JP4293755B2 - External preparation for skin containing pyridonecarboxylic acid compound - Google Patents

Description

「式中、Ｒ^１は、水素原子を；Ｒ^２は、置換されていてもよいシクロアルキル基を；Ｒ^３は、水素原子、ハロゲン原子、置換されていてもよいアルキル、アルコキシもしくはアルキルチオ基、ヒドロキシル基、アミノ基またはニトロ基を；Ｒ^４は、置換されていてもよいアルキルまたはアルコキシ基を；Ｚは、ハロゲン原子、ヒドロキシル基、置換されていてもよいアルキル、アルケニル、シクロアルキル、アルコキシ、アルキルチオおよびアミノ基から選ばれる一つ以上の基で置換されていてもよいピリジン−４−イルまたはピリジン−３−イル基をそれぞれ示す。」
で表されるキノロンカルボン酸またはその塩が挙げられる。
【００１０】
一般式［１］の式中において、シクロアルキル基とは、シクロプロピル、シクロペンチルおよびシクロヘキシルなどのＣ_3-6シクロアルキル基を；アルキル基とは、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチルおよびペンチルなどの直鎖状または分枝鎖状Ｃ_1-6アルキル基を；アルコキシ基とは、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシおよびペンチルオキシなどの直鎖状または分枝鎖状Ｃ_1-6アルコキシ基を；アルキルチオ基とは、メチルチオ、エチルチオ、n-プロピルチオ、イソプロピルチオ、n-ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオおよびペンチルチオなどの直鎖状または分枝鎖状Ｃ_1-6アルキルチオ基を；アルケニル基とは、ビニルおよびアリルなどの直鎖状または分枝鎖状Ｃ_2-6アルケニル基を；ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を、それぞれ意味する。
【００１１】
また、Ｒ²におけるシクロアルキル基；Ｒ³におけるアルキル基、アルコキシ基またはアルキルチオ基；Ｒ⁴におけるアルキル基またはアルコキシ基の置換基並びにＺのピリジル基における置換基であるアルキル、アルケニル、シクロアルキル、アルコキシ、アルキルチオまたはアミノ基のさらなる置換基として、ハロゲン原子、ヒドロキシル基、アミノ基、アルキルアミノ基（メチルアミノ、エチルアミノ、プロピルアミノ、ブチルアミノ、ペンチルアミノ、ヘキシルアミノ、ジメチルアミノ、ジエチルアミノ、メチルエチルアミノ、ジプロピルアミノ、ジブチルアミノおよびジペンチルアミノなどの直鎖状または分枝鎖状Ｃ_1-6アルキル基で置換されたアミノ基）、アルキル基、アルコキシ基、アリール基（フェニル、ナフチルなど）、シクロアルキル基、アルケニル基およびハロゲン原子で置換されたアルキル基が挙げられる。
【００１２】
一般式［１］おいて、Ｒ^１が水素原子；Ｒ^２がシクロアルキル基；Ｒ^３が水素原子；Ｒ^４がアルキル基；Ｚがアルキルアミノ基で置換されたピリジン−３−イル基であるキノロンカルボン酸が好ましく、具体的には、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が挙げられる。
また、本発明に用いられるピリドンカルボン酸系化合物は、その塩を含み、その使用量は、特に限定されないが、通常、皮膚外用剤中に0.01％〜20％、好ましくは、0.8〜5％であればよい。
【００１３】
本発明で使用されるピリドンカルボン酸系化合物の塩としては、通常知られているアミノ基などの塩基性基またはヒドロキシル基もしくはカルボキシル基などの酸性基における塩が挙げられる。塩基性基における塩としては、たとえば、塩酸、臭化水素酸および硫酸などの鉱酸との塩；酒石酸、ギ酸、フマル酸、マレイン酸、リンゴ酸およびクエン酸などの有機カルボン酸との塩；並びにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸およびナフタレンスルホン酸などのスルホン酸との塩が、また、酸性基における塩としては、たとえば、ナトリウムおよびカリウムなどのアルカリ金属との塩；カルシウムおよびマグネシウムなどのアルカリ土類金属との塩；アンモニウム塩；並びにリジン、アルギニンおよびオルニチンなどのアミノ酸、トリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ−ベンジル−β−フェネチルアミン、１−エフェナミン並びにＮ,Ｎ'−ジベンジルエチレンジアミンなどの含窒素有機塩基との塩などが挙げられる。
【００１４】
本発明の皮膚外用剤に用いられる炭素数９〜２２の脂肪族カルボン酸としては、たとえば、ペラルゴン酸、３−ノネン酸、カプリン酸、９−デセン酸、ラウリン酸、パルミトレイン酸、オレイン酸、リノール酸、リノレン酸、リシノール酸などの炭素数９〜２２の脂肪族カルボン酸、好ましくは、炭素数９〜１８の脂肪族カルボン酸さらに好ましくは、オレイン酸が挙げられ、これらを単独または二種以上併用してもよい。
また、本発明に用いられる炭素数９〜２２の脂肪族カルボン酸の使用量は、特に限定されないが、皮膚外用剤中に0.01％〜10％であればよく、好ましくは、0.5〜5％であればよい。
【００１５】
