CN101553220A - Omega-3 fatty acids and dyslipidemic agent for reduction of APO-B levels - Google Patents

Omega-3 fatty acids and dyslipidemic agent for reduction of APO-B levels Download PDF

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CN101553220A
CN101553220A CNA2007800456667A CN200780045666A CN101553220A CN 101553220 A CN101553220 A CN 101553220A CN A2007800456667 A CNA2007800456667 A CN A2007800456667A CN 200780045666 A CN200780045666 A CN 200780045666A CN 101553220 A CN101553220 A CN 101553220A
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fatty acid
omega
dyslipidemia
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罗洛夫·M·L·龙根
罗伯特·A·沙尔威茨
道格拉斯·克林
小拉尔夫·T·多伊尔
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Reliant Pharmaceuticals Inc
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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

Abstract

Methods of utilizing a combined administration or a unit dosage of a combination of a dyslipidemic agent and omega-3 fatty acids for the reduction of apolipoprotein-B levels. The methods are especially useful in the treatment of patients with hypercholesterolemia, hypertriglyceridemia, mixed dyslipidemia, coronary heart disease (CHD), vascular disease, atherosclerotic disease and related conditions, and for the prevention or reduction of cardiovascular, cardiac, and vascular events.

Description

Be used to reduce the omega-fatty acid of APO-B level and the medicine of dyslipidemia
The application requires the priority of No. 60/850,280, the U.S. Provisional Application submitted on October 10th, 2006, and its full content is hereby incorporated by.
Technical field
The present invention relates to use the unit dose of the combination (combination) of the medicine of the medicine (dyslipidemic agent) of individually dosed dyslipidemia and omega-fatty acid or dyslipidemia and omega-fatty acid to reduce the method for apo-B level.This method is particularly useful for treatment and suffers from the patient of constitutional hypertriglyceridemia or hypercholesterolemia or Combination dyslipidemia, coronary heart disease (CHD), angiopathy, atherosclerosis and associated conditions, and is used for prevention or reduces cardiovascular and angiopathy (event).
Background of invention
In the mankind, cholesterol and triglyceride are the part protein-lipid complex in the blood flow, and can be separated into high density lipoprotein (HDL), intermediate density lipoprotein (IDL) (IDL), low density lipoprotein, LDL (LDL) and very low density lipoprotein (VLDL) (VLDL) fraction by supercentrifugation.Cholesterol and triglyceride synthesize in liver, and enter to VLDL, and are released in the blood plasma.High-caliber T-CHOL (always-C), LDL-C and apo-B (apo-B, the membrane complex of LDL-C and VLDL-C) cause that atherosis and HDL-C of human artery and transferring composite thereof, apolipoprotein-A (apo-A) level reduce, this is relevant with development of atherosclerosis.In addition, the variation of people's cardiovascular morbidity and mortality rate changes with the level of TC and LDL-C with being directly proportional and changes inversely with the level of HDL-C.In addition, research worker has been found that non--HDL cholesterol (non--HDL-C), it is determined by deduct HDL-C from TC, is the important indication of hypertriglyceridemia, angiopathy, atherosclerosis and associated conditions.Non--HDL-C granule contains apo-B as film-compound apolipoprotein.Although non--HDL-C is good the measuring of the total amount of the cholesterol that exists in the atherogenic apo-B of the containing granule, directly measure the measured value preferably that apo-B can provide the atherogenic grain amount of per unit serum.
Although LDL-C has kept the lipid value that is generally used for estimating cardiovascular risk, apo-B can reflect the lipid risk preferably.Sniderman, Am.J.Cardiol.90 (suppl): 48i-541 (2002) summarizes at the evidence of the LDL-C level of predicting coronary heart disease risk and being better than calculating for the value of supporting apo-B.
Cardiovascular diseases (CVD) is the generalized term that comprises multiple disease and disease.It refers to any disease of the arbitrary part of various piece of the cardiovascular system of being made up of heart and all blood vessels of whole body.The disease of heart comprises coronary heart disease, CHD, cardiomyopathy, valvular heart disease, pericardial disease, congenital heart disease (for example, constriction, atrium or ventricular septal defect), and heart failure.The disease of blood vessel comprises arteriosclerosis, atherosclerosis, hypertension, apoplexy, vascular dementia, aneurysm, peripheral arterial disease, intermittent claudication, vasculitis, vein incompetence, venous thrombosis, varicosis, and lymphedema.Some patients can receive its CVD of treatment, such as blood vessel or coronary artery revascularization (angioplasty that uses or do not use support to insert, or blood vessel transplantation).The cardiovascular diseases of some types is geneogenous, but a lot of for acquired in life, and owing to bad custom, such as sitting behavior and smoking.The CVD of some types also can cause further cardiac problems, get involved such as angina pectoris, main bad cardiovascular disease (MACEs) and/or main coronary artery disease (MCEs) such as myocardial infarction (MI) or coronary artery, perhaps even dead (heart or cardiovascular), this has emphasized to make great efforts the importance of treatment and prevention CVD.
The known risks and assumptions that reduces CVD is paid close attention in primary prevention work, or to stop their development, its purpose be the generation that delays or prevent CVD, MACEs or MCEs.Secondary prevention work is paid close attention to the recurrence and the reduction that reduce CVD and is suffered from mortality in said patients, MACEs or the MCEs that makes a definite diagnosis CVD.
MACEs comprises cardiac death, other cardiovascular death, (it comprises that myocardial infarction (MI) and coronary artery intervention are such as coronary artery revascularization to MCEs, angioplasty, percutaneous coronary endoluminal vascular plasty (PTCA), percutaneous coronary is got involved (PCI) and coronary artery bypass graft (CAB) (CABG)), by being in hospital that unstable angina pectoris causes, apoplexy, transient ischemic attack (TIA) and by being in hospital and/or interventional therapy that peripheral arterial disease (PAD) causes.
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, the 3rd report (being also referred to as " NCEP ATP III ") of NIH PublicationNo.02-5215 (in JIUYUE, 2002), be hereby incorporated by, provide and reduced the suggestion for the treatment of about cholesterol reducing in the works of CHD risk.In ATP III, CHD is defined as symptom type ischemic heart disease, comprises MI, stable type or unstable angina pectoris, tests the myocardial ischemia of confirmation and the medical history of coronary artery surgery by no aggressive.This ATP III shows that LDL-C is the primary target of lipid treatment, and other lipid that needs to regulate comprises triglyceride (TG), non--HDL-C and HDL-C.Apo-B is listed in the risk factor of formation.And substituting the ATP III not preparation of LDL-C as the primary target of lipid treatment, it shows that limited epidemiology and clinical trial evidence are supported in that apo-B is better than LDL-C in the danger forecasting.
The guideline of ATP III is to regulate the intensity of the treatment that reduces LDL-C to be adapted to the absolute risk of individual CHD.The risk evaluation be divided into short-term (≤10-) and long-term (＞10-) CHD risk, and LDL-C target (goal) is correspondingly regulated.In addition, ATP III has proved conclusively the three class risks of CHD, and it improves the LDL-C target: the CHD of conclusive evidence and CHD risk equivalent (risk equivalents), multiple (2+) risk factor and 0-1 risk factor.The CHD and the CHD risk equivalent of conclusive evidence comprise CHD, other clinical atherosclerosis, diabetes and multiple risk factor, and 10-risk＞20% of CHD.The main independently risk factor of proving conclusively in the risk factor of counting comprises smoking (cigarette smoking), hypertension, low HDL-C, sends out family history and the age of CHD morning.
