JP2004269460A - Prophylactic and therapeutic agent for peptic ulcer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new prophylactic and therapeutic agent for peptic ulcer capable of improving a morbid state of peptic ulcer such as NSAID-causing injury of gastric mucous membrane by effectively acting on peptic ulcer in a slight amount used without accompanying adverse effect. <P>SOLUTION: The prophylactic and therapeutic agent for peptic ulcer comprises a chromanol glycoside represented by general formula (1) (wherein R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each same or different hydrogen atom or lower alkyl group; R<SP>5</SP>is a hydrogen atom, a lower alkyl group or a lower acyl group; X is a monosaccharide residue or an oligosaccharide residue in which a hydrogen atom of a hydroxy group in the sugar residue may be substituted by a lower alkyl group or a lower acyl group; n is an integer of 0-6; m is an integer of 1-6). <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

【００１１】
（ただし、式中、Ｒ^１ 、Ｒ^２ 、Ｒ^３ およびＲ^４ は同一または異なる水素原子または低級アルキル基を表し、Ｒ^５ は水素原子、低級アルキル基または低級アシル基を表し、Ｘは糖残基中の水酸基の水素原子が低級アルキル基または低級アシル基で置換されていてもよい単糖残基またはオリゴ糖残基を表し、ｎは０〜６の整数であり、およびｍは１〜６の整数である）で表されるクロマノール配糖体を含有してなる消化性潰瘍の予防および治療剤である。
【００１２】
本発明はまた、前記クロマノール配糖体は２−（α−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オールである前記消化性潰瘍の予防および治療剤である。
【００１３】
本発明はさらに、水性製剤である前記消化性潰瘍の予防および治療剤である。
【００１４】
本発明はさらに、前記消化性潰瘍は、非ステロイド系抗炎症剤惹起性消化性潰瘍である前記消化性潰瘍の予防および治療剤である。
【００１５】
本発明はさらに、前記消化性潰瘍は、非ステロイド系抗炎症剤惹起性胃粘膜傷害である前記消化性潰瘍の予防および治療剤である。
【００１６】
【発明の実施の形態】
本発明の消化性潰瘍の予防および治療剤は、前記一般式（１）で表されるクロマノール配糖体を有効成分とすることを特徴とするものである。
【００１７】
前記一般式（１）において、Ｒ^１ 、Ｒ^２ 、Ｒ^３ 、Ｒ^４ およびＲ^５ の低級アルキル基としては、炭素原子数が１〜８、好ましくは１〜６の低級アルキル基がよく、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ペンチル基、イソペンチル基、ヘキシル基、ヘプチル基、オクチル基等が挙げられる。これらの中では、メチル基またはエチル基が好ましい。また、Ｒ^５ の低級アシル基としては、炭素原子数が１〜８、好ましくは１〜６の低級アシル基がよく、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基、ヘキサノイル基、ヘプタノイル基、オクタノイル等が挙げられる。これらの中では、アセチル基、プロピオニル基またはブチリル基が好ましい。また、Ｘの単糖残基としては、グルコース、ガラクトース、フコース、キシロース、マンノース、ラムノース、フルクトース、アラビノース、リキソース、リボース、アロース、アルトロース、イドース、タロース、デオキシリボース、２−デオキシリボース、キノボース、アベクオース等の糖残基が挙げられる。Ｘのオリゴ糖残基としては、上記単糖が２〜４個結合したもの、例えばマルトース、ラクトース、セロビオース、ラフィノース、キシロビオース、スクロースの糖残基等が挙げられる。これらの中ではグルコース、ガラクトース、フコース、キシロース、ラムノース、マンノース、フルクトース等の単糖残基が好ましい。また、Ｘの糖残基中の水酸基の水素原子は低級アルキル基、好ましくは炭素原子数が１〜８の低級アルキル基、または低級アシル基、好ましくは炭素原子数が１〜１０の低級アシル基で置換されていてもよい。さらに、ｎは０〜６、好ましくは１〜４の整数であり、ｍは１〜６、好ましくは１〜３の整数である。一般式（１）で表されるクロマノール配糖体の好ましい例としては、２−（α−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−ガラクトピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｌ−フコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（α−Ｌ−ラムノピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−キシロピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（β−Ｄ−フルクトフラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール、２−（α−Ｄ−マンノピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール等が挙げられる。
【００１８】
本発明に用いられるクロマノール配糖体は、例えば特開平７−１１８２８７号公報、特開平９−２４９６８８号公報、特開平１１−２１２９１号公報に記載の方法により、下記一般式（２）：
【００１９】
【化３】

