WO2007007686A1 - 心血管イベント発症予防用組成物 - Google Patents
心血管イベント発症予防用組成物 Download PDFInfo
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- WO2007007686A1 WO2007007686A1 PCT/JP2006/313609 JP2006313609W WO2007007686A1 WO 2007007686 A1 WO2007007686 A1 WO 2007007686A1 JP 2006313609 W JP2006313609 W JP 2006313609W WO 2007007686 A1 WO2007007686 A1 WO 2007007686A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- composition for preventing cardiovascular events Composition for preventing cardiovascular events
- the present invention relates to a composition for preventing onset of cardiovascular events and prevention of Z or recurrence, characterized by containing at least icosapentate ethyl ester (hereinafter abbreviated as EPA-E).
- EPA-E icosapentate ethyl ester
- arteriosclerotic diseases such as myocardial infarction, angina pectoris and cerebral infarction, and in some cases there is a risk of death.
- a therapeutic method for arteriosclerotic disease a therapeutic method such as a drug treatment or a blood vessel reconstruction is generally used.
- Hyperlipidemia is relatively easy to treat, and coronary artery disease is treated by a powerful treatment of hyperlipidemia with 3-hydroxy-3-methyldaltalcoenzyme A reductase inhibitor (hereinafter abbreviated as HMG-CoA RI).
- HMG-CoA RI 3-hydroxy-3-methyldaltalcoenzyme A reductase inhibitor
- Results have been obtained in large-scale clinical trials. For example, when pravastatin sodium was orally administered to male patients with hyperlipidemia who had no history of myocardial infarction for an average of 4. 9 years, serum T-Cho levels decreased by 20% and serum LDL-Cho levels decreased by 26% Serum HDL-Cho levels increased by 5% and serum TG decreased by 12%.
- Non-Patent Document 1 the incidence decreased by 31% when non-fatal myocardial infarction and cardiovascular death were combined.
- patients with a history of angina pectoris or myocardial infarction When pastatin was administered orally for an average of 4 years, serum T Cho concentration decreased by 25%, serum LDL—Cho concentration decreased by 35%, serum HDL—Cho concentration increased by 8%, and serum TG increased by 10%.
- serum T Cho concentration decreased by 25%
- serum LDL—Cho concentration decreased by 35%
- serum HDL—Cho concentration increased by 8%
- serum TG increased by 10%.
- the incidence of major cardiovascular events decreased by 34% (see Non-Patent Document 2).
- Patent Document 1 discloses that cardiovascular events are suppressed by the 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 brand names Epadel 1 ⁇ and Evadale S TM (Mochida Pharmaceutical Co., Ltd.), 600 mg once, 3 times daily Immediately after meals (however, if serum TG abnormalities are present, depending on the degree, increase the dose to 900 mg at a time up to 3 times a day) to give a serum T-Cho concentration of 3-6% It has been reported that serum TG is reduced by 14 to 20% (see Non-Patent Document 5) and that these effects are expected to have an effect on cardiovascular events in hyperlipidemic patients (Non-Patent Document 6). reference)
- cardiovascular reconstruction which is a surgical treatment method such as PTCA and coronary stenting
- cardiovascular events are likely to occur after the operation.
- cardiovascular events after PTCA include restenosis of the PTCA site (generally more than 50% of the PTCA expansion)
- the rate of restenosis which is often due to the appearance of new lesions, is often recognized within 30 months before and after 6 months.
- the rate of restenosis 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 to use aspirin and ticlovidin (clopidogrel) at the time of stent insertion, and aspirin and cilostazol are also used to prevent stent thrombosis (Non-patent Document 7 p. 245 to 246). Management is particularly important.
- Non-Patent Documents 8-11 There have been attempts to administer fish oil or ⁇ 3 fatty acids for restenosis in the unstable period after cardiovascular reconstruction, but there are reports that it is effective and invalid, and reconstruction is performed. There is also the view that pre-administration is necessary.
