JP4874482B2 - Pharmaceutical composition containing aspirin - Google Patents
Pharmaceutical composition containing aspirin Download PDFInfo
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- JP4874482B2 JP4874482B2 JP2001386850A JP2001386850A JP4874482B2 JP 4874482 B2 JP4874482 B2 JP 4874482B2 JP 2001386850 A JP2001386850 A JP 2001386850A JP 2001386850 A JP2001386850 A JP 2001386850A JP 4874482 B2 JP4874482 B2 JP 4874482B2
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- pharmaceutical composition
- tetrahydrothieno
- cyclopropylcarbonyl
- fluorobenzyl
- acetoxy
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【０００１】
【発明の属する技術分野】
本発明は、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンを有効成分として含有する医薬組成物［特に、血栓又は塞栓によって引き起こされる疾病の予防又は治療（特に、治療）のための医薬組成物］に関する。
【０００２】
【従来の技術】
２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンは、特開平６−４１１３９号公報に記載され、優れた血小板凝集抑制作用を有する化合物である。又、アスピリンは、弱いながら血小板凝集抑制作用を有することが知られている。しかしながら、これらの薬剤を組み合わせた医薬は、知られていない。
【０００３】
【発明が解決しようとする課題】
本発明者等は、さらに優れた血小板凝集抑制作用を有し、かつ、さらに毒性が少ない医薬について研究を重ねた結果、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンとを組み合わせて使用することにより、上記課題が解決されることを見出すに至った。
【０００４】
本発明は、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンを有効成分として含有する医薬組成物［特に、血栓又は塞栓によって引き起こされる疾病の予防又は治療（特に、治療）のための医薬組成物］、又は２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンを同時又は時間を変えて投与するための医薬組成物［特に、血栓又は塞栓によって引き起こされる疾病の予防又は治療（特に、治療）のための医薬組成物］を提供する。
【０００５】
【課題を解決するための手段】
本発明の有効成分の一つである２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩は、公知化合物であり、例えば、特開平６−４１１３９号公報、特願２０００−２０５３９６号又は特願２０００−２６６７８０号に記載されている。その平面構造式を以下に示す。
【０００６】
【化１】
２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンの「薬理上許容される塩」は、例えば、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩；硝酸塩；過塩素酸塩；硫酸塩；燐酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のようなハロゲンで置換されてもよいＣ1−Ｃ4アルカンスルホン酸塩；ベンゼンスルホン酸塩、ｐ−トルエンスルホン酸塩のようなＣ1−Ｃ4アルキルで置換されてもよいＣ6−Ｃ10アリ−ルスルホン酸塩；酢酸、りんご酸、フマ−ル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩のようなＣ1−Ｃ6脂肪酸塩；又はグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり得、好適には、ハロゲン化水素酸塩又はＣ1−Ｃ6脂肪酸塩であり、特に好適には、塩酸塩又はマレイン酸塩である。
【０００８】
又、本発明の有効成分である２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩は、大気中に放置しておくことにより、水分を吸収したり、吸着水がついたりして、水和物となる場合があり、そのような水和物も本発明に包含される。
【０００９】
更に、本発明の有効成分である２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン等又はその薬理上許容される塩は、ある種の有機溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明に包含される。
【００１０】
更に又、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンは、不斉炭素を有し、それに基づく光学異性体が存在するが、それらの光学異性体及び光学異性体の混合物も本発明に包含される。
【００１１】