【００２０】
（ただし、式中、Ｒ^１ ，Ｒ^２ ，Ｒ^３ 、Ｒ^４ 、Ｒ^５ およびｎは前記と同義である）で表される２−置換アルコールおよびオリゴ糖類を相当する糖転位作用を触媒する酵素の存在下に反応させ、２−置換アルコールの２位の水酸基に対して特異的に糖の特定の水酸基を結合させることからなる酵素反応によって製造される（酵素法）。
【００２１】
上記反応において原料として用いられる一般式（２）で表される２−置換アルコール（以下、単に「２−置換アルコール」という）は公知の物質であり、例えば、特公平１−４３７５５号公報や特公平１−４９１３５号公報等に開示された方法により得ることができる。また、例えば、一般式（２）中、Ｒ^１ 、Ｒ^２ 、Ｒ^３ およびＲ^４ がメチル基、Ｒ^５ が水素原子であり、ｎが１である２−置換アルコールは、α−トコフェロールのクロマン環の２位のフィチル基がカルボキシル基で置換された構造を有する６−ヒドロキシ−２，５，７，８−テトラメチルクロマン−２−カルボン酸（商品名「トロロックス（Ｔｒｏｌｏｘ）」）を水素化リチウムアルミニウムの存在下においてジエチルエーテル中で加熱還流処理すること等により容易に得ることができる。
【００２２】
また、本発明に用いられるクロマノール配糖体は、特願平１０−７５５９９号に記載の方法により、前記２−置換アルコールの６位の水酸基を保護基で保護したもの（以下「糖受容体」という）とアノマー位に脱離基を導入し他の水酸基を保護基で保護した糖の誘導体（以下、「糖供与体」という）とを縮合反応させることによっても製造できる（有機合成法）。
【００２３】
上記反応において使用される糖供与体糖供与体は、周知の方法により糖の全ての水酸基へ保護基を導入し、次いでアノマー位を脱離基に置換することにより容易に調製することができる。
【００２４】
上記酵素法または有機合成法により得られたクロマノール配糖体は、一般的に、極めて高い水溶性（約１００ｇ／１００ｍｌ）を有し、かつ油溶性にも富む（オクタノール／水系分配係数＞３）両親媒性分子である。いいかえると、本発明によるクロマノール配糖体は、高い脂質親和性を備えた水溶性ビタミンＥであるということができる。したがって、本発明によるクロマノール配糖体は、従来の水に不溶性あるいは貧溶性のビタミンＥ誘導体とは異なり、水に溶解して使用しても高い脂質親和性を保つので、細胞膜を透過しさらに細胞内にも入ることができ、消化性潰瘍を飛躍的に改善する。また、上記反応により得られたクロマノール配糖体は、熱安定性およびｐＨ安定性に関してもトコフェロール、トロロックスまたは２−置換アルコールに比べて著しく向上するものである。
【００２５】
本発明の消化性潰瘍の予防および治療剤は、前記クロマノール配糖体を製薬上許容される担体と配合したまたは製薬上許容される溶剤に溶解もしくは懸濁した組成物として、経口的または非経口的に患者に投与することにより、食道潰瘍（逆流性）、胃潰瘍、十二指腸潰瘍、空腸潰瘍等の消化性潰瘍、特にＮＳＡＩＤ惹起性消化性潰瘍の予防および治療剤として利用することができる。
【００２６】
本剤を経口投与用とする場合には、前記クロマノール配糖体を単体で、または適当な添加剤、例えば、乳糖、ショ糖、マンニット、トウモロコシデンプン、合成もしくは天然ガム、結晶セルロース等の賦形剤、デンプン、セルロース誘導体、アラビアゴム、ゼラチン、ポリビニルピロリドン等の結合剤、カルボシキメチルセルーロースカルシウム、カルボシキメチルセルーロースナトリウム、デンプン、コーンスターチ、アルギン酸ナトリウム等の崩壊剤、タルク、ステアリン酸マグネシウム、ステアリン酸ナトリウム等の滑沢剤、炭酸カルシウム、炭酸ナトリウム、リン酸カルシウム、リン酸ナトリウム等の充填剤または希釈剤等と適宜混合して、錠剤、散剤（粉末）、丸剤、および顆粒剤等の固形製剤にすることができる。また、硬質または軟質のゼラチンカプセル等を用いてカプセル剤としてもよい。さらに、前記クロマノール配糖体を、精製水、生理食塩水等の一般的に用いられる不活性希釈剤に溶解して、必要に応じて、この溶液に浸潤剤、乳化剤、分散助剤、界面活性剤、甘味料、フレーバー、芳香物質等を適宜添加することにより、シロップ剤、エリキシル剤等の液状製剤とすることもできる。
【００２７】
また、本発明の消化性潰瘍の予防および治療剤を非経口投与用とする場合には、前記クロマノール配糖体を精製水、リン酸緩衝液等の適当な緩衝液、生理的食塩水、リンガー溶液、ロック溶液等の生理的塩類溶液、エタノール、グリセリンおよび慣用される界面活性剤等と適当に組み合わせた滅菌された水溶液、非水溶液、懸濁液、リポソームまたはエマルジョンとして、好ましくは注射用滅菌水溶液として、静脈内、皮下、筋肉内等に投与される。この際、液状製剤は、生理学的なｐＨ、好ましくは６〜８の範囲内のｐＨを有することが好ましい。上述したうち、好ましい製剤や投与形態等は、担当の医師によって選択される。
【００２８】
本発明の消化性潰瘍の予防および治療剤に含まれるクロマノール配糖体の濃度は、投与形態、疾病の種類や重篤度や目的とする投与量などによって様々であるが、一般的には、原料の全質量に対して０．１〜１００質量％、好ましくは１〜９０質量％である。特に、本発明の製剤が経口投与される場合には、原料の全質量に対して１〜１００質量％、好ましくは５〜９０質量％であり、非経口投与される場合には、原料の全体積に対して０．１〜９０体積％、好ましくは１〜８０体積％であることが好ましい。この際、クロマノール配糖体の濃度が前記上限値を超えると過剰な投与量に見合った改善効果が得られず、前記下限値未満であると改善効果が十分に期待できずいずれも好ましくない。
【００２９】
本発明の消化性潰瘍の予防および治療剤の上記投与量は、患者の年齢、体重及び症状、目的とする投与形態や方法、治療効果、および処置期間等によって異なり、正確な量は医師により決定されるものであるが、通常、本剤が経口投与される場合には、クロマノール配糖体の投与量換算で、０．１〜１００００ｍｇ／ｋｇ体重／日の投与量の範囲であり、１日１〜３回に分けて投与される。この際、１日当たりの経口投与量が多い場合には、１回に複数個の錠剤等の製剤を投与してもよい。また、本発明の消化性潰瘍の予防および治療剤を非経口投与する場合には、クロマノール配糖体の投与量換算で、０．０１〜１０００ｍｇ／ｋｇ体重／日の投与量になるように１日１〜３回に分けて投与される。
【００３０】
【実施例】
本発明の消化性潰瘍の予防および治療剤の消化性潰瘍の改善効果を、以下に述べる薬理試験により確認した。
【００３１】
クロマノール配糖体として、特開平７−１１８２８７号公報の実施例１に記載の方法で製造した下記式（３）で示される２−（α−Ｄ−グルコピラノシル）メチル−２，５，７，８−テトラメチルクロマン−６−オール（ＴＭＧ）を用いた。
【００３２】
【化４】

