JP2004002320A - Liquid matrix causing in-vivo phase transition and liquid oral preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid pharmaceutical matrix which easily solubilizes, disperses or suspends a drug, is easily swallowed as it is in a liquid state, exhibits high operability in sterilization and the like, is stable, has effects for masking bitterness, and controls the delivery speed of a drug by in-vivo gelation, and also to provide an oral liquid preparation utilizing the same. <P>SOLUTION: The liquid matrix is a liquid adjuvant which makes it easy to swallow a drug and contains a water-soluble polymer which gels under an acidic condition, where the gel has a breaking stress of at least about 3.0×10<SP>3</SP>N/m<SP>2</SP>. The oral liquid preparation exhibits high-level sustained releasability though it is liquid. <P>COPYRIGHT: (C)2004,JPO

Description

【００８０】
【表２】

【００８１】
尚、アルギン酸ナトリウムの構成成分は、β−Ｄ−マンヌロン酸及びα−Ｌ−グルロン酸のナトリウム塩であり、これら糖酸のナトリウム塩の分子量は共に約２１７で糖１つにつき１つずつカルボキシル基を有するので、それぞれのアルギン酸ナトリウム濃度におけるカルボキシル基のモル数を、概算することができる。
【００８２】
表１及び表２の結果より、本発明の液状マトリックスを均一にゲル化させるために金属陽イオンを遊離する不溶性塩類を含有させる場合には、水溶性高分子がその構造中に有するカルボキシル基又はスルホン酸基と不溶性塩類が有する金属陽イオンとのモル比は、前者１に対して後者は少なくとも１以上であることが好ましいことが分かった。
【００８３】
（実施例２）
２種の水溶性高分子を混合して様々なゲル強度（ゲル剪断応力）を有するゲルに転換するよう液剤を調整し、薬剤の徐放性試験を行なった。
【００８４】
蒸留水１００ｍｌに水溶性高分子としてκカラギーナンとローカストビーンガムとを混合比を変えて加え、十分に攪拌し、様々なゲル強度を有するゲルに転換するような液状マトリックスを複数調製した。更に最終濃度が０．０２％となるようにリボフラビンを加え、ｐＨを７．４に調整して液剤を調製した。
【００８５】
このリボフラビン−液状マトリックス１ｍｌを、日本薬局方崩壊試験１液３０ｍｌが入ったチューブの中に壁面を通じて垂らし、リボフラビン−液状マトリックスが胃内に導入された場合の再現実験を行なった。リボフラビン−液状マトリックスは、崩壊試験１液と接触すると同時にゲル化した。それぞれのゲル強度は、破断応力（Ｎ／ｍ^２）として、山電クリープメーターＨＣ２−３８０５で測定した。
【００８６】
当該ゲルを崩壊試験１液中に完全に落し込んだ後、３７℃で震盪して１２０分後のリボフラビンの放出を測定した。この放出されたリボフラビンの定量法は、「第十三改正日本薬局方解説書」廣川書店、１９９６年のＣ−２６６０〜２６６７に従い、４４５ｎｍにおける吸光度を測定して比色定量した。当初ゲル内のリボフラビン量を１００として、崩壊試験１液中に放出されたリボフラビン量のパーセンテージを計算した。ゲル強度とリボフラビンとの放出率との関係を図１に示す。
【００８７】
図１に示した通り、ゲル強度が高い程リボフラビンはゲル内に担持され薬剤は徐放性を示す。即ち、３７℃で震盪して１２０分後においてもゲル内に薬剤が残存していれば、徐放性を有していると評価できる。一方、ゲル強度が低いとリボフラビンは直に放出され、徐放性を示すことができない。即ち、通常、徐放性のないゲルの場合、３７℃の崩壊試験１液に浸漬した場合、直ちに薬剤を放出し、約２０分でゲルとしての形状を喪失する。ここで、３７℃に加温した崩壊試験１液に１２０分間浸漬し、ゲル中に薬剤が１０％以上残存する場合を、徐放性を得るための最低ゲル強度とした。得られた結果より、この時の破断応力は、約３．００×１０^２Ｎ／ｍ^２であった。
【００８８】
（実施例３）
蒸留水１００ｍｌにアルギン酸ナトリウム１ｇ、ＬＭペクチン１ｇをそれぞれ加えて完全に溶解した後、炭酸カルシウム１ｇを加えて十分に攪拌し、液状マトリックスを２つ作製した。この溶液にリボフラビン１００ｍｇを加えて溶解し、ｐＨを７．４に調製した。
【００８９】
このリボフラビン−液状マトリックス１ｍｌを、実施例２と同様に処理してゲル化させた。当該ゲルの強度を実施例２と同様に測定したところ、１％アルギン酸ナトリウムのもので１．０２×１０^４Ｎ／ｍ^２、１％ＬＭペクチンのもので５．５９×１０^３Ｎ／ｍ^２であった。当該ゲルからのリボフラビン放出量を測定した。当初ゲル内のリボフラビン量を１００として、崩壊試験１液中に放出されたリボフラビン量のパーセンテージを計算した。その結果を図２に示す。
【００９０】
図２に示した通り、水溶性高分子としてアルギン酸を用いた場合、ＬＭペクチンを用いた場合共に、リボフラビンは急激に試験液中に放出されることなく徐々に放出されていることがわかった。従って、本発明の経口液剤は、高い徐放性を示すことが実証された。
【００９１】
（実施例４）
蒸留水１００ｍｌにアルギン酸ナトリウム１ｇを加えて完全に溶解した後、炭酸カルシウム１ｇを加えて十分に攪拌し、液状マトリックスを作製した。この溶液にアセトアミノフェン（吉富ファイン化学株式会社）１０ｍｇを加えて溶解し、ｐＨを７．４に調製した。
【００９２】
このアセトアミノフェン−液状マトリックス１ｍｌを、１００ｍｌの日本薬局方崩壊試験１液に滴下し、アセトアミノフェン−液状マトリックスが胃内に導入された場合の再現実験を行なった。滴下されたアセトアミノフェン−液状マトリックスは直ちにゲル化された。当該ゲルの強度は、１．０２×１０^４Ｎ／ｍ^２だった。このゲルからのアセトアミノフェンの放出を測定した。この放出されたアセトアミノフェンの定量法は、「第十三改正日本薬局方解説書」廣川書店、１９９６年のＣ−６９〜７３に従い、２４４ｎｍにおける吸光度を測定して比色定量した。当初ゲル内のアセトアミノフェン量を１００として、崩壊試験１液中に放出されたアセトアミノフェン量のパーセンテージを計算した。その結果を図３に示す。
【００９３】
図３に示した通り、アセトアミノフェン−液状マトリックスが胃内に導入された場合には、水溶性高分子がゲル化し、アセトアミノフェンが徐々に放出されていることがわかった。従って、本発明の経口液剤は、高い徐放性を示すことが証明された。
【００９４】
（実施例５）
実施例４で調整したアセトアミノフェン−液状マトリックスを１２１℃で３０分間高圧滅菌処理後、自然減圧し供試試料とした。
【００９５】
対象例として、特許文献２（特開平８−９９８８５号公報）の記載を参考にして粘度安定性制酸性組成物を調整した。即ち、アルギン酸ナトリウム２．５ｇ及び水酸化アルミニウム／炭酸マグネシウムゲル（５６％Ａｌ_２Ｏ_３，４％ＭｇＯ）２８ｇを精製水約７５ｍｌに加え、約８０℃で３０分攪拌した。この加熱した反応混合物を、約２５℃に保った炭酸マグネシウム３５ｇの水性懸濁液約４００ｍｌ中へ攪拌しながら速やかに混和した。更にアルギン酸ナトリウム４７．５ｇをこの混合物に加え、キサンタンガム１ｇ、炭酸カルシウム１５ｇ及び炭酸水素カリウム１０ｇをそれぞれ添加した後、精製水を加えて１ｌにした。調製した対象例を、本発明のアセトアミノフェン−液状マトリックスと同様に、高圧滅菌処理した。
【００９６】
両試料の高圧滅菌処理後の様子を図４に示す。
【００９７】
図４の通り、本発明の経口液剤は高圧滅菌処理を施しても安定した状態を保つのに対し、対象例では完全に水層とゲル層に分離した。従って、本発明の経口液剤は、滅菌操作性が非常に高いことが分かった。
【００９８】
（実施例６）
実施例２と同様に、蒸留水１００ｍｌに（ｉ）０．５％アルギン酸−０．５％ペクチン、（ｉｉ）１％アルギン酸−１％ペクチンとなるように２種ずつの水溶性高分子を加えて完全に溶解した後、リン酸カルシウム１ｇを加えて十分に攪拌し、液状マトリックスを調製した。この溶液にリボフラビン１００ｍｇを加えて溶解し、ｐＨを７．４に調製した。
【００９９】
調製した２種の液状薬剤をそれぞれ日本薬局方崩壊試験１液に６時間浸漬してゲル化させた。当該ゲルの強度は、０．５％アルギン酸−０．５％ペクチンのもので３．０２×１０^３Ｎ／ｍ^２、１％アルギン酸−１％ペクチンのもので１．００×１０^４Ｎ／ｍ^２だった。当該ゲルを取出し、付着した日本薬局方崩壊試験１液を濾紙により除去した後、日本薬局方崩壊試験２液に浸漬することにより、リボフラビン−液状マトリックスが胃を経て更に小腸へ移行された場合の再現実験を行なった。ゲルから放出されたリボフラビンの放出を、実施例２と同様に測定した。その結果を図５に示す。
【０１００】
図５に示す通り、本発明の経口液剤においては、その構成成分である水溶性高分子の選択或いは組合わせを工夫することにより、ゲルの物理的強度を調節し、胃内のみならず小腸においてもゲルの崩壊を制御することができ、高い徐放性を発揮できることが分かった。
【０１０１】
（実施例７）
健常成人男性６名を被験者として、種々の濃度（粘度）に調製したアルギン酸ナトリウム水溶液を使用して、服用の容易性について官能試験を行なった。結果を表３に示す。
【０１０２】
【表３】

【０１０３】
本実施例の結果により、服用の容易性を考慮すれば、液状マトリックスの粘度は３．０×１０^{− １}Ｐａ・ｓ以下が好ましいことが明らかとなった。
【０１０４】
（実施例８）
健常成人男性６名を被験者として、１％の濃度に調製したアルギン酸ナトリウム水溶液２０ｍｌに苦味成分として塩化マグネシウム５０ｍｇを加えたものを使用して、苦味のマスキング効果について官能試験を行なった。対象例としては、水２０ｍｌに塩化マグネシウム５０ｍｇを加えたものを使用した。結果を表４に示す。
【０１０５】
【表４】

【０１０６】
本試験の結果により、本発明の液状マトリックスは、薬剤等の苦味をマスキングする効果を有することが明らかとなった。
【０１０７】
（実施例９）
蒸留水にジェランガム及びＬＭペクチンを溶解し、それぞれの濃度が０．５％になるように混合した液状マトリックスを調製した。この液状マトリックス１０ｍｌにリボフラビン１０ｍｇを加えて溶解し、ｐＨを７．４に調整した。
【０１０８】
このリボフラビン−液状マトリックス１ｍｌを日本薬局方崩壊試験１液に滴下し、リボフラビン−液状マトリックスが胃内投与された場合の再現実験を行なった。その結果、滴下されたリボフラビン−液状マトリックスは、滴下と同時にゲル化した。当該ゲルの強度は、３．００×１０^４Ｎ／ｍ^２だった。このゲルからのリボフラビンの放出を、実施例２と同様に測定した。更に実施例６と同様に、日本薬局方崩壊試験２液への溶出も調べた。結果を図６に示す。
【０１０９】
この結果に示す通り、ゲル内のリボフラビンは、急激に放出されることはなく、徐々に崩壊試験１及び２液中に溶出した。このことから、本発明の経口液剤は、胃内においても小腸内においても高い徐放性を示すことが実証された。
【０１１０】
（実施例１０）
下表５〜９の組成を有する本発明の液状製剤を調製した。
【０１１１】
【表５】

