JP2004131442A - Agent for operation of glaucoma - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having excellent activities for preventing adhesion of the passage of a drainage of aqueous humor and filtration bleb formed in the operation of glaucoma, especially the filtration operation of the glaucoma. <P>SOLUTION: The agent for the operation of the glaucoma contains diphenyl 1-(N-succinyl-L-valyl-prolylamino)-2-phenylethanesulfonate or an optical isomer thereof as an active ingredient. The agent is especially useful as the agent for the operation of the adhesion of the glaucoma because the agent prevents the adhesion in the operation of the glaucoma, especially prevents the adhesion of the passage of the drainage of the aqueous humor and the filtration bleb formed in the filtration operation of the glaucoma, and maintains the good filtration bleb having rich blood vessels and less prone to cause infection. <P>COPYRIGHT: (C)2004,JPO

Description

【０００７】
で表わされる１−（Ｎ−スクシニル−Ｌ−バリル−Ｌ−プロリルアミノ）−２−フェニルエタンホスホン酸　ジフェニルエステル（Ｓｕｃ−Ｖａｌ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２）は、キマーゼ阻害剤として知られ、さらにこの化合物のＤ体及びＬ体の二種の光学異性体のうち、Ｌ体にキマーゼ阻害活性が認められている。（例えば、非特許文献４〜７、特許文献１参照）。この化合物は、血管新生阻害剤として、血管新生に伴う疾患、例えば眼科領域における糖尿病性網膜症、血管新生緑内障などの予防又は治療剤として期待されている（例えば、特許文献２参照）。また、外科手術の分野では腹部手術時の癒着を防止することが知られている（例えば、非特許文献８参照）。しかし、この化合物が緑内障手術時に用いられたとの報告はいまだなされていない。
【０００８】
【特許文献１】
米国特許第５５４３３９６号明細書
【特許文献２】
特開２００１−１１４６９９号公報
【非特許文献１】
眼科手術、日本眼科手術学会、１９９９年、１２巻、１号、Ｐ．４５−５０
【非特許文献２】
新しい眼科、メディカル葵出版、２０００年、１７巻（臨時増刊号）、ｐ．９３−９５
【非特許文献３】
青柳美香、他６名、「マイトマイシンＣを併用した線維柱帯切除術の治療成績」、［ｏｎｌｉｎｅ］、飯田市立病院医誌、インターネット＜ＵＲＬ：ｈｔｔｐ：／／ｗｗｗ．ｉｍｈ．ｉｉｄａ．ｎａｇａｎｏ．ｊｐ／ｐｒｏ／ｉｈｏｕ／ｓｏｕｋａｎ／ｓｏｕｋａｎ．ｐｄｆ＞
【非特許文献４】
Ｂｉｏｃｈｅｍｉｓｔｒｙ、（米国）、Ａｍｅｒｉｃａｎ　Ｃｈｅｍｉｃａｌ　Ｓｏｃｉｅｔｙ、１９９１年、３０巻、２号、ｐ．４８５−４９３
【非特許文献５】
Ｍｅｔｈｏｄｓ　ｏｆ　Ｅｎｚｙｍｏｌｏｇｙ、（米国）、Ａｃａｄｅｍｉｃ　Ｐｒｅｓｓ、１９９４年、２４４巻、ｐ．４２３−４４１
【非特許文献６】
Ｔｈｅ　ＥＭＢＯ　Ｊｏｕｒｎａｌ、（英国）、Ｏｘｆｏｒｄ　Ｕｎｉｖｅｒｓｉｔｙ　Ｐｒｅｓｓ、１９９６年、１５巻、２０号、ｐ．５４８１−５４９１
【非特許文献７】
Ｔｅｔｒａｈｅｄｒｏｎ　Ｌｅｔｔｅｒｓ、（英国）、Ｅｌｓｅｖｉｅｒ　Ｓｃｉｅｎｃｅ、１９９５年、３６巻、２５号、ｐ．４４５１−４４５４
【非特許文献８】
Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、（オランダ）、Ｅｌｓｅｖｉｅｒ　Ｓｃｉｅｎｃｅ、２００２年、４３５巻、ｐ．２６５−２６７
【０００９】
【発明が解決しようとする課題】
かかる実状の下、緑内障手術時の癒着を防止できる薬剤、特に緑内障濾過手術において、形成された房水流出路及び濾過胞の癒着がなく、さらに良好に機能できる濾過胞を維持できる薬剤の開発が望まれている。