The LDL-C target of three class risk factors is as follows:
Risk factor The LDL-C target
CHD and CHD risk equivalent ＜100mg/dl
Multiple (2+) risk factor ＜130mg/dl*
The 0-1 risk factor ＜160mg/dl
* for have the 10-risk＞the LDL-C target of 20% people's multiple risk factor is＜100mg/dl.ATP III has also listed the percentile LDL-C target based on the 10-risk of CHD:
The 10-risk The LDL-C target
＞20％ ＜100mg/dl
10-20％ ＜130mg/dl
＜10% and multiple (2+) risk factor ＜130mg/dl
＜10% and the 0-1 risk factor ＜160mg/dl
Medicament, medicine and omega-fatty acid such as dyslipidemia, be used for the treatment of myocardial infarction (post-myocardial infarction) (MI), and adult's EHL of hypercholesterolemia and hypertriglyceridemia, they classify as " cardiovascular disease " usually.
The medicine of dyslipidemia generally includes HMG CoA reductase inhibitor (inhibin), cholesterol absorption inhibitor, nicotinic acid and derivant such as nicotiamide, the special class (fibrates) of shellfish, bile acid chelating agent, MTP inhibitor, lxr agonist and/or antagonist and PPAR agonist and/or antagonist.
Inhibin, it is 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, has been used to treat for example hyperlipemia and atherosclerosis.Typically, the inhibin monotherapy has been used for the treatment of cholesterol levels, especially as patient during not in acceptable LDL-C level.Inhibin inhibitory enzyme HMG-CoA reductase, the speed that this enzyme control volume inner cholesterol produces.Thereby inhibin by slowing down cholesterol generation and the ability by increasing liver to remove already present LDL-cholesterol cholesterol reducing in the blood.Therefore, the main effect of inhibin is to reduce the LDL-C level.Inhibin has demonstrated and has reduced CHD risk about 1/3rd.Yet inhibin only demonstrates has suitable effect to the TG-HDL axle.The monotherapy of the multiple inhibin of also known use reduces the apo-B level significantly, for example, compares reduction about 25 to about 40% with baseline.Referring to, for example, people such as Ballantyne, Am.Heart be (5) J.151: 975.e1-975.e9 (2006).
Cholesterol absorption inhibitor such as ezetimibe (ezetimibe) and MD-0727, is a class blood fat reducing chemical compound, and it optionally suppresses the intestinal absorption of cholesterol.Ezetimibe acts on the brush border of small intestinal, and reduces bile and the absorption of dietary cholesterol exposure from small intestinal to enterocyte.The result of study of 2006 WorldCardiology Congress report shows that the combination of ezetimibe and simvastatin has than the apo-B level more positively charged effect of independent simvastatin in hypercholesterolemiapatients patients.People such as Orse, Effects Of Ezetimibe/simvastatin On Lipoprotein Subclasses InPatients With Hypercholesterolemia, 2006 World Cardiology Congress-posterpresentation; People such as Ballantyne, Effects of Ezetimibe/simvastatin Compared toSimvastatin Monotherapy in Reducing C-Reactive Protein and Low DensityLipoprotein-Cholesterol, 2006 World Cardiology Congress-posterpresentation.
Cetp (CETP) inhibitor such as Tuo Chepu (torcetrapib), suppresses the CETP molecule, wherein, cholesterol is transferred to the LDL form from the HDL form.Therefore, suppress this molecule for increasing the method likely of HDL cholesterol levels.It is reported when giving, and when with itself and inhibin combination medicine-feeding, Tuo Chepu also reduces the level of LDL-C and apo-B with monotherapy.People such as Bhardwaj, Indian J.Pharmacol.37:46 (2005).
Nicotinic acid (nicotinic acid or 3-picolinic acid) had been used for the treatment of hyperlipemia and atherosclerosis in the past.Known nicotinic acid hypercholesterolemia reducing, LDL-C and triglyceride and increase HDL-C.Also known nicotinic acid treatment reduces the serum levels of apo-B.Yet, because nicotinic acid is treated the influence that the change in value of caused independent lipid and lipoprotein can be subjected to the seriousness and the type of potential dyslipidemias.In a research, to compare with combination of ezetimibe-simvastatin or independent rosuvastatin, the nicotinic acid of low dosage adds that atorvastatin (20mg) or rosuvastatin (10mg) have reduced the apo-B level.People such as McKenney, Atherosclerosis (suppl): 174.Abstract Tu-W27:4 (2006).
Special class such as the fenofibrate of shellfish, bezafibrate, chlorine Bei Te and gemfibrozil are the PPAR-alfa agonists, and it is used for reducing the lipoprotein that is enriched in triglyceride the patient, to reduce HDL and to reduce atherogenic-Mi LDL.The special class of shellfish is administered orally in this type of patient usually.
Fenofibrate or 2-[4-(4-chlorobenzene formacyl) phenoxy group]-2-methyl-propanoic acid, 1-Methylethyl ester belongs to the special class of shellfish, and is because it is in the effectiveness that reduces aspect blood triglyceride and the cholesterol levels, known to a lot of year of medical active component.Fenofibrate is the active component of the non-constant of dissolubility in water, and fenofibrate is limited in gastral absorption.The treatment of 40 to 300mg fenofibrate can make resulting hypercholesterolemia reduction by 20 to 25% and make triglyceride reduce by 40 to 50% every day.
Bile acid chelating agent such as colestyramine, colestipol and colesevelam, is the medicine of a class conjugated bile acid, and it stops the again absorption of bile acid from digestive system, and the cholesterol reducing level.The routine of bile acid chelating agent act as and reduces LDL-cholesterol about 10 to 20%.Low dose of chelating agen can produce effectively the LDL-cholesterol and reduce.A research has reported that the combined therapy that uses fluvastatin and colestyramine has produced apo-B level significant, dose dependent and reduced.People such as Bard, Am.J.Cardiol., 76 (2): 65A-70A (2005).
The MTP inhibitor is such as the secretion of known inhibition cholesterol of implitapide (implitapide) and triglyceride.
Liver X receptor (LXRs) is " a cholesterol sensor ", the expression of gene that its governing response relates in the lipid metabolism of specificity oxygen sterin part (people such as Repa, Annu.Rev.Cell Dev.Biol.16:459-481 (2000)).Lxr agonist and antagonist are for dyslipidemia and atherosclerotic potential medicine.
The PPAR-gamma agonist such as thiazolidinedione, pioglitazone and rosiglitazone, has demonstrated to improving cardiovascular risk and atherosclerotic surrogate markers thing (marker).For example, thiazolidinedione reduces C-reactive protein and common carotid artery inner membrance middle level (intema-media) thickness.Non--thiazolidinedione, such as for Sai Gelieta (tesaglitazar), naviglitizar and Mo Geta azoles (muraglitazar), be dual α/γ PPAR agonist.These chemical compounds are used to reduce glucose, insulin, triglyceride and free fatty.In a research, rosiglitazone demonstrates and reduces the apo-B level significantly.People such as Goldberg, Diabetes Care28 (7): 1547-1554 (2005).
Part PPAR-gamma agonist/antagonist such as metaglidasen, is used for the treatment of type ii diabetes.
Marine oil is also referred to as fish oil usually, is the good source of two kinds of omega-fatty acids (eicosapentaenoic acid (EPA) and docosahexenoic acid (DHA)), has been found that its scalable lipid metabolism.Have been found that omega-fatty acid to the cardiovascular diseases, mild hypertension especially, the risk factor of hypertriglyceridemia and have useful effect for coagulation factor VII phosphatide complexes activity.Omega-fatty acid reduces serum triglycerides, increases serum hdl-cholesterol, reduces systolic blood pressure and diastolic blood pressure and pulse rate, and the activity that reduces blood coagulation factor VII phosphatide complexes.In addition, omega-fatty acid appears as well tolerable, and does not cause any serious adverse.
A kind of omega-fatty acid of this type of form is the concentrate of the ω-3 that obtains from fish oil, long-chain, polyunsaturated fatty acid, and it contains DHA and EPA, and it is with trade mark Omacor
Figure A20078004566600091
Sell, be called Lovaza now TMThe omega-fatty acid of one this type of form of class is described in, for example, United States Patent (USP) 5,502,077,5,656,667 and 5,698,594, be hereby incorporated by separately.
