JP3084090B2 - Antiplasmin agent - Google Patents
Antiplasmin agentInfo
- Publication number
- JP3084090B2 JP3084090B2 JP03159539A JP15953991A JP3084090B2 JP 3084090 B2 JP3084090 B2 JP 3084090B2 JP 03159539 A JP03159539 A JP 03159539A JP 15953991 A JP15953991 A JP 15953991A JP 3084090 B2 JP3084090 B2 JP 3084090B2
- Authority
- JP
- Japan
- Prior art keywords
- glabridine
- antiplasmin agent
- inflammation
- plasmin
- plasmin activity
- 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.)
- Expired - Lifetime
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、紫外線刺激等により生
じた皮膚の炎症の治療に有効な抗プラスミン剤に関する
ものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antiplasmin agent which is effective for treating skin inflammation caused by ultraviolet irradiation or the like.
【０００２】[0002]
【従来の技術】紫外線刺激等により生じた皮膚の炎症、
その他肌荒れ、日焼け、熱傷、湿疹などの皮膚炎症を治
療する手段としては、従来、アズレンなどの消炎剤、ビ
タミンＣ等のビタミン剤、スルファジアジンなどの殺菌
剤、ジフェンヒドラミンなどの抗ヒスタミン剤、バシト
ラシンなどの抗生物質、フルオシノロンアナセトナイド
などの副腎皮質ホルモン剤などを適宜併用することが行
われている。しかしながら、これらの薬剤は局所適用に
おける安全性や有効性の点で必ずしも満足できるもので
はなく、また、他の薬剤と併用すると効果を示さない場
合があるなどの問題点があった。一般に、炎症は生態に
有害な刺激に対する生体の防御反応と考えられ、生体組
織に対して局所刺激が加えられるとまず急性滲出性炎症
が生じ、血管拡張、血管透過性亢進、白血球の遊走が認
められる。引き続いて、単核細胞浸潤、結合組織の増
殖、血管の新生などの修復が起こる。これらは、生体を
正常な状態へ復帰させようとする動的な防御反応と考え
られるが、しばしば、生体にとってはもとの有害刺激よ
りもはるかに有害な結果を生むことになる。2. Description of the Related Art Skin irritation caused by ultraviolet light stimulation, etc.
Other means of treating skin inflammation such as rough skin, sunburn, burns, eczema, etc. are conventionally anti-inflammatory agents such as azulene, vitamins such as vitamin C, bactericides such as sulfadiazine, antihistamines such as diphenhydramine, and antibiotics such as bacitracin. In addition, corticosteroids such as fluocinolone anacetonide and the like are appropriately used in combination. However, these drugs are not always satisfactory in terms of safety and efficacy in topical application, and have problems in that they may not show any effect when used in combination with other drugs. In general, inflammation is considered to be a defense reaction of a living body against a harmful stimulus to ecology, and when local stimuli are applied to living tissues, acute exudative inflammation occurs first, and vasodilation, increased vascular permeability, and leukocyte migration are observed. Can be This is followed by repairs such as mononuclear cell infiltration, connective tissue proliferation, and vascularization. These are thought to be dynamic defensive reactions that attempt to return the organism to its normal state, but often produce far more harmful consequences for the organism than the original noxious stimuli.
【０００３】炎症の上記各段階の病理的変化に関与する
化学的メジエーターとしては、ヒスタミン、セロトニン
などの活性アミン、ブラジキニンなどの活性ペプチド、
プラスミン、カリクレインなどの蛋白分解酵素、遅反応
性物質、プロスタグランジンなどの脂質がよく知られて
いる。特に、皮膚炎症については生体内の線溶系に関与
する蛋白分解酵素であるプラスミンとの関係がよく知ら
れており、日焼け、熱傷、湿疹、接触性皮膚炎、エリテ
マトーデス等の皮膚疾患においてプラスミン活性が上昇
し、それが炎症亢進の一原因となっていると考えられて
いる。従来、過剰のプラスミン活性を抑制する薬剤とし
ては、トラネキサム酸などがあった。The chemical mediators involved in the above-mentioned pathological changes of inflammation include active amines such as histamine and serotonin, active peptides such as bradykinin, and the like.