【００１０】
【課題を解決するための手段】
そこで、本発明者らは鋭意研究を行ったところ、式（１）
【００１１】
【化２】

【００１２】
で表わされる１−（Ｎ−スクシニル−Ｌ−バリル−Ｌ−プロリルアミノ）−２−フェニルエタンホスホン酸　ジフェニルエステル（Ｓｕｃ−Ｖａｌ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２：以下、ＶＰＦと記載することもある。）が、緑内障濾過手術において癒着を防止する効果に優れるとともに、この化合物が血管新生阻害作用を有するという公知事実の予想に反して、濾過胞の血管が豊富に形成され、さらに、マイトマイシンＣに見られるような濾過胞の脆弱化を起こすことがなく、緑内障手術用剤、特に緑内障濾過手術用剤として有用であることを見出し、本発明を完成した。
【００１３】
すなわち、本発明は、１−（Ｎ−スクシニル−Ｌ−バリル−Ｌ−プロリルアミノ）−２−フェニルエタンホスホン酸ジフェニルエステル又はその光学異性体を有効成分とする緑内障手術用剤を提供するものである。
【００１４】
【発明の実施の形態】
本発明の緑内障手術用剤の有効成分であるＶＰＦとしては、その光学異性体であるＬ体を用いることもできる。
【００１５】
緑内障手術としては、レーザー治療、緑内障濾過手術、緑内障非濾過手術、毛様体破壊術、周辺虹彩切除術などを挙げることができるが、このなかで、緑内障濾過手術に用いるのが好ましい。
緑内障濾過手術としては、線維柱帯切除術、非穿孔性線維柱帯切除術、全層濾過手術、セトン（Ｓｅｔｏｎ）手術などが挙げられ、このなかで線維柱帯切除術又は非穿孔性線維柱帯切除術に用いるのが好ましい。
また、レーザー治療としては、レーザー採光切開術、レーザー隅角形成術、レーザー線維柱帯形成術、レーザー毛様体光凝固術などが挙げられ、緑内障非濾過手術としては、線維柱帯切開術、ビスコカナロストミィ（Ｖｉｓｃｏｃａｎａｌｏｓｔｏｍｙ）、隅角切開術、隅角癒着解離術などが挙げられ、毛様体破壊術としては、冷凍凝固術、レーザー毛様体凝固術などが挙げられる。
【００１６】
ＶＰＦは、主として非経口投与されるが、経口でも投与することができる。例えば、非経口投与剤としては、点眼剤、液剤、眼軟膏剤、注射剤などの製剤が挙げられ、特に点眼剤又は液剤が好ましい。また、経口投与剤としては、散剤、顆粒剤、カプセル剤、錠剤などの固形製剤が挙げられる。これらの製剤は、ＶＰＦに、薬学的に許容される製剤添加剤などを加え、常法により製造することができる。
【００１７】
例えば、点眼剤又は液剤を調製する場合には、ＶＰＦに、必要に応じて塩化ナトリウム、濃グリセリン、マンニトールなどの等張化剤；エデト酸ナトリウム、クエン酸ナトリウムなどの安定化剤；塩化ベンザルコニウム、塩化ベンゼトニウム、クロロブタノール、パラオキシ安息香酸エステル類などの防腐剤；プロピレングリコール、ポリエチレングリコール、ポリオキシエチレンソルビタンモノオレエート、ステアリン酸ポリオキシル４０、ポリオキシエチレン硬化ヒマシ油などの溶解補助剤；リン酸水素ナトリウム、リン酸二水素ナトリウム、ホウ酸、四ホウ酸ナトリウム（ホウ砂）、塩酸、水酸化ナトリウムなどのｐＨ調節剤などを用い、常法により点眼剤又は液剤とすればよい。また、ｐＨは眼科で使用されるために許容される範囲内であればよいが、ｐＨ４〜８の範囲であることが好ましい。
眼軟膏剤を調製する場合には、白色ワセリン、流動パラフィンなどの汎用される基剤を用いて、常法により製剤化すればよい。
注射剤を調製する場合には、ＶＰＦを、必要に応じて塩酸、水酸化ナトリウム、リン酸水素ナトリウム、リン酸二水素ナトリウムなどのｐＨ調節剤；塩化ナトリウムなどの等張化剤とともに注射用蒸留水に溶解し、無菌濾過してアンプルに充填するか、更にマンニトール、ゼラチンなどを加えて、真空下で凍結乾燥し、用時溶解型の注射剤としてもよい。
【００１８】
経口投与用の固形製剤を調製する場合、ＶＰＦに、必要に応じて乳糖、デンプン、結晶セルロース、乳酸カルシウム、リン酸水素カルシウムなどの賦形剤；白糖、ヒドロキシプロピルセルロース、ポリビニルピロリドンなどの結合剤；カルメロースカルシウムなどの崩壊剤；ステアリン酸マグネシウム、タルクなどの滑沢剤を混合し、常法により製剤化すればよい。また、これらの固形製剤をヒドロキシプロピルメチルセルロースフタレート、メタアクリル酸・メタアクリル酸メチルコポリマーなどの腸溶性基剤で被覆して腸溶性製剤とすることもできる。
【００１９】
ＶＰＦの用量は、手術の状態によって適宜選択できるが、点眼剤又は液剤であれば、ＶＰＦとして０．０００１〜５質量／体積％（以下、Ｗ／Ｖ％と記載する）、好ましくは０．０００２〜１Ｗ／Ｖ％のものを手術時に直接手術部位に滴下する又は脱脂綿、ガーゼ、スポンジ、吸水紙などに含ませて手術部位に塗布又は一時留置して投与することができる。また、手術後の治癒状況を確認しながら、１日１〜数回点眼することができる。経口剤又は注射剤であれば、一人あたり通常１日０．００１〜１０００ｍｇを１日１回又は数回に分けて投与するのが好ましい。