Suffer from blood levels that the patient of Combination dyslipidemia or hypercholesterolemia has the LDL cholesterol usually greater than 190mg/dl, triglyceride levels is that 200mg/dl or higher and apo-B level are greater than 0.9g/l.In many patients that suffer from hypertriglyceridemia, hypercholesterolemia and/or Combination dyslipidemia, the use of diet and single medicine therapy can not fully reduce LDL cholesterol, triglyceride and/or apo-B level usually to reach desired value.In these patients, need the complementary combinations treatment of the medicine and the omega-fatty acid of dyslipidemia.
Many researchs after testing the synergy of omega-fatty acid and inhibin treatment to the apo-B level.Although the most of conclusive evidence of these researchs inhibin reduces the apo-B level significantly, most studies is also reported and is used the treatment of increase omega-fatty acid not reduce the apo-B level significantly.
People such as Hong have studied fish oil and the effect of simvastatin in the patient who suffers from coronary heart disease and Combination dyslipidemia.The patient who has the baseline triglyceride levels and be 292.8mg/dl or 269.5mg/dl uses 10-20mg/ days Simvastatin Treatment 6-12 weeks at first.After this patient uses simvastatin and placebo or simvastatin and 3g/ days fish oil (Meilekang TM) treatment.Compare with placebo with baseline, combined therapy has reduced triglyceride levels significantly.In addition, compare, increased the HDL-C level on the combined therapy numerical value, and reduced the LDL-C level on the numerical value with baseline.Yet the variation of this HDL-C level and LDL-C level is not significant on the statistics.The level of apo-B raises in the combined therapy group, and the apo-B level reduces on the numerical value in placebo group.People such as Hong, Chin.Med.Sci.J.19:145-49 (2004).
People such as Contacos have studied the effect to the patient that suffers from combined hyperlipidemia of fish oil and pravastatin.The patient who has the baseline triglyceride levels and be 4.6 to 5.5mmol/l (404 to 483mg/dl) originally treated for 6 weeks, used 40mg/ days pravastatins, 6g/ days fish oil (Himega TM, contain the omega-fatty acid of 3g, wherein the EPA/DHA ratio is 2: 1), or placebo.After this, all patients use pravastatin and fish oil to treat for 12 weeks again.The treatment of initial use pravastatin reduces the LDL-C level significantly.The combined therapy of pravastatin and fish oil is triglyceride reducing and LDL-C level significantly also.Yet, fish oil being joined the pravastatin monotherapy cause the only increase on the numerical value of LDL-C level, it is not significant on the statistics.Use treatment with fish oil triglyceride reducing level significantly separately, but increase the LDL-C level.Compare (not comparing with baseline) with the independent treatment of fish oil, the combined therapy of this group reduces the LDL-C level significantly.Use the pravastatin treatment to reduce the apo-B level significantly.Numerically reduce the apo-B level further with the combined therapy of fish oil, however it is reported this further reduce compare with the pravastatin monotherapy not remarkable.People such as Contacos, Arterioscl.Thromb.13:1755-62 (1993).
People such as Grekas have reported about the pravastatin of the low-dosage in the dyslipidemia after renal transplantation and the combined therapy of fish oil.(T-CHOL＞200mg/dl) and the 30 routine renal transplant recipients that are in immunosuppressant therapy give standard diet 4 weeks, then treat for 8 weeks with the 20mg pravastatin to having the persistence hypercholesterolemia.Baseline triglyceride levels in the diet stage is 184mg/dl.Be the standard diet in other 4 weeks after this stage, use the 20mg pravastatin to add 1g fish oil (Prolipid) 8 weeks of treatment then.Baseline triglyceride levels in the diet stage is 169mg/dl.The apo-B level uses diet+inhibin treatment significantly not reduce.Yet, it is reported that diet+inhibin+fish oil has reduced the apo-B level significantly.People such as Grekas, Nephron (2001) 88:329-333.People's results of study such as Grekas appear as uncertain, and given independent use pravastatin is treated this research and do not demonstrated and reduce the apo-B level significantly.Show PRAVACHOL
Figure A20078004566600101
(pravastatin) reduces the apo-B level that raises as the additive of diet in the patient who suffers from primary hypercholesterolemia and Combination dyslipidemia.Therefore, people such as Grekas studies and uses pravastatin not demonstrate the fact that significant apo-B reduces to make that this result of study is queried.
People such as Huff find that the combination of diet fish oil and lovastatin is reduced in very low density lipoprotein (VLDL) (VLDL) in the piglets and the apo-B level in low density lipoprotein, LDL (LDL) fraction.Yet combined therapy and fish oil monotherapy have only been compared in this research, and not comparison combination treatment and inhibin monotherapy.People such as Huff, Arteroscl.Thromb., 12 (8): 901-910 (August 1992).
People such as Jula have studied the effect to hypercholesterolemia male patient's multiple serum lipids of diet and simvastatin.After the open placebo phase, the patient is assigned as " habitual diet " or " diet treatment " group.The diet treatment is made of Mediterranean cuisine (Mediterranean-type diet), wherein is no more than 10% energy and comes from saturated and trans-undersaturated fatty acid; The cholesterol picked-up is no more than 250mg/ days; The omega-fatty acid picked-up in plant and source, ocean is 4g/ days at least, and the ratio of ω-6 fatty acid and omega-fatty acid is less than 4; And the picked-up of fruit, vegetable and soluble fiber increases.Then the patient is assigned as with double blinding, cross-mode and accepts 20mg/ days simvastatins or 12 weeks of placebo.Patient in Diet Therapy group and simvastatin group has reduced the apo-B level significantly.It is reported that the interaction between two variablees is significant.People such as Jula, JAMA 287 (5): 598-605 (2002).
U.S. Patent Application Publication requires to comprise a kind of method by drug treatment Drug therapy patient for No. 2003/0170643, (post-ERpre-secretory proteolysis PERPP) reduces apo-B and/or contain the lipoprotein of apo-B-and/or the plasma concentration of the composition of atherogenic lipoprotein to the proteolysis of this medicine before by secretion behind the stimulating er.
After deliberation inhibin and Omacor
Figure A20078004566600111
The effect of omega-fatty acid.For example, people such as Hansen has studied lovastatin (40mg/ days) and 6g/ days Omacor Omega-fatty acid makes up the effect to the patient who suffers from hypercholesterolemia.The patient who has the baseline triglyceride levels and be 1.66mmol/l (about 146mg/dl) uses 6g/ days Omacor
Figure A20078004566600113
Treated for 6 weeks, then use 40mg/ days lovastatins to treat other 6 weeks, and Omacor
Figure A20078004566600114
With last 6 weeks of lovastatin combined therapy.The lovastatin monotherapy causes increasing the HDL-C level significantly, and triglyceride reducing and LDL-C level significantly.Behind the combined therapy, triglyceride and LDL-C level reduce further significantly.The apo-B level uses the lovastatin monotherapy to reduce significantly, and further numerically reduces apo-B when adding omega-fatty acid, although this further reduction does not show that or not is significant comparing with the lovastatin monotherapy.People such as Hansen, Arterioscl.Thromb.14 (2): 223-229 (February 1994).
