CN101553221A - Statin and omega-3 fatty acids for reduction of APO-B levels - Google Patents
Statin and omega-3 fatty acids for reduction of APO-B levels Download PDFInfo
- Publication number
- CN101553221A CN101553221A CNA2007800456489A CN200780045648A CN101553221A CN 101553221 A CN101553221 A CN 101553221A CN A2007800456489 A CNA2007800456489 A CN A2007800456489A CN 200780045648 A CN200780045648 A CN 200780045648A CN 101553221 A CN101553221 A CN 101553221A
- Authority
- CN
- China
- Prior art keywords
- fatty acid
- omega
- level
- apo
- patient group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Methods of utilizing a combined administration or a unit dosage of a combination of an HMG-CoA inhibitor and omega-3 fatty acids for the reduction of apolipoprotein-B levels. The methods are especially useful in the treatment of- patients with hypertriglyceridemia or hypercholesterolemia or 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
The application is the part continuation application of No. 11/742,292, the U. S. application submitted on April 30th, 2007, and requires the priority of No. 60/850,280, the temporary patent application submitted on October 10th, 2006, and its content is hereby incorporated by.
Technical field
The present invention relates to use the unit dose of the combination of combination medicine-feeding HMG-CoA inhibitor and omega-fatty acid or HMG-CoA inhibitor and omega-fatty acid to reduce the method for apo-B (Apo-B) level.This method is particularly useful for treatment and suffers from the patient of hypertriglyceridemia or hypercholesterolemia or Combination dyslipidemia, coronary heart disease (CHD), angiopathy, atherosclerosis and associated conditions, and is used for prevention or reduces cardiovascular, heart 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 danger, Apo-B can reflect lipid danger preferably.Sniderman, Am.J.Cardiol.90 (suppl): 48i-54i (2002) summarizes at the evidence of predicting the LDL-C level that coronary heart disease is dangerous and be 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 |
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (be called the HMG-CoA inhibitor, or " inhibin "), be 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-C 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.
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
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, hypertriglyceridemia and/or hypercholesterolemia has LDL-C usually greater than 190mg/dl, triglyceride levels is 200mg/dl or higher, and/or the Apo-B level is 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-C, triglyceride and/or Apo-B level usually to reach desired value.In these patients, need the complementary combinations treatment of inhibin and omega-fatty acid.
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 is the triglyceride reducing level 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.To having the baseline triglyceride levels is that the patient of 4.6 to 5.5mmol/l (404 to 483mg/dl) originally treated for 6 weeks, uses 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 treated for 12 weeks again with pravastatin and fish oil.The treatment of initial use pravastatin reduces the LDL-C level significantly.The combined therapy of pravastatin and fish oil has also reduced triglyceride and LDL-C level significantly.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 do not 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
(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
The effect of omega-fatty acid.For example, people such as Hansen studied lovastatin (40mg/ days) with 6g/ days
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) used 6g/ days
Treated for 6 weeks, then use 40mg/ days lovastatins to treat other 6 weeks, and
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, the atorvastatin treatment was used 2g/ days
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 the 4g/ days 4 under fasting state to the male patient who suffers from dyslipidemia obesity, insulin-opposing
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
And placebo; Atorvastatin and
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
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
(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.Fatty Acids Eicosanoids, Invited Pap.Int ' l Congr.4th, 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
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
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 in double-blind trial
Or 24 weeks of placebo treatment, thereafter in open research two groups all accept
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 independent use HMG-CoA inhibitor.This method be particularly useful for treatment in the patient as one or more following diseases among the people patient: hypertriglyceridemia, hypercholesterolemia, Combination dyslipidemia, 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 using HMG-CoA inhibitor and omega-fatty acid to reduce the method for Apo-B level, it is suitable for treating one or more following diseases: hypertriglyceridemia, hypercholesterolemia, Combination dyslipidemia, angiopathy, atherosclerosis and associated conditions, and/or be used for prevention or reduce cardiovascular and/or angiopathy.
