JP4751257B2 - Composition for preventing cardiovascular events - Google Patents

Description

  The present invention relates to a composition for preventing the onset and / or recurrence of a cardiovascular event characterized by containing at least icosapentic acid ethyl ester (hereinafter abbreviated as EPA-E).

  The number of patients with lifestyle-related diseases such as diabetes, hyperlipidemia and hypertension is increasing due to the westernization of diet. These diseases eventually lead to arteriosclerotic diseases such as myocardial infarction, angina pectoris and cerebral infarction, and in some cases there is a risk of death. As treatment methods for arteriosclerotic diseases, treatment with drugs, surgical treatment methods such as vascular reconstruction, and the like are generally used.

  To prevent arteriosclerotic diseases or improve quality of life, it is important to reduce risk factors such as hyperlipidemia, diabetes, hypertension, and smoking habits as much as possible. As a result of the main epidemiological studies examining the incidence of hyperlipidemia and coronary artery disease, serum total cholesterol (hereinafter abbreviated as T-Cho) concentration or serum triglyceride (hereinafter abbreviated as TG) concentration and onset of coronary artery disease Positive correlation is shown. In particular, the serum low density lipoprotein cholesterol (hereinafter abbreviated as LDL-Cho) concentration has a stronger positive correlation, while the serum high density lipoprotein cholesterol (hereinafter abbreviated as HDL-Cho) concentration has a negative correlation. .

Hyperlipidemia is relatively easy to treat, and coronary arteries can be treated with potent hyperlipidemia treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (hereinafter abbreviated as HMG-CoA RI). Results have been obtained in large clinical trials that the onset of disease has been suppressed. For example, when pravastatin sodium is orally administered to male patients with hyperlipidemia who have no history of myocardial infarction for an average of 4.9 years, the serum T-Cho concentration decreases by 20% and the serum LDL-Cho concentration decreases by 26%. The serum HDL-Cho level increased by 5% and the serum TG decreased by 12%. As a result, the combined incidence of non-fatal myocardial infarction and cardiovascular death decreased by 31% (see Non-Patent Document 1). In addition, when simvastatin was orally administered to patients with angina pectoris or myocardial infarction for an average of 5.4 years, serum T-Cho concentration decreased by 25%, serum LDL-Cho concentration decreased by 35%, and serum HDL-Cho concentration Increased by 8% and serum TG decreased by 10%, resulting in a 34% decrease in the incidence of major cardiovascular events (see Non-Patent Document 2).
In other large-scale clinical trials using HMG-CoA RI, the rate of decreasing the incidence of cardiovascular events is about 20 to 30% (see, for example, Non-Patent Document 3). There is no.

  For patients within 3 months after the onset of acute myocardial infarction, a ω3 polyunsaturated fatty acid composition containing 850-882 mg of EPA-E and docosahexaenoic acid ethyl ester (hereinafter abbreviated as DHA-E) per day The combined incidence of cardiovascular death, non-fatal myocardial infarction, and non-fatal cerebral infarction combined with oral administration of capsules for 3.5 years decreased the incidence by 20%, of which cardiovascular death decreased by 30% It has been reported that non-lethal cardiovascular events were not effective (see Non-Patent Document 4). In addition, it has been reported that mortality decreased by administering 1 g of essential fatty acid containing 85% of EPA-E and DHA-E per day for 3.5 years to patients with a history of myocardial infarction. (See Patent Document 1). Patent Document 2 discloses that cardiovascular events are suppressed by a combined use of EPA or DHA and a cholesterol synthesis inhibitor.

High-purity EPA-E is marketed in Japan as an antihyperlipidemic drug under the trade names Epadale ^™ and Epadale S ^™ (Mochida Pharmaceutical Co., Ltd.). When abnormalities of serum TG are exhibited, the serum T-Cho concentration is 3 to 6% and serum TG is 14 to 20 by oral administration (increase up to 900 mg once, 3 times a day) depending on the degree. % (See Non-Patent Document 5) and these effects are expected to have an effect on cardiovascular events in hyperlipidemic patients (see Non-Patent Document 6).