Proteolytic enzymes such as plasmin and kallikrein, slow-reacting substances, and lipids such as prostaglandins are well known. In particular, regarding skin inflammation, the relationship with plasmin, a proteolytic enzyme involved in the fibrinolytic system in vivo, is well known, and plasmin activity is observed in skin diseases such as sunburn, burns, eczema, contact dermatitis, and lupus erythematosus. Rise, which is thought to be a cause of increased inflammation. Conventionally, tranexamic acid has been used as a drug for suppressing excessive plasmin activity.
【０００４】[0004]
【発明が解決しようとする課題】本発明の目的は、上述
のようなプラスミン活性の異常上昇が関与する皮膚炎症
の治療に有効な外用薬剤を提供することにある。SUMMARY OF THE INVENTION An object of the present invention is to provide a topical drug which is effective for treating skin inflammation associated with abnormal plasmin activity as described above.
【０００５】[0005]
【課題を解決するための手段】上記目的を達成すること
に成功した本発明は、グラブリジンからなる抗プラスミ
ン剤を提供するものである。SUMMARY OF THE INVENTION The present invention, which has successfully achieved the above object, provides an antiplasmin agent comprising glabridine.
【０００６】[0006]
【作用】グラブリジンは下記〔化１〕の構造式を有する
化合物であって、天然には甘草の１種である Glycyrrhi
za glabra Linne var.（ソ連、アフガン、トルコカンゾ
ウ）に微量含まれており、その薬理作用については抗菌
作用およびメラニン生成抑制作用が知られている（特開
平１−３１１０１１号公報）。Glabridin is a compound having the following structural formula and is naturally a kind of licorice, Glycyrrhi.
It is contained in trace amounts in za glabra Linne var. (USSR, Afghanistan, Turkey fern), and its pharmacological action is known to have an antibacterial action and an inhibitory action on melanin production (Japanese Patent Application Laid-Open No. 3111011).
【化１】 Embedded image
【０００７】本発明は、このグラブリジンについて上記
公知の薬理作用とは異なるプラスミン活性抑制作用を確
認し、プラスミン活性の異常上昇が関与する皮膚炎症の
治療に有効であることを見いだしたことに基づくもので
ある。グラブリジンを含有する甘草からグラブリジンを
抽出するには、この甘草の根部またはその水（もしくは
アンモニア水）抽出残渣（たとえばグリチルリチンを抽
出した残渣）を酢酸エチル、塩化メチレン、エーテル、
クロロホルム等の有機溶媒で抽出処理し、得られた抽出
物を適宜精製すればよい。The present invention is based on the finding that this glabridine has an inhibitory action on plasmin activity different from the above-mentioned known pharmacological actions, and has been found to be effective in treating skin inflammation involving an abnormal increase in plasmin activity. It is. In order to extract glabridine from licorice containing glabridin, the licorice root or its water (or ammonia water) extraction residue (eg, glycyrrhizin extracted residue) is extracted with ethyl acetate, methylene chloride, ether,
Extraction treatment may be performed with an organic solvent such as chloroform, and the obtained extract may be appropriately purified.
【０００８】グラブリジンからなる本発明の抗プラスミ
ン剤は、単独で、または他の薬剤と共に、適当な基材に
含有させて外用薬とするほか、化粧水、クリーム、乳
液、パックなど、各種化粧料に含有させて用いることが
できる。本発明の抗プラスミン剤は、外用薬または化粧
料に含有させて使用するとき、グラブリジンとしての濃
度が約０.０１〜５.０％になるようにすることが望まし
い。The antiplasmin agent of the present invention comprising glabridine, alone or together with other drugs, is contained in a suitable base material to be used as an external preparation, and various cosmetics such as lotions, creams, emulsions, packs, etc. Can be used. When the antiplasmin agent of the present invention is used by being contained in an external medicine or cosmetic, it is desirable that the concentration of glabridine be about 0.01 to 5.0%.