【０１１２】
【表６】

【０１１３】
【表７】

【０１１４】
【表８】

【０１１５】
【表９】

【０１１６】
上記表中Ｎｏ．２，３，６，８，９，１０，１４，１６，２１および２６に示した液状製剤１ｍＬを、人工胃液（日本薬局方崩壊試験液１液）１０ｍＬを入れたシャーレーへ緩やかに加えたところ、いずれも人工胃液中に触れると直ちにゲル化した。
【０１１７】
このゲル化した製剤をＨ．ピロリの培養液（ＣＦＵ：１×１０^７，１×１０^８，１×１０^９／ｍＬ，１０％非働化ウマ血清添加Ｂｒｕｃｅｌｌａ　ｂｒｏｔｈ）１０ｍｌに浸漬し、キャンピバッグ（ＢＢＬ）を使って３７℃で２４時間微好気培養した。同様に、陰性対象として抗菌剤を含まないゲルのみを、陽性対象としてアモキシシリン０．５ｇとクラリスロマイシン０．２ｇを添加し培養した。
【０１１８】
２４時間後、それぞれ培養液を１０％非働化ウマ血清添加Ｍ−ＢＨＭピロリ寒天培地（（株）日研生物医学研究所）に塗抹し、３７℃で７日間培養後、Ｈ．ピロリの有無を調べることにより判定した。抗菌活性の判定は、菌が消滅しているか明らかに減っている場合を陽性、菌がそのまま増殖していた場合を陰性（−）とした。結果を下表１０に示す。
【０１１９】
【表１０】

【０１２０】
上記結果より、本発明の液状製剤は胃液により速やかにゲル化するとともに、抗菌剤をそのまま投与した場合と同様の活性を示すことが明らかとなった。
【０１２１】
尚、一般的に抗生物質は強酸性に弱く、経口投与すると胃酸により活性が低下するが、本発明の液状製剤は抗菌剤がゲルによって保護されているので、胃内であってもそのまま抗菌活性を維持することが可能であり、Ｈ．ピロリ感染を治療できることが想定される。
【０１２２】
（実施例１１）
先ず、公知方法（平山ら，　ジャーナル　オブ　ガストロエンテロロジー（Ｊ．　Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ），　第３１巻，　第７５５〜７５７頁（１９９６年））に準じて、Ｈ．ピロリ（ＡＴＣＣ４３５０４）を１０％非働化ウマ血清添加ｂｒｕｃｅｌｌａ　ｂｒｏｔｈ（ＢＢＬ）で微好気培養後、１×１０^９ＣＦＵ（コロニー形成ユニット）／ｍＬに調整した。
【０１２３】
次に、雄性スナネズミ（ＭＧＳ／Ｓｅａ，体重約６０ｇ）を１群３〜４匹使用し、２４時間絶食させた後、１匹当たり上記Ｈ．ピロリ培養液２００μｌ（２×１０^８ＣＦＵ）を、ラット用経口ゾンデを用いて胃内に接種した。
【０１２４】
菌接種７日後、公知方法（清水ら，　キャンサー　リサーチ（Ｃａｎｃｅｒ　Ｒｅｓｅａｒｃｈ），　第６０巻，　第１５１２〜１５１４頁（２０００年））の方法に準じて、除菌治療剤を１日に朝晩２回の投与を２日間行なった。
【０１２５】
除菌治療剤として実施例１０Ｎｏ．２３の液状製剤（ペクチンとジェランガムから成る液状マトリックスに抗菌剤として塩酸ミノサイクリンを添加したもの）を投与した。これを抗菌剤の投与量に換算すると、１回当たり１７ｍｇ／体重ｋｇの投与量となる。
【０１２６】
対照として０．５％ＣＭＣ溶液のみ、及び保険適用されているランソプラゾール（プロトンポンプ阻害剤），アモキシシリン（抗生物質），クラリスロマイシン（抗生物質）それぞれ１０，３，３０ｍｇ／体重ｋｇからなる３剤併用薬を投与した。
【０１２７】
除菌判定は、採取した胃粘膜組織を培養し、１０％非働化ウマ血清添加Ｂｒｕｃｅｌｌａ　ｂｒｏｔｈ（ＢＢＬ）培地で２４時間微好気培養後、１０％非働化ウマ血清添加Ｍ−ＢＨＭピロリ寒天培地に塗抹して３７℃で７日間微好気培養を行ない、Ｈ．ピロリを検出することにより行なった。
【０１２８】
薬剤の有効及び無効の判定は、現在の除菌治療法である３剤併用薬を投与したスナネズミの胃粘膜組織から検出したＨ．ピロリ数が、投与した元の菌数（１×１０^９ＣＦＵ／ｍＬ）のおよそ０．００１％、即ち、１×１０^４ＣＦＵ／ｍＬであったことから、これと同じあるいはそれ以下の菌数を有効とした。結果を表１１に示す。
【０１２９】
【表１１】

【０１３０】
上記結果から、本発明に係るＮｏ．２３の液状製剤によれば、現行の除菌治療法である３剤併用療法と同じ程度の除菌効果が得られることが明らかにされた。
【０１３１】
Ｎｏ．２３の液状製剤は、胃酸によって胃粘膜表層でゲル化することで、ゲル中に含まれる塩酸ミノサイクリンが胃酸による急激な加水分解から保護され、しかもＨ．ピロリが存在する粘膜表層そのものに対して直接しかも持続的に薬剤を放出して、充分な抗菌効果を得たことによると考えられる。
【０１３２】
一方、３剤併用薬の投与では、Ｈ．ピロリは減少するものの、３剤併用薬の薬剤投与量が非常に多いことから、小腸から大腸までの消化管全域において鬱血が見られ、特に、十二指腸が鬱血とともに腫大し、胆嚢が肥大化するという副作用が生じていた。また、プロトンポンプ阻害剤により胃酸分泌を抑制した為か、胃が大きく膨満するとともに、噴門部から食道にかけて赤く炎症を呈した。
【０１３３】
しかしながら、本発明の液状製剤を投与した場合は、このような副作用は全く認められなかった。
【０１３４】
（実施例１２）
胃内視鏡検査で胃炎と判定され、しかも生検サンプルの培養試験でＨ．陽性と判定された３０〜５０歳の患者３名に、実施例１０のＮｏ．１に準じて、アモキシシリン７５０ｍｇ、クラリスロマイシン２００ｍｇを加えた液状製剤２００ｍＬを、毎日就寝前に服用させ、１週間続けた。投与終了後、尿素呼気試験法によりＨ．ピロリの有無を判定した。結果を下表１２に示す。
【０１３５】
【表１２】

【０１３６】
現在、保険適用されているランソプラゾール，アモキシシリン，クラリスロマイシンの３剤併用方法では、１日当たりランソプラゾール６０ｍｇ，アモキシシリン１，５００ｍｇ，クラリスロマイシン４００ｍｇを７日間投与する。一方、上記結果より、本発明の経口液状製剤では、プロトンポンプ阻害剤であるランソプラゾールが不要となり、抗生物質２剤併用ですみ、しかも、上記投与量のそれぞれ半分、即ち、１日当たりアモキシシリン７５０ｍｇ，クラリスロマイシン２００ｍｇを投与することで充分な効果を示すことが明らかとなった。
【０１３７】
それに加え、被験者には、３剤併用の除菌治療で従来報告されている逆流性食道炎，下痢，味覚異常などの副作用やその他の副作用と考えられる所見は認めなかった。従って、本発明の経口液状製剤による除菌治療剤によって、これまで以上の副作用が出現する可能性は低いと考えられ、日常の生活を維持しながら無理なく除菌できることが実証された。
【０１３８】
（実施例１３）
下表１３〜１５の組成を有する本発明の液状製剤を調製した。
【０１３９】
【表１３】

【０１４０】
【表１４】

【０１４１】
【表１５】

【０１４２】
（実施例１４）酢酸慢性潰瘍モデルラットを使った治療効果試験
体重２００ｇ前後のウイスター系雄生ラット２４匹を８群に分け１晩絶食させた後、それぞれのラットに酢酸潰瘍を作製した。即ち、ラットにネンブタール麻酔を施し正中線に沿って開腹して胃を取り出した後、胃体部と幽門部の境界部に１００％酢酸を十分染み込ませた脱脂を充填した直径１０ｍｍの円筒を漿膜面に約３０秒間押し当て、漿膜面に付着した酢酸を無菌ガーゼで拭き取り、腹部を縫合した。６週間後、対照として無処置の群よりラット１匹を無作為に取り出して屠殺・解剖し、潰瘍が形成されていることを確認した。
【０１４３】
当該ラット各３匹ずつに、Ｎｏ．３８の塩酸セトラキサラート液状製剤，Ｎｏ．３０のシメチジン液状製剤、およびＮｏ．３７のテプレノン液状製剤それぞれを０．５ｍｌづつ１日１回，２週間続けて胃内に投与し、液状製剤投与群とした。対照として、それぞれの薬剤の精製水溶液を各３匹づつ３群へ（陽性対照）、液状マトリックスのみからなる液状製剤３匹１群（陰性対照）、及び精製水のみを３匹１群（無処置群）へ同様に投与した。
【０１４４】
７週目，８週目に対照として無処置のラットを無作為に１匹づつ屠殺、開腹し、胃潰瘍が形成されていることを再確認した。それぞれのラットは、８週目で屠殺して潰瘍面積を計り、岡部らの方法（Ｏｋａｂｅ　Ｓ，　Ｒｏｔｈ　ＪＬＡ，　Ｐｆｅｉｔｔｅｒ　ＣＪ：　Ａ　ｍｅｔｈｏｄ　ｆｏｒ　ｅｘｐｅｒｉｍｅｎｔａｌ　ｐｅｎｅｔｒａｔｉｎｇ　ｇａｓｔｒｉｃ　ａｎｄ　ｄｕｏｄｅｎａｌ　ｕｌｃｅｒｓ　ｉｎ　ｒａｔｓ．　Ｏｂｓｅｒｖａｔｉｏｎ　ｏｎ　ｎｏｒｍａｌ　ｈｅａｌｉｎｇ．　Ａｍｅｒ　Ｊ　Ｄｉｇ　Ｄｉｓ１６：　２７７−２８４，　１９７１）に基づいて潰瘍係数を求めた。潰瘍係数は、１〜１０ｍｍ^２を１とし、１１〜２０ｍｍ^２までを２、２１〜３０ｍｍ^２までを３とした。結果を表１６に示す。
【０１４５】
【表１６】