本発明の皮膚外用剤に用いられるピロリドン誘導体としては、たとえば、２−ピロリドン；５−メチル−２−ピロリドン；Ｎ−メチル−２−ピロリドン、Ｎ−エチル−２−ピロリドン、Ｎ−ブチル−２−ピロリドン、Ｎ−ヘキシル−２−ピロリドン、Ｎ−オクチル−２−ピロリドン、Ｎ−ドデシル−２−ピロリドンおよびＮ−ラウリル−２−ピロリドンなどのＮ−アルキルピロリドンが挙げられ、好ましくは、Ｎ−メチル−２−ピロリドンが挙げられ、これらを単独または二種以上併用してもよい。
また、本発明に用いられるピロリドン誘導体の使用量は、特に限定されないが、たとえば、皮膚外用剤中に0.1％〜50％であればよく、好ましくは、4〜30％であればよい。
【００１６】
本発明に用いられる多価アルコールとしては、たとえば、エチレングリコール、グリセリン、プロピレングリコール、ポリエチレングリコール、トリメチレングリコール、１,２−ブチレングリコール、１,３−ブチレングリコール、２,３−ブチレングリコール、テトラメチレングリコール、ペンタメチレングリコール、ジエチレングリコール、ジプロピレングリコール、トリエチレングリコール、ポリプロピレングリコール、テトラエチレングリコール、ジグリセリン、トリグリセリン、テトラグリセリン、ポリグリセリンなどが挙げれられ、好ましくは、プロピレングリコール、グリセリンおよびポリエチレングリコール400が挙げられ、これらの多価アルコールは、それぞれ単独で使用してもよく、また、二種以上を組み合わせて使用してもよい。
また、本発明に用いられる多価アルコールの使用量は、特に限定されないが、たとえば、皮膚外用剤中に1〜50％、好ましくは、4〜30％であればよい。
上記中、プロピレングリコール、ポリエチレングリコール400およびグリセリンについては、本発明皮膚外用剤に使用した場合、皮膚刺激抑制剤としての効果も有する。
【００１７】
本発明の皮膚外用剤は、ピリドンカルボン酸系化合物、ピロリドン誘導体、炭素数９〜２２の脂肪族カルボン酸および多価アルコールに加え、さらに、塩基を使用することが好ましい。本発明で使用される塩基としては、ｐＨを調整する作用を有している化合物であれば特に限定されないが、たとえば、水酸化ナトリウム、水酸化カリウムおよび水酸化リチウムなどの金属水酸化物；モノエタノールアミン、モノイソプロパノールアミン、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および２−アミノ−２−メチル−１,３−プロパンジオールなどのヒドロキシ低級アルキルアミンなどが挙げられ、好ましくは、ヒドロキシ低級アルキルアミンが挙げられる。さらに、好ましくは、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およびトリエタノールアミンが挙げられ、よりさらに好ましくは、ジイソプロパノールアミンが挙げられる。
これらの塩基は、それぞれ、単独で使用してもよく、また、二種以上を組み合わせて使用してもよい。また、これらの皮膚外用剤に配合される塩基の使用量は、特に限定されないが、より具体的には、たとえば、皮膚外用剤中に0.01〜20％、さらに好ましくは、1〜5％であればよい。また、本発明の皮膚外用剤が塩基により調整される場合、好ましい皮膚外用剤のｐＨは9.5〜11である。
【００１８】
本発明の皮膚外用剤は、さらに、水溶性高分子を使用することができる。本発明の皮膚外用剤で使用される水溶性高分子としては、たとえば、ポリビニルアルコール、ポリビニルメチルエーテル、ポリビニルピロリドンおよびカルボキシビニルポリマー（カーボポール）などのビニル系高分子；ポリエチレングリコール400、ポリエチレングリコール4000、ポリエチレングリコール20000、ポリエチレングリコール4000000およびポリエチレングリコール600000などのポリオキシエチレン系高分子；ポリオキシエチレンポリオキシプロピレン共重合体共重合系高分子；ポリアクリル酸ナトリウム、ポリエチルアクリレートおよびポリアクリルアミドなどのアクリル系高分子；ポリエチレンイミン、カチオンポリマー、メチルセルロース、疎水化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並びにヒドロキシプロピルセルロースなどが挙げられ、好ましくは、カルボキシビニルポリマーが挙げられ、これらの水溶性高分子は、それぞれ、単独で使用してもよく、また、二種以上を組み合わせて使用してもよい。
また、本発明に用いられる水溶性高分子の使用量は、特に限定されないが、たとえば、皮膚外用剤中に0.1〜５％、好ましくは、0.7〜2％であればよい。
【００１９】
本発明の皮膚外用剤は、構成成分を適宜混合し、そのまま用いてもよいが、使用感や適用のしやすさなどを考慮し、軟膏製剤、ゲル製剤、クリーム製剤、ローション製剤、乳剤、粘着テープ剤などに使用される医薬上許容される基剤、賦形剤、担体および希釈剤などの製剤助剤中に混合して使用すればよく、たとえば、軟膏製剤、ゲル製剤およびローション製剤として使用することが好ましい。
投与量および投与回数は、患者の年齢、体重および症状に応じて適宜選択できるが、通常、経皮製剤が薬効を発揮しうる量を１日、１回から数回に分割して経皮投与すればよく、たとえば、薬剤が化合物Ａの場合、１日30〜2000mgを１回から数回、経皮投与すればよい。
【００２０】
【発明の実施の形態】
以下、実施例および参考例を挙げて本発明を更に具体的に説明するが、本発明は、これらの実施例に限定するものではない。
【実施例】
化合物Ａ：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