【０００９】[0009]
実施例１：甘草からグラブリジンの単離 甘草・Glycyrrhizaglabra Linne var.の根の細切物１kg
を１０００mlの酢酸エチルと共に２時間還流下に加熱し
て、酢酸エチル可溶成分を抽出した。抽出液の溶媒を留
去し、さらに減圧乾燥して、２８ｇの抽出物を得た。こ
れを７０(v/v)％エタノール１０００mlに溶解し、不溶
物を濾別し、濾液を合成吸着剤・ダイヤイオンＨＰ−２
０のカラム（２００ml）に流してグラブリジンを吸着さ
せた。次いで、７０(v/v)％エタノールでカラムを洗浄
したのち８０(v/v)％エタノール２５００mlでグラブリ
ジンを溶出させ、溶出液を５００mlずつのフラクション
に分画した。第三のフラクションにグラブリジンを認
め、これを減圧濃縮後、減圧乾燥して、約２.５ｇの粗
グラブリジンを得た。この粗精製物をベンゼン／ヘキサ
ン（４／２）で再結晶精製し、精製グラブリジンの結晶
１.１ｇを得た。Example 1: Isolation of glabridine from licorice 1 kg of root cuts of licorice Glycyrrhizaglabra Linne var.
Was heated under reflux with 1000 ml of ethyl acetate for 2 hours to extract ethyl acetate-soluble components. The solvent of the extract was distilled off and dried under reduced pressure to obtain 28 g of the extract. This was dissolved in 1000 ml of 70% (v / v) ethanol, the insoluble matter was filtered off, and the filtrate was used as a synthetic adsorbent, Diaion HP-2.
The column was passed through a column No. 0 (200 ml) to adsorb glabridine. Next, the column was washed with 70 (v / v)% ethanol, and glabridine was eluted with 2500 ml of 80 (v / v)% ethanol. The eluate was fractionated into 500 ml fractions. Glabridine was recognized in the third fraction, which was concentrated under reduced pressure and dried under reduced pressure to obtain about 2.5 g of crude glabridine. The crude product was recrystallized and purified with benzene / hexane (4/2) to obtain 1.1 g of purified glabridine crystals.
【００１０】実施例２ 実施例１で得られたグラブリジンについてプラスミン活
性抑制作用を調べた。 (1) 試料溶液の調製 下記およびの溶液を調製した。 グラブリジン５mg／40(v/v)％エタノール10ml グラブリジン１０mg／40(v/v)％エタノール10ml (2) フィブリンプレートの調製 ウォレンの方法（Wallen et al. Hamostasis，4,110,19
75）に準じ、加熱した０.１５Ｍ食塩加０.０１Ｍリン酸
緩衝液（pＨ７.８）１０mlにアガロース１００mgを溶解
後、４０℃に冷却した。これにプラスミノーゲン除去フ
ィブリノーゲン（第一化学薬品）１６.６mgを溶解させ
た。得られた溶液にトロンビン溶液（１００単位／ml；
持田製薬）０.１mlを滴下した後、シャーレ（径９cm）
に注ぎ、放冷し、中心に直径６mmの穴を開けてプラスミ
ノーゲン除去フィブリノーゲンを調製した。Example 2 The plasmin activity inhibitory effect of glabridine obtained in Example 1 was examined. (1) Preparation of sample solution The following solutions were prepared. Gravlidine 5 mg / 40 (v / v)% ethanol 10 ml Gravlidine 10 mg / 40 (v / v)% ethanol 10 ml (2) Preparation of fibrin plate Warren's method (Wallen et al. Hamostasis, 4,110,19)
According to 75), 100 mg of agarose was dissolved in 10 ml of heated 0.01 M phosphate buffer (pH 7.8) containing 0.15 M salt, and then cooled to 40 ° C. 16.6 mg of plasminogen-removed fibrinogen (Daiichi Pure Chemicals) was dissolved therein. A thrombin solution (100 units / ml;
Mochida Pharmaceutical) After dropping 0.1ml, Petri dish (diameter 9cm)
The mixture was allowed to cool, and a hole having a diameter of 6 mm was formed at the center to prepare plasminogen-free fibrinogen.