【０１４６】
上記結果から、本発明に係る液状製剤は胃潰瘍の治療効果を示すことが実証された。但し、シメチジンなどの攻撃因子抑制型よりも、組織修復作用のあるテプレノン或いは粘液産生・分泌促進作用のある塩酸セトラキサートが、胃潰瘍に対してより有効である傾向が認められた。
【０１４７】
一方、薬剤溶液を直接投与した場合（陽性対照）であっても潰瘍の縮小効果が見られたが、その効果は本発明の液状製剤よりも劣るものであった。
【０１４８】
従って、本発明の液状製剤は、従来の製剤よりも潰瘍治療効果が高いことが実証された。
【０１４９】
（実施例１５）インドメタシン潰瘍ラットモデルによる液状製剤の治療効果
体重２００ｇ前後のウイスター系雄生ラット１８匹を、実験群５匹と対照群（陽性対照群として５匹，陰性対照群として５匹）、そして潰瘍発生の確認のための無処置群３匹の４群に分けた。これらを２４時間絶食させた後、１％カルボキシメチルセルロース（ＣＭＣ）溶液に懸濁したインドメタシン（ＩＮＤ）２０ｍｇ／体重ｋｇを、ラット胃内投与ゾンデを使って経口投与してインドメタシン潰瘍を引発させた。予備試験においては、３時間目にインドメタシンの血中濃度が最大になり、胃体にびらん性出血が見られた。
【０１５０】
インドメタシン投与３時間後、Ｎｏ．４１のプロスタグランジン（ＰＧＥ１）液状製剤（薬剤としてアルプロスタジルアルファデクスを含有）および陽性対照として精製水に溶解したＰＧＥ１溶液をＰＧＥ１投与量が３．３μｇ／体重ｋｇとなる様に、そして陰性対照として液状マトリックスのみを、更に、潰瘍発生の確認の為に精製水のみを投与した無処置群にそれぞれ投与し、その１時間後より給餌を行った。無処置群についてはインドメタシン投与３時間後、その他の群では２４時間後にそれぞれのラットを屠殺、解剖し、胃内の潰瘍、出血有無の状態を判定した。
【０１５１】
絶食ラットを使ったインドメタシン潰瘍は、ヒトと異なり、幽門前庭部に潰瘍を発生することなく胃体に発生するので、判定は出血の有無を基に行った。即ち、出血なしを陰性（−）、痕跡程度の出血を（±）、点状出血を（＋）、及び広範に出血している状態を（＋＋）とした。結果を表１７に示す。
【０１５２】
【表１７】

【０１５３】
絶食ラットを使ったインドメタシン潰瘍モデルにおいて、胃体部の出血性びらんは、Ｈ２ブロッカー，制酸剤，抗コリン剤，プロトンポンプインヒビター，プロスタグランジン製剤，粘膜保護剤などにより抑制されることが知られている（岡部進、消化性潰瘍の実験モデル、日本臨床、４２：４３−４７，１９７９年）。その一方において、２４時間絶食後に１時間だけ再摂食させたラットでは胃体部病変は抑制され、ヒト潰瘍と同様に幽門前庭から小腸にまたがり潰瘍が発生する。この幽門前庭部潰瘍には、プロスタグランジン製剤以外全て効果がないことも知られている（Ｓａｔｏｈ，　Ｈ．，　ｅｔ　ａｌ．，　Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ，　８１：　７１９−７２５，　１９８１）。
【０１５４】
上記結果から、今回実施した２４時間絶食インドメタシン潰瘍ラットにおいて、胃粘膜のサイトプロテクション効果を有するプロスタグランジン（ＰＥＧ１）の胃内投与により、明らかに出血症状は改善した。
【０１５５】
しかしＰＥＧ１は、そのまま投与するよりも本発明の液状製剤とした方が効果は高まることが、本発明により明らかにされた。このことは、本発明の液状製剤であれば、液状マトリックスが胃内で胃酸によりゲル化して胃粘膜を物理的に保護すると共に、薬剤（本実施例ではＰＥＧ１）を持続放出することにより、ＰＥＧ１が患部でより有効に利用され、潰瘍部を治療できる結果であると考えられる。
【０１５６】

