JPWO2011010456A1 - NSAIDs含有外用剤及び当該外用剤の製造方法 - Google Patents
NSAIDs含有外用剤及び当該外用剤の製造方法 Download PDFInfo
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- JPWO2011010456A1 JPWO2011010456A1 JP2011523554A JP2011523554A JPWO2011010456A1 JP WO2011010456 A1 JPWO2011010456 A1 JP WO2011010456A1 JP 2011523554 A JP2011523554 A JP 2011523554A JP 2011523554 A JP2011523554 A JP 2011523554A JP WO2011010456 A1 JPWO2011010456 A1 JP WO2011010456A1
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- nsaids
- trehalose
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Abstract
Description
本発明において,凍結乾燥工程は,減圧下で凍結状態の試料から水を昇華させる工程である。凍結乾燥工程は,以下の工程で行われる。(1)試料(混合溶液)を室温4℃,常圧下に2〜3時間置き,冷却する(冷却工程)。(2)室温−50℃,常圧下に12〜15時間置き,凍結させる(凍結工程)。(3)室温−20℃,常圧下に4〜6時間置き結晶化させる。(結晶化工程)。(4)室温−50℃,常圧下に14〜16時間置き,再凍結させる(再凍結工程)。(5)室温−13℃,圧力10〜20kPa下(高真空下)に24〜26時間置く(第1乾燥工程)。(6)室温24℃,圧力10〜20kPa下(高真空下)に10〜121時間置く(第2乾燥工程)。(7)室温24℃,常圧下に置く。このように凍結乾燥法では,低温で凍結させ,高真空下で水分(氷)を昇華させて除いていく。本発明の凍結乾燥物は,上記の方法で製造できる。しかし,上記工程に限定されるものではなく,当業者であれば,適宜各工程の温度,圧力,時間などのパラメータに変更を加えることができる。
本発明において,流動層造粒乾燥工程は,水分を含む試料に温風を当てて流動させながら,造粒乾燥する工程である。流動層造粒乾燥工程は,公知の流動層造粒乾燥機を用いて以下の工程で行われる。(1)試料(混合溶液)を撹拌しながら,温度50〜100℃,風速1〜2m/sの温風を10〜30分あてる(略乾燥工程)。(2)試料に温度20〜50℃,風速2〜3m/sの温風30分〜1時間あてる(造粒工程)。(3)試料に温度50〜100℃,風速1〜2m/sの温風を30分〜2時間あてる(乾燥工程)。(4)試料に温度5〜20℃,風速1〜2m/sの冷風を10〜60分あてる(冷却工程)。このように流動造粒乾燥工程では,試料に温風をあて,試料を空中で流動させながら,乾燥させることで造粒していく。本発明の分子間化合物は,上記工程で製造することができる。しかし,上記工程に限定されるものではなく,当業者であれば,試料の水分量などに応じて,適宜各工程の温度,風速等のパラメータを変更することができる。
本発明において,スプレードライ(噴霧乾燥)工程は,試料溶液を熱風とともに細い孔径のノズルから噴霧し,チャンバー内で微小な液滴とし,短時間で乾燥させる工程である。スプレードライ工程は,公知のスプレードライヤー(噴霧乾燥機)を用いて,以下の工程で行われる。(1)試料(混合溶液)を孔径0.5〜1mmのノズルから,100〜300℃の熱風とともに,チャンバー内に,空気圧0.5〜2.5kg/m2,流量25〜50L/minで噴霧する(噴霧工程)。(2)噴霧した試料に温度150〜300℃,速度0.5〜1m/sの熱風をあて,30秒〜5分乾燥させる(乾燥工程)。このようにスプレードライ工程では,試料を高温チャンバー内にスプレーしてできた微小な液滴に熱風をあてることで,分子間化合物が造粒される。本発明の分子間化合物は,上記工程で製造することができる。しかし,本発明は,上記工程に限定されるものではなく,当業者であれば,適宜各工程の温度,時間等のパラメータを変更することができる。