On the other hand, as an option for treatment of ischemic heart disease, cardiovascular reconstruction, which is a surgical treatment method such as PTCA and coronary stenting, is widely performed mainly for severely ill patients. Cardiovascular events are likely to occur after surgery. For example, cardiovascular events after PTCA are often due to restenosis at the site where PTCA is performed (generally refers to progression of stenosis of 50% or more of enlargement due to PTCA) and appearance of new lesions, and the restenosis rate is 30 to 40 It is often recognized within 6 months at around%. Although the restenosis rate is reduced by using a stent, it cannot be said to be reliable (Non-patent Document 7 p.237).
Antiplatelet drugs are often used for drug therapy after cardiovascular reconstruction. For example, it is common knowledge that aspirin and ticlopidine (clopidogrel) are administered in combination at the time of stent insertion, and aspirin and cilostazol are also administered together to prevent stent thrombosis (Non-patent Document 7, p. 245 to 246). Management is particularly important.
There are cases where fish oil or ω3 fatty acid has been tried for restenosis in the unstable period after cardiovascular reconstruction, but there are reports that it is effective and invalid, and before reconstruction There is also a view that administration from is necessary. (Non-Patent Documents 8 to 11)
Reported that HMG-CoA RI, pravastatin, was administered for 2 years after PTCA, the restenosis rate decreased, and was effective in suppressing events (Non-Patent Document 12), 3-4 years immediately after percutaneous coronary intervention Although there has been a report that administration of fluvastatin has suppressed the onset of cardiac events (Non-patent Document 13), there is a demand for improvement of a therapeutic method that enables further suppression of cardiovascular events.

The New England Journal of the Medicine, 1995, 333, p1301-1307. The Lancet, 1994, 344, November 9, p1383-1389 Archives of Internal Medicine, 1999, 159, 1, p1793-1802. The Lancet, 1999, 354, August 7th, p447-455. Pharmaceutical interview form EPA formulation Epadale TM capsule 300, revised in July 2002, January 2003, p21-22 American Heart Journal, 2003, 146, 4, p613-620 Today's treatment guideline, 2003, School of Medicine, General Editor, Toru Yamaguchi, Mitsuo Kitahara p273, p245-246 J Am Coll Cardiol, May 17, 2005, 45 (10), p1723-8. Am Heart J, June 2002, 143 (6), E5 J Am Coll Cardiol, May 1999, 33 (6), p1619-26. Am J Cardiol 1996, 77, p31-36 Am J Cardiol, 1 October 2000, 86 (7), p742-6 JAMA, June 26, 2002, 287 (24), p3215-22. International Publication No. 00/48592 Pamphlet (Special Publication 2002-537252) US Pat. No. 6,159,993

  The object of the present invention is that cardiovascular disease death is still a major cause of death, and there are many cardiovascular events that cannot be prevented by treatment with HMG-CoA RI, and these cardiovascular events are problematic. The object is to provide a composition for preventing event onset and / or recurrence.

The present inventor has conducted intensive research to solve the above-mentioned problems, and as a result, EPA-E has prevented cardiovascular events from occurring and / or recurrence, and in particular, cardiovascular that occurs after an unstable period has passed after cardiovascular reconstruction. The present invention was completed by discovering that it has a preventive action against event onset and / or recurrence. That is, the present invention
(1) A composition for preventing the onset and / or recurrence of cardiovascular events, comprising at least EPA-E as an active ingredient.
Specifically,
(2) A composition for preventing the onset and / or recurrence of a cardiovascular event in a hyperlipidemic patient undergoing HMG-CoA RI treatment, containing at least EPA-E as an active ingredient.
(3) A composition for preventing the onset and / or recurrence of cardiovascular events in patients with a history of acute myocardial infarction, comprising at least EPA-E as an active ingredient.
(4) A composition for preventing the onset and / or recurrence of a cardiovascular event that occurs after an unstable period has passed after cardiovascular reconstruction, comprising at least EPA-E as an active ingredient.
(5) The composition according to (4), wherein administration is started after an unstable period has elapsed after cardiovascular reconstruction.
(6) A composition for preventing the onset and / or recurrence of a cardiovascular event for a patient after 6 months have passed since the execution of cardiovascular reconstruction, comprising at least EPA-E as an active ingredient.

