JP2007238598A - Composition for preventing stroke recurrence - Google Patents
Composition for preventing stroke recurrence Download PDFInfo
- Publication number
- JP2007238598A JP2007238598A JP2006307035A JP2006307035A JP2007238598A JP 2007238598 A JP2007238598 A JP 2007238598A JP 2006307035 A JP2006307035 A JP 2006307035A JP 2006307035 A JP2006307035 A JP 2006307035A JP 2007238598 A JP2007238598 A JP 2007238598A
- Authority
- JP
- Japan
- Prior art keywords
- stroke
- epa
- recurrence
- composition
- onset
- 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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Abstract
Description
本発明は、少なくともイコサペント酸エチルエステル（以下ＥＰＡ−Ｅと略記する）を含有することを特徴とする脳卒中の発症および／または再発を予防する為の組成物に関する。 The present invention relates to a composition for preventing the onset and / or recurrence of stroke, characterized by containing at least icosapentic acid ethyl ester (hereinafter abbreviated as EPA-E).
脳卒中は、脳出血、脳梗塞などに代表される脳血管障害により、急激に意識障害、神経症状が出現する病態と定義され、厚生労働省発表による平成１６年の日本人の死因順位別死亡数では第３位に位置している。幸いにして死亡に至らなかった場合においても、その後遺症は、患者の日常生活の質（ＱＯＬ）に重大な影響を与えることが多く、また、一度発症すると再発し易いということもあり、社会問題の一つになっている。
脳卒中は、高血圧との関連が古くから知られており、発症または再発を予防するために、種々の降圧薬による血圧管理が提唱、実践され、その結果として、脳出血型の脳卒中による死亡数は確かに減少した。
しかしながら、食生活の欧米化により糖尿病、高脂血症や高血圧症などのいわゆる生活習慣病患者が増加するにつれ、日本人における脳卒中の病型も変化し、現在では、日本の脳卒中病型の内訳は、脳梗塞約８０％、脳出血約１５％、くも膜下出血約５％となっている。
食生活の欧米化に伴って、脳梗塞が増加するようになってからは、生活習慣病の中でも、特に高脂血症が注目され、コレステロール、とりわけ、悪玉コレステロールとも呼ばれる低比重リポ蛋白−コレステロール（ＬＤＬ−Ｃ）を改善することにより、動脈硬化性疾患、すなわち、心筋梗塞や脳梗塞などを予防することが提唱されてきた。
Stroke is defined as a pathological condition in which consciousness disorder and neurological symptoms suddenly appear due to cerebrovascular disorders represented by cerebral hemorrhage, cerebral infarction, etc., and the number of deaths by rank of death of Japanese in 2004 published by the Ministry of Health, Labor and Welfare It is in 3rd place. Fortunately, even if the patient does not die, the sequelae often have a significant impact on the patient's quality of life (QOL), and once they develop, they can easily recur. It has become one of
Stroke has long been known to be associated with hypertension, and blood pressure management with various antihypertensive drugs has been proposed and practiced to prevent onset or recurrence, and as a result, the number of deaths from cerebral hemorrhagic stroke is certain. Decreased.
However, as the number of patients with lifestyle-related diseases such as diabetes, hyperlipidemia and hypertension increases due to the westernization of dietary habits, the type of stroke in Japanese people has changed, and now the breakdown of stroke types in Japan Is about 80% cerebral infarction, about 15% cerebral hemorrhage, and about 5% subarachnoid hemorrhage.
With the increase in cerebral infarction with the westernization of dietary habits, hyperlipidemia has attracted particular attention among lifestyle-related diseases, and cholesterol, especially low-density lipoprotein-cholesterol, also called bad cholesterol It has been proposed to prevent arteriosclerotic diseases such as myocardial infarction and cerebral infarction by improving (LDL-C).
このような背景の中で、強力な血中コレステロール低下作用を有する３−ヒドロキシ−３−メチルグルタリルコエンザイムＡ還元酵素阻害剤（ＨＭＧ−ＣｏＡ ＲＩ）、いわゆるスタチン製剤による各種の臨床試験（例えば、ＫＬＩＳ、ＰＡＴＥ、Ｊ−ＬＩＴ、等）が本邦においても実施され、脳梗塞発症予防におけるスタチンの一応の有効性が示唆された。しかしながら、脳卒中の二次予防、すなわち、再発予防に関しては、今なお満足な結果が得られていないのが現状である。 In such a background, various clinical trials using a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-CoARI), a so-called statin preparation, which has a strong blood cholesterol lowering action (for example, KLIS, PATE, J-LIT, etc.) were also implemented in Japan, suggesting the effectiveness of statin in preventing cerebral infarction. However, at present, satisfactory results have not yet been obtained for secondary prevention of stroke, that is, prevention of recurrence.
高脂血症の改善作用を有する別の化合物の一例として、多価不飽和脂肪酸が知られている。多価不飽和脂肪酸は、分子内に複数の炭素−炭素二重結合を有する脂肪酸と定義され、二重結合の位置により、ω−３系、ω−６系などに分類される。ω−３系の多価不飽和脂肪酸としてはα−リノレン酸、イコサペント酸（ＥＰＡ）、ドコサヘキサエン酸（ＤＨＡ）などが、ω−６系の多価不飽和脂肪酸としてはリノール酸、γ−リノレン酸、アラキドン酸などが知られている。多価不飽和脂肪酸は、天然物由来の成分であり、抗動脈硬化作用、血小板凝集抑制作用、血中脂質低下作用、抗炎症作用、抗癌作用、中枢作用など、多彩な作用を示し、安全性も高いことから各種食品に配合されたり、健康食品あるいは医薬品として市販されている。 As an example of another compound having an action for improving hyperlipidemia, polyunsaturated fatty acids are known. Polyunsaturated fatty acids are defined as fatty acids having a plurality of carbon-carbon double bonds in the molecule, and are classified into ω-3 series, ω-6 series, etc., depending on the position of the double bond. Examples of ω-3 polyunsaturated fatty acids include α-linolenic acid, icosapentenoic acid (EPA), and docosahexaenoic acid (DHA). Examples of ω-6 polyunsaturated fatty acids include linoleic acid and γ-linolenic acid. Arachidonic acid and the like are known. Polyunsaturated fatty acids are components derived from natural products, and exhibit a variety of actions, such as anti-arteriosclerotic action, platelet aggregation inhibitory action, blood lipid lowering action, anti-inflammatory action, anticancer action, and central action, and are safe Because of its high properties, it is blended in various foods and is marketed as health foods or pharmaceuticals.
ω−３系多価不飽和脂肪酸であるＥＰＡのエチルエステル（ＥＰＡ−Ｅ）およびＤＨＡのエチルエステル（ＤＨＡ−Ｅ）の混合物を３．５年間服用することにより、心筋梗塞既往患者の死亡率が減少したとの報告がある（特許文献１参照）。しかしながら、当該文献には、ＥＰＡ−ＥおよびＤＨＡ−Ｅが、脳卒中の発症および／または再発を予防することを開示または示唆する記載はない。 By taking a mixture of omega-3 polyunsaturated fatty acid ethyl ester of EPA (EPA-E) and ethyl ester of DHA (DHA-E) for 3.5 years, the mortality rate of patients with a history of myocardial infarction There is a report that it has decreased (see Patent Document 1). However, this document does not disclose or suggest that EPA-E and DHA-E prevent the onset and / or recurrence of stroke.
また、ＥＰＡおよびＤＨＡを含有する魚油を服用することにより、脳に血液を供給する動脈のアテローム性動脈硬化の症状を示す患者の脳損傷を予防することに関する示唆がある（特許文献２参照）。しかしながら、当該文献は、頚動脈血管内膜切除術施行患者の頚動脈プラークについて組織学的に検討したものであり、脳損傷および／または脳卒中の予防効果について具体的に示したものではない。 In addition, there is a suggestion related to preventing brain damage in patients who exhibit symptoms of atherosclerosis in arteries supplying blood to the brain by taking fish oil containing EPA and DHA (see Patent Document 2). However, this document is a histological examination of the carotid artery plaque of a patient undergoing carotid endarterectomy, and does not specifically show the effect of preventing brain damage and / or stroke.
近年、動物実験の結果や、小規模の臨床所見から、生活習慣病の改善効果を有する各種薬剤が、ヒトにおける動脈硬化性疾患を予防し得るものか確認することを目的として、多くの大規模臨床試験が計画され、実践されている。しかしながら、必ずしも期待通りの結果が得られていないのが現状であり、とりわけ、脳卒中の二次予防については、暗中模索状態が続いている。 In recent years, many large-scale studies have been conducted with the aim of confirming whether various drugs that have an effect of improving lifestyle-related diseases can prevent arteriosclerotic diseases in humans from the results of animal experiments and small-scale clinical findings. Clinical trials are planned and practiced. However, the current situation is that the expected results are not always obtained. In particular, in the secondary prevention of stroke, a state of groping in the dark continues.
高純度ＥＰＡ−ＥはエパデールおよびエパデールＳ（持田製薬社製）の商品名で高脂血症治療薬として日本で市販されており、１回６００ｍｇ、１日３回食直後、（ただし、トリグリセリド（ＴＧ）の異常を呈する場合には、その程度により、１回９００ｍｇ、１日３回まで増量して）経口投与することにより、血清Ｔ−Ｃｈｏ濃度を３〜６％、血清ＴＧを１４〜２０％減少させる（非特許文献１参照）こと、およびこれら作用から高脂血症患者の心血管イベントに対する効果が期待され、大規模臨床試験を実施した結果、スタチンとの併用により心イベント抑制効果を有することが２００５年のアメリカ心臓病学会年会において発表された（非特許文献２および３参照）。しかしながら、当該文献には、ＥＰＡ−Ｅが、脳卒中の発症および／または再発を予防することを開示または示唆する記載はない。 High-purity EPA-E is marketed in Japan as an antihyperlipidemic drug under the trade names Epadale and Epadale S (manufactured by Mochida Pharmaceutical Co., Ltd.). If abnormalities of (TG) are exhibited, the serum T-Cho concentration is 3 to 6% and the serum TG is 14 to 20 by oral administration (increased to 900 mg at a time, 3 times a day). % (See Non-patent Document 1) and these effects are expected to have an effect on cardiovascular events in hyperlipidemic patients. It was announced at the 2005 Annual Meeting of the American College of Cardiology (see Non-Patent Documents 2 and 3). However, this document does not disclose or suggest that EPA-E prevents the onset and / or recurrence of stroke.