【００１１】(3) プラスミン活性抑制率の測定 アムブルスらの方法（Ambrus et al.，Pediatrics,32,1
0,1963）に準じ、前記(1) で調製した試料溶液０.１ml
にプラスミン溶液（０.４単位／ml；シグマ社）０.１ml
を加え、３０分後、プレートの穴に２０μlずつ注入し
た。３７℃で２０時間放置し、溶解面積を測定し、試料
溶液を添加しないプレートのフィブリン溶解面積を比較
し、プレート活性抑制率を求めた。なお、対照として、
抗プラスミン剤であるトラネキサム酸についても同様の
試験を行なった。上記試験の結果は下記のとおりであっ
た。 試料溶液 プラスミン活性抑制率 グラブリジン（５mg/10ml） ５３％ グラブリジン（１０mg/10ml） ８５％ トラネキサム酸（１０mg/10ml） ２０％(3) Measurement of the inhibition rate of plasmin activity The method of Ambrus et al. (Ambrus et al., Pediatrics, 32, 1)
0,1963), 0.1 ml of the sample solution prepared in (1) above.
0.1 ml of plasmin solution (0.4 units / ml; Sigma)
And after 30 minutes, inject 20 μl into the wells of the plate
Was. Leave at 37 ° C for 20 hours, measure the dissolution area,
Comparison of fibrin dissolving area of plate without adding solution
Then, the plate activity inhibition rate was determined. In addition, as a control,
The same applies to tranexamic acid, an antiplasmin agent.
The test was performed. The results of the above test are as follows:
Was.Sample solution Plasmin activity suppression rate Gravlidine (5mg / 10ml) 53% Gravlidine (10mg / 10ml) 85% Tranexamic acid (10mg / 10ml) 20%
【００１２】実施例３：熱傷治療用軟膏への配合例 ポリエチレングリコール（４００） ４９.８％ ポリエチレングリコール（４０００） ４９.８％ アクリノール微粉末 ０.２％ グラブリジン ０.２％ 上記組成の熱傷治療用軟膏を製造し、これを、１〜２度
の熱傷を受けた患者７名の熱傷部位の約１／２に塗布し
た。残りの１／２の部位には、対照薬品としてチンク油
を塗布した。その結果は下記のとおりであった。 塗布薬 著効 有効 無効 グラブリジン添加軟膏 ６人 １人 ０ チンク油 ３人 ４人 ０Example 3: Example of formulation in ointment for burn treatment Polyethylene glycol (400) 49.8% Polyethylene glycol (4000) 49.8% Acrynol fine powder 0.2% Grabradine 0.2% Burn treatment of the above composition Ointment is prepared and this is 1-2 times
Applied to about 1/2 of the burn site of 7 patients who had burns
Was. In the other half, tinc oil is used as a control drug.
Was applied. The results were as follows.Topical medicine Remarkable effect Effectiveness Invalid Gravlidine-added ointment 6 people 1 person 0 Tink oil 3 people 4 people 0
【００１３】実施例４：日焼け炎症防止化粧水への配
合例 エタノール １５％ モノラウリン酸ポリオキシエチレンソルビタン(20EO) １.０％ パラオキシ安息香酸 ０.２％ 香料 ０.２％ グラブリジン ０.３％ グリセリン ５％ 1,3-ブチレングリコール ６.０％ 精製水 残部 均一溶液にした上記，を混合して化粧水を調製し、
これを２０〜２５歳の女子２０名に、海水浴の際、背中
と腕に塗布させた。その結果、全員に顕著な炎症防止効
果が認められた。また、グラブリジンによる皮膚刺激反
応は全く認められなかった。Example 4: Formulation in a lotion for preventing sunburn inflammation Ethanol 15% Polyoxyethylene sorbitan monolaurate (20EO) 1.0% Paraoxybenzoic acid 0.2% Fragrance 0.2% Grabradine 0.3% Glycerin 5% 1,3-butylene glycol 6.0% Purified water Remaining
This was applied to 20 females of 20 to 25 years old on the back and arms when bathing in the sea. As a result, a remarkable anti-inflammatory effect was observed for all. Also, no skin irritation reaction due to glabridine was observed.