(7) The composition according to any one of (4) to (6) above, wherein the administration is started after 6 months have passed since the cardiovascular reconstruction operation, and the administration is continued for at least 2 years.
(8) Cardiovascular reconstruction is percutaneous coronary lumen expansion (PTCA), percutaneous intracoronary thrombolysis (PTCR), directional coronary artery decolectomy (DCA), coronary stenting, coronary artery bypass The composition according to any one of the above (4) to (7), which is an operation (AC bypass operation).
(9) The composition according to any one of (1) to (8), wherein the content ratio of EPA-E in all fatty acids and derivatives thereof is 96.5% by weight or more.
(10) The composition according to any one of (1) to (9) above, wherein the composition is orally administered immediately after a meal at 1.8 g / day to 2.7 g / day.
(11) The composition according to any one of (1) to (10) above, which is used in combination with HMG-CoA RI.
(12) The composition according to any one of (1) to (11) above, wherein the patient has hyperlipidemia.
(13) The composition according to any one of (1) to (12) above, wherein the other preferable fatty acid contained is DHA-E.
(14) A method for preventing the onset and / or recurrence of a cardiovascular event, comprising administering the composition according to any one of (1) to (13) above.
(15) Use of EPA-E for producing the composition according to any one of (1) to (13) above.

  The composition of the present invention containing EPA, that is, containing at least EPA-E as an active ingredient is useful for preventing the onset and / or recurrence of cardiovascular events. In particular, it is useful for prevention of the onset and / or recurrence of hyperlipidemia patients or cardiovascular events that develop and / or recur despite treatment with HMG-CoA RI in hyperlipidemia patients.

The composition of the present invention is also expected to have an effect of preventing the onset and / or recurrence of cardiovascular events that occur after an unstable period has passed after cardiovascular reconstruction.
When the composition of the present invention is used in combination with HMG-CoA RI, the effect thereof is further synergistically enhanced. In patients with a history of cardiovascular events, particularly in patients after 6 months of cardiovascular reconstruction. It can be expected to further enhance the effect of preventing the onset and / or recurrence of cardiovascular events, and is clinically useful.

The present invention is described in detail below.
The first aspect of the present invention is a composition for preventing onset and / or recurrence of cardiovascular events, which contains EPA-E as an active ingredient.
Any composition containing at least EPA-E as an active ingredient and preventing the onset and / or recurrence of cardiovascular events is included in the present invention, and in particular, cardiovascular death, fatal myocardial infarction, sudden cardiac death, Examples are non-lethal myocardial infarction, cardiovascular reconstruction, new onset of resting angina and exertion angina, and compositions for prevention of angina destabilization. Examples of administration subjects include all humans who need to prevent the onset of cardiovascular events, and particularly hyperlipidemic patients are exemplified. 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 ω3 long-chain unsaturated fatty acids, particularly DHA-E. 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, but preferred composition ratios include EPA-E / DHA-E. Is preferably 0.8 or more, more preferably 1.0 or more, and 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 ω6 type, particularly arachidonic acid content, preferably less than 2% by weight, and more preferably less than 1% by weight.

According to a second aspect of the present invention, there is provided a composition for preventing onset and / or recurrence of a cardiovascular event in a hyperlipidemic patient undergoing HMG-CoA RI treatment, characterized by containing at least EPA-E It is. HMG-CoA RI includes all substances having a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitory action, 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.

The third aspect of the present invention is a composition for preventing the onset and / or recurrence of cardiovascular events in patients with a history of acute myocardial infarction, which contains at least EPA-E as an active ingredient.
In the second and third aspects of the present invention, preferred embodiments of the type of cardiovascular event, the EPA-E content ratio in the total fatty acids, the daily dose, and the other long-chain fatty acid content ratios are the first aspect described above. It is the same.

