JP2004115500A - Medicinal composition including hmg-coa reductase inhibitor - Google Patents
Medicinal composition including hmg-coa reductase inhibitor Download PDFInfo
- Publication number
- JP2004115500A JP2004115500A JP2003279533A JP2003279533A JP2004115500A JP 2004115500 A JP2004115500 A JP 2004115500A JP 2003279533 A JP2003279533 A JP 2003279533A JP 2003279533 A JP2003279533 A JP 2003279533A JP 2004115500 A JP2004115500 A JP 2004115500A
- Authority
- JP
- Japan
- Prior art keywords
- hmg
- nitric oxide
- coa reductase
- reductase inhibitor
- oryzanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title claims abstract description 58
- 239000000203 mixture Substances 0.000 title claims abstract description 39
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 145
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する医薬組成物（特に、血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持若しくは向上するための医薬組成物、或いは、血中脂質を改善するための医薬組成物）に関する。 The present invention relates to a pharmaceutical composition containing an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine (particularly, promoting the synthesis of vascular endothelial nitric oxide and / or maintaining the blood concentration of vascular endothelial nitric oxide or A pharmaceutical composition for improving blood lipids or a pharmaceutical composition for improving blood lipids).
古くから「ヒトは血管とともに老いる」と言われてきたが、それには加齢や各種疾病等による血管内皮由来一酸化窒素（ＮＯ）の産生減少、すなわち内皮型ＮＯ合成酵素（ｅＮＯＳ）活性の低下が深く関わっていることが最近判ってきた。 It has long been said that "humans age with blood vessels", but this includes decreased production of vascular endothelial-derived nitric oxide (NO) due to aging and various diseases, that is, endothelial NO synthase (eNOS) activity. It has recently been found that the decline is deeply involved.
血管内皮の機能障害は動脈硬化の発症・進展に深く関係し、ｅＮＯＳから産生されるＮＯの低下がその大きな原因であると言われている。血管壁由来のＮＯは、血管弛緩、血小板の凝集抑制、好中球の内皮細胞への付着抑制、血管平滑筋細胞の遊走・増殖抑制、ＬＤＬ酸化抑制、等の面から抗動脈硬化作用を示す（例えば、非特許文献１参照。）。 障害 Dysfunction of the vascular endothelium is deeply related to the onset and progression of arteriosclerosis, and it is said that the decrease in NO produced from eNOS is the major cause. NO derived from vascular wall exhibits anti-atherosclerotic effects in terms of vasorelaxation, inhibition of platelet aggregation, inhibition of neutrophil adhesion to endothelial cells, inhibition of vascular smooth muscle cell migration / proliferation, inhibition of LDL oxidation, etc. (For example, see Non-Patent Document 1.)
動物試験でＮＯ合成阻害により動脈硬化症が憎悪することからも、動脈硬化発症・進展に直接寄与することが判る（例えば、非特許文献２参照。）。 Heterogeneous arteriosclerosis is aggravated by inhibition of NO synthesis in animal tests, indicating that it directly contributes to the onset and progression of arteriosclerosis (for example, see Non-Patent Document 2).
ヒトにおいても血管内皮産生ＮＯは血管保護的に多面的に働くため、心血管系疾患の治療に、血管内皮機能を温存・改善する治療戦略は重要である。ｅＮＯＳ活性を向上させる薬剤としてスタチン剤、Ｌ−アルギニン、ＡＣＥ阻害剤、アンジオテンシンIIタイプ１受容体拮抗薬、ホルモン、一部のＣａ拮抗薬が知られており、また、ＮＯの失活を防止することにより間接的にＮＯ作用を助長するビタミンＣ、ビタミンＥ、プロブコール等の抗酸化剤も有効であるとされている（例えば、非特許文献３参照。）。 も Even in humans, vascular endothelium-producing NO acts pleiotropically in vasoprotection. Therefore, a therapeutic strategy for preserving and improving vascular endothelial function is important in treating cardiovascular diseases. Statin agents, L-arginine, ACE inhibitors, angiotensin II type 1 receptor antagonists, hormones, and some Ca antagonists are known as agents for improving eNOS activity, and prevent NO inactivation. Antioxidants such as vitamin C, vitamin E, and probucol, which indirectly promote NO action, are also considered to be effective (for example, see Non-Patent Document 3).
なお、ビタミンＣについては、ｅＮＯＳ活性も上昇させることが明らかにされている（例えば、非特許文献４参照。）。 ビ タ ミ ン It has been clarified that vitamin C also increases eNOS activity (for example, see Non-Patent Document 4).
また、漢方薬の構成生薬ではニンジン、オウギ、オウゴンに血管のＮＯ産生刺激作用が見出されている（例えば、非特許文献５参照。）。 で は In addition, carbohydrates, carrots, and gougins have been found to have a vascular NO production stimulating effect in the constituent herbs of Chinese medicine (for example, see Non-Patent Document 5).
なお、ＮＯ合成酵素（ＮＯＳ）は血管内皮以外にも存在し、全身の循環調節において重要な役割を果たす。ＮＯ産生低下が認められている疾患としては、高血圧、高脂血症、動脈硬化、虚血性心疾患、心不全、血栓症等の循環器疾患、喘息、慢性閉塞性肺疾患、肺高血圧、ＡＲＤＳ（成人呼吸窮迫症候群）等の呼吸器疾患、肝障害、肝硬変、胃腸粘膜障害、肥厚性幽門狭窄症、膵炎等の消化器疾患、脳虚血、脳梗塞、脳循環不全、老年性痴呆等の脳血管障害、腎障害、インポテンツ等の腎・泌尿器疾患、妊娠中毒症等の産婦人科疾患、感染症・免疫疾患、糖尿病、熱傷、又は、その他薬剤性にＮＯ産生の低下が認められる疾患が数多く知られている（例えば、特許文献１参照。）。 In addition, NO synthase (NOS) exists not only in vascular endothelium but also plays an important role in systemic circulation regulation. Diseases in which decreased NO production is recognized include cardiovascular diseases such as hypertension, hyperlipidemia, arteriosclerosis, ischemic heart disease, heart failure and thrombosis, asthma, chronic obstructive pulmonary disease, pulmonary hypertension, ARDS ( Adult respiratory distress syndrome), liver disorders, liver cirrhosis, gastrointestinal mucosal disorders, hypertrophic pyloric stenosis, digestive disorders such as pancreatitis, cerebral ischemia, cerebral infarction, cerebral circulatory failure, senile dementia, etc. Vascular disorders, renal disorders, renal and urinary diseases such as impotence, obstetrics and gynecology diseases such as preeclampsia, infectious diseases and immunological diseases, diabetes, burns, and many other diseases in which NO reduction is observed in pharmaceutical properties It is known (for example, refer to Patent Document 1).