【００１４】[0014]
【発明の効果】上述のように、グラブリジンからなる本
発明の抗プラスミン剤は少量で顕著な使用効果が達成さ
れ、有害な副作用も認められない。また、グラブリジン
は化学的にも安定な物質であるから、多くの化粧料、外
用剤等に自由に配合することができる。したがって、本
発明によれば日焼け、熱傷、湿疹、接触性皮膚炎、エリ
テマトーデス等、プラスミン活性の異常上昇が関与して
いる皮膚疾患の予防ないし治療に安全で有効な新たな手
段が提供されることになる。As described above, the antiplasmin agent of the present invention comprising glabridine achieves a remarkable use effect with a small amount, and has no harmful side effects. In addition, since glabridine is a chemically stable substance, it can be freely blended in many cosmetics, external preparations and the like. Therefore, according to the present invention, a safe and effective new means is provided for the prevention or treatment of skin diseases associated with abnormally increased plasmin activity, such as sunburn, burns, eczema, contact dermatitis, lupus erythematosus, etc. become.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ Ａ６１Ｐ 29/00 Ａ６１Ｐ 29/00 Ｃ０７Ｄ 493/04 １０１ Ｃ０７Ｄ 493/04 １０１Ｃ (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/357 A61K 7/00 C07D 493/04 101 ＣＡ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ) ＥＭＢＡＳＥ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 identification code FI A61P 29/00 A61P 29/00 C07D 493/04 101 C07D 493/04 101C (58) Fields surveyed (Int. Cl. 7 , DB Name) A61K 31/357 A61K 7/00 C07D 493/04 101 CA (STN) MEDLINE (STN) REGISTRY (STN) EMBASE (STN)
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03159539A JP3084090B2 (en) | 1991-06-04 | 1991-06-04 | Antiplasmin agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03159539A JP3084090B2 (en) | 1991-06-04 | 1991-06-04 | Antiplasmin agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0570349A JPH0570349A (en) | 1993-03-23 |
| JP3084090B2 true JP3084090B2 (en) | 2000-09-04 |
Family
ID=15695975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP03159539A Expired - Lifetime JP3084090B2 (en) | 1991-06-04 | 1991-06-04 | Antiplasmin agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3084090B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0544090U (en) * | 1991-11-18 | 1993-06-15 | 美佐子 百瀬 | Clothes hanger |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3796340B2 (en) * | 1997-11-18 | 2006-07-12 | 株式会社ノエビア | Serine protease inhibitor |
| JP2004250368A (en) * | 2003-02-19 | 2004-09-09 | Maruzen Pharmaceut Co Ltd | Agent for improving ultraviolet-induced cell damage |
| CN1295230C (en) | 2005-02-05 | 2007-01-17 | 上海奥利实业有限公司 | Production of high-purity glabrene |
| EP1859834B1 (en) | 2005-03-15 | 2015-05-06 | Maruzen Pharmaceuticals Co., Ltd. | Anti-inflammatory agent |
| CN113754676B (en) * | 2021-09-17 | 2022-11-25 | 西安绿天生物技术有限公司 | Preparation method of water-soluble glabridin with high bioavailability |
-
1991
- 1991-06-04 JP JP03159539A patent/JP3084090B2/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0544090U (en) * | 1991-11-18 | 1993-06-15 | 美佐子 百瀬 | Clothes hanger |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0570349A (en) | 1993-03-23 |
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