A fourth aspect of the present invention is a composition for preventing the onset and / or recurrence of a cardiovascular event that occurs after the unstable period after the execution of cardiovascular reconstruction, comprising at least EPA-E as an active ingredient. is there. In the present invention, the unstable period after performing cardiovascular reconstruction refers to a time when a cardiovascular event is likely to occur due to the cardiovascular reconstruction itself, and refers to about three months after the operation. Therefore, the fourth aspect of the present invention is preferably a composition for preventing the onset and / or recurrence of a cardiovascular event that occurs after 6 months have passed since the execution of cardiovascular reconstruction. That is, cardiovascular events such as restenosis in unstable periods caused by cardiovascular reconstruction itself are excluded. In the present invention, the cardiovascular reconstruction is not particularly limited, and in particular, percutaneous coronary lumen expansion (hereinafter abbreviated as PTCA), percutaneous intracoronary thrombolysis (hereinafter abbreviated as PTCR), directionality Examples include coronary atherectomy (hereinafter abbreviated as DCA), coronary stenting, and coronary artery bypass (hereinafter abbreviated as AC bypass).
A fifth aspect of the present invention is a composition for preventing the onset and / or recurrence of a cardiovascular event for a patient who has passed an unstable period after performing cardiovascular reconstruction, comprising at least EPA-E as an active ingredient Preferably, it is a composition for preventing the onset and / or recurrence of a cardiovascular event in a patient after 6 months have passed since cardiovascular reconstruction.
The composition of the fourth and fifth aspects of the present invention contains EPA-E as an active ingredient, and is administered to a patient who has escaped the unstable period after performing cardiovascular reconstruction, preferably a patient who has passed 6 months Is done.
Cardiovascular events that occur after the unstable period are thought to develop by a mechanism different from cardiovascular events such as restenosis in the unstable period caused by vascular reconstruction itself, but the incidence of cardiovascular events is high. The fourth and fifth compositions of the present invention are preferably administered after the unstable period after performing cardiovascular reconstruction, specifically, 6 months after the operation, and continuously administered over a long period of time. Prevention of the onset and / or recurrence of cardiovascular events that develop after the unstable period has elapsed, especially by continuous administration over a long period of 2 years or more, preferably 3.5 years or more, more preferably 5 years or more Is particularly effective.
The compositions of the fourth and fifth aspects of the present invention contain EPA-E as an active ingredient, and the EPA-E content ratio and dose in all fatty acids are not particularly limited as long as the effects of the present invention are obtained. EPA-E has a high purity, for example, the EPA-E content ratio in the total fatty acids and derivatives thereof is preferably 40% by weight or more, more preferably 90% by weight or more, and 96.5% by weight or more. More preferred. 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 ω3 long-chain unsaturated fatty acids, particularly DHA-E. 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, but preferred composition ratios include EPA-E / DHA-E. Is preferably 0.8 or more, more preferably 1.0 or more, and 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 ω6 type, particularly arachidonic acid content, preferably less than 2% by weight, and more preferably less than 1% by weight.

The composition according to the first to fifth aspects of the present invention is suitable for healthy individuals or humans who have risk factors for cardiovascular events such as hyperlipidemia, diabetes, and hypertension, or patients who have been treated with HMG-CoA RI. In contrast, oral administration has the effect of preventing the onset and / or recurrence of cardiovascular events, but is not limited to these specific patients. In addition, the composition of the present invention has a combined effect with HMG-CoA RI, and can further prevent the onset and / or recurrence of cardiovascular events.
Compared to fish oil or fish oil concentrate, the composition of the present invention has less undesirable impurities for cardiovascular events such as saturated fatty acids and arachidonic acid, and exerts its effects without problems of overnutrition and vitamin A overdose. It 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 cardiovascular events that is clinically practical for the first time was obtained.