【００２０】
【実施例】
以下に実施例、製造例を挙げて本発明を具体的に説明するが、本発明はこれら実施例、製造例に限定されるものではない。
【００２１】
製造例１．１−（Ｎ−スクシニル−Ｌ−バリル−Ｌ−プロリルアミノ）−２−フェニルエタンホスホン酸ジフェニルエステル（Ｓｕｃ−Ｖａｌ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２）の製造非特許文献４記載の方法により製造した。なお、以下でＣｂｚはベンジルオキシカルボニル基、Ｖａｌはバリン残基、Ｐｈｅ^Ｐはフェニルエタンホスホン酸残基、Ｐｈはフェニル基を示す。
Ｃｂｚ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２　０．５８４ｇをメタノール５０ｍＬに溶解し、５質量％パラジウム−炭素０．１ｇを加え、水素雰囲気下、室温で２時間攪拌した。触媒を濾過により除去し、得られたＰｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２をテトラヒドロフラン２０ｍＬに溶解し、０℃にてＣｂｚ−Ｖａｌ−ＯＨ　０．２５ｇ、Ｎ，Ｎ−ジシクロヘキシルカルボジイミド０．２ｇを加え、同温にて６時間攪拌した後、室温にて一晩攪拌した。ジシクロヘキシルウレアを濾過により除去し、有機層を水、４Ｗ／Ｖ％重曹水、水、１０Ｗ／Ｖ％クエン酸水溶液、水の順番に洗浄した。硫酸マグネシウムで乾燥後、溶媒留去することにより、油状物を得た。この油状物を酢酸エチル３０ｍＬに溶解し、無水コハク酸０．１ｇと５質量％パラジウム−炭素０．１ｇを加え、水素雰囲気下で薄層クロマトグラフが１スポットになるまで攪拌した。触媒を濾過により除去し、有機層を数回水で洗浄した。乾燥後、有機溶媒を除去し、吸湿性固体として生成物０．４５ｇを得た。
融点：５０−５３℃
^３１Ｐ　ＮＭＲ：１９．７５，　１９．２３ｐｐｍ，　ピーク高さ比１：１．
【００２２】
製造例２．Ｌ−１−（Ｎ−スクシニル−Ｌ−バリル−Ｌ−プロリルアミノ）−２−フェニルエタンホスホン酸ジフェニルエステル（Ｌ−ＶＰＦ）の製造
非特許文献４及び５記載の方法を利用して製造した。以下でＺはベンジロキシカルボニル基、Ｂｏｃはｔ−ブチロキシカルボニル基、ＷＳＣＤは塩酸１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド、ＨＯＢｔは１−ヒドロキシベンゾトリアゾール、ＤＭＦはジメチルホルムアミドを示す。
【００２３】
（１）ＤＬ−Ｐｈｅ^Ｐ（ＯＰｈ）_２・ＨＢｒの合成
フェニルアセトアルデヒド２８．３ｍＬを酢酸４５ｍＬに溶解し、カルバミン酸ベンジルエステル２４．４ｇ及びトリフェニルホスファイト５０．０ｇを加え、８５℃で１．５時間攪拌した。有機溶媒を減圧留去後、残渣を室温まで冷却し、メタノール４００ｍＬを加え、−２０℃で摩擦し結晶化した。得られた粉体を濾過し、冷メタノールで洗浄し、減圧乾燥することによりＺ−ＤＬ−Ｐｈｅ^Ｐ（ＯＰｈ）_２　３２．９ｇを得た。このようにして得られたＺ−ＤＬ−Ｐｈｅ^Ｐ（ＯＰｈ）_２　１４．３ｇを２５Ｗ／Ｖ％臭化水素の酢酸溶液３０ｍＬに溶解し、室温で１時間攪拌した。反応液にエーテルを加え、析出した固体を濾過し、得られた固体をさらにエーテルで洗浄し減圧乾燥することによりＤＬ−Ｐｈｅ^Ｐ（ＯＰｈ）_２・ＨＢｒ１２．０ｇを得た。
【００２４】
（２）Ｂｏｃ−Ｖａｌ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２の光学異性体の合成
ＤＬ−Ｐｈｅ^Ｐ（ＯＰｈ）_２・ＨＢｒ１１．５ｇ、Ｂｏｃ−Ｐｒｏ−ＯＨ　５．５３ｇ及びＨＯＢｔ　３．５８ｇをＤＭＦ７０ｍＬに溶解し、氷冷下、ＷＳＣＤ　４．７０ｍＬを滴下した。室温で３．５時間攪拌した後、溶媒留去し、酢酸エチルを加えた。得られた反応液を酸及びアルカリ溶液で洗浄し、硫酸マグネシウムで乾燥した。溶媒留去後、アセトン‐エーテル溶液から一方の光学異性体を晶析させ、濾過することにより除去した。ろ液を減圧留去後、残渣を中圧シリカゲルクロマトグラフ法（トルエン：酢酸エチル５：１）にて精製することによりＢｏｃ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２の光学異性体５．１０ｇを得た。この化合物４．９８ｇを冷４．９ｍｏｌ／Ｌ塩酸のジオキサン溶液３７ｍＬに溶解し、室温で１時間攪拌し、その後溶媒留去し減圧乾燥した。残渣をＤＭＦ　４０ｍＬに溶解し、Ｂｏｃ−Ｖａｌ−ＯＨ　２．０６ｇ及びＨＯＢｔ　１．３５ｇを加えた。氷冷下、ＷＳＣＤ　１．７７ｍＬを滴下した後、室温で１晩攪拌した。反応液に酢酸エチルを加え、酸及びアルカリ溶液で洗浄した。これを硫酸マグネシウムで乾燥後、溶媒留去することにより無色油状物としてＢｏｃ−Ｖａｌ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２の光学異性体６．２６ｇを得た。