【００３３】
胃粘膜傷害改善効果確認試験
ラットにアスピリン（ＡＳＰ）を経口投与することにより、アスピリン惹起性ラット胃粘膜傷害モデルを作製し、胃粘膜障害の指標としてびらんおよび潰瘍面積（ｅｒｏｓｉｏｎ ｉｎｄｅｘ）、胃粘膜の脂質過酸化の指標としてチオバルビツール酸反応物質（ｔｈｉｏｂａｒｂｉｔｕｒｉｃ ａｃｉｄ ｒｅａｃｔｉｖｅ ｓｕｂｓｔａｎｃｅｓ：ＴＢＡ−ＲＳ）量、胃粘膜内好中球集積の指標としてミエロペルオキシダーゼ（ｍｙｅｌｏｐｅｒｏｘｉｄａｓｅ：ＭＰＯ）活性、および胃粘膜内炎症性サイトカインとしてＣＩＮＣ−１量についてそれぞれ評価した。
【００３４】
８週令の雄性ＳＤ系ラット（１群３〜８匹、体重１８０〜２００ｇ）を用い、１８時間絶食後、ＡＳＰ２００ｍｇ／ｋｇおよび０．１５Ｎ塩酸０．５ｍｌ／２００ｇを経口投与した。ＴＭＧを生理食塩水にて所定濃度に調整後、ＡＳＰ投与３０分前に腹腔内投与した。ＡＳＰ投与３時間後に脱血屠殺して胃を摘出し各評価に供した。なお、ＡＳＰとＴＭＧのいずれも投与しなかった群をノーマル群とした。
（１）びらんおよび潰瘍面積
摘出したラットの胃の出血性びらん病変の面積を、スクエア−グリッドを用いてｍｍ^２ 単位で測定した。結果を表１に示す。
【００３５】
【表１】

【００３６】
（２）ＴＢＡ−ＲＳ量
＜ＴＢＡ−ＲＳの測定法＞
Ｏｈｋａｗａ法により測定した（Ｈ．Ｏｈｋａｗａ，ｅｔ ａｌ．：Ａｎａｌ．Ｂｉｏｃｈｅｍ．，９５（１９７９）３５１−３５８）。胃を摘出後、大弯にて切開し、胃粘膜を２枚のスライドグラスで剥離し、１．５ｍｌの１０ｍＭ酸緩衝液＋３０ｍＭ塩化カリウム溶液でホモジネートした。そのうち０．２ｍｌに蒸留水０．６ｍｌおよび８．１％ナトリウムジサルフェート０．２ｍｌを加え、ｐＨ３．５の２０％酢酸緩衝液１．５ｍｌ、０．８％ＴＢＡ１．５ｍｌおよび１％ＢＨＴ４０μｌを加え、９５℃で１時間加熱した後１０分間冷却した。さらに、蒸留水１．０ｍｌおよびブタノールピリジン（ブタノール：ピリジン＝１５：１）５．０ｍｌを加え攪拌した。これを室温で３，０００ｒｐｍで１０分間遠心し、得られた上清を波長５３５ｎｍにて分光光度計で吸光度を測定した。胃粘膜ホモジネート０．２ｍｌおよび蒸留水０．６ｍｌの代わりに蒸留水０．８ｍｌとしたものをブランク、蒸留水０．３ｍｌおよびＴＥＰ０．５ｍｌとしたものを標準として、両者から検量曲線を得て検体のＴＢＡ−ＲＳを測定した。
【００３７】
【表２】

【００３８】
（３）ＭＰＯ活性
＜ＭＰＯ活性測定法＞
Ｏ−ジアニシジン−過酸化水素反応により測定した（Ｊ．Ｅ．Ｋｒｒａｗｉｓｚ，ｅｔ ａｌ．：Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ，８７（１９８４）１３４４−１３５０）。胃を摘出後、大弯にて切開し、胃粘膜を２枚のスライドグラスで剥離し、１．５ｍｌの１０ｍＭリン酸緩衝液＋３０ｍＭ塩化カリウム溶液でホモジネートした。そのうち１．０ｍｌを４℃、４０，０００ｇで１５分間遠心分離し、得られた沈澱物に３００μｌの０．５％ＨＴＡＢ（５０ｍＭリン酸緩衝液）を加え再溶解させ、これをさらに４℃、４０，０００ｇで１５分間遠心分離し、得られた上清を検体とした。ｐＨ６．０の５０ｍＭリン酸カリウム緩衝液に０１６．７ｍｇのＯ−ジアニシジンジヒドロクロライドを溶解し、さらに０．５％過酸化水素水１００μｌを混合して調製した反応溶液９５０μｌに、検体５０μｌを加え、波長４６０ｎｍにおける吸光度変化を分光光度計で測定した。２５℃で１分間あたり１μｍｏｌの過酸化水素水を変化させるＭＰＯの量を１単位（Ｕ）とした。
【００３９】
【表３】