本発明の目的は、脳卒中は依然として主要な死亡原因であり、ＨＭＧ−ＣｏＡ ＲＩによる治療を行なっても予防できない脳卒中が多数存在し問題となっている状況において、脳卒中の発症および／または再発を予防するための組成物を提供することにある。 It is an object of the present invention to prevent the onset and / or recurrence of a stroke in a situation where the stroke is still a major cause of death and there are many strokes that cannot be prevented by treatment with HMG-CoA RI. It is in providing the composition for doing.
本発明者は、上記の課題を解決すべく鋭意研究を行ったところ、ＥＰＡ−Ｅが脳卒中の発症および／または再発の予防、特に脳卒中発症後６ヶ月を経過した後の患者における脳卒中再発の予防作用を有することを見出し、本発明を完成した。すなわち、本発明は、
（１）少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中の発症および／または再発を予防するための組成物である。
具体的に、
（２）少なくともＥＰＡ−Ｅを有効成分として含有する、高脂血症患者の脳卒中の発症および／または再発を予防するための組成物である。
（３）少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中既往患者の脳卒中再発を予防するための組成物である。
（４）少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中発症後６ヶ月を経過した後の患者の脳卒中再発を予防するための組成物である。
（５）全脂肪酸およびその誘導体中のＥＰＡ−Ｅ含量比が９６．５質量％以上である上記（１）ないし（４）のいずれかに記載の組成物である。
（６）ＥＰＡ−Ｅ１．８ｇ／日〜２．７ｇ／日で経口投与することを特徴とする上記（１）ないし（５）のいずれかに記載の組成物である。
（７）ＨＭＧ−ＣｏＡ ＲＩと併用することを特徴とする（１）ないし（６）のいずれかに記載の組成物である。
（８）投与開始から３年経過以降の脳卒中再発予防効果に優れる（１）ないし（７）のいずれかに記載の組成物である。
（９）血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とする（１）ないし（８）のいずれかに記載の組成物である。
（１０）上記（１）ないし（９）のいずれかに記載の組成物を投与する、脳卒中の発症および／または再発を予防する方法である。
（１１）上記（１）ないし（９）のいずれかに記載の組成物を製造するためのＥＰＡ−Ｅの使用である。
The present inventor conducted intensive research to solve the above-mentioned problems, and as a result, EPA-E prevented the onset and / or recurrence of stroke, particularly prevention of stroke recurrence in patients after 6 months after the onset of stroke. It discovered that it had an effect | action, and completed this invention. That is, the present invention
(1) A composition for preventing the onset and / or recurrence of stroke, comprising at least EPA-E as an active ingredient.
Specifically,
(2) A composition for preventing the onset and / or recurrence of stroke in a hyperlipidemic patient, comprising at least EPA-E as an active ingredient.
(3) A composition for preventing recurrence of stroke in a patient with a history of stroke, comprising at least EPA-E as an active ingredient.
(4) A composition for preventing recurrence of stroke in a patient after 6 months from the onset of stroke, comprising at least EPA-E as an active ingredient.
(5) The composition according to any one of (1) to (4), wherein the content ratio of EPA-E in all fatty acids and derivatives thereof is 96.5% by mass or more.
(6) The composition according to any one of (1) to (5) above, wherein EPA-E is orally administered at 1.8 g / day to 2.7 g / day.
(7) The composition according to any one of (1) to (6), which is used in combination with HMG-CoA RI.
(8) The composition according to any one of (1) to (7), which is excellent in preventing the recurrence of stroke after 3 years from the start of administration.
(9) The composition according to any one of (1) to (8), wherein the subject has a serum TG / HDL-C ratio of 3.75 or more.
(10) A method for preventing the onset and / or recurrence of stroke, which comprises administering the composition according to any one of (1) to (9) above.
(11) Use of EPA-E for producing the composition according to any one of (1) to (9) above.
上記のような少なくともＥＰＡ−Ｅを有効成分として含有する、本発明の組成物は、脳卒中の発症および／または再発の予防に有用である。特に、高脂血症患者でＨＭＧ−ＣｏＡ ＲＩによる治療を行なったにもかかわらず発症および／または再発する脳卒中、あるいは特に脳卒中発症後６ヶ月を経過した後の患者における脳卒中の再発の予防効果が期待される。
また、本発明の組成物はＨＭＧ−ＣｏＡ ＲＩと併用することによりその効果は相乗的に増強され、脳卒中の発症および／または再発、特に脳卒中発症後６ヶ月を経過した後の患者における脳卒中の再発の予防効果をさらに高めることが期待でき、臨床上有用である。
The composition of the present invention containing at least EPA-E as an active ingredient as described above is useful for preventing the onset and / or recurrence of stroke. In particular, the effect of preventing stroke recurrence in patients with hyperlipidemia who develop and / or relapse despite treatment with HMG-CoA RI, or in particular after 6 months after the onset of stroke. Be expected.
In addition, the composition of the present invention is synergistically enhanced when used in combination with HMG-CoA RI, and the onset and / or recurrence of stroke, particularly the recurrence of stroke in a patient after 6 months from the onset of stroke. It can be expected to further enhance the preventive effect, and is clinically useful.
以下に本発明を詳細に説明する。
本発明の第一の態様は、少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中の発症および／または再発を予防するための組成物である。あるいは、本発明の第一の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する、脳卒中の発症および／または再発を予防するための組成物である。
The present invention is described in detail below.
The first aspect of the present invention is a composition for preventing the onset and / or recurrence of stroke, containing at least EPA-E as an active ingredient. Alternatively, a first aspect of the present invention is a composition for preventing the onset and / or recurrence of stroke, containing at least EPA-E and / or DHA-E as an active ingredient.
脳卒中、すなわち、脳血管障害により急激に意識障害、神経症状が出現する病態の発症および／または再発予防であればすべて含まれるが、特に脳出血（高血圧性脳内出血、等）、脳梗塞、一過性脳虚血発作、くも膜下出血、脳血栓（アテローム血栓性脳梗塞、等）、脳塞栓（心原性脳塞栓症、等）、ラクナ梗塞などの発症および／または再発予防が例示される。投与対象は、脳卒中の発症の予防が必要なヒトはすべて含まれるが、特に高脂血症患者が例示される。 This includes all stroke prevention, ie, consciousness disorder due to cerebrovascular disorder, pathogenesis of neurological symptoms and / or prevention of recurrence, but especially cerebral hemorrhage (hypertensive intracerebral hemorrhage, etc.), cerebral infarction, transient Onset and / or recurrence prevention of cerebral ischemic attack, subarachnoid hemorrhage, cerebral thrombus (atherothrombotic cerebral infarction, etc.), cerebral embolism (cardiogenic cerebral embolism, etc.), and lacunar infarction are exemplified. Examples of administration subjects include all humans who need to prevent the onset of stroke, and particularly hyperlipidemic patients.
本発明の効果が得られれば全脂肪酸中のＥＰＡ−Ｅ含量比および投与量は特に問わないが、ＥＰＡ−Ｅは高純度のもの、例えば、全脂肪酸およびその誘導体中のＥＰＡ−Ｅ含量比が４０質量％以上のものが好ましく、９０質量％以上のものが更に好ましく、９６．５質量％以上のものが更に好ましい。１日投与量はＥＰＡ−Ｅとして、０．３〜６ｇ／日、好ましくは０．９〜３．６ｇ／日、更に好ましくは１．８〜２．７ｇ／日が例示される。他に含有されるに好ましい脂肪酸としてはω−３系長鎖不飽和脂肪酸、特に、ＤＨＡ−Ｅが挙げられる。本発明の効果が得られればＥＰＡ−Ｅ／ＤＨＡ−Ｅの組成比、全脂肪酸中のＥＰＡ−ＥおよびＤＨＡ−Ｅ（以下、ＥＰＡ−Ｅ＋ＤＨＡ−Ｅ）の含量比およびＥＰＡ−Ｅ＋ＤＨＡ−Ｅの投与量は特に問わないが、好ましい組成比として、ＥＰＡ−Ｅ／ＤＨＡ−Ｅは、０．８以上であることが好ましく、更に好ましくは、１．０以上、より好ましくは、１．２以上である。ＥＰＡ−Ｅ＋ＤＨＡ−Ｅは高純度のもの、例えば、全脂肪酸およびその誘導体中のＥＰＡ−Ｅ＋ＤＨＡ−Ｅ含量比が４０質量％以上のものが好ましく、８０質量％以上のものが更に好ましく、９０質量％以上のものが更に好ましい。１日投与量はＥＰＡ−Ｅ＋ＤＨＡ−Ｅとして、０．３〜１０ｇ／日、好ましくは０．５〜６ｇ／日、更に好ましくは１〜４ｇ／日が例示される。他の長鎖飽和脂肪酸含量は少ないことが好ましく、長鎖不飽和脂肪酸でもω−６系、特にアラキドン酸含量は少ないことが望まれ、２質量％未満が好ましく、１質量％未満が更に好ましい。 As long as the effects of the present invention are obtained, the EPA-E content ratio and dose in total fatty acids are not particularly limited, but EPA-E has a high purity, for example, the EPA-E content ratio in total fatty acids and derivatives thereof. 40% by weight or more is preferable, 90% by weight or more is more preferable, and 96.5% by weight or more is more preferable. The daily dosage is 0.3 to 6 g / day, preferably 0.9 to 3.6 g / day, and more preferably 1.8 to 2.7 g / day as EPA-E. Other preferable fatty acids to be contained include ω-3 long-chain unsaturated fatty acids, particularly DHA-E. If the effects of the present invention are obtained, the composition ratio of EPA-E / DHA-E, the content ratio of EPA-E and DHA-E (hereinafter referred to as EPA-E + DHA-E) in all fatty acids, and the administration of EPA-E + DHA-E The amount is not particularly limited, but as a preferred composition ratio, EPA-E / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, more preferably 1.2 or more. . EPA-E + DHA-E is of high purity, for example, EPA-E + DHA-E content ratio in total fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 80% by mass or more, and 90% by mass The above is more preferable. The daily dose is exemplified as EPA-E + DHA-E, 0.3 to 10 g / day, preferably 0.5 to 6 g / day, and more preferably 1 to 4 g / day. The content of other long-chain saturated fatty acids is preferably low, and even long-chain unsaturated fatty acids are desired to have a low ω-6 type, particularly arachidonic acid content, preferably less than 2% by mass, and more preferably less than 1% by mass.