People such as Nordoy have studied the effect for the patient who suffers from hyperlipemia of atorvastatin and omega-fatty acid.The patient who has the baseline triglyceride levels and be 3.84mmol/l (about 337mg/dl) or 4.22mmol/l (about 371mg/dl) uses 10mg/ days atorvastatins to treat for 5 weeks.After this, 2g/ days Omacor are used in the atorvastatin treatment
Figure A20078004566600115
Or placebo carries out other 5 weeks of supplement therapy.Compare with baseline, the atorvastatin monotherapy has increased the HDL-C level significantly, and triglyceride, LDL-C and apo-B level reduce significantly.Compare with independent atorvastatin, combined therapy further increases the HDL-C level.Compare with the atorvastatin monotherapy, further reduce slightly on the numerical value when triglyceride, LDL-C and apo-B level are used combined therapy; Yet this reduction is not remarkable.People such as Nordoy, Nutr.Metab.Cardiovasc.Dis. (2001) 11:7-16.
People such as Chan have studied atorvastatin (40mg/ days) and 4g/ days 4Omacor under fasting state to the male patient who suffers from dyslipidemia obesity, insulin-opposing
Figure A20078004566600116
Combined therapy.Having the baseline triglyceride levels is 6 weeks of patient treatment of 1.7 to 2.0mmol/l (about 150 to 170mg/dl), uses: 40mg/ days atorvastatins and placebo; 4g/ days Omacor
Figure A20078004566600121
And placebo; Atorvastatin and Omacor
Figure A20078004566600122
Combination; Or the combination of placebo.The atorvastatin monotherapy reduces the apo-B level significantly.Compare with placebo group, combined therapy also reduces the apo-B level significantly.Yet, by Omacor
Figure A20078004566600123
Caused effect is not remarkable.People such as Chan, Diabetes, 51:2377-2386 (Aug.2002).
People such as Nordoy have studied 40mg/ days lovastatins and 6g/ days Omacor (being also referred to as " K-85 ") do not have the effectiveness of the combined therapy among cardiovascular diseases's the patient in the hypercholesterolemia of suffering from family.This research comprises 3 interventional therapy cycles, each 6 time-of-week, and the washing time by 6 weeks interrupts.Carry out behind the interventional therapy 12 weeks of final test the last time.Use the omega-fatty acid monotherapy that the apo-B level is numerically reduced slightly, and use the lovastatin monotherapy that the apo-B level is reduced significantly.Compare with baseline, combined therapy also lowers the apo-B level significantly.Yet this reduction does not show that it is compared with the lovastatin monotherapy is significant.People such as Nordoy, Essent.FattyAcids Eicosanoids, Invited Pap.Int ' l Congr.4 Th, 256-61 (1998).
People such as Nordoy have also studied effectiveness and the safety of using simvastatin and omega-fatty acid to treat in suffering from the patient of hyperlipemia.The patient who has the baseline triglyceride levels and be 2.76mmol/l (about 243mg/dl) or a 3.03mmol/l (about 266mg/dl) uses 20mg/ days simvastatins or 5 weeks of placebo treatment, and all then patients use 20mg/ days other 5 weeks of Simvastatin Treatment.After this, the patient re-uses 4g/ days Omacor Or other 5 weeks of placebo treatment.Administration omega-fatty acid and simvastatin have caused the moderate reduction of serum total cholesterol and triglyceride levels to reduce, and the reduction on the little numerical value of apo-B level.Yet the effect of omega-fatty acid is not remarkable.People such as Nordoy, J.of Internal Medicine, 243:163-170 (1998).
People detection such as Durrington Omacor
Figure A20078004566600126
Effectiveness, safety and toleration among the patient who is combined in the hypertriglyceridemia of proving conclusively coronary heart disease and continuing of ω-3 acid and simvastatin.Patient's (the average patient serum triglyceride level is 4.6mmol/l) with average baselining triglyceride levels＞2.3mmol/l uses 10-40mg/ days simvastatins and 2g/ days Omacor in double-blind trial Or 24 weeks of placebo treatment, thereafter in open research two groups all accept Omacor
Figure A20078004566600128
Other 24 weeks.Compare with the baseline monotherapy, combined therapy has reduced triglyceride levels significantly in 12 weeks.In addition, the VLDL cholesterol levels in these patients has reduced 30-40%.Compare with the baseline monotherapy, the LDL-C level only reduces after 48 weeks significantly, although (not remarkable on the statistics) reduces on 12 and 24 all numerical value.Use omega-fatty acid and simvastatin monotherapy, the apo-B level demonstrates the reduction of (not remarkable on the statistics) on the slight numerical value.People such as Durrington, Heart, 85:544-548 (2001).
Summary of the invention
Still there is the unsatisfied demand that has the method that the apo-B level of increase reduces for monotherapy in the prior art than the medicine of independent use dyslipidemia.This method be particularly useful for treatment in the patient as one or more following diseases among the people patient: hypercholesterolemia, hypertriglyceridemia, Combination dyslipidemia, coronary heart disease (CHD), angiopathy, atherosclerosis and associated conditions, and/or be used for prevention or reduction cardiovascular and/or angiopathy.
Embodiments more of the present invention provide the combination of the medicine that uses dyslipidemia and omega-fatty acid to reduce the method for apo-B level, it is suitable for treating one or more following diseases: hypercholesterolemia, hypertriglyceridemia, Combination dyslipidemia, coronary heart disease, angiopathy, atherosclerosis and associated conditions, and/or be used for prevention or reduce cardiovascular and angiopathy.
Embodiments more of the present invention comprise the method for patient's blood lipid treatment, comprise medicine and omega-fatty acid to the dyslipidemia of patient's effective dosage, wherein the apo-B level among the patient is compared with the medicine of independent use dyslipidemia and has been lowered.
In other embodiments, the present invention includes the method for the apo-B level that reduces patient group, comprise patient group is provided, and by to described patient group with the combination of the medicine of the amount administration dyslipidemia of the apo-B level of comparing the described patient group of effective reduction with the treatment of the medicine of independent use dyslipidemia and omega-fatty acid to reduce described patient group's apo-B level.In preferred embodiments, this patient group has at least a following disease: hypertriglyceridemia, hypercholesterolemia, Combination dyslipidemia, angiopathy and/or atherosclerosis and associated conditions.
In other embodiments, the medicine of this dyslipidemia and omega-fatty acid be with the single medicine compositions administration as combination product, for example, unit dose, it comprises the medicine and the omega-fatty acid of dyslipidemia.
In preferred embodiments, this pharmaceutical composition comprises Lovaza TMOmega-fatty acid, as be described in United States Patent (USP) 5,502 is in 077,5,656,667 and 5,698,594.In other embodiment preferred, this pharmaceutical composition comprises omega-fatty acid, and its content is at least 40 weight % of the total fatty acid content of said composition.
In other embodiment preferred, this omega-fatty acid is included as the EPA and the DHA of at least 50 weight % of the total fatty acid content of described compositions, and the weight ratio EPA of this EPA and DHA: DHA is 99: 1 to 1: 99, preferred 1: 2 to 2: 1.
In embodiment of the present invention (variation), the medicine of this dyslipidemia is an inhibin, include but not limited to Pitavastatin (pitavastatin), simvastatin (simvastatin), rosuvastatin (rosuvastatin), pravastatin (pravastatin), atorvastatin (atorvastatin), lovastatin (lovastatin) and fluvastatin (fluvastatin).In preferred embodiments, be simvastatin at the inhibin that is used in combination with omega-fatty acid.
In one aspect of the invention, combination product uses in treatment suffers from the patient of constitutional hypertriglyceridemia or hypercholesterolemia or Combination dyslipidemia.
In other preferred embodiment of the present invention, before the medicine of administration first time dyslipidemia and omega-fatty acid combination, triglyceride levels in described patient's (or described patient group) the serum, i.e. baseline is for about 200 to about 499mg/dl.
The present invention also comprises the purposes of the medicine of dyslipidemia and the medicine that omega-fatty acid uses of effective dose in preparation arbitrary Therapeutic Method as herein described.
For a person skilled in the art, other features and advantages of the present invention according to following detection or according to the present invention practice what instructed is conspicuous.
