CN101590240A - The compositions and the purposes that contain Angiotensin, Ta Ting and folic acid - Google Patents
The compositions and the purposes that contain Angiotensin, Ta Ting and folic acid Download PDFInfo
- Publication number
- CN101590240A CN101590240A CNA2008101142235A CN200810114223A CN101590240A CN 101590240 A CN101590240 A CN 101590240A CN A2008101142235 A CNA2008101142235 A CN A2008101142235A CN 200810114223 A CN200810114223 A CN 200810114223A CN 101590240 A CN101590240 A CN 101590240A
- Authority
- CN
- China
- Prior art keywords
- folic acid
- losartan
- group
- atorvastatin
- content
- Prior art date
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- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 title claims abstract description 325
- 239000011724 folic acid Substances 0.000 title claims abstract description 179
- 235000019152 folic acid Nutrition 0.000 title claims abstract description 179
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 title claims description 147
- 229960000304 folic acid Drugs 0.000 title claims description 147
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 124
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 89
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of pharmaceutical composition that contains angiotensin ii receptor antagonist, stanin fat-reducing medicament and folacin compound.This pharmaceutical composition comprises acceptable carrier on the folacin compound of stanin fat-reducing medicament, pharmaceutical dosage of angiotensin ii receptor antagonist, the pharmaceutical dosage of pharmaceutical dosage and the pharmaceutics.The invention still further relates to this pharmaceutical composition and be used for preventing, treat or delay purposes in the medicine of the purposes of medicine of hypertension companion dyslipidemia and the target organ damage that hypertension companion dyslipidemia causes, the invention still further relates to this pharmaceutical composition is used for reducing the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension companion dyslipidemia causes in preparation purposes in preparation.Belong to pharmaceutical field.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains angiotensin ii receptor antagonist (ARB), stanin fat-reducing medicament and folic acid, and this pharmaceutical composition is used for preventing, treat or delays purposes in the medicine of the purposes of medicine of hypertension companion dyslipidemia and the target organ damage that hypertension companion dyslipidemia causes in preparation, the invention still further relates to this pharmaceutical composition is used for reducing the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension companion dyslipidemia causes in preparation purposes.Belong to pharmaceutical field.
Background technology
The cardiovascular disease main hazard factor comprises: hypertension, dyslipidemia, smoking, age (〉=55 years old), male, apoplexy history, peripheral arterial disease, diabetes, albuminuria, left ventricular hypertrophy, familial history of coronary artery disease and homocysteine etc.The risk factor of cardiovascular disease takes place seldom separately, but usually mutual association is present in patient's body.In causing the risk factor of apoplexy, hypertension is most important and modal reason.Every decline 5～10mmHg of systolic pressure or the every decline 2～5mmHg of diastolic pressure, apoplexy is dangerous to reduce by 30%～40%.Blood pressure lowering therapeutic test cooperative groups (BPLTC) meta-analysis shows, the blood pressure difference of-4/-3mmHg can make the apoplexy relative risk reduce by 23%.Hypertension and dyslipidemia are two kinds of concurrent cardiovascular disease risk factor the most general, and the hyperpietic above 50% is attended by dyslipidemia.Homocysteine also has been proved in the hyperpietic and has reached 70%.The rising of blood pressure, blood fat and homocysteine level can sharply increase the incidence rate of cardiovascular disease and the danger of coronary heart disease, and a large amount of clinical researches show that the M ﹠ M that reduces cardiovascular disease must control effectively from many target spots.
Yet most of patients does not reach gratifying curative effect, and one of its reason is degree of the adhering to problem of prescribed treatment, and it is that the M ﹠ M of cardiovascular disease raises that the treatment that the patient more than 50% selects to stop this class multiple medicines ball because of degree of adhering to reason causes.Therefore, simplify prescription and can strengthen patient's degree of adhering to the minimizing pill burden.Clinical verified, " Caduet " The combined that the compound medicines amlodipine and the atorvastatin at hypertension complicated with hyperlipemia of present unique listing is combined into is used and can obviously be brought high blood pressure down and blood cholesterol levels, can make the cardiovascular patient more than 80% reach target blood pressure and target LDL-C level.The cardiovascular patient that amlodipine and atorvastatin are united for the hypertensive patients dyslipidemia still has certain limitation.Patient's target organ damage also needs further control and intervenes, and the prevention of cardiovascular event or treatment do not obtain the checking of clinical data yet.Because it is to reduce cardiovascular diseases's death and invalid total danger to greatest extent that treatment suffers from cardiovascular disease patient's main purpose; therefore, a kind of hypertension and hyperlipemia pharmaceutical composition that has target organ protection function and reduce cardiovascular and cerebrovascular vessel incident danger of exploitation has great clinical meaning for the treatment of cardiovascular disease.