本発明の第二の態様は、少なくともＥＰＡ−Ｅを含有することを特徴とする高脂血症患者の脳卒中の発症および／または再発予防の為の組成物である。あるいは、本発明の第二の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを含有することを特徴とする高脂血症患者の脳卒中の発症および／または再発予防の為の組成物である。 A second aspect of the present invention is a composition for preventing the onset and / or recurrence of stroke in a hyperlipidemic patient, characterized by containing at least EPA-E. Alternatively, a second aspect of the present invention is a composition for preventing the onset and / or recurrence of stroke in a hyperlipidemic patient, characterized by containing at least EPA-E and / or DHA-E. .
本発明の第三の態様は、少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中既往患者の脳卒中再発を予防するための組成物である。あるいは、本発明の第三の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する、脳卒中既往患者の脳卒中再発を予防するための組成物である。
本発明の第二および第三の態様、また、後述する第四〜第十四の態様における、脳卒中の種類、全脂肪酸中のＥＰＡ−Ｅ含量比、全脂肪酸中のＥＰＡ−Ｅ＋ＤＨＡ−Ｅ含量比、ＥＰＡ−Ｅ／ＤＨＡ−Ｅ組成比、１日投与量、および他の長鎖脂肪酸含有比、等の好ましい態様は上記の第一の態様と同様である。
The third aspect of the present invention is a composition for preventing recurrence of stroke in a patient with a history of stroke, comprising at least EPA-E as an active ingredient. Alternatively, the third aspect of the present invention is a composition for preventing stroke recurrence in a patient with a history of stroke, which contains at least EPA-E and / or DHA-E as an active ingredient.
Types of stroke, EPA-E content ratio in total fatty acid, EPA-E + DHA-E content ratio in total fatty acid in the second and third aspects of the present invention and in the fourth to fourteenth aspects described later Preferred embodiments such as the EPA-E / DHA-E composition ratio, daily dose, and other long chain fatty acid content ratios are the same as in the first embodiment.
本発明の第四の態様は、少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中発症後６ヶ月を経過した後の患者の脳卒中再発を予防するための組成物である。あるいは、本発明の第四の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する、脳卒中発症後６ヶ月を経過した後の患者の脳卒中再発を予防するための組成物である。本態様における脳卒中の種類、全脂肪酸中のＥＰＡ−Ｅ含量比、全脂肪酸中のＥＰＡ−Ｅ＋ＤＨＡ−Ｅ含量比、ＥＰＡ−Ｅ／ＤＨＡ−Ｅ組成比、１日投与量、および他の長鎖脂肪酸含有比、等の好ましい態様は、上記の第一の態様と同様である。投与対象は直近の脳卒中発症後６ヶ月以上経過した患者であり、脳卒中急性期を過ぎた患者が対象である。 The fourth aspect of the present invention is a composition for preventing stroke recurrence in a patient after 6 months from the onset of stroke, containing at least EPA-E as an active ingredient. Alternatively, the fourth aspect of the present invention is a composition for preventing stroke recurrence in a patient after 6 months from the onset of stroke, comprising at least EPA-E and / or DHA-E as an active ingredient. is there. Types of stroke in this embodiment, EPA-E content ratio in total fatty acids, EPA-E + DHA-E content ratio in total fatty acids, EPA-E / DHA-E composition ratio, daily dose, and other long chain fatty acids The preferred embodiments such as the content ratio are the same as those in the first embodiment. The administration target is a patient who has passed 6 months or more after the latest stroke onset, and a patient who has passed the acute stroke phase.
本発明の第五の態様は、少なくともＥＰＡ−Ｅを有効成分として含有する、投与開始から３年経過以降の脳卒中の再発予防効果に優れる組成物である。具体的には、少なくともＥＰＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、３年以上継続して投与することにより、ＥＰＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で１５％以上、同４年および５年経過時で３０％以上、脳卒中の発症率が低下する。特に、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とする場合には、少なくともＥＰＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、３年以上継続して投与することにより、ＥＰＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で２０％以上、同４年および５年経過時で４０％以上、脳卒中の発症率が低下する。あるいは、本発明の第五の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する、投与開始から３年経過以降の脳卒中の再発予防効果に優れる組成物である。具体的には、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、３年以上継続して投与することにより、ＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で１５％以上、同４年および５年経過時で３０％以上、脳卒中の発症率が低下する。特に、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とする場合には、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、３年以上継続して投与することにより、ＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で２０％以上、同４年および５年経過時で４０％以上、脳卒中の発症率が低下する。 The fifth aspect of the present invention is a composition that contains at least EPA-E as an active ingredient and is excellent in the effect of preventing recurrence of stroke after 3 years from the start of administration. Specifically, a control for non-administration of EPA-E is achieved by continuously administering a composition containing at least EPA-E as an active ingredient and preventing the onset and / or recurrence of stroke for 3 years or more. Compared to the group, the incidence of stroke is reduced by 15% or more after 3 years from the start of administration and 30% or more after 4 and 5 years. In particular, when the subject has a serum TG / HDL-C ratio of 3.75 or more, a composition for containing at least EPA-E as an active ingredient and preventing the onset and / or recurrence of stroke is provided. By administering continuously for 3 years or more, compared with the control group not administered with EPA-E, 20% or more after 3 years from the start of administration, 40% or more after 4 or 5 years, stroke The incidence of is reduced. Or the 5th aspect of this invention is a composition excellent in the recurrence prevention effect of the stroke after 3 years from the administration start containing at least EPA-E and / or DHA-E as an active ingredient. Specifically, by continuously administering EPA-E and / or DHA-E as an active ingredient, and a composition for preventing the onset and / or recurrence of stroke for 3 years or more, -Compared to the control group not administered with E and / or DHA-E, the incidence of stroke is reduced by 15% or more after 3 years from the start of administration and 30% or more after 4 and 5 years. In particular, when a patient having a serum TG / HDL-C ratio of 3.75 or more is included, at least EPA-E and / or DHA-E is contained as an active ingredient to prevent the onset and / or recurrence of stroke. Is administered continuously for 3 years or more, compared with the control group not administered with EPA-E and / or DHA-E, 20% or more after 3 years from the start of administration. The incidence of stroke decreases by 40% or more at the age of 5 years.
本発明の第六の態様は、少なくともＥＰＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、ＨＭＧ−ＣｏＡ ＲＩとの併用により、３年以上継続して投与することにより、ＥＰＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で１５％以上、同４年および５年経過時で３０％以上、脳卒中の発症率が低下する効果を有する組成物である。特に、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とする場合には、少なくともＥＰＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、ＨＭＧ−ＣｏＡ ＲＩとの併用により、３年以上継続して投与することにより、ＥＰＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で２０％以上、同４年および５年経過時で４０％以上、脳卒中の発症率が低下する効果を有する組成物である。あるいは、本発明の第六の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、ＨＭＧ−ＣｏＡ ＲＩとの併用により、３年以上継続して投与することにより、ＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で１５％以上、同４年および５年経過時で３０％以上、脳卒中の発症率が低下する効果を有する組成物である。特に、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とする場合には、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有し、脳卒中の発症および／または再発を予防するための組成物を、ＨＭＧ−ＣｏＡ ＲＩとの併用により、３年以上継続して投与することにより、ＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅ非投与の対照群に比し、投与開始から３年経過時で２０％以上、同４年および５年経過時で４０％以上、脳卒中の発症率が低下する効果を有する組成物である。 According to a sixth aspect of the present invention, a composition for containing at least EPA-E as an active ingredient and preventing the onset and / or recurrence of stroke is continued for 3 years or more in combination with HMG-CoA RI. As compared with the control group not administered with EPA-E, the incidence of stroke is reduced by 15% or more after 3 years from the start of administration and 30% or more after 4 years and 5 years. It is a composition having an effect. In particular, when the subject has a serum TG / HDL-C ratio of 3.75 or more, a composition for containing at least EPA-E as an active ingredient and preventing the onset and / or recurrence of stroke is provided. In combination with HMG-CoA RI, administration continued for 3 years or more, compared to a control group not administered with EPA-E, 20% or more after 3 years from the start of administration, It is a composition having an effect of reducing the incidence of stroke by 40% or more at the time of year. Alternatively, the sixth aspect of the present invention comprises at least EPA-E and / or DHA-E as an active ingredient, and a composition for preventing the onset and / or recurrence of stroke with HMG-CoA RI. By continuous administration for 3 years or more, 15% or more at the lapse of 3 years from the start of administration, 4 years and 5 years, compared to the control group not administered with EPA-E and / or DHA-E. It is a composition having an effect of reducing the incidence of stroke by 30% or more at the time of passage. In particular, when a patient having a serum TG / HDL-C ratio of 3.75 or more is included, at least EPA-E and / or DHA-E is contained as an active ingredient to prevent the onset and / or recurrence of stroke. 3 years from the start of administration as compared to the EPA-E and / or DHA-E non-administered control group by continuously administering the composition to be used in combination with HMG-CoA RI for 3 years or more. It is a composition having an effect of reducing the incidence of stroke by 20% or more at the time of passage, and 40% or more at the time of the same 4 years or 5 years.
本発明の第七の態様は、少なくともＥＰＡ−Ｅを有効成分として含有する組成物を、３年以上継続して投与することを特徴とする、脳卒中の発症および／または再発を予防する方法である。あるいは、本発明の第七の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する組成物を、３年以上継続して投与することを特徴とする、脳卒中の発症および／または再発を予防する方法である。 A seventh aspect of the present invention is a method for preventing the onset and / or recurrence of stroke, which comprises continuously administering a composition containing at least EPA-E as an active ingredient for 3 years or more. . Alternatively, according to a seventh aspect of the present invention, there is provided an onset of stroke and / or characterized by continuously administering a composition containing at least EPA-E and / or DHA-E as an active ingredient for 3 years or more. Or a method to prevent recurrence.