上記３、２、５、４、８、１を加えた後、７を加えながら撹拌および約65℃の加温を繰り返し、さらに９を加え、撹拌し、pH10.22の溶液を得た。得られた溶液に６を加え、撹拌し、ゲル製剤を得た。
【００２１】

上記２、３、４、５を順に加え、撹拌した。得られた混合物に１を加え、70〜80℃で加温後、８および９を加えながら加温および撹拌を繰り返し、ｐＨを10.79に調整した。さらに、６および７を加え、70〜80℃で加温し、撹拌した。一晩放置後、１０を加え、再び70〜80℃で加温溶解後、撹拌し、室温に戻し、軟膏製剤を得た。
【００２２】

上記３、２、４、８、１を順に加え、撹拌後、６を加え、撹拌した。つぎに、５を加えた後、７を加えながら撹拌し、pHを調整し、さらに９を加えて攪拌し、pH10.36のゲル製剤を得た。
【００２３】

上記２、３、４、８、５を順に加え、撹拌した。ついで６を加え、撹拌後、１を加え、撹拌した。さらに７を加えながら撹拌し、pHを調整し、さらに９を加えて攪拌し、pH10.34のゲル製剤を得た。
【００２４】

上記８および６を加え、撹拌し、７を加え、撹拌し、1を加え、撹拌した。得られた混合物に別に調整した２、３、４、５の混合溶媒を数回に分けて撹拌しながら加えた。得られた混合物に９を加え、撹拌後、一晩放置し、pH10.04のゲル製剤を得た。
【００２５】

上記２、３、４、１の順に加え、撹拌し、７を加え、撹拌後、８を加え撹拌した。つぎに５および６を加え、撹拌を繰り返し、pH10.17のゲル製剤を得た。
【００２６】

上記２、４、３の順に加え、撹拌後、９を加え、撹拌した。ついで５および６を加え、撹拌し、１を加え、撹拌した。さらに７を加え、撹拌後、８を加えながら撹拌および約60℃の加温を繰り返し、pHを調整し、pH10.28のゲル製剤を得た。
【００２７】

上記２、４、３を順に加え、撹拌後、５を加え、撹拌した。ついで７を加え、撹拌し、１を加え、撹拌した。さらに、６を加えながら撹拌することによりpHを調整し、pH10.38のゲル製剤を得た。
【００２８】

上記２、３、４、５を順に加え、撹拌し、ついで、７を加え、撹拌した。得られた混合物に１を加え撹拌し、約60℃で加温する。さらに、６を加えながら加温および撹拌を繰り返し、pHを調整し、pH10.29のローション製剤を得た。
【００２９】

上記１、５を順に加え、撹拌後、３を加え、撹拌した。ついで、２を加え、撹拌し、７を加え、撹拌後、４を加え、撹拌した。ついで６を加えながら撹拌および約65℃の加温を繰り返し、８を加えた。さらに６を加え、撹拌し、pHを調整し、pH10.18のゲル製剤を得た。
【００３０】

上記１、３、２、４、７を順に加え、撹拌後、約75℃に加温した。つぎに、６を加えながら加温および撹拌を繰り返し、８を加え、撹拌し、pHを10.07に調整した。つぎに５を加え、撹拌し、ゲル製剤を得た。
【００３１】
上記で得られたまたは試験例記載の方法で製造した製剤について、以下の試験を行った。
試験例１（溶解性試験）
下記、表１の組成からなる溶液に1重量部の化合物Ａを添加する。得られた懸濁液に、5mol/l 水酸化ナトリウム水溶液により調製した化合物Ａのモル数に対して0.138重量部、0.055重量部、0.028重量部、0.000重量部水酸化ナトリウムを含む溶液を加えた。これを３種類の溶媒［Ａ］（Ｎ−メチル−2−ピロリドン、イソプロパノール、精製水）のそれぞれについて調製した。得られた12種類の溶液にさらに化合物Ａが溶け残る充分量を添加した後、加温とともに激しく攪拌し、懸濁液を得た。
【００３２】
【表１】

「表中、溶媒［Ａ］は、Ｎ−メチル−2−ピロリドン、イソプロパノール、精製水から選択される溶媒を意味する。」
【００３３】
室温にて4日間放置後、未溶解の化合物Ａを遠心分離し、上澄のpHおよび化合物Ａの濃度（溶解度）を測定した。結果を表２に示す。
【００３４】
【表２】