Embodiments more of the present invention comprise the method for patient's lipid treatment, comprise that to the HMG-CoA of patient's effective dosage inhibitor and omega-fatty acid wherein the Apo-B level among the patient is compared with independent use HMG-CoA inhibitor for treating 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 amount administration HMG-CoA inhibitor of the Apo-B level of comparing the described patient group of effective reduction with independent use HMG-CoA inhibitor for treating 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, this HMG-CoA inhibitor and omega-fatty acid be with the single medicine compositions administration as combination product, for example, unit dose, it comprises HMG-CoA inhibitor and omega-fatty acid.
In embodiment of the present invention (variation), this HMG-CoA inhibitor is selected from Pitavastatin (pitavastatin), atorvastatin (atorvastatin), rosuvastatin (rosuvastatin), fluvastatin (fluvastatin), lovastatin (lovastatin), pravastatin (pravastatin) and simvastatin (simvastatin).
In preferred embodiments, this pharmaceutical composition comprises Lovaza
TMOmega-fatty acid, as be described in United States Patent (USP) 5,502,077,5,656,667 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 compositions.
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 preferred embodiments, the HMG-CoA inhibitor that is used in combination with omega-fatty acid is a simvastatin.
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 combined therapy administration first time HMG-CoA inhibitor and omega-fatty acid, 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 HMG-CoA inhibitor 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 use HMG-CoA inhibitor and omega-fatty acid reduces the Apo-B level, and it has surpassed the level that independent use HMG-CoA inhibitor for treating is reached.Method of the present invention is particularly useful for treating one or more following diseases: hypertriglyceridemia, hypercholesterolemia, Combination dyslipidemia, angiopathy, atherosclerosis and associated conditions, and/or be used for prevention or reduce cardiovascular and/or angiopathy.
In a preferred embodiment of the invention, 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 compare and/or further compare with independent use HMG-CoA inhibitor for treating with baseline uses the present invention that 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 omega-fatty acid and HMG-CoA inhibitor, the administration simultaneously of wherein said omega-fatty acid and HMG-CoA inhibitor, for example, with the pharmaceutical composition of single fixed dosage or with the administration simultaneously of independent compositions.
In other preferred embodiment, administration comprises omega-fatty acid and HMG-CoA inhibitor, wherein HMG-CoA inhibitor and omega-fatty acid separate administration, but in the scheme of co-administered treatment.For example, the HMG-CoA inhibitor 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 administration omega-fatty acid and HMG-CoA inhibitor 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; HMG-CoA inhibitor or omega-fatty acid 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 HMG-CoA inhibitor for treating before the combined therapy of HMG-CoA inhibitor and omega-fatty acid.Other activating agent (except omega-fatty acid) also can use before HMG-CoA inhibitor and omega-fatty acid combined therapy.
In preferred embodiments, present invention resides in the method for lipid treatment among the patient group, comprise to the HMG-CoA of described patient group's effective dosage inhibitor and omega-fatty acid, wherein behind the described patient group of administration, described patient group's triglyceride levels and Apo-B level are compared reduction with the matched group of independent use HMG-CoA inhibitor for treating, and preferred described patient group's HDL-C level is compared with the matched group of independent use HMG-CoA inhibitor for treating 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 lipid treatment among the patient group, comprise to the HMG-CoA of described patient group's effective dosage inhibitor and omega-fatty acid, 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 independent use HMG-CoA inhibitor for treating, LDL-C is increased surpass 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 lipid treatment among the patient group, comprise to the HMG-CoA of described patient group's effective dosage inhibitor and omega-fatty acid, wherein behind the described patient group of administration, following at least one item of described patient group: (a) non--HDL-C level, (b) total cholesterol level, (c) triglyceride levels, (d) the Apo-B level is compared reduction with the matched group of independent use HMG-CoA inhibitor for treating, and preferred described patient group's HDL-C level is compared increase with the matched group of independent use HMG-CoA inhibitor for treating, LDL-C is increased surpass 1% of baseline.
In other preferred embodiment, present invention resides in the method for lipid treatment among the patient group, comprise to the HMG-CoA of described patient group's effective dosage inhibitor and omega-fatty acid, wherein behind the described patient group of administration, non--HDL-C level of described patient group is compared reduction with the matched group of independent use HMG-CoA inhibitor for treating.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 compare the described patient group's of effective reduction the triglyceride levels and the amount administration HMG-CoA inhibitor of Apo-B level and the combination of omega-fatty acid, and do not increase the LDL-C level with independent use HMG-CoA inhibitor for treating to described patient group.