スタチン剤は、生体においてＨＭＧ−ＣｏＡリダクターゼを特異的かつ拮抗的に阻害して血中コレステロール量を低下させる薬物であるが、上述のようにｅＮＯＳ活性向上作用も知られている。しかしながら、ガンマーオリザノール及びチアミン類については、ｅＮＯＳ活性向上作用についての報告はなく、さらに、スタチン剤と、ガンマーオリザノール及び／又はチアミン類との併用で、相乗的に血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持・向上作用が得られることは知られていない。 Statins are drugs that specifically and competitively inhibit HMG-CoA reductase in living organisms to lower blood cholesterol levels, but are also known to have an eNOS activity-enhancing effect as described above. However, for gamma-oryzanol and thiamines, there is no report on the eNOS activity-enhancing activity. Furthermore, the combined use of statins and gamma-oryzanol and / or thiamines synergistically promotes synthesis of vascular endothelial nitric oxide and It is not known that the effect of maintaining / improving vascular endothelial nitric oxide blood concentration is obtained.
また、ガンマーオリザノール及び／又はチアミン類との併用により相乗的に血中脂質が低下することも知られていない。
本発明者らは、ＨＭＧ−ＣｏＡリダクターゼ阻害剤と、ガンマーオリザノール及び／又はチアミン類との併用による薬理作用について鋭意研究を重ねた結果、当該併用により、血管内皮性酸化窒素の合成が促進されること、血管内皮性酸化窒素血中濃度が維持若しくは向上されること、及び、血中脂質が改善されることを見出し、本発明を完成させるに至った。
The present inventors have conducted intensive studies on the pharmacological effects of a combination of an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines. As a result, the combination promotes the synthesis of vascular endothelial nitric oxide. The present inventors have found that the blood concentration of vascular endothelial nitric oxide is maintained or improved, and that the blood lipid is improved, thereby completing the present invention.
本発明は、
（１）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する医薬組成物
に関する。
上記のうち、医薬組成物は、
（２）ＨＭＧ−ＣｏＡリダクターゼ阻害剤がプラバスタチン、ロバスタチン、シンバスタチン、フルバスタチン、リバスタチン、アトルバスタチン、ピタバスタチン及びロスバスタチンからなる群から選ばれる１種又は２種以上である、（１）に記載された組成物、
（３）ＨＭＧ−ＣｏＡリダクターゼ阻害剤がシンバスタチン又はアトルバスタチンからなる群から選ばれる１種又は２種以上である、（１）に記載された組成物、
（４）チアミン類がチアミン、ジセチアミン、オクトチアミン、シコチアミン、ビスイブチアミン、ビスベンチアミン、フルスルチアミン、プロスルチアミン、ベンフォチアミン及び／又はそれらの塩からなる群から選ばれる１種又は２種以上である、（１）乃至（３）から選択されるいずれか１に記載された組成物、
（５）チアミン類がベンフォチアミンである、（１）乃至（３）から選択されるいずれか１に記載された組成物、
（６）血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持若しくは向上するための、（１）乃至（５）から選択されるいずれか１に記載された組成物、
（７）血中脂質を改善するための、（１）乃至（５）から選択されるいずれか１に記載された組成物、
（８）ＨＭＧ−ＣｏＡリダクターゼ阻害剤がシンバスタチンである、（７）に記載された組成物、
（９）血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下に起因する疾病を予防若しくは治療するための、（１）乃至（５）から選択されるいずれか１に記載された組成物、
（１０）血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下を引き起こす疾病を予防若しくは治療するための、（１）乃至（５）から選択されるいずれか１に記載された組成物、
（１１）循環器疾患、脳血管障害、腎・泌尿器疾患、糖尿病、或いは、薬剤によりＮＯ産生の低下が引き起こされた状態を予防若しくは治療するための、（１）乃至（５）から選択されるいずれか１に記載された組成物、
（１２）高い血中脂質濃度に起因する疾病を予防若しくは治療するための、（１）乃至（５）から選択されるいずれか１に記載された組成物、
（１３）ＨＭＧ−ＣｏＡリダクターゼ阻害剤及びガンマーオリザノールを必須の成分として含有する、（１２）に記載された組成物、及び
（１４）高脂血症又は動脈硬化を予防若しくは治療するための、（１）乃至（５）から選択されるいずれか１に記載された組成物
である。
更に、本発明は、
（１５）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを、同時に又は時間をおいて別々に投与することにより血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持若しくは向上するための、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類との組み合わせ、
（１６）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを、同時に又は時間をおいて別々に投与することにより血中脂質を改善するための、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類との組み合わせ、
（１７）血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持若しくは向上するための、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類との併用、
（１８）血中脂質を改善するための、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類との併用
を提供する。
更に、本発明は、
（１９）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを、同時に又は時間をおいて別々に投与することによる、血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持若しくは向上する方法、及び
（２０）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを、同時に又は時間をおいて別々に投与することによる、血中脂質を改善する方法
を提供する。
The present invention
(1) A pharmaceutical composition comprising an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines.
Among the above, the pharmaceutical composition is
(2) The composition according to (1), wherein the HMG-CoA reductase inhibitor is one or more selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, and rosuvastatin. ,
(3) The composition according to (1), wherein the HMG-CoA reductase inhibitor is one or more members selected from the group consisting of simvastatin and atorvastatin,
(4) The thiamine is at least one member selected from the group consisting of thiamine, dicetiamine, octiamine, sicotiamine, bisibutiamine, bisbenthamine, fursultiamine, prosultiamine, benfotiamine and / or salts thereof. The composition according to any one of (1) to (3), which is at least one species.
(5) The composition according to any one of (1) to (3), wherein the thiamine is benfotiamine;
(6) The composition according to any one of (1) to (5), for promoting the synthesis of vascular endothelial nitric oxide and / or maintaining or improving the blood concentration of vascular endothelial nitric oxide. ,
(7) The composition according to any one of (1) to (5) for improving blood lipid,
(8) The composition according to (7), wherein the HMG-CoA reductase inhibitor is simvastatin.
(9) Any one of (1) to (5) for preventing or treating a disease caused by a decrease in vascular endothelial nitric oxide synthase activity and / or a decrease in vascular endothelium-derived blood nitric oxide concentration. The described composition,
(10) The method according to any one of (1) to (5), for preventing or treating a disease that causes a decrease in vascular endothelial nitric oxide synthase activity and / or a decrease in vascular endothelium-derived blood nitric oxide concentration. Composition,
(11) selected from (1) to (5) for preventing or treating cardiovascular disease, cerebrovascular disease, renal / urinary disease, diabetes, or a condition in which a decrease in NO production is caused by a drug. A composition according to any one of the preceding claims,
(12) The composition according to any one of (1) to (5), for preventing or treating a disease caused by a high blood lipid concentration,
(13) The composition according to (12), which contains an HMG-CoA reductase inhibitor and gamma-oryzanol as essential components, and (14) a composition for preventing or treating hyperlipidemia or arteriosclerosis. The composition according to any one of 1) to (5).