もう一つの有効成分であるアスピリンは、鎮痛解熱剤等として、周知の化合物である。
【００１２】
【発明の実施の形態】
２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンを有効成分として含有する本発明の医薬（特に、血栓又は塞栓によって引き起こされる疾病の予防又は治療のための組成物）は、優れた血小板凝集抑制作用及び血栓形成抑制作用を有し、しかも、その作用発現が早く、毒性が弱いため、例えば、安定または不安定狭心症などを含む血小板凝集によって誘発される疾患；不安定狭心症、脳虚血発作、血管形成術、血管内膜切除術もしくはステント留置後の再狭窄のようなアテローム性動脈硬化症または糖尿病に伴う血栓塞栓形成疾患のような心臓血管および脳血管系の疾患；あるいは血栓崩壊後の再血栓症、梗塞、虚血由来の痴呆、末梢動脈疾患、血液透析もしくは心房性細動に伴うまたは血管補綴もしくは大動脈−冠動脈バイパス使用の間の血栓塞栓形成疾患等のような、血栓又は塞栓によって引き起こされる疾病の予防剤又は治療剤（特に、治療剤）として有用である。又、本発明の医薬は、温血動物用（特に、ヒト用）である。
【００１３】
本発明によれば、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンは、それらが組み合わせられ、使用されることにより各々の単剤と比べ、優れた効果を示す。又、このような効果は、必ずしも２系統の薬剤が同時に体内に存在していなくてももたらされる。即ち、２系統の薬剤が同時にある程度以上の血中濃度を有さなくても効果を示すのである。推測によれば、本発明に使用される２系統の薬剤は、共に、生体内に取り込まれて受容体に到達すれば、生体内の「スイッチ」を入れる作用を果たし、従って、投与後の経過時間につれてもはやその血中濃度では作用を示さないように見えても、実際は「スイッチ」はすでに入っており、一方の系統の物質が有する血栓又は塞栓によって引き起こされる疾病の予防または治療効果が奏される。この状態において、他方の系統の薬剤が投与されると、その薬剤が有する血栓又は塞栓によって引き起こされる疾病の予防又は治療効果に加えて、先に投与された薬剤の効果が合さり、優れた効果が得られる。勿論、臨床上は両系統の薬剤が同時に投与されることが便宜であり、それゆえ、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンは、配合剤の形態で投与することができる。製剤技術上、両薬剤を物理的に同時に混合することが好ましくない場合は、それぞれの単剤を同時に投与することもできる。また、前述のとおり、２系統の薬剤は同時に投与しなくても優れた効果を奏するので、それぞれの単剤を適当な間隔を置いて相前後して投与することもできる。かかる２系統の薬剤によりもたらされる優れた効果が達成されるのに許容される最大限の２系統薬剤の投与間隔は、臨床上または動物実験により確認することができる。
【００１４】
本発明において使用される２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンの投与ル−トは、一般的に経口ル−トである。しかし、他の投与ル−ト、例えば、静脈ルート等も使用され得る。従って、２系統の薬剤は、それぞれ単独で別々の単位投与形態に、又は混合して物理的に１個の単位投与形態に調製することができる。かかる単位投与形態は、たとえば、散剤、顆粒剤、錠剤、カプセル剤等であり得、以下に示すように、通常の製剤技術により調製することができる。
【００１５】
これらの製剤は、賦形剤（例えば、乳糖、白糖、葡萄糖、マンニトール、ソルビトールのような糖誘導体；トウモロコシデンプン、バレイショデンプン、α澱粉、デキストリンのような澱粉誘導体；結晶セルロースのようなセルロース誘導体；アラビアゴム；デキストラン；プルランのような有機系賦形剤；及び、軽質無水珪酸、合成珪酸アルミニウム、珪酸カルシウム、メタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体；燐酸水素カルシウムのような燐酸塩；炭酸カルシウムのような炭酸塩；硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げることができる。）、滑沢剤（例えば、ステアリン酸、ステアリン酸カルシウム、ステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；ビーズワックス、ゲイ蝋のようなワックス類；硼酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；ＤＬロイシン；ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸、珪酸水和物のような珪酸類；及び、上記澱粉誘導体を挙げることができる。）、結合剤（例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリエチレングリコール、及び、前記賦形剤と同様の化合物を挙げることができる。）、崩壊剤（例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体；カルボキシメチルスターチ、カルボキシメチルスターチナトリウムのような化学修飾された澱粉・セルロース類；架橋ポリビニルピロリドン；又は上記澱粉誘導体を挙げることができる。）、乳化剤（例えば、ベントナイト、ビーガムのようなコロイド性粘土；水酸化マグネシウム、水酸化アルミニウムのような金属水酸化物；ラウリル硫酸ナトリウム、ステアリン酸カルシウムのような陰イオン界面活性剤；塩化ベンザルコニウムのような陽イオン界面活性剤；及び、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル、ショ糖脂肪酸エステルのような非イオン界面活性剤を挙げることができる。）、安定化剤（例えば、メチルパラベン、プロピルパラベンのようなパラヒドロキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール、フェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール、クレゾールのようなフェノール類；チメロサール；デヒドロ酢酸；及び、ソルビン酸を挙げることができる。）、矯味矯臭剤（例えば、通常使用される、甘味料、酸味料、香料等を挙げることができる。）、希釈剤等の添加剤を用いて周知の方法で製造される。