Phrase " is compared with independent use HMG-CoA inhibitor for treating " 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, lipid, mark (marker), 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 embodiments of the invention, reduce or increase some level (such as reducing the Apo-B level) separately on the HMG-CoA inhibitor statistics significantly, and the combined therapy of HMG-CoA inhibitor and omega-fatty acid reduces or increases this level on the statistics further significantly.
Compare with independent use HMG-CoA inhibitor for treating, except reducing the Apo-B level, method and composition of the present invention also is used in and reduces one or more following blood proteins, lipid or marker levels 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 independent use HMG-CoA inhibitor for treating, 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 independent use HMG-CoA inhibitor for treating, 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 independent use HMG-CoA inhibitor for treating, 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 independent use HMG-CoA inhibitor for treating, 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 independent use HMG-CoA inhibitor for treating, 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%, and/or further compares reduction at least about 10% with independent use HMG-CoA inhibitor for treating, preferably at least about 15%.
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 independent use HMG-CoA inhibitor for treating, 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 independent use HMG-CoA inhibitor for treating, 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 independent use HMG-CoA inhibitor for treating, preferably at least about 10%.
Preferably, the HDL-C level is compared with baseline and/or with independent use HMG-CoA inhibitor for treating can be increased at least about 2%, preferably at least about 3%.
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 independent use HMG-CoA inhibitor for treating preferably at least about 5%.
Usually, the HMG-CoA inhibitor act as dose dependent, that is dosage is high more, therapeutic effect is good more.Therefore yet the effect of each HMG-CoA inhibitor is different, and a kind of level of therapeutical effect of HMG-CoA inhibitor is can not be inevitable directly related with the level of the therapeutical effect of other HMG-CoA inhibitor.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., 1327Lysaker, 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.
The ratio of EPA: DHA 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 includes 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 combination product of HMG-CoA inhibitor and spissated omega-fatty acid can be with capsule, tablet 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.
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 HMG-CoA inhibitor can with greater than, be equal to or less than conventional complete dosage (full-strength dose) administration as single administration product.For example, the HMG-CoA inhibitor 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, for every gram omega-fatty acid, the amount of HMG-CoA inhibitor can be generally about 0.5mg to 80mg, and more preferably from about 1mg is to about 40mg, and 2.5mg 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 HMG-CoA inhibitor and omega-fatty acid is individually dosed or unit dose formulations.
Pravastatin, its known with
(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
(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
(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
(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
(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
(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.
Pitavastatin is current to go on the market in Japan.With the combination medicine-feeding of omega-fatty acid in, for the omega-fatty acid of every dosage, the dosage of Pitavastatin is 0.25 to 20mg, preferred 0.5 to 10mg, and more preferably 1 to 7.5mg.
The daily dose of HMG-CoA inhibitor and spissated omega-fatty acid can be together with 1 to 10 dosed administration, and the preferred dosage number is every day 1 to 4 time, most preferably every day 1 to 2 time.Although can use other form of medication of the unit dose that HMG-CoA inhibitor and spissated omega-fatty acid can be provided, 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 HMG-CoA inhibitor and/or omega-fatty acid reduce, and still keep or even increase the effectiveness of each active component.