【００４０】
（４）ＣＩＮＣ−１量
＜ＣＩＮＣ−１測定法＞
胃を摘出後、大弯にて切開し、胃粘膜を２枚のスライドグラスで剥離し、１．５ｍｌの１０ｍＭリン酸緩衝液＋３０ｍＭ塩化カリウム溶液でホモジネートした。このホモジネートを４℃、４０，０００ｇで１５分間遠心分離し、得られた上清を検体とし、Ｒａｔ ＧＲＯ／ＣＩＮＣ−１測定キット−ＩＢＬ（免疫生物研究所製）を用いてＣＩＮＣ−１を測定した。
【００４１】
【表４】

【００４２】
表１の結果より、アスピリン負荷による胃粘膜の傷害は、ＴＭＧの前投与により用量依存的に有意に抑制されることがわかった。
【００４３】
また、表２および表３の結果より、脂質過酸化の指標である胃粘膜内ＴＢＡ−ＲＳ、および好中球集積の指標である胃粘膜内ＭＰＯ活性は、アスピリン投与により優位に上昇し、ＴＭＧの前投与により有意に抑制されることがわかった。
【００４４】
さらに、表４の結果より、胃粘膜内炎症性サイトカインを測定したところ、ＣＩＮＣ−１はアスピリン投与により有意な上昇を示し、ＴＭＧの前投与により有意に抑制されることがわかった。
【００４５】
急性毒性試験
本発明の消化性潰瘍の予防および治療剤について急性毒性試験を行い、その安全性を確認した。４〜５週令のＩＣＲ系マウスを１群３匹として用い、クロマノール配糖体として上記と同じＴＭＧを５％アラビアゴム液に懸濁した後、ＴＭＧ換算で５００ｍｇ／ｋｇを経口投与して１週間観察した。この際、対照群として５％アラビアゴム液を０．３ｍｌ経口投与した。その結果、いずれの投与群においてもマウスの死亡例は認められなかった。
【００４６】
製剤例１
ＴＭＧ１００ｇ、乳糖８００ｇおよびトウモロコシデンプン１００ｇをブレンダーで混合して散剤を得た。
【００４７】
製剤例２
ＴＭＧ１００ｇ、乳糖４５０ｇおよび低置換度ヒドロキシプロピルセルロース１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液３５０ｇを加えて混練した。これを押出し造粒機を用いて造粒、乾燥して顆粒剤を得た。
【００４８】
製剤例３
ＴＭＧ１００ｇ、乳糖５５０ｇ、トウモロコシデンプン２１５ｇ、結晶セルロース１３０ｇおよびステアリン酸マグネシウム５ｇをブレンダーで混合した後、錠剤機で打錠して錠剤を得た。
【００４９】
製剤例４
ＴＭＧ１０ｇ、乳糖１１０ｇ、トウモロコシデンプン５８ｇおよびステアリン酸マグネシウム２ｇをＶ型混合機を用いて混合した後、３号カプセルに１８０ｍｇずつ充填してカプセル剤を得た。
【００５０】
製剤例５
ＴＭＧ２００ｍｇおよびグルコース１００ｍｇを精製水２ｍｌに溶解した後濾過し、濾液を２ｍｌアンプルに分注、封入した後滅菌して注射剤を得た。
【００５１】
製剤例６
ＴＭＧ１ｇ、エタノール３ｇ、ヒドロキシエチルセルロース０．２ｇおよびパラオキシ安息香酸メチル０．１ｇを精製水１００ｍｌに混合溶解してローション剤を得た。
【００５２】
【発明の効果】
上述したように、本発明の消化性潰瘍の予防および治療剤は、水溶性のクロマノール配糖体を有効成分とするので、ＮＳＡＩＤ惹起性胃粘膜傷害等の消化性潰瘍の病態を飛躍的に改善することができるとともに、副作用を伴わないので極めて安全に使用することができる。
【００５３】
また、本発明の本発明の消化性潰瘍の予防および治療剤は、高い水溶性を有するクロマノール配糖体を有効成分とするので、有効成分を高濃度で含有する水性製剤とすることができ、保存安定性が高いうえ、少用量で効果的に作用して消化性潰瘍を予防および治療することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel agent for preventing and treating peptic ulcer. More specifically, the present invention relates to a prophylactic and therapeutic agent for peptic ulcer containing a water-soluble chromanol glycoside as an active ingredient.
[0002]
[Prior art]
A major cause of peptic ulcers such as gastric ulcer is gastric mucosal injury caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin. The mechanism of action of NSAID-induced gastric mucosal injury is caused by factors such as deficiency of endogenous prostaglandin (PG) in gastric mucosa due to cyclooxygenase (COX) inhibition, decreased secretion of bicarbonate ions, and decreased mucosal blood flow. More thought. In addition, neutrophil dynamics and inflammation inside and outside blood vessels have recently been regarded as a cause of NSAID-induced gastric mucosal injury, and a decrease in endogenous PG disrupts leukotriene (LT) / PG balance. then, ischemia reperfusion similar conditions appeared by vascular攣宿also enhanced expression and activation of adhesion molecules CD11b / CD18 to aspirin and indomethacin itself and LTB ₄ by neutrophils on balls, and through the TNFα Adhesion and interaction between both cells due to enhanced expression of adhesion molecules on leukocytes and vascular endothelial cells may cause mucosal damage through various mechanisms such as endothelial damage, leukocyte embolism, and neutrophil extravasation. (See Non-Patent Document 1).
[0003]
Currently, as a therapeutic agent for NSAID induced peptic ulcer, histamine H ₂ receptor antagonists such as cimetidine, proton pump inhibitors such as omeprazole, although prostaglandin formulations like of misoprostol or the like is used, There is a need for the development of more effective and safe agents for preventing and treating peptic ulcers.
[0004]
On the other hand, the chromanol glycoside used in the present invention is a known compound (see Patent Document 1, Patent Document 2, and Patent Document 3). The chromanol glycoside is obtained by substituting the phytyl group at the 2-position of the chroman ring of α-tocopherol, which is a typical vitamin E, with an alcohol, and further linking a sugar, and has high water solubility and excellent water solubility. Has antioxidant action. However, it has not been known that the chromanol glycoside is used as an agent for preventing and treating the above-mentioned peptic ulcer.
[0005]
[Non-patent document 1]
Norimasa Yoshida, "NSAID-induced gastric mucosal injury and neutrophil-endothelium interaction", Gastroenterology, (Publisher), (Date of issue), Vol. 31, No. 2, p. 121-128
[Patent Document 1]
JP-A-7-118287 [Patent Document 2]
JP-A-9-249688 [Patent Document 3]
JP-A-11-21291
[Problems to be solved by the invention]
The present invention has been made in view of the above-mentioned problems of the prior art, and has as its object the purpose of the present invention is to effectively act in a small dose without causing side effects and to treat peptic ulcer such as NSAID-induced gastric mucosal injury. It is an object of the present invention to provide a novel preventive and therapeutic agent for peptic ulcer which can improve the pathological condition of ulcer.
[0007]
Another object of the present invention is to provide a novel prophylactic and therapeutic agent for peptic ulcer, which can be prepared as an aqueous preparation containing an active ingredient at a high concentration and has excellent stability and absorbability.
[0008]
[Means for Solving the Problems]
The present inventors have conducted extensive studies on NSAID-induced gastric mucosal injury, and as a result, have found that the chromanol glycoside can treat NSAID-induced gastric mucosal injury extremely effectively, and completed the present invention.
[0009]
That is, the present invention provides the following general formula (1)
[0010]
Embedded image

