significantly improved, and the anti-inflammatory and analgesic effect can be significantly improved. The present invention has been completed by further study based on such knowledge.
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)ジクロフェナク及び／又はその薬学的に許容される塩、(B)セルロース系水溶性高分子化合物、並びに(C) 非イオン性界面活性剤を含有することを特徴とする、外用医薬組成物。
項２． 前記(B)成分がヒドロキシプロピルセルロースである、項１に記載の外用医薬組成物。
項３． 前記(C)成分がポリオキシアルキレン硬化ヒマシ油及び／又はポリオキシアルキレンソルビタン脂肪酸エステルである、項１又は２に記載の外用医薬組成物。
項４． 前記(C)成分がポリオキシエチレン硬化ヒマシ油及び／又はオレイン酸ポリオキシエチレンソルビタンである、項１〜３のいずれかに記載の外用医薬組成物。
項５． ゲル剤又は液剤である、項１〜４のいずれかに記載の外用医薬組成物。
項６． (A)ジクロフェナク及び／又はその薬学的に許容される塩を含む外用医薬組成物の消炎鎮痛作用の向上方法であって、前記外用医薬組成物に、(B)セルロース系水溶性高分子化合物、並びに(C)非イオン性界面活性剤を配合することを特徴とする、消炎鎮痛作用の向上方法。
項７． 前記(B)成分がヒドロキシプロピルセルロースである、項６に記載の消炎鎮痛作用の向上方法。
項８． 前記(C)成分がポリオキシエチレン硬化ヒマシ油及び／又はオレイン酸ポリオキシエチレンソルビタンである、項７又は８に記載の消炎鎮痛作用の向上方法。
That is, the present invention provides the following aspects of the invention.
Item 1. An external pharmaceutical composition comprising (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) a cellulosic water-soluble polymer compound, and (C) a nonionic surfactant. .
Item 2. Item 2. The topical pharmaceutical composition according to Item 1, wherein the component (B) is hydroxypropylcellulose.
Item 3. Item 3. The topical pharmaceutical composition according to Item 1 or 2, wherein the component (C) is a polyoxyalkylene hydrogenated castor oil and / or a polyoxyalkylene sorbitan fatty acid ester.
Item 4. Item 4. The external pharmaceutical composition according to any one of Items 1 to 3, wherein the component (C) is polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan oleate.
Item 5. Item 5. The topical pharmaceutical composition according to any one of Items 1 to 4, which is a gel or a liquid.
Item 6. (A) Diclofenac and / or a method for improving the anti-inflammatory analgesic effect of an externally applied pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, wherein the externally applied pharmaceutical composition, (B) a cellulose-based water-soluble polymer compound, And (C) a method for improving an anti-inflammatory and analgesic action, which comprises mixing a nonionic surfactant.
Item 7. Item 7. The method for improving an anti-inflammatory and analgesic effect according to Item 6, wherein the component (B) is hydroxypropyl cellulose.
Item 8. Item 9. The method for improving an anti-inflammatory and analgesic effect according to Item 7 or 8, wherein the component (C) is polyoxyethylene hydrogenated castor oil and / or polyoxyethylene sorbitan oleate.
本発明の外用医薬組成物によれば、ジクロフェナク及び／又はその薬学的に許容される塩が、セルロース系水溶性高分子化合物と非イオン性界面活性剤と共存することにより、その消炎作用が格段に向上しており、優れた消炎鎮痛作用を発揮することができる。従って、本発明の外用医薬組成物は、肩こり、筋肉痛、関節痛等の緩和又は治癒に卓効を示すことができる。 According to the external pharmaceutical composition of the present invention, diclofenac and / or a pharmaceutically acceptable salt thereof coexist with a cellulosic water-soluble polymer compound and a nonionic surfactant, so that the anti-inflammatory effect is remarkable. And can exhibit excellent anti-inflammatory and analgesic effects. Therefore, the pharmaceutical composition for external use of the present invention can show an excellent effect on alleviation or cure of stiff shoulder, muscle pain, joint pain and the like.
１．外用医薬組成物
本発明の外用医薬組成物は、(A)ジクロフェナク及び／又はその薬学的に許容される塩、(B)セルロース系水溶性高分子化合物、並びに(C)非イオン性界面活性剤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. External pharmaceutical composition The external pharmaceutical composition of the present invention comprises (A) diclofenac and / or a pharmaceutically acceptable salt thereof, (B) a cellulosic water-soluble polymer compound, and (C) a nonionic surfactant. It is characterized by containing. Hereinafter, the external pharmaceutical composition of the present invention will be described in detail.
(A)ジクロフェナク及び／又はその薬学的に許容される塩
本発明の外用医薬組成物は、消炎鎮痛成分として、ジクロフェナク及び／又はその塩（以下、「(A)成分」と表記することもある）を含有する。
(A) Diclofenac and / or a pharmaceutically acceptable salt thereof The topical pharmaceutical composition of the present invention comprises diclofenac and / or a salt thereof (hereinafter, sometimes referred to as “(A) component”) as an anti-inflammatory analgesic component. ).
ジクロフェナクとは、２−（２−（２，６−ジクロロフェニルアミノ）フェニル）酢酸とも称される非ステロイド系の公知化合物である。 Diclofenac is a known nonsteroidal compound also called 2- (2- (2,6-dichlorophenylamino) phenyl) acetic acid.
ジクロフェナクの塩としては、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、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；アンモニアとの塩；ジメチルアミン、ジエチルアミン、トリメチルアミン、トリエチルアミン等の第１級、第２級若しくは第３級のアルキルアミンとの塩；モノエタノールアミン、ジエタノールアミン、ジイソプロパノールアミン、トリエタノールアミン、トリイソプロパノールアミン等の第１級、第２級若しくは第３級のアルカノールアミンとの塩等が挙げられる。これらの中でも、好ましくはアルカリ金属塩、更に好ましくはナトリウム塩が挙げられる。これらのジクロフェナクの塩は、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。 The salt of diclofenac is not particularly limited as long as it is pharmaceutically acceptable. For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; salt with ammonia; Salts with primary, secondary or tertiary alkylamines such as amines, diethylamine, trimethylamine and triethylamine; primary salts such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine and triisopropanolamine; And salts with secondary or tertiary alkanolamines. Among them, preferred are alkali metal salts, and more preferred are sodium salts. One of these diclofenac salts may be used alone, or two or more of them may be used in combination.