Among the 5-10 in past, angiotensin receptor antagonist (ARB) has been established its status as effective antihypertensive drug, and ARB has efficacy of antihypertensive treatment preferably, and its toleration is identical with placebo.In blood pressure lowering, type 2 diabetes mellitus patient and diabetic nephropathy patient there is organ protection preferably; hyperpietic and normotensive patient's long-term treatment for central force depletion also can benefit; therefore; this class medicine gets the nod in the world, and is widely used in the treatment of clinical hypertension therapeutic and diabetic nephropathy.The ARB hypotensor divides 3 classes: and hexichol tetramisole class (losartan. telmisartan. Candesartan. irbesartan etc.), non-hexichol tetramisole class (eprosartan) and non-heterocyclic (valsartan).LIFE, SCORE, JIKEI HEART research waits and follows the confirmation of card evidence, and ARB is as hypertension one line medication, effectively reducing and controlling blood pressure, reversing LVH, prevent and treat aspect diabetes and the prevention atrial fibrillation effect certainly, in the generation of prevention apoplexy and the originating party face is significant again.
Stanin fat-reducing medicament is the general name of plain enzyme hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor of limit of liver synthesis cholesterol, hypercholesterolemia reducing and low-density lipoprotein cholesterol effectively, slight high density lipoprotein increasing cholesterol, be used for the treatment of hypercholesterolemia and combined hyperlipidemia familial clinically, and the control of coronary heart disease and apoplexy.Stanin fat-reducing medicament commonly used both at home and abroad at present has atorvastatin, simvastatin, Pitavastatin, pravastatin, lovastatin, fluvastatin etc.
Folic acid promptly is confirmed as far back as 1948 to the important Nutrition of human body, and human (or other animals) can cause megaloblastic anemia and leukopenia as lacking folic acid.In addition, increasing in recent years research concern folic acid can be prevented and treated coronary sclerosis, myocardial damage and the myocardial infarction etc. because of hyperhomocysteinemiainjury causes.
Still do not find the report that ARB, stanin fat-reducing medicament and folate coupling are used in the clinical and existing research, based on above many-sided consideration, we study the use in conjunction of ARB, stanin fat-reducing medicament and folic acid, have obtained gratifying result.
Summary of the invention
The purpose of this invention is to provide a kind of hypertension and hyperlipemia pharmaceutical composition that has target organ protection function and reduce cardiovascular and cerebrovascular vessel incident danger.The present invention also provides this pharmaceutical composition to be used for preventing, treat or to delay purposes in the medicine of the purposes of medicine of hypertension companion dyslipidemia and the target organ damage that hypertension companion dyslipidemia causes in preparation, and the present invention also provides this pharmaceutical composition to be used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension companion dyslipidemia causes in preparation.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) angiotensin ii receptor antagonist of pharmaceutical dosage;
(2) stanin fat-reducing medicament of pharmaceutical dosage;
(3) folacin compound of pharmaceutical dosage; And
(4) acceptable carrier on the pharmaceutics.
The ARB of above-mentioned pharmaceutical dosage is selected from a kind of in losartan (Losartan), telmisartan (telmisartan), Candesartan (candesartan), irbesartan (irbesartan), eprosartan (eprosartan), valsartan (Valsartan), the Olmesartan (olmesartan), and content is 2～200mg.