[0011]
(Wherein, R ¹ , R ² , R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups, R ⁵ represents a hydrogen atom, a lower alkyl group or a lower acyl group, and X represents a sugar residue. A hydrogen atom of a hydroxyl group in the group represents a monosaccharide residue or an oligosaccharide residue which may be substituted with a lower alkyl group or a lower acyl group, n is an integer of 0 to 6, and m is 1 to 6 Which is an integer of 1), which is a prophylactic and therapeutic agent for peptic ulcer, comprising a chromanol glycoside represented by the formula:
[0012]
The present invention is also the agent for preventing and treating peptic ulcer, wherein the chromanol glycoside is 2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol. .
[0013]
The present invention is further an agent for preventing and treating the peptic ulcer, which is an aqueous preparation.
[0014]
The present invention is further an agent for preventing and treating the peptic ulcer, wherein the peptic ulcer is a nonsteroidal anti-inflammatory drug-induced peptic ulcer.
[0015]
The present invention is further an agent for preventing and treating the peptic ulcer, wherein the peptic ulcer is a nonsteroidal anti-inflammatory drug-induced gastric mucosal injury.
[0016]
BEST MODE FOR CARRYING OUT THE INVENTION
The prophylactic and therapeutic agent for peptic ulcer of the present invention is characterized by comprising a chromanol glycoside represented by the general formula (1) as an active ingredient.
[0017]
In the general formula (1), the lower alkyl group of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is preferably a lower alkyl group having 1 to 8, preferably 1 to 6 carbon atoms. , Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, octyl and the like. Among them, a methyl group or an ethyl group is preferred. As the lower acyl group for R ^5, a lower acyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms is preferred, and examples thereof include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group. , Isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like. Among these, an acetyl group, a propionyl group or a butyryl group is preferred. Examples of the monosaccharide residue of X include glucose, galactose, fucose, xylose, mannose, rhamnose, fructose, arabinose, lyxose, ribose, allose, altrose, idose, talose, deoxyribose, 2-deoxyribose, quinobiose, Sugar residues such as avequose; Examples of the oligosaccharide residue of X include those in which 2 to 4 of the above-mentioned monosaccharides are bonded, for example, sugar residues of maltose, lactose, cellobiose, raffinose, xylobiose, and sucrose. Among them, monosaccharide residues such as glucose, galactose, fucose, xylose, rhamnose, mannose and fructose are preferred. Further, the hydrogen atom of the hydroxyl group in the sugar residue of X is a lower alkyl group, preferably a lower alkyl group having 1 to 8 carbon atoms, or a lower acyl group, preferably a lower acyl group having 1 to 10 carbon atoms. May be substituted. Further, n is an integer of 0 to 6, preferably 1 to 4, and m is an integer of 1 to 6, preferably 1 to 3. Preferred examples of the chromanol glycoside represented by the general formula (1) include 2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol and 2- (β -D-galactopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-L-fucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6 -Ol, 2- (α-L-rhamnopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-D-xylopyranosyl) methyl-2,5,7,8-tetra Methylchroman-6-ol, 2- (β-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol, 2- (β-D-fructofuranosyl) methyl-2, 5,7,8-tetramethi Chroman-6-ol, 2- (α-D- mannopyranosyl) methyl-2,5,7,8-tetramethyl-chroman-6-ol, and the like.
[0018]
The chromanol glycoside used in the present invention can be prepared, for example, by the method described in JP-A-7-118287, JP-A-9-249688, or JP-A-11-21291, by the following general formula (2):
[0019]
Embedded image