The combination of HMG-CoA inhibitor of the present invention and 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 the level of the initial triglyceride 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
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 at least one dosage Lovaza
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
| The Omacor treatment: the intermediate value % with respect to baseline changes | Placebo treatment: the intermediate value % with respect to baseline changes | Difference (% intermediate value) | The p-value | |
| Non--HDL-C | -9.0％ | -2.2％ | -6.8％ | ＜0.0001 |
| LDL-C | +0.7％ | -2.8％ | +3.5％ | 0.0522 |
| Apo-B | -4.2％ | -1.9％ | -2.3％ | 0.0232 |
| TG | -29.5％ | -6.3％ | -23.2％ | ＜0.0001 |
| VLDL-C | -27.5％ | -7.2％ | -20.3％ | ＜0.0001 |
| Total C | -4.8％ | -1.7％ | -3.1％ | 0.0013 |
| HDL-C | +3.4％ | -1.2％ | +4.6％ | ＜0.0001 |
| TC/HDL | -9.6％ | -0.7％ | -8.9％ | ＜0.0001 |
| RLP-C | -36.0％ | -10.6％ | -25.4％ | ＜0.0001 |
| Lp-PLA2 | -12.8％ | -4.7％ | -8.1％ | 0.0019 |
| Apo-C3 | -7.8％ | +3.9％ | -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
Table 3
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 the variation of the reduction of placebo treatment Apo-B and 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
Table 4B
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, carries out statistical analysis based on meansigma methods
Table 5
*Because the variable in the subgroup is a normal distribution, carries 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
*Because the variable in the subgroup is a normal distribution, carries 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
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, carries out statistical analysis based on meansigma methods
Table 8
*Because the variable in the subgroup is a normal distribution, carries out statistical analysis based on meansigma methods
Be hereby incorporated by at this all list of references full content of quoting.
Claims (20)
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 amount administration HMG-CoA inhibitor of the Apo-B level of comparing the described patient group of effective reduction with independent use HMG-CoA inhibitor for treating and omega-fatty acid to reduce described patient group's Apo-B level.
2. 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.
3. the process of claim 1 wherein that described patient group's LDL-cholesterol levels is 100mg/dL at least.
4. 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.
5. the process of claim 1 wherein that described patient group's LDL-cholesterol levels is 130mg/dL at least.
6. the process of claim 1 wherein that non--HDL-cholesterol levels of described patient group is 130mg/dL at least.
7. 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.
8. 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.
9. the process of claim 1 wherein that described HMG-CoA inhibitor is selected from Pitavastatin, atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin and simvastatin.
10. the process of claim 1 wherein that described HMG-CoA inhibitor comprises simvastatin.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. the process of claim 1 wherein that 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.
17. 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.
18. the process of claim 1 wherein that described omega-fatty acid and described HMG-CoA inhibitor are together with the unit dosage forms administration.
19. the process of claim 1 wherein that it is 200 to 499mg/dl that described patient group has the baseline triglyceride levels.
20. the process of claim 1 wherein the increase of avoiding the LDL-C level.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85028006P | 2006-10-10 | 2006-10-10 | |
| US60/850,280 | 2006-10-10 | ||
| US11/742,292 | 2007-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101553221A true CN101553221A (en) | 2009-10-07 |
Family
ID=39283166
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800456489A Pending CN101553221A (en) | 2006-10-10 | 2007-09-07 | Statin and omega-3 fatty acids for reduction of APO-B levels |