The stanin fat-reducing medicament of above-mentioned pharmaceutical dosage is selected from atorvastatin (atorvastatin), simvastatin (simvastatin), Pitavastatin (pitavastatin), lovastatin (lovastatin), fluvastatin (fluvastatin), pravastatin (pravastatin), Rosuvastatin (rosuvastatin rosuvastatin), itavastatin (itavastatin), the Buddhist nun cuts down his spit of fland (nisvastatin), bervastatin (bervastatin), mevastatin (mevastatin), or a kind of in the cerivastatin (cerivastatin), content is 2～200mg.
The folacin compound of above-mentioned pharmaceutical dosage is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is a losartan, and content is 50～100mg; The stanin fat-reducing medicament of described pharmaceutical dosage is an atorvastatin, and content is 10～80mg; Described folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is a losartan, and content is 50～100mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a simvastatin, and content is 5～40mg; Described folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is a losartan, and content is 50～100mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a Pitavastatin, and content is 1～4mg; Described folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is a telmisartan, and content is 40～80mg; The stanin fat-reducing medicament of described pharmaceutical dosage is an atorvastatin, and content is 10～80mg; Described folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is a telmisartan, and content is 40～80mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a simvastatin, and content is 5～40mg; Described folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is a telmisartan, and content is 40～80mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a Pitavastatin, and content is 1～4mg; Described folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is an irbesartan, and content is 150～300mg; The stanin fat-reducing medicament of described pharmaceutical dosage is an atorvastatin, and content is 10～80mg; Described folacin compound is a folic acid, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is an irbesartan, and content is 150～300mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a simvastatin, and content is 5～40mg; Described folacin compound is a folic acid, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the ARB of described pharmaceutical dosage is an irbesartan, and content is 150～300mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a Pitavastatin, and content is 1～4mg; Described folacin compound is a folic acid, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
We use in the research process of pharmaceutical composition provided by the invention to the treatment of hypertension companion dyslipidemia, emphatically at target-organ protection and the dangerous aspect of reduction cardiovascular and cerebrovascular vessel incident.The target organ damage that hypertension companion dyslipidemia causes comprises left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or hypertension retinopathy.When above-mentioned these target organ damages still can not give effective control, then develop into more serious consequence, be the generation of cardiovascular and cerebrovascular vessel incident, the cardiovascular and cerebrovascular vessel incident comprises angina pectoris, myocardial infarction, heart failure, cerebral infarction or cerebral hemorrhage, and wherein cerebral infarction and cerebral hemorrhage are collectively referred to as apoplexy.Therefore, treatment hypertension companion dyslipidemia patient's main purpose is to reduce the death of cardiovascular and cerebrovascular disease and invalid total danger to greatest extent, and target-organ protection and blood pressure lowering develop simultaneously, and is the core of hypertension companion dyslipidemia treatment.
Discover that pharmaceutical composition provided by the invention not only has decompression lipid-lowering effect and also has target organ protection function; When ARB, stanin fat-reducing medicament and folacin compound are share, can work in coordination with blood pressure lowering, and its synergism is better than and only uses ARB/ folic acid bigeminy compound hypertension medicine, also be better than and singly use ARB, difference all has statistical significance.When ARB, stanin fat-reducing medicament and folacin compound are share, can work in coordination with blood fat reducing, and its synergism is better than and only uses stanin fat-reducing medicament/folic acid bigeminy compound hypertension medicine, also be better than and singly use stanin fat-reducing medicament, difference all has statistical significance.
When ARB, stanin fat-reducing medicament and folacin compound are share; can also work in coordination with the intensifier target organ protection; and its synergism is better than only uses ARB/ stanin fat-reducing medicament bigeminy compound hypertension medicine, also is better than list and uses folacin compound, and difference all has statistical significance.
Further, in experiment, we find, when ARB, stanin fat-reducing medicament and folacin compound are share, can collaboratively reduce cardiovascular and cerebrovascular vessel incident danger, and effect is better than only uses ARB/ stanin fat-reducing medicament bigeminy compound hypertension medicine, also is better than list and uses folacin compound, and difference all has statistical significance.
Therefore, the invention provides pharmaceutical composition that the folacin compound of the stanin fat-reducing medicament of ARB, pharmaceutical dosage of above-mentioned pharmaceutical dosage and pharmaceutical dosage forms is used for preventing, treating or delay the medicine of hypertension companion dyslipidemia in preparation purposes.