Further, the present invention provides
(15) The HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine are simultaneously or separately administered separately to promote the synthesis of vascular endothelial nitric oxide and / or to increase the blood volume of vascular endothelial nitric oxide. A combination of an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines for maintaining or improving the concentration,
(16) An HMG-CoA reductase inhibitor and gamma-oryzanol for improving blood lipids by simultaneously or separately administering the HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines separately And / or combinations with thiamines,
(17) a combination of an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine for promoting the synthesis of vascular endothelial nitric oxide and / or maintaining or improving the blood concentration of vascular endothelial nitric oxide;
(18) To provide a combination of an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine for improving blood lipids.
Further, the present invention provides
(19) Stimulation of vascular endothelial nitric oxide synthesis and / or vascular endothelial nitric oxide blood by separately or simultaneously administering an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines (20) a method for improving blood lipids by administering a HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine simultaneously or separately at an interval. I will provide a.
上記（１９）のうち、好適な方法は、
（２１）血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下に起因する疾病を予防若しくは治療するための、（１９）に記載された方法、
（２２）血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下を引き起こす疾病を予防若しくは治療するための、（１９）に記載された方法、及び
（２３）循環器疾患、脳血管障害、腎・泌尿器疾患、糖尿病、或いは、薬剤によりＮＯ産生の低下が引き起こされた状態を予防若しくは治療するための、（１９）に記載された方法
であり、上記（２０）のうち、好適な方法は、
（２４）高い血中脂質濃度に起因する疾病を予防若しくは治療するための、（２０）に記載された方法、及び
（２５）高脂血症又は動脈硬化を予防若しくは治療するための、（２０）に記載された方法
である。
更に本発明は、
（２６）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する、血管内皮性酸化窒素の合成促進及び／又は血管内皮性酸化窒素血中濃度の維持若しくは向上するための医薬組成物を製造するための、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類の使用、及び、
（２７）ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する、血中脂質を改善するための医薬組成物を製造するための、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類の使用
を提供する。
本発明の医薬組成物の成分の一つである「ＨＭＧ−ＣｏＡリダクターゼ阻害剤」とは、コレステロール生合成系の律速酵素であるＨＭＧ（３−ヒドロキシ−３−メチルグリタリル）−ＣｏＡ還元酵素を特異的かつ拮抗的に阻害する薬剤である。血中コレステロールを低下させることから、本来、高脂血症の治療剤として使用される。そのようなＨＭＧ−ＣｏＡ還元酵素阻害剤としては、微生物由来の天然物質、それから誘導される半合成物質、及び全合成化合物のすべてが含まれ、例えば、特開昭５７−２２４０号公報（ＵＳＰ４３４６２２７）に記載された、（＋）−（３Ｒ，５Ｒ）−３，５−ジヒドロキシ−７−［（１Ｓ，２Ｓ，６Ｓ，８Ｓ，８ａＲ）−６−ヒドロキシ−２−メチル−８−［（Ｓ）−２−メチルブチリルオキシ］−１，２，６，７，８，８ａ−ヘキサヒドロ−１−ナフチル］ヘプタン酸（以下、プラバスタチンと省略する。）、特開昭５７−１６３３７４号公報（ＵＳＰ４２３１９３８）に記載された、（＋）−（１Ｓ，３Ｒ，７Ｓ，８Ｓ，８ａＲ）−１，２，３，７，８，８ａ−ヘキサヒドロ−３，７−ジメチル−８−［２−［（２Ｒ，４Ｒ）−テトラヒドロ−４−ヒドロキシ−６−オキソ−２Ｈ−ピラン−２−イル］エチル］−１−ナフチル （Ｓ）−２−メチルブチレート（以下、ロバスタチンと省略する。）、特開昭５６−１２２３７５号公報（ＵＳＰ４４４４７８４）に記載された、（＋）−（１Ｓ，３Ｒ，７Ｓ，８Ｓ，８ａＲ）−１，２，３，７，８，８ａ−ヘキサヒドロ−３，７−ジメチル−８−［２−［（２Ｒ，４Ｒ）−テトラヒドロ−４−ヒドロキシ−６−オキソ−２Ｈ−ピラン−２−イル］エチル］−１−ナフチル ２，２−ジメチルブチレート（以下、シンバスタチンと省略する。）、特表昭６０−５０００１５号公報（ＵＳＰ４７３９０７３）に記載された、（±）（３Ｒ*，５Ｓ*，６Ｅ）−７−［３−（４−フルオロフェニル）−１−（１−メチルエチル）−１Ｈ−インド−ル−２−イル］−３，５−ジヒドロキシ−６−ヘプテン酸（以下、フルバスタチンと省略する。）、特開平１−２１６９７４号公報（ＵＳＰ５００６５３０）に記載された、（３Ｒ，５Ｓ，６Ｅ）−７−［４−（４−フルオロフェニル）−２，６−ジ−（１−メチルエチル）−５−メトキシメチルピリジン−３−イル］−３，５−ジヒドロキシ−６−ヘプテン酸（以下、リバスタチンと省略する。）、特開平３−５８９６７号公報（ＵＳＰ５２７３９９５）に記載された、（３Ｒ，５Ｓ）−７−［２−（４−フルオロフェニル）−５−（１−メチルエチル）−３−フェニル−４−フェニルアミノカルボニル−１Ｈ−ピロ−ル−１−イル］−３，５−ジヒドロキシヘプタン酸（以下、アトルバスタチンと省略する。）、特開平１−２７９８６６号公報（ＵＳＰ５８５４２５９及びＵＳＰ５８５６３３６）に記載された、（Ｅ）−３，５−ジヒドロキシ−７−［４’−（４’’−フルオロフェニル）−２’−シクロプロピル−キノリン−３’−イル］−６−ヘプテン酸（以下、ピタバスタチンと省略する。）又は特開平５−１７８８４１号公報（ＵＳＰ５２６０４４０）に記載された、（＋）−（３Ｒ，５Ｓ）−７−［４−（４−フルオロフェニル）−６−イソプロピル−２−（Ｎ−メチル−Ｎ−メタンスルフォニルアミノ）ピリミジン−５−イル］−３，５−ジヒドロキシ−６（Ｅ）−ヘプテン酸（以下、ロスバスタチンと省略する。）のようなスタチン化合物を挙げることができる。また、本発明の医薬組成物の成分であるＨＭＧ−ＣｏＡリダクターゼ阻害剤は、上記ＨＭＧ−ＣｏＡリダクターゼ阻害剤が記載されている公報に開示されている他のＨＭＧ−ＣｏＡリダクターゼ阻害剤も含有する。
Among the above (19), a preferred method is
(21) The method described in (19) for preventing or treating a disease caused by a decrease in vascular endothelial nitric oxide synthase activity and / or a decrease in vascular endothelium-derived blood nitric oxide concentration,
(22) The method described in (19) for preventing or treating a disease which causes a decrease in vascular endothelial nitric oxide synthase activity and / or a decrease in vascular endothelium-derived blood nitric oxide concentration, and (23) a cardiovascular disease The method described in (19) for preventing or treating a cerebrovascular disorder, a renal / urinary disease, diabetes, or a condition in which a decrease in NO production is caused by a drug; The preferred method is
(24) The method according to (20) for preventing or treating a disease caused by a high blood lipid concentration, and (25) the method for preventing or treating hyperlipidemia or arteriosclerosis. ).