本発明の第八の態様は、血清ＴＧ／ＨＤＬ−Ｃ比が１以上、好ましくは２以上、より好ましくは３．７５以上の患者を対象とする、少なくともＥＰＡ−Ｅを有効成分として含有する、脳卒中の発症および／または再発を予防するための組成物である。あるいは、本発明の第八の態様は、血清ＴＧ／ＨＤＬ−Ｃ比が１以上、好ましくは２以上、より好ましくは３．７５以上の患者を対象とする、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する、脳卒中の発症および／または再発を予防するための組成物である。 The eighth aspect of the present invention is directed to a patient having a serum TG / HDL-C ratio of 1 or more, preferably 2 or more, more preferably 3.75 or more, and contains at least EPA-E as an active ingredient. A composition for preventing the onset and / or recurrence of a stroke. Alternatively, according to an eighth aspect of the present invention, at least EPA-E and / or DHA- directed to a patient having a serum TG / HDL-C ratio of 1 or more, preferably 2 or more, more preferably 3.75 or more. A composition containing E as an active ingredient for preventing the onset and / or recurrence of stroke.
本発明の第九の態様は、少なくともＥＰＡ−Ｅを有効成分として含有することを特徴とする、高脂血症患者の脳卒中の再発予防の為の組成物である。あるいは、本発明の第九の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有することを特徴とする、高脂血症患者の脳卒中の再発予防の為の組成物である。本発明の第九の態様における、脳卒中の種類、全脂肪酸中のＥＰＡ−Ｅ含量比、全脂肪酸中のＥＰＡ−Ｅ＋ＤＨＡ−Ｅ含量比、ＥＰＡ−Ｅ／ＤＨＡ−Ｅ組成比、１日投与量、および他の長鎖脂肪酸含有比、等の好ましい態様は上記の第一の態様と同様である。 A ninth aspect of the present invention is a composition for preventing recurrence of stroke of a hyperlipidemic patient, characterized by containing at least EPA-E as an active ingredient. Alternatively, a ninth aspect of the present invention is a composition for preventing recurrence of stroke of a hyperlipidemic patient, characterized by containing at least EPA-E and / or DHA-E as an active ingredient. . In the ninth aspect of the present invention, the type of stroke, the EPA-E content ratio in the total fatty acids, the EPA-E + DHA-E content ratio in the total fatty acids, the EPA-E / DHA-E composition ratio, the daily dose, Preferred embodiments such as the content ratio of other long chain fatty acids and the like are the same as those in the first embodiment.
本発明の第十の態様は、ＨＭＧ−ＣｏＡ ＲＩと併用することを特徴とする、少なくともＥＰＡ−Ｅを有効成分として含有する脳卒中の再発予防の為の組成物であり、別の言い方をすると、ＨＭＧ−ＣｏＡ ＲＩが必要とされている患者における、ＨＭＧ−ＣｏＡ ＲＩと併用するための、少なくともＥＰＡ−Ｅを有効成分として含有する脳卒中の再発予防の為の組成物である。あるいは、本発明の第十の態様は、ＨＭＧ−ＣｏＡ ＲＩと併用することを特徴とする、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する脳卒中の再発予防の為の組成物であり、別の言い方をすると、ＨＭＧ−ＣｏＡ ＲＩが必要とされている患者における、ＨＭＧ−ＣｏＡ ＲＩと併用するための、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する脳卒中の再発予防の為の組成物である。 A tenth aspect of the present invention is a composition for preventing recurrence of stroke containing at least EPA-E as an active ingredient, characterized by being used in combination with HMG-CoA RI. In other words, A composition for preventing recurrence of stroke containing at least EPA-E as an active ingredient for use in combination with HMG-CoA RI in a patient in need of HMG-CoA RI. Alternatively, a tenth aspect of the present invention is a composition for preventing recurrence of stroke, comprising at least EPA-E and / or DHA-E as an active ingredient, which is used in combination with HMG-CoA RI. Yes, in other words, recurrence of stroke containing at least EPA-E and / or DHA-E as an active ingredient for use with HMG-CoA RI in patients in need of HMG-CoA RI It is a composition for prevention.
ＨＭＧ−ＣｏＡ ＲＩは、３−ヒドロキシ−３−メチルグルタリルコエンザイムＡ還元酵素阻害作用を有する物はすべて含まれるが、医薬投与可能なものが好ましい。具体的には、プラバスタチン、シンバスタチン、ロバスタチン、フルバスタチン、セリバスタチン、アトルバスタチン、ピタバスタチン、ロスバスタチンおよびこれらの塩、誘導体からなる群から選ばれる少なくとも１つであることが好ましく、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、アトルバスタチン、ピタバスタチンあるいはロスバスタチンが更に好ましく、プラバスタチンあるいはシンバスタチンが更に好ましい。塩としては、医薬投与可能なものであればすべて含まれるが、特にナトリウム塩あるいはカルシウム塩、例えば、プラバスタチンナトリウム、フルバスタチンナトリウム、セリバスタチンナトリウム、アトルバスタチンカルシウム、ピタバスタチンカルシウムおよびロスバスタチンカルシウムが好ましい。本明細書においては、特に断らない限り、例えば「プラバスタチン」にはプラバスタチンの塩の態様も含まれる。 HMG-CoA RI includes all those having a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitory activity, but those that can be administered pharmaceutically are preferred. Specifically, it is preferably at least one selected from the group consisting of pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin and salts, derivatives thereof, pravastatin, lovastatin, simvastatin, fluvastatin Atorvastatin, pitavastatin or rosuvastatin is more preferable, and pravastatin or simvastatin is more preferable. Any salt can be used as long as it is pharmaceutically administrable, and sodium or calcium salts such as pravastatin sodium, fluvastatin sodium, cerivastatin sodium, atorvastatin calcium, pitavastatin calcium and rosuvastatin calcium are particularly preferable. In the present specification, unless otherwise specified, for example, “pravastatin” includes a salt form of pravastatin.
本発明の第十一の態様は、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とし、ＨＭＧ−ＣｏＡ ＲＩと併用するための、少なくともＥＰＡ−Ｅを有効成分として含有する脳卒中の発症および／または再発を予防するための組成物であり、別の言い方をすると、ＨＭＧ−ＣｏＡ ＲＩが必要とされている患者のうち、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とし、ＨＭＧ−ＣｏＡ ＲＩと併用するための、少なくともＥＰＡ−Ｅを有効成分として含有する脳卒中の再発予防の為の組成物である。あるいは、本発明の第十一の態様は、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とし、ＨＭＧ−ＣｏＡ ＲＩと併用するための、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する脳卒中の発症および／または再発を予防するための組成物であり、別の言い方をすると、ＨＭＧ−ＣｏＡ ＲＩが必要とされている患者のうち、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者を対象とし、ＨＭＧ−ＣｏＡ ＲＩと併用するための、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する脳卒中の再発予防の為の組成物である。ＨＭＧ−ＣｏＡ ＲＩが必要とされている患者は、多くの場合、高脂血症に罹患している。
本発明の第七〜第十一の態様の組成物は、好ましくは、脳卒中既往のある患者のための組成物であり、特に好ましくは、脳卒中発症後６ケ月を経過した後の患者、すなわち、脳卒中急性期を経過した後の患者のための組成物である。
The eleventh aspect of the present invention is intended for patients with a serum TG / HDL-C ratio of 3.75 or more, and for use in combination with HMG-CoA RI, which contains at least EPA-E as an active ingredient. It is a composition for preventing onset and / or recurrence, and in other words, among patients who require HMG-CoA RI, patients whose serum TG / HDL-C ratio is 3.75 or more. A composition for preventing recurrence of stroke containing at least EPA-E as an active ingredient for use in combination with HMG-CoA RI. Alternatively, an eleventh aspect of the present invention is directed to a patient having a serum TG / HDL-C ratio of 3.75 or more, and at least EPA-E and / or DHA-E for use in combination with HMG-CoA RI. In other words, among the patients in need of HMG-CoA RI, the serum TG / HDL-C ratio is a composition for preventing the onset and / or recurrence of stroke. Is a composition for preventing recurrence of stroke containing at least EPA-E and / or DHA-E as an active ingredient for use in combination with HMG-CoA RI for patients with a ≥3.75. Patients in need of HMG-CoA RI often suffer from hyperlipidemia.
The composition according to the seventh to eleventh aspects of the present invention is preferably a composition for a patient with a history of stroke, and particularly preferably a patient after 6 months from the onset of stroke, A composition for a patient after the acute stroke phase.
本発明の第十二の態様は、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者に対し、当該血清ＴＧ／ＨＤＬ−Ｃ比が３．７５未満、より好ましくは、１未満になるまで、少なくともＥＰＡ−Ｅを有効成分として含有する組成物を投与することによる、脳卒中の発症および／または再発を予防する方法である。あるいは、本発明の第十二の態様は、血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者に対し、当該血清ＴＧ／ＨＤＬ−Ｃ比が３．７５未満、より好ましくは、１未満になるまで、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する組成物を投与することによる、脳卒中の発症および／または再発を予防する方法である。 According to a twelfth aspect of the present invention, a patient having a serum TG / HDL-C ratio of 3.75 or more has a serum TG / HDL-C ratio of less than 3.75, more preferably less than 1. A method for preventing the onset and / or recurrence of stroke by administering a composition containing at least EPA-E as an active ingredient. Alternatively, in a twelfth aspect of the present invention, the serum TG / HDL-C ratio is less than 3.75, more preferably less than 1, for a patient having a serum TG / HDL-C ratio of 3.75 or more. Until now, it is a method for preventing the onset and / or recurrence of stroke by administering a composition containing at least EPA-E and / or DHA-E as an active ingredient.
本発明の第十三の態様は、少なくともＥＰＡ−Ｅを有効成分として含有する組成物を投与することを特徴とする、脳卒中の発症および／または再発を予防する方法である。あるいは、本発明の第十三の態様は、少なくともＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを有効成分として含有する組成物を投与することを特徴とする、脳卒中の発症および／または再発を予防する方法である。 A thirteenth aspect of the present invention is a method for preventing the onset and / or recurrence of stroke, which comprises administering a composition containing at least EPA-E as an active ingredient. Alternatively, the thirteenth aspect of the present invention is a method for preventing the onset and / or recurrence of stroke, which comprises administering a composition containing at least EPA-E and / or DHA-E as an active ingredient It is.