【００３５】
溶媒［Ａ］を含むそれぞれの組成物溶液の化合物Ａの溶解度とpHのプロットより近似曲線を求め、その曲線より外挿し、pH10.30における溶解度を求めた。その結果、薬剤溶解濃度は、溶媒［Ａ］がＮ−メチル−2−ピロリドン（本出願記載の組成物）では12913μg/mL、イソプロパノールでは、9680μg/mL、精製水では3931μg/mLであった。
この結果より、Ｎ−メチル−2−ピロリドンを用いた本出願記載の組成物では、同一pHにおいて薬剤の濃度を高く設定でき、有効成分の効率よい皮膚透過を行わせることができる。
【００３６】
試験例２（In vitro皮膚透過性試験）
雄性ＩＣＲ系マウスを頚椎脱臼後、電気バリカンおよび電気シェーバーでマウス背部皮膚表面を剃毛した。剃毛した部分を剥離し、皮膚内側の脂肪分を除去後、生理食塩水に浸し、一晩冷蔵で保存した。ポリエチレングリコール400とリン酸塩緩衝液を1：1で混合した溶液を煮沸処理にて脱気した後、フランツ型拡散セルのレシーバー側に加え、余分な水分を除いた上記皮膚をセルに装着した。ドナー側に被験製剤を各々0.5mLずつ載せ、レシーバー溶液を37℃に保った。ドナー側は、アルミ箔およびフィルム（パラフィルム：アメリカン・ナショナル・カン製）で覆い、レシーバー溶液を24時間後に採取し、各々の薬物量を測定した。結果を表３に示す。
【００３７】
【表３】
−−−−−−−−−−−−−−−−−
被験製剤 累積透過量(μg/cm²)
−−−−−−−−−−−−−−−−−
実施例１ 363
実施例３ 830
実施例６ 705
実施例８ 317
参考例１ 173
参考例２ 45
−−−−−−−−−−−−−−−−−
【００３８】
試験例３（抗菌力比較試験）
雄性ＩＣＲ系マウスを用い、麻酔後電気シェーバーにて背部の毛を剃毛した。100℃に加熱した分銅（φ20mm）を剃毛背部皮膚へ当て、熱傷瘡を作成し、1時間後、熱傷瘡の皮下にS.aureus SA 113の菌液0.2ml（1.0×10⁷CFU／マウス）またはP.acnes JCM6425の菌液0.2ml（5.0×10⁶CFU／マウス）を接種した。菌液接種2時間後に各試験製剤（実施例３製剤、ナジフロキサシン1％クリーム（市販品）、クリンダマイシン1％ゲル（市販品）、ゲンタマイシン0.1％クリーム（市販品）10mgを熱傷瘡に塗布した。菌液接種24時間後に試験製剤を除去し、熱傷瘡の部分を剥離し、滅菌生理食塩液中でホモジネートした。得られたホモジネート溶液を滅菌生理食塩液で希釈後、50mM塩化マグネシウムを含むミューラー・ヒントン寒天培地で広げ、37℃で24時間培養後のコロニー数を測定した。菌液接種24時間後の皮膚あたりのコロニー形成数単位の対数値（ＬｏｇＣＦＵ／ヒフ）を表４および表５に示す。
【００３９】
【表４】
菌液接種２時間後に試験薬剤を塗布した群のコロニー数（S.aureus SA 113）
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
試験薬剤名
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
コントロール 7.32
実施例３ 5.77
ナジフロキサシン 6.26
クリンダマイシン 5.74
ゲンタマイシン 6.84
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
【００４０】
【表５】
菌液接種２時間後に試験薬剤を塗布した群のコロニー数（P.acnes JCM 6425）
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
試験薬剤名
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
コントロール 6.96
実施例３ 4.70
ナジフロキサシン 6.10
クリンダマイシン 5.60
ゲンタマイシン 6.01
−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
この結果より、本発明皮膚外用剤は、市販薬剤と比較しても顕著に生菌数の減少が認められ、極めて良好な治療効果を有することが示された。
【００４１】
【発明の効果】
本発明皮膚外用剤は、ピリドンカルボン酸系化合物を有効成分として配合し、皮膚に塗布することにより、局所作用を目的とする有効成分が皮膚内に速やかに、深く浸透して伝染性膿痂疹および尋常性座瘡を含む表在性皮膚感染症などの疾患に優れた治療効果を発揮し、加えて、適用部位に殆んど刺激を与えない皮膚外用剤である。また、本発明皮膚外用剤は、有効で安全性が高く、薬剤耐性菌に対しても効果を示し、さらに疾患の治療期間を短縮することができる。[0001]
[Industrial application fields]
The present invention relates to an external preparation for skin which contains a pyridonecarboxylic acid compound and exhibits a therapeutic effect on superficial skin infections including infectious impetigo and acne vulgaris.
[0002]
[Prior art]
The surface of the skin is called a skin stratum corneum, and has a physiological function as a barrier for preventing foreign substances from entering the body and preventing leakage of body fluids from the body. For this reason, sufficient transdermal absorbability cannot be obtained simply by blending an active ingredient in a base that has been commonly used in external preparations. In conventional external preparations, the skin permeability of the active ingredient is a major problem. It has become.
[0003]
In general, the effect of topical therapy with antibacterial agents is largely influenced by the thickness of the stratum corneum at the lesion and the strength of penetration of the antibacterial agent into the stratum corneum in addition to the antibacterial activity of the drug. That is, it is important that the antibacterial preparation has the antibacterial agent dissolved completely and uniformly, has a strong penetrating power, excellent drug stability, and high affinity for the skin.
[0004]
For example, as a method for treating acne vulgaris, external therapies in which various antibacterial agents are applied to affected areas in the form of creams, ointments, liquids and the like are frequently used, but it is difficult to completely cure them. One reason for this is that normal skin bacteria such as staphylococci and acne bacteria generally grow inside the stratum corneum that covers the outermost layer of the skin. It is difficult to penetrate the skin.