[0020]
(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined above) and an enzyme that catalyzes a sugar translocation effect corresponding to a 2-substituted alcohol and an oligosaccharide. In the presence of a saccharide, and specifically produced by an enzymatic reaction comprising binding a specific hydroxyl group of a sugar to a hydroxyl group at the 2-position of a 2-substituted alcohol (enzymatic method).
[0021]
The 2-substituted alcohol represented by the general formula (2) (hereinafter, simply referred to as “2-substituted alcohol”) used as a raw material in the above reaction is a known substance. It can be obtained by a method disclosed in, for example, Japanese Patent Publication No. 1-49135. Further, for example, in the general formula (2), a 2-substituted alcohol in which R ¹ , R ² , R ³ and R ⁴ are a methyl group, R ⁵ is a hydrogen atom, and n is 1 is α-tocopherol chroman. 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid having a structure in which the phytyl group at the 2-position of the ring is substituted by a carboxyl group (trade name “Trolox”) is converted to hydrogen. It can be easily obtained by heating and refluxing in diethyl ether in the presence of lithium aluminum chloride.
[0022]
The chromanol glycoside used in the present invention is obtained by protecting the hydroxyl group at the 6-position of the 2-substituted alcohol with a protecting group by the method described in Japanese Patent Application No. 10-75599 (hereinafter referred to as “sugar acceptor”). ) And a sugar derivative in which a leaving group is introduced at the anomeric position and another hydroxyl group is protected with a protecting group (hereinafter, referred to as “sugar donor”), by a condensation reaction (organic synthesis method).
[0023]
The sugar donor used in the above reaction can be easily prepared by introducing a protecting group into all the hydroxyl groups of the sugar by a well-known method, and then replacing the anomeric position with a leaving group.
[0024]
Chromanol glycosides obtained by the above-mentioned enzymatic method or organic synthesis method generally have extremely high water solubility (about 100 g / 100 ml) and are also highly oil-soluble (octanol / water-based partition coefficient> 3). It is an amphiphilic molecule. In other words, it can be said that the chromanol glycoside according to the present invention is a water-soluble vitamin E with high lipophilicity. Therefore, unlike conventional water-insoluble or poorly soluble vitamin E derivatives, the chromanol glycosides of the present invention maintain high lipophilicity even when used in water, so that they can penetrate cell membranes and It can also get inside and improve peptic ulcer dramatically. In addition, the chromanol glycoside obtained by the above-mentioned reaction has significantly improved thermal stability and pH stability as compared with tocopherol, trolox or 2-substituted alcohol.
[0025]
The prophylactic and therapeutic agent for peptic ulcer of the present invention may be administered orally or parenterally as a composition in which the chromanol glycoside is mixed with a pharmaceutically acceptable carrier or dissolved or suspended in a pharmaceutically acceptable solvent. By specifically administering to patients, it can be used as a prophylactic and therapeutic agent for peptic ulcers such as esophageal ulcer (reflux), gastric ulcer, duodenal ulcer, and jejunal ulcer, particularly NSAID-induced peptic ulcer.
[0026]
When the present preparation is to be administered orally, the chromanol glycoside alone or a suitable additive such as lactose, sucrose, mannitol, corn starch, synthetic or natural gum, crystalline cellulose or the like can be used. Excipients, binders such as starch, cellulose derivatives, gum arabic, gelatin, polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, corn starch, sodium alginate, talc, magnesium stearate , Tablets, powders (powder), pills, granules, etc., by mixing as appropriate with lubricants such as sodium stearate, fillers or diluents such as calcium carbonate, sodium carbonate, calcium phosphate and sodium phosphate. It can be a solid preparation. Also, capsules may be prepared using hard or soft gelatin capsules or the like. Further, the chromanol glycoside is dissolved in a commonly used inert diluent such as purified water or physiological saline, and if necessary, a wetting agent, an emulsifier, a dispersing aid, a surfactant is added to the solution. Liquid preparations such as syrups and elixirs can also be prepared by the proper addition of agents, sweeteners, flavors and aromatics.
[0027]
When the prophylactic and therapeutic agent for peptic ulcer of the present invention is used for parenteral administration, the chromanol glycoside may be purified water, a suitable buffer such as a phosphate buffer, physiological saline, Ringer's solution. Solutions, physiological saline solutions such as Locke's solution, sterile aqueous solutions, non-aqueous solutions, suspensions, liposomes or emulsions suitably combined with ethanol, glycerin and commonly used surfactants, preferably sterile aqueous solutions for injection As intravenous, subcutaneous, intramuscular, etc. At this time, the liquid preparation preferably has a physiological pH, preferably a pH in the range of 6 to 8. Of the above, preferred formulations and dosage forms are selected by the attending physician.
[0028]
The concentration of chromanol glycoside contained in the preventive and therapeutic agent for peptic ulcer of the present invention varies depending on the administration form, the type and severity of the disease or the intended dose, but generally, It is 0.1 to 100% by mass, preferably 1 to 90% by mass, based on the total mass of the raw materials. In particular, when the formulation of the present invention is administered orally, it is 1 to 100% by mass, preferably 5 to 90% by mass relative to the total mass of the raw material, and when administered parenterally, the total amount of the raw material is It is preferably from 0.1 to 90% by volume, preferably from 1 to 80% by volume, based on the product. At this time, if the concentration of the chromanol glycoside exceeds the upper limit, an improvement effect commensurate with the excessive dose cannot be obtained, and if the concentration is less than the lower limit, the improvement effect cannot be sufficiently expected, and neither is preferable.
[0029]
The above dose of the prophylactic and therapeutic agent for peptic ulcer of the present invention depends on the patient's age, body weight and symptoms, the intended dosage form and method, the therapeutic effect, the treatment period, etc., and the exact amount is determined by a doctor. Usually, when the drug is orally administered, the dose is 0.1 to 10000 mg / kg body weight / day in terms of the dose of chromanol glycoside, It is administered in 1 to 3 divided doses. At this time, when the daily oral dose is large, a plurality of preparations such as tablets may be administered at one time. In addition, when the prophylactic and therapeutic agent for peptic ulcer of the present invention is administered parenterally, the amount of chromanol glycoside should be adjusted so as to be 0.01 to 1000 mg / kg body weight / day in terms of the dose. It is administered in 1 to 3 times a day.
[0030]
【Example】
The peptic ulcer improvement effect of the preventive and therapeutic agent for peptic ulcer of the present invention was confirmed by the pharmacological test described below.
[0031]
As a chromanol glycoside, 2- (α-D-glucopyranosyl) methyl-2,5,7,8 represented by the following formula (3) produced by the method described in Example 1 of JP-A-7-118287. -Tetramethylchroman-6-ol (TMG) was used.
[0032]
Embedded image