本発明の外用医薬組成物において、(A)成分として、ジクロフェナク及びその塩の中から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、好ましくはジクロフェナクの塩、更に好ましくはジクロフェナクのアルカリ金属塩、特に好ましくはジクロフェナクナトリウムが挙げられる。 In the external pharmaceutical composition of the present invention, as the component (A), one kind may be selected from diclofenac and salts thereof and used alone, or two or more kinds may be used in combination. Among the components (A), diclofenac salts are preferable, alkali metal salts of diclofenac are more preferable, and diclofenac sodium is particularly preferable.
本発明の外用医薬組成物における(A)成分の含有量については、特に制限されないが、例えば０．２〜２重量％、好ましくは０．５〜１．５重量％、更に好ましくは０．７〜１．３重量％が挙げられる。 The content of the component (A) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.2 to 2% by weight, preferably 0.5 to 1.5% by weight, and more preferably 0.7% by weight. To 1.3% by weight.
(B)セルロース系水溶性高分子化合物
本発明の外用医薬組成物は、消炎鎮痛作用を向上させるために、セルロース系水溶性高分子化合物（以下、「(B)成分」と表記することもある）を含有する。本発明の外用医薬組成物では、当該(B)成分と共に後述する(C)成分を一体として含むことにより、ジクロフェナク及び／又はその塩による消炎鎮痛作用を飛躍的に向上させ、優れた消炎鎮痛作用を発揮させることが可能になっている。
(B) Cellulose-based water-soluble polymer compound The external pharmaceutical composition of the present invention is a cellulose-based water-soluble polymer compound (hereinafter, may be referred to as "component (B)" in order to improve the anti-inflammatory and analgesic effect. ). In the external pharmaceutical composition of the present invention, the component (C) described below is integrally contained together with the component (B), thereby dramatically improving the anti-inflammatory analgesic effect of diclofenac and / or a salt thereof, and an excellent anti-inflammatory analgesic effect. Can be demonstrated.
セルロース系水溶性高分子化合物とは、セルロースの水酸基の一部を酸化アルキレン等で修飾することによって水に不溶性のセルロースが水溶性に変換された化合物である。本発明で使用されるセルロース系水溶性高分子化合物としては、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、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース（別名：ヒプロメロース）、ヒドロキシエチルセルロースおよびカルボキシメチルセルロースを挙げることができる。これらのセルロース系水溶性高分子化合物は、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。これらのセルロース系水溶性高分子化合物の中でも、消炎作用をより一層向上させるという観点から、好ましくは、ヒドロキシプロピルセルロースが挙げられる。 The cellulose-based water-soluble polymer compound is a compound in which water-insoluble cellulose is converted to water-soluble by modifying a part of the hydroxyl groups of cellulose with alkylene oxide or the like. The cellulosic water-soluble polymer compound used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (alias: hypromellose), Hydroxyethyl cellulose and carboxymethyl cellulose can be mentioned. These cellulose-based water-soluble polymer compounds may be used alone or in a combination of two or more. Among these cellulose-based water-soluble polymer compounds, hydroxypropyl cellulose is preferably used from the viewpoint of further improving the anti-inflammatory effect.
本発明で使用されるセルロース系水溶性高分子化合物の分子量については、特に制限されず、使用するセルロース系水溶性高分子化合物の種類等に応じて適宜設定すればよい。 The molecular weight of the cellulosic water-soluble polymer compound used in the present invention is not particularly limited, and may be appropriately set according to the type of the cellulosic water-soluble polymer compound used.
ヒドロキシプロピルセルロースの粘度としては、特に限定されないが、例えば、２％水溶液の粘度（２０℃、Ｂ型粘度計）として２〜５０００ｍＰａ・ｓ程度のものが挙げられる。このようなヒドロキシプロピルセルロースは、ＮＩＳＳＯ ＨＰＣ（Ｌ、Ｍ、Ｈ、ＳＬ、ＳＳＬ）（日本曹達株式会社）等として商業的に入手可能である。 The viscosity of the hydroxypropylcellulose is not particularly limited. For example, the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) is about 2 to 5000 mPa · s. Such hydroxypropylcellulose is commercially available as NISSO HPC (L, M, H, SL, SSL) (Nippon Soda Co., Ltd.) or the like.
ヒドロキシエチルメチルセルロースの粘度としては、特に限定されないが、例えば、２％水溶液の粘度（２０℃、Ｂ型粘度計）として７０００〜１００００ｍＰａ・ｓ程度のものが挙げられる。このようなヒドロキシエチルメチルセルロースは、メセロース８０Ｈ（巴工業株式会社）等として商業的に入手可能である。 The viscosity of hydroxyethylmethylcellulose is not particularly limited, and for example, a viscosity of about 7000 to 10000 mPa · s as the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) can be used. Such hydroxyethyl methylcellulose is commercially available as Mecellose 80H (Tome Industry Co., Ltd.) or the like.
ヒドロキシプロピルメチルセルロースの粘度としては、特に限定されないが、例えば、２％水溶液の粘度（２０℃、Ｂ型粘度計）として２〜１００００ｍＰａ・ｓ程度のものが挙げられる。このようなヒドロキシプロピルメチルセルロースは、メトローズ６５ＳＨ−４００、６５ＳＨ−１５００、６５ＳＨ−４０００、９０ＳＨ−４００、９０ＳＨ−４０００（信越化学工業株式会社）等として商業的に入手可能である。 The viscosity of the hydroxypropylmethylcellulose is not particularly limited, and for example, a viscosity of about 2 to 10000 mPa · s as the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) can be mentioned. Such hydroxypropyl methylcellulose is commercially available as Metrose 65SH-400, 65SH-1500, 65SH-4000, 90SH-400, 90SH-4000 (Shin-Etsu Chemical Co., Ltd.) and the like.