The preferred embodiment explanation
The present invention preferably relates to the medicine and the omega-fatty acid that use dyslipidemia and reduces the apo-B level, the level that its medicine treatment that has surpassed independent use dyslipidemia is reached.Method of the present invention is particularly useful for treating constitutional hypertriglyceridemia or hypercholesterolemia or Combination dyslipidemia, coronary heart disease, angiopathy, atherosclerosis and associated conditions, and/or is used for prevention or reduces cardiovascular and/or angiopathy.In preferred embodiments, patient's baseline apo-B level is greater than 0.9g/l, and use the present invention is reduced to the apo-B level less than 0.9g/l.
In some embodiments, non--HDL-C level of patient is 130mg/dl at least, more preferably 160mg/dl at least, and use the present invention to compare with baseline and/or further compare with the medicine treatment of independent use dyslipidemia the apo-B level is reduced preferably at least 2%.
In some embodiments, patient LDL-C level raise (for example, 100mg/dl at least, 100mg/dl and at least less than 130mg/dl, at least 130mg/dl, or 160mg/dl at least) and/or triglyceride levels raise (for example, 150mg/dl, 200mg/dl at least at least, 200-499mg/dl, or 500mg/dl at least), and if both all have, can assert that the patient has the Combination dyslipidemia.
In some embodiments, the invention provides new combination.In preferred embodiments, this combination comprises the medicine of omega-fatty acid and dyslipidemia, the administration simultaneously of the medicine of wherein said omega-fatty acid and dyslipidemia, for example, with the pharmaceutical composition of single fixed dosage or with the administration simultaneously of independent compositions.
In other preferred embodiment, administration comprises the medicine of omega-fatty acid and dyslipidemia, the wherein medicine of dyslipidemia and omega-fatty acid separate administration, but in the scheme of co-administered treatment.For example, the medicine of dyslipidemia can be administered once every day, and omega-fatty acid is administered twice every day.Those skilled in the art openly can recognize according to of the present invention, the exact dose of the medicine of administration omega-fatty acid and dyslipidemia and scheme can change according to many factors, such as, for example, the order of severity of route of administration, disease, other altogether sick (comorbidity), and the use of other medicines.
In some embodiments, medication required for protection is a gamma therapy, is meant for disease or its therapy for the given first kind of disease.In other embodiments; medication required for protection is two gamma therapies; be meant when an initial therapy (gamma therapy; for example; the medicine or the omega-fatty acid of dyslipidemia are treated separately) can not play the treatment that fully gives as the time spent; consider therapeutic goal, or fully act on when stopping, for example because the physiological change among the patient or the variation of CHD risk factor.
In some embodiments, the present invention is suitable for primary prevention.In other embodiments, the present invention is suitable for secondary prevention.
In preferred embodiments, selected patient group is accepting the treatment of the medicine of dyslipidemia before the combined therapy of the medicine of dyslipidemia and omega-fatty acid.Other activating agent (except omega-fatty acid) also can use before the medicine of dyslipidemia and omega-fatty acid combined therapy.
In preferred embodiments, present invention resides in the method for blood lipid treatment among the patient group, comprise medicine and omega-fatty acid to the dyslipidemia of described patient group's effective dosage, and wherein behind the described patient group of administration, the matched group of the medicine treatment of described patient group's triglyceride levels and apo-B level and independent use dyslipidemia is compared reduction, and described patient group's HDL-C level is compared with the matched group of the medicine treatment of independent use dyslipidemia and/or compared increase with baseline.Preferably, described patient group's baseline triglyceride levels is 200 to 499mg/dl.
In other preferred embodiment, present invention resides in the method for blood lipid treatment among the patient group, comprise medicine and omega-fatty acid to the dyslipidemia of described patient group's effective dosage, and wherein behind the described patient group of administration, described patient group's triglyceride levels is compared reduction with the apo-B level with the matched group of the medicine treatment of independent use dyslipidemia, and the LDL-C increase is no more than 1% of baseline.Preferably, described patient group's baseline triglyceride levels is 200 to 499mg/dl.
In other preferred embodiment, present invention resides in the method for blood lipid treatment among the patient group, comprise medicine and omega-fatty acid to the dyslipidemia of described patient group's effective dosage, wherein behind the described patient group of administration, non--HDL-C level of described patient group, total cholesterol level, triglyceride levels is compared reduction with the apo-B level with the matched group of the medicine treatment of independent use dyslipidemia, and described patient group's HDL-C level is compared increase with the matched group of the medicine of independent use dyslipidemia treatment, and the LDL-C increase is no more than 1% of baseline.
In other preferred embodiment, present invention resides in the method for blood lipid treatment among the patient group, comprise medicine and omega-fatty acid to the dyslipidemia of described patient group's effective dosage, and wherein behind the described patient group of administration, non--HDL-C level of described patient group is compared reduction with the matched group of the medicine of independent use dyslipidemia treatment.Preferably, described patient group's baseline triglyceride levels is 200 to 499mg/dl.
In other preferred embodiment, the present invention includes the triglyceride levels that reduces patient group and apo-B level and do not increase the method for described patient group's LDL-C level, comprise patient group is provided, and by reducing described patient group's triglyceride levels and apo-B level to described patient group with the medicine of the amount administration dyslipidemia of the triglyceride levels of comparing the described patient group of effective reduction with independent use HMG-CoA reductase inhibitor and apo-B level and the combination of omega-fatty acid, and do not increase the LDL-C level.
Phrase " is compared with the medicine treatment of independent use dyslipidemia " can refer to identical patient or the patient group of treatment in different treatment groups, or treat similar patient or patient group (promptly, consider concrete blood protein or lipid, such as cholesterol or triglyceride levels, belong to of a sort patient).Be meant according to the term " reduction " of the method for embodiment and " increase " and reduce significantly on the statistics or to increase, meet its implication common and custom, that is, the probability of variation is 5% or littler (p=0.05 or littler), more preferably 2.5% or littler (p=0.025 or littler).In some embodiments of the present invention, reduce or increase some level (such as reducing the apo-B level) on the medicine statistics of independent dyslipidemia significantly, and the combined therapy of the medicine of dyslipidemia and omega-fatty acid reduces or increases this level on the statistics further significantly.
Compare with the medicine treatment of independent use dyslipidemia, except reducing the apo-B level, method and composition of the present invention also is used in and reduces arbitrary following lipid level in the patient of treatment or patient group: non--the HDL-C level, triglyceride levels, VLDL-C level, total C level, RLP-C level, Lp-PLA2 level and/or Apo-C3 level.Compare with the medicine treatment of independent use dyslipidemia, method and composition of the present invention also can be used for increasing the HDL-C level.Preferably, compare, use method and composition of the present invention and do not increase the LDL-C level with baseline.
Preferably, non--HDL-C level is compared with baseline and can be reduced at least about 5%, preferably at least about 7%, and/or further compares reduction at least about 5% with the medicine treatment of independent use dyslipidemia, preferably at least about 7%.
Preferably, triglyceride levels is compared with baseline and can be reduced at least about 20%, preferably at least about 25%, and/or further compares reduction at least about 10% with the medicine treatment of independent use dyslipidemia, preferably at least about 15%, more preferably at least about 20%.
Preferably, the VLDL-C level is compared with baseline and can be reduced at least about 15%, preferably at least about 20%, more preferably at least about 25%, and/or further compare reduction at least about 10% with the medicine treatment of independent use dyslipidemia, preferably at least about 15%, more preferably at least about 20%.
Preferably, total C level is compared with baseline and can be reduced at least about 3%, preferably at least about 5%, and/or further compares reduction at least about 2% with the medicine treatment of independent use dyslipidemia, preferably at least about 3%.
Preferably, the RLP-C level is compared with baseline and can be reduced at least about 15%, preferably at least about 20%, more preferably at least about 25%, and/or further compare reduction at least about 10% with the medicine treatment of independent use dyslipidemia, preferably at least about 15%, more preferably at least about 20%.