[0033]
Gastric mucosal injury improving effect confirmation test Aspirin (ASP) -induced rat gastric mucosal injury model was prepared by orally administering aspirin (ASP) to rats, and erosion and ulcer area (erosion index) were used as indicators of gastric mucosal injury. , The amount of thiobarbituric acid reactive substances (TBA-RS) as an index of lipid peroxidation in the gastric mucosa, myeloperoxidase (MPO) activity as an index of neutrophil accumulation in the gastric mucosa, and gastric mucosa Each was evaluated for the amount of CINC-1 as an endoinflammatory cytokine.
[0034]
Using 8-week-old male SD rats (3 to 8 rats per group, weighing 180 to 200 g), ASP 200 mg / kg and 0.15 N hydrochloric acid 0.5 ml / 200 g were orally administered after a 18-hour fast. TMG was adjusted to a predetermined concentration with physiological saline, and then administered intraperitoneally 30 minutes before ASP administration. Three hours after the ASP administration, the blood was removed and sacrificed, and the stomach was removed and used for each evaluation. The group to which neither ASP nor TMG was administered was defined as a normal group.
(1) Erosion and ulcer area The area of hemorrhagic erosion lesion in the stomach of the excised rat was measured in mm ² using a square grid. Table 1 shows the results.
[0035]
[Table 1]

[0036]
(2) TBA-RS amount <Method of measuring TBA-RS>
It was measured by the Ohkawa method (H. Ohkawa, et al .: Anal. Biochem., 95 (1979) 351-358). After removal of the stomach, the stomach was cut open at a greater curvature, the gastric mucosa was peeled off with two slide glasses, and homogenized with 1.5 ml of 10 mM acid buffer + 30 mM potassium chloride solution. 0.6 ml of distilled water and 0.2 ml of 8.1% sodium disulphate were added to 0.2 ml of the mixture, and 1.5 ml of 20% acetate buffer at pH 3.5, 1.5 ml of 0.8% TBA and 40 μl of 1% BHT were added. At 95 ° C. for 1 hour and then cooled for 10 minutes. Further, 1.0 ml of distilled water and 5.0 ml of butanolpyridine (butanol: pyridine = 15: 1) were added and stirred. This was centrifuged at 3,000 rpm for 10 minutes at room temperature, and the resulting supernatant was measured for absorbance at 535 nm with a spectrophotometer. Calibration curves were obtained from both samples using a blank with 0.8 ml of distilled water instead of 0.2 ml of gastric mucosa homogenate and 0.6 ml of distilled water, and a standard with 0.3 ml of distilled water and 0.5 ml of TEP as standard. Was measured for TBA-RS.
[0037]
[Table 2]

[0038]
(3) MPO activity <MPO activity measurement method>
It was measured by the O-dianisidine-hydrogen peroxide reaction (JE Krrawisz, et al .: Gastroenterology, 87 (1984) 1344-1350). After the stomach was removed, the stomach was cut open at the greater curvature, the gastric mucosa was peeled off with two slide glasses, and homogenized with 1.5 ml of 10 mM phosphate buffer + 30 mM potassium chloride solution. 1.0 ml thereof was centrifuged at 40,000 g for 15 minutes at 4 ° C., and the resulting precipitate was re-dissolved by adding 300 μl of 0.5% HTAB (50 mM phosphate buffer). After centrifugation at 40,000 g for 15 minutes, the obtained supernatant was used as a sample. Add 50 μl of the sample to 950 μl of a reaction solution prepared by dissolving 016.7 mg of O-dianisidine dihydrochloride in 50 mM potassium phosphate buffer at pH 6.0, and further mixing with 100 μl of 0.5% hydrogen peroxide solution. The change in absorbance at a wavelength of 460 nm was measured with a spectrophotometer. The amount of MPO that changes 1 μmol of hydrogen peroxide solution per minute at 25 ° C. was defined as 1 unit (U).
[0039]
[Table 3]