Further, the present invention
(26) A pharmaceutical composition containing an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine for promoting the synthesis of vascular endothelial nitric oxide and / or maintaining or improving the blood concentration of vascular endothelial nitric oxide in blood. Use of an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines to produce a product, and
(27) An HMG-CoA reductase inhibitor, gamma-oryzanol and / or thiamine for producing a pharmaceutical composition for improving blood lipids, comprising a HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamines. Or the use of thiamines.
The “HMG-CoA reductase inhibitor”, which is one of the components of the pharmaceutical composition of the present invention, specifically refers to HMG (3-hydroxy-3-methylglutaryl) -CoA reductase, which is a rate-limiting enzyme in the cholesterol biosynthesis system. And it is a drug that inhibits antagonistically. Since it lowers blood cholesterol, it is originally used as a therapeutic agent for hyperlipidemia. Such HMG-CoA reductase inhibitors include all natural substances derived from microorganisms, semi-synthetic substances derived therefrom, and all synthetic compounds. For example, JP-A-57-2240 (US Pat. No. 4,346,227) (+)-(3R, 5R) -3,5-dihydroxy-7-[(1S, 2S, 6S, 8S, 8aR) -6-hydroxy-2-methyl-8-[(S) -2-methylbutyryloxy] -1,2,6,7,8,8a-hexahydro-1-naphthyl] heptanoic acid (hereinafter abbreviated as pravastatin), JP-A-57-163374 (US Pat. No. 4,231,938). (+)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- [2-[(2R, 4R) -te Lahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl (S) -2-methylbutyrate (hereinafter abbreviated as lovastatin), JP-A-56-122375. (+)-(1S, 3R, 7S, 8S, 8aR) -1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- [2-] described in Japanese Patent Publication (USP 4,444,784). [(2R, 4R) -tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl] ethyl] -1-naphthyl 2,2-dimethylbutyrate (hereinafter abbreviated as simvastatin), special table described in Akira 60-500015 Patent Publication (USP4739073), (±) ( 3R *, 5S *, 6E) -7- [3- (4- fluorophenyl) -1- (1-methylethyl) -1H Indole-2-yl] -3,5-dihydroxy-6-heptenoic acid (hereinafter abbreviated as fluvastatin), described in JP-A-1-216974 (USP5006530), (3R, 5S, 6E) -7- [4- (4-Fluorophenyl) -2,6-di- (1-methylethyl) -5-methoxymethylpyridin-3-yl] -3,5-dihydroxy-6-heptenoic acid ( Hereinafter, it is abbreviated as rivastatin.) And (3R, 5S) -7- [2- (4-fluorophenyl) -5- (1-methylethyl) described in JP-A-3-58967 (US Pat. No. 5,273,995). -3-phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl] -3,5-dihydroxyheptanoic acid (hereinafter abbreviated as atorvastatin), JP-A 1-2 No. 9866 (US Pat. No. 5,854,259 and US Pat. No. 5,856,336), and (E) -3,5-dihydroxy-7- [4 ′-(4 ″ -fluorophenyl) -2′-cyclopropyl-quinolin-3′-yl. ] -6-heptenoic acid (hereinafter abbreviated as pitavastatin). ) Or (+)-(3R, 5S) -7- [4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-) described in JP-A-5-178841 (US Pat. No. 5,260,440). Statin compounds such as [N-methanesulfonylamino) pyrimidin-5-yl] -3,5-dihydroxy-6 (E) -heptenoic acid (hereinafter abbreviated as rosuvastatin) can be mentioned. Further, the HMG-CoA reductase inhibitor, which is a component of the pharmaceutical composition of the present invention, also contains other HMG-CoA reductase inhibitors disclosed in the publication describing the above-mentioned HMG-CoA reductase inhibitor.
以下に、ＨＭＧ−ＣｏＡリダクターゼ阻害剤の代表的なものの平面構造式を示す。 平面 Below, the planar structural formula of a typical HMG-CoA reductase inhibitor is shown.
「ガンマーオリザノール」は、主に米糠油や米胚芽油より抽出される、ステロール若しくはトリテルペンアルコールと、フェルラ酸がエステル結合した化合物、又はそれらの混合物を意味する。
"Gamma-oryzanol" means a compound in which sterol or triterpene alcohol and ferulic acid are ester-linked, mainly extracted from rice bran oil or rice germ oil, or a mixture thereof.
「チアミン類」としては、チアミン、ジセチアミン、オクトチアミン、シコチアミン、ビスイブチアミン、ビスベンチアミン、フルスルチアミン、プロスルチアミンもしくはベンフォチアミン又はその塩を挙げることが出来、好適にはベンフォチアミンである。 Examples of the "thiamines" include thiamine, dicetiamine, octiamine, sicotiamine, bisibutiamine, bisbenthamine, fursultiamine, prosultiamine or benfotiamine or salts thereof, and preferably benfotiamine It is.
本発明において、含有される上記各成分は、薬理学上許容される塩として含有されていても良く、そのような塩としては、
成分が塩基性官能基を持つ場合には、例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ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、リン酸塩等の無機酸塩；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低級有機スルホン酸塩；ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のようなアリールスルホン酸塩；オルニチン酸塩、グルタミン酸塩のようなアミノ酸塩；及びフマル酸、コハク酸、クエン酸、酒石酸、シュウ酸、マレイン酸のようなカルボン酸塩を挙げることができ、
成分が酸性官能基をもつ場合には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩、亜鉛塩、銅塩、ニッケル塩、コバルト塩等の金属塩；アンモニウム塩のような無機塩、ｔ−オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ−メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ−ベンジル−フェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩を挙げる事ができ、例えばプラバスタチンの場合、好適にはプラバスタチンナトリウムであり、例えばアトルバスタチンの場合、好適にはアトルバスタチンカルシウム水和物である。
In the present invention, each of the above-mentioned components may be contained as a pharmacologically acceptable salt.
When the component has a basic functional group, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfuric acid Inorganic salts such as salts and phosphates; lower organic sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; such as benzenesulfonate and p-toluenesulfonate Aryl sulfonates; amino acid salts such as ornithate and glutamate; and carboxylate salts such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, maleic acid,
When the component has an acidic functional group, alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, iron salt, zinc salt, copper Metal salts such as salts, nickel salts, cobalt salts and the like; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methyl glue. Kamin salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt , Tris (hydroxy Examples thereof include amine salts such as organic salts such as methyl) aminomethane salt. For example, in the case of pravastatin, pravastatin sodium is preferable, and in the case of atorvastatin, for example, atorvastatin calcium hydrate is preferable.