【０１５７】

【０１５８】

【０１５９】

【０１６０】

【０１６１】

【０１６２】

【０１６３】

【０１６４】

【０１６５】

【０１６６】

【０１６７】
【発明の効果】
本発明の液状マトリックスは、薬剤を容易に可溶化、分散化或いは懸濁化することができ、液状であるため嚥下が容易であり、滅菌等の操作性が高く安定であり、苦味のマスキング効果も有し、且つ生体内でゲル化することにより薬剤の放出速度を制御することができる。従って、本発明の液状マトリックスに薬剤を含有させた経口液状製剤は、液状であるにも関わらず高い徐放性を有するという従来にない効果を有するものである。
【０１６８】
特に、薬剤として抗Ｈ．ピロリ活性を示す薬効成分を配合した経口液状製剤は、胃内へ導入されることによってゲル化するため、酸性条件に弱い薬効成分を保護しつつ徐々に崩壊して薬効成分を放出することから、含有すべき薬効成分含有量と投与回数を低減することができ、副作用を生じ難い。
【０１６９】
それと共に、上記液状製剤は、胃酸分泌を抑制するプロトンポンプ阻害剤等を必要としないため、当該薬剤による副作用も発生することもない。
【０１７０】
以上より、Ｈ．ピロリ感染症治療に適用される本発明に係る液状製剤は、従来の抗Ｈ．ピロリ剤に比してプロトンポンプ阻害剤を必要としないという特に優れた特長を有するため、ヘリコバクター・ピロリ感染症治療剤として非常に有効である。
【０１７１】
また、「薬剤」として胃潰瘍または十二指腸潰瘍の治療効果を有するものを配合した経口液状製剤も、同様に薬剤徐放性を享有する共に、特に高い治療効果を示す。即ち、従来の抗潰瘍製剤と異なり、薬剤を直接患部へ持続的に徐放できるため、薬剤の利用率が高く且つ副作用を低減できるからである。
【０１７２】
従って、胃潰瘍または十二指腸潰瘍の治療のために使用される本発明に係る液状薬剤も、従来の抗潰瘍薬に比して投与量を低減できることから副作用が生じ難い上に治療効果自体も高いため、非常に有用である。
【図面の簡単な説明】
【図１】ゲル強度（破断応力）とゲルからのリボフラビンの放出との関係を表す図
【図２】本発明の経口液状製剤からのリボフラビンの持続放出を表す図
【図３】本発明の経口液状製剤からのアセトアミノフェンの持続放出を表す図
【図４】本発明の液状マトリックスと対象例をオートクレーブした様子
【図５】２種の水溶性高分子を含む本発明の経口液状製剤からのリボフラビンの持続放出を表す図
【図６】本発明の経口液剤からのリボフラビンの持続放出を表す図[0001]
[Technical field to which the present invention pertains]
The present invention relates to a liquid matrix capable of controlling the release of a drug by undergoing a phase transition from a liquid state to a gel in a living body, and an oral liquid preparation containing the liquid matrix and the drug. That is, the present invention is a liquid matrix that can be orally administered, and can exert an action of controlling the release rate of a drug by gelling in the stomach.
[0002]
The present invention also relates to a method of using an aqueous solution of a water-soluble polymer that gels under acidic conditions as a component of an oral liquid preparation having sustained release.
[0003]
[Prior art]
Generally, most of the dosage forms are oral administration, and the dosage form is mainly solid preparations such as powders, granules, pills, tablets, capsules and the like.
[0004]
However, liquid preparations that are easy to take are preferred for infants and the elderly who originally have difficulty taking the drug, and patients who have dysphagia due to diseases such as sequelae of stroke, traumatic cerebral contusion, cerebral palsy and Parkinson's disease. It is.
[0005]
On the other hand, in recent years, a drug delivery system, which is a technique for releasing a drug at a desired place (such as a small intestine or an affected part) in consideration of the side effects of the drug, has been actively developed. That is, by devising the composition of the preparation, the release rate of the drug is controlled by utilizing the rate at which the preparation is disintegrated by being digested in the digestive tract. For example, Patent Document 1 discloses a biodegradable polymer hydrogel in which a drug is released in response to biodegradation.
[0006]
However, heretofore, there has been no technique capable of controlling the release rate of a drug at the same time as a liquid preparation. In other words, in the case of a solid preparation, the release rate of a drug can be controlled by utilizing the rate at which the preparation is generally disintegrated by being digested in the digestive tract, but in the case of a liquid preparation, the drug is originally solubilized and the like. Controlling the release rate is extremely unlikely.
[0007]
For example, the preparation described in Patent Document 1 contains a water-soluble polymer as a component for controlling the release of a drug in a living body. However, since the preparation is a gel preparation, it is ingested by dysphagia patients and the like. Not easy.
[0008]
In contrast, oral administration of liquid preparations is the most effective method of administration for infants, the elderly, dysphagic patients, and patients with large doses of drugs. Since it cannot be sustained, the number of doses cannot be reduced. In addition, the liquid preparation has good absorbability of the drug and the blood concentration tends to increase rapidly, so that a side effect may be caused. Therefore, if the essential problems of these liquid preparations can be solved, it is possible to enhance the therapeutic effect such as reducing the number of doses and reducing side effects, in addition to the original feature of ease of administration, and improving the patient's efficacy. You can enjoy many medical benefits such as improving compliance.
[0009]
In addition, many drugs are hardly soluble or have poor stability when solubilized, and some of them have an essential problem in preparing a liquid preparation. Furthermore, if the bitterness of a drug or the like can be masked, resistance to drug administration to an infant or the like can be reduced.
[0010]
By the way, Patent Document 2 discloses a viscosity-stable aqueous antacid composition comprising an antacid substance and an alginate, which may contain magnesium carbonate. However, the composition is a gel (eg, magnesium alginate) having a certain or higher viscosity from the beginning, and is not always easy to swallow. Further, the gel-like substance has a great difficulty in drug production that sterilization is not easy because the gel and water are separated under high pressure or high heat.
[0011]
Further, a preparation containing an acid neutralizing agent (antacid substance) such as an alkaline earth metal is also disclosed in Patent Document 3. The formulation is composed of pectin, which can form an aggregated gel under acidic pH, buffer and acid neutralizer, forms buoyant raft in stomach and forms raft in acidic environment in stomach. It is intended to prevent the gastric contents from flowing back into the esophagus and to maintain the efficacy. Patent Document 4 also discloses a composition containing an antacid and a gelling agent, and is also intended to maintain the efficacy.
[0012]
However, since these contain a large amount of antacid substances, a gel having sufficient strength cannot be formed by neutralizing the inside of the stomach, and the durability of the drug effect is not sufficient. In addition, it is difficult to obtain the patient's compliance with the administration due to the large amount to be drunk. Above all, when gastric ulcers occur due to gastric mucosal damage, etc., there is a disadvantage that administration of only an antacid is no longer a fundamental treatment, so it can not be a therapeutic agent for gastric ulcers etc. .
[0013]
By the way, in recent years, a bacterium named Helicobacter pylori has been isolated from human gastric mucosa, and it is involved in about 80% or more of the causes of gastritis. Also, peptic ulcers, particularly, duodenal ulcers It has also become clear that this is one of the major causes of recurrence. Furthermore, it has been found that if the infection of Helicobacter pylori persists, gastric mucosal atrophy progresses and epithelial metaplasia occurs, leading to progression to gastric cancer.
[0014]
Therefore, the elimination of Helicobacter pylori (hereinafter referred to as "H. pylori") is a fundamental treatment for gastritis and gastric ulcer, etc., and the FDA in the United States issued a macrolide antibiotic in 1995. And omepralozole or ranitidine bismuth as a gastric acid secretion inhibitor. Helicobacter pylori eradication therapy was recommended. In Japan, five years later, in September 2000, a three-drug combination of lansoprazole, a proton pump inhibitor, and two antibiotics, lactam-type amoxicillin and macrolide-type clarithromycin, was given in the stomach. H. in duodenal ulcers. It was approved as a eradication therapy for H. pylori infection. Thereafter, in February 2002, a triple therapy using omeprazole was also approved as described above. Helicobacter pylori eradication therapy has been widely used as a curative treatment for a large number of lesions such as duodenitis, sinus erosion, erosive duodenitis and peptic ulcer.
[0015]
However, H. Since the antibiotics used for H. pylori are vulnerable to strong acidic conditions, antibacterial activity must be supplemented by administering a large amount. On the other hand, large doses of antibiotics tend to cause side effects. Then, H. In eradication treatment of H. pylori, it is important to reduce gastric acid secretion by using a proton pump inhibitor in combination with an antibacterial agent and to increase the utilization of the antibacterial agent.
[0016]
However, these proton pump inhibitors are associated with impaired gastric acid secretion, proliferation of various bacteria in the stomach, stomach distension after administration, and the occurrence of reflux esophagitis caused by rapid secretion of gastric acid by rebound. Despite the side effects of H. The dosage used for eradication treatment of H. pylori is quite large, more than twice the amount usually used. In addition, the fact that about several percent of patients have no effect on proton pump inhibitors is also a factor that inhibits eradication treatment.
[0017]
For ulcers in the stomach and duodenum, H. et al. In addition to eradication of H. pylori, treatment of the ulcer itself has also been performed. However, conventional ulcer treatment agents are absorbed by the gastrointestinal tract after oral ingestion, metabolized by the liver via the portal vein, and then carried to the affected area by blood to act on mucosal epithelial cells that have formed ulcers. There was no direct effect on the affected area directly. Therefore, not only is the drug utilization low, but the problem of side effects cannot be avoided.
[0018]
[Patent Document 1]
JP-A-8-231435 (Claim 1 etc.)
[Patent Document 2]
JP-A-8-99885 (Claim 1 etc.)
[Patent Document 3]
Japanese Patent No. 2710375 (Claim 1 etc.)
[Patent Document 4]
Japanese Patent Publication No. 46-21672 (Claim 1 etc.)
[0019]
[Problems to be solved by the invention]
As described above, gel preparations considering drug release properties and preparations that gel in the stomach have been known, but none of the preparations are liquid and have a sustained drug release property.
[0020]
In addition, H. et al. As a method for treating H. pylori infection, a method in which a proton pump inhibitor that can cause serious side effects is not administered has been required. Furthermore, a method for treating gastric ulcer and duodenal ulcer which has few side effects and is highly effective has been demanded.
[0021]
Therefore, the problem to be solved by the present invention is that the drug can be easily solubilized, dispersed or suspended, is easily swallowed in a liquid state, has high operability such as sterilization, and is stable. It is an object of the present invention to provide a liquid matrix as a liquid pharmaceutical swallowing aid which has an effect of masking bitterness and the like and can control the release rate of a drug by gelling in a living body.
[0022]
Further, one of the objects of the present invention is to provide a liquid preparation using the above-mentioned liquid matrix. In particular, an object of the present invention is to provide an H. coli which has been required to have a better method of removing bacteria. An object of the present invention is to provide a liquid preparation effective against H. pylori and a liquid preparation having a therapeutic effect on gastric ulcer and duodenal ulcer.
[0023]
[Means for Solving the Problems]
The present inventors have conducted intensive studies on the components of the formulation to solve the above-mentioned problems, and found that a water-soluble polymer that gels under acidic conditions is used to appropriately define the breaking stress after gelation. Thus, they have found that the above problems can be solved, and have completed the present invention.
[0024]
That is, the liquid matrix of the present invention is a liquid adjuvant that facilitates swallowing of a drug, contains a water-soluble polymer that gels under acidic conditions, and has a breaking stress of about 3.00 × 10 3²N / m²Or more (preferably 2.00 × 10³N / m²Above). The preparation having such a configuration can exhibit a sustained-release property of the drug by undergoing phase transition in the stomach after administration even though the preparation is liquid.
[0025]
The viscosity of the liquid matrix before gelation was 3.0 × 10^{− 1}Pa · s or less (more preferably about 1.0 × 10^{− 1}Pa · s or less). This is because a low-viscosity preparation can be administered to patients with dysphagia while reducing pain, and it is easy to obtain patient compliance.
[0026]
Further, the liquid matrix of the present invention preferably contains an insoluble salt that releases a polyvalent metal cation under acidic conditions, and as the insoluble salt, an alkaline earth metal salt of an inorganic acid is preferable. Furthermore, as the water-soluble polymer contained in the liquid matrix of the present invention, those having a carboxyl group and / or a sulfonic acid group in the chemical structure thereof (both a carboxyl group and a sulfonic acid group may be contained) ) Is preferred, and specifically, a combination of alginate, pectin, alginic acid or a salt thereof and pectin, or a combination of gellan gum or gellan gum and pectin is preferred. This is because in the stomach, a gel having a breaking stress equal to or more than a specified value is more reliably formed and a high drug sustained release property is exhibited.
[0027]
The oral liquid preparation according to the present invention is characterized by containing the liquid matrix and a drug, and has the characteristics of the liquid matrix as it is. That is, it is particularly easy to swallow because it is a liquid preparation and masks the bitterness and the like of the drug, and has a characteristic of exhibiting sustained release of the drug by gelling in the stomach.
[0028]
The above drugs include anti-H. Those exhibiting H. pylori activity are preferred. The oral liquid preparation is prepared according to the conventional H. Unlike the method of eradication of H. pylori, a proton pump inhibitor is not required, and in addition to requiring a large amount of administration, antibiotics that are likely to cause side effects can be reduced and the pharmacological action is maintained. Can show a high effect.
[0029]
Such anti-H. Specific examples of the drug exhibiting pylori activity include at least one selected from the group consisting of penicillins, macrolides, tetracyclines, cepham antibiotics and pyridonecarboxylic acid-based synthetic antibacterials, furthermore, amoxicillin, One or more selected from the group consisting of clarithromycin, roxithromycin, minocycline hydrochloride, cefaclor, cephalexin, ofloxacin, tosfloxacin tosylate, and levofloxacin can be mentioned. These have high anti-H. Despite exhibiting H. pylori activity, it was weak to a strongly acidic environment, and thus could not sufficiently exhibit its antibacterial activity by the conventional administration method. However, in the case of an oral liquid preparation using the liquid matrix according to the present invention, the dose of these drugs can be reduced to a range where side effects are unlikely to be exhibited, and their antibacterial activity can be exhibited.
[0030]
The above-mentioned oral liquid preparation naturally has a sustained drug release property which is the largest characteristic of the liquid matrix according to the present invention, and this is also a feature that is remarkably superior to conventional liquid preparations.
[0031]
As the above-mentioned drug, those having a therapeutic effect on gastric ulcer or duodenal ulcer are also suitable. With such a liquid drug, the affected matrix can be coated and protected by gelling of the liquid matrix in the stomach, and the drug can act directly on the affected site by sustained sustained release of the drug. It has a high therapeutic effect and can reduce side effects. Further, in the treatment of duodenal ulcer, the liquid preparation of the present invention gelled in the antrum of the stomach of the stomach can act on the duodenum from the pylorus by sustained sustained release of the drug. It is also conceivable that the gelled preparation gradually transported to the duodenum by wrapping around the affected part of the duodenum by entanglement and directly release the drug directly to the affected part. Therefore, the liquid preparation is very useful as a therapeutic agent for gastric ulcer and duodenal ulcer.
[0032]
As the above drug having a therapeutic effect on gastric ulcer or duodenal ulcer, a protective factor promoting type is preferable. This is because the experiments described below show that a liquid preparation using the liquid matrix according to the present invention for treating gastric ulcer or duodenal ulcer has a high therapeutic effect of a protective factor promoting type drug.
[0033]
Prostaglandins are preferred as the above-mentioned protective factor promoting drug. Prostaglandins have an effect of increasing mucosal blood flow and an effect of increasing mucus secretion, and have already been used as a therapeutic agent for gastric ulcer and duodenal ulcer.
[0034]
Since the oral liquid preparation contains the liquid matrix according to the present invention as a component, it naturally has sustained drug release, and this is a feature that is significantly superior to conventional liquid preparations.
[0035]
Furthermore, the method according to the present invention is characterized in that an aqueous solution of a water-soluble polymer that gels under acidic conditions is used as a component of an oral liquid preparation having sustained release. The method of the present invention also directly shows the characteristics of the liquid matrix according to the present invention.
[0036]
BEST MODE FOR CARRYING OUT THE INVENTION
The greatest feature of the liquid matrix according to the present invention is that it is liquid in a normal state, so that a relatively large amount of drug can be added, and it is easy to swallow. This makes it possible to gradually release the drug, thereby maintaining its efficacy. That is, when the liquid matrix according to the present invention enters the stomach via the esophagus in a liquid state, the water-soluble polymer as a component thereof is gelled by the strong acidity of the stomach acid.
[0037]
Therefore, in the oral liquid preparation according to the present invention, as in the case of conventional liquid preparations, the drug is sent to the small intestine immediately after reaching the stomach to absorb the drug as an active ingredient, and after the blood concentration of the drug sharply increases, etc. It is not suddenly lowered, but is gradually sent to the small intestine by peristalsis of the stomach, whereby the absorption of the drug and the development of the medicinal effect are continuously performed.
[0038]
Hereinafter, embodiments of the present invention exhibiting such characteristics and effects thereof will be described.
[0039]
The “water-soluble polymer that gels under acidic conditions” is not particularly limited as long as it is pharmacologically acceptable and gelates with stomach acid. For example, alginic acid or a salt thereof, pectin, gellan gum or these And the like. Furthermore, even those which do not gel themselves under acidic conditions, such as gum arabic, carrageenan, tamarind seed gum, guar gum, xanthan gum, curdlan, hyaluronic acid or locust bean gum, can be made acidic by combining with gellan gum. Those that gel under the conditions can also be mentioned. In such a combination, a combination of gellan gum and pectin, carrageenan or locust bean gum is preferred. A combination of alginic acid or a salt thereof with locust bean gum is also suitable.
[0040]
In order to form a gel having a high physical strength in order to exhibit a higher sustained release property, it is preferable to crosslink the water-soluble polymer with a polyvalent metal cation. The water-soluble polymer used in this case is not particularly limited as long as it is water-soluble in a normal state and is gelled by the addition of a polyvalent metal cation, but is pharmacologically acceptable. It is necessary. Examples of such a water-soluble polymer include alginates such as sodium alginate and propylene glycol alginate; vinyl compounds such as carboxyvinyl polymer, sodium polyacrylate and polyvinyl alcohol; cellulose derivatives such as carboxymethylcellulose gum, carboxymethylcellulose and carboxyethylcellulose. Plant polysaccharides such as konjac mannan, pectin, carrageenan, and guar gum; microbial polysaccharides such as dextran; and combinations of two or more of these.
[0041]
The mechanism by which these water-soluble polymers gel by polyvalent metal cations is not always clear, but for example, an egg box in which two carboxyl groups in the polymer are coordinately crosslinked by the polyvalent metal cation. A model has been proposed. According to this model, two carboxyl groups present in the polymer are coordinately crosslinked by one divalent cation, and the water-soluble polymer gels. Therefore, if a sufficient amount of divalent cations is present relative to the carboxyl groups present in the polymer, a gel having a high cross-linking density can be obtained. A low gel is obtained. Therefore, after grasping the amount of carboxyl groups present in the “water-soluble polymer gelled by the polyvalent metal cation”, “insoluble salts that release the polyvalent metal cation under acidic conditions” and “ By determining the content of the "water-soluble polymer that gels with the valent metal cation," it becomes possible to control the properties of the gel formed in the stomach, and thus to control the sustained release of the drug. it can. Further, in consideration of the above-mentioned egg box model, the “water-soluble polymer gelled by the polyvalent metal cation” used in the present invention has a carboxyl group or a sulfonic acid group (both of which have a carboxyl group or a sulfonic group) in its structure. May be included.).