So far, antibiotics such as erythromycin, clindamycin, and tetracycline have been used as therapeutic agents, but side effects due to long-term administration and an increase in resistant bacteria are major problems. Further, JP-A-2-275820 discloses 6,7-dihydro-9-fluoro-8- (4-hydroxy-1-piperidyl) -5-methyl-1-oxo-1H, 5H-benzo [i, j] An external antibacterial agent containing quinolidine-2-carboxylic acid as an active ingredient and further containing a hydroxy lower alkylamine is described. In addition, the skin external preparation which consists of pyridone carboxylic acid, isopropanol, propylene glycol, tri ((beta) -oxyethyl) amine, sodium hydroxide, and purified water is disclosed by the Example.
However, they are not sufficient in terms of skin irritation, skin permeability and / or the time required for treatment.
[0005]
[Problems to be solved by the invention]
In the preparation of an external preparation for skin, an active ingredient intended for local action quickly penetrates deeply into the skin to exert an excellent effect, and a preparation with little irritation to the application site has been strongly demanded.
[0006]
[Means for Solving the Problems]
Under such circumstances, as a result of earnest research, the present inventors have found a skin external preparation containing a pyridonecarboxylic acid compound, a pyrrolidone derivative, an aliphatic carboxylic acid having 9 to 22 carbon atoms and a polyhydric alcohol. The invention has been completed.
[0007]
That is, the present invention includes a pyridone carboxylic acid compound as an active ingredient, and when applied to the skin, the active ingredient intended for local action penetrates quickly and deeply into the skin, causing contagious impetigo and The present invention provides an external preparation for skin that exhibits an excellent therapeutic effect on diseases such as superficial skin infections including acne vulgaris, and that is less irritating to the application site. Furthermore, a more excellent external preparation for skin can be obtained by adding a base to the above composition.
Further, quinolonecarboxylic acid derivatives or salts thereof described in International Publication WO99 / 51588, in particular, 1-cyclopropyl-8-methyl-7- [5-methyl-6- (methylamino) -3-pyridyl] -4 -Oxo-1,4-dihydro-3-quinolinecarboxylic acid (hereinafter referred to as Compound A) has a broad antibacterial spectrum against gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, chlamydia and drug-resistant gram-positive bacteria. It was a compound having strong antibacterial activity, and the skin external preparation of the present invention containing this compound was found to be extremely effective and highly safe, effective against drug-resistant bacteria, and shortening the treatment period of diseases.
The present invention is described in detail below. In addition, all ratios are shown by weight ratio.
[0008]
Although it does not specifically limit as a pyridone carboxylic acid type compound used for this invention, A quinolone drug (life science company, 1991), a pharmaceutical manual 5th edition (pharmaceutical industry bulletin company, 1992), and the 5th edition supplement (medicine) Pyridonecarboxylic acid-based compounds having antibacterial activity, such as those described in Ogokpo (1994), Monthly Mix Vol. 29, No. 3, No. 376) (Mix Corp., 2001) Norfloxacin, levofloxacin, sparfloxacin, ciprofloxacin hydrochloride, tosfloxacin tosylate, sitafloxacin, moxifloxacin hydrochloride, enoxacin, fleloxacin, gatifloxacin, lomefloxacin hydrochloride, grepafloxacin hydrochloride, oramfloxacin , Caderofloxacin, Pullrifloxacin, Trovafloxacin mesylate, Esenofloxacin , Clinafloxacin hydrochloride, ethenofloxacin, alatrofloxacin mesylate, fundfloxacin hydrochloride, irloxacin, gemifloxacin, 1-cyclopropyl-8-difluoromethoxy-7-[(1R)- 2,3-dihydro-1-methyl-1H-isoindol-5-yl] -1,4-dihydro-4-oxo-3-quinolonecarboxylic acid, 1-cyclopropyl-8-difluoromethoxy-7-mesylate [(1R) -2,3-dihydro-1-methyl-1H-isoindol-5-yl] -1,4-dihydro-4-oxo-3-quinolonecarboxylic acid monohydrate, SS-732, SS-734, KRQ-10018, A-99058. L, T-3811, T-3811 methanesulfonate, bicyclic pyridonecarboxylic acid compounds such as WQ-2743, WQ-3034 and Y-688 and tricyclics such as pazufloxacin, pazufloxacin mesylate, ofloxacin, nadifloxacin Examples include pyridonecarboxylic acid compounds.
[0009]
Furthermore, the following general formula [1]
[Chemical formula 2]