【００１６】
本発明において使用される２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンの投与量と投与比率は、個々の薬剤の活性、患者の症状、年齢、体重等の種々の条件により大幅に変化し得る。
【００１７】
一般的に言って、投与量（ｍｇ薬量／回）は、経口投与の場合、1回当たり下限０．１ｍｇ（好適には、１ｍｇ）、上限１０００ｍｇ（好適には、５００ｍｇ）であり、静脈投与の場合、1回当たり下限０．０１ｍｇ（好適には、０．１ｍｇ）、上限５００ｍｇ（好適には、２５０ｍｇ）であり、成人に対して、１日当り１乃至７回症状に応じて、それぞれを同時に、または時間を異にして別々に、投与することができる。
【００１８】
一般的に言って、２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンの投与量比率は、重量比で、１：５００乃至５００：１の範囲内である。
【００１９】
【実施例】
以下に、実施例及び製剤例をあげて、本発明をさらに詳細に説明するが、本発明の範囲はこれらに限定されるものではない。
【００２０】
実施例１
血栓形成抑制作用
試験動物は、７週齢のＳＤ系雄性ラットを日本ＳＬＣより購入して、一群６匹として使用した。
【００２１】
２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジンは、特開平６−４１１３９号に記載された方法で製造して、使用し、アスピリンは、シグマ化学（株）より購入したものを使用した。両化合物は、５％（ｗ／ｖ）アラビアゴム液に懸濁し、各試験動物には、１ｍｌ／ｋｇとなるように適宜希釈して、経口投与した。
【００２２】
Ｕｍｅｔｓｕらにより報告されたラット動静脈シャント血栓モデル［Ｔｈｒｏｍｂ．Ｈａｅｍｏｓｔ．，ｖｏｌ．３９，７４−８３（１９７８）］を若干改良した方法で試験化合物の抗血栓作用を評価した。
【００２３】
シャントチューブは以下のように作製した。すなわち、長さ１２ｃｍの医療用シリコンチューブ［内径：１．５ｍｍ、外径：２．５ｍｍ、カネカ・メディックス（株）より購入］の両端に７ｃｍのシリコン被覆したポリエチレンチューブ［内径：０．５ｍｍ、外径：１．０ｍｍ、夏目製作所（株）より購入］を、０．７ｃｍの医療用シリコンチューブ［内径：１．０ｍｍ、外径：１．５ｍｍ、カネカ・メディックス（株）より購入］をコネクターに用いて連結した。１２ｃｍのシリコンチューブ内に長さ１０ｃｍの手術用絹糸を設置した。
【００２４】
各試験動物を、ペントバルビタールナトリウム（アボットラボラトリーから購入）を４０ｍｇ／ｋｇ腹腔内注射することにより麻酔し、頚静脈及び反対側の頚動脈を露出させた。ヘパリン溶液［３０ｕｎｉｔ／ｋｇ、扶桑薬品工業（株）より購入］を満たしたシャントチューブをカニュレーションして、動静脈シャントを形成した。
【００２５】
試験化合物を経口投与し、２時間後に血液をシャント内に循環させはじめた。
血液の循環を始めてから３０分後、シャントチューブをはずし、絹糸に付着した血栓重量を測定した。結果を表１に示す。なお、成績は、平均±標準誤差（Ｎ＝６）で表示されている。
【００２６】
【表１】
【表２】
【００２８】
【発明の効果】
２−アセトキシ−５−（α−シクロプロピルカルボニル−２−フルオロベンジル）−４，５，６，７−テトラヒドロチエノ［３，２−ｃ］ピリジン又はその薬理上許容される塩とアスピリンを有効成分として含有する本発明の医薬（特に、血栓又は塞栓によって引き起こされる疾病の予防又は治療のための組成物）は、優れた血小板凝集抑制作用及び血栓形成抑制作用を有し、しかも、その作用発現が早く、毒性が弱いため、例えば、安定または不安定狭心症などを含む血小板凝集によって誘発される疾患；不安定狭心症、脳虚血発作、血管形成術、血管内膜切除術もしくはステント留置後の再狭窄のようなアテローム性動脈硬化症または糖尿病に伴う血栓塞栓形成疾患のような心臓血管および脳血管系の疾患；あるいは血栓崩壊後の再血栓症、梗塞、虚血由来の痴呆、末梢動脈疾患、血液透析もしくは心房性細動に伴うまたは血管補綴もしくは大動脈−冠動脈バイパス使用の間の血栓塞栓形成疾患等のような、血栓又は塞栓によって引き起こされる疾病の予防剤又は治療剤（特に、治療剤）として有用である。又、本発明の医薬は、温血動物用（特に、ヒト用）である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof. The present invention relates to a pharmaceutical composition [in particular, a pharmaceutical composition for the prevention or treatment (particularly, treatment) of diseases caused by thrombus or embolism] containing aspirin as an active ingredient.