【００２５】
（３）Ｌ−ＶＰＦの合成
Ｂｏｃ−Ｖａｌ−Ｐｒｏ−Ｐｈｅ^Ｐ（ＯＰｈ）_２の光学異性体５．８６ｇを冷４．９ｍｏｌ／Ｌ塩酸のジオキサン溶液３５ｍＬに溶解し、室温で１時間攪拌した。溶媒留去し減圧乾燥した。残渣をＤＭＦ　３５ｍＬに溶解し、無水コハク酸１．０２ｇを加え、トリエチルアミン２．３６ｍＬを滴下した後、室温で２時間攪拌した。氷冷下、１ｍｏｌ／Ｌ塩酸により反応液をｐＨ１．０に調整し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、溶媒留去後、黄色油状物として粗精製の標題化合物を得た。この油状物を逆相液体クロマトグラフ法（カラム：ＹＭＣ　ＯＤＳ　ＳＨ−３６３−５、３０×２５０ｍｍ、移動相：０．１Ｗ／Ｖ％トリフルオロ酢酸水溶液：アセトニトリル（６０：４０〜３０：７０））を用いて精製した後、凍結乾燥することにより無色粉末として標題化合物２．３０ｇを得た。
元素分析：
計算値　Ｃ_３４Ｈ_４０Ｎ_３Ｏ_８Ｓ：Ｃ，６２．８６；Ｈ，６．２１；Ｎ，６．４７％
計算値　Ｃ_３４Ｈ_４０Ｎ_３Ｏ_８Ｓ・８Ｈ_２Ｏ・０．５ＴＦＡ：Ｃ，５８．３０；Ｈ，５．８８；Ｎ，５．８３％
実測値：Ｃ，５８．３４；Ｈ，５．９４；Ｎ，５．５１％
比旋光度：［α］_Ｄ ^２８：−３６．５°（ｃ　１．０，２ｍｏｌ／Ｌ　ＮａＯＨ）
なお、比旋光度は、得られたＬ−ＶＰＦを加水分解してＰｈｅ^Ｐ（ＯＨ）_２として測定し、非特許文献７の文献値（−３７．０°）との比較から、Ｌ体であることを確認した。
【００２６】
実施例１．薬理試験
試験方法
正常犬６匹のそれぞれ片眼に線維柱帯切除術を施行した。このとき、それぞれ２眼ずつに１０μｍｏｌ／ＬのＶＰＦ生理食塩液、０．４ｍｇ／ｍＬのマイトマイシンＣ生理食塩液又は生理食塩液を含ませたマイクロスポンジＭ．Ｑ．Ａ（（株）イナミ製：特殊急速吸水紙）を強膜フラップの上下に３分間留置することにより、薬物の投与を行った。
手術後１４日目に眼球を摘出し、各群のうち１眼はキマーゼ活性測定、１眼は組織をアザン染色し、光学顕微鏡にて対比観察した。キマーゼ活性は、ヒト精製キマーゼを用い血管、２０巻、４号、ｐ２０７−２１１、１９９７年（日本心脈管作動物質学会）に従い測定した。
【００２７】
濾過胞部のキマーゼ活性は、ＶＰＦを投与したもの、マイトマイシンＣを投与したもの及び薬物を投与しなかったもので、それぞれ１．４５７、３．５９４及び８．９３３ｍＵ／ｍｇタンパク質であった。濾過胞部の組織所見は薬物を投与しなかったものと比較して、マイトマイシンＣを投与したものは膠原線維の密度が低く、結膜上皮も薄かった。これに対し、ＶＰＦを投与した場合は、膠原線維の密度はさらに低かったが、血管を豊富に含んだ濾過胞が形成されており、さらに、結膜上皮は薬物を併用しなかったものと同程度の厚みであった。
ＶＰＦは併用した線維柱帯切除術において、房水流出路及び濾過胞部の癒着を抑制し、血管が豊富で感染を起こしにくい濾過胞を維持することができた。
【００２８】
実施例２．点眼剤
Ｌ−ＶＰＦ　　　　　　　　　　　　１ｍｇ
マンニトール　　　　　　　　３５００ｍｇ
ポリソルベート８０　　　　　１０００ｍｇ
パラオキシ安息香酸メチル　　　１００ｍｇ
パラオキシ安息香酸プロピル　　　５０ｍｇ
滅菌精製水　　　　　　　　　全１００ｍＬ
上記処方の点眼液を調製し、無菌濾過した後、ポリプロピレン製の点眼容器に５ｍＬずつ充填した。
【００２９】
実施例３．経口剤

上記処方に従い、ＶＰＦ、乳糖、バレイショデンプン、結晶セルロース及びヒドロキシプロピルセルロースを混合し、水を加えて錬合した後、スクリーンで押し出して造粒した。顆粒を乾燥した後、ステアリン酸マグネシウムを加えて製錠した。
【００３０】
【発明の効果】
１−（Ｎ−スクシニル−Ｌ−バリル−Ｌ−プロリルアミノ）−２−フェニルエタンホスホン酸ジフェニルエステルは、緑内障手術において癒着を防止し、特に緑内障濾過手術時に形成される房水流出路及び濾過胞の癒着がなく、血管が豊富で感染を起こしにくい良好な濾過胞を維持することから、特に、緑内障濾過手術用剤として有用である。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a medicament having an excellent effect of preventing adhesion of aqueous humor outflow tract and filtration bleb formed in glaucoma surgery, particularly glaucoma filtration surgery.