Preferably, the Lp-PLA2 level is compared with baseline and can be reduced at least about 5%, preferably at least about 7%, more preferably at least about 10%, and/or further compare reduction at least about 3% with the medicine treatment of independent use dyslipidemia, preferably at least about 5%, more preferably at least about 7%.
Preferably, the apo-B level is compared with baseline and can be reduced at least about 3%, preferably at least about 4%, and/or further compares reduction at least about 1% with the medicine treatment of independent use dyslipidemia, preferably at least about 2%.
Preferably, the Apo-C3 level is compared with baseline and can be reduced at least about 5%, preferably at least about 7%, and/or further compares reduction at least about 8% with the medicine treatment of independent use dyslipidemia, preferably at least about 10%.
Preferably, the HDL-C level is compared with baseline can be increased at least about 2%, preferably at least about 3%, and/or further compares increase at least about 3% with the medicine treatment of independent use dyslipidemia, preferably at least about 5%.
Preferably, compare the also ratio of hypercholesterolemia reducing and HDL-C of the present invention with baseline,, more preferably at least about 10%, and/or further compare reduction at least about 5%, preferably at least about 10% with the medicine treatment of independent use dyslipidemia preferably at least about 5%.
The present invention can comprise it has been generally acknowledged that the present known of safe dose or the medicine of known dyslipidemia in the future.The medicine of preferred dyslipidemia comprises that HMG CoA reductase inhibitor comprises inhibin, cholesterol absorption inhibitor is such as, but not limited to ezetimibe, nicotinic acid and derivant are such as nicotiamide, the CETP inhibitor is such as, but not limited to Tuo Chepu, the special class of shellfish is such as, but not limited to fenofibrate, bezafibrate, chlorine Bei Te and gemfibrozil, bile acid chelating agent is such as, but not limited to colestyramine, colestipol and Kao Laiwei storehouse, the MTP inhibitor is such as, but not limited to being disclosed in WO 00/38725 and Science, 282,23 October 1998, those among the pp.751-754 are hereby incorporated by, lxr agonist and/or antagonist, with PPAR agonist and antagonist (such as, but not limited to PPAR-α, PPAR-γ, PPAR-δ, PPAR-α/γ, the PPAR-gamma/delta, PPAR-α/δ and PPAR-α/gamma/delta agonist, antagonist and partial agonist and/or antagonist) such as, but not limited to thiazolidinedione, non-thiazolidinedione and metaglidasen.What extensively can get now has six kinds of inhibin: atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and simvastatin.The 7th kind of inhibin, Pitavastatin is in clinical trial.The 8th kind of inhibin, cerivastatin has been removed from American market when writing this paper.Yet, to those skilled in the art believable be cerivastatin can with embodiment couplings more of the present invention, if cerivastatin finally determines it is safe and efficient words.
Usually, the medicine of dyslipidemia act as dose dependent, that is, dosage is high more, therapeutic effect is good more.Therefore yet the effect of the medicine of each dyslipidemia is different, and a kind of level of therapeutical effect of medicine of dyslipidemia is can not be inevitable directly related with the level of the therapeutical effect of the medicine of other dyslipidemia.Yet those skilled in the art can recognize the suitable dose that will give concrete patient based on the order of severity of experience and disease.
Term " omega-fatty acid " comprises natural or synthetic omega-fatty acid as used herein, or its pharmaceutically acceptable ester, derivant, conjugate (referring to, for example, people such as Zaloga, people such as No. 2004/0254357, U.S. Patent Application Publication and Horrobin, United States Patent (USP) 6,245, No. 811, be hereby incorporated by separately), precursor or its salt and composition thereof.That the example of omega-fatty acid oil includes but not limited to is unsaturated more than the ω-3, long-chain fatty acid such as eicosapentaenoic acid (EPA), docosahexenoic acid (DHA), and alpha-linolenic acid; Ester such as monoglyceride, diglyceride and triglyceride that omega-fatty acid and glycerol form; And ester such as the fatty acid methyl ester and the fatty acid ethyl ester of omega-fatty acid and primary alconol, secondary alcohol or tertiary alcohol formation.Preferred omega-fatty acid oil is long-chain fatty acid such as EPA or DHA, its triglyceride, and its ethyl ester, and composition thereof.This omega-fatty acid or its ester, derivant, conjugate, precursor, salt and composition thereof can with their pure form uses or as oily composition such as fish oil, the fish oil concentrate of preferred purification uses.The omega-fatty acid commercial examples that is suitable for the present invention's use comprises Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare a.s., 1327 Lysaker, Norway).
Preferred compositions comprises United States Patent (USP) 5,502, and the omega-fatty acid of quoting in 077,5,656,667 and 5,698,694 all is hereby incorporated by it.
Another preferred compositions comprises omega-fatty acid, and its content is at least 40 weight %, preferred at least 50 weight %, more preferably at least 60 weight %, even more preferably at least 70 weight %, most preferably at least 80 weight %, or even at least 90 weight %.Preferably, this omega-fatty acid comprises EPA and the DHA of at least 50 weight %, more preferably at least 60 weight %, even more preferably at least 70 weight %, most preferably at least 80%, all 84 weight % according to appointment.Preferred this omega-fatty acid comprises about 5 to about 100 weight %, and more preferably from about 25 to about 75 weight %, even more preferably from about 40 to about 55 weight %, and the EPA of 46 weight % most preferably from about.Preferred this omega-fatty acid comprises about 5 to about 100 weight %, and more preferably from about 25 to about 75 weight %, even more preferably from about 30 to about 60 weight %, and the DHA of 38 weight % most preferably from about.Above-mentioned all percentage ratios are the percentage by weight with respect to total fatty acid content in the compositions, except as otherwise noted.Percentage by weight can even can use other form according to the present invention, but be preferably based on the ethyl ester form of omega-fatty acid based on free acid or ester-formin.
EPA: the DHA ratio can be 99: 1 to 1: 99, and preferred 4: 1 to 1: 4, more preferably 3: 1 to 1: 3, most preferably 2: 1 to 1: 2.This omega-fatty acid can comprise pure EPA or pure DHA.
This omega-fatty acid compositions is optional to comprise chemical antioxidants, such as alpha tocopherol, oil, such as the mixture of soybean oil and partially hydrogenated vegetable oil and lubricant such as fractionated coconut oil, lecithin and above-mentioned substance.
The omega-fatty acid of most preferred form is Lovaza TMω-3 acid (Lysaker Norway), and preferably comprises following feature (every dosage form) for K85EE, Pronova BiocareA.S.:
Test Minima Maximum
Eicosapentaenoic acid C20:5 430mg/g 495mg/g
Docosahexenoic acid C22:6 347mg/g 403mg/g
EPA and DHA 800mg/g 880mg/g
Total n-3 fatty acid 90％(w/w)
The medicine of dyslipidemia and the combination product of spissated omega-fatty acid can be with capsule, tablets as known in the art, can be scattered in the powder in the beverage, or another kind of solid oral dosage form, liquid, Perle, coating Perle are (referring to U. S. application 11/716,020, be hereby incorporated by) or other regular dosage form such as the liquid oral form administration in capsule.In some embodiments, capsule comprises hard capsule.This combination product also can be included in the liquid that is suitable for injecting or infuses.Active component of the present invention also can-active pharmaceutical ingredient non-with one or more (being also referred to as " excipient " usually in this article) administration.Non--active component for example plays solubilising, suspending, thickening, dilution, emulsifying, stable, anticorrosion, protection, painted, seasoning, and the effect that active component is made applicatory and effective preparation, said preparation safety, convenience, and be suitable for using.