The present invention also provides aforementioned pharmaceutical compositions to be used for preventing, treat or to delay the purposes of the medicine of the target organ damage that hypertension companion dyslipidemia causes in preparation.The target organ damage that hypertension companion dyslipidemia causes, be meant because the secondary lesion of organs such as the heart that hypertension and/or dyslipidemia cause, brain, kidney, eye, comprise that apoplexy, atherosclerosis, coronary heart disease, left ventricular hypertrophy, angina pectoris, myocardial infarction, acute coronary syndrome, cardiac function go down, optimum arteriolar nephrosclerosis, heart failure, arrhythmia, primary cardiac all standing, renal function go down, pernicious arteriolar nephrosclerosis, peripheral arterial disease, retinal arteriosclerosis or hypertension retinopathy.
The present invention also provides aforementioned pharmaceutical compositions to be used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension companion dyslipidemia causes in preparation.Wherein reduce cardiovascular and cerebrovascular vessel incident danger and be meant reduction apoplexy, acute coronary syndrome, angina pectoris, myocardial infarction, heart failure, arrhythmia, primary cardiac all standing or the high-risk incidence rate of coronary heart disease.
Also contain the pharmaceutics acceptable carrier in the pharmaceutical composition provided by the invention, can be made into common oral preparation, comprise conventional tablet, capsule, granule etc., described pharmaceutically acceptable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc. belongs to this area general knowledge.
The dosage form of pharmaceutical composition provided by the invention includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, the single chamber controlled release tablet, two chambers controlled release tablet, the pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/the position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, granule, oral liquid, dosage form such as membrane or patch, wherein preferred tablet, capsule or granule.
According to the present invention, pharmaceutical composition also can be meant the medicine box that contains two or three independent medicines.When " pharmaceutical composition " was meant the medicine box that contains two independent medicines, above-mentioned " Combined drug box " was a kind of case type container, the drug regimen of built-in multiple dosage form, and take description." Combined drug box " more is applicable to personalized medicine; Contain ARB and stanin fat-reducing medicament in first medicine, contain folacin compound in second medicine.When " pharmaceutical composition " was meant the medicine box that contains three independent medicines, above-mentioned " Combined drug box " was a kind of case type container, the drug regimen of built-in multiple dosage form, and take description; Contain ARB in first medicine, contain stanin fat-reducing medicament in second medicine, contain folacin compound in the 3rd medicine.In this medicine box two or three independently medicine can concomitant dosing, also can be in a kind of pharmaceutical preparation or in different pharmaceutical preparation sequential administration.
The invention has the beneficial effects as follows: pharmaceutical composition provided by the invention has obvious synergism.Studies show that the pharmaceutical composition that the folacin compound of the stanin fat-reducing medicament of ARB, pharmaceutical dosage of pharmaceutical dosage and pharmaceutical dosage is formed has protective effect and lipoid peroxidization resistant to inner skin cell function, and effect is better than ARB/ stanin fat-reducing medicament bigeminy; Aspect the function and protecting of target organ kidney, the effect of pharmaceutical composition provided by the invention significantly is better than the medication of ARB/ stanin fat-reducing medicament bigeminy; Aspect the target organ heart, area of collagen (PVCA) is represented two kinds of principal modes---the lesion degree of interstitial fibrosis and perivascular fibrosis of myocardial fibrosis pathological changes respectively around myocardial collagen fraction by volume (CVF) and the myocardial vascular, it is the leading indicator of weighing cardiac remodeling, and the degree of cardiac remodeling is the basis of embodying cardiac function, can strengthen the stiffness index of locular wall as the collagen content increase, reduce ventricular compliance and cause the ventricular diastole functional defect, studies show that pharmaceutical composition provided by the invention is applied in the cardiac function protecting aspect and has obvious synergism, and be better than the medication of ARB/ stanin fat-reducing medicament bigeminy; Aspect the target organ kidney, the curative effect of pharmaceutical composition provided by the invention is better than the medication of ARB/ stanin fat-reducing medicament bigeminy equally; Aspect blood vessel, three application of the present invention also have synergism, and the reduction effect of aorta wall plaque area is better than above-mentioned bigeminy medication.