[0002]
[Prior art]
Aqueous humor serves to nourish tissues such as the cornea, lens and vitreous, is produced in the ciliary body, passes through the pupil and the trabecular meshwork at the angle, collects in Schlemm's canal, and flows into veins. Glaucoma is a disease in which intraocular pressure increases due to increased resistance of the aqueous humor outflow tract and obstruction of the aqueous humor outflow tract, resulting in damage to the optic nerve and loss of visual field. Types of glaucoma include closed-angle glaucoma, where the angle is blocked by the iris, open-angle glaucoma, which has an open angle but poor aqueous humor flow in the trabecular meshwork, and normal-tension glaucoma. , Congenital glaucoma and secondary glaucoma.
[0003]
In the treatment of glaucoma, drug treatment using a β-blocker, a prostaglandin preparation or the like is usually performed, and the intraocular pressure is controlled. If pharmacotherapy is not effective, surgical treatment is given to improve aqueous humor flow. Surgical treatment of glaucoma includes laser treatment, filtration surgery, non-filtration surgery, ciliary destruction, peripheral iridectomy, and the like. In these operations, the outflow of aqueous humor is often blocked by adhesions after the operation, and the intraocular pressure lowering effect cannot be maintained in many cases.
Among them, trabeculectomy, which is an excellent example of glaucoma filtration surgery and has an excellent intraocular pressure lowering effect, makes a small hole at the border between the sclera and cornea of the eyeball, and through the hole, the anterior chamber and the subconjunctiva An aqueous humor outflow tract is formed by a scleral half-layer valve provided between the scleral membranes. This operation forms a reservoir of aqueous humor called a filtration bleb in the conjunctiva, which drains aqueous humor to lower intraocular pressure. be able to. However, depending on the patient, the aqueous humor outflow tract and the filtration bleb may adhere due to the proliferation of fibroblasts, and as a result, the intraocular pressure will rise again and glaucoma will progress. In recent years, antimetabolites such as mitomycin C and 5-fluorouracil have been administered to the surgical site (the scleral half-layer valve site and the subconjunctiva surrounding it) to prevent adhesion by preventing the proliferation of fibroblasts. The bleb is maintained and the surgical outcome is improving.
[0004]
However, the filtration bleb formed by trabeculectomy combined with the antimetabolite mitomycin C has a thin and fragile conjunctival epithelium as its wall and lacks blood vessels, so it can function as a barrier to the outside world. It is pointed out that the risk of infection is high. Infection not only spreads into the anterior chamber and causes endophthalmitis, but when it reaches the vitreous, it has a profound effect on prognosis (for example, see Non-Patent Documents 1 and 2). In addition, since the filtration bleb is weakened by the combined use of mitomycin C, leakage of aqueous humor is recognized several days after the operation or a long time after the operation, and reoperation may be required. Furthermore, it has been pointed out that trabeculectomy combined with mitomycin C may cause severe scleral complications such as keratoconjunctival epithelial disorder, scleral softening, and scleral perforation (for example, Non-Patent Documents) 3).
[0005]
On the other hand, the following equation (1)
[0006]
Embedded image

[0007]
In represented 1-(N-succinyl -L- valyl -L- Puroriruamino) -2-phenylethane phosphonic acid diphenyl ester ^{(Suc-Val-Pro-Phe} P (OPh) 2) is known as chymase inhibitors, Furthermore, of the two optical isomers of this compound, the D-form and the L-form, the L-form has a chymase inhibitory activity. (For example, see Non-Patent Documents 4 to 7 and Patent Document 1). This compound is expected as an angiogenesis inhibitor as a prophylactic or therapeutic agent for diseases associated with angiogenesis, such as diabetic retinopathy and neovascular glaucoma in the ophthalmic field (for example, see Patent Document 2). In the field of surgery, it is known to prevent adhesion during abdominal surgery (for example, see Non-Patent Document 8). However, it has not been reported that this compound was used during glaucoma surgery.