本発明において、含有される各成分のうち水和物又は溶媒和物を形成し得るものは、水和物又は溶媒和物として医薬組成物に含有されていてもよい。 In the present invention, among the components contained in the present invention, those which can form a hydrate or a solvate may be contained in the pharmaceutical composition as a hydrate or a solvate.
本発明における、「各種疾病」とは、血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下に起因する疾病、又は、血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下を引き起こす疾病を意味し、例えば、高血圧、高脂血症、動脈硬化、虚血性心疾患、心不全、血栓症、肺高血圧、再狭窄症又は末梢循環障害等の循環器疾患、肺高血圧、脳虚血、脳梗塞、脳循環不全又は老年性痴呆等の脳血管障害、腎障害又はインポテンツ等の腎・泌尿器疾患、糖尿病、或いは、薬剤によりＮＯ産生の低下が引き起こされた状態を含有する。 In the present invention, “various diseases” refers to diseases caused by a decrease in vascular endothelial nitric oxide synthase activity and / or a decrease in vascular endothelium-derived blood nitric oxide concentration, or a decrease in vascular endothelial nitric oxide synthase activity and / or It means a disease that causes a decrease in endothelium-derived blood nitric oxide concentration, such as circulation such as hypertension, hyperlipidemia, arteriosclerosis, ischemic heart disease, heart failure, thrombosis, pulmonary hypertension, restenosis or peripheral circulatory disorder. Cerebrovascular disorders such as renal diseases, pulmonary hypertension, cerebral ischemia, cerebral infarction, cerebral circulatory insufficiency or senile dementia, renal disorders or renal or urinary disorders such as impotence, diabetes, or a decrease in NO production due to drugs Contains the state.
なお、上記「各種疾病」の初期段階においては際立った自覚症状はなく、自己判断は容易ではないが、本発明における「各種疾病」に関わる自覚症状としては、例えば、頭痛、めまい、しびれ又はしびれ感、四肢の冷感、肩こり、皮膚・筋肉の萎縮或いは陰縮等が挙げられる。従って、これら自覚症状に対して本発明の医薬組成物を使用することで、上記疾患を初期段階で治療することができる。 In the initial stage of the above-mentioned "various diseases", there are no noticeable subjective symptoms, and self-determination is not easy.However, the subjective symptoms related to "various diseases" in the present invention include, for example, headache, dizziness, numbness or numbness. Sensation, cold limbs, stiff shoulders, atrophy or involution of skin and muscles, and the like. Therefore, the above-mentioned diseases can be treated at an early stage by using the pharmaceutical composition of the present invention for these subjective symptoms.
本発明において、「血中脂質を改善する」とは、血中脂質を臨床上意義のある程度に低下させることを意味し、即ち、血中トリグリセライドを低下させること、血中ＬＤＬを低下させること又は血中総コレステロールを低下させることを意味する。
本発明の組成物に含まれるＨＭＧ−ＣｏＡリダクターゼ阻害剤、例えば、プラバスタチン、ロバスタチン、シンバスタチン、フルバスタチン、リバスタチン、アトルバスタチン、ピタバスタチン又はロスバスタチンは、特開昭５７−２２４０号公報（ＵＳＰ４３４６２２７）、特開昭５７−１６３３７４号公報（ＵＳＰ４２３１９３８）、特開昭５６−１２２３７５号公報（ＵＳＰ４４４４７８４）、特表昭６０−５０００１５号公報（ＵＳＰ４７３９０７３）、特開平１−２１６９７４号公報（ＵＳＰ５００６５３０）、特開平３−５８９６７号公報（ＵＳＰ５２７３９９５）、特開平１−２７９８６６号公報（ＵＳＰ５８５４２５９及びＵＳＰ５８５６３３６）又は特開平５−１７８８４１号公報（ＵＳＰ５２６０４４０）に記載の方法に従い、容易に製造することができる。
In the present invention, "improving blood lipids" means lowering blood lipids to a clinically significant degree, that is, lowering blood triglycerides, lowering blood LDL, or It means lowering total blood cholesterol.
The HMG-CoA reductase inhibitors contained in the composition of the present invention, for example, pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin or rosuvastatin are disclosed in JP-A-57-2240 (USP4346227), No. 57-163374 (US Pat. No. 4,231,938), JP-A-56-122375 (US Pat. No. 4,444,784), JP-T-60-500015 (US Pat. No. 4,73,073), JP-A-1-216974 (US Pat. No. 5,065,530), and JP-A-3-58967. JP-A-52739395, JP-A-1-279866 (US Pat. No. 5,854,259 and US Pat. No. 5,856,336) or JP-A-5-178841 (US Pat. No. 5,260,440). Therefore, it is possible to easily manufacture.
また、本発明のガンマーオリザノールは、市販されているもの（例えば、理研ビタミン(株)製のもの）を入手するか、又は、公知の方法で製造したものを使用することができる。 ガ ン マ As the gamma-oryzanol of the present invention, a commercially available product (for example, manufactured by Riken Vitamin Co., Ltd.) can be obtained, or a product manufactured by a known method can be used.
さらに、チアミン類は、例えば第１４改正日本薬局方及び日本薬局方外医薬品規格等に収載されており容易に入手できる。
本発明の「ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する医薬組成物」は、ＨＭＧ−ＣｏＡリダクターゼ阻害剤及びガンマーオリザノール若しくはチアミン類を必須の成分として含有し、所望により、製剤化のための添加物を含有していてもよく、更に、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール若しくはチアミン類との併用作用に悪影響を与えない範囲で他の成分を含有していてもよい。好適には、ＨＭＧ−ＣｏＡリダクターゼ阻害剤及びガンマーオリザノール及び／又はチアミン類のみを有効成分として含有し、更に製剤化のための添加物を含有する医薬組成物である。
Further, thiamines are listed in, for example, the 14th Revised Japanese Pharmacopoeia and the Japanese Pharmacopoeia Non-Pharmaceutical Standards, and are readily available.
The “pharmaceutical composition containing an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine” of the present invention contains an HMG-CoA reductase inhibitor and gamma-oryzanol or thiamine as essential components, and if desired. May contain additives for formulation, and may further contain other components in a range that does not adversely affect the combined action of the HMG-CoA reductase inhibitor and gamma-oryzanol or thiamines. Good. Preferably, it is a pharmaceutical composition containing only the HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine as active ingredients, and further containing additives for formulation.
本発明の医薬組成物の具体的な剤形としては、例えば、錠剤、細粒剤（散剤を含む）、カプセル、液剤（シロップ剤を含む）等をあげることができ、各剤形に適した添加剤や基材を適宜使用し、日本薬局方等に記載された通常の方法に従い、製造することができる。 Specific dosage forms of the pharmaceutical composition of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups), and the like. It can be produced according to a usual method described in Japanese Pharmacopoeia and the like, using additives and base materials as appropriate.
上記各剤形において、その剤形に応じ、通常使用される各種添加剤を使用することもできる。 に お い て In each of the above dosage forms, various commonly used additives can be used according to the dosage form.