The relation of blood pressure and cardiovascular event danger is successive, consistent, and be independent of other risk factor, and blood pressure is high more, and the danger that apoplexy, heart failure, myocardial infarction and nephropathy take place is just big more; Dyslipidemia also has the similar feature of this class.Therefore reduce cardiovascular and cerebrovascular vessel incident danger, accompany the treatment of dyslipidemia to have important clinical significance for hypertension.Treatment of diseases such as " cardiovascular and cerebrovascular vessel incident danger " and above-mentioned target organ damage are distinguishing.So-called " cardiovascular and cerebrovascular vessel incident danger " is meant the risk of an individual patients with respect to whole crowd's generation cardiovascular and cerebrovascular disease.Nearly more than ten years, in the cardiovascular and cerebrovascular disease research field, " reducing cardiovascular and cerebrovascular vessel incident danger " more and more becomes the leading indicator of weighing curative effect of medication or therapeutic scheme, and some large-scale clinical trials all are to select this class index as clinical endpoint in the world.The pharmaceutical composition that the folacin compound of the ARB of pharmaceutical dosage provided by the invention, the stanin fat-reducing medicament of pharmaceutical dosage and pharmaceutical dosage is formed has obvious synergism aspect the reduction apoplexy incidence rate, and its effect significantly is better than the effect that ARB/ stanin fat-reducing medicament bigeminy is used.
As seen; pharmaceutical composition provided by the invention has obvious synergism; its synergism is the effect of coordinating protection inner skin cell function, collaborative antioxidation, coordinating protection cardiorenal function, collaborative prevention or delays atheromatous plaque formation effect, the collaborative apoplexy incidence rate that reduces; and in above-mentioned these pharmacological actions, pharmaceutical composition effect provided by the invention all is better than only containing the bigeminy pharmaceutical composition of ARB and stanin fat-reducing medicament.Therefore, for prior art the significant meaning of improving is arranged.
In view of the beneficial effect of above-mentioned cooperative effect in clinical, the present invention also provides pharmaceutical composition that the folacin compound of the stanin fat-reducing medicament of ARB, pharmaceutical dosage of above-mentioned pharmaceutical dosage and pharmaceutical dosage forms to be used for preventing, treat or to delay the purposes of the medicine of hypertension companion dyslipidemia, target organ damage that hypertension companion dyslipidemia causes or hypertension companion dyslipidemia relevant disease in preparation; The present invention also provides aforementioned pharmaceutical compositions to be used for reducing the purposes of the medicine of cardiovascular and cerebrovascular vessel incident danger in preparation.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
The present invention will be further described below in conjunction with the specific embodiment, and the experiment support of pharmacological action sees the following specific embodiment for details.
The specific embodiment
Embodiment 1: losartan+atorvastatin+folic acid is to the target organ protection function of hypertension companion dyslipidemia rat
1. prepare the composite model animal
SD rat, adaptability are fed and begin test after 5 days.Carry out two kidneys, one tong art, preparation 2K1C hypertension model animal.After raising for 6 weeks, measure rat blood pressure (measuring three times averages), be considered as the model success as blood pressure＞140mmHg, model group begins to irritate every day stomach fat milk (cholesterol 10g, propylene glycol 20ml, cholate 2g, tween 80 20ml, propylthiouracil 1g, Oleum Arachidis hypogaeae semen 20ml, sucrose 20g, dissolving back adding distil water is to 200ml) 10ml/kg and freely drink water (containing 1% methionine), rat fasting 10h eye socket is taken a blood sample places the EDTA anticoagulant tube to irritate 4 week of stomach fat milk back (irritating fat milk blood pressure of repetition measurements after 2 weeks), 4000prm, centrifugal 10 minutes, separated plasma was measured GLU (blood glucose), TC (T-CHOL) and TG (triglyceride).
In above-mentioned animal pattern, choose the administration of dividing into groups of hypertension companion dyslipidemia animal, 16 weeks of administration time.