[0040]
(4) CINC-1 amount <CINC-1 measurement method>
After the stomach was removed, the stomach was cut open at the greater curvature, the gastric mucosa was peeled off with two slide glasses, and homogenized with 1.5 ml of 10 mM phosphate buffer + 30 mM potassium chloride solution. The homogenate is centrifuged at 40,000 g for 15 minutes at 4 ° C., and the obtained supernatant is used as a sample, and CINC-1 is measured using a Rat GRO / CINC-1 measurement kit-IBL (manufactured by Institute of Immunology). did.
[0041]
[Table 4]

[0042]
From the results in Table 1, it was found that damage to the gastric mucosa due to aspirin loading was significantly suppressed in a dose-dependent manner by pre-administration of TMG.
[0043]
Also, from the results in Tables 2 and 3, TBA-RS in the gastric mucosa, which is an indicator of lipid peroxidation, and MPO activity in the gastric mucosa, which is an indicator of neutrophil accumulation, were significantly increased by aspirin administration. Was found to be significantly suppressed by pre-administration.
[0044]
Furthermore, from the results in Table 4, when the inflammatory cytokine in the gastric mucosa was measured, it was found that CINC-1 showed a significant increase by aspirin administration and was significantly suppressed by the pre-administration of TMG.
[0045]
Acute toxicity test An acute toxicity test was performed on the preventive and therapeutic agent for peptic ulcer of the present invention to confirm its safety. Using 4 to 5 week old ICR mice as a group, 3 mice were suspended in 5% gum arabic solution of the same TMG as a chromanol glycoside, and then 500 mg / kg in terms of TMG was orally administered. Observed for a week. At this time, 0.3 ml of a 5% gum arabic solution was orally administered as a control group. As a result, no death cases were observed in any of the administration groups.
[0046]
Formulation Example 1
A powder was obtained by mixing 100 g of TMG, 800 g of lactose and 100 g of corn starch with a blender.
[0047]
Formulation Example 2
After mixing 100 g of TMG, 450 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 350 g of a 10% aqueous solution of hydroxypropylcellulose was added and kneaded. This was granulated using an extruder and dried to obtain granules.
[0048]
Formulation Example 3
After 100 g of TMG, 550 g of lactose, 215 g of corn starch, 130 g of crystalline cellulose and 5 g of magnesium stearate were mixed with a blender, the mixture was tabletted with a tablet machine to obtain tablets.
[0049]
Formulation Example 4
TMG (10 g), lactose (110 g), corn starch (58 g), and magnesium stearate (2 g) were mixed using a V-type mixer, and the mixture was filled in No. 3 capsules by 180 mg to obtain capsules.
[0050]
Formulation Example 5
200 mg of TMG and 100 mg of glucose were dissolved in 2 ml of purified water and filtered, and the filtrate was dispensed into 2 ml ampules, sealed, and sterilized to obtain an injection.
[0051]
Formulation Example 6
A lotion was obtained by mixing and dissolving 1 g of TMG, 3 g of ethanol, 0.2 g of hydroxyethylcellulose, and 0.1 g of methyl paraoxybenzoate in 100 ml of purified water.
[0052]
【The invention's effect】
As described above, since the prophylactic and therapeutic agent for peptic ulcer of the present invention contains a water-soluble chromanol glycoside as an active ingredient, it dramatically improves the pathology of peptic ulcer such as NSAID-induced gastric mucosal injury. And can be used extremely safely because it has no side effects.
[0053]
Further, the preventive and therapeutic agent for peptic ulcer of the present invention of the present invention has a high water-soluble chromanol glycoside as an active ingredient, so that an aqueous preparation containing a high concentration of the active ingredient can be obtained. In addition to having high storage stability, it can be effectively used in a small dose to prevent and treat peptic ulcer.

Claims (5)

The following general formula (1)

(Wherein, R ¹ , R ² , R ³ and R ⁴ represent the same or different hydrogen atoms or lower alkyl groups, R ⁵ represents a hydrogen atom, a lower alkyl group or a lower acyl group, and X represents a sugar residue. A hydrogen atom of a hydroxyl group in the group represents a monosaccharide residue or an oligosaccharide residue which may be substituted with a lower alkyl group or a lower acyl group, n is an integer of 0 to 6, and m is 1 to 6 A prophylactic and therapeutic agent for peptic ulcer, comprising a chromanol glycoside represented by the formula: The preventive and therapeutic agent for peptic ulcer according to claim 1, wherein the chromanol glycoside is 2- (α-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol. The agent for preventing and treating peptic ulcer according to claim 1 or 2, which is an aqueous preparation. The preventive and therapeutic agent for peptic ulcer according to any one of claims 1 to 3, wherein the peptic ulcer is a nonsteroidal anti-inflammatory drug-induced peptic ulcer. The preventive and therapeutic agent for peptic ulcer according to any one of claims 1 to 4, wherein the peptic ulcer is a nonsteroidal anti-inflammatory drug-induced gastric mucosal injury.