“Wherein R ¹ represents a hydrogen atom; R ² represents an optionally substituted cycloalkyl group; R ³ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl, alkoxy or alkylthio group, R ⁴ is an optionally substituted alkyl or alkoxy group; Z is a halogen atom, a hydroxyl group, an optionally substituted alkyl, alkenyl, cycloalkyl, alkoxy, Each represents a pyridin-4-yl or pyridin-3-yl group optionally substituted with one or more groups selected from alkylthio and amino groups. "
And quinolonecarboxylic acid represented by
[0010]
In the general formula [1], the cycloalkyl group is a C _3-6 cycloalkyl group such as cyclopropyl, cyclopentyl, and cyclohexyl; the alkyl group is methyl, ethyl, n-propyl, isopropyl, n- Linear or branched C _1-6 alkyl group such as butyl, isobutyl, sec-butyl, tert-butyl and pentyl; alkoxy group means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Linear or branched C _1-6 alkoxy groups such as isobutoxy, sec-butoxy, tert-butoxy and pentyloxy; alkylthio group means methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio , Isobutylthio, sec-butylthio, tert-butylthio, pentylthio and the like linear or branched C _1-6 alkylthio An alkenyl group means a linear or branched C _2-6 alkenyl group such as vinyl and allyl; and a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, respectively. .
[0011]
In addition, a cycloalkyl group in R ² ; an alkyl group, an alkoxy group or an alkylthio group in R ³ ; a substituent of the alkyl group or alkoxy group in R ^{4 and} a substituent in the pyridyl group of Z, alkyl, alkenyl, cycloalkyl, alkoxy As further substituents of alkylthio or amino group, halogen atom, hydroxyl group, amino group, alkylamino group (methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino , Amino groups substituted with linear or branched C _1-6 alkyl groups such as dipropylamino, dibutylamino and dipentylamino), alkyl groups, alkoxy groups, aryl groups (phenyl, naphthyl, etc.), Examples thereof include a loalkyl group, an alkenyl group, and an alkyl group substituted with a halogen atom.
[0012]
In the general formula [1], R ¹ is a hydrogen atom; R ² is a cycloalkyl group; R ³ is a hydrogen atom; R ⁴ is an alkyl group; Z is a pyridin-3-yl group substituted with an alkylamino group Quinolonecarboxylic acids are preferred, specifically 1-cyclopropyl-8-methyl-7- [5-methyl-6- (methylamino) -3-pyridyl] -4-oxo-1,4-dihydro-3. -Quinoline carboxylic acids.
Further, the pyridonecarboxylic acid compound used in the present invention includes a salt thereof, and the amount used is not particularly limited, but is usually 0.01% to 20%, preferably 0.8 to 5% in the external preparation for skin. I just need it.
[0013]
Examples of the salt of the pyridonecarboxylic acid-based compound used in the present invention include generally known salts such as an amino group or an acidic group such as a hydroxyl group or a carboxyl group. Examples of salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, fumaric acid, maleic acid, malic acid and citric acid; And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and as salts in acidic groups, for example, alkali metals such as sodium and potassium Salts of alkaline earth metals such as calcium and magnesium; ammonium salts; and amino acids such as lysine, arginine and ornithine, trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diet Amine, dicyclohexylamine, procaine, dibenzylamine, N- benzyl -β- phenethylamine, 1-Efenamin and N, and salts with nitrogen-containing organic bases such as N'- dibenzylethylenediamine and the like.
[0014]
Examples of the aliphatic carboxylic acid having 9 to 22 carbon atoms used in the external preparation for skin of the present invention include pelargonic acid, 3-nonenoic acid, capric acid, 9-decenoic acid, lauric acid, palmitoleic acid, oleic acid, and linol. C9-C22 aliphatic carboxylic acid such as acid, linolenic acid, ricinoleic acid, etc., preferably C9-18 aliphatic carboxylic acid, more preferably oleic acid, these may be used alone or in combination You may use together.
The amount of the aliphatic carboxylic acid having 9 to 22 carbon atoms used in the present invention is not particularly limited, but may be 0.01% to 10% in the external skin preparation, preferably 0.5 to 5%. I just need it.
[0015]
Examples of the pyrrolidone derivative used in the external preparation for skin of the present invention include 2-pyrrolidone; 5-methyl-2-pyrrolidone; N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, N-butyl-2- N-alkylpyrrolidones such as pyrrolidone, N-hexyl-2-pyrrolidone, N-octyl-2-pyrrolidone, N-dodecyl-2-pyrrolidone and N-lauryl-2-pyrrolidone are preferable, and N-methyl- 2-pyrrolidone is mentioned, and these may be used alone or in combination of two or more.
Moreover, the usage-amount of the pyrrolidone derivative used for this invention is although it does not specifically limit, For example, it may be 0.1%-50% in a skin external preparation, Preferably, it may be 4-30%.
[0016]
Examples of the polyhydric alcohol used in the present invention include ethylene glycol, glycerin, propylene glycol, polyethylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, tetra Examples include methylene glycol, pentamethylene glycol, diethylene glycol, dipropylene glycol, triethylene glycol, polypropylene glycol, tetraethylene glycol, diglycerin, triglycerin, tetraglycerin, polyglycerin and the like, preferably propylene glycol, glycerin and polyethylene glycol. These polyhydric alcohols may be used alone or in combination of two or more. Good.
Moreover, the usage-amount of the polyhydric alcohol used for this invention is although it does not specifically limit, For example, it may be 1-50% in a skin external preparation, Preferably, it may be 4-30%.
Among the above, propylene glycol, polyethylene glycol 400 and glycerin also have an effect as a skin irritation inhibitor when used in the skin external preparation of the present invention.
[0017]
The external preparation for skin of the present invention preferably uses a base in addition to the pyridone carboxylic acid compound, the pyrrolidone derivative, the aliphatic carboxylic acid having 9 to 22 carbon atoms and the polyhydric alcohol. The base used in the present invention is not particularly limited as long as it is a compound having an action of adjusting pH. For example, metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; Examples include hydroxy lower alkyl amines such as ethanolamine, monoisopropanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine and 2-amino-2-methyl-1,3-propanediol, preferably hydroxy A lower alkylamine is mentioned. Furthermore, preferably, monoethanolamine, diethanolamine, diisopropanolamine and triethanolamine are mentioned, and still more preferably, diisopropanolamine is mentioned.
These bases may be used alone or in combination of two or more. In addition, the amount of base used in these external preparations for skin is not particularly limited, but more specifically, for example, 0.01 to 20% in skin external preparations, and more preferably 1 to 5%. That's fine. Moreover, when the skin external preparation of this invention is adjusted with a base, the pH of a preferable skin external preparation is 9.5-11.
[0018]
The skin external preparation of the present invention can further use a water-soluble polymer. Examples of the water-soluble polymer used in the external preparation for skin of the present invention include vinyl polymers such as polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone and carboxyvinyl polymer (Carbopol); polyethylene glycol 400, polyethylene glycol 4000 Polyoxyethylene polymers such as polyethylene glycol 20000, polyethylene glycol 4000000 and polyethylene glycol 600000; polyoxyethylene polyoxypropylene copolymer copolymers; acrylics such as sodium polyacrylate, polyethyl acrylate and polyacrylamide Polymers: polyethyleneimine, cationic polymer, methylcellulose, hydrophobized hydroxypropylmethylcellulose, hydroxyethylcellulose and hydroxy Cypropyl cellulose and the like can be mentioned, and preferably, carboxyvinyl polymer can be mentioned, and these water-soluble polymers may be used alone or in combination of two or more.
Moreover, the usage-amount of the water-soluble polymer used for this invention is although it does not specifically limit, For example, it may be 0.1-5% in a skin external preparation, Preferably, it may be 0.7-2%.
[0019]
The external preparation for skin of the present invention may be used as it is by mixing the components as appropriate, but in consideration of the feeling of use and ease of application, ointment preparation, gel preparation, cream preparation, lotion preparation, emulsion, adhesive What is necessary is just to mix and use in formulation adjuvants, such as a pharmaceutically acceptable base used for a tape agent, an excipient | filler, a carrier, and a diluent, for example, an ointment formulation, a gel formulation, and a lotion formulation. It is preferable to do.
The dose and the number of doses can be appropriately selected according to the age, weight and symptoms of the patient. Usually, the amount that the transdermal preparation can exert its medicinal effect is divided into 1 to several times a day, and transdermally administered. For example, when the drug is Compound A, 30 to 2000 mg per day may be administered transdermally once to several times.
[0020]
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLES Hereinafter, although an Example and a reference example are given and this invention is demonstrated further more concretely, this invention is not limited to these Examples.
【Example】
Compound A: 1-cyclopropyl-8-methyl-7- [5-methyl-6- (methylamino) -3-pyridyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid

