JPWO2019131929A1 - 抗炎症剤 - Google Patents
抗炎症剤 Download PDFInfo
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- JPWO2019131929A1 JPWO2019131929A1 JP2019562193A JP2019562193A JPWO2019131929A1 JP WO2019131929 A1 JPWO2019131929 A1 JP WO2019131929A1 JP 2019562193 A JP2019562193 A JP 2019562193A JP 2019562193 A JP2019562193 A JP 2019562193A JP WO2019131929 A1 JPWO2019131929 A1 JP WO2019131929A1
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- acne
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- skin
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- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Description
細菌のうち、グラム陽性菌としては、例えば、プロピオニバクテリウム・アクネス、スタフィロコッカス・エピデルミデス、スタフィロコッカス・アウレウス又はストレプトコッカス・ピオゲネス等が挙げられ、グラム陰性菌としては、エッシェリヒア・コリ、クレブジエラ・ニューモニエ、プロテウス・ミラビリス、セラチア・マルセッセンス又はシュードモーナス・エルギノーザ等が挙げられる。
これらの細菌は、ざ瘡や皮膚感染症等の原因菌として知られ、主な治療法として、軽度から中等度ではナジフロキサシン、クリンダマイシン等の外用抗菌剤、中等度から重度ではミノサイクリン、ロキシスロマイシン等の経口抗菌剤が繁用されている。
真菌としては、例えば、カンジダ・アルビカンス、トリコフィトン・メンタグロファイテス、トリコフィトン・ルブルム、トリコフィトン・トンシュランス、ミクロスポリウム・カニス、ミクロスポリウム・ジプセウム、エピデルモフィトン・フロコッサム、マラセチア・レストリクタ、マラセチア・グロボーサ、マラセチア・フルフル等が挙げられる。
真菌が引き起こす皮膚疾患に対しては、例えば、アモロルフィン塩酸塩、ケトコナゾール、ミコナゾール、イトラコナゾール、エフィナコナゾール、ルリコナゾール又はテルビナフィン塩酸塩等の抗真菌薬もよく使われる。
また、外用抗菌剤に関しては、新たな抗菌剤として、化合物Aを有効成分として含有する外用剤が開発されている(例えば、特許文献1、特許文献2を参照)。
(1)1−シクロプロピル−8−メチル−7−[5−メチル−6−(メチルアミノ)−3−ピリジル]−4−オキソ−1,4−ジヒドロ−3−キノリンカルボン酸及び/又はその医薬上許容される塩を有効成分として含有する、微生物によって生じる皮膚炎症に対して抗炎症作用を有することを特徴とする医薬組成物。
(2)微生物によって生じる皮膚炎症が、表在性皮膚感染症及び/又は化膿性炎症を伴うざ瘡において生じるものである、上記(1)に記載の医薬組成物。
(3)表在性皮膚感染症が、毛包炎、毛瘡、化膿性汗孔周囲炎及び/又は伝染性膿痂疹である、上記(2)に記載の医薬組成物。
(4)化膿性炎症を伴うざ瘡が、尋常性ざ瘡、新生児ざ瘡及び/又は集簇性ざ瘡である、上記(2)に記載の医薬組成物。
(5)微生物によって生じる皮膚炎症が、グラム陽性菌及び/又はグラム陰性菌によって生じるものである、上記(1)〜(4)のいずれかに記載の医薬組成物。
また、化合物Aは、グラム陽性菌、グラム陰性菌、嫌気性菌、クラミジア及び薬剤耐性グラム陽性菌に対して幅広い抗菌スペクトルと強い抗菌活性を有している。
附属器関連感染症としては、例えば、毛包炎、毛瘡、化膿性汗孔周囲炎を挙げることができる。
非附属器関連感染症としては、例えば、伝染性膿痂疹を挙げることができる。
本発明に係る「抗炎症作用」とは、この炎症を抑える作用を意味し、化合物Aは微生物によって引き起こされる皮膚疾患の炎症を特に抑えることができる。
そのため、微生物によって引き起こされる皮膚炎症に対しては、抗菌作用だけでなく、抗炎症作用が重要である。
1)試験物質
本試験では、以下の抗菌薬を試験物質として用いた。
・化合物A(力価:99.7%)
・ナジフロキサシン(力価:99.9%)
・クリンダマイシン(力価:99.0%)
2)使用菌株
2013年に尋常性ざ瘡患者より分離したプロピオニバクテリウム・アクネスを用いた。
3)正常ヒト表皮角化細胞
正常ヒト表皮角化細胞(サーモフィッシャー・サイエンティフィック株式会社製)はHumedia−KB2(倉敷紡績株式会社製)を使用して培養した。試験時は正常ヒト表皮角化細胞の培養液に上記試験物質(いずれも終濃度1〜30μg/mL)を添加し、続けて、加熱処理したプロピオニバクテリウム・アクネス(109CFU/mL)懸濁液を添加した。薬効評価に必要なサイトカイン産生量が認められることから、正常ヒト角化細胞の刺激に用いるプロピオニバクテリウム・アクネスは109CFU/mLとした。
4)試験薬液の調製