[0002]
[Prior art]
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine is described in JP-A-6-41139, It is a compound having an excellent platelet aggregation inhibitory action. In addition, aspirin is known to have a platelet aggregation inhibitory action although it is weak. However, a medicine combining these drugs is not known.
[0003]
[Problems to be solved by the invention]
As a result of repeated studies on a pharmaceutical having a further excellent platelet aggregation inhibitory action and less toxicity, the present inventors have found that 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl)- By using 4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof in combination with aspirin, the inventors have found that the above problems can be solved.
[0004]
The present invention relates to 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof. Pharmaceutical composition containing aspirin as an active ingredient [especially pharmaceutical composition for prevention or treatment (especially treatment) of diseases caused by thrombus or embolism], or 2-acetoxy-5- (α-cyclopropylcarbonyl) -2-Fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof and aspirin at the same time or at different times [ In particular, a pharmaceutical composition for the prevention or treatment (especially treatment) of diseases caused by thrombi or emboli is provided.
[0005]
[Means for Solving the Problems]
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or its pharmacology which is one of the active ingredients of the present invention The salts allowed above are known compounds and are described in, for example, JP-A-6-41139, Japanese Patent Application No. 2000-205396 or Japanese Patent Application No. 2000-266780. The planar structural formula is shown below.
[0006]
[Chemical 1]
“Pharmaceutically acceptable salts” of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine include, for example: Hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate; perchlorate; sulfate; phosphate; methanesulfonate, trifluoromethanesulfone Acid, C 1 -C 4 alkane sulfonate which may be substituted with halogen such as ethane sulfonate; C 1 -C 4 alkyl substituted with benzene sulfonate, p-toluene sulfonate C 6 -C 10 aryl sulfonates; C 1 -C 6 such as acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate Fatty acid salt; or glycine salt, Emissions, arginine, ornithine salts, can be a glutamate, an amino acid salt such as aspartate, preferably a hydrohalic acid salt or C 1 -C 6 fatty acid salt, particularly preferably hydrochloric acid Salt or maleate.
[0008]
In addition, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which is an active ingredient of the present invention, or its pharmacologically Acceptable salts may become hydrates by absorbing moisture or adsorbed water when left in the atmosphere, and such hydrates are also included in the present invention. Is done.
[0009]
Furthermore, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine, which is an active ingredient of the present invention, or the pharmacology thereof The top acceptable salts may absorb certain organic solvents and become solvates, and such solvates are also encompassed by the present invention.
[0010]
Furthermore, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine has an asymmetric carbon, Although there are optical isomers based, these optical isomers and mixtures of optical isomers are also encompassed by the present invention.
[0011]
Another active ingredient, aspirin, is a well-known compound as an analgesic antipyretic and the like.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof and aspirin as active ingredients The medicament of the present invention (in particular, a composition for the prevention or treatment of diseases caused by thrombi or emboli) has an excellent platelet aggregation inhibitory action and thrombus formation inhibitory action, and its action is manifested. Diseases induced by platelet aggregation, including early or weak toxicity, eg, stable or unstable angina; unstable angina, cerebral ischemic attack, angioplasty, endomectomy or stent placement Cardiovascular and cerebrovascular diseases such as thromboembolization disease associated with atherosclerosis or diabetes after subsequent restenosis; or rethrombosis after thrombolysis Diseases caused by thrombosis or embolism, such as, thromboembolism disease associated with hemorrhage, ischemia-derived dementia, peripheral arterial disease, hemodialysis or atrial fibrillation or during vascular prosthesis or aorto-coronary bypass It is useful as a preventive or therapeutic agent (especially a therapeutic agent). The medicament of the present invention is for warm-blooded animals (particularly for humans).