After adding 3, 2, 5, 4, 8, 1 above, stirring and heating at about 65 ° C. were repeated while 7 was added, and further 9 was added and stirred to obtain a solution having a pH of 10.22. 6 was added to the resulting solution and stirred to obtain a gel preparation.
[0021]

The above 2, 3, 4, 5 were added in order and stirred. 1 was added to the obtained mixture, and after heating at 70-80 degreeC, heating and stirring were repeated, adding 8 and 9, and pH was adjusted to 10.79. Furthermore, 6 and 7 were added, and it heated at 70-80 degreeC, and stirred. After leaving overnight, 10 was added, and the mixture was again dissolved by heating at 70 to 80 ° C., then stirred and returned to room temperature to obtain an ointment preparation.
[0022]

The above 3, 2, 4, 8, 1 were added in order, and after stirring, 6 was added and stirred. Next, 5 was added, followed by stirring while adding 7. The pH was adjusted, and 9 was further added and stirred to obtain a gel preparation having a pH of 10.36.
[0023]

The above 2, 3, 4, 8, 5 were added in order and stirred. Then 6 was added and after stirring, 1 was added and stirred. The mixture was further stirred while adding 7 to adjust the pH, and further 9 was added and stirred to obtain a gel preparation having a pH of 10.34.
[0024]

Add 8 and 6 above and stir, add 7 and stir, add 1 and stir. Separately added 2, 3, 4, and 5 mixed solvents were added to the resulting mixture in several portions while stirring. 9 was added to the obtained mixture, and after stirring, the mixture was allowed to stand overnight to obtain a gel preparation having a pH of 10.04.
[0025]

It added in order of said 2, 3, 4, 1 and stirred, 7 was added, and after stirring, 8 was added and stirred. Next, 5 and 6 were added, and stirring was repeated to obtain a gel preparation having a pH of 10.17.
[0026]

It added in order of said 2,4,3, and 9 was added and stirred after stirring. Then 5 and 6 were added and stirred, 1 was added and stirred. Further, 7 was added, and after stirring, stirring and heating at about 60 ° C. were repeated while adding 8, and the pH was adjusted to obtain a gel preparation having a pH of 10.28.
[0027]

The above 2, 4 and 3 were added in order, and after stirring, 5 was added and stirred. Then 7 was added and stirred, 1 was added and stirred. Furthermore, the pH was adjusted by stirring while adding 6 to obtain a gel preparation having a pH of 10.38.
[0028]

The above 2, 3, 4, 5 were added in order and stirred, then 7 was added and stirred. Add 1 to the resulting mixture, stir and warm to about 60 ° C. Further, heating and stirring were repeated while adding 6 to adjust the pH to obtain a lotion preparation having a pH of 10.29.
[0029]

The above 1 and 5 were added in order, and after stirring, 3 was added and stirred. Then, 2 was added and stirred, 7 was added, and after stirring, 4 was added and stirred. Next, stirring and heating at about 65 ° C. were repeated while 6 was added, and 8 was added. Furthermore, 6 was added, and the mixture was stirred and the pH was adjusted to obtain a gel preparation having a pH of 10.18.
[0030]

The above 1, 3, 2, 4, 7 were added in order, and after stirring, the mixture was heated to about 75 ° C. Next, heating and stirring were repeated while 6 was added, 8 was added and stirred, and the pH was adjusted to 10.07. Next, 5 was added and stirred to obtain a gel preparation.
[0031]
The following tests were conducted on the preparations obtained above or manufactured by the methods described in Test Examples.
Test Example 1 (Solubility test)
1 part by weight of Compound A is added to a solution having the composition shown in Table 1 below. A solution containing 0.138 parts by weight, 0.055 parts by weight, 0.028 parts by weight, and 0.000 parts by weight of sodium hydroxide with respect to the number of moles of Compound A prepared with a 5 mol / l sodium hydroxide aqueous solution was added to the resulting suspension. . This was prepared for each of the three solvents [A] (N-methyl-2-pyrrolidone, isopropanol, purified water). A sufficient amount of the compound A remaining undissolved in the 12 types of solutions thus obtained was added, followed by vigorous stirring with heating to obtain a suspension.
[0032]
[Table 1]