As used herein, the term “icosapentaic acid” is all-cis-5,8,11,14,17-icosapentaic acid (all-cis-5,8,11,14,17-icosapentaenoic acid).
In the present specification, the term “cardiovascular event” is a general term for pathological changes that occur in the cardiovascular, and includes cardiovascular death (fatal myocardial infarction, sudden cardiac death), non-fatal myocardial infarction, cardiovascular reconstruction. (PTCA, PTCR, DCA, coronary stenting, AC bypass), new onset of resting angina or exertion angina, instability of angina (hospitalization, PTCA, PTCR, DCA, coronary stenting) Surgery, AC bypass, and other cardiovascular reconstruction).
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), This 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).
In the present specification, the term “combination with HMG-CoA RI” includes an embodiment in which a composition containing EPA-E as an active ingredient and HMG-CoA RI are administered simultaneously, and an embodiment in which the composition is administered separately. When administered simultaneously, it can be a compounding agent or two agents. When administered separately, the composition containing EPA-E as an active ingredient can be administered before or after HMG-CoA RI. Further, the dose and administration ratio of the composition containing EPA-E as an active ingredient and HMG-CoA RI can be arbitrarily set. Here, the preferable example of HMG-CoA RI used together is the same as the HMG-CoA RI exemplified in the second aspect of the present invention.

  The composition according to the first to fifth aspects of the present invention has the effect of preventing the onset and / or recurrence of cardiovascular events when administered alone, and particularly the onset and / or recurrence of cardiovascular events that cannot be prevented by administration of HMG-CoA RI. A preventive effect is expected. 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. Further preventive effects can be exerted by co-administration with CoA RI.

The composition of the first to fifth aspects of the present invention may contain a pharmaceutically acceptable excipient in addition to the active ingredient. 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.
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.
Note that Epadale ^™ and Epadale S ^{™, which} are high-purity EPA-E-containing soft capsules, are already marketed in Japan as safe occlusive arteriosclerosis and hyperlipidemia treatment agents with few side effects. The EPA-E content ratio is 96.5% by mass or more. In addition, a soft capsule containing about 46% by mass of EPA-E and about 38% by mass of DHA-E (Omacol, Omacor ^™ (Ross Products, Ross Products)) has already been marketed in the US and the like as a therapeutic agent for hyperTG. Has been. These can also be obtained and used.

The dose and administration period of the composition for preventing the onset and / or recurrence of the cardiovascular event of the present invention are an amount and a period sufficient to exhibit the intended effect, and its dosage form, administration method, 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 3.5 years or more, and even more preferably 5 years or more. Onset and / or recurrence of cardiovascular events It is desirable to continue administration as long as the risk level is high. In some cases, a drug holiday of about 1 day to 3 months, preferably about 1 week to 1 month can be provided.
The dosage of HMG-CoA RI used in combination with the composition of the first to fifth aspects of the present invention is preferably used within the range of dosage and administration of the drug alone, The dosage form, administration method, and number of administrations per day can be appropriately increased or decreased depending on the degree of symptoms, body weight, sex, age, and the like. In the case of oral administration, 0.05 to 200 mg / day, preferably 0.1 to 100 mg / day, is administered once or twice, but if necessary, the whole amount may be divided into several times. Good. It is also possible to reduce the dose according to the dose of EPA-E.
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 each usage. Can be administered in combination.
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.
The composition according to the first to fifth aspects of the present invention can be used in combination with other drugs such as anti-platelet drugs such as aspirin, ticlopidine, clopidogrel, cilostazol; warfarin, heparin, ximelagatran ( anticoagulants such as ximelagataran); angiotensin II receptor antagonists (candesartan, losartan, etc.), angiotensin converting enzyme inhibitors, calcium channel antagonists (amlodipine, cilnidipine, etc.), antihypertensive drugs such as α1 blockers; Glucosidase inhibitor (voglibose, acarbose, etc.), biguanide, thiazolidinedione (pioglitazone, rosiglitazone, riboglitazone, etc.), fast-acting insulin secretagogue (mitiglinide, nateglinide, etc.) Antidiabetics such as HMG-CoA RI, fibrate drugs, squalene synthase inhibitors (TAK-475, etc.), cholesterol absorption inhibitors (eg ezetimibe), etc. It can be used in combination with at least one selected from symptomatic drugs. The compositions of the first to fifth aspects of the present invention can be used by being packaged in one package together with the above HMG-CoA RI and / or at least one other drug in order to enhance convenience.