Excipient comprises surfactant; such as Capryol 90; the glycerol of long-chain fatty acid and the mixture of macrogol ester; the Oleum Ricini of polyethoxylated; glyceride; oleoyl polyethyleneglycol glyceride (oleoyl macrogol glycerides), PGML, propylene glycol dicaprylate/dicaprate; polyethylene-polypropylene glycol copolymer; with the polyethylene glycol oxide Arlacel-80, cosolvent such as ethanol, glycerol; Polyethylene Glycol; and propylene glycol and oily such as Oleum Cocois, olive oil or sunflower oil.The use of surfactant, cosolvent, oil or its combination is normally known in the pharmaceutical field, and is understandable for those skilled in the art, and the surfactant of any suitable can use with the present invention and embodiment thereof.
Spissated omega-fatty acid can with every day about 0.1g to about 10g, more preferably from about 1g is to about 8g, and the most preferably from about extremely amount administration of about 6g of 2g.In one embodiment, omega-fatty acid is with nearly 4g/ days amount administration.
The medicine of dyslipidemia can with greater than, be equal to or less than conventional complete dosage (full-strength dose) administration as single administration product.For example, the medicine of dyslipidemia can be with the 10-100% as the conventional complete dosage of single administration product, preferably about 25-100%, most preferably from about 50-80% administration.In one embodiment of the invention, the medicine of dyslipidemia is HMG-CoA reductase inhibitor or inhibin, and for every gram omega-fatty acid, its amount can be generally about 0.5mg to 80mg, more preferably from about 1mg is to about 40mg, and 5mg about 20mg extremely most preferably from about.Daily dose can be at about 2mg to about 320mg, and preferably about 4mg is to about 160mg scope.
In some embodiments of the present invention, the formulated in combination of the medicine of dyslipidemia and omega-fatty acid is individually dosed or unit dose.In preferred embodiments, the medicine of this dyslipidemia is to be selected from following inhibin: Pitavastatin, atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and simvastatin.
Pravastatin, it is known to Pravachol
Figure A20078004566600201
(by Bristol-Myers Squibb, Princeton, NJ makes) sell, for hydrophilic.Pravastatin is not being eaten food that is is being absorbed best on an empty stomach.With the combination medicine-feeding of spissated omega-fatty acid in, for the spissated omega-fatty acid of every dosage, the dosage of pravastatin is preferably 2.5 to 80mg, preferred 5 to 60mg, and more preferably 10 to 40mg.In one embodiment, the combination product that uses pravastatin is at sack time or contiguous sack time, and for example, at 10 o'clock in evening took.
Lovastatin, it is with title Mevacor
Figure A20078004566600211
(Merck, Whitehouse Station NJ) sell, for hydrophobic.Be different from pravastatin, lovastatin should be taken with canteen, and correspondingly, in some embodiments, the combination product of spissated omega-fatty acid and lovastatin should be taken with food.With the combination medicine-feeding of spissated omega-fatty acid in, for the spissated omega-fatty acid of every dosage, the dosage of lovastatin is preferably 2.5 to 100mg, preferred 5 to 80mg, and more preferably 10 to 40mg.
Simvastatin, it is with title Zocor
Figure A20078004566600212
(Merck, Whitehouse Station NJ) sell, for hydrophobic.With the combination medicine-feeding of spissated omega-fatty acid in, for the spissated omega-fatty acid of every dosage, the dosage of simvastatin be every day preferred 1 to 80mg, preferred 2 to 60mg, and more preferably 5 to 40mg.
Atorvastatin, it is with title Lipitor
Figure A20078004566600213
(Pfizer, New York NY) sell, and for hydrophobic, it is known as synthetic inhibin.With the combination medicine-feeding of spissated omega-fatty acid in, for the spissated omega-fatty acid of every dosage, the dosage of atorvastatin is preferably 2.5 to 100mg, preferred 5 to 80mg, and more preferably 10 to 40mg.
Fluvastatin, it is with title Lescol
Figure A20078004566600214
(Novartis, New York NY) sell, and are hydrophilic, and it is known as synthetic inhibin.With the combination medicine-feeding of spissated omega-fatty acid in, for the spissated omega-fatty acid of every dosage, the dosage of fluvastatin is 5 to 160mg, preferred 10 to 120mg, and more preferably 20 to 80mg.
Rosuvastatin is with title Crestor
Figure A20078004566600215
(Astra Zeneca, Wilmington DE) sell.With the combination medicine-feeding of spissated omega-fatty acid in, for the spissated omega-fatty acid of every dosage, the dosage of rosuvastatin is 1 to 80mg, preferred 2 to 60mg, and more preferably 5 to 40mg.
The medicine of dyslipidemia and the daily dose of spissated omega-fatty acid can be together with 1 to 10 dosed administrations, and the preferred dosage number is every day 1 to 4 time, most preferably every day 1 to 2 time.Administration is preferably oral administration, although can use other form of medication of the unit dose of medicine that dyslipidemia can be provided and spissated omega-fatty acid, preferred administration is an oral administration.
In some embodiments, compare preparation of the present invention with prior art formulations and make the effect of each active component improve, be administered once or twice with the complete dosage of routine.In other embodiments, compare preparation of the present invention with prior art formulations and can make the dosage of the medicine of dyslipidemia and/or omega-fatty acid reduce, and still keep or even increase the effectiveness of each active component.
The medicine of dyslipidemia of the present invention and the combination of spissated omega-fatty acid can greater than the independent any expections combination of two kinds of medicines or add and effect.And, the combination of two kinds of medicines or add and effect may depend on initial triglyceride levels in the blood samples of patients.For example, if patient's triglyceride levels is commonly referred to be normally less than 150mg/dL, if in about 150-199mg/dL, think, if think high, and if 500mg/dL or higher then think very high at about 200-499mg/dL at the edge height.The present invention can be less than 48 weeks, preferably in 24 weeks, more preferably in 12 weeks, and most preferably in 8 weeks, be used for will " very high " triglyceride levels be reduced to " height " or " edge height ".The present invention also can be less than 48 weeks, preferably in 24 weeks, more preferably in 12 weeks, and most preferably are used for the triglyceride levels of " height " is reduced to " edge height " or " normally " in 8 weeks.
Embodiment
Clinical research: carry out at random, double blinding, placebo-comparative study to be to estimate the Lovaza that makes up in the hypertriglyceridemia patient TMEffectiveness and safety with Simvastatin Treatment
Carry out at random, the clinical research of double blinding, placebo-contrast uses Lovaza to estimate in the hypertriglyceridemia patient TMOmega-fatty acid and simvastatin (Zocor
Figure A20078004566600221
) the effectiveness and the safety of combined therapy.The patient uses 40mg/ days at least 8 weeks of Simvastatin Treatment at first, carries out base line measurement then.If patient's baseline triglyceride levels be higher than normal value (〉=150mg/dl) and their LDL-C be higher than 10% o'clock at the most of NCEP ATP III target, this patient is suitable for recruiting and random packet.To 259 patient's random packet altogether, and accept the Lovaza of at least one dosage TMOmega-fatty acid or placebo, and among these patients 229 have the baseline triglyceride levels between 200 and 499mg/dl between.After the initial therapy, then use 4g/ days Lovaza with the double blinding pattern TMIn other 8 weeks of omega-fatty acid or placebo treatment, continue the inhibin treatment simultaneously.243 patients have finished this research.
Following table 1 has shown the result that the variation to multiple lipid and inflammatory parameter and mark obtains.