[0008]
[Patent Document 1]
US Pat. No. 5,543,396 [Patent Document 2]
Japanese Patent Application Laid-Open No. 2001-114699 [Non-Patent Document 1]
Ophthalmic Surgery, Japanese Society of Ophthalmic Surgery, 1999, Vol. 12, No. 1, p. 45-50
[Non-patent document 2]
New Ophthalmology, Medical Aoi Shuppan, 2000, Vol. 17, extra edition, p. 93-95
[Non-Patent Document 3]
Mika Aoyagi and 6 others, "Treatment results of trabeculectomy combined with mitomycin C", [online], Iida City Hospital Medical Journal, Internet <URL: http: // www. imh. iida. Nagano. jp / pro / ihou / soukan / soukan. pdf>
[Non-patent document 4]
Biochemistry, (USA), American Chemical Society, 1991, Vol. 30, No. 2, p. 485-493
[Non-Patent Document 5]
Methods of Enzymology, (USA), Academic Press, 1994, 244, p. 423-441
[Non-Patent Document 6]
The EMBO Journal, (UK), Oxford University Press, 1996, Vol. 15, No. 20, p. 5481-5491
[Non-Patent Document 7]
Tetrahedron Letters, (UK), Elsevier Science, 1995, 36, 25, p. 4451-4454
[Non-Patent Document 8]
European Journal of Pharmacology, (Netherlands), Elsevier Science, 2002, 435, p. 265-267
[0009]
[Problems to be solved by the invention]
Under such circumstances, development of a drug capable of preventing adhesion during glaucoma surgery, particularly a drug capable of maintaining a well-functioning filtration bleb without adhesion of the formed aqueous humor outflow tract and filtration bleb in glaucoma filtration surgery is desired. It is rare.
[0010]
[Means for Solving the Problems]
Thus, the present inventors have conducted intensive research and found that equation (1)
[0011]
Embedded image

[0012]
In represented by 1-(N-succinyl -L- valyl -L- Puroriruamino) -2-phenylethane phosphonic acid diphenyl ester ^{(Suc-Val-Pro-Phe} P (OPh) 2: hereinafter sometimes referred to as VPF ) Is excellent in preventing adhesions in glaucoma filtration surgery, and contrary to the publicly known fact that this compound has an angiogenesis inhibitory action, blood vessels of filtration bleb are formed abundantly, and mitomycin C The present inventors have found that they are useful as a glaucoma surgery agent, particularly as a glaucoma filtration surgery agent, without causing weakening of the filtration bleb as seen, and completed the present invention.
[0013]
That is, the present invention provides an agent for glaucoma surgery containing 1- (N-succinyl-L-valyl-L-prolylamino) -2-phenylethanephosphonic acid diphenyl ester or an optical isomer thereof as an active ingredient. .
[0014]
BEST MODE FOR CARRYING OUT THE INVENTION
As the active ingredient of the glaucoma surgical agent of the present invention, the L-isomer, which is an optical isomer thereof, can also be used.
[0015]
Examples of glaucoma surgery include laser treatment, glaucoma filtration surgery, glaucoma non-filtration surgery, ciliary body destruction surgery, peripheral iridotomy, and the like. Among them, it is preferable to use glaucoma filtration surgery.
Glaucoma filtration surgery includes trabeculectomy, non-perforated trabeculectomy, full-thickness filtration surgery, Seton surgery, among which trabeculectomy or non-perforated trabecula It is preferably used for band resection.
In addition, the laser treatment includes laser light incision, laser angle angulation, laser trabeculoplasty, laser ciliary photocoagulation, and the like, as glaucoma non-filtering surgery, trabeculotomy, Viscocanalostomy, angle incision, angle adhesion dissociation, and the like can be mentioned, and ciliary body destruction can be cryocoagulation, laser ciliary coagulation, and the like.
[0016]
VPF is primarily administered parenterally, but can also be administered orally. For example, examples of the parenteral administration preparation include formulations such as eye drops, liquid preparations, eye ointments, injections, and the like. Particularly, eye drops or liquid preparations are preferable. In addition, examples of the oral administration preparation include solid preparations such as powders, granules, capsules, and tablets. These preparations can be manufactured by a conventional method by adding a pharmaceutically acceptable preparation additive or the like to VPF.
[0017]
For example, in the case of preparing eye drops or liquid preparations, VPF may be used, if necessary, with a tonicity agent such as sodium chloride, concentrated glycerin, mannitol; a stabilizer such as sodium edetate, sodium citrate; Preservatives such as sodium, benzethonium chloride, chlorobutanol, and paraoxybenzoic acid esters; dissolution aids such as propylene glycol, polyethylene glycol, polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil; An eye drop or liquid may be prepared by a conventional method using a pH adjuster such as sodium hydrogen oxyoxide, sodium dihydrogen phosphate, boric acid, sodium tetraborate (borax), hydrochloric acid, sodium hydroxide and the like. Further, the pH may be within a range allowed for use in ophthalmology, but is preferably within a range of pH 4 to 8.
In the case of preparing an ophthalmic ointment, it may be formulated by a conventional method using a commonly used base such as white petrolatum or liquid paraffin.
When preparing an injection, VPF is distilled for injection with a pH adjuster such as hydrochloric acid, sodium hydroxide, sodium hydrogen phosphate and sodium dihydrogen phosphate as required; an isotonic agent such as sodium chloride. It may be dissolved in water and sterile-filtered and filled into ampoules, or mannitol, gelatin or the like may be further added and freeze-dried under vacuum to prepare a dissolvable injection before use.
[0018]
When preparing a solid preparation for oral administration, excipients such as lactose, starch, crystalline cellulose, calcium lactate, and calcium hydrogen phosphate are added to VPF as needed; binders such as sucrose, hydroxypropylcellulose, and polyvinylpyrrolidone A disintegrating agent such as carmellose calcium; a lubricant such as magnesium stearate or talc may be mixed and formulated into a preparation by a conventional method. In addition, these solid preparations can be coated with an enteric base such as hydroxypropylmethylcellulose phthalate, methacrylic acid / methyl methacrylate copolymer to form enteric preparations.