- Non-patent Document 12 Reported that pravastatin, an HMG-CoA RI, was administered for 2 years after PTCA and the restenosis rate decreased and was effective in suppressing events (Non-patent Document 12), 3-4 years immediately after percutaneous coronary artery inter-pension Although there is a report that administration of flupastatin has suppressed the onset of cardiac events (Non-patent Document 13), there is a desire for improvement of the therapy that enables further suppression of cardiovascular events.
- Non-patent literature l The New England Journal of the Medicine, 1995, 333 ⁇ , pl301-1307
- Non-Patent Document 2 The Lancet, 1994, 344 ⁇ , November 9th, pl383-1389
- Non-patent Document 3 Archives of Internal Medicine, 1999, 159 ⁇ , No.1, pl79
- Non-patent literature 4 The Lancet, 1999, 354 ⁇ , August 7th, p 447-455
- Non-patent literature 5 Pharmaceutical interview form EPA formulation Epadale TM capsule 300
- Non-patent literature 6 American Heart Journal, 2003, 146 ⁇ , No. 4, p613-620
- Non-patent literature 7 Today's treatment guidelines, 2003, School of Medicine, General Editor, Toru Yamaro, Mitsuo Kitahara p273, p245- 246
- Non-Patent Document 8 J Am Coll Cardiol, 2005, May 17 ⁇ , 45 (10), pl723—8
- Non-Patent Document 9 Am Heart J, June 2002, 143 (6), E5
- Non-patent literature 10 J Am Coll Cardiol, May 1999, 33 (6), pl619—26
- Non-patent literature 11 Am J Cardiol 1996, 77, p31—36
- Non-Patent Document 12 Am J Cardiol, 2000 October 1st, 86 (7), p742—6
- Non-Patent Document 13 JAMA, June 26, 2002, 287 (24), p3215-22
- Patent Document 1 International Publication No. 00Z48592 Pamphlet (Special Table 2002-537252)
- Patent Document 2 US Patent No. 6159993
- the object of the present invention is that death from cardiovascular disease is still a major cause of death, and there are many cardiovascular events that cannot be prevented even after treatment with HMG-Co A RI. Therefore, the object is to provide a composition for preventing the onset and / or recurrence of these cardiovascular events.
- the present inventor conducted intensive research to solve the above-mentioned problems. After EPA-E passed the unstable period after the onset of cardiovascular events and prevention of Z or recurrence, especially after cardiovascular reconstruction. The present invention was completed by finding that it has a preventive action against the onset of cardiovascular events and Z or recurrence. That is, the present invention
- a composition for preventing the onset of cardiovascular events and Z or recurrence comprising at least EPA-E as an active ingredient.
- composition containing at least EPA-E as an active ingredient for preventing the onset of cardiovascular events and Z or recurrence in hyperlipidemic patients undergoing HMG-Co A RI treatment (2) A composition containing at least EPA-E as an active ingredient for preventing the onset of cardiovascular events and Z or recurrence in hyperlipidemic patients undergoing HMG-Co A RI treatment.
- composition for preventing the onset of cardiovascular events and Z or recurrence in patients with a history of acute myocardial infarction comprising at least EPA-E as an active ingredient.
- Cardiovascular reconstruction is percutaneous coronary lumen dilatation (PTCA), percutaneous intracoronary thrombectomy (PTCR), directional coronary artery resection (DCA), coronary stenting, coronary artery Any of the above compositions (4) or (7), which is bypass technique (AC bypass technique).
- PTCA percutaneous coronary lumen dilatation
- PTCR percutaneous intracoronary thrombectomy
- DCA directional coronary artery resection
- coronary stenting coronary artery Any of the above compositions (4) or (7), which is bypass technique (AC bypass technique).
- the content ratio of EPA-E in all fatty acids and derivatives thereof is 96.5% by weight or more.