ヒドロキシエチルセルロースの粘度としては、特に限定されないが、例えば、１％水溶液の粘度（２０℃、Ｂ型粘度計）として６０〜６０００ｍＰａ・ｓ程度のものが挙げられる。このようなヒドロキシエチルセルロースは、ＨＥＣダイセル（ＳＰ２００、ＳＰ６００、ＳＰ８５０、ＳＰ９００、ＳＥ５５０、ＳＥ８５０、ＳＥ９００、ＥＰ８５０、ＥＥ８２０）（ダイセルファインケム株式会社）等として商業的に入手可能である。 The viscosity of the hydroxyethylcellulose is not particularly limited. For example, the viscosity of a 1% aqueous solution (20 ° C., B-type viscometer) is about 60 to 6000 mPa · s. Such hydroxyethylcellulose is commercially available as HEC DAICEL (SP200, SP600, SP850, SP900, SE550, SE850, SE900, EP850, EE820) (Daicel FineChem Ltd.) and the like.
カルボキシメチルセルロースの粘度としては、特に限定されないが、例えば、１％水溶液の粘度（２０℃、Ｂ型粘度計）として１０〜１８０００ｍＰａ・ｓ程度のものが挙げられる。このようなカルボキシメチルセルロースは、ＣＭＣダイセル（１１２０、１１８０、１２５０、１３３０、２２６０）（ダイセル化学株式会社）等として商業的に入手可能である。 The viscosity of carboxymethylcellulose is not particularly limited. For example, the viscosity of a 1% aqueous solution (20 ° C., B-type viscometer) is about 10 to 18000 mPa · s. Such carboxymethyl cellulose is commercially available as CMC Daicel (1120, 1180, 1250, 1330, 2260) (Daicel Chemical Co., Ltd.) or the like.
本発明の外用医薬組成物における(B)成分の含有量については、特に制限されないが、例えば０．０１〜１０重量％、好ましくは０．１〜８重量％、更に好ましくは０．３〜５重量％が挙げられる。 The content of the component (B) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.01 to 10% by weight, preferably 0.1 to 8% by weight, and more preferably 0.3 to 5% by weight. % By weight.
また、本発明の外用医薬組成物において、(A)成分に対する(B)成分の比率については、各成分の前記含有量の範囲に基づいて定まるが、より一層効果的に消炎鎮痛作用を発揮させるという観点から、(A)成分１００重量部当たり、(B)成分が０．５５〜５０００重量部、好ましくは６〜１６００重量部、更に好ましくは２３〜７１５重量部となる範囲が挙げられる。 In the external pharmaceutical composition of the present invention, the ratio of the component (B) to the component (A) is determined based on the range of the content of each component, but more effectively exerts an anti-inflammatory analgesic effect. From the viewpoint, the range of 0.5 to 5000 parts by weight, preferably 6 to 1600 parts by weight, more preferably 23 to 715 parts by weight of the component (B) per 100 parts by weight of the component (A) is exemplified.
(C)非イオン性界面活性剤
本発明の外用医薬組成物は、消炎鎮痛作用を高めるために、前記(A)成分と(B)成分と共に、非イオン性界面活性剤（以下、「(C)成分」と表記することもある）を含有する。
(C) Nonionic surfactant The topical pharmaceutical composition of the present invention, together with the component (A) and the component (B), comprises a nonionic surfactant (hereinafter, referred to as "(C ) Component).
本発明で使用される非イオン性界面活性剤（(C)成分）としては、薬学的に許容できることを限度として特に制限されないが、例えば、ポリオキシアルキレン硬化ヒマシ油、ポリオキシアルキレンソルビタン脂肪酸エステル、ポリオキシアルキレン脂肪酸エステル、アルキレングリコール脂肪酸エステル、ポリオキシアルキレンアルキルエーテル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシアルキレン脂肪酸グリセリル、グリセリンアルキルエーテル、アルキルグルコシド等が挙げられる。 The nonionic surfactant (component (C)) used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, polyoxyalkylene hydrogenated castor oil, polyoxyalkylene sorbitan fatty acid ester, Polyoxyalkylene fatty acid ester, alkylene glycol fatty acid ester, polyoxyalkylene alkyl ether, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyalkylene fatty acid glyceryl, glycerin alkyl ether, alkyl glucoside and the like can be mentioned.
ポリオキシアルキレン硬化ヒマシ油としては、具体的には、ポリオキシエチレン(５)硬化ヒマシ油、ポリオキシエチレン(１０)硬化ヒマシ油、ポリオキシエチレン(２０)硬化ヒマシ油、ポリオキシエチレン(３０)硬化ヒマシ油、ポリオキシエチレン(４０)硬化ヒマシ油、ポリオキシエチレン(５０)硬化ヒマシ油、ポリオキシエチレン(６０)硬化ヒマシ油、ポリオキシエチレン(８０)硬化ヒマシ油、ポリオキシエチレン(１００)硬化ヒマシ油等のポリオキシエチレン硬化ヒマシ油が挙げられる。 As the polyoxyalkylene hydrogenated castor oil, specifically, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (30) Hardened castor oil, polyoxyethylene (40) hardened castor oil, polyoxyethylene (50) hardened castor oil, polyoxyethylene (60) hardened castor oil, polyoxyethylene (80) hardened castor oil, polyoxyethylene (100) And polyoxyethylene hydrogenated castor oil such as hydrogenated castor oil.