本発明の第十四の態様は、脳卒中の発症および／または再発を予防するための組成物を製造するためのＥＰＡ−Ｅの使用である。あるいは、本発明の第十四の態様は、脳卒中の発症および／または再発を予防するための組成物を製造するためのＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅの使用である。 The fourteenth aspect of the present invention is the use of EPA-E for manufacturing a composition for preventing the onset and / or recurrence of stroke. Alternatively, the fourteenth aspect of the present invention is the use of EPA-E and / or DHA-E for the manufacture of a composition for preventing the onset and / or recurrence of stroke.
本発明の効果が得られれば全脂肪酸中のＥＰＡ−Ｅ含量比および投与量は特に問わないが、ＥＰＡ−Ｅは高純度のもの、例えば、全脂肪酸およびその誘導体中のＥＰＡ−Ｅ含量比が４０質量％以上のものが好ましく、９０質量％以上のものが更に好ましく、９６．５質量％以上のものが更に好ましい。１日投与量はＥＰＡ−Ｅとして、０．３〜６ｇ／日、好ましくは０．９〜３．６ｇ／日、更に好ましくは１．８〜２．７ｇ／日が例示される。他に含有されるに好ましい脂肪酸としてはω−３系長鎖不飽和脂肪酸、特に、ＤＨＡ−Ｅが挙げられる。本発明の効果が得られればＥＰＡ−Ｅ／ＤＨＡ−Ｅの組成比、全脂肪酸中のＥＰＡ−Ｅ＋ＤＨＡ−Ｅの含量比およびＥＰＡ−Ｅ＋ＤＨＡ−Ｅの投与量は特に問わないが、好ましい組成比として、ＥＰＡ−Ｅ／ＤＨＡ−Ｅは、０．８以上であることが好ましく、更に好ましくは、１．０以上、より好ましくは、１．２以上である。ＥＰＡ−Ｅ＋ＤＨＡ−Ｅは高純度のもの、例えば、全脂肪酸およびその誘導体中のＥＰＡ−Ｅ＋ＤＨＡ−Ｅ含量比が４０質量％以上のものが好ましく、８０質量％以上のものが更に好ましく、９０質量％以上のものが更に好ましい。１日投与量はＥＰＡ−Ｅ＋ＤＨＡ−Ｅとして、０．３〜１０ｇ／日、好ましくは０．５〜６ｇ／日、更に好ましくは１〜４ｇ／日が例示される。他の長鎖飽和脂肪酸含量は少ないことが好ましく、長鎖不飽和脂肪酸でもω−６系、特にアラキドン酸含量は少ないことが望まれ、２質量％未満が好ましく、１質量％未満が更に好ましい。 As long as the effects of the present invention are obtained, the EPA-E content ratio and dose in total fatty acids are not particularly limited, but EPA-E has a high purity, for example, the EPA-E content ratio in total fatty acids and derivatives thereof. 40% by weight or more is preferable, 90% by weight or more is more preferable, and 96.5% by weight or more is more preferable. The daily dosage is 0.3 to 6 g / day, preferably 0.9 to 3.6 g / day, and more preferably 1.8 to 2.7 g / day as EPA-E. Other preferable fatty acids to be contained include ω-3 long-chain unsaturated fatty acids, particularly DHA-E. As long as the effect of the present invention is obtained, the composition ratio of EPA-E / DHA-E, the content ratio of EPA-E + DHA-E in all fatty acids, and the dose of EPA-E + DHA-E are not particularly limited. , EPA-E / DHA-E is preferably 0.8 or more, more preferably 1.0 or more, and still more preferably 1.2 or more. EPA-E + DHA-E is of high purity, for example, EPA-E + DHA-E content ratio in total fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 80% by mass or more, and 90% by mass The above is more preferable. The daily dose is exemplified as EPA-E + DHA-E, 0.3 to 10 g / day, preferably 0.5 to 6 g / day, and more preferably 1 to 4 g / day. The content of other long-chain saturated fatty acids is preferably low, and even long-chain unsaturated fatty acids are desired to have a low ω-6 type, particularly arachidonic acid content, preferably less than 2% by mass, and more preferably less than 1% by mass.
本発明の組成物は、ＥＰＡ−Ｅおよび／またはＤＨＡ−Ｅを含有し、健常人あるいは高脂血症、糖尿病、高血圧等の脳卒中の危険因子を有するヒトに対して経口投与することにより脳卒中の発症および／または再発を予防する効果を有している。特に、高脂血症患者でＨＭＧ−ＣｏＡ ＲＩによる治療を行なったにもかかわらず発症および／または再発する脳卒中の予防効果を有している。また、本発明の組成物はＨＭＧ−ＣｏＡ ＲＩとの併用効果を有し、併用することでさらに脳卒中の発症および／または再発を予防することが可能である。 The composition of the present invention contains EPA-E and / or DHA-E, and is orally administered to a healthy person or a human having a risk factor for stroke such as hyperlipidemia, diabetes, and hypertension. Has the effect of preventing onset and / or recurrence. In particular, it has a prophylactic effect on stroke that develops and / or recurs despite hyperlipidemia patients treated with HMG-CoA RI. In addition, the composition of the present invention has a combined effect with HMG-CoARI, and it is possible to further prevent the onset and / or recurrence of stroke by using in combination.
本発明の組成物は、脳卒中の発症および／または再発を予防する為に通常用いられる薬剤、例えば、アスピリン、チクロピジン、クロピドグレル（clopidogrel）、シロスタゾールなどの抗血小板薬；ワルファリン、ヘパリン、キシメラガトラン（ximelagatran）などの抗凝固薬；アンジオテンシンＩＩ受容体拮抗薬（カンデサルタン、ロサルタン、等）、アンジオテンシン変換酵素阻害薬、カルシウムチャネル拮抗薬（アムロジピン、シルニジピン、等）、α１遮断薬などの高血圧治療薬；αグルコシダーゼ阻害薬（ボグリボース、アカルボース、等）、ビグアナイド系薬剤、チアゾリジンジオン系薬剤（ピオグリタゾン、ロシグリタゾン、リボグリタゾン、等）、速効型インスリン分泌促進剤（ミチグリニド、ナテグリニド、等）などの糖尿病用薬または耐糖能異常改善薬；上述のＨＭＧ−ＣｏＡ ＲＩ、フィブラート系薬剤、スクアレン合成酵素阻害剤（ＴＡＫ−４７５等）、コレステロール吸収阻害剤（エゼチミブ等）などの抗高脂血症薬、などから選ばれる少なくとも１つと適宜組み合わせて用いることができる。なお、本発明の組成物は、利便性を高めるために、上記ＨＭＧ−ＣｏＡ ＲＩおよび／またはその他の少なくとも１種の薬剤とともに１つの包装体に包装されて使用することもできる。 The composition of the present invention is a drug that is commonly used to prevent the onset and / or recurrence of stroke, for example, antiplatelet drugs such as aspirin, ticlopidine, clopidogrel, cilostazol; warfarin, heparin, ximelagatran Anticoagulants such as: angiotensin II receptor antagonist (candesartan, losartan, etc.), angiotensin converting enzyme inhibitor, calcium channel antagonist (amlodipine, cilnidipine, etc.), antihypertensive drugs such as α1 blocker; α glucosidase inhibitor Drugs for diabetes such as drugs (voglibose, acarbose, etc.), biguanides, thiazolidinediones (pioglitazone, rosiglitazone, riboglitazone, etc.), fast-acting insulin secretagogues (mitiglinide, nateglinide, etc.) Or anti-hyperlipidemic drugs such as HMG-CoA RI, fibrate drugs, squalene synthase inhibitors (TAK-475 etc.), cholesterol absorption inhibitors (ezetimibe etc.), etc. It can be used in appropriate combination with at least one selected. In addition, in order to improve the convenience, the composition of this invention can also be packaged and used for the said HMG-CoA RI and / or other at least 1 sort (s) of other chemical | medical agents.
本発明の組成物は魚油あるいは魚油の濃縮物に比べ、飽和脂肪酸やアラキドン酸等の脳卒中に対して好ましくない不純物が少なく、栄養過多やビタミンＡ過剰摂取の問題もなく作用効果を発揮することが可能である。また、エステル体のため主にトリグリセリド体である魚油等に比べて酸化安定性が高く、通常の酸化防止剤添加により十分安定な組成物を得ることが可能である。従って、ＥＰＡ−Ｅを用いることで、初めて臨床上実用可能な脳卒中の発症および／または再発の予防用の組成物が得られた。 Compared to fish oil or fish oil concentrate, the composition of the present invention has less undesirable impurities for strokes such as saturated fatty acids and arachidonic acid, and can exert its effects without problems of overnutrition and vitamin A overdose. Is possible. Further, since it is an ester, it has a higher oxidation stability than fish oil or the like, which is mainly a triglyceride, and a sufficiently stable composition can be obtained by adding a normal antioxidant. Therefore, by using EPA-E, a composition for preventing the onset and / or recurrence of stroke that is clinically practical for the first time was obtained.
本明細書において、「イコサペント酸」の語は、全−シス−５，８，１１，１４，１７−イコサペント酸（all-cis-5,8,11,14,17-icosapentaenoic acid）である。 In this specification, the term "icosapentaenoic acid" is all-cis-5,8,11,14,17-icosapentaenoic acid (all-cis-5,8,11,14,17-icosapentaenoic acid).
本明細書において、「脳卒中」の語は、脳血管障害により急激に意識障害、神経症状が出現する病態と定義され、脳出血（高血圧性脳内出血、等）、脳梗塞、一過性脳虚血発作、くも膜下出血、脳血栓（アテローム血栓性脳梗塞、等）、脳塞栓（心原性脳塞栓症、等）、ラクナ梗塞などを含む。 In the present specification, the term “stroke” is defined as a pathological condition in which consciousness disorder and neurological symptoms suddenly appear due to cerebrovascular disorder, such as cerebral hemorrhage (hypertensive intracerebral hemorrhage, etc.), cerebral infarction, transient cerebral ischemia. Includes seizures, subarachnoid hemorrhage, cerebral thrombus (atherothrombotic cerebral infarction, etc.), cerebral embolism (cardiogenic cerebral embolism, etc.), lacunar infarction and the like.