- a method for preventing the onset and Z or recurrence of a cardiovascular event comprising administering the composition according to any one of (1) to (13) above.
- composition of the present invention containing EPA that is, containing at least EPA-E as an active ingredient, is useful for preventing the onset of cardiovascular events and Z or recurrence. Especially when hyperlipidemia patients or hyperlipidemia patients were treated with HMG-CoA RI. Regardless of the onset and z or recurrence of cardiovascular events, it is useful in preventing the onset and z or recurrence.
- composition of the present invention is also expected to be effective in preventing the onset and z or recurrence of cardiovascular events that occur after the instability period after the execution of cardiovascular reconstruction.
- composition of the present invention When the composition of the present invention is used in combination with HMG-Co A RI, the effect is further synergistically enhanced. Patients with a history of cardiovascular events, especially after 6 months after cardiovascular reconstruction It can be expected to further enhance the prevention of cardiovascular events and Z or recurrence in patients and is clinically useful.
- the first aspect of the present invention is a composition for preventing cardiovascular event onset and Z or recurrence containing EPA-E as an active ingredient.
- compositions 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, particularly cardiovascular death, fatal myocardial infarction, sudden cardiac death, Examples include compositions for preventing non-fatal myocardial infarction, cardiovascular reconstruction, new onset of resting angina and exertion angina, and destabilization of angina.
- the administration target includes all humans who need prevention of the onset of cardiovascular events, and is particularly exemplified by hyperlipidemic patients. If the effect of the present invention is obtained, the EPA-E content ratio and dose in all fatty acids are not particularly limited, but EPA-E is of high purity, for example, EPA-E content ratio in total fatty acids and derivatives thereof.
- the daily dose is exemplified as EPA-E by 0.3 to 6 g / ⁇ , preferably 0.9 to 3.6 g / ⁇ , and more preferably 1.8 to 2.7 gZ days.
- composition ratio of EPA-EZDHA-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 a preferred composition ratio is 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
- the content ratio of EPA-E + DHAE in all fatty acids and derivatives thereof is preferably 40% by mass or more, more preferably 80% by mass or more, and still more preferably 90% by mass or more.
- the daily dose is EPA—E + DHA—E, from 0.3 to: LOgZ days, preferably 0.5 to 6 gZ days, more preferably 1 to 4 gZ days.
- Other long-chain saturated fatty acids are preferred even in the case of long-chain unsaturated fatty acids, which are preferred to be low in ⁇ 6, especially arachidonic acid content, preferably less than 2% by weight, more preferably less than 1% by weight .
- HMG-CoA RI includes all those having a 3-hydroxy-1,3-methylglutarcoenzyme A reductase inhibitory activity, but preferably those that can be administered in medicine. Specifically, it is preferable that at least one of pravastatin, simpastatin, oral pastatin, flunostatin, cerivastatin, atonolepastatin, pitapastatin, rospastatin and their salts, and the group power of derivative power is also selected. More preferred is pravastatin or simvastatin, more preferably nostatin, oral pastatin, simpastatin, flupastatin, atonolepastatin, pitavastatin or rospastatin.
- Salts include all pharmaceutically administrable powers, especially sodium or calcium salts such as pravastatin sodium, flupastatin sodium, seripastatin sodium, atorvastatin calcium, pitapastatin calcium and oral spastatin Calcium is preferred.
- pravastatin includes a salt form of pravastatin.
- a third aspect of the present invention is a composition for preventing the onset and Z or recurrence of cardiovascular events in patients with a history of acute myocardial infarction, which contains at least EPA-E as an active ingredient.
- 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 embodiment described above. It is the same.
- a fourth aspect of the present invention is a cardiovascular reconstitution containing at least EPA-E as an active ingredient. It is a composition for preventing the onset and z or recurrence of a cardiovascular event that occurs after the unstable period has passed since construction.