ポリオキシアルキレンソルビタン脂肪酸エステルとしては、例えば、脂肪酸の炭素数が１０〜２６のポリオキシエチレンソルビタン脂肪酸エステルが挙げられ、より具体的には、モノステアリン酸ポリオキシエチレンソルビタン（ポリソルベート60）、オレイン酸ポリオキシエチレンソルビタン（ポリソルベート80）、モノパルミチン酸ポリオキシエチレンソルビタン（ポリソルベート40）等が挙げられる。 Examples of the polyoxyalkylene sorbitan fatty acid ester include a polyoxyethylene sorbitan fatty acid ester having a fatty acid having 10 to 26 carbon atoms. More specifically, polyoxyethylene sorbitan monostearate (polysorbate 60), oleic acid Polyoxyethylene sorbitan (polysorbate 80), polyoxyethylene sorbitan monopalmitate (polysorbate 40) and the like.
ポリオキシアルキレン脂肪酸エステルとしては、例えば、脂肪酸の炭素数が１０〜２６のポリオキシエチレン脂肪酸エステル、脂肪酸の炭素数が１０〜２６のポリオキシプロピレン脂肪酸エステル等が挙げられる。 Examples of the polyoxyalkylene fatty acid ester include a polyoxyethylene fatty acid ester having 10 to 26 carbon atoms of a fatty acid and a polyoxypropylene fatty acid ester having 10 to 26 carbon atoms of a fatty acid.
アルキレングリコール脂肪酸エステルとしては、例えば、脂肪酸の炭素数が１０〜２６のエチレングリコール脂肪酸エステル、脂肪酸の炭素数が１０〜２６のプロピレングリコール脂肪酸エステルが挙げられ、具体的には、モノステアリン酸プロピレングリコール等が挙げられる。 Examples of the alkylene glycol fatty acid ester include an ethylene glycol fatty acid ester having 10 to 26 carbon atoms of a fatty acid and a propylene glycol fatty acid ester having 10 to 26 carbon atoms of a fatty acid, and specifically, propylene glycol monostearate. And the like.
ポリオキシアルキレンアルキルエーテルとしては、例えば、アルキル基の炭素数が１０〜２６のポリオキシエチレンアルキルエーテル、アルキル基の炭素数が１０〜２６のポリオキシプロピレンアルキルエーテル等が挙げられ、具体的には、ポリオキシエチレンセチルエーテルが挙げられる。 Examples of the polyoxyalkylene alkyl ether include a polyoxyethylene alkyl ether having an alkyl group having 10 to 26 carbon atoms, a polyoxypropylene alkyl ether having an alkyl group having 10 to 26 carbon atoms, and specifically, And polyoxyethylene cetyl ether.
グリセリン脂肪酸エステルとしては、例えば、脂肪酸の炭素数が１０〜２６のグリセリン脂肪酸エステルが挙げられ、具体的には、モノステアリン酸グリセリル、モノステアリン酸グリセリンリンゴ酸等が挙げられる。 Examples of the glycerin fatty acid ester include glycerin fatty acid esters having 10 to 26 carbon atoms in the fatty acid, and specific examples include glyceryl monostearate and glyceryl malate monostearate.
ポリグリセリン脂肪酸エステルとしては、例えば、脂肪酸の炭素数が１０〜２６のポリグリセリン脂肪酸エステルが挙げられ、具体的には、モノイソステアリン酸ポリグリセリル、ジイソステアリン酸ポリグリセリル等が挙げられる。 Examples of the polyglycerin fatty acid ester include a polyglycerin fatty acid ester having 10 to 26 carbon atoms in the fatty acid, and specifically, polyglyceryl monoisostearate, polyglyceryl diisostearate and the like.
ソルビタン脂肪酸エステルとしては、例えば、脂肪酸の炭素数が１０〜２６のソルビタン脂肪酸エステルが挙げられ、具体的には、ソルビタンモノイソステアレート、ソルビタンモノラウレート、ソルビタンモノパルミテート、ソルビタンモノステアレート、ペンタ−２−エチルヘキシル酸ジグリセロールソルビタン、テトラ−２−エチルヘキシル酸ジグリセロールソルビタン等が挙げられる。 Examples of sorbitan fatty acid esters include, for example, sorbitan fatty acid esters having 10 to 26 carbon atoms of fatty acids, and specifically, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, Diglycerol sorbitan penta-2-ethylhexylate, diglycerol sorbitan tetra-2-ethylhexylate, and the like.
ポリオキシアルキレン脂肪酸グリセリルとしては、例えば、脂肪酸の炭素数が１０〜２６のポリオキシエチレン脂肪酸グリセリルが挙げられ、具体的には、ポリオキシエチレンモノヤシ油脂肪酸グリセリル等が挙げられる。 Examples of the polyoxyalkylene fatty acid glyceryl include polyoxyethylene fatty acid glyceryl having 10 to 26 carbon atoms in the fatty acid, and specific examples include polyoxyethylene monococo oil fatty acid glyceryl.
グリセリンアルキルエーテルとしては、例えば、アルキル基の炭素数が２〜１００のグリセリンアルキルエーテルが挙げられる。 Examples of the glycerin alkyl ether include a glycerin alkyl ether having an alkyl group having 2 to 100 carbon atoms.
アルキルグルコシドとしては、例えば、アルキル基の炭素数が２〜１００のアルキルグルコシドが挙げられる。 Examples of the alkyl glucoside include an alkyl glucoside having an alkyl group having 2 to 100 carbon atoms.
これらの非イオン性界面活性剤の内、ポリオキシアルキレン基を含む非イオン性界面活性剤については、そのポリオキシアルキレンの付加モル数は、特に制限されないが、例えば２０〜８０モル、好ましくは４０〜６０モルが挙げられる。 Among these nonionic surfactants, for the nonionic surfactant containing a polyoxyalkylene group, the number of moles of the polyoxyalkylene is not particularly limited, but is, for example, 20 to 80 mol, preferably 40 mol. To 60 mol.