本明細書において、「高脂血症患者」の語は、血清Ｔ−Ｃｈｏ濃度増加、血清ＬＤＬ−Ｃｈｏ濃度増加、血清ＨＤＬ−Ｃｈｏ濃度低下あるいは血清ＴＧが増加した患者である。狭義には、高コレステロール血症（血清Ｔ−Ｃｈｏ濃度が約２２０ｍｇ／ｄＬ以上、更に狭義には２５０ｍｇ／ｄＬ以上）、高ＬＤＬ−Ｃｈｏ血症（血清ＬＤＬ−Ｃｈｏ濃度が１４０ｍｇ／ｄＬ以上）、低ＨＤＬ−Ｃｈｏ血症（血清ＨＤＬ−Ｃｈｏ濃度が４０ｍｇ／ｄＬ未満）あるいは高ＴＧ血症（血清ＴＧが１５０ｍｇ／ｄＬ以上）のいずれか１つを満たす患者を指す。各脂質の血清中濃度は、通常、空腹時に採血された検体を用いて、公知の方法により測定、算出することができる。血清ＴＧ／ＨＤＬ−Ｃ比は、血清トリグリセリド（ＴＧ）濃度を血清ＨＤＬ−コレステロール（ＨＤＬ−Ｃ）で除した値である。 As used herein, the term “hyperlipidemic patient” is a patient who has increased serum T-Cho concentration, increased serum LDL-Cho concentration, decreased serum HDL-Cho concentration, or increased serum TG. In a narrow sense, hypercholesterolemia (serum T-Cho concentration is about 220 mg / dL or more, more narrowly 250 mg / dL or more), high LDL-Choemia (serum LDL-Cho concentration is 140 mg / dL or more), It refers to a patient who satisfies either one of low HDL-Choemia (serum HDL-Cho concentration is less than 40 mg / dL) or hyperTGemia (serum TG is 150 mg / dL or more). The serum concentration of each lipid can usually be measured and calculated by a known method using a sample collected on an empty stomach. The serum TG / HDL-C ratio is a value obtained by dividing the serum triglyceride (TG) concentration by serum HDL-cholesterol (HDL-C).
ＴＧ／ＨＤＬ−Ｃ比は、健常人を対象としたMaruyamaらの報告（J. Atheroscler. Thromb.，１０，１８６−１９１（２００３））において、ＬＤＬの粒子径と逆相関することが知られており、ＴＧ／ＨＤＬ−Ｃ比が１の時、ＬＤＬの粒径が２５．５ｎｍとなる相関関係が確認されている。ＬＤＬの中で、粒径２５．５ｎｍ以下のものは、別名、超悪玉コレステロールと呼ばれるｓｄＬＤＬ（small, dense ＬＤＬ）であり、強力な動脈硬化促進性を有することから、近年、ＴＧ／ＨＤＬ−Ｃ比は、動脈硬化性疾患の予後を判断する指標の一つとして注目されている。上述の相関関係から、ＴＧ／ＨＤＬ−Ｃ比が１以上でｓｄＬＤＬが出現し、動脈硬化性疾患のリスクが高まると考えられるが、本願においては、ＴＧの基準値である１５０ｍｇ／ｄＬと、ＨＤＬ−Ｃの基準値である４０ｍｇ／ｄＬから、血清ＴＧ／ＨＤＬ−Ｃ比のカットオフ値を３．７５に設定した。血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者群は、血中ｓｄＬＤＬ濃度が高く、脳卒中の発症リスクが高いと想定される。ＴＧ高値、ＨＤＬ−Ｃ低値とも、それぞれ、動脈硬化性疾患のリスクファクターと考えられている。また、ＴＧが４００ｍｇ／ｄＬ以上の場合、高カイロミクロン血症が疑われるが、高カイロミクロン血症は、動脈硬化促進性ではないと考えられている。この観点から、実施例における、登録時のＴＧ／ＨＤＬ−Ｃ比の値に基づく解析結果については、登録時のＴＧが４００以上の症例を解析対象から除外している。 In the report of Maruyama et al. (J. Atheroscler. Thromb., 10, 186-191 (2003)) targeting healthy individuals, the TG / HDL-C ratio is known to be inversely correlated with the LDL particle size. In addition, when the TG / HDL-C ratio is 1, a correlation is confirmed that the LDL particle size is 25.5 nm. Among LDLs, those having a particle size of 25.5 nm or less are sdLDL (small, dense LDL), also called super-bad cholesterol, and have a strong ability to promote arteriosclerosis. Therefore, in recent years, TG / HDL-C Ratio is attracting attention as one of the indicators for determining the prognosis of arteriosclerotic disease. From the above correlation, it is considered that sdLDL appears when the TG / HDL-C ratio is 1 or more, and the risk of arteriosclerotic disease is increased. In the present application, the reference value of TG, 150 mg / dL, and HDL The cut-off value of the serum TG / HDL-C ratio was set to 3.75 from the reference value of -C of 40 mg / dL. A group of patients with a serum TG / HDL-C ratio of 3.75 or higher has a high blood sdLDL concentration and is assumed to have a high risk of developing stroke. Both high TG values and low HDL-C values are considered risk factors for arteriosclerotic diseases. Moreover, when TG is 400 mg / dL or more, hyperchylomicronemia is suspected, but it is considered that hyperchylomicronemia is not pro-arteriosclerotic. From this viewpoint, as for the analysis result based on the value of the TG / HDL-C ratio at the time of registration in the examples, cases having a TG of 400 or more at the time of registration are excluded from the analysis target.
本明細書において、「ＥＰＡ−ＥとＨＭＧ−ＣｏＡ ＲＩとの併用」の語は、ＥＰＡ−ＥとＨＭＧ−ＣｏＡ ＲＩとを同時に投与する態様と、別々に投与する態様が含まれる。同時に投与される場合、配合剤とすることも２剤とすることもできる。別々に投与される場合、ＥＰＡ−ＥをＨＭＧ−ＣｏＡ ＲＩより先に投与することも後に投与することもできる。また、ＥＰＡ−ＥとＨＭＧ−ＣｏＡ ＲＩの投与量および投与比率は任意に設定することができる。 In the present specification, the term “combination of EPA-E and HMG-CoA RI” includes a mode in which EPA-E and HMG-CoA RI are administered simultaneously and a mode in which they are administered separately. When administered simultaneously, it can be a compounding agent or two agents. When administered separately, EPA-E can be administered before or after HMG-CoA RI. Moreover, the dosage and administration ratio of EPA-E and HMG-CoA RI can be arbitrarily set.
本明細書において、「ＥＰＡ−Ｅおよび／またはＤＨＡ−ＥとＨＭＧ−ＣｏＡ ＲＩとの併用」の語は、ＥＰＡ−Ｅおよび／またはＤＨＡ−ＥとＨＭＧ−ＣｏＡ ＲＩとを同時に投与する態様と、別々に投与する態様が含まれる。同時に投与される場合、配合剤とすることも２剤とすることもできる。別々に投与される場合、ＥＰＡ−Ｅおよび／またはＤＨＡ−ＥをＨＭＧ−ＣｏＡ ＲＩより先に投与することも後に投与することもできる。また、ＥＰＡ−Ｅおよび／またはＤＨＡ−ＥとＨＭＧ−ＣｏＡ ＲＩの投与量および投与比率は任意に設定することができる。 In the present specification, the term “combination of EPA-E and / or DHA-E and HMG-CoA RI” means that EPA-E and / or DHA-E and HMG-CoA RI are administered simultaneously, Embodiments that are administered separately are included. When administered simultaneously, it can be a compounding agent or two agents. When administered separately, EPA-E and / or DHA-E can be administered prior to or after the HMG-CoA RI. Moreover, the dose and administration ratio of EPA-E and / or DHA-E and HMG-CoA RI can be arbitrarily set.
本発明の組成物は、単独投与で脳卒中の発症および／または再発予防作用を有し、特にＨＭＧ−ＣｏＡ ＲＩ単独投与では予防できない脳卒中の発症および／または再発の予防効果が期待される。また、ＥＰＡ−Ｅは、血清Ｔ−Ｃｈｏ濃度および血清ＴＧ低下作用のほかに、アラキドン酸カスケード阻害に基づく血小板凝集抑制作用等のＨＭＧ−ＣｏＡ ＲＩとは異なる薬理作用を有しており、ＨＭＧ−ＣｏＡ ＲＩとの併用投与で上記効果を発揮させることもできる。 The composition of the present invention has the effect of preventing the onset and / or recurrence of stroke when administered alone, and is expected to have the effect of preventing the onset and / or recurrence of stroke that cannot be prevented by administration of HMG-CoA RI alone. EPA-E has a pharmacological action different from HMG-CoA RI such as platelet aggregation inhibitory action based on arachidonic acid cascade inhibition in addition to serum T-Cho concentration and serum TG lowering action. The above effects can also be exerted by co-administration with CoA RI.
ＥＰＡ−ＥおよびＤＨＡ−Ｅは高度に不飽和であるため、抗酸化剤たとえばブチレート化ヒドロキシトルエン、ブレチート化ヒドロキシアニソール、プロピルガレート、没食子酸、医薬として許容されうるキノンおよびα−トコフェロールを有効量含有させることが望ましい。 Since EPA-E and DHA-E are highly unsaturated, contain effective amounts of antioxidants such as butylated hydroxytoluene, brecitrated hydroxyanisole, propyl gallate, gallic acid, pharmaceutically acceptable quinones and α-tocopherol It is desirable to make it.
製剤の剤形としては、錠剤、カプセル剤、マイクロカプセル剤、顆粒剤、細粒剤、散剤、経口用液体製剤、シロップ剤、ゼリー剤の形で、経口で患者に投与されるが、とりわけカプセルたとえば、軟質カプセルやマイクロカプセルに封入しての経口投与が好ましい。
なお、高純度ＥＰＡ−Ｅ含有軟カプセル剤であるエパデールおよびエパデールＳは副作用の発現が少ない安全な閉塞性動脈硬化症および高脂血症治療薬として既に日本で市販されており、全脂肪酸中のＥＰＡ−Ｅ含量比は９６．５質量％以上である。また、ＥＰＡ−Ｅを約４６質量％およびＤＨＡ−Ｅを約３８質量％含有する軟質カプセル剤（オマコール、Omacor（ロスプロダクツ、Ross Products））が高ＴＧ血症治療薬として既にアメリカ等で市販されている。これらを入手して使用することもできる。
The dosage form of the preparation is orally administered to patients in the form of tablets, capsules, microcapsules, granules, fine granules, powders, liquid preparations for oral use, syrups, and jelly, but especially capsules For example, oral administration in a soft capsule or microcapsule is preferable.