- the unstable period after the cardiovascular reconstruction is performed means that a cardiovascular event caused by the cardiovascular reconstruction itself is likely to occur! /, The time !, and about 3 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. In other words, cardiovascular events such as restenosis in unstable periods caused by cardiovascular reconstruction itself are excluded.
- cardiovascular reconstruction is not particularly limited, but is particularly percutaneous coronary lumen dilatation (hereinafter abbreviated as PTCA), percutaneous intracoronary thrombolysis (hereinafter abbreviated as PTCR), direction Examples include coronary atherectomy (hereinafter abbreviated as DCA), coronary stenting, and coronary artery bypass (hereinafter abbreviated as AC bypass).
- PTCA percutaneous coronary lumen dilatation
- PTCR percutaneous intracoronary thrombolysis
- DCA coronary atherectomy
- AC bypass coronary artery bypass
- a fifth aspect of the present invention is a composition for preventing onset of cardiovascular events and Z or recurrence for a patient who has passed an unstable period after performing cardiovascular reconstruction, comprising at least EPA-E as an active ingredient
- it is a composition for preventing the onset and Z or recurrence of a cardiovascular event in a patient 6 months after cardiovascular reconstruction.
- composition according to the fourth and fifth aspects of the present invention contains EPA-E as an active ingredient, and is administered to patients who have escaped the unstable period after cardiovascular reconstruction, preferably 6 months. Given.
- Cardiovascular events that occur after the unstable period have a high incidence of force S and cardiovascular events that are thought to develop by a mechanism different from cardiovascular events such as restenosis in the unstable period caused by vascular reconstruction itself .
- the fourth and fifth compositions of the present invention are preferably administered after a period of anxiety after cardiovascular reconstruction, specifically, 6 months after the operation, and continuously over a long period of time.
- 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 can be obtained.
- EPA-E is of high purity, for example, EPA-E content ratio in total fatty acids and derivatives thereof is preferably 40% by weight or more, more preferably 90% by weight or more, more preferably 96. More preferably, the amount is more than%.
- the daily dose is exemplified as EPA-E from 0.3 to 6 gZ days, preferably from 0.9 to 3.6 gZ days, more preferably from 1.8 to 2.7 gZ days.
- composition ratio of EPA-EZDHA-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 a preferred composition ratio is 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 highly pure, 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. More preferred is 90% by mass or more.
- the daily dose is EPA—E + DHA—E, from 0.3 to: LOgZ days, preferably 0.5 to 6 gZ days, more preferably 1 to 4 gZ days.
- Other long-chain saturated fatty acids are preferred even in the case of long-chain unsaturated fatty acids, which are preferred to be low in ⁇ 6, especially arachidonic acid content, preferably less than 2% by weight, more preferably less than 1% by weight .
- the composition of the first aspect of the present invention is a healthy person, a human having a risk factor for cardiovascular events such as hyperlipidemia, diabetes, and hypertension, or a patient who has been treated with HMG-CoA RI.
- Oral administration has the effect of preventing the onset of cardiovascular events and Z or recurrence, but is not limited to these specific patients.
- the composition of the present invention has a combined effect with HMG-CoA RI, and can further prevent the onset of cardiovascular events and Z or recurrence.
- the composition of the present invention is effective without over-nutrition and vitamin A overdose problems with less undesirable impurities for cardiovascular events such as saturated fatty acids and arachidonic acid. Is possible.
- a usual anti-oxidation agent which is an ester and has a higher acid / acid stability than fish oil, which is mainly a triglyceride body. Therefore, by using EPA-E, the first clinically practical composition for preventing the onset of cardiovascular events and Z or recurrence was obtained.
- icosapentaenoic acid means all-cis 5, 8, 11, 14, 17-icosapentaenoic acid (all-cis- 5, 8, 11, 14, 17- icosapentaenoic acid ).