これらの非イオン性界面活性剤の中でも、消炎作用をより一層向上させるという観点から、好ましくはポリオキシアルキレン硬化ヒマシ油、ポリオキシアルキレンソルビタン脂肪酸エステル；より好ましくはポリオキシエチレン硬化ヒマシ油、ポリオキシエチレンソルビタン脂肪酸エステル；更に好ましくはポリオキシエチレン硬化ヒマシ油、脂肪酸の炭素数が５〜２００のポリオキシエチレンソルビタン脂肪酸エステル；特に好ましくはポリオキシエチレン硬化ヒマシ油、オレイン酸ポリオキシエチレンソルビタン（ポリソルベート80）；最も好ましくはポリオキシエチレン硬化ヒマシ油が挙げられる。 Among these nonionic surfactants, from the viewpoint of further improving the anti-inflammatory effect, preferably polyoxyalkylene-hardened castor oil, polyoxyalkylene sorbitan fatty acid ester; more preferably polyoxyethylene-hardened castor oil, polyoxy Ethylene sorbitan fatty acid ester; more preferably polyoxyethylene hydrogenated castor oil; polyoxyethylene sorbitan fatty acid ester having 5 to 200 carbon atoms of fatty acid; particularly preferably polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan oleate (polysorbate 80) ); Most preferably, polyoxyethylene hydrogenated castor oil.
これらの非イオン性界面活性剤は、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 nonionic surfactants may be used alone or in a combination of two or more.
また、(C)成分として、２種以上の非イオン性界面活性剤を使用する場合、その組合せ態様については、特に制限されないが、好適な組合せの一例として、２種以上のポリオキシエチレン硬化ヒマシ油の組合せ、特に好ましくはポリオキシエチレン(４０)硬化ヒマシ油（以下、(Ca)成分と表記することもある）とポリオキシエチレン(６０)硬化ヒマシ油（以下、(Cb)成分と表記することもある）との組合せが例示される。(B)成分として、(Ca)成分と(Cb)成分を組み合わせて使用する場合、その混合比については特に制限されないが、一例として、(Ca)成分１００重量部当たり、(Cb)成分が１００〜１０００重量部、好ましくは２００〜４００重量部が例示される。 When two or more nonionic surfactants are used as the component (C), the mode of combination is not particularly limited, but as an example of a suitable combination, two or more polyoxyethylene cured castors are used. A combination of oils, particularly preferably polyoxyethylene (40) hydrogenated castor oil (hereinafter sometimes referred to as the (Ca) component) and polyoxyethylene (60) hydrogenated castor oil (hereinafter referred to as the (Cb) component) In some cases). When the component (B) is used in combination with the component (Ca) and the component (Cb), the mixing ratio is not particularly limited, but as an example, the component (Cb) is 100 parts by weight per 100 parts by weight of the component (Ca). To 1000 parts by weight, preferably 200 to 400 parts by weight.
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、特に制限されないが、例えば０．１〜２０重量％、好ましくは１〜１５重量％、更に好ましくは３〜１０重量％が挙げられる。 The content of the component (C) in the external pharmaceutical composition of the present invention is not particularly limited, but is, for example, 0.1 to 20% by weight, preferably 1 to 15% by weight, and more preferably 3 to 10% by weight. Can be
また、本発明の外用医薬組成物において、(A)成分に対する(C)成分の比率については、各成分の前記含有量の範囲に基づいて定まるが、より一層効果的に消炎鎮痛作用を発揮させるという観点から、(A)成分１００重量部当たり、(C)成分が５〜１００００重量部、好ましくは６６〜３０００重量部、更に好ましくは２３０〜１４３０重量部となる範囲が挙げられる。 Further, in the external pharmaceutical composition of the present invention, the ratio of the component (C) to the component (A) is determined based on the content range of each component, but more effectively exerts an anti-inflammatory analgesic effect. From the viewpoint, the range of 5 to 10,000 parts by weight, preferably 66 to 3000 parts by weight, more preferably 230 to 1430 parts by weight, per 100 parts by weight of the component (A) is exemplified.
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、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；ニコチン酸ベンジルエステル、トコフェロール酢酸エステル、トウガラシチンキ等の血行促進剤；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。
Other Ingredients The external pharmaceutical composition of the present invention may contain a pharmacological component, if necessary, in addition to the aforementioned components, as long as the effects of the present invention are not hindered. The pharmacological components that can be added to 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, and stearyl glycyrrhizinate; diphenylimidazole, diphenhydramine and the like Pharmaceutically acceptable salts, antihistamines such as chlorpheniramine maleate; lidocaine and its pharmaceutically acceptable salts, dibucaine and its pharmaceutically acceptable salts, local anesthetics such as ethyl aminobenzoate; nicotine Blood circulation promoters such as benzyl acid ester, tocopherol acetate, and pepper tincture; Arnica tincture, oak extract, sanshishi extract, horse chestnut extract, funnel extract, belladonna extract, touki extract, sicon extract, sanshoe Herbal medicines such as vinegar and the like.
また、本発明の外用医薬組成物には、所望の製剤形態にするために、水性基剤、油性基剤等の基剤を含むことができる。 In addition, the external pharmaceutical composition of the present invention may contain a base such as an aqueous base or an oil base in order to obtain a desired formulation.
前記水性基剤としては、例えば、水；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−ブタノール等の低級アルコール；グリセリン、プロピレングリコール、ジプロピレングリコール、ブチレングリコール、ポリエチレングリコール等の多価アルコール等が挙げられる。 Examples of the aqueous base include water; lower alcohols such as ethanol, propanol, isopropanol, n-butanol, sec-butanol and tert-butanol; and polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, butylene glycol and polyethylene glycol. And hydric alcohols.
油性基剤としては、非極性油、極性油等が挙げられる。非極性油としては、具体的には、パラフィン、イソパラフィン等の炭化水素類；スクワラン、ワックス等が挙げられる。また、極性油としては、具体的には、脂肪族モノカルボン酸エステル、トリグリセライド、脂肪族ジカルボン酸ジエステル、脂肪族ジカルボン酸アルキレングリコールエステル、高級脂肪酸等が挙げられる。 Examples of the oil base include non-polar oils and polar oils. Specific examples of the nonpolar oil include hydrocarbons such as paraffin and isoparaffin; squalane and wax. Specific examples of the polar oil include aliphatic monocarboxylic acid esters, triglycerides, aliphatic dicarboxylic acid diesters, aliphatic dicarboxylic acid alkylene glycol esters, and higher fatty acids.