[0019]
The dose of the VPF can be appropriately selected depending on the condition of the operation. For an eye drop or a liquid, the VPF is 0.0001 to 5% by mass / volume% (hereinafter referred to as W / V%), preferably 0.0002.の も の 1 W / V% can be administered by directly dropping it to the surgical site at the time of surgery or by applying it to the surgical site in a absorbent cotton, gauze, sponge, water-absorbing paper or the like, or temporarily placing it in place. In addition, it can be instilled once or several times a day while checking the healing status after the operation. In the case of oral preparations or injections, it is preferable to administer 0.001 to 1000 mg per person per day, once or several times a day.
[0020]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples and Production Examples, but the present invention is not limited to these Examples and Production Examples.
[0021]
Production Example 1.1 Production of 1- (N-succinyl-L-valyl-L-prolylamino) -2-phenylethanephosphonic acid diphenyl ester (Suc-Val-Pro-Phe ^P (OPh) ₂ ) Manufactured by the method. In the following, Cbz indicates a benzyloxycarbonyl group, Val indicates a valine residue, Phe ^P indicates a phenylethanephosphonic acid residue, and Ph indicates a phenyl group.
0.584 g of Cbz-Pro-Phe ^P (OPh) ₂ was dissolved in 50 mL of methanol, 0.1 g of 5% by mass palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, the obtained Pro-Phe ^P (OPh) ₂ was dissolved in 20 mL of tetrahydrofuran, and 0.25 g of Cbz-Val-OH and 0.2 g of N, N-dicyclohexylcarbodiimide were added at 0 ° C. After stirring at the same temperature for 6 hours, the mixture was stirred at room temperature overnight. Dicyclohexylurea was removed by filtration, and the organic layer was washed with water, 4 W / V% aqueous sodium bicarbonate, water, 10 W / V% aqueous citric acid, and water in that order. After drying over magnesium sulfate, the solvent was distilled off to obtain an oil. This oil was dissolved in 30 mL of ethyl acetate, 0.1 g of succinic anhydride and 0.1 g of 5% by mass palladium-carbon were added, and the mixture was stirred under a hydrogen atmosphere until thin-layer chromatography became one spot. The catalyst was removed by filtration and the organic layer was washed several times with water. After drying, the organic solvent was removed to give 0.45 g of the product as a hygroscopic solid.
Melting point: 50-53 ° C
³¹ P NMR: 19.75, 19.23 ppm, peak height ratio 1: 1.
[0022]
Production Example 2. Production of L-1- (N-succinyl-L-valyl-L-prolylamino) -2-phenylethanephosphonic acid diphenyl ester (L-VPF) Production was carried out using the methods described in Non-Patent Documents 4 and 5. In the following, Z represents a benzyloxycarbonyl group, Boc represents a t-butyloxycarbonyl group, WSCD represents 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HOBt represents 1-hydroxybenzotriazole, and DMF represents dimethylformamide. .
[0023]
(1) Synthesis of DL-Phe ^P (OPh) ₂ · HBr 28.3 mL of phenylacetaldehyde was dissolved in 45 mL of acetic acid, 24.4 g of benzyl carbamic acid and 50.0 g of triphenyl phosphite were added. Stir for 5 hours. After evaporating the organic solvent under reduced pressure, the residue was cooled to room temperature, 400 mL of methanol was added, and the mixture was crystallized by friction at -20 ° C. The resulting powder was filtered, washed with cold methanol to give _{^{Z-DL-Phe P (OPh}} ) 2 32.9g dried under reduced pressure. 14.3 g of Z-DL-Phe ^P (OPh) ₂ thus obtained was dissolved in 30 mL of a 25 W / V% hydrogen bromide acetic acid solution, and stirred at room temperature for 1 hour. Ether was added to the reaction solution, and the precipitated solid was filtered and the resulting solid washed further dried under vacuum with ether to give a _{^{DL-Phe P (OPh) 2}} · HBr12.0g.
[0024]
(2) Synthesis of optical isomer of Boc-Val-Pro-Phe ^P (OPh) ₂ 11.5 g of DL-Phe ^P (OPh) ₂ · HBr, 5.53 g of Boc-Pro-OH and 3.58 g of HOBt in 70 mL of DMF It melt | dissolved, and 4.70 mL of WSCD was dripped under ice cooling. After stirring at room temperature for 3.5 hours, the solvent was distilled off, and ethyl acetate was added. The obtained reaction solution was washed with an acid and alkali solution, and dried over magnesium sulfate. After distilling off the solvent, one of the optical isomers was crystallized from the acetone-ether solution and removed by filtration. After evaporating the filtrate under reduced pressure, the residue was purified by medium pressure silica gel chromatography (toluene: ethyl acetate 5: 1) to obtain 5.10 g of an optical isomer of Boc-Pro-Phe ^P (OPh) _2. Was. 4.98 g of this compound was dissolved in 37 mL of a cold 4.9 mol / L hydrochloric acid in dioxane, stirred at room temperature for 1 hour, and then the solvent was distilled off and dried under reduced pressure. The residue was dissolved in DMF (40 mL), and Boc-Val-OH (2.06 g) and HOBt (1.35 g) were added. After 1.77 mL of WSCD was added dropwise under ice cooling, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, which was washed with an acid and alkali solution. After drying the over magnesium sulfate to give ^{Boc-Val-Pro-Phe P} (OPh) 2 optical isomers 6.26g as a colorless oil by the solvent was distilled off.