- cardiovascular event is a general term for pathological changes that occur in the cardiovascular system. Cardiovascular death (fatal myocardial infarction, sudden cardiac death), non-fatal myocardial infarction, cardiovascular reconstruction Surgery (PTCA, PTCR, DCA, coronary stenting, AC bypass), new onset of resting angina or exertion angina, instability of angina (hospitalization, PTCA, PTCR, DCA, coronary stent Indwelling, AC binos, and other cardiovascular reconstruction).
- PTCA PTCR
- DCA coronary stenting
- AC bypass cardiovascular reconstruction Surgery
- new onset of resting angina or exertion angina instability of angina
- instability of angina hospitalization, PTCA, PTCR, DCA, coronary stent Indwelling, AC binos, and other cardiovascular reconstruction.
- hyperlipidemic patient means increased serum T-cho concentration and increased serum LDL-cho concentration! ]
- Patients with decreased serum HDL-cho concentration or increased serum TG are examples of the
- hypercholesterolemia (serum T-Cho concentration is about 220 mgZdl or more, and more narrowly, 250 mgZdl or more), high LDL-Choemia (serum LDL-Cho concentration is 140 mgZdl or more), low HDL- Cho
- dysemia serum HDL—Cho concentration less than 40 mgZdl
- hyper-TGemia hyper-TGemia
- 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.
- the composition containing EPA-E as the active ingredient can be administered before or after HMG-CoA RI.
- the dosage and administration ratio of the composition containing EPA-E as an active ingredient and HMG-CoA RI can be arbitrarily set.
- a preferred example of the HMG-CoA RI used in combination is the same as the HMG-CoA RI exemplified in the second aspect of the present invention.
- the composition of the fifth aspect has a cardiovascular event onset and Z or recurrence preventive action when administered alone, and particularly has a cardiovascular event onset and Z that cannot be prevented by administration of HMG-CoA RI. Or the prevention effect of recurrence is expected.
- EPA-E has pharmacological actions 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 effect can be exerted by combined administration with HMG-CoA RI.
- the composition of the fifth aspect is pharmaceutically acceptable in addition to the active ingredient.
- the resulting excipient can be included. Because EPA-E and DHA-E are highly unsaturated, antioxidants such as butyrate hydroxytoluene, brechtoyl hydroxyasol, propyl gallate, gallic acid, pharmaceutically acceptable quinones and It is desirable to contain an effective amount of ⁇ -tocopherol.
- the dosage form of the preparation is tablet, capsule, microcapsule, granule, fine granule, powder, oral liquid preparation, syrup, jelly, etc. Oral administration in capsules such as soft capsules and microcapsules is preferred.
- the dosage and duration of the composition for preventing the onset and Z or recurrence of the cardiovascular event of the present invention are set to an amount and duration sufficient to exhibit the intended effect. However, it may be adjusted according to the dosage form, administration method, number of administrations per day, symptom severity, body weight, age, etc.
- EPA-E is administered in a dose of 0.3 to 6 gZ days, preferably 0.9 to 3.6 gZ days, more preferably 1.8 to 2.7 gZ days.
- the entire dose may be administered once or divided into several doses.
- the duration of administration is 1 year or more, preferably 2 years or more, more preferably 3.5 years or more, more preferably 5 years or more.
- Onset of cardiovascular events and Z or recurrence It is desirable to continue administration while the high risk level continues.
- 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 fifth aspect of the first power of the present invention is preferably used within the range of dosage and dosage of the drug alone.
- the type, 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, etc.
- 0.05 to 200 mgZ days preferably 0.1 to:
- the ability to administer LOOmgZ days in 1 or 2 doses The entire dose may be given in several doses as needed . It is also possible to reduce the dose according to the dose of EPA-E.