Table 1
Lovaza TMTreatment: compare intermediate value % with baseline and change Lovaza TMTreatment: compare meansigma methods % with baseline and change Placebo treatment: compare intermediate value % with baseline and change Placebo treatment: compare meansigma methods % with baseline and change Difference (% intermediate value) The p-value
Non--HDL-C -9.0％ -7.9％ -2.2％ -1.5％ -6.8％ ＜0.0001
LDL-C +0.7％ +3.1％ -2.8％ -1.9％ +3.5％ 0.0522
Apo-B -4.2％ -3.8％ -1.9％ -1.2％ -2.3％ 0.0232
TG -29.5％ -28.2％ -6.3％ -3.5％ -23.2％ ＜0.0001
VLDL-C -27.5％ -23.8％ -7.2％ -4.8％ -20.3％ ＜0.0001
Total C -4.8％ -4.7％ -1.7％ -1.5％ -3.1％ 0.0013
HDL-C +3.4％ +4.1％ -1.2％ -1.1％ +4.6％ ＜0.0001
TC/HDL -9.6％ -8.0％ -0.7％ +0.1％ -8.9％ ＜0.0001
RLP-C -36.0％ -29.0％ -10.6％ +0.1％ -25.4％ ＜0.0001
Lp-PLA2 -12.8％ -10.7％ -4.7％ -1.4％ -8.1％ 0.0019
Apo-C3 -7.8％ -7.1％ +3.9％ +3.8％ -11.7％ 0.0002
Following table 2 and 3 has shown is passing through Lovaza respectively TMThe LDL-C target that reaches in the research that treatment and placebo treatment carry out.
Table 2
Figure A20078004566600231
Table 3
Figure A20078004566600232
The more detailed analysis that apo-B reduces as the function of baseline LDL-C and non--HDL-C level confirms Lovaza TMTreatment has significantly and the ability that increases reducing the apo-B level under increase LDL-C and non--HDL-C baseline values, yet placebo treatment causes the irregular and non-significant variation of apo-B level.
Table 4A, 4B and 5 demonstrate for concrete LDL-C and non--HDL-C patient subgroups, use Lovaza TMOr placebo treatment apo-B reduces and the variation of other lipid parameter.Higher LDL-C (〉=100mg/dL) and non--HDL-C (〉=130mg/dL) under the baseline values, Lovaza TMReduce apo-B, and under lower baseline values, with respect to placebo by Lovaza TMCaused apo-B changes not remarkable.As if table 4B demonstrates under higher LDL-C baseline values, reduces the effect of apo-B even more remarkable, and be accompanied by the reduction of LDL-C level.
Table 4A
Figure A20078004566600241
Table 4B
Figure A20078004566600251
Figure A20078004566600252
Variable is not normal distribution usually, therefore carries out statistical analysis based on intermediate value except as otherwise noted
* because the variable in the subgroup is a normal distribution, carry out statistical analysis based on meansigma methods
Table 5
Variable is not normal distribution usually, therefore carries out statistical analysis based on intermediate value except as otherwise noted
* because the change in the subgroup heavily is normal distribution, carry out statistical analysis based on meansigma methods
Table 6 demonstrates for being higher than 200mg/dL triglyceride baseline values with respect to being lower than this level, uses Lovaza TMOr the variation of the reduction of placebo treatment apo-B and other lipid parameter.Higher triglyceride baseline values (〉=200mg/dL) under, Lovaza TMReduce apo-B, and under low baseline triglyceride levels, with respect to placebo by Lovaza TMIt is inapparent that caused apo-B changes.
Table 6
Figure A20078004566600271
Figure A20078004566600272
Variable is not normal distribution usually, therefore carries out statistical analysis based on intermediate value except as otherwise noted
* because the variable in the subgroup is a normal distribution, carry out statistical analysis based on meansigma methods
Table 7 and 8 demonstrates for concrete LDL-C/ triglyceride and non--HDL-C/ triglyceride patient subgroup, uses Lovaza TMOr the variation of the reduction of placebo treatment apo-B and other lipid parameter.The higher LDL-C of combination (〉=100mg/dL) and triglyceride (〉=200mg/dL) baseline values and non--HDL-C of making up (〉=130mg/dL) and triglyceride (〉=200mg/dL) under the baseline values, Lovaza TMReduce apo-B, and under low baseline values, with respect to placebo by Lovaza TMIt is inapparent that caused apo-B changes.
Table 7
Figure A20078004566600281
Figure A20078004566600282
Variable is not normal distribution usually, therefore carries out statistical analysis based on intermediate value except as otherwise noted
* because the variable in the subgroup is a normal distribution, carry out statistical analysis based on meansigma methods
Table 8
Figure A20078004566600291
Variable is not normal distribution usually, therefore carries out statistical analysis based on intermediate value except as otherwise noted
* because the variable in the subgroup is a normal distribution, carry out statistical analysis based on meansigma methods
Be hereby incorporated by at this all list of references full content of quoting.

Claims (22)

1. reduce the method for patient group's apo-B level, comprise patient group is provided, and by to described patient group with the combination of the medicine of the amount administration dyslipidemia of the apo-B level of comparing the described patient group of effective reduction with the treatment of the medicine of independent use dyslipidemia and omega-fatty acid to reduce described patient group's apo-B level.
2. the method for claim 1, the medicine of wherein said dyslipidemia is selected from HMG CoA reductase inhibitor, cholesterol absorption inhibitor, CETP inhibitor, nicotinic acid and derivant, the special class of shellfish, bile acid chelating agent, MTP inhibitor, lxr agonist and/or antagonist and PPAR agonist, antagonist and/or partial agonist/antagonist.
3. the process of claim 1 wherein that described patient group has at least a following disease or disease: hypertriglyceridemia, hypercholesterolemia, Combination dyslipidemia, angiopathy and atherosclerosis.
4. the process of claim 1 wherein that described patient group's LDL-cholesterol levels is 100mg/dL at least.
5. the process of claim 1 wherein that described patient group's LDL-cholesterol levels is for 100mg/dL at least and less than 130mg/dL.
6. the process of claim 1 wherein that described patient group's LDL-cholesterol levels is 130mg/dL at least.
7. the process of claim 1 wherein that non--HDL-cholesterol levels of described patient group is 130mg/dL at least.
8. the process of claim 1 wherein that described patient group's LDL-cholesterol levels is 200mg/dL at least for 100mg/dL and triglyceride levels at least.
9. the process of claim 1 wherein that non--HDL-cholesterol levels of described patient group is 200mg/dL at least for 130mg/dL and triglyceride levels at least.
10. the process of claim 1 wherein that the content of this omega-fatty acid is at least 40 weight % of the total fatty acid content of described compositions.
11. the process of claim 1 wherein that the content of this omega-fatty acid is at least 80 weight % of the total fatty acid content of described compositions.
12. the process of claim 1 wherein that this omega-fatty acid is included as the EPA and the DHA of at least 80 weight % of the total fatty acid content of described compositions.
13. the process of claim 1 wherein that this omega-fatty acid is included as about 40% EPA to about 55 weight % of the total fatty acid content of described compositions.
14. the process of claim 1 wherein that this omega-fatty acid is included as about 30% DHA to about 60 weight % of the total fatty acid content of described compositions.
15. the process of claim 1 wherein that this omega-fatty acid comprises the ester that ester, omega-fatty acid and primary alconol, secondary alcohol or the tertiary alcohol of ω-3 polyunsaturated long-chain fatty acids, omega-fatty acid and glycerol formation form, or its mixture.
16. the process of claim 1 wherein that described omega-fatty acid comprises EPA: the ratio of DHA is 2: 1 to 1: 2 EPA and DHA.
17. the process of claim 1 wherein the medicine separate administration of this omega-fatty acid and dyslipidemia.
18. the process of claim 1 wherein the medicine administration simultaneously of this omega-fatty acid and dyslipidemia.
19. the process of claim 1 wherein medicine administration in the co-therapy scheme of this omega-fatty acid and dyslipidemia.
20. the process of claim 1 wherein medicine administration together in unit dosage forms of this omega-fatty acid and dyslipidemia.
21. the process of claim 1 wherein that it is 200 to 499mg/dl that described patient group has the baseline triglyceride levels.
22. the process of claim 1 wherein the increase of avoiding the LDL-C level.
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