各試験物質を適量の0.1N・水酸化ナトリウム水溶液に溶解させた後、Humedia−KB2で希釈した。
5)各種炎症性メディエーター抑制効果の評価指標
上記正常ヒト角化細胞を24時間培養後、上清を回収し、上清中のIL−6及びIL−8濃度をELISA法にて測定した。測定には市販のELISAキット(アールアンドディーシステムズ株式会社製)を使用した。IL−6及びIL−8の阻害率は、コントロール(試験薬液非添加)群の産生量を100%とした時の変化率で算出した。
6)結果
化合物A及びナジフロキサシンのみが、IL−6及びIL−8の産生を抑制した。さらに、ナジフロキサシンがIL−6に対しては3μg/mL、IL−8に対しては10μg/mL以上で産生抑制効果を示したのに対し、化合物Aでは1μg/mLから濃度依存的にIL−6及びIL−8に対する産生抑制効果を示し、化合物Aが極めて優れた抗炎症効果を有することが明らかとなった。
1)試験物質、使用菌株、試験薬液
本試験で用いた試験物質、使用菌株及び試験薬液は、試験1に準ずる方法で得た。
2)ヒト単球株化細胞
ヒト単球株化細胞THP−1(以下、THP−1)(ECACC細胞株)はRPMI1640(サーモフィッシャー・サイエンティフィック株式会社製)を使用して培養した。試験時はヒト単球株化細胞の培養液に上記試験物質(いずれも終濃度1〜30μg/mL)を添加し、続けて加熱処理したプロピオニバクテリウム・アクネス(108CFU/mL)懸濁液を添加した。薬効評価に必要なサイトカイン産生量が認められることから、ヒト単球株化細胞の刺激に用いるプロピニバクテリウム・アクネスは108CFU/mLとした。
3)各種炎症性メディエーター抑制効果の評価指標
上記正常ヒト角化細胞を24時間培養後、上清を回収し、上清中のIL−1β、IL−6、IL−8、TNF−α濃度をELISA法にて測定した。測定にはELISAキット(アールアンドディーシステムズ株式会社製)を使用した。また、IL−1β、IL−6、IL−8及びTNF−αの阻害率は、コントロール(試験薬液非添加)群の産生量を100%とした時の変化率で算出した。
4)結果
化合物Aは1μg/mLから濃度依存的にIL−6、IL−8及びTNF−αの産生抑制作用を示し、化合物Aが極めて優れた抗炎症効果を有することが明らかとなった。
1)試験物質、使用菌株
本試験で用いた試験物質、使用菌株は、試験1に準ずる方法で得た。
2)ラットの耳介炎症モデル
雄性SD(Sprague Dawley)ラット(7週齢、日本チャールス・リバー株式会社製)の右耳介内側に、プロピオニバクテリウム・アクネスの死菌25mg含有懸濁液を50 μL皮内投与し、炎症を惹起した。
3)プロピオニバクテリウム・アクネスの死菌含有懸濁液
プロピオニバクテリウム・アクネスの死菌25mgを生理食塩水に加え、プロピオニバクテリウム・アクネスの死菌含有懸濁液(50μL)とした。
4)試験薬液の調製
以下の組成の試験薬液を調製した。
・コントロール群:アセトン(和光純薬工業株式会社)。
・アセトン群:アセトン(和光純薬工業株式会社)。
・ステロイド群:0.1%ベタメタゾン(シグマ アルドリッチ社製)をアセトンに溶解。
・基剤群:化合物A2%含有ローションの基剤。基剤は、ヒドロキシエチルセルロース、1,3−ブチレングリコール、エタノール、エデト酸ナトリウム水和物、チオ硫酸ナトリウム水和物、pH調節剤から成る。
・化合物A2%含有ローション群:化合物A及び上記基剤から成る。)
5)炎症抑制効果の評価
上記試験薬液を30μL塗布した直後のラットの右耳介内側に、コントロール群には生理食塩水を、それ以外の群にはプロピオニバクテリウム・アクネスの死菌含有懸濁液50μLを皮内投与した。皮内投与2時間後に、ラット耳介の厚さをデジタルシックネスゲージ(株式会社ミツトヨ製)で測定した。
6)結果
コントロール群と比較して、アセトン群では有意に耳介厚が増加した(P<0.001 vs コントロール群,Student’s t−test)。アセトン群と基剤群では同程度の耳介肥厚が認められた。この耳介肥厚は化合物A2%含有ローション又はステロイド群で有意に抑制された(化合物A2%含有ローション群:P<0.001 vs 基剤群,Aspirin−Welch t−test,ステロイド群:P<0.001 vs アセトン群,Student’s t−test)。
Claims (5)
- 1−シクロプロピル−8−メチル−7−[5−メチル−6−(メチルアミノ)−3−ピリジル]−4−オキソ−1,4−ジヒドロ−3−キノリンカルボン酸及び/又はその医薬上許容される塩を有効成分として含有する、微生物によって生じる皮膚炎症に対して抗炎症作用を有することを特徴とする医薬組成物。
- 微生物によって生じる皮膚炎症が、表在性皮膚感染症及び/又は化膿性炎症を伴うざ瘡において生じるものである、請求項1に記載の医薬組成物。
- 表在性皮膚感染症が、毛包炎、毛瘡、化膿性汗孔周囲炎及び/又は伝染性膿痂疹である、請求項2に記載の医薬組成物。
- 化膿性炎症を伴うざ瘡が、尋常性ざ瘡、新生児ざ瘡及び/又は集簇性ざ瘡である、請求項2に記載の医薬組成物。
- 微生物によって生じる皮膚炎症が、グラム陽性菌及び/又はグラム陰性菌によって生じるものである、請求項1〜4のいずれか1項に記載の医薬組成物。
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