[0013]
According to the present invention, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof. Salt and aspirin are combined and used to show superior effects compared to each single agent. Further, such an effect is brought about even if two systems of drugs are not present in the body at the same time. In other words, the effect is exhibited even if the two drugs do not have a certain level of blood concentration at the same time. According to the speculation, both of the two drugs used in the present invention act to turn on the “switch” in the living body when they are taken into the living body and reach the receptor. Although it seems that it no longer works at that blood concentration over time, in fact the “switch” has already been turned on and is effective in preventing or treating diseases caused by thrombi or emboli possessed by one family of substances. The In this state, when the drug of the other system is administered, in addition to the preventive or therapeutic effect of the disease caused by the thrombus or embolism possessed by the drug, the effect of the previously administered drug is combined and an excellent effect Is obtained. Of course, clinically, it is convenient to administer both drugs simultaneously. Therefore, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7- Tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof and aspirin can be administered in the form of a combination drug. When it is not preferable to mix both drugs physically at the same time due to formulation technology, each single drug can be administered simultaneously. In addition, as described above, since the two drugs do not have to be administered at the same time, excellent effects can be obtained, so that each single agent can be administered at an appropriate interval. The maximum interval between two drugs that are allowed to achieve the excellent effects provided by these two drugs can be confirmed clinically or by animal experiments.
[0014]
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof used in the present invention The administration route for salt and aspirin is generally an oral route. However, other administration routes such as intravenous routes can also be used. Thus, the two systems of drugs can each be prepared separately in separate unit dosage forms, or mixed into a physically single unit dosage form. Such unit dosage forms can be, for example, powders, granules, tablets, capsules, etc., and can be prepared by conventional formulation techniques as described below.
[0015]
These formulations include excipients (eg sugar derivatives such as lactose, sucrose, sucrose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate and magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate; and lubricants (eg, stearic acid, calcium stearate, metal stearate such as magnesium stearate) Salt; Talc; Wax like beeswax, gay wax Borax; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; anhydrous silicic acid, silicic acid hydrate And the above-mentioned starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, and the same compounds as the above-mentioned excipients). Disintegrants (eg, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as sodium carboxymethylcellulose internally crosslinked; carboxymethyl starch, Chemically modified starch / celluloses such as sodium carboxymethyl starch; cross-linked polyvinyl pyrrolidone; or the above starch derivatives can be mentioned), emulsifiers (for example, colloidal clays such as bentonite and bee gum; magnesium hydroxide, Metal hydroxides such as aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate and calcium stearate; cationic surfactants such as benzalkonium chloride; and polyoxyethylene alkyl ethers, polyoxyethylene Nonionic surfactants such as sorbitan fatty acid esters and sucrose fatty acid esters), stabilizers (for example, parahydroxybenzoates such as methylparaben and propylparaben; chlorobutanol and benzyl) Alcohols, alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols, phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid and the. ), Flavoring agents (for example, commonly used sweeteners, acidulants, fragrances and the like), and additives such as diluents, and the like.
[0016]
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof used in the present invention The dosage and dosage ratio of salt and aspirin can vary greatly depending on various conditions such as individual drug activity, patient symptoms, age, weight and the like.
[0017]
Generally speaking, the dose (mg dose / dose) is 0.1 mg (preferably 1 mg) per dose and 1000 mg (preferably 500 mg) per dose for oral administration. In the case of administration, the lower limit is 0.01 mg (preferably 0.1 mg) and the upper limit is 500 mg (preferably 250 mg) per dose. For adults, 1 to 7 times per day, depending on symptoms Can be administered simultaneously or separately at different times.
[0018]
Generally speaking, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof The dose ratio of salt to aspirin is in the range of 1: 500 to 500: 1 by weight.
[0019]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples and formulation examples, but the scope of the present invention is not limited thereto.
[0020]
Example 1
Thrombogenesis-inhibiting test test animals were 7 week old SD male rats purchased from Japan SLC and used as 6 animals per group.
[0021]
2-Acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine is a method described in JP-A-6-41139. The aspirin used was purchased from Sigma Chemical Co., Ltd. Both compounds were suspended in 5% (w / v) gum arabic solution, and each test animal was orally administered after appropriately diluting to 1 ml / kg.
[0022]
Rat arteriovenous shunt thrombus model reported by Umetsu et al. [Thromb. Haemost. , Vol. 39, 74-83 (1978)], the antithrombotic action of the test compound was evaluated.