“In the table, the solvent [A] means a solvent selected from N-methyl-2-pyrrolidone, isopropanol, and purified water.”
[0033]
After standing at room temperature for 4 days, undissolved compound A was centrifuged, and the pH of the supernatant and the concentration (solubility) of compound A were measured. The results are shown in Table 2.
[0034]
[Table 2]

[0035]
An approximate curve was obtained from the plot of the solubility and pH of Compound A in each composition solution containing the solvent [A], and extrapolated from the curve to determine the solubility at pH 10.30. As a result, the drug dissolution concentration was 12913 μg / mL for N-methyl-2-pyrrolidone (a composition described in the present application), 9860 μg / mL for isopropanol, and 3931 μg / mL for purified water.
From this result, in the composition described in the present application using N-methyl-2-pyrrolidone, the concentration of the drug can be set high at the same pH, and efficient skin permeation of the active ingredient can be performed.
[0036]
Test Example 2 (In vitro skin permeability test)
After male ICR mice were dislocated from the cervical spine, the skin surface of the back of the mice was shaved with an electric clipper and an electric shaver. The shaved portion was peeled off, the fat content on the inside of the skin was removed, then immersed in physiological saline, and stored overnight in the refrigerator. After degassing a mixture of polyethylene glycol 400 and phosphate buffer 1: 1 with boiling treatment, it was added to the receiver side of the Franz diffusion cell, and the above skin with excess water removed was attached to the cell. . 0.5 mL of each test preparation was placed on the donor side, and the receiver solution was kept at 37 ° C. The donor side was covered with aluminum foil and film (Parafilm: manufactured by American National Can), and the receiver solution was collected after 24 hours, and the amount of each drug was measured. The results are shown in Table 3.
[0037]
[Table 3]
-----------------
Test preparation Cumulative permeation amount (μg / cm ² )
-----------------
Example 1 363
Example 3 830
Example 6
Example 8 317
Reference Example 1 173
Reference Example 2 45
-----------------
[0038]
Test example 3 (antibacterial activity comparison test)
Using an ICR mouse, the back hair was shaved with an electric shaver after anesthesia. A weight (φ20mm) heated to 100 ° C was applied to the shaved back skin to create a heat sore. After 1 hour, 0.2 ml (1.0 x 10 ⁷ CFU / mouse) of S.aureus SA 113 was subcutaneously in the heat sore. ) Or 0.2 ml (5.0 × 10 ⁶ CFU / mouse) of P. acnes JCM6425 bacterial solution. Each test preparation (Example 3 preparation, nadifloxacin 1% cream (commercial product), clindamycin 1% gel (commercial product), and gentamicin 0.1% cream (commercial product) 10 mg were applied to heat acne 2 hours after inoculation with the bacterial solution. 24 hours after inoculation with the bacterial solution, the test preparation was removed, the part of the heat sore was peeled off, and homogenized in sterile physiological saline.The obtained homogenate solution was diluted with sterile physiological saline and then Mueller containing 50 mM magnesium chloride.・ The number of colonies was measured after spreading on Hinton agar and culturing for 24 hours at 37 ° C. The logarithmic values (Log CFU / hiff) of the number of colonies forming per skin 24 hours after inoculation with the bacterial solution are shown in Table 4 and Table 5. Show.
[0039]
[Table 4]
Number of colonies in the group to which the test drug was applied 2 hours after inoculation with the bacterial solution (S. aureus SA 113)
------------------------------
Test drug name ------------------------------
Control 7.32
Example 3 5.77
Nadifloxacin 6.26
Clindamycin 5.74
Gentamicin 6.84
------------------------------
[0040]
[Table 5]
Number of colonies in the group to which the test drug was applied 2 hours after inoculation (P.acnes JCM 6425)
------------------------------
Test drug name ------------------------------
Control 6.96
Example 3 4.70
Nadifloxacin 6.10
Clindamycin 5.60
Gentamicin 6.01
------------------------------
From these results, it was shown that the skin external preparation of the present invention has a markedly reduced number of viable bacteria as compared with a commercially available drug and has a very good therapeutic effect.
[0041]
【The invention's effect】
The external preparation for skin of the present invention contains a pyridone carboxylic acid compound as an active ingredient, and when applied to the skin, the active ingredient intended for local action penetrates rapidly and deeply into the skin, and contagious impetigo. In addition, it is an external preparation for skin that exhibits an excellent therapeutic effect on diseases such as superficial skin infections including acne vulgaris, and hardly gives any irritation to the application site. In addition, the external preparation for skin of the present invention is effective and highly safe, is effective against drug-resistant bacteria, and can shorten the disease treatment period.

Claims (1)

1-cyclopropyl-8-methyl-7- [5-methyl-6- (methylamino) -3-pyridyl] -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid or a salt thereof , N-methyl An external preparation for skin comprising 2-pyrrolidone , oleic acid, propylene glycol, carboxyvinyl polymer and hydroxy lower alkylamine .