[0042]
Of these, particularly preferred are alginic acid, alginates, pectin, combinations of alginic acid or its salts with pectin, gellan gum, combinations of pectin and julan gum, combinations of carrageenan and locust bean gum, and gellan gum and gum arabic. And sodium alginate and gellan gum are most suitable. For pectin, when a gel having high physical strength is required, LM pectin having a low degree of methylation is preferable, and when such physical strength is not desired, HM pectin may be used.
[0043]
In addition, the physical strength of the gel can be adjusted by combining two or more water-soluble polymers in addition to selecting a water-soluble polymer and adding a polyvalent metal cation. For example, a gel having high physical strength in a living body can be formed by combining alginic acid or a salt thereof with pectin, gellan gum and pectin, or carrageenan and locust bean gum, and devising the mixing ratio. The liquid matrix converted into a gel of high physical strength in the living body is transferred to the small intestine by gastric peristalsis without directly disintegrating in the stomach, and gradually disintegrates from the small intestine onwards, resulting in high drug sustained release. Demonstrate.
[0044]
Further, a liquid matrix is added by adding polyethylene glycol, polyethylene glycol / polypropylene glycol block copolymer, etc .; animal proteins such as gelatin, casein, collagen, etc .; and starch-based water-soluble polymers such as soluble starch, methyl starch, etc. Modification of the gel itself and the gel can also be achieved.
[0045]
Further, the liquid matrix of the present invention may be used as an anti-H. When applied to H. pylori preparations, the active drug remains in the stomach for a longer time than when the drug is simply drunk with water. be able to. Furthermore, when the liquid matrix of the present invention gels in the stomach, it may also crosslink with the mucous layer of the stomach and exert a long-lasting drug effect. That is, H. H. pylori is protected by the mucous layer on the surface of the stomach because it is weak to strong acidity. Drugs contained in H. pylori oral liquid preparations can exert their medicinal effects without being affected by stomach acid.
[0046]
As described above, the property of gradually disintegrating in the stomach and the stability and small intestine in the stomach by adjusting the selection and combination of the water-soluble polymer and the presence or absence of the metal cation and the amount of addition are adjusted. A gel having various properties such as disintegration properties can be formed in a living body, and controlled release can be controlled so that the activity of the drug can be maximized.
[0047]
As a measure of the physical strength after gelation of the liquid matrix of the present invention, its breaking stress is about 3.00 × 10²N / m²It is necessary to be. If the breaking stress is less than this, sustained release of the drug cannot be maintained. Here, “about 3.00 × 10²N / m²“More than” means 3.00 × 10 by rounding off the second decimal place.²N / m²It means the above numerical value, specifically 2.95 × 10²N / m²The above values are referred to. The breaking stress is 8.70 × 10²N / m²More preferably, 2.00 × 10³N / m²That is all.
[0048]
The relationship between the concentration of the water-soluble polymer contained in the present invention and the viscosity of the liquid matrix or the physical strength of the gel greatly varies depending on the properties of the water-soluble polymer, and thus the concentration is not particularly limited. However, it is generally recommended that the concentration be from 0.01 to 10% by weight.
[0049]
The `` insoluble salts that release polyvalent metal cations under acidic conditions '' used in the present invention show insolubility or poor solubility in neutral and weakly basic aqueous solutions, but dissolve under acidic conditions. It has the property of releasing polyvalent metal cations. The insoluble salts are not particularly limited as long as they are pharmacologically acceptable, but those containing a divalent or trivalent metal cation are suitable. For example, barium carbonate, barium sulfate, strontium carbonate, calcium carbonate Alkaline earth metal salts of inorganic acids such as calcium, calcium phosphate, magnesium dihydrogen phosphate, magnesium aluminate silicate, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate; synthetic aluminum silicate, aluminum phosphate, etc. Light metal salts of inorganic acids; hydroxides such as magnesium hydroxide, alumina magnesium hydroxide, aluminum hydroxide, and dried aluminum hydroxide gel; alkaline earth metals such as magnesium oxide; synthetic hydrotalcite; dihydroxyaluminum amino acetate; Dihydroxyal Um aminoacetate; and sucrose esters aluminum salts.
[0050]
Here, the term "insoluble" generally refers to a substance that requires 10,000 g or more of water to dissolve 1 g of a sample, and the term "poorly soluble" refers to a substance that dissolves 1 g of a sample, Although those requiring 000 to 10,000 g of water are shown, the solubility of the insoluble salts may be higher than these as long as the object of the present invention can be achieved.
[0051]
The content of the “insoluble salts” is preferably about 10% by mass or less, more preferably about 5% by mass or less, based on the total mass of the liquid matrix or the medical preparation. Here, “about” indicates that the number is obtained by rounding off. For example, “about 10% by mass or less” specifically means “less than 10.5% by mass”. The lower limit of the amount of the “insoluble salts” to be contained is determined by the amount of the “water-soluble polymer gelled by the metal cation” to be contained and the desired degree of crosslinking of the gel in the stomach.
[0052]
The molar ratio of the carboxyl group or sulfonic acid group that the water-soluble polymer has in its structure and the polyvalent metal cation that the insoluble salt has is preferably 1 to 10 for the former, more preferably 1 to 10. The former is 1 to 3, and the latter is 3 to 5.
[0053]
The liquid matrix according to the present invention is prepared by dissolving a “water-soluble polymer that gels under acidic conditions” in water.
[0054]
The “water” used here is not particularly limited as long as it is a pharmacologically acceptable aqueous solvent, but preferably includes distilled water and physiological saline, and more preferably distilled water.
[0055]
In making the liquid matrix according to the present invention contain "insoluble salts which release polyvalent metal cations under acidic conditions", it is preferable to first dissolve a water-soluble polymer in water and then add the insoluble salts. This is because insoluble salts are insoluble or hardly soluble in water. Further, in order to uniformly disperse the insoluble salts in the liquid matrix, ultrasonic treatment or the like may be performed. Further, the prepared liquid matrix is preferably subjected to a sterilization treatment such as high-pressure sterilization in order to be used pharmacologically.
[0056]
Further, when an insoluble salt is contained, the liquid property of the liquid matrix according to the present invention needs to be neutral or basic so that the insoluble salt does not dissolve, and the stability of the added drug should be considered. For example, it is necessary to be neutral or weakly basic. Further, when a drug or the like to be added contains a polyvalent metal cation or shows an acidic property, it is necessary to adjust the pH of the liquid matrix in consideration of its properties in advance. The acid or base used for the adjustment is not particularly limited as long as it is pharmacologically acceptable, but hydrochloric acid or sodium hydroxide solution is preferably used.
[0057]
The liquid matrix according to the present invention may be any of pharmacologically acceptable salts, surfactants, coloring agents, flavors, acidulants, sweeteners, preservatives (paraben, sodium benzoate, etc.) according to the purpose. ) May be added, and the scope of the present invention is not limited at all by this.
[0058]
The viscosity of the prepared liquid matrix is 3.0 × 10^{− 1}Pa · s or less, more preferably about 2.0 × 10^{− 1}Pa · s or less, more preferably about 1.0 × 10^{− 1}Pa · s or less, particularly 1.0 × 10^{− 1}It is preferably Pa · s or less. If the viscosity exceeds this range, infants and patients with dysphagia will have pain when swallowing the liquid matrix according to the present invention. Therefore, for patients who have more difficulty swallowing, it is recommended that the viscosity of the liquid matrix be lower. Here, “about 2.0 × 10^{− 1}“Pa · s or less” means that 2.0 × 10^{− 1}A numerical value that is Pa · s or less, specifically, 2.5 × 10^{− 1}It means less than Pa · s. Similarly, “about 1.0 × 10^{− 1}Pa · s or less ”means 1.5 × 10^{− 1}It means less than Pa · s.
[0059]
The “drug” to be blended with the liquid matrix in the oral liquid preparation of the present invention is not particularly limited, and two or more kinds may be blended as well as one kind alone. If it is soluble and stable, it may be used by mixing it as it is. If it is hardly soluble, it may be made into a conjugate using cyclodextrin or the like, solubilized and stabilized. In addition, those which are hardly soluble may be dispersed or suspended as they are. That is, since the liquid matrix of the present invention has a dispersing effect on the drug, even if the drug is insoluble or hardly soluble, the drug can be dispersed therein and the precipitation of the drug is suppressed. can do.
[0060]
The “drug” to be incorporated in the oral liquid preparation of the present invention includes, for example, nervous systems such as hypnotic sedatives, anxiolytics, antiepileptics, antipyretic analgesics and anti-inflammatory agents, antiparkinson agents, agents for psychiatric nerves, general cold agents Drugs: Cardiovascular drugs such as drugs for arrhythmia, diuretics, antihypertensives, vasoconstrictors, vasodilators, drugs for hyperlipidemia, etc .; respiratory stimulants, antitussives, expectorants, antitussive expectorants, bronchodilators Gastrointestinal drugs such as antidiarrheal, intestinal medicine, peptic ulcer, gastric digestive agent, laxative, carrier, gastric ulcer and duodenal ulcer, etc .; various hormones; Urogenital and anal drugs such as organ preparations, uterine constrictors, etc .; vitamins, nutrient tonics, drugs for blood and body fluids, drugs for liver diseases, antidote, drugs for addictive addiction, drugs for gout, enzyme preparations , Diabetes, Cell Remedies, Tumors, Allergies Anti H. Antibiotics including pylori, chemotherapeutic agents, biological preparations, drugs for parasites, metabolic drugs such as opium alkaloids, non-alkaloids, etc. can be mentioned, but are not limited to these. Absent.
[0061]
In addition, dl-methylephedrine hydrochloride, noscapine, dextromethorphan hydrobromide, dihydrocodeine phosphate, dihydrocodeine / ephedrine compounding agent used for the treatment of pediatric asthma may be added to the liquid matrix of the present invention. Since the drug activity can be maintained and the number of times of administration can be reduced, it is very effective for treating infants.
[0062]
Furthermore, for the terminal treatment of terminal cancer patients, morphine-based preparations and codeine-based preparations are administered alone or in combination for the purpose of alleviating cancer pain, but these are solid preparations. Although liquids that are easy to drink are desirable for patients with terminal cancer, they cannot be sustained if they are used as liquids. However, if the liquid matrices of the present invention are utilized, they can be administered to patients as persistent pain relievers.
[0063]
Furthermore, when used for gastric ulcer or gastritis, antiinflammatory ulcers include methylthionine preparations, azulene preparations, crude drug extract preparations, or aceglutamide, ardioxa, urogastron, ecabet sodium, cetraxate hydrochloride, pirenzepine hydrochloride, venexate hydrochloride, enprostil , Ornoprostil, gefarnate, sucralfate, sulpiride, sofacolcon, teprenone, troxipide, plaunotol, progluside, polaprezinc, irsogladine maleate, misoprostol and the like.
[0064]
Notwithstanding the above, anti-H. An oral liquid preparation containing a substance exhibiting H. pylori activity is particularly effective. That is, since the oral liquid preparation of the present invention is mere "liquid", it can be easily administered to the elderly and dysphagic persons, and also has a complicated reticular structure immediately after being taken into the stomach. And spread into the stomach wall (crypt), which is difficult to penetrate with a gel preparation or the like, and then gels due to the strong acidity of hydrochloric acid, which is the center of gastric acid secreted from the fundus lining. Therefore, the liquid preparation of the present invention protects the gastric mucosa over the details in the stomach and allows the medicinal ingredient to be released gradually and continuously at the affected part, so that it is very useful for diseases such as gastritis and gastric ulcer. It is valid. Furthermore, when the liquid matrix of the present invention gels in the stomach, it may also crosslink with the mucous layer of the stomach and exert a long-lasting drug effect. That is, H. H. pylori is protected by the mucous layer on the surface of the stomach because it is weak to strong acidity. Drugs contained in H. pylori oral liquid preparations can exert their medicinal effects without being affected by stomach acid.
[0065]
As “a medicinal ingredient exhibiting anti-H. Pylori activity”, H. Although it can be used without particular limitation as long as it is effective against H. pylori and is pharmacologically acceptable, for example, penicillin antibiotics such as amoxicillin; macrolide antibiotics such as clarithromycin, roxithromycin, azithromycin; Tetracycline antibiotics such as minocycline hydrochloride; cepham antibiotics such as cefaclor, cephalexin and cefdinir; and pyridonecarboxylic synthetic antibacterial agents such as ofloxacin, tosfloxacin tosylate, levofloxacin, norfloxacin, gatifloxacin; metronidazole; And one or more of these can be selected for use.
[0066]
Of these, particularly preferred are amoxicillin, clarithromycin, roxithromycin, minocycline hydrochloride, cefaclor, cephalexin, ofloxacin, tosfloxacin tosylate, levofloxacin, and two or more of these are used in combination. It is also recommended that There is no limitation as long as it has a strong antibacterial activity against H. pylori.
[0067]
Regardless of the above, an oral liquid preparation containing a therapeutic agent for gastric ulcer or duodenal ulcer as a “drug” also shows a particularly high effect. This is because, unlike conventional anti-ulcer preparations, the drug can be continuously and sustainedly released directly to the affected area, so that the drug utilization is high and side effects can be reduced.
[0068]
"Drugs with therapeutic effect on gastric ulcers or duodenal ulcers" are mainly "aggressive factor-suppressing" drugs that suppress gastric acid secretion itself and aggressive factors that cause ulcers, and mainly protect gastric mucosa The drug can be classified as a "protective factor-promoting type" drug having an effect of promoting repair of a ulcer site or the like, but the drug used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. However, it is preferable not to use an antacid, such as aluminum hydroxide or sodium hydrogen carbonate, which directly neutralizes the stomach acid itself. This is because the gelation of the liquid matrix according to the present invention is inhibited, and there is a possibility that the drug sustained release property is not exhibited.
[0069]
Examples of the above-mentioned agents having a therapeutic effect on gastric ulcer or duodenal ulcer of the "aggressive factor suppressing type" include proton pump inhibitors such as omeprazole, lansoprazole and rabeprazole; H2 blockers such as cimetidine, ranitidine and famotidine; and selective drugs such as pirenzepyrine. Muscarinic receptor antagonists; examples include anti-gastrin drugs such as proglumide, secretin, and urogastron. Examples of "protective factor-promoting" agents having a therapeutic effect on gastric ulcer or duodenal ulcer include, for example, ulcer lesion protecting agents such as sucralfate and azulene; and tissue repair promoting agents such as aldioxa, gefarnate, ecabet sodium and L-glutamine. Drugs: mucosal and secretagogues such as teprenone, praunotor, ornoprostil, emprostil, rebamipide; gastric mucosal microcirculation improvers such as cetraxate hydrochloride, sofacolcon, sulpiride, benexate hydrochloride betadex; sodium azulene sulfonate And other local anti-inflammatory drugs; and prostaglandins such as PGE1 (alprostadil alphadex) and PGE2.
[0070]
Among the “aggressive factor suppressing type” drug and the “protective factor promoting type” drug, the “protective factor promoting type” drug is more preferable. If gastric acid secretion itself is suppressed, the original defense ability and the like by gastric acid are also reduced, and there is a risk of infection by various bacteria.
[0071]
As the “drug having a therapeutic effect on gastric ulcer or duodenal ulcer”, prostaglandins are particularly preferable. This is because the effect of the liquid preparation according to the present invention containing prostaglandins has been demonstrated not only in the past as a gastrointestinal ulcer drug but also in the examples described below.
[0072]
There is no particular limitation on the timing of mixing the drug with the liquid matrix of the present invention, and the drug may be mixed when taken. For example, a drug whose stability is impaired by being dissolved in water or the like is preferably mixed immediately before taking the drug.
[0073]
Even if the drug is blended with the liquid matrix of the present invention, the viscosity before and after the blending hardly changes, but the viscosity after blending is 3.0 × 10 3 like the liquid matrix.^{− 1}Pa · s or less, more preferably about 2.0 × 10^{− 1}Pa · s or less, more preferably about 1.0 × 10^{− 1}Pa · s or less, particularly 1.0 × 10^{− 1}It is preferably Pa · s or less. In addition, sterilization treatment such as high-pressure sterilization may be performed after compounding the medicine.
[0074]
The present invention is configured as described above, and the liquid matrix according to the present invention is useful as a swallowing aid of a drug because it is liquid and has a masking effect such as bitterness, and furthermore, it gels in vivo. The drug also exhibits sustained release.
[0075]
Therefore, the liquid oral preparation containing the liquid matrix according to the present invention as a component has the above-mentioned effects as it is, and not only is easy to swallow, but also has a sustained release of the drug. Even in this case, it is possible to maintain the drug efficacy without rapidly increasing the blood concentration, and it is also possible to reduce the number of administrations.
[0076]
In the oral liquid preparation of the present invention, anti-H. Those containing a pylori agent are particularly effective. Conventionally, effective treatment methods have not been established. In Helicobacter pylori eradication treatment, the amount of antibiotics and the like can be reduced without using a proton pump inhibitor in combination, so that these side effects can be suppressed. Further, a liquid preparation containing a drug having a therapeutic effect on gastric ulcer or duodenal ulcer can exert a very high therapeutic effect because it can act directly on the ulcer part.
[0077]
Hereinafter, the present invention will be described in more detail with reference to Examples and Preparation Examples, but the scope of the present invention is not limited thereto.
[0078]
【Example】
(Example 1)
Sodium alginate was added to distilled water to prepare 10 ml each of aqueous solutions of various concentrations of water-soluble polymer, and various amounts of calcium carbonate or calcium phosphate as insoluble salts were added thereto to prepare a liquid matrix. To each of them, 5 ml of 1 solution of the Japanese Pharmacopoeia Disintegration Test was added, and a reproduction experiment was conducted when the liquid matrix of the present invention was introduced into the stomach, and the state of gelation was observed. The results are shown in Tables 1 and 2.
[0079]
[Table 1]