例えば、錠剤の場合、乳糖、結晶セルロース等を賦形剤として、メタケイ酸アルミン酸マグネシウム又は酸化マグネシウム等を安定化剤として、ヒドロキシプロピルセルロース等をコーテイング剤として、ステアリン酸マグネシウム等を滑沢剤として使用することができ、
細粒剤及びカプセル剤の場合、乳糖又は精製白糖等を賦形剤として、メタケイ酸アルミン酸マグネシウム又は酸化マグネシウム等を安定化剤として、トウモロコシデンプン等を吸着剤として、ヒドロキシプロピルセルロース等を結合剤として、使用することができる。
For example, in the case of tablets, lactose, crystalline cellulose or the like as an excipient, magnesium metasilicate aluminate or magnesium oxide as a stabilizer, hydroxypropyl cellulose or the like as a coating agent, magnesium stearate or the like as a lubricant Can be used,
In the case of fine granules and capsules, lactose or purified sucrose is used as an excipient, magnesium aluminate metasilicate or magnesium oxide is used as a stabilizer, corn starch is used as an adsorbent, and hydroxypropyl cellulose is used as a binder. As can be used.
上記各剤形において、必要に応じ、クロスポビドン等の崩壊剤；ポリソルベート等の界面活性剤；ケイ酸カルシウム等の吸着剤；三二酸化鉄、カラメル等の着色剤；安息香酸ナトリウム等の安定剤；ｐＨ調節剤；香料；等を添加することもできる。 In each of the above dosage forms, if necessary, disintegrators such as crospovidone; surfactants such as polysorbate; adsorbents such as calcium silicate; coloring agents such as iron sesquioxide and caramel; stabilizers such as sodium benzoate; pH adjusters; fragrances; and the like can also be added.
本発明において、「併用」とは、二つ以上の有効成分を、同時に、又は時間をおいて別々に人体に投与する方法である。 に お い て In the present invention, the “combination” is a method in which two or more active ingredients are administered to a human body simultaneously or separately at intervals.
本発明における医薬組成物を投与する際は、組成物のそれぞれの成分を同時に、又は、時間をおいて別々に投与することが出来る。 投 与 When administering the pharmaceutical composition of the present invention, each component of the composition can be administered simultaneously or separately at a later time.
上記の「同時に」投与するとは、全く同時に投与することの他、薬理学上許される程度に相前後した時間に投与することも含むものである。その投与形態は、ほぼ同じ時間に投与できる投与形態であれば特に限定はないが、単一の組成物であることが好ましい。 投 与 The term “simultaneous administration” includes administration at exactly the same time as well as administration at approximately the same time as pharmacologically permitted. The administration form is not particularly limited as long as it can be administered at substantially the same time, but is preferably a single composition.
また上記の「時間をおいて別々に」投与するとは、異なった時間に別々に投与できる投与形態であれば特に限定はないが、例えば、１の成分を投与し、次いで、決められた時間後に、他の成分を投与する方法が挙げられる。 In addition, the above-mentioned "separately after administration" is not particularly limited as long as it can be administered separately at different times. For example, one component is administered, and then after a predetermined time. And a method of administering other components.
また、投与する組成物の成分が、合わせて３種以上ある場合には、「同時に、又は、時間を置いて別々に」投与するとは、それらの全てを同時に投与する方法、各々時間を置いて別々に投与する方法、２種以上を同時に投与し時間を置いて残りの薬剤を投与する方法、又は、２種以上を時間を置いて投与して、残りの薬剤を同時に投与する方法等を含む。
In addition, when there are three or more components of the composition to be administered, “administering simultaneously or separately at an interval” means that all of them are administered simultaneously, Includes methods of separate administration, methods of simultaneously administering two or more species and administering the remaining drugs at a time, or methods of administering two or more species at a time and administering the remaining drugs simultaneously .
本発明の、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する医薬組成物は、血管内皮性酸化窒素の合成を促進する作用、血管内皮性酸化窒素血中濃度を維持若しくは向上する作用、及び血中脂質が改善を改善する作用を有するので、血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下に起因する疾病、血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下を引き起こす疾病、或いは、高い血中脂質濃度に起因する疾病の予防若しくは治療のための医薬として有用であり、例えば、高血圧、高脂血症、動脈硬化、虚血性心疾患、心不全、血栓症、肺高血圧、再狭窄症又は末梢循環障害等の循環器疾患、肺高血圧、脳虚血、脳梗塞、脳循環不全又は老年性痴呆等の脳血管障害、腎障害又はインポテンツ等の腎・泌尿器疾患、糖尿病、或いは、薬剤によりＮＯ産生の低下が引き起こされた状態の予防若しくは治療のための医薬として有用である。
本発明において、ＨＭＧ−ＣｏＡリダクターゼ阻害剤の投与量は、ＨＭＧ−ＣｏＡリダクターゼ阻害剤の種類、剤形等により異なるが、通常、1日あたり１mg乃至２００mgであり、好適には1日あたり５mg乃至１６０mgである。
The pharmaceutical composition containing an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine according to the present invention has an effect of promoting the synthesis of vascular endothelial nitric oxide, maintaining the blood concentration of vascular endothelial nitric oxide or Diseases caused by reduced vascular endothelial nitric oxide synthase activity and / or reduced vascular endothelial-derived blood nitric oxide concentration, and vascular endothelial nitric oxide synthase activity It is useful as a medicament for the prevention or treatment of a disease that causes a decrease in blood nitric oxide concentration derived from vascular endothelium and / or a disease caused by a high blood lipid concentration, such as hypertension, hyperlipidemia, Cardiovascular disease such as arteriosclerosis, ischemic heart disease, heart failure, thrombosis, pulmonary hypertension, restenosis or peripheral circulatory disorder, pulmonary hypertension, cerebral ischemia, cerebral infarction, cerebral circulation Cerebrovascular disorders such as all or senile dementia, renal-urinary diseases such as renal failure or impotence, diabetes, or is useful as a medicament for the prevention or treatment of a condition decrease in NO production caused by the drug.
In the present invention, the dosage of the HMG-CoA reductase inhibitor varies depending on the type of the HMG-CoA reductase inhibitor, the dosage form, and the like, but is usually 1 mg to 200 mg per day, preferably 5 mg to 200 mg per day. 160 mg.
本発明において、ガンマーオリザノールの投与量は、通常、1日あたり１０mg乃至１０００mgであり、好適には1日あたり１００mg乃至６００mgである。 に お い て In the present invention, the dose of gamma-oryzanol is usually 10 mg to 1000 mg per day, preferably 100 mg to 600 mg per day.