- pravastatin sodium (mevalotin “ ⁇ tablets” fine granules (Sankyo)), sympastatin (Lipobas tablets (Ariyu Pharmaceutical)), flupastatin sodium (Locoll TM tablets (Nonorettis Pharma and Tanabe Seiyaku)), atorvastatin Calcium Hydrate (Lipitor TM Tablets (ASTELLA PHARMACEUTICAL and Huaizaichi Pharmaceutical)), Pitapastatin Calcium (RIVA Tablets (Kowa and Sankyo)), and Lospastatin Calcium (Crestor TM Tablets (AstraZene & Shionogi)) Is already marketed in Japan as an antihyperlipidemic agent, and oral pastatin (Mebacol TM tablets (Merck)) is already on the market as an antihyperlipidemic agent in the United States. At least one can be obtained and administered in appropriate combinations according to the respective usage.
- Each preferred daily dose is 5-60 mg, preferably 10-20 mg for pravastatin sodium, 2.5-60 mg, preferably 5-20 mg for simpastatin, 10-180 mg, preferably 20 for fluvastatin sodium.
- ⁇ 60mg, 5 ⁇ 120mg for atorvastatin calcium hydrate, preferably 10 ⁇ 40mg, 0.5 ⁇ 12mg for pitapastatin calcium, preferably 1 ⁇ 4mg, 1.25 ⁇ 60mg for rospastatin calcium preferable 2.5 to 20 mg, 5 to 160 mg, preferably
- the composition of the first aspect and the fifth aspect of the present invention is a composition according to the patient's condition, such as an antiplatelet agent such as aspirin, ticlopidine, clopidogrel, cilostazol, ⁇ rufaline, heparin, Anticoagulants such as ximelagatran; angiotensin ⁇ receptor antagonists (candesartan, oral sultan, etc.), angiotensin converting enzyme inhibitors, calcium channel antagonists (amlodipine, syl-dipine, etc.), a 1 Antihypertensive drugs such as blockers; alpha-darcosidase inhibitors (bodaribose, fakal Bose, etc.), biguanide drugs, thiazolidinedione drugs (piodaritazone, rosiglitazone, riboglitazone, etc.), fast-acting insulin secretagogues (mitiglinide, nateglinide, etc.
- Serum T Cho over 250 mg Zdl for men 40 to 75 years old, women postmenopausal to 75 years for prevention of EPA—E cardiovascular events and prevention of Z or recurrence for 5 years Observed over a long period of time.
- the data were collected from about 2,900 participating institutions, about 4,900 participating doctors and 8,465 participating patients, with sufficient number of cases, randomized, and rigorous as a comparative study. .
- 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.
- untreated patients are preferred, but if antihyperlipidemic drugs are administered more than 6 months before the start of the study, a 4-week withdrawal period (8 weeks for Probucol TM) is recommended. I decided to put it. Within 6 months before test start If an antihyperlipidemic drug was administered to the patient, it was possible to participate without withdrawal, continued in the case of HMG-Co A RI, and switched to HMG-CoA RI in the other cases.
- cardiovascular events such as restenosis in unstable period, which may be caused by cardiovascular events in unstable period after the onset of myocardial infarction, and in the unstable period after cardiovascular reconstruction
- post-acute myocardial infarction Patients within 6 months and those within 6 months after cardiovascular reconstruction were excluded from the study, and patients who had passed 6 months or more from both events considered to have entered a stable period were included.
- Epadel 1 ⁇ (Mochida Pharmaceutical) as EPA-E was usually administered orally once daily at 600 mg for adults 3 times daily. However, if serum TG abnormality is present, the dose can be increased up to 900 mg at a time and 1 to 3 times.
- HMG-CoA RI includes pravastatin sodium (mevalotin TM tablets' fine granules (Sankyo)), sympastatin (Lipobas TM tablets (Ariyu Pharmaceutical Co., Ltd.))
- ⁇ is atorpastatin calcium hydrate (Lipitor 1 ⁇ tablets (ASTELLA Pharmaceutical and Were administered orally in the prescribed dosage range.