本発明において,乾燥粉砕造粒工程は,水分を含む試料を乾燥させた後,粉砕することで造粒物を得る工程である。乾燥粉砕造粒工程は,以下の工程で行われる。(1)試料(混合溶液)に50〜80℃の温風をあてながら,撹拌速度10〜100回転/分で1〜5時間撹拌する(乾燥工程)。(2)乾燥した試料に5〜15℃の冷風をあて,冷却させる(冷却工程)。(3)冷却させた試料を粉砕機で粉砕する(粉砕工程)。(4)粉砕した試料を所定サイズのふるい機でふるいにかける(ふるい工程)。このように乾燥粉砕造粒工程では,一度大きな塊として製造した試料を粉砕することで所望サイズの粒が製造される。本発明の分子間化合物は,上記工程で製造することができる。しかし,上記工程に限定されるものではなく,当業者であれば,適宜各工程の温度,時間等のパラメータを変更することができる。
1.被験物質
NSAIDsとして,アスピリン,インドメタシン,イブプロフェン,ジクロフェナクナトリウムを使用した。アスピリン,インドメタシン,イブプロフェンは和光純薬工業株式会社から,ジクロフェナクナトリウムはカイマン(Cayman)化学株式会社から購入した。トレハロースは株式会社林原生物化学研究所製,カルボキシメチルセルロース・ナトリウム(CMC・Na)は第一工業製薬株式会社製のものを使用した。
トレハロースは精製水(ミリQグレード(milliQ水))にて30%(w/v)溶液を調製した。各種NSAIDsは,エチルアルコール(99.5%)にて適量を溶解し,トレハロース溶液と望ましい比率にて混合し,十分に撹拌した後,凍結乾燥機(東京理化器機株式会社製,EYELA 凍結乾燥機,FDU−1100)を用いて48時間以上乾燥させた。
(1)トレハロースをミリQ(milliQ)水に溶解し,30w/v%トレハロース溶液を作製した。
(2)1.0gNSAIDsを2.0mLエチルアルコールに溶解した。
(3)必要量のトレハロース溶液を各NSAIDs溶解エチルアルコール溶液に添加した。インドメタシン及びイブプロフェンは,この段階で必要量のトレハロース溶液を全量加えると沈殿する。そのため,沈殿しない最大量のトレハロース溶液を添加したのち,10〜20分程度撹拌した。
(4)最終エチルアルコール濃度が10%以下(より好ましくは5%以下)になるように,milliQ水を適量加えた。アスピリン及びジクロフェナクナトリウムは,沈殿がほぼ見られないので,この段階で10〜20分程度撹拌した。
(5)凍結乾燥機(東京理化器機株式会社製,EYELA 凍結乾燥機,FDU−1100)にかけ,48時間以上乾燥させた。
NSAIDs(インドメタシン,イブプロフェン,アスピリン,ジクロフェナク,ピロキシカム,及びメフェナム酸)とトレハロースの分子間相互作用を検討するために示差走査熱量測定法(DSC)を用いて測定を行った。それぞれ,トレハロース単独,NSAIDs単独,トレハロースとNSAIDsの混合物,トレハロースとNSAIDsとの凍結乾燥物に対してDSCを用いて測定を行った。トレハロースとNSAIDsの重量比は下記表5に示した。
そして,凍結乾燥物の第1のピーク及び第2のピークの頂点の絶対値は,ピロキシカム単独のDSC曲線における90〜105℃及び195〜205℃のピーク頂点の絶対値よりも大きい。このように混合物と凍結乾燥物とでDSCの結果が異なり,さらにピロキシカム単独と凍結乾燥物のDSCの結果も異なることから,ピロキシカムとトレハロースを共溶解後,凍結乾燥することで,ピロキシカムとトレハロースの分子間化合物が形成されたことが明らかになった。
NSAIDs含有軟膏製剤の細胞生存率への影響について,ヒト皮膚再構築モデルであるテストスキン(TEST SKIN)(TOYOBO社製)を用いて検討した。表2に示したNSAIDsとトレハロースを含む分子間化合物製剤は,NSAIDsとトレハロースを含む混合溶液を凍結乾燥させることで得られた。各NSAIDs含有軟膏剤は,各NSAIDsが下記表2の右側に示した最終濃度(w/v%)となるように,各分子間化合物製剤と親水軟膏とを混合することで得られた。シリコンリングでシーリングしたテストスキン表面に各NSAIDs含有軟膏剤100mgを塗布した。その後,テストスキンを37℃インキュベータ内で20時間培養した。