  The effects of the composition of the present invention will be shown below with experimental examples and examples, but the present invention is not limited to these examples.

Experimental Example 1 (Prophylaxis of long-term cardiovascular event onset by EPA-E)
Test method EPA-E prevents the onset and / or recurrence of cardiovascular events in hyperlipidemic patients 40-75 years old for men whose serum T-Cho concentration is 250 mg / dl or more and postmenopausal to 75 years for women Was observed over a long period of 5 years. A large, randomized, open-label, comparative study between the EPA-E group (9,326 cases) and the control group (9,319 cases), with patient background factors in the control group and EPA-E group at the start of the study, In other words, groups were randomly assigned so that there was no difference in age, gender ratio, past complications, HMG-CoARI type ratio, serum lipid concentration, and the like. In both groups, HMG-CoA RI was administered as a dietary instruction and base drug.
The data was collected from about 2,900 institutions, about 4,900 doctors, and 18,465 patients, with sufficient number of cases, randomization, and rigorousness as a comparative study. For example, in the selection of participating patients, confirmation of serum T-Cho concentration was determined by measuring twice at intervals of 2 to 4 weeks. In the case of measurement by fasting blood sampling after adhering to sufficient dietary guidance and after withdrawal of antihyperlipidemic drug, it was acceptable even once. Non-treated patients are preferred, but if antihyperlipidemic drugs are administered at least 6 months before the start of the study, a 4 week withdrawal period (8 weeks for Probucol ^TM ) should be provided. It was. If an antihyperlipidemic drug was administered within 6 months before the start of the study, it was possible to participate without withdrawal, continued in the case of HMG-CoA RI, and switched to HMG-CoA RI in the other cases .
In order to exclude cardiovascular events such as restenosis in unstable period considered to be caused by cardiovascular events in unstable period after onset of myocardial infarction and post-cardiovascular reconstruction unstable period, 6 after acute myocardial infarction Patients within a month and patients within 6 months after cardiovascular reconstruction were excluded from the study, and patients who had passed more than 6 months from both events considered to have entered a stable period were included. In addition, patients with unstable angina pectoris, patients with a history or complication of severe heart disease (severe arrhythmia, heart failure, cardiomyopathy, valvular disease, congenital heart disease, etc.), 6 months after onset of cerebrovascular disorder Patients who are not suitable for studying the prevention of long-term cardiovascular events that are the purpose of this study, such as patients who are within 5%, patients with severe liver disease or renal disease, and patients who are judged inappropriate by the attending physician Excluded.
As EPA-E, Epadale ^™ (Mochida Pharmaceutical) was usually orally administered 600 mg once an adult 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.
Pravastatin sodium (Mevalotin ^™ tablets, fine granules (Sankyo)), simvastatin (Lipobas ^™ tablets (Ashiyu Pharmaceutical)) or atorvastatin calcium hydrate (Lipitor ^™ tablets (Astellas Pharma and Pfizer Pharmaceutical)) are used as HMG-CoA RI Each was administered orally within the prescribed dosage range.
Serum lipid (T-Cho, HDL-Cho and TG) concentrations are measured periodically for 5 years from the start of the test to the end of the test, and LDL-Cho is measured using T-Cho-HDL-Cho- (TG / 5). Calculated by the calculation formula. In addition, cardiovascular events (cardiovascular death (fatal myocardial infarction, sudden cardiac death), non-fatal myocardial infarction, cardiovascular reconstruction, new onset of resting angina / working angina pectoris, angina failure The onset of stabilization (hospitalization, cardiovascular reconstruction) was observed.
This study is based on the “Guideline for conducting post-marketing surveillance of pharmaceutical products (GPMSP)” and is based on the “Guideline for conducting clinical trials of pharmaceutical products (GPP)”. Was done below. Prior to conducting the study, the study was explained to the patient himself and consent was obtained for voluntary participation in the study.