[0023]
The shunt tube was produced as follows. That is, a 12 cm long medical silicone tube [inner diameter: 1.5 mm, outer diameter: 2.5 mm, purchased from Kaneka Medix Co., Ltd.] on both ends of a 7 cm silicon-coated polyethylene tube [inner diameter: 0.5 mm, Outer diameter: 1.0 mm, purchased from Natsume Seisakusho Co., Ltd.], 0.7 cm medical silicone tube [Inner diameter: 1.0 mm, Outer diameter: 1.5 mm, purchased from Kaneka Medix Co., Ltd.] And connected. A 10 cm-long surgical silk thread was placed in a 12 cm silicon tube.
[0024]
Each test animal was anesthetized by intraperitoneal injection of 40 mg / kg sodium pentobarbital (purchased from Abbott Laboratories) to expose the jugular vein and contralateral carotid artery. A shunt tube filled with a heparin solution [30 units / kg, purchased from Fuso Pharmaceutical Co., Ltd.] was cannulated to form an arteriovenous shunt.
[0025]
Test compounds were administered orally and after 2 hours blood began to circulate in the shunt.
After 30 minutes from the start of blood circulation, the shunt tube was removed and the weight of the thrombus adhering to the silk thread was measured. The results are shown in Table 1. The grades are expressed as mean ± standard error (N = 6).
[0026]
[Table 1]
[Table 2]
[0028]
【Effect of the invention】
2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof and aspirin as active ingredients The medicament of the present invention (in particular, a composition for the prevention or treatment of diseases caused by thrombi or emboli) has an excellent platelet aggregation inhibitory action and thrombus formation inhibitory action, and its action is manifested. Diseases induced by platelet aggregation, including early or weak toxicity, eg, stable or unstable angina; unstable angina, cerebral ischemic attack, angioplasty, endomectomy or stent placement Cardiovascular and cerebrovascular diseases such as thromboembolization disease associated with atherosclerosis or diabetes after subsequent restenosis; or rethrombosis after thrombolysis Diseases caused by thrombosis or embolism, such as, thromboembolism disease associated with hemorrhage, ischemia-derived dementia, peripheral arterial disease, hemodialysis or atrial fibrillation or during vascular prosthesis or aorto-coronary bypass use It is useful as a preventive or therapeutic agent (especially a therapeutic agent). The medicament of the present invention is for warm-blooded animals (particularly for humans).
Claims (17)
Priority Applications (1)
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| JP2001386850A JP4874482B2 (en) | 2000-12-25 | 2001-12-20 | Pharmaceutical composition containing aspirin |
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| JP2000-392983 | 2000-12-25 | ||
| JP2000392983 | 2000-12-25 | ||
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| JP2001386850A JP4874482B2 (en) | 2000-12-25 | 2001-12-20 | Pharmaceutical composition containing aspirin |
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| KR20080016647A (en) * | 2005-06-17 | 2008-02-21 | 일라이 릴리 앤드 캄파니 | Dosage regimen for prasugrel |
| CA2672157C (en) * | 2006-12-07 | 2016-07-26 | Daiichi Sankyo Company, Limited | Method for producing solid preparation |
| EP2100606A4 (en) * | 2006-12-07 | 2009-12-30 | Daiichi Sankyo Co Ltd | Film-coated preparation having improved stability |
| EP2100610A4 (en) * | 2006-12-07 | 2009-12-02 | Daiichi Sankyo Co Ltd | Pharmaceutical composition containing low-substituted hydroxypropylcellulose |
| CA2672154C (en) * | 2006-12-07 | 2014-11-18 | Daiichi Sankyo Company, Limited | Pharmaceutical composition having improved storage stability |
| TWI428151B (en) | 2006-12-07 | 2014-03-01 | Daiichi Sankyo Co Ltd | Solid formulations containing mannitol or lactose |
| MX2009011619A (en) | 2007-04-27 | 2010-01-18 | Cydex Pharmaceuticals Inc | Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use. |
| WO2010132711A1 (en) | 2009-05-13 | 2010-11-18 | Cydex Pharmaceuticals, Inc. | Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same |
| WO2011065444A1 (en) * | 2009-11-27 | 2011-06-03 | 学校法人東海大学 | Antithrombotic agent |
| US9757395B2 (en) | 2012-12-20 | 2017-09-12 | Otitopic Inc. | Dry powder inhaler and methods of use |
| US9757529B2 (en) | 2012-12-20 | 2017-09-12 | Otitopic Inc. | Dry powder inhaler and methods of use |
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