- Serum lipid (T Cho, HDL—Cho and TG) concentrations are measured periodically for 5 years until the end of the test, and LDL—Cho is calculated as T—Cho—HDL—Cho— (TGZ5) Calculated with
- cardiovascular events cardiac death (fatal myocardial infarction, sudden cardiac death), non-fatal myocardial infarction, cardiovascular reconstruction, resting angina pectoris Stabilization (hospitalization, cardiovascular reconstruction)
- the onset was observed.
- Table 1 shows the total number of cardiovascular events that occurred during the observation period of 5 years, the incidence (%), and the odds ratio of the EPA-E group to the control group.
- the odds ratio is the EPA—E group incidence rate.
- the Z control group incidence rate, the cardiovascular event incidence rate is ⁇ (control cardiovascular event incidence rate, EPA—E cardiovascular event incidence rate. ) Cardiovascular event incidence in the Z control group ⁇ X 100 respectively.
- the incidence of cardiovascular events in the control group was 20.12% and 21.54%, compared with those with no history of myocardial infarction and those with no cardiovascular reconstruction. Compared to 2.53% and 2.44% of the incidence of cardiovascular events, it was significantly higher.
- the odds ratio was 0.74 for patients with a history of myocardial infarction and 0.671 for patients with a history of myocardial infarction, 0.811 for patients with no history of myocardial infarction, and for patients with no cardiovascular reconstruction.
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Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0613704-0A BRPI0613704A2 (pt) | 2005-07-08 | 2006-07-07 | composição para impedir o inìcio e/ou a recorrência de eventos cardiovasculares |
KR1020137031446A KR101465717B1 (ko) | 2005-07-08 | 2006-07-07 | 심혈관 이벤트 발병 예방용 조성물 |
CN200680024615.1A CN101217952B (zh) | 2005-07-08 | 2006-07-07 | 用于预防心血管事件发病的组合物 |
KR1020087000212A KR101465715B1 (ko) | 2005-07-08 | 2006-07-07 | 심혈관 이벤트 발병 예방용 조성물 |
EP06780884.0A EP1790339B1 (en) | 2005-07-08 | 2006-07-07 | Composition for prevention of occurrence of cardiovascular event |
ES06780884.0T ES2489741T3 (es) | 2005-07-08 | 2006-07-07 | Composición para la prevención de la aparición de acontecimientos cardiovasculares |
CA2570763A CA2570763C (en) | 2005-07-08 | 2006-07-07 | Composition for preventing onset of cardiovascular events |
NO20065384A NO20065384L (no) | 2005-07-08 | 2006-11-22 | Preparat til forhindring av fremkomst av kardiovaskulaere hendelser |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005-200503 | 2005-07-08 | ||
JP2005200503 | 2005-07-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007007686A1 true WO2007007686A1 (ja) | 2007-01-18 |
Family
ID=37637079
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2006/313609 WO2007007686A1 (ja) | 2005-07-08 | 2006-07-07 | 心血管イベント発症予防用組成物 |
Country Status (11)
Country | Link |
---|---|
US (3) | US8367725B2 (ja) |
EP (1) | EP1790339B1 (ja) |
JP (1) | JP5809115B2 (ja) |
KR (2) | KR101465715B1 (ja) |
CN (2) | CN101217952B (ja) |
BR (1) | BRPI0613704A2 (ja) |
CA (1) | CA2570763C (ja) |
ES (1) | ES2489741T3 (ja) |
NO (1) | NO20065384L (ja) |
TW (1) | TWI412361B (ja) |
WO (1) | WO2007007686A1 (ja) |
Cited By (1)
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---|---|---|---|---|
WO2007142118A1 (ja) * | 2006-05-31 | 2007-12-13 | Mochida Pharmaceutical Co., Ltd. | 多重リスク患者の心血管イベント発症予防用組成物 |