前記脂肪族モノカルボン酸エステルとしては、例えば、ミリスチン酸イソプロピル、パルミチン酸イソプロピル、ミリスチン酸オクチルドデシル、イソノナン酸イソトリデシル、イソノナン酸イソノニル、２−エチルヘキサン酸セチル、ミリスチン酸ミリスチル、イソステアリン酸ヘキサデシル、オクタン酸セチル、イソオクタン酸セチル等が挙げられる。これらの脂肪族モノカルボン酸エステルは、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。 Examples of the aliphatic monocarboxylic acid esters include, for example, isopropyl myristate, isopropyl palmitate, octyldodecyl myristate, isotridecyl isononanoate, isononyl isononanoate, cetyl 2-ethylhexanoate, myristyl myristate, hexadecyl isostearate, octanoic acid Cetyl, cetyl isooctanoate and the like can be mentioned. These aliphatic monocarboxylic acid esters may be used alone or in a combination of two or more.
前記トリグリセライドとしては、例えば、トリアシルグリセロール、トリパルミチン、トリパルミチン酸グリセリル、トリイソオクタン酸グリセリル、１−パルミトイル−２，３−ジオレオイルグリセロール、１，３−ジオレオイル−２−パルミトイルグリセロール、１−パルミトオレオイル−２−ステアロイル−３−リノレオイルグリセロール、１−リノレオイル−２−パルミトオレオイル−３−ステアロイルグリセロール等が挙げられる。これらのトリグリセライドは、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。 Examples of the triglyceride include triacylglycerol, tripalmitin, glyceryl tripalmitate, glyceryl triisooctanoate, 1-palmitoyl-2,3-dioleoylglycerol, 1,3-dioleoyl-2-palmitoylglycerol, 1- Palmitooleoyl-2-stearoyl-3-linoleoylglycerol, 1-linoleoyl-2-palmitooleoyl-3-stearoylglycerol, and the like. One of these triglycerides may be used alone, or two or more thereof may be used in combination.
前記脂肪族ジカルボン酸ジエステルとしては、例えば、セバシン酸ジエチル、セバシン酸ジイソプロピル、セバシン酸ジオクチル、アジピン酸ジエチル、アジピン酸ジイソプロピル、アジピン酸ジブチル、アジピン酸ジイソブチル、アジピン酸ジオクチル等が挙げられる。これらの脂肪族ジカルボン酸ジエステルは、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。 Examples of the aliphatic dicarboxylic acid diester include diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diethyl adipate, diisopropyl adipate, dibutyl adipate, diisobutyl adipate, dioctyl adipate and the like. These aliphatic dicarboxylic diesters may be used alone or in combination of two or more.
前記脂肪族ジカルボン酸アルキレングリコールエステルとしては、例えば、ジオクタン酸ネオペンチルグリコール、ジカプリン酸プロピレングリコール、ジオレイン酸エチレングリコール、ジステアリン酸エチレングリコール等が挙げられる。これらの脂肪族ジカルボン酸アルキレングリコールエステルは、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。 Examples of the aliphatic dicarboxylic acid alkylene glycol ester include neopentyl glycol dioctanoate, propylene glycol dicaprate, ethylene glycol dioleate, ethylene glycol distearate, and the like. These aliphatic dicarboxylic acid alkylene glycol esters may be used alone or in a combination of two or more.
前記高級脂肪酸としては、例えば、炭素数１２〜２６の脂肪酸が挙げられる。このような高級脂肪酸としては、具体的には、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、ベヘニン酸、イソステアリン酸、オレイン酸、リノール酸、リノレイン酸、ドコサヘキサエン酸、エイコサペンタエン酸等が挙げられる。これらの高級脂肪酸は、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。 Examples of the higher fatty acids include fatty acids having 12 to 26 carbon atoms. Specific examples of such higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, oleic acid, linoleic acid, linoleic acid, docosahexaenoic acid, eicosapentaenoic acid, and the like. . These higher fatty acids may be used alone or in combination of two or more.
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（非イオン性界面活性剤以外）、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。 Furthermore, the external pharmaceutical composition of the present invention may contain, as necessary, other additives usually used in the external pharmaceutical composition, in addition to the components described above. Such additives include, for example, pH adjusters, surfactants (other than nonionic surfactants), emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, chelating agents, Examples include a thickener, a fragrance, and a coloring agent.
本発明の外用医薬組成物に配合可能な界面活性剤（非イオン性界面活性剤以外）については、特に制限されず、例えば、陰イオン性界面活性剤、陽イオン性界面活性剤、両イオン性界面活性剤が挙げられる。これらの界面活性剤は、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。 The surfactant (other than the nonionic surfactant) that can be incorporated into the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include an anionic surfactant, a cationic surfactant, and a zwitterionic surfactant. Surfactants. One of these surfactants may be used alone, or two or more thereof may be used in combination.
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、ヒアルロン酸、キサンタンガム等が挙げられる。 The thickener that can be added to the external pharmaceutical composition of the present invention is not particularly limited, and examples thereof include hyaluronic acid and xanthan gum.
ｐＨ
発明の外用医薬組成物のｐＨは、６．１以上に設定される。前記(A)〜(D)成分を含み、且つｐＨを６．１以上に設定することによって、消炎作用を飛躍的に向上させ、優れた消炎鎮痛作用を発揮させることが可能になる。
pH
The pH of the pharmaceutical composition for external use of the invention is set to 6.1 or more. By including the components (A) to (D) and setting the pH to 6.1 or more, the anti-inflammatory effect can be dramatically improved, and an excellent anti-inflammatory and analgesic effect can be exhibited.
発明の外用医薬組成物のｐＨとして、より一層効果的に消炎鎮痛作用を発揮させるという観点から、好ましくは６．１〜７．４、更に好ましくは６．１〜７．１、特に好ましくは６．１〜６．６が挙げられる。 The pH of the externally applied pharmaceutical composition of the present invention is preferably 6.1 to 7.4, more preferably 6.1 to 7.1, particularly preferably 6 from the viewpoint of exhibiting an anti-inflammatory and analgesic effect more effectively. .1 to 6.6.