[0080]
[Table 2]

[0081]
The components of sodium alginate are sodium salts of β-D-mannuronic acid and α-L-guluronic acid, and the molecular weights of the sodium salts of these sugar acids are both about 217, and the carboxyl group is one for each sugar. Therefore, the number of moles of the carboxyl group at each concentration of sodium alginate can be roughly estimated.
[0082]
From the results in Tables 1 and 2, when the liquid matrix of the present invention contains an insoluble salt that releases a metal cation in order to gel uniformly, the water-soluble polymer has a carboxyl group or It was found that the molar ratio of the sulfonic acid group to the metal cation of the insoluble salt is preferably at least 1 for the former and at least 1 for the latter.
[0083]
(Example 2)
The liquid preparation was adjusted so that two kinds of water-soluble polymers were mixed to convert into gels having various gel strengths (gel shear stress), and a sustained release test of the drug was performed.
[0084]
To 100 ml of distilled water, kappa carrageenan and locust bean gum were added as water-soluble polymers at different mixing ratios, and the mixture was sufficiently stirred to prepare a plurality of liquid matrices capable of converting into gels having various gel strengths. Further, riboflavin was added so that the final concentration became 0.02%, and the pH was adjusted to 7.4 to prepare a liquid preparation.
[0085]
1 ml of the riboflavin-liquid matrix was dropped through a wall surface into a tube containing 30 ml of the Japanese Pharmacopoeia Disintegration Test 1 solution, and a reproduction experiment was conducted in the case where the riboflavin-liquid matrix was introduced into the stomach. The riboflavin-liquid matrix gelled upon contact with Disintegration Test Solution 1. Each gel strength is determined by the breaking stress (N / m²) Was measured with a Sanden creep meter HC2-3805.
[0086]
After the gel was completely dropped into one solution of disintegration test, the mixture was shaken at 37 ° C., and the release of riboflavin after 120 minutes was measured. The released riboflavin was quantified by measuring the absorbance at 445 nm in accordance with "13th Revised Japanese Pharmacopoeia", Hirokawa Shoten, 1996, C-2660-2667. With the amount of riboflavin in the gel initially being 100, the percentage of the amount of riboflavin released in the disintegration test 1 solution was calculated. FIG. 1 shows the relationship between the gel strength and the release rate of riboflavin.
[0087]
As shown in FIG. 1, the higher the gel strength, the more riboflavin is carried in the gel, and the more slowly the drug is released. That is, if the drug remains in the gel even after 120 minutes of shaking at 37 ° C., it can be evaluated as having sustained release. On the other hand, when the gel strength is low, riboflavin is released directly and cannot exhibit sustained release. That is, in the case of a gel having no sustained release, usually, when immersed in one solution of the disintegration test at 37 ° C., the drug is immediately released, and the gel shape is lost in about 20 minutes. Here, the gel was immersed in one solution of disintegration test heated to 37 ° C. for 120 minutes, and the case where 10% or more of the drug remained in the gel was defined as the minimum gel strength for obtaining sustained release. From the results obtained, the breaking stress at this time was about 3.00 × 10²N / m²Met.
[0088]
(Example 3)
After 1 g of sodium alginate and 1 g of LM pectin were added to 100 ml of distilled water to completely dissolve, 1 g of calcium carbonate was added and sufficiently stirred to prepare two liquid matrices. 100 mg of riboflavin was added to this solution and dissolved to adjust the pH to 7.4.
[0089]
1 ml of this riboflavin-liquid matrix was treated and gelled as in Example 2. When the strength of the gel was measured in the same manner as in Example 2, the strength was 1% sodium alginate and 1.02 × 10 5⁴N / m²5.59 × 10 with 1% LM pectin³N / m²Met. The amount of riboflavin released from the gel was measured. With the amount of riboflavin in the gel initially being 100, the percentage of the amount of riboflavin released in the disintegration test 1 solution was calculated. The result is shown in FIG.
[0090]
As shown in FIG. 2, it was found that riboflavin was gradually released without being rapidly released into the test solution in both cases where alginic acid was used as the water-soluble polymer and LM pectin was used. Therefore, it was demonstrated that the oral liquid preparation of the present invention exhibited high sustained release.
[0091]
(Example 4)
After adding 1 g of sodium alginate to 100 ml of distilled water and completely dissolving it, 1 g of calcium carbonate was added and sufficiently stirred to prepare a liquid matrix. To this solution, 10 mg of acetaminophen (Yoshitomi Fine Chemical Co., Ltd.) was added and dissolved to adjust the pH to 7.4.
[0092]
1 ml of this acetaminophen-liquid matrix was dropped into 100 ml of the Japanese Pharmacopoeia Disintegration Test Solution 1 to perform a reproduction experiment in which the acetaminophen-liquid matrix was introduced into the stomach. The dropped acetaminophen-liquid matrix immediately gelled. The strength of the gel was 1.02 × 10⁴N / m²was. The release of acetaminophen from this gel was measured. The released acetaminophen was quantified by measuring the absorbance at 244 nm according to "13th Revised Japanese Pharmacopoeia", Hirokawa Shoten, 1996, C-69-73. With the amount of acetaminophen in the gel initially being 100, the percentage of the amount of acetaminophen released in one solution of the disintegration test was calculated. The result is shown in FIG.
[0093]
As shown in FIG. 3, it was found that when the acetaminophen-liquid matrix was introduced into the stomach, the water-soluble polymer gelled and acetaminophen was gradually released. Therefore, it was proved that the oral liquid preparation of the present invention exhibited high sustained release.
[0094]
(Example 5)
The acetaminophen-liquid matrix prepared in Example 4 was subjected to a high-pressure sterilization treatment at 121 ° C. for 30 minutes, and then naturally decompressed to obtain a test sample.
[0095]
As a target example, a viscosity-stable antacid composition was prepared with reference to the description of Patent Document 2 (JP-A-8-99885). That is, 2.5 g of sodium alginate and aluminum hydroxide / magnesium carbonate gel (56% Al₂O₃, 4% MgO) was added to about 75 ml of purified water, and the mixture was stirred at about 80 ° C. for 30 minutes. The heated reaction mixture was rapidly mixed with stirring into about 400 ml of an aqueous suspension of 35 g of magnesium carbonate maintained at about 25 ° C. Further, 47.5 g of sodium alginate was added to this mixture, 1 g of xanthan gum, 15 g of calcium carbonate and 10 g of potassium hydrogen carbonate were added, and purified water was added to make 1 liter. The prepared example was autoclaved in the same manner as the acetaminophen-liquid matrix of the present invention.
[0096]
FIG. 4 shows the state after the high-pressure sterilization of both samples.
[0097]
As shown in FIG. 4, the oral liquid preparation of the present invention maintained a stable state even after being subjected to the high-pressure sterilization treatment, whereas in the target example, the oral liquid preparation was completely separated into an aqueous layer and a gel layer. Therefore, it was found that the oral liquid preparation of the present invention had extremely high sterilization operability.
[0098]
(Example 6)
As in Example 2, two water-soluble polymers were added to 100 ml of distilled water so that (i) 0.5% alginic acid-0.5% pectin and (ii) 1% alginic acid-1% pectin. After complete dissolution, 1 g of calcium phosphate was added and the mixture was sufficiently stirred to prepare a liquid matrix. 100 mg of riboflavin was added to this solution and dissolved to adjust the pH to 7.4.
[0099]
Each of the two prepared liquid drugs was immersed in the Japanese Pharmacopoeia Disintegration Test Solution 1 for 6 hours to gel. The strength of the gel was 3.02 × 10 3 with 0.5% alginic acid-0.5% pectin.³N / m²1.00 × 10 with 1% alginic acid-1% pectin⁴N / m²was. The riboflavin-liquid matrix was further transferred to the small intestine via the stomach by removing the gel and removing the attached Japanese Pharmacopoeia Disintegration Test Solution 1 with a filter paper, and then immersing the gel in the Japanese Pharmacopoeia Disintegration Test Solution 2. A reproduction experiment was performed. The release of riboflavin released from the gel was measured as in Example 2. The result is shown in FIG.
[0100]
As shown in FIG. 5, in the oral liquid preparation of the present invention, the physical strength of the gel is adjusted by devising the selection or combination of the water-soluble polymers that are the constituents thereof, not only in the stomach but also in the small intestine. It was also found that the gel could control the disintegration of the gel and exhibited high sustained release.
[0101]
(Example 7)
Using six healthy adult males as subjects, a sensory test was conducted on the ease of taking a solution using sodium alginate aqueous solutions prepared at various concentrations (viscosity). Table 3 shows the results.
[0102]
[Table 3]