組織を傷つけないように,表面に塗布した軟膏を洗浄した。MTT溶解アッセイ培地でさらに3時間培養後,MTT発色を確認し,培養皮膚をパンチで切断した。切断した組織片を0.04Mの塩酸−イソプロピルアルコール(HCl−IPA)溶液300μLに浸漬し,室温,遮光下にて青色ホルマザンを16時間抽出した。抽出溶液を分光光度計にて測定した。570nmの吸光度より細胞の生存率を算出した。その結果を図7に示した。図7において,符号treはトレハロースを示し,indoはインドメタシンを示し,(lyo)は凍結乾燥を示し,dicはジクロフェナクを示し,ibuはイブプロフェンを示し,piroはピロキシカムを示し,felはフェルビナクを示す。また,図7における「コントロール」は,軟膏を添加せずに培養皮膚単体で20時間培養し,その後,上記と同様の手順でMTTアッセイを行った場合を示しており,対照実験に相当する。したがって,図7における「コントロール」は,細胞生存率100%の基準となっている。
NSAIDsとトレハロースとの混合物と,NSAIDsとトレハロースとの分子間化合物との細胞毒性を検証する実験(細胞毒性試験)を行った。
具体的には,重量比が1:20のジクロフェナク−マルトース(Dic−Mal)凍結乾燥物を,ジクロフェナクの最終濃度が1mMとなるようにDMEM培地(シグマ社製)に添加し,完全に溶解させた。この培地を上皮細胞Ca9−22細胞に加え,16時間培養した。その後,細胞の生存率を測定した。細胞生存率の測定には,インビトロジェン社製,Molecular Probes(登録商標)のLIVE/DEAD生存率毒性キットを用いた。
実施例1と同様にして5−ASAについてもDSC実験を行った。図15は,トレハロース単独,5−ASA単独,5−ASA・トレハロース混合,あるいは5−ASA・トレハロース凍結乾燥物のDSC結果を示す図面に替わるグラフである。
実施例1と同様にしてケトプロフェンについてもDSC実験を行った。図16は,トレハロース単独,ケトプロフェン単独,ケトプロフェン・トレハロース混合,あるいはケトプロフェン・トレハロース凍結乾燥物のDSC結果を示す図面に替わるグラフである。
実施例1と同様にしてナプロキセンについてもDSC実験を行った。図17は,トレハロース単独,ナプロキセン単独,ナプロキセン・トレハロース混合,あるいはナプロキセン・トレハロース凍結乾燥物のDSC結果を示す図面に替わるグラフである。
Claims (24)
- 非ステロイド系消炎鎮痛剤(NSAIDs)と2糖類との分子間化合物を含み,これにより,NSAIDs誘発性皮膚障害を抑制する外用剤。
- 前記分子間化合物は,
前記NSAIDsと前記2糖類とを含む混合溶液を乾燥させて得られたものである,
請求項1に記載の外用剤。 - 前記2糖類は,トレハロースであり,
前記分子間化合物は,
前記NSAIDsと前記トレハロースとを10:1〜1:50の重量比で含む,
請求項1に記載の外用剤。 - 前記NSAIDsは,酸性NSAIDsである,請求項1に記載の外用剤。
- 前記NSAIDsは,
インドメタシン,イブプロフェン,アスピリン,ジクロフェナクナトリウム,メフェナム酸,ピロキシカム,ロキソプロフェン,ケトプロフェン,フルルビブロフェン,サリチル酸グリコール,グリチルレチン酸,ロキソニン,スプロフェン,ブフェキサマク,ウフェナマート,ジメチルイソプロピルアズレン,5−アミノサルチル酸及びナプロキセンのいずれか1つ又は2つ以上を含む,
請求項1に記載の外用剤。 - 前記NSAIDsは,フェルビナクである,
請求項1に記載の外用剤。 - 油脂性基剤をさらに含む,請求項1に記載の外用剤。
- 共溶媒をさらに含む,請求項1に記載の外用剤。
- 局所麻酔剤をさらに含む,請求項1に記載の外用剤。
- リドカイン,テトラカイン,プロカイン,ジブカイン,ベンゾカイン,ブピバカイン,メピバカイン,アミノ安息香酸エチル,パラブチルアミノ安息香酸ジエチルアミノエチル,メプリルカイン,オキシポリエトキシドデカン,ロートエキス,又はその塩のいずれかの1種又は2種以上をさらに含む,請求項1に記載の外用剤。
- 前記NSAIDsは,インドメタシンであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線の第1のピークと第2のピークの頂点が,それぞれ80〜95℃と260〜270℃に存在する,