[0025]
(3) Synthesis of L-VPF 5.86 g of the optical isomer of Boc-Val-Pro-Phe ^P (OPh) ₂ was dissolved in 35 mL of a cold 4.9 mol / L hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and dried under reduced pressure. The residue was dissolved in DMF (35 mL), succinic anhydride (1.02 g) was added, and triethylamine (2.36 mL) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was adjusted to pH 1.0 with 1 mol / L hydrochloric acid under ice cooling, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off to give the crude title compound as a yellow oil. This oil was subjected to reverse phase liquid chromatography (column: YMC ODS SH-363-5, 30 × 250 mm, mobile phase: 0.1 W / V% trifluoroacetic acid aqueous solution: acetonitrile (60:40 to 30:70)). After purification using, freeze-drying gave 2.30 g of the title compound as a colorless powder.
Elemental analysis:
Calculated value C ₃₄ H ₄₀ N ₃ O ₈ S: C, 62.86; H, 6.21; N, 6.47%
Calculated value C ₃₄ H ₄₀ N ₃ O ₈ S · 8H ₂ O · 0.5 TFA: C, 58.30; H, 5.88; N, 5.83%
Found: C, 58.34; H, 5.94; N, 5.51%.
Specific rotation: [α] _D ²⁸ : -36.5 ° (c 1.0, 2 mol / L NaOH)
The specific rotation was measured as Phe ^P (OH) ₂ by hydrolyzing the obtained L-VPF. From comparison with the literature value of Non-Patent Document 7 (−37.0 °), the specific rotation was calculated for the L-form. I confirmed that there is.
[0026]
Embodiment 1 FIG. Pharmacological Test Test Method Trabeculectomy was performed on one eye of each of six normal dogs. At this time, microsponge M.I. containing 10 μmol / L physiological saline, 0.4 mg / mL mitomycin C physiological saline or physiological saline in each of two eyes. Q. A (manufactured by Inami Co., Ltd .: special quick water-absorbing paper) was placed above and below the scleral flap for 3 minutes to administer the drug.
On the 14th day after the operation, the eyes were enucleated, and one eye of each group was measured for chymase activity, and one eye was stained with Azan and the tissue was compared and observed with an optical microscope. Chymase activity was measured using purified human chymase according to Blood Vessels, Vol. 20, No. 4, p. 207-211, 1997 (Japanese Society of Cardiovascular Agents).
[0027]
The chymase activity of the filter vesicles was 1.457, 3.594, and 8.933 mU / mg protein in those to which VPF was administered, those to which mitomycin C was administered, and those to which no drug was administered. The histological findings of the bleb vesicles showed that those treated with mitomycin C had a lower collagen fiber density and thinner conjunctival epithelium than those without drug administration. In contrast, when VPF was administered, the density of collagen fibers was still lower, but filtration vesicles containing abundant blood vessels were formed, and the conjunctival epithelium was comparable to that without the drug. It was the thickness of.
In the trabeculectomy combined with VPF, the adhesion of the aqueous humor outflow tract and the filtration bleb part was suppressed, and the filtration bleb that was rich in blood vessels and hardly caused infection could be maintained.
[0028]
Embodiment 2. FIG. Eye drops L-VPF 1mg
Mannitol 3500mg
Polysorbate 80 1000mg
Methyl paraoxybenzoate 100mg
Propyl paraoxybenzoate 50mg
100 mL of sterile purified water
An ophthalmic solution having the above formulation was prepared, sterile-filtered, and then filled into polypropylene ophthalmic containers in an amount of 5 mL each.
[0029]
Embodiment 3 FIG. Oral preparation

According to the above formula, VPF, lactose, potato starch, crystalline cellulose and hydroxypropylcellulose were mixed, water was added and kneaded, and the mixture was extruded with a screen and granulated. After drying the granules, magnesium stearate was added to make tablets.
[0030]
【The invention's effect】
1- (N-succinyl-L-valyl-L-prolylamino) -2-phenylethanephosphonic acid diphenyl ester prevents adhesion in glaucoma surgery, particularly adhesion of aqueous humor outflow tract and filtration bleb formed during glaucoma filtration surgery. It is particularly useful as an agent for glaucoma filtration surgery because it maintains good filtration vesicles that are abundant in blood vessels and are less likely to cause infection.

Claims (3)

An agent for glaucoma surgery comprising 1- (N-succinyl-L-valyl-L-prolylamino) -2-phenylethanephosphonic acid diphenyl ester or an optical isomer thereof as an active ingredient. The agent for glaucoma surgery according to claim 1, wherein the glaucoma surgery is glaucoma filtration surgery. The glaucoma surgery agent according to claim 1 or 2, wherein the dosage form of the glaucoma surgery agent is an eye drop or a liquid preparation.