Results Serum T-Cho, LDL-Cho, and TG concentrations in both groups decreased and the serum HDL-Cho concentration did not change during the observation period of 5 years. In particular, serum TG concentration decreased more in the EPA-E group.
Table 1 shows the total number of cardiovascular event cases, incidence (%), and odds ratio of the EPA-E group to the control group in the observation period of 5 years. The odds ratio is a formula for the incidence of the EPA-E group / the incidence of the control group, and the suppression rate of the cardiovascular event incidence is {(cardiovascular event incidence of the control group−cardiovascular event onset of the EPA-E group. Rate) / cardiovascular event incidence in the control group} × 100.

ＥＰＡ−Ｅ投与により、全例の５年間に渡る心血管イベント発症率は２．８１％と対照群の心血管イベント発症率の３．４８％に比べて減少した。オッズ比は０．８０８であり、心血管イベント発症率はＥＰＡ−Ｅ投与により対照群に比べて約１９％減少した。
すなわち、ＥＰＡ−Ｅ投与による心血管イベント発症および／または再発予防効果が確認された。
また、心筋梗塞既往患者および心血管再建術施行患者においては、対照群の心血管イベント発症率が２０．１２％および２１．５４％と心筋梗塞非既往患者および心血管再建術非施行患者での心血管イベント発症率の２．５３％および２．４４％に比して著明に高かった。一方、オッズ比はＥＰＡ−Ｅ投与により、心筋梗塞既往患者で０．７４４および心血管再建術施行患者で０．６７１と心筋梗塞非既往患者の０．８１１および心血管再建術非施行患者の０．８６２に比して著明に小さく、心血管イベント発症率は対照群に比べてＥＰＡ−Ｅ投与により心筋梗塞既往患者で約２６％および心血管再建術施行患者で約３３％減少した。
以上より、心筋梗塞既往患者および心血管再建術施行患者においてＥＰＡ−Ｅ投与による著明な心血管イベント発症予防効果が確認された。

By administration of EPA-E, the incidence of cardiovascular events over 5 years in all cases decreased to 2.81% compared to 3.48% of cardiovascular events in the control group. The odds ratio was 0.808, and the incidence of cardiovascular events was reduced by about 19% by EPA-E administration compared to the control group.
That is, the effect of preventing the onset and / or recurrence of cardiovascular events by EPA-E administration was confirmed.
In patients with a history of myocardial infarction and patients undergoing cardiovascular reconstruction, the incidence of cardiovascular events in the control group was 20.12% and 21.54%. The incidence of cardiovascular events was significantly higher than 2.53% and 2.44%. On the other hand, the odds ratio was 0.744 for patients with a history of myocardial infarction, 0.671 for patients with a history of myocardial infarction, 0.811 for patients with no history of myocardial infarction, and 0 for patients with no cardiovascular reconstruction. The incidence of cardiovascular events was significantly reduced by about 26% in patients with a history of myocardial infarction and about 33% in patients undergoing cardiovascular reconstruction compared to the control group.
From the above, a significant cardiovascular event onset prevention effect by EPA-E administration was confirmed in patients with a history of myocardial infarction and patients undergoing cardiovascular reconstruction.

Claims (6)

Containing ethyl icosapentate as an active ingredient,
It is administered in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor,
For patients who have passed the unstable period after performing cardiovascular reconstruction,
A composition for preventing the onset of cardiovascular events. The composition according to claim 1 , wherein the administration is started after 6 months have passed since the cardiovascular reconstruction operation, and the administration is continued for at least 2 years. Cardiovascular reconstruction includes percutaneous coronary lumen dilatation (PTCA), percutaneous intracoronary thrombolysis (PTCR), directional coronary angioplasty (DCA), coronary stenting, coronary artery bypass surgery ( The composition according to claim 1 or 2 , wherein the composition is AC bypass. It said patient, composition according to any one of 3 to no請Motomeko 1, characterized in that it is hyperlipidemia. The composition according to any one of claims 1 to 4, wherein the content ratio of ethyl ester of icosapentate in all fatty acids and derivatives thereof is 96.5% by weight or more. The composition according to any one of claims 1 to 5 , which is orally administered at 1.8 g / day to 2.7 g / day of icosapentic acid ethyl ester.