| CNA2007800456667A Pending CN101553220A (en) | 2006-10-10 | 2007-10-10 | Omega-3 fatty acids and dyslipidemic agent for reduction of APO-B levels |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800456667A Pending CN101553220A (en) | 2006-10-10 | 2007-10-10 | Omega-3 fatty acids and dyslipidemic agent for reduction of APO-B levels |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP2089014A4 (en) |
| JP (1) | JP2010505956A (en) |
| KR (1) | KR20090080070A (en) |
| CN (2) | CN101553221A (en) |
| AU (1) | AU2007307007A1 (en) |
| BR (1) | BRPI0719182A2 (en) |
| CA (1) | CA2672919A1 (en) |
| EA (2) | EA018734B1 (en) |
| MX (1) | MX2009003921A (en) |
| WO (1) | WO2008045465A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824636A (en) * | 2012-08-15 | 2012-12-19 | 四川大学 | Pharmaceutical composition containing statins and polyunsaturated fatty acid and application thereof |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8784886B2 (en) | 2006-03-09 | 2014-07-22 | GlaxoSmithKline, LLC | Coating capsules with active pharmaceutical ingredients |
| WO2008088415A1 (en) * | 2006-10-18 | 2008-07-24 | Reliant Pharmaceuticals, Inc. | Omega-3 fatty acids for reduction of lp-pla2 levels |
| PL2334295T3 (en) | 2008-09-02 | 2017-12-29 | Amarin Pharmaceuticals Ltd | Pharmaceutical composition comprising eicosapentaenoic acid and nicotinic acid and methods of using same |
| MX2011008448A (en) | 2009-02-10 | 2012-02-28 | Amarin Pharma Inc | Use of eicosapentaenoic acid ethyl ester for treating hypertriglyceridemia. |
| EP2424521A4 (en) | 2009-04-29 | 2015-03-04 | Amarin Pharmaceuticals Ie Ltd | Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same |
| CN102458109B (en) | 2009-04-29 | 2015-02-11 | 阿马里纳制药公司 | Stable pharmaceutical composition and methods of using same |
| KR102012111B1 (en) | 2009-06-15 | 2019-08-19 | 아마린 파마, 인크. | Compositions and methods for lowering triglycerides without raising ldl-c levels in a subject on concomitant statin therapy |
| SG10201405994UA (en) | 2009-09-23 | 2014-10-30 | Amarin Pharmaceuticals Ie Ltd | Pharmaceutical Composition Comprising Omega-3 Fatty Acid And Hydroxy-derivative Of A Statin And Methods Of Using Same |
| NZ712068A (en) | 2010-11-29 | 2017-03-31 | Amarin Pharmaceuticals Ie Ltd | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
| US11712429B2 (en) | 2010-11-29 | 2023-08-01 | Amarin Pharmaceuticals Ireland Limited | Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity |
| EP2775837A4 (en) | 2011-11-07 | 2015-10-28 | Amarin Pharmaceuticals Ie Ltd | Methods of treating hypertriglyceridemia |
| US11291643B2 (en) | 2011-11-07 | 2022-04-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating hypertriglyceridemia |
| WO2013103958A1 (en) | 2012-01-06 | 2013-07-11 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering levels of high-sensitivity (hs-crp) in a subject |
| SG11201408769QA (en) | 2012-06-29 | 2015-01-29 | Amarin Pharmaceuticals Ie Ltd | Methods of reducing the risk of a cardiovascular event in a subject on statin therapy |
| WO2014034871A1 (en) * | 2012-08-30 | 2014-03-06 | 株式会社 三和化学研究所 | Drug for preventing or treating dyslipidemia |
| US20150265566A1 (en) | 2012-11-06 | 2015-09-24 | Amarin Pharmaceuticals Ireland Limited | Compositions and Methods for Lowering Triglycerides without Raising LDL-C Levels in a Subject on Concomitant Statin Therapy |
| US20140187633A1 (en) | 2012-12-31 | 2014-07-03 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis |
| US9814733B2 (en) | 2012-12-31 | 2017-11-14 | A,arin Pharmaceuticals Ireland Limited | Compositions comprising EPA and obeticholic acid and methods of use thereof |
| US9452151B2 (en) | 2013-02-06 | 2016-09-27 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing apolipoprotein C-III |
| US9624492B2 (en) | 2013-02-13 | 2017-04-18 | Amarin Pharmaceuticals Ireland Limited | Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof |
| 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 |
| US20140271841A1 (en) | 2013-03-15 | 2014-09-18 | Amarin Pharmaceuticals Ireland Limited | Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin |
| US10966968B2 (en) | 2013-06-06 | 2021-04-06 | Amarin Pharmaceuticals Ireland Limited | Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof |
| US20150065572A1 (en) | 2013-09-04 | 2015-03-05 | Amarin Pharmaceuticals Ireland Limited | Methods of treating or preventing prostate cancer |