請求項1に記載の外用剤。 - 前記NSAIDsは,イブプロフェンであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線の第3のピークと第4のピークの頂点が,それぞれ175〜190℃と130〜145℃に存在する,
請求項1に記載の外用剤。 - 前記NSAIDsは,アスピリンであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線の第1のピークと第2のピークの頂点が,それぞれ110〜120℃と135〜145℃に存在する,
請求項1に記載の外用剤。 - 前記NSAIDsは,ジクロフェナクナトリウムであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線の第1のピークと第2のピークの頂点が,それぞれ90〜100℃と130〜145℃に存在する,
請求項1に記載の外用剤。 - 前記NSAIDsは,メフェナム酸であり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線の第1のピークと第2のピークの頂点が,それぞれ225〜235℃と90〜110℃に存在し,さらに,180〜190℃及び250〜265℃にもピークが存在する,
請求項1に記載の外用剤。 - 前記NSAIDsは,ピロキシカムであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線の第1のピークと第2のピークの頂点が,90〜105℃と195〜205℃に存在し,前記195〜205℃における第2のピークは,190〜220℃におけるメインピークである,
請求項1に記載の外用剤。 - 前記NSAIDsは,5−アミノサルチル酸であり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線が207〜215℃にピークが存在し,95〜105℃にピークが存在しない曲線である,
請求項1に記載の外用剤。 - 前記NSAIDsは,ケトプロフェンであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線が90〜95℃及び230〜235℃にピークが存在し,180〜220℃にピークが存在しない曲線である,
請求項1に記載の外用剤。 - 前記NSAIDsは,ナプロキセンであり,
前記分子間化合物は,
示差走査熱量測定法(DSC)による測定で得られたDSC曲線が90〜95℃及び234〜237℃にピークが存在し,225〜233℃にピークが存在しない曲線である,
請求項1に記載の外用剤。 - 前記2糖類は,マルトースである,
請求項1に記載の外用剤。 - 前記2糖類は,トレハロース,マルトース,ショ糖,及びラクトースから選択された1つ以上を含む,
請求項1に記載の外用剤。 - 非ステロイド系消炎鎮痛剤(NSAIDs)と2糖類とを含む混合溶液を調製する工程と,
前記混合溶液を乾燥させる工程と,
を含み,
前記乾燥させる工程は,乾燥させた混合溶液と基剤とを混合する工程を含み,
これにより,前記NSAIDsと前記2糖類とが分子間化合物を形成することでNSAIDs誘発性皮膚障害を抑制することが可能な外用剤を製造する,
外用剤の製造方法。 - 非ステロイド系消炎鎮痛剤(NSAIDs)と2糖類とを含む混合溶液を調製する工程と,
前記混合溶液を乾燥させる工程と,
乾燥させた前記混合溶液と,基剤と,共溶媒とを混合する工程と,
を含み,
これにより,前記混合溶液の乾燥により得られる分子間化合物と,前記共溶媒と,前記基剤との混合物である外用剤を製造する,
外用剤の製造方法。 - 前記2糖類は,トレハロース,マルトース,ショ糖,及びラクトースから選択された1つ以上を含む,
請求項23又は請求項24に記載の外用剤の製造方法。
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JP2000212065A (ja) | 1999-01-14 | 2000-08-02 | Tendou Seiyaku Kk | 肛門用坐剤 |
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