[0103]
According to the results of the present example, the viscosity of the liquid matrix is 3.0 × 10^{− 1}It became clear that Pa · s or less was preferable.
[0104]
(Example 8)
A sensory test was conducted on the masking effect of bitterness using 6 healthy adult males as subjects using 20 ml of an aqueous sodium alginate solution adjusted to a concentration of 1% and 50 mg of magnesium chloride as a bitter component. As a target example, a solution obtained by adding 50 mg of magnesium chloride to 20 ml of water was used. Table 4 shows the results.
[0105]
[Table 4]

[0106]
The results of this test revealed that the liquid matrix of the present invention has an effect of masking the bitter taste of drugs and the like.
[0107]
(Example 9)
Gellan gum and LM pectin were dissolved in distilled water, and a liquid matrix was prepared by mixing them so that the respective concentrations became 0.5%. 10 mg of riboflavin was added to and dissolved in 10 ml of this liquid matrix, and the pH was adjusted to 7.4.
[0108]
1 ml of this riboflavin-liquid matrix was dropped into the Japanese Pharmacopoeia Disintegration Test 1 solution, and a reproduction experiment was performed when the riboflavin-liquid matrix was administered intragastrically. As a result, the dropped riboflavin-liquid matrix gelled simultaneously with the dropping. The strength of the gel was 3.00 × 10⁴N / m²was. Release of riboflavin from this gel was measured as in Example 2. Further, similarly to Example 6, the dissolution into the Japanese Pharmacopoeia disintegration test 2 liquid was also examined. FIG. 6 shows the results.
[0109]
As shown in the results, the riboflavin in the gel was not released rapidly, but was gradually eluted in the disintegration tests 1 and 2. This proved that the oral liquid preparation of the present invention exhibited high sustained release properties both in the stomach and in the small intestine.
[0110]
(Example 10)
Liquid preparations of the present invention having the compositions shown in Tables 5 to 9 below were prepared.
[0111]
[Table 5]

[0112]
[Table 6]

[0113]
[Table 7]

[0114]
[Table 8]

[0115]
[Table 9]

[0116]
No. in the above table. 1 mL of the liquid preparation shown in 2,3,6,8,9,10,14,16,21 and 26 was gently added to a petri dish containing 10 mL of artificial gastric juice (one solution of Japanese Pharmacopoeia disintegration test liquid). Both gelled immediately upon contact with artificial gastric juice.
[0117]
This gelled formulation is H. pylori culture (CFU: 1 × 10⁷, 1 × 10⁸, 1 × 10⁹/ ML, 10 ml of 10% inactivated horse serum-supplemented Brucella broth) and microaerobic culture at 37 ° C. for 24 hours using a Campi bag (BBL). Similarly, only a gel containing no antimicrobial agent was added as a negative control, and 0.5 g of amoxicillin and 0.2 g of clarithromycin were added as positive controls and cultured.
[0118]
After 24 hours, each culture solution was smeared on M-BHM pylori agar medium (Niken Biomedical Research Institute Co., Ltd.) supplemented with 10% inactivated horse serum, and cultured at 37 ° C. for 7 days. It was determined by examining the presence or absence of H. pylori. The antibacterial activity was evaluated as positive when the bacteria had disappeared or had clearly decreased, and as negative (-) when the bacteria were growing as they were. The results are shown in Table 10 below.
[0119]
[Table 10]

[0120]
From the above results, it has been clarified that the liquid preparation of the present invention rapidly gels in gastric juice and shows the same activity as that when the antibacterial agent is administered as it is.
[0121]
In general, antibiotics are weakly acidic and their activity is reduced by stomach acid when administered orally. However, the liquid preparation of the present invention has antibacterial activity even in the stomach because the antibacterial agent is protected by a gel. Can be maintained; It is envisioned that H. pylori infection can be treated.
[0122]
(Example 11)
First, according to a known method (Hirayama et al., {Journal of Gastroenterology}, J. Gastroenterology, Vol. 31, pp. 755-757 (1996)), the method described in H. Yamamoto et al. H. pylori (ATCC 43504) was microaerobic cultured in Brucella @ broth (BBL) supplemented with 10% inactivated horse serum, and then 1 × 10⁹It was adjusted to CFU (colony forming unit) / mL.
[0123]
Next, 3 to 4 male gerbils (MGS / Sea, body weight: about 60 g) were used per group, and they were fasted for 24 hours. H. pylori culture 200 μl (2 × 10⁸CFU) was inoculated intragastrically using an oral probe for rats.
[0124]
Seven days after the bacterial inoculation, the antibacterial therapeutic agent is administered twice a day in the morning and evening according to a known method (Shimizu et al., Cancer Research, Vol. 60, pp. 1512-1514 (2000)). The administration was performed for 2 days.
[0125]
Example 10 Twenty-three liquid preparations (a liquid matrix composed of pectin and gellan gum to which minocycline hydrochloride was added as an antibacterial agent) were administered. When this is converted into the dose of the antibacterial agent, the dose is 17 mg / kg of body weight per dose.
[0126]
As a control, 0.5% CMC solution alone, and 3 drugs consisting of 10,3,30 mg / kg body weight each of lansoprazole (proton pump inhibitor), amoxicillin (antibiotic) and clarithromycin (antibiotic) covered by insurance The concomitant drug was administered.
[0127]
The eradication determination was performed by culturing the collected gastric mucosal tissue, microaerobic culturing in a Brucella broth (BBL) medium supplemented with 10% inactivated horse serum for 24 hours, and then placing it on an M-BHM pylori agar medium supplemented with 10% inactivated horse serum. After smearing, microaerobic culture was performed at 37 ° C. for 7 days. Performed by detecting H. pylori.
[0128]
The efficacy and ineffectiveness of the drug were determined by the gastric mucosal tissue of gerbils to which the triple drug, which is the current eradication therapy, was administered. The H. pylori count was the original bacterial count (1 × 10⁹CFU / mL), ie about 1 × 10⁴Since it was CFU / mL, the same or less bacterial count was considered effective. Table 11 shows the results.
[0129]
[Table 11]

[0130]
From the above results, No. 1 according to the present invention. According to the 23 liquid preparations, it was clarified that the same degree of eradication effect can be obtained as with the triple therapy which is the current eradication therapy.
[0131]
No. The liquid formulation of No. 23 gelled on the surface layer of the stomach mucosa by stomach acid, thereby protecting minocycline hydrochloride contained in the gel from rapid hydrolysis by stomach acid. It is considered that the drug was directly and continuously released to the mucosal surface layer where pylori was present, and a sufficient antibacterial effect was obtained.
[0132]
On the other hand, in the administration of the triple drug, H. H. pylori is reduced, but due to the very large dose of the triple drug, congestion is observed throughout the gastrointestinal tract from the small intestine to the large intestine, especially the duodenum enlarges with congestion and the gallbladder becomes enlarged That side effect had occurred. In addition, the gastric swelling was greatly increased, probably due to suppression of gastric acid secretion by the proton pump inhibitor, and red inflammation was exhibited from the cardia to the esophagus.
[0133]
However, when the liquid preparation of the present invention was administered, such side effects were not observed at all.
[0134]
(Example 12)
Gastroscopy was determined by gastroscopy and gastrointestinal biopsy samples were tested for gastritis. No. 30 of Example 10 was given to three patients aged 30 to 50 determined to be positive. According to the above, 200 mL of a liquid preparation containing 750 mg of amoxicillin and 200 mg of clarithromycin was taken daily before going to bed and continued for one week. After completion of the administration, the urea was tested by the urea breath test. The presence or absence of H. pylori was determined. The results are shown in Table 12 below.
[0135]
[Table 12]