本発明の外用医薬組成物におけるｐＨの調整は、塩酸、酢酸、乳酸、クエン酸等の薬学的に許容される酸や、水酸化ナトリウム、水酸化カリウム等の薬学的に許容されるアルカリを添加することによって行うことができる。 The pH of the external pharmaceutical composition of the present invention is adjusted by adding a pharmaceutically acceptable acid such as hydrochloric acid, acetic acid, lactic acid or citric acid, or a pharmaceutically acceptable alkali such as sodium hydroxide or potassium hydroxide. You can do this by doing
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、第十六改正日本薬局方 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 The formulation of the external pharmaceutical composition of the present invention is not particularly limited as long as it can be applied transdermally, and examples thereof include liquids (including lotions, sprays, aerosols, and emulsions), Foams, ointments, creams, gels, patches and the like can be mentioned. Among these, a liquid agent or a gel agent is preferable. Preparation into these dosage forms can be carried out by formulating with an additive according to the dosage form according to a known method described in the 16th Revised Japanese Pharmacopoeia General Rules for Preparations and the like.
使用態様
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の投与量は、投与する部位、治療すべき症状の程度等に応じて適宜設定されるが、投与する局所部位１ｃｍ２当たり、ジクロフェナク及び／又はその薬学的に許容される塩の１回当たりの投与量が１０〜５００ｍｇ程度となる量であることが望ましい。
The pharmaceutical composition for external use of the invention is used by external application to a topical (skin) where antiphlogistic analgesia is required. The dose of the external pharmaceutical composition of the present invention is appropriately set depending on the site to be administered, the degree of the symptom to be treated, and the like, but per 1 cm 2 of the local site to be administered, diclofenac and / or its pharmaceutically acceptable amount. It is desirable that the dose per dose of the salt be about 10 to 500 mg.
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。 The topical pharmaceutical composition of the present invention is used as an anti-inflammatory analgesic for external use, such as shoulder pain, joint pain, lower back pain, muscle pain, tendonitis (hand / wrist pain), elbow pain (tennis elbow, etc.), bruise pain associated with stiff shoulders , Sprain pain, bone fracture pain, neuralgia, osteoarthritis, arthritis and the like.
２．消炎鎮痛作用の向上方法
前述するように、前記(A)成分を含む外用医薬組成物において、前記(B)〜(C)成分を含有させることによって、外用医薬組成物の消炎鎮痛作用を向上させることができる。従って、本発明は、更に、(A)ジクロフェナク及び／又はその薬学的に許容される塩を含む外用医薬組成物の消炎鎮痛作用の向上方法であって、当該外用医薬組成物に、(B)セルロース系水溶性高分子化合物、並びに(C)非イオン性界面活性剤を配合することを特徴とする、消炎鎮痛作用の向上方法を提供する。
2. Method for improving anti-inflammatory analgesic effect As described above, in the external pharmaceutical composition containing the component (A), the components (B) to (C) are added to improve the anti-inflammatory analgesic effect of the external pharmaceutical composition. be able to. Accordingly, the present invention further provides (A) a method for improving the anti-inflammatory and analgesic effect of an external pharmaceutical composition comprising diclofenac and / or a pharmaceutically acceptable salt thereof, wherein the external pharmaceutical composition comprises (B) Disclosed is a method for improving an anti-inflammatory and analgesic action, which comprises mixing a cellulosic water-soluble polymer compound and (C) a nonionic surfactant.
これらの消炎鎮痛作用の向上方法において、使用される成分の種類や配合量、外用医薬組成物のｐＨや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。 In these methods for improving anti-inflammatory analgesic action, the types and amounts of components used, pH and formulation of the topical pharmaceutical composition, and the like are as described in the above-mentioned “1. .
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。 Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.
試験例１：各成分の組み合わせと消炎作用の関係（薬理試験）
表１に示す組成の外用医薬組成物（ゲル剤）を調製した。各外用医薬組成物の消炎作用を評価するために、以下の試験を行った。なお、以下の実施例及び比較例の外用医薬組成物のｐＨの測定は、２５℃の温度条件下にて行った。
Test Example 1: Relationship between combination of each component and anti-inflammatory effect (pharmacological test)
An external pharmaceutical composition (gel) having the composition shown in Table 1 was prepared. The following tests were performed to evaluate the anti-inflammatory effect of each topical pharmaceutical composition. In addition, the measurement of the pH of the pharmaceutical composition for external use of the following Examples and Comparative Examples was performed under a temperature condition of 25 ° C.
ラット（Slc:Wistar系、雄、馴化後７週齢）の飼育馴化終了後に、足容積測定装置（ＭＫ−１０１ＣＭＰ、室町機械株式会社）により右後足容積を測定し、各群の右後足容積の平均値が均一となるように３群に分けた（１群８匹）。 After rearing and acclimation of rats (Slc: Wistar strain, male, 7 weeks old after acclimation), the volume of the right hind paw was measured using a paw volume measuring device (MK-101 CMP, Muromachi Kikai Co., Ltd.), and the right hind paw of each group was measured. The groups were divided into three groups so that the average value of the volumes was uniform (8 animals per group).
各群のラットの右後足に各外用医薬組成物２２０ｍｇを塗布し、その直後に無麻酔下で１重量％カラゲニン溶液１００μｌを右後足蹠皮内に投与して、急性炎症を惹起させた。投与から２、４、及び６時間後に、足容積測定装置（ＭＫ−１０１ＣＭＰ、室町機械株式会社）により右後足容積を測定した。また、コントロールとして、外用医薬組成物の投与を行わなかったこと以外は、前記と同条件で右後足容積を測定した。各右後足容積の測定値を用いて、以下の算出式に従って足容積増加率を評価した。なお、惹起された急性炎症の程度は、足容積増加の程度に反映されるため、足容積増加率が低い程、消炎作用が強いことを意味する。 Each topical pharmaceutical composition (220 mg) was applied to the right hind paw of each group of rats, and immediately thereafter, 100 μl of a 1% by weight carrageenin solution was intradermally administered to the right hind footpad under anesthesia to induce acute inflammation. . Two, four, and six hours after the administration, the right hind paw volume was measured by a paw volume measurement device (MK-101 CMP, Muromachi Kikai Co., Ltd.). In addition, as a control, the volume of the right hind paw was measured under the same conditions as above except that the administration of the external pharmaceutical composition was not performed. Using the measured value of the right hind paw volume, the paw volume increase rate was evaluated according to the following formula. Since the degree of the induced acute inflammation is reflected in the degree of increase in foot volume, the lower the rate of increase in foot volume, the stronger the anti-inflammatory effect.