| US9585859B2 (en) | 2013-10-10 | 2017-03-07 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy |
| AU2014381733B2 (en) * | 2014-02-05 | 2020-09-03 | Newamsterdam Pharma B.V. | Cholesteryl ester transfer protein (CETP) inhibitor and pharmaceutical compositions comprising said inhibitor for use in the treatment or prevention of cardiovascular diseases |
| US10561631B2 (en) | 2014-06-11 | 2020-02-18 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing RLP-C |
| US10172818B2 (en) | 2014-06-16 | 2019-01-08 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids |
| 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 |
| TW201900160A (en) | 2017-05-19 | 2019-01-01 | 愛爾蘭商艾瑪琳製藥愛爾蘭有限公司 | Compositions and Methods for Lowering Triglycerides in a Subject Having Reduced Kidney Function |
| US11058661B2 (en) | 2018-03-02 | 2021-07-13 | Amarin Pharmaceuticals Ireland Limited | Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L |
| KR102296068B1 (en) | 2018-09-24 | 2021-09-02 | 애머린 파마슈티칼스 아일랜드 리미티드 | Methods of Reducing the Risk of a Cardiovascular Event in a Subject |
| KR20240012390A (en) | 2021-04-21 | 2024-01-29 | 애머린 파마슈티칼스 아일랜드 리미티드 | How to Reduce Your Risk of Heart Failure |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004014359A1 (en) * | 2001-03-16 | 2004-02-19 | Thomas Jefferson University | Regulation of apob in treatment and drug screening for cardiovascular and metabolic disorders or syndromes |
| US20060211762A1 (en) * | 2004-12-06 | 2006-09-21 | Rongen Roelof M | Omega-3 fatty acids and dyslipidemic agent for lipid therapy |
| BRPI0612908A2 (en) * | 2005-07-18 | 2010-12-07 | Reliant Phamaceuticals Inc | pharmaceutical compositions comprising azetidinone-based cholesterol absorption inhibitors and omega-3 fatty acids and methods of treatment using them |
-
2007
- 2007-09-07 EA EA200970359A patent/EA018734B1/en not_active IP Right Cessation
- 2007-09-07 CN CNA2007800456489A patent/CN101553221A/en active Pending
- 2007-10-10 MX MX2009003921A patent/MX2009003921A/en unknown
- 2007-10-10 KR KR1020097009523A patent/KR20090080070A/en not_active Application Discontinuation
- 2007-10-10 WO PCT/US2007/021631 patent/WO2008045465A1/en active Application Filing
- 2007-10-10 CN CNA2007800456667A patent/CN101553220A/en active Pending
- 2007-10-10 JP JP2009532391A patent/JP2010505956A/en active Pending
- 2007-10-10 EA EA200970360A patent/EA200970360A1/en unknown
- 2007-10-10 BR BRPI0719182-0A2A patent/BRPI0719182A2/en not_active Application Discontinuation
- 2007-10-10 CA CA002672919A patent/CA2672919A1/en not_active Abandoned
- 2007-10-10 AU AU2007307007A patent/AU2007307007A1/en not_active Abandoned
- 2007-10-10 EP EP07852630A patent/EP2089014A4/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102824636A (en) * | 2012-08-15 | 2012-12-19 | 四川大学 | Pharmaceutical composition containing statins and polyunsaturated fatty acid and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0719182A2 (en) | 2014-10-21 |
| AU2007307007A1 (en) | 2008-04-17 |
| EA200970359A1 (en) | 2009-10-30 |
| MX2009003921A (en) | 2009-08-31 |
| CN101553220A (en) | 2009-10-07 |
| CA2672919A1 (en) | 2008-04-17 |
| EA200970360A1 (en) | 2009-10-30 |
| EP2089014A4 (en) | 2009-12-09 |
| EP2089014A1 (en) | 2009-08-19 |
| KR20090080070A (en) | 2009-07-23 |
| WO2008045465A1 (en) | 2008-04-17 |
| EA018734B1 (en) | 2013-10-30 |
| JP2010505956A (en) | 2010-02-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101553221A (en) | Statin and omega-3 fatty acids for reduction of APO-B levels | |
| US8871800B2 (en) | Statin and omega-3 fatty acids for reduction of Apo-B levels | |
| AU2007307282B2 (en) | Statin and omega-3 fatty acids for reduction of Apo-B levels | |
| US20110092563A1 (en) | Statin and omega-3 fatty acids for lipid therapy | |
| CA2589654C (en) | Omega-3 fatty acids and dyslipidemic agent for lipid therapy | |
| US20060211763A1 (en) | Treatment with Statin and Omega-3 Fatty Acids and a Combination Product Thereof | |
| US20110092552A1 (en) | Treatment and Prevention of Major Adverse Cardiovascular Events or Major Coronary Events by Administering Omega-3 Fatty Acids | |
| CN101098690A (en) | Omega-3 fatty acids and dyslipidemic agent for lipid therapy | |
| JP2014024859A (en) | Omega-3 fatty acid for reduction of lp-pla2 level |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20091007 |