In addition, Epadale and Epadale S, which are high-purity EPA-E-containing soft capsules, are already marketed in Japan as safe therapeutic agents for obstructive arteriosclerosis and hyperlipidemia with few side effects. The EPA-E content ratio is 96.5% by mass or more. In addition, a soft capsule (Omacol, Omacor (Ross Products)) containing about 46% by mass of EPA-E and about 38% by mass of DHA-E has already been marketed in the United States as a therapeutic agent for hyperTG. ing. These can also be obtained and used.
本発明の脳卒中の発症および／または再発を予防するための組成物の投与量および投与期間は対象となる作用を現すのに十分な量および期間とされるが、その剤形、投与方法、１日当たりの投与回数、症状の程度、体重、年齢等によって適宜増減することができる。経口投与する場合はＥＰＡ−Ｅとして０．３〜６ｇ／日、好ましくは０．９〜３．６ｇ／日、更に好ましくは１．８〜２．７ｇ／日を３回に分けて投与するが、必要に応じて全量を１回あるいは数回に分けて投与してもよい。投与時間は食中ないし食後が好ましく、食直後（３０分以内）投与が更に好ましい。上記投与量を経口投与する場合、投与期間は１年以上、好ましくは２年以上、更に好ましくは３年以上、とりわけ好ましくは５年以上であるが、脳卒中の発症および／または再発の危険度が高い状態が続いている間は投与を継続することが望ましい。場合により１日〜３ヵ月程度、好ましくは１週間〜１ヵ月程度の休薬期間を設けることもできる。 The dose and administration period of the composition for preventing the onset and / or recurrence of the stroke of the present invention are an amount and a period sufficient to exert the intended effect. The dosage may be adjusted according to the number of administrations per day, the degree of symptoms, body weight, age, etc. In the case of oral administration, 0.3 to 6 g / day, preferably 0.9 to 3.6 g / day, more preferably 1.8 to 2.7 g / day as EPA-E is administered in three divided doses. If necessary, the whole amount may be administered once or divided into several times. The administration time is preferably during or after meals, more preferably immediately after meals (within 30 minutes). When the above dose is administered orally, the administration period is 1 year or more, preferably 2 years or more, more preferably 3 years or more, and particularly preferably 5 years or more. However, the risk of stroke onset and / or recurrence is high. It is desirable to continue administration while high conditions continue. In some cases, a drug holiday of about 1 day to 3 months, preferably about 1 week to 1 month can be provided.
ＨＭＧ−ＣｏＡ ＲＩの投与量はその薬剤の用法・用量の範囲内が好ましいが、その種類、剤形、投与方法、１日当たりの投与回数、症状の程度、体重、性別、年齢等によって適宜増減することができる。経口投与する場合は０．０５〜２００ｍｇ／日、好ましくは０．１〜１００ｍｇ／日を２〜３回に分けて投与するが、必要に応じて全量を１回あるいは数回に分けて投与してもよい。また、ＥＰＡ−Ｅの投与量に応じて減量することも可能である。 The dosage of HMG-CoA RI is preferably within the range of dosage and administration of the drug, but it may be appropriately increased or decreased depending on the type, dosage form, administration method, number of administrations per day, symptom level, body weight, sex, age, etc. be able to. In the case of oral administration, 0.05 to 200 mg / day, preferably 0.1 to 100 mg / day, is administered in 2 to 3 divided doses, and the entire dose is administered once or in several divided doses as necessary. May be. It is also possible to reduce the dose according to the dose of EPA-E.
なお、プラバスタチンナトリウム（メバロチンTM錠・細粒（三共））、シンバスタチン（リポバスTM錠（萬有製薬））、フルバスタチンナトリウム（ローコールTM錠（ノバルティスファーマおよび田辺製薬））、アトルバスタチンカルシウム水和物（リピトールTM錠（アステラス製薬およびファイザー製薬））、ピタバスタチンカルシウム（リバロTM錠（興和および三共））、およびロスバスタチンカルシウム（クレストールTM錠（アストラゼネカおよび塩野義製薬））は高脂血症治療薬として既に日本で市販されており、また、ロバスタチン（メバコールTM錠（メルク））は高脂血症治療薬として既にアメリカで市販されており、これらの薬剤から少なくとも１つを入手してそれぞれの用法に従って適宜組み合わせて投与することができる。 In addition, pravastatin sodium (mevalotin TM tablets / fine granules (Sankyo)), simvastatin (Lipobas TM tablets (Ariyu Pharmaceutical)), fluvastatin sodium (Locall TM tablets (Novatis Pharma and Tanabe Seiyaku)), atorvastatin calcium hydrate ( Lipitor ™ tablets (Astellas and Pfizer), pitavastatin calcium (Rivalo ™ tablets (Kowa and Sankyo)), and rosuvastatin calcium (Crestor ™ tablets (AstraZeneca and Shionogi)) have already been used as antihyperlipidemic drugs Lovastatin (Mevacol ™ tablets (Merck)) is already marketed in the United States as a hyperlipidemic agent, and at least one of these drugs is obtained and appropriately used according to the respective usage. Can be administered in combination.
それぞれの、好ましい一日用量は、プラバスタチンナトリウムでは５〜６０ｍｇ、好ましくは１０〜２０ｍｇ、シンバスタチンでは２．５〜６０ｍｇ、好ましくは５〜２０ｍｇ、フルバスタチンナトリウムでは１０〜１８０ｍｇ、好ましくは２０〜６０ｍｇ、アトルバスタチンカルシウム水和物では５〜１２０ｍｇ、好ましくは１０〜４０ｍｇ、ピタバスタチンカルシウムでは０．５〜１２ｍｇ、好ましくは１〜４ｍｇ、ロスバスタチンカルシウムでは１．２５〜６０ｍｇ、好ましくは２．５〜２０ｍｇ、ロバスタチンでは５〜１６０ｍｇ、好ましくは１０〜８０ｍｇ、セリバスタチンナトリウムでは０．０７５〜０．９ｍｇ、好ましくは０．１５〜０．３ｍｇがそれぞれ例示されるが、これらに限定されない。 Each preferred daily dose is 5-60 mg, preferably 10-20 mg for pravastatin sodium, 2.5-60 mg, preferably 5-20 mg for simvastatin, 10-180 mg, preferably 20-60 mg for fluvastatin sodium, 5-120 mg for atorvastatin calcium hydrate, preferably 10-40 mg, 0.5-12 mg for pitavastatin calcium, preferably 1-4 mg, 1.25-60 mg for rosuvastatin calcium, preferably 2.5-20 mg, for lovastatin Examples are 5 to 160 mg, preferably 10 to 80 mg, and cerivastatin sodium are 0.075 to 0.9 mg, preferably 0.15 to 0.3 mg, but are not limited thereto.
以下に、本発明組成物の効果を実施例をもって示すが、本発明はこれらに限定されるものではない。
実施例１（ＥＰＡ−Ｅの長期脳卒中発症予防作用）
試験方法
本試験は、２００５年のアメリカ心臓病学会年会において発表された高純度ＥＰＡ製剤に関する大規模臨床試験であるＪＥＬＩＳ（Japan ＥＰＡ Lipid Intervention Study）で得られた結果の一部を解析して得られたものである。なお、当該学会ではＥＰＡが冠動脈イベントの抑制効果を有することについて発表されたが、ＥＰＡの脳卒中に対する効果については開示も示唆もされていない（ＪＥＬＩＳの概要についてはMedical Tribune、２００５年１１月１７日発行、特別企画第３部、ｐ７５−７６、および、Circulation、１１２巻、２１号、ｐ３３６２−３３６３（２００５）参照）。
すなわち、ＪＥＬＩＳ試験の対象患者（血清Ｔ−Ｃｈｏ濃度が２５０ｍｇ／ｄＬ以上である男性は４０〜７５歳、女性は閉経後〜７５歳の高脂血症患者；脳卒中発症後急性期の患者を対象外とするために脳卒中発症後６ケ月以内の患者は試験対象から除外）１８，６４５例（ＥＰＡ−Ｅ群（９，３２６例）と対照群（９，３１９例））のうち、脳卒中（脳血栓、脳塞栓、脳出血、くも膜下出血、一過性脳虚血発作）既往を有するＥＰＡ−Ｅ群４８５名、対照群４５７名、について、投与開始から５年間の脳卒中再発の有無を観察し、解析した。さらに、登録時の血清ＴＧ／ＨＤＬ−Ｃ比が確認できた症例（ただし、ＴＧ値が４００ｍｇ／ｄＬ以上の症例を除く）について、登録時の血清ＴＧ／ＨＤＬ−Ｃ比の値で３群に分けた結果についても同様に解析した。ＥＰＡ−Ｅ群は、エパデール（持田製薬）を、通常、成人１回６００ｍｇを１日３回毎食直後に経口投与した。ただし、血清ＴＧの異常を呈する場合は、その程度により１回９００ｍｇ、１日３回まで増量できることとした。また、両群ともベース薬（基礎治療）として、プラバスタチンナトリウム（メバロチンTM錠・細粒（三共））、シンバスタチン（リポバスTM錠（萬有製薬））あるいはアトルバスタチンカルシウム水和物（リピトールTM錠（アステラス製薬およびファイザー製薬））を使用し、それぞれ定められた用法・用量の範囲で経口投与した。
The effects of the composition of the present invention will be shown below with examples, but the present invention is not limited to these examples.
Example 1 (Prolonged stroke prevention effect of EPA-E)
Test Method This study analyzed a part of the results obtained in the Japan EPA Lipid Intervention Study (JELIS), a large-scale clinical study on a high-purity EPA formulation presented at the 2005 Annual Meeting of the American College of Cardiology. It is obtained. In addition, although the EPA has announced that the EPA has a coronary event suppression effect, the disclosure does not disclose or suggest the effect of EPA on stroke (Medical Tribune for an overview of JELIS, November 17, 2005) Issue, Special Planning Part 3, p75-76 and Circulation, Vol. 112, No. 21, p. 3362-3363 (2005)).