本発明において、チアミン類の投与量は、チアミン類の種類、剤形等により異なるが、通常、1日０．５mg乃至５００mgであり、好適には1日あたり５mg乃至２００mgである。
本発明の医薬組成物が固形製剤の場合において含有されるＨＭＧ−ＣｏＡリダクターゼ阻害剤の重量％は、通常、０．００５乃至３％であり、好適には、０．０３乃至２％であり、例えば、シンバスタチンの場合は通常、０．００５乃至３％であり、好適には、０．０３乃至２％であり、アトルバスタチンの場合は通常、０．０１乃至５％であり、好適には、０．０５乃至３％であり、
ガンマーオリザノールを含有する場合は通常、０．５乃至９０％であり、好適には、３乃至６０％であり、
チアミン類を含有する場合は通常、０．２乃至４０％であり、好適には、１乃至３０％である。
In the present invention, the dose of the thiamine varies depending on the type, dosage form and the like of the thiamine, but is usually 0.5 mg to 500 mg per day, preferably 5 mg to 200 mg per day.
When the pharmaceutical composition of the present invention is a solid preparation, the weight% of the HMG-CoA reductase inhibitor is usually 0.005 to 3%, preferably 0.03 to 2%, For example, in the case of simvastatin, it is usually 0.005 to 3%, preferably 0.03 to 2%, and in the case of atorvastatin, it is usually 0.01 to 5%, preferably 0 to 5%. 0.05 to 3%,
When containing gamma-oryzanol, it is usually 0.5 to 90%, preferably 3 to 60%,
When thiamines are contained, the content is usually 0.2 to 40%, preferably 1 to 30%.
本発明の医薬組成物が液剤の場合において、ＨＭＧ−ＣｏＡリダクターゼ阻害剤の含有量は通常、０．００５乃至５mg/mLであり、好適には、０．０３乃至３mg/mLであり、例えば、シンバスタチンの含有量は通常、０．００５乃至５mg/mLであり、好適には、０．０３乃至３mg/mLであり、アトルバスタチンの含有量は通常、０．０１乃至１０mg/mLであり、好適には、０．０５乃至５mg/mLであり、
ガンマーオリザノールを含有する場合、その含有量は通常、２乃至２００mg/mLであり、好適には、１０乃至１００mg/mLであり、
チアミン類を含有する場合、その含有量は通常、１乃至１００mg/mLであり、好適には、５乃至５０mg/mLである。
When the pharmaceutical composition of the present invention is a liquid preparation, the content of the HMG-CoA reductase inhibitor is usually 0.005 to 5 mg / mL, preferably 0.03 to 3 mg / mL, for example, The content of simvastatin is usually 0.005 to 5 mg / mL, preferably 0.03 to 3 mg / mL, and the content of atorvastatin is usually 0.01 to 10 mg / mL. Is 0.05 to 5 mg / mL,
When gamma-oryzanol is contained, its content is usually 2 to 200 mg / mL, preferably 10 to 100 mg / mL,
When a thiamine is contained, its content is usually 1 to 100 mg / mL, preferably 5 to 50 mg / mL.
（実施例）
以下に、実施例等を示し、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。
実施例１ 錠剤
（１）成分
(Example)
Hereinafter, the present invention will be described in more detail by way of Examples and the like, but the scope of the present invention is not limited thereto.
Example 1 Tablet (1) ingredients
上記成分及び分量をとり、日局製剤総則「錠剤」の項に準じて錠剤を製する。
実施例２ 細粒剤
（１）成分
Example 2 Fine granule (1) component
上記成分及び分量をとり、日局製剤総則「顆粒剤」の項に準じて細粒剤を製する。
実施例３ カプセル剤
（１）成分
Example 3 Capsule (1) ingredient
上記成分及び分量をとり、日局製剤総則「顆粒剤」の項に準じて細粒剤を製した後、カプセルに充填して硬カプセル剤を製する。
実施例４ シロップ剤
（１）成分
Example 4 Syrup (1) ingredient
上記成分及び分量をとり、日局製剤総則「シロップ剤」の項に準じてシロップ剤を製した後、褐色ガラス瓶に充填してシロップ剤を製する。
（試験例）
試験例１ 血中窒素酸化物量及び血中脂質量の評価試験
（１）被験物質
シンバスタチン及びアトルバスタチンカルシウムは(株)ケムテックラボ製造のものを、ガンマーオリザノールは理研ビタミン(株)製の、またベンフォチアミンは三共(株)製のものを使用した。
（２）動物
試験動物としては、Covance Research Products Inc.からビーグル犬雄を５箇月齢で購入し、約１箇月間の検疫および馴化飼育後に使用した。
（３）投与剤形、製剤の調整方法および製剤の保存方法
試験動物毎の体重をもとに算出した必要量の被験物質を、TORPAC社のゼラチンカプセル（１／２オンス）に充填した。充填後、カプセルは動物毎に区分されたケースに入れ、投与時まで冷蔵保存した。
（４）投与経路および投与期間
被験物質を充填したカプセルは、１日１回９：００〜１２：３０の間に、試験動物に強制経口投与した。なお、試験動物は投与前２乃至３時間絶食させた。
(Test example)
Test Example 1 Evaluation test of blood nitrogen oxide content and blood lipid content (1) Test substances Simvastatin and atorvastatin calcium were manufactured by Chemtech Lab Co., Ltd., and gamma-oryzanol was manufactured by Riken Vitamin Co., Ltd. and benfotiamine Used was manufactured by Sankyo Co., Ltd.
(2) Animals As test animals, beagle dogs and males were purchased from Covance Research Products Inc. at the age of 5 months and used after quarantine and acclimatization for about 1 month.
(3) Preparation of dosage form, preparation method and storage method of preparation A required amount of the test substance calculated based on the body weight of each test animal was filled in a TORPAC gelatin capsule (1/2 oz). After filling, the capsules were placed in cases classified for each animal and kept refrigerated until administration.
(4) Administration route and administration period The capsules filled with the test substance were orally administered to the test animals once a day between 9:00 and 12:30. The test animals were fasted for 2 to 3 hours before administration.
投与期間は１１日間とした。
（５）被験試料の調製
カプセル投与前−１４および−７日（投与開始前第２週および第１週）、投与後４日、８日、１２日に、橈側皮静脈から約１０ｍL採血した。なお、採血前約１８時間、試験動物は絶食させた。
The administration period was 11 days.
(5) Preparation of Test Sample Approximately 10 mL of blood was collected from the cephalic vein on days -14 and -7 before capsule administration (second and first weeks before administration) and on days 4, 8, and 12 after administration. The test animals were fasted for about 18 hours before blood collection.
得られた血液を試験管にとり、室温で３０分から１時間放置後、遠心分離（約１６００×ｇ、１０分間）して得られた血清を用いた。
（６）試験方法
一酸化窒素合成酵素（ＮＯＳ）により生成されたＮＯは、速やかに硝酸イオン（ＮＯ3 -）と亜硝酸イオン（ＮＯ2 -）に変換される。血中窒素酸化物総濃度（ＮＯｘ）はＨＰＬＣ法を用いて求めたＮＯ3 -とＮＯ2 -の和として算出した。
The obtained blood was placed in a test tube, left at room temperature for 30 minutes to 1 hour, and centrifuged (about 1600 × g, 10 minutes) to use the serum obtained.