[0136]
At present, the three-drug combination method of lansoprazole, amoxicillin and clarithromycin, which is covered by insurance, administers lansoprazole 60 mg, amoxicillin 1,500 mg and clarithromycin 400 mg per day for 7 days. On the other hand, from the above results, in the oral liquid preparation of the present invention, lansoprazole, which is a proton pump inhibitor, is not required, and only two antibiotics need to be used in combination. In addition, each of the above dosages is half, that is, 750 mg of amoxicillin per day, Claris. It was revealed that administration of 200 mg of romycin shows a sufficient effect.
[0137]
In addition, the subjects did not have any side effects such as reflux esophagitis, diarrhea, dysgeusia, or any other side effects that have been reported previously in the eradication treatment with the triple agent. Therefore, it is considered that there is a low possibility that the side effect of the antibacterial agent using the oral liquid preparation of the present invention will cause more side effects than before, and it has been demonstrated that the agent can be easily removed while maintaining daily life.
[0138]
(Example 13)
Liquid preparations of the present invention having the compositions shown in Tables 13 to 15 below were prepared.
[0139]
[Table 13]

[0140]
[Table 14]

[0141]
[Table 15]

[0142]
(Example 14) A therapeutic effect test using an acetic acid chronic ulcer model rat
Twenty-four male Wistar rats weighing about 200 g were divided into eight groups and fasted overnight, after which acetic acid ulcers were produced in each rat. That is, a rat is anesthetized with Nembutal, laparotomy is performed along the median line, and the stomach is taken out. After that, a 10 mm diameter cylinder filled with defatted soaked with 100% acetic acid at the boundary between the stomach body and the pylorus is used as a serosa. The acetic acid adhering to the serosal surface was wiped off with sterile gauze, and the abdomen was sutured. Six weeks later, as a control, one rat was randomly removed from the untreated group, sacrificed and dissected, and it was confirmed that an ulcer was formed.
[0143]
No. 3 was given to each of the three rats. No. 38, a liquid formulation of cetraxalate hydrochloride, No. 30 cimetidine liquid formulation; Each of the 37 teprenone liquid preparations was administered to the stomach once a day for 2 weeks, 0.5 ml each, to give a liquid preparation administration group. As a control, a purified aqueous solution of each drug was divided into three groups of three animals each (positive control), one group of three liquid preparations consisting only of a liquid matrix (negative control), and one group of three purified water alone (no treatment) Group).
[0144]
At week 7 and week 8, untreated rats were randomly sacrificed one by one as a control, and laparotomy was performed to confirm again that a gastric ulcer was formed. Each rat was sacrificed at the 8th week, and the ulcer area was measured, and the area of the ulcer was measured, and the method of Okabe et al. (Okabe S, Roth JLA, Pfeitter CJ: Amethod for experimental penetrating physicians and doctors. Dig Dis16: 277-284, 1971) to determine the ulcer index. Ulcer index is 1-10mm²Is 1 and 11 to 20 mm²Up to 2, 21 to 30 mm²Up to 3. Table 16 shows the results.
[0145]
[Table 16]

[0146]
From the above results, it was demonstrated that the liquid preparation according to the present invention exhibited a therapeutic effect on gastric ulcer. However, it was found that teprenone having a tissue repairing action or cetraxate hydrochloride having a mucus production / secretion promoting action tended to be more effective for gastric ulcer than an aggressive factor suppressing type such as cimetidine.
[0147]
On the other hand, even when the drug solution was directly administered (positive control), an ulcer reduction effect was observed, but the effect was inferior to that of the liquid preparation of the present invention.
[0148]
Therefore, it was demonstrated that the liquid preparation of the present invention had a higher ulcer treatment effect than the conventional preparation.
[0149]
(Example 15) Therapeutic effect of a liquid preparation using an indomethacin ulcer rat model
Eighteen male Wistar rats weighing around 200 g were divided into four groups: five experimental groups and a control group (five as a positive control group and five as a negative control group), and three untreated groups for confirmation of ulcer development. Divided into groups. After being fasted for 24 hours, indomethacin (IND) 20 mg / kg body weight suspended in a 1% carboxymethylcellulose (CMC) solution was orally administered using a gastric administration probe in rats to induce indomethacin ulcer. . In the preliminary test, the blood concentration of indomethacin reached the maximum at 3 hours, and erosive bleeding was observed in the stomach.
[0150]
3 hours after the administration of indomethacin, 41 prostaglandin (PGE1) liquid preparation (containing alprostadil alfadex as a drug) and a PGE1 solution dissolved in purified water as a positive control so that the PGE1 dose was 3.3 μg / kg body weight, and negative. As a control, only the liquid matrix was further administered to an untreated group to which only purified water was administered to confirm the occurrence of ulcer, and feeding was performed 1 hour after that. The rats were sacrificed and dissected 3 hours after administration of indomethacin in the untreated group and 24 hours in the other groups, and the state of gastric ulcer and bleeding was determined.
[0151]
Unlike in humans, indomethacin ulcers using fasted rats occur in the stomach without causing ulcers in the antrum vestibule, so the judgment was based on the presence or absence of bleeding. That is, no bleeding was negative (-), trace bleeding was (±), petechiae was (+), and extensive bleeding was (++). Table 17 shows the results.
[0152]
[Table 17]

[0153]
In an indomethacin ulcer model using fasted rats, hemorrhagic erosion in the stomach body is known to be suppressed by H2 blockers, antacids, anticholinergic agents, proton pump inhibitors, prostaglandin preparations, mucosal protective agents, etc. (Susumu Okabe, experimental model of peptic ulcer, Japanese clinical practice, 42: 43-47, 1979). On the other hand, in rats fed for 1 hour after a 24-hour fast, gastric corpus lesions are suppressed, and ulcers that extend from the pyloric vestibule to the small intestine similarly to human ulcers occur. It is also known that this pyloric vestibular ulcer has no effect other than the prostaglandin preparation (Satoh, H., et．al., Gastroenterology, 81: 719-725, 1981).
[0154]
From the above results, the intragastric administration of prostaglandin (PEG1) having a cytoprotective effect on the gastric mucosa in the 24-hour fasted indomethacin ulcer rats performed this time clearly improved the bleeding symptoms.
[0155]
However, according to the present invention, it was revealed that the effect of PEG1 in the liquid preparation of the present invention was higher than in the case of direct administration. This means that in the case of the liquid preparation of the present invention, the liquid matrix gels in the stomach with stomach acid and physically protects the gastric mucosa, and at the same time releases the drug (PEG1 in this example) in a sustained manner. Is considered to be a result that can be used more effectively in the affected area to treat the ulcer.
[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]
【The invention's effect】
The liquid matrix of the present invention can easily solubilize, disperse, or suspend a drug, is easy to swallow because it is liquid, has high operability such as sterilization, is stable, and has a masking effect of bitterness. Also, the drug release rate can be controlled by gelling in vivo. Therefore, the oral liquid preparation containing a drug in the liquid matrix of the present invention has an unprecedented effect of having a high sustained release property despite being liquid.
[0168]
In particular, anti-H. Since the oral liquid preparation containing a pharmacologically active ingredient showing pylori activity gels when introduced into the stomach, it gradually disintegrates and releases the pharmacologically active ingredient while protecting the vulnerable to acidic conditions. The content of the pharmaceutically active ingredient to be contained and the number of times of administration can be reduced, and side effects are less likely to occur.
[0169]
At the same time, since the liquid preparation does not require a proton pump inhibitor or the like that suppresses gastric acid secretion, there is no side effect caused by the drug.
[0170]
From the above, H. The liquid preparation according to the present invention which is applied to the treatment of H. pylori infection includes a conventional anti-H. Compared to H. pylori, it has a particularly excellent feature that it does not require a proton pump inhibitor, and thus is very effective as a therapeutic agent for Helicobacter pylori infection.
[0171]
In addition, an oral liquid preparation containing a "drug" that has a therapeutic effect on gastric ulcer or duodenal ulcer also exhibits sustained release of the drug and shows a particularly high therapeutic effect. That is, unlike conventional anti-ulcer preparations, since the drug can be continuously and sustainedly released directly to the affected area, the drug utilization is high and side effects can be reduced.
[0172]
Therefore, the liquid drug according to the present invention used for the treatment of gastric ulcer or duodenal ulcer is also less likely to produce side effects because the dose can be reduced compared to conventional anti-ulcer drugs, and the therapeutic effect itself is high, Very useful.
[Brief description of the drawings]
FIG. 1 is a diagram showing a relationship between gel strength (rupture stress) and release of riboflavin from a gel.
FIG. 2 is a diagram showing sustained release of riboflavin from the oral liquid preparation of the present invention.
FIG. 3 is a diagram showing sustained release of acetaminophen from the oral liquid preparation of the present invention.
FIG. 4 shows a state in which the liquid matrix of the present invention and a target example are autoclaved.
FIG. 5 is a diagram showing sustained release of riboflavin from an oral liquid preparation of the present invention containing two water-soluble polymers.
FIG. 6 is a diagram showing sustained release of riboflavin from the oral solution of the present invention.

Claims (21)

A liquid adjuvant that facilitates swallowing of drugs, containing a water-soluble polymer that gels under acidic conditions, and the gel has a breaking stress of about 3.00 × 10 ² N / m ² or more. A liquid matrix, characterized in that: The liquid matrix according to claim 1, wherein the gel has a breaking stress of 2.00 × 10 ³ N / m ² or more. The viscosity of the liquid matrix, 3.0 × ^{10 -} 1 The liquid matrix according to claim 1 or 2 Pa · s or less. The liquid matrix according to any one of claims 1 to 3, further comprising an insoluble salt that releases a polyvalent metal cation under acidic conditions. The liquid matrix according to claim 4, wherein the insoluble salt is an alkaline earth metal salt of an inorganic acid. The liquid matrix according to any one of claims 1 to 5, wherein the water-soluble polymer has a carboxyl group and / or a sulfonic acid group in its chemical structure. The liquid matrix according to any one of claims 1 to 5, wherein the water-soluble polymer is an alginate. The liquid matrix according to any one of claims 1 to 5, wherein the water-soluble polymer is pectin. The liquid matrix according to any one of claims 1 to 5, wherein the water-soluble polymer is a combination of alginic acid or a salt thereof and pectin. The liquid matrix according to any one of claims 1 to 5, wherein the water-soluble polymer is gellan gum or a combination of gellan gum and pectin. The liquid matrix according to claim 1 or less 1 Pa · s ^- the viscosity of the liquid matrix of about 1.0 × ^10. An oral liquid preparation comprising the liquid matrix according to any one of claims 1 to 11 and a drug. 13. The oral liquid preparation according to claim 12, wherein the drug exhibits anti-Helicobacter pylori activity. 14. The oral liquid preparation according to claim 12 or 13, wherein the drug is at least one selected from the group consisting of penicillins, macrolides, tetracyclines, cephams, and pyridonecarboxylic acid-based synthetic antibacterials. . 15. The oral liquid preparation according to claim 14, wherein the drug is one or more selected from the group consisting of amoxicillin, clarithromycin, roxithromycin, minocycline hydrochloride, cefaclor, cephalexin, ofloxacin, tosfloxacin tosylate, and levofloxacin. The oral liquid preparation according to any one of claims 12 to 15, wherein the liquid matrix shows sustained release of the drug by gelling in the stomach. The oral liquid preparation according to claim 12, wherein the drug has a therapeutic effect on gastric ulcer or duodenal ulcer. The oral liquid preparation according to claim 17, wherein the drug having a therapeutic effect on gastric ulcer or duodenal ulcer is a protective factor-promoting type. 19. The oral liquid preparation according to claim 18, wherein, among the above-mentioned drugs having a therapeutic effect on gastric ulcer or duodenal ulcer, those having a protective factor promoting type are prostaglandins. The oral liquid preparation according to any one of claims 17 to 19, wherein the liquid matrix shows sustained release of the drug by gelling in the stomach. A method comprising using an aqueous solution of a water-soluble polymer that gels under acidic conditions as a component of an oral liquid preparation having sustained release.

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