足容積相対増加率（％）＝Ｘ／Ｙ×１００
Ｘ：カラゲニン投与後の各測定時点の値
Ｙ：カラゲニン投与前の値
Foot volume relative increase rate (%) = X / Y × 100
X: value at each measurement time point after carrageenin administration Y: value before carrageenin administration
得られた結果を図１に示す。この結果から、ジクロフェナクナトリウムと共に、ヒドロキシプロピルセルロース、及びポリオキシエチレン硬化ヒマシ油を併用した場合（実施例１）では、ジクロフェナクナトリウムを単独で含む場合（比較例１）に比べて、格段に高い消炎作用が認められた。 The results obtained are shown in FIG. From these results, when hydroxypropylcellulose and polyoxyethylene hydrogenated castor oil were used together with diclofenac sodium (Example 1), the quenching was significantly higher than when diclofenac sodium was used alone (Comparative Example 1). An effect was observed.
試験例２：各成分の組み合わせと消炎作用の関係（ヒト試験）
表２に示す組成の外用医薬組成物（液状）を調製した。各外用医薬組成物の消炎作用を評価するために、以下の試験を行った。
Test Example 2: Relationship between combination of each component and anti-inflammatory effect (human test)
An external pharmaceutical composition (liquid) having the composition shown in Table 2 was prepared. The following tests were performed to evaluate the anti-inflammatory effect of each topical pharmaceutical composition.
肩こりを実感している被験者４名の肩に各外用医薬組成物を適量（０．５ｇ）を塗布した。次いで、塗布２時間後での間、経時的に、「肩こりを感じる」を１０点、「肩こりを感じない」を０点とするＶＡＳ（Visual Analogue Scale）評価を行い、各外用医薬組成物の塗布による肩こり度合を評点化し、外用医薬組成物毎に肩こり度合の評点の平均値を算出した。 An appropriate amount (0.5 g) of each pharmaceutical composition for external use was applied to the shoulders of four subjects experiencing stiff shoulders. Then, during 2 hours after application, a VAS (Visual Analogue Scale) evaluation was performed with the time “10” for “feeling shoulder stiffness” and the point “0 for no feeling stiff shoulder”. The degree of shoulder stiffness due to application was scored, and the average value of the scores of shoulder stiffness was calculated for each of the externally applied pharmaceutical compositions.
得られた結果を図２に示す。この結果から、ジクロフェナクナトリウムと共にセルロース系水溶性高分子化合物ならびに非イオン性界面活性剤を含有する外用医薬組成物を使用した場合（実施例２及び３）では、セルロース系水溶性高分子化合物または非イオン性界面活性剤のいずれかのみを使用した場合（比較例２及び３）、ジクロフェナクナトリウムを単独で含有する場合（比較例４）に比して、肩こり度が著しく改善していることが確認された。以上の結果から、ジクロフェナクナトリウムと共に、セルロース系水溶性高分子化合物、及び非イオン性界面活性剤を併用することによって、初めて優れた消炎鎮痛作用が得られることが明らかとなった。また、実施例の外用医薬組成物の中でも、非イオン性界面活性剤としてポリオキシエチレン硬化ヒマシ油を使用した場合（実施例２）には、より一層優れた消炎鎮痛作用が得られることが明らかとなった。 FIG. 2 shows the obtained results. From these results, when an external pharmaceutical composition containing a cellulose-based water-soluble polymer compound and a nonionic surfactant together with diclofenac sodium (Examples 2 and 3), the cellulose-based water-soluble polymer compound or non-cellulose was used. When only one of the ionic surfactants was used (Comparative Examples 2 and 3), it was confirmed that the degree of shoulder stiffness was significantly improved as compared with the case where diclofenac sodium was solely contained (Comparative Example 4). Was done. From the above results, it was clarified that an excellent anti-inflammatory analgesic effect was obtained for the first time by using a cellulose-based water-soluble polymer compound and a nonionic surfactant together with diclofenac sodium. In addition, in the topical pharmaceutical compositions of Examples, when polyoxyethylene hydrogenated castor oil was used as the nonionic surfactant (Example 2), it was clear that a more excellent anti-inflammatory and analgesic effect was obtained. It became.
処方例
表３及び表４に示す組成の外用医薬組成物（ゲル状）を調製した。得られた各外用医薬組成物の消炎作用について前記試験例２と同様の方法で試験したところ、いずれも優れた消炎作用が認められた。
Formulation Examples Pharmaceutical compositions for external use (gels) having the compositions shown in Tables 3 and 4 were prepared. The anti-inflammatory action of each of the obtained external pharmaceutical compositions was tested in the same manner as in Test Example 2 above, and all excellent anti-inflammatory actions were observed.
Claims (4)
前記外用医薬組成物に、(B)ヒドロキシプロピルセルロース、及び(C)ポリオキシアルキレン硬化ヒマシ油を配合することを特徴とする、消炎鎮痛作用の向上方法。 (A) A method for improving the anti-inflammatory and analgesic effect of an externally applied pharmaceutical composition comprising diclofenac and / or a pharmaceutically acceptable salt thereof,
A method for improving an anti-inflammatory and analgesic effect, comprising blending (B) hydroxypropylcellulose and (C) polyoxyalkylene-hardened castor oil into the external pharmaceutical composition.
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