In other words, patients targeted for the JELIS test (hyperlipidemic patients 40 to 75 years old for men with serum T-Cho concentrations of 250 mg / dL or more, and postmenopausal to 75 years for women; patients in the acute phase after stroke onset) Patients out of the 6 months after the onset of stroke were excluded from the study) because of out of 18,645 cases (EPA-E group (9,326 cases) and control group (9,319 cases)). , Cerebral embolism, cerebral hemorrhage, subarachnoid hemorrhage, transient cerebral ischemic attack) 485-person in EPA-E group and 457 patients in control group were observed and analyzed for the recurrence of stroke for 5 years from the start of administration did. Furthermore, for cases in which the serum TG / HDL-C ratio at the time of registration was confirmed (except for cases with a TG value of 400 mg / dL or more), the serum TG / HDL-C ratio at the time of registration was classified into 3 groups. The divided results were similarly analyzed. In the EPA-E group, Epadale (Mochida Pharmaceutical Co., Ltd.) was usually orally administered at an adult dose of 600 mg three times a day immediately after meals. However, when serum TG abnormality was observed, the dose could be increased up to 900 mg at a time, up to 3 times a day. In both groups, pravastatin sodium (mevalotin TM tablets / fine granules (Sankyo)), simvastatin (Lipovas TM tablets (Ariyu Pharmaceutical)) or atorvastatin calcium hydrate (Lipitor TM tablets (Astellas) Pharmaceuticals and Pfizer Pharmaceuticals)) and were orally administered within the prescribed dosage range.
結果
観察期間５年における脳卒中発症（再発）例数、発症率（％）およびＥＰＡ−Ｅ群の対照群に対するオッズ比の集計結果を表１に示す。オッズ比はＥＰＡ−Ｅ群の発症率／対照群の発症率の計算式で、脳卒中の発症率の抑制率は{（対照群の脳卒中の発症率−ＥＰＡ−Ｅ群の脳卒中の発症率）／対照群の脳卒中の発症率}×１００の計算式でそれぞれ算出した。
Stroke development in results observation period 5 years (recurrent) Example number, the counting result odds ratio for incidence (%) and EPA-E group in the control group shown in Table 1. The odds ratio is a formula for calculating the incidence of the EPA-E group / the incidence of the control group, and the suppression rate of the incidence of the stroke is {(the incidence of the stroke in the control group−the incidence of the stroke in the EPA-E group) / The incidence was calculated using the formula: Stroke rate of control group} × 100.
ＥＰＡ−Ｅ投与により、脳卒中既往を有する患者の５年間に渡る脳卒中発症率は６．８％と対照群の脳卒中の発症率の１０．５％に比べて低値を示した。オッズ比は０．６４８であり、脳卒中の発症率はＥＰＡ−Ｅ投与により対照群に比べて約３５％減少した。すなわち、ＥＰＡ−Ｅ投与による脳卒中の発症および／または再発予防効果が確認された。 By administration of EPA-E, the stroke incidence rate over 5 years for patients with a history of stroke was 6.8%, which was lower than the 10.5% rate of stroke incidence in the control group. The odds ratio was 0.648, and the incidence of stroke was reduced by about 35% compared to the control group by EPA-E administration. That is, the effect of stroke onset and / or recurrence prevention by EPA-E administration was confirmed.
また、群間での背景（喫煙、糖尿病、等）の偏りを考慮して統計解析した上記データについて、脳卒中の発症率を縦軸に、試験開始後の時間経過を横軸にとり作成したグラフを図１に、投与開始から１〜５年経過時の脳卒中の発症率およびＥＰＡ−Ｅ投与群における抑制率を表２に示す。 In addition, for the above data that was statistically analyzed considering the bias of background (smoking, diabetes, etc.) between groups, a graph was created with the incidence of stroke on the vertical axis and the time course after the start of the test on the horizontal axis. FIG. 1 shows the incidence of stroke after 1 to 5 years from the start of administration and the suppression rate in the EPA-E administration group.
ＥＰＡ−Ｅ投与により、脳卒中発症率が減少していることが認められるが、特に、投与開始から３年経過以降において、脳卒中発症率の減少が著しいことが確認された。 It has been confirmed that the EPA-E administration reduces the stroke incidence rate, but it has been confirmed that the stroke incidence rate is particularly markedly reduced after 3 years from the start of administration.
また、発症した脳卒中の種類別に、対照群とＥＰＡ−Ｅ投与群の発症例数を確認したところ、脳血栓および梗塞系の合計について、表３に示す結果となった。また、出血系の合計についても、ＥＰＡ−Ｅ投与群で、発症例、発症率とも低値であった。 Moreover, when the number of onset cases of the control group and the EPA-E administration group was confirmed according to the type of stroke that occurred, the results shown in Table 3 were obtained for the total of cerebral thrombosis and infarct system. In addition, the total number of bleeding cases was also low in the EPA-E administration group in both the onset cases and the onset rate.
同様に、登録時の血清ＴＧ／ＨＤＬ−Ｃ比が確認できた症例（ただし、ＴＧ値が４００ｍｇ／ｄＬ以上の症例を除く）について、登録時の血清ＴＧ／ＨＤＬ−Ｃ比の値で３群に分けたそれぞれの群について、観察期間５年における脳卒中発症（再発）例数、発症率（％）およびＥＰＡ−Ｅ群の対照群に対するオッズ比の集計結果を表４に示す。
オッズ比はＥＰＡ−Ｅ群の発症率／対照群の発症率の計算式で、脳卒中の発症率の抑制率は{（対照群の脳卒中の発症率−ＥＰＡ−Ｅ群の脳卒中の発症率）／対照群の脳卒中の発症率}×１００の計算式でそれぞれ算出した。
Similarly, for cases in which the serum TG / HDL-C ratio at the time of registration was confirmed (excluding cases with a TG value of 400 mg / dL or more), the values of the serum TG / HDL-C ratio at the time of registration were 3 groups. Table 4 shows the number of stroke onset (recurrence) cases, incidence (%), and odds ratio of the EPA-E group with respect to the control group for each group divided into 2 groups.
The odds ratio is a formula for calculating the incidence of the EPA-E group / the incidence of the control group, and the suppression rate of the incidence of the stroke is {(the incidence of the stroke in the control group−the incidence of the stroke in the EPA-E group) / The incidence was calculated using the formula: Stroke rate of control group} × 100.
表４の結果から、登録時の血清ＴＧ／ＨＤＬ−Ｃ比が高いほど、脳卒中の発症率が高い傾向にあることが確認された。ＥＰＡ−Ｅ投与により、脳卒中の既往を有する５年間に渡る脳卒中発症率は対照群の発症率に比べて低値を示した。すなわち、血清ＴＧ／ＨＤＬ−Ｃ比が１未満の群では、対照群、ＥＰＡ−Ｅ群とも脳卒中の発症は認められなかったが、登録時の血清ＴＧ／ＨＤＬ−Ｃ比が１以上３．７５未満の群では、ＥＰＡ−Ｅ群の脳卒中発症率は５．７４％と対照群の脳卒中の発症率の９．０％に比べて低く、登録時の血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の群においても、ＥＰＡ−Ｅ群の脳卒中発症率は７．４％と対照群の脳卒中の発症率の１４．３％に比べて低値を示した。オッズ比は、それぞれ０．６４０および０．５１９であり、脳卒中の発症率はＥＰＡ−Ｅ投与により対照群に比べてそれぞれ約３６％、約４８％減少した。すなわち、ＥＰＡ−Ｅ投与による脳卒中の発症および／または再発予防効果が確認され、よりリスクの高いと想定される群において、ＥＰＡ−Ｅの効果がより高いという結果となった。 From the results in Table 4, it was confirmed that the higher the serum TG / HDL-C ratio at the time of registration, the higher the incidence of stroke. By administration of EPA-E, the stroke incidence over 5 years with a history of stroke was lower than that in the control group. That is, in the group having a serum TG / HDL-C ratio of less than 1, no onset of stroke was observed in either the control group or the EPA-E group, but the serum TG / HDL-C ratio at the time of registration was 1 or more and 3.75. In the EPA-E group, the stroke incidence in the EPA-E group is 5.74%, which is lower than the 9.0% stroke incidence in the control group, and the serum TG / HDL-C ratio at registration is 3.75. Also in the above group, the stroke incidence rate of the EPA-E group was 7.4%, which was lower than the stroke incidence rate of 14.3% of the control group. The odds ratios were 0.640 and 0.519, respectively, and the incidence of stroke was reduced by about 36% and about 48%, respectively, by administration of EPA-E compared to the control group. That is, the effect of EPA-E administration on the prevention of stroke onset and / or recurrence was confirmed, and the results showed that the effect of EPA-E was higher in the group that was assumed to be higher in risk.
また、登録時の血清ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者の脳卒中の発症率を縦軸に、試験開始後の時間経過を横軸にとり作成したグラフを図２に、投与開始から１〜５年経過時の脳卒中の発症率およびＥＰＡ−Ｅ投与群における抑制率を表５に示す。 In addition, a graph in which the vertical axis represents the stroke incidence of patients with a serum TG / HDL-C ratio of 3.75 or more at the time of registration and the horizontal axis represents the time course after the start of the test is shown in FIG. Table 5 shows the incidence of stroke after 1 to 5 years and the suppression rate in the EPA-E administration group.
ＥＰＡ−Ｅ投与により、脳卒中発症率が減少していることが認められるが、特に、投与開始から３年経過以降において、脳卒中発症率の減少が著しいことが確認された。また、表２に示した、全症例での経時的な結果と比較して、ＴＧ／ＨＤＬ−Ｃ比が３．７５以上の患者については、超悪玉コレステロールと呼ばれるｓｄＬＤＬ濃度がより高いと想定され、その結果として、脳卒中の発症リスクがより高いと想定される群に関する解析にも関わらず、１〜５年後のすべての計測点において、より高い抑制率が観察された。
以上より、脳卒中既往患者においてＥＰＡ−Ｅ投与による著明な脳卒中発症予防効果が確認された。
It has been confirmed that the EPA-E administration reduces the stroke incidence rate, but it has been confirmed that the stroke incidence rate is particularly markedly reduced after 3 years from the start of administration. In addition, compared to the results over time shown in Table 2, the sdLDL concentration called super-bad cholesterol is assumed to be higher for patients with a TG / HDL-C ratio of 3.75 or more. As a result, a higher inhibition rate was observed at all measurement points 1 to 5 years later, despite the analysis regarding the group that is assumed to have a higher risk of stroke occurrence.
From the above, a significant stroke prevention effect by EPA-E administration was confirmed in patients with a history of stroke.
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