(6) Test Method NO generated by nitric oxide synthase (NOS) is promptly converted to nitrate ions (NO 3 − ) and nitrite ions (NO 2 − ). The blood nitrogen oxide total concentration (NOx) was calculated as the sum of NO 3 − and NO 2 − obtained using the HPLC method.
また、総コレステロールは酵素的測定法、HDLはホモジニアス法、LDLは化学修飾酵素法、ALPはBessey-Lowry法を用いた。なお、測定には臨床化学自動分析装置（TBA-120FR、東芝製）を使用した。
（試験結果）
シンバスタチン又はアトルバスタチンカルシウムと、ガンマーオリザノール又はベンフォチアミンそれぞれの各投与量における単剤および配合剤における血中窒素酸化物総濃度（ＮＯｘ）を、投与２週間前および１週間前の各種血液中のＮＯｘの平均を１００として換算して求めた。
Total cholesterol was measured by an enzymatic assay, HDL by a homogeneous method, LDL by a chemically modified enzyme method, and ALP by a Bessey-Lowry method. An automatic clinical chemistry analyzer (TBA-120FR, manufactured by Toshiba) was used for the measurement.
(Test results)
The simvastatin or atorvastatin calcium and the total blood nitrogen oxide concentration (NOx) of each of the single agent and the combination at each dose of gamma-oryzanol or benfotiamine were measured for NOx in various blood two weeks before and one week before administration. Was calculated by assuming the average as 100.
また、シンバスタチン及びガンマーオリザノールそれぞれの各投与量における単剤および配合剤における各種血中脂質量を、投与２週間前および１週間前の各種血中脂質量の平均を１００として換算して求めた。 In addition, the amount of various blood lipids in the single agent and the combination at each dose of simvastatin and gamma-oryzanol was determined by converting the average of the amount of various blood lipids two weeks before and one week before administration as 100.
得られた結果を表５から表９に示す。なお、各値とも１郡５匹の平均値である。
Tables 5 to 9 show the obtained results. In addition, each value is an average value of 5 animals per county.
また、表７乃至表９から明らかなように、シンバスタチンとガンマーオリザノールとを組み合わせることにより顕著な血中脂質の低下効果が発現した。
Further, as is clear from Tables 7 to 9, the combination of simvastatin and gamma-oryzanol exhibited a remarkable blood lipid lowering effect.
本発明の、ＨＭＧ−ＣｏＡリダクターゼ阻害剤とガンマーオリザノール及び／又はチアミン類とを含有する医薬組成物は、血管内皮性酸化窒素の合成を促進する作用、血管内皮性酸化窒素血中濃度を維持若しくは向上する作用、及び血中脂質が改善を改善する作用を有するので、血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下に起因する疾病、血管内皮酸化窒素合成酵素活性低下及び／又は血管内皮由来血中酸化窒素濃度低下を引き起こす疾病、或いは、高い血中脂質濃度に起因する疾病の予防若しくは治療のための医薬として有用であり、例えば、高血圧、高脂血症、動脈硬化、虚血性心疾患、心不全、血栓症、肺高血圧、再狭窄症又は末梢循環障害等の循環器疾患、肺高血圧、脳虚血、脳梗塞、脳循環不全又は老年性痴呆等の脳血管障害、腎障害又はインポテンツ等の腎・泌尿器疾患、糖尿病、或いは、薬剤によりＮＯ産生の低下が引き起こされた状態の予防若しくは治療のための医薬として有用である。 The pharmaceutical composition containing an HMG-CoA reductase inhibitor and gamma-oryzanol and / or thiamine according to the present invention has an effect of promoting the synthesis of vascular endothelial nitric oxide, maintaining the blood concentration of vascular endothelial nitric oxide or Diseases caused by reduced vascular endothelial nitric oxide synthase activity and / or reduced vascular endothelial-derived blood nitric oxide concentration, and vascular endothelial nitric oxide synthase activity because they have an action of improving blood lipids and an action of improving blood lipids. It is useful as a medicament for the prevention or treatment of a disease that causes a decrease in the blood nitric oxide concentration derived from vascular endothelium and / or a disease caused by a high blood lipid concentration, such as hypertension, hyperlipidemia, Cardiovascular disease such as arteriosclerosis, ischemic heart disease, heart failure, thrombosis, pulmonary hypertension, restenosis or peripheral circulatory disorder, pulmonary hypertension, cerebral ischemia, cerebral infarction, cerebral circulation Failure or cerebrovascular disorders such as senile dementia, renal-urinary diseases such as renal failure or impotence, diabetes, or is useful as a medicament for the prevention or treatment of a condition decrease in NO production caused by the drug.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005026117A1 (en) * | 2003-09-11 | 2005-03-24 | Astellas Pharma Inc. | Preventive for cerebral stroke recurrence |
| JP2010513430A (en) * | 2006-12-18 | 2010-04-30 | カルドズ・アーベー | New combinations for use in the treatment of inflammatory disorders |
| JP5336847B2 (en) * | 2006-06-29 | 2013-11-06 | 第一三共株式会社 | Treatment of chronic obstructive pulmonary disease with statins |
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| JP2000508659A (en) * | 1996-04-17 | 2000-07-11 | メルク エンド カンパニー インコーポレーテッド | Combination therapy to reduce cardiovascular disease-related risks |
| JP2001511444A (en) * | 1997-07-31 | 2001-08-14 | コス ファーマスーティカルズ、インコーポレイテッド | Combination of an HMG-CoA reductase inhibitor and a nicotinic acid compound and method for treating hyperlipidemia once a day at night |
| JP2001224309A (en) * | 2000-02-10 | 2001-08-21 | Nisshin Oil Mills Ltd:The | Edible oil-and-fat having function to ameliorate lipid in blood |
| WO2002034261A1 (en) * | 2000-10-23 | 2002-05-02 | Sankyo Company, Limited | Compositions for improving lipids in blood |
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| JPS54135740A (en) * | 1978-04-13 | 1979-10-22 | Otsuka Nobuhiro | Method of dissolving oryznol to greases or their products |
| JP2000508659A (en) * | 1996-04-17 | 2000-07-11 | メルク エンド カンパニー インコーポレーテッド | Combination therapy to reduce cardiovascular disease-related risks |
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| JP2001224309A (en) * | 2000-02-10 | 2001-08-21 | Nisshin Oil Mills Ltd:The | Edible oil-and-fat having function to ameliorate lipid in blood |
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| WO2005026117A1 (en) * | 2003-09-11 | 2005-03-24 | Astellas Pharma Inc. | Preventive for cerebral stroke recurrence |
| JP5336847B2 (en) * | 2006-06-29 | 2013-11-06 | 第一三共株式会社 | Treatment of chronic obstructive pulmonary disease with statins |
| JP2010513430A (en) * | 2006-12-18 | 2010-04-30 | カルドズ・アーベー | New combinations for use in the treatment of inflammatory disorders |
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