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US9662307B2 (en) | 2013-02-19 | 2017-05-30 | The Regents Of The University Of Colorado | Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof |
US9283201B2 (en) | 2013-03-14 | 2016-03-15 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for treating or preventing obesity in a subject in need thereof |
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US10406130B2 (en) | 2016-03-15 | 2019-09-10 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
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- 2006-07-07 KR KR1020087000212A patent/KR101465715B1/ko active IP Right Grant
- 2006-07-07 CN CN200680024615.1A patent/CN101217952B/zh active Active
- 2006-07-07 CN CN201110449012.9A patent/CN102526733B/zh active Active
- 2006-07-07 EP EP06780884.0A patent/EP1790339B1/en active Active
- 2006-07-07 BR BRPI0613704-0A patent/BRPI0613704A2/pt not_active IP Right Cessation
- 2006-07-07 KR KR1020137031446A patent/KR101465717B1/ko active IP Right Grant
- 2006-07-07 CA CA2570763A patent/CA2570763C/en active Active
- 2006-07-07 US US11/481,956 patent/US8367725B2/en active Active
- 2006-07-07 WO PCT/JP2006/313609 patent/WO2007007686A1/ja active Application Filing
- 2006-07-07 TW TW095124859A patent/TWI412361B/zh active
- 2006-07-07 ES ES06780884.0T patent/ES2489741T3/es active Active
- 2006-11-22 NO NO20065384A patent/NO20065384L/no not_active Application Discontinuation
-
2012
- 2012-07-13 JP JP2012157914A patent/JP5809115B2/ja active Active
- 2012-11-08 US US13/672,405 patent/US9198892B2/en active Active
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2015
- 2015-10-29 US US14/926,839 patent/US20160045469A1/en not_active Abandoned
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007142118A1 (ja) * | 2006-05-31 | 2007-12-13 | Mochida Pharmaceutical Co., Ltd. | 多重リスク患者の心血管イベント発症予防用組成物 |
US8802718B2 (en) | 2006-05-31 | 2014-08-12 | Mochida Pharmaceuticals Co., Ltd. | Composition for preventing the occurrence of cardiovascular event in multiple risk patient |
US8853256B2 (en) | 2006-05-31 | 2014-10-07 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing the occurrence of cardiovascular event in multiple risk patient |
US9700537B2 (en) | 2006-05-31 | 2017-07-11 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing the occurrence of cardiovascular event in multiple risk patient |
US10716775B2 (en) | 2006-05-31 | 2020-07-21 | Mochida Pharmaceutical Co., Ltd. | Composition for preventing the occurrence of cardiovascular event in multiple risk patient |
Also Published As
Publication number | Publication date |
---|---|
US20070021504A1 (en) | 2007-01-25 |
CN102526733B (zh) | 2014-09-03 |
TW200740430A (en) | 2007-11-01 |
CN101217952B (zh) | 2014-03-12 |
US20130065956A1 (en) | 2013-03-14 |
EP1790339A4 (en) | 2009-11-11 |
EP1790339B1 (en) | 2014-06-04 |
NO20065384L (no) | 2008-03-07 |
CN101217952A (zh) | 2008-07-09 |
JP2012193211A (ja) | 2012-10-11 |
KR20080024511A (ko) | 2008-03-18 |
JP5809115B2 (ja) | 2015-11-10 |
US20160045469A1 (en) | 2016-02-18 |
KR20130137055A (ko) | 2013-12-13 |
BRPI0613704A2 (pt) | 2011-02-01 |
EP1790339A8 (en) | 2008-07-09 |
CN102526733A (zh) | 2012-07-04 |
KR101465717B1 (ko) | 2014-12-01 |
CA2570763C (en) | 2011-08-23 |
US9198892B2 (en) | 2015-12-01 |
TWI412361B (zh) | 2013-10-21 |
EP1790339A1 (en) | 2007-05-30 |
KR101465715B1 (ko) | 2014-11-27 |
ES2489741T3 (es) | 2014-09-02 |
CA2570763A1 (en) | 2007-01-08 |
US8367725B2 (en) | 2013-02-05 |
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