2. observation index
2.1 reach 8 weeks of administration before the blood pressure administration, respectively measure blood pressure 16 weeks one time, observe the influence of medication to 2K1C hypertension companion hyperlipemia rat blood pressure.
2.2 blood glucose and blood fat: administration is got blood and is measured plasma cholesterol (using kit measurement) and blood sugar level with biochemical process after finishing.
2.3 endotheliocyte and anti-oxidation function: the same blood of getting, serum NO level, ET-1, SOD, the horizontal biochemical process of MDA are measured.
2.4 cardiorenal function: myocardium hydroxyproline determination is got left ventricular free wall cardiac muscular tissue, be prepared into cardiac muscular tissue's homogenate of 10%, press hydroxyproline testing cassete description, digestion method is measured myocardium hydroxyproline content, press collagen content=hydroxyproline content * 7.46, be converted into collagen content.Small artery is observed through abdominal aortic cannulation in the kidney, and behind the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, the formalin with 10% is poured into fixing under 10～12kPa, separate left kidney, the place cuts kidney from the hilus renalis, places 4% formaldehyde fixing, conventional dehydration, paraffin embedding, transverse section, HE dyeing.Choosing external diameter under the optical microscope is the interior small artery of kidney of 50～100 μ m, measures small artery internal diameter, wall thickness in the kidney, calculated wall thickness internal diameter ratio.Each specimen is measured 4 and is small artery in the cross section wall, gets its meansigma methods.
2.5 atheromatous plaque area: gather the aorta sample, detect aorta lipid plaque area with image analytical method.
Measurement data represents that with x ± s data statistics is handled and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
3. experimental result
3.1 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia rat blood pressure
Model group and normal rats compare, and systolic pressure continues significantly to raise (P＜0.01); Administration is preceding except that the normal control group, other respectively organize the blood pressure level zero difference, each administration group and model group are relatively after the administration, losartan folk prescription group, losartan+atorvastatin compound recipe group and three joint group systolic pressures all can effectively descend, and losartan+atorvastatin compound recipe group hypotensive effect is more obvious than the effect of folk prescription group; Losartan+atorvastatin+folic acid (5.0+1.0+0.08mg/kg) three joint group hypotensive effects then not only are better than the folk prescription group, also are better than compound recipe group (p＜0.05 or 0.01).See table 1 for details.
Table 1 losartan+atorvastatin+folic acid is to the influence (X ± SD n) of hypertension companion's dyslipidemia rat systolic pressure (mmHg)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.2 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia rat to blood glucose and blood fat
Model group and normal rats compare, and blood glucose and blood fat be obviously rising (P＜0.01) all; Each administration group and model group compare after the administration, atorvastatin folk prescription group, and losartan+atorvastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively descend, and losartan+atorvastatin compound recipe group hypoglycemic lipid-lowering effect is more obvious than the effect of folk prescription group; Losartan+atorvastatin+folic acid (5.0+1.0+0.08mg/kg) three joint group effect for reducing fat then not only are better than the folk prescription group, also are better than compound recipe group (p＜0.05 or 0.01).See table 2 for details.
Table 2 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia rat blood sugar and blood fat (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.3 losartan+atorvastatin+folic acid is to hypertension companion's dyslipidemia rat endotheliocyte and anti-oxidation function influence
Model group and normal rats compare, and ET-1 and MDA level obviously raise, and NO and SOD level then obviously reduce (p＜0.01); Each administration group and model group compare after the administration, atorvastatin folk prescription group, and losartan+atorvastatin compound recipe group and three joint group index of correlation levels all can effectively be adjusted, and losartan+atorvastatin compound recipe group hypoglycemic lipid-lowering effect is more obvious than the effect of folk prescription group; Losartan+atorvastatin+folic acid (5+1.0+0.08mg/kg) three joint group effects then not only are better than the folk prescription group, also are better than compound recipe group (p＜0.05 or 0.01).See table 3 for details.
Table 3 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia rat endotheliocyte and anti-oxidation function (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.4 losartan+atorvastatin+folic acid is to the influence of cardiac function
Fibrosis index PVCA all significantly increases around model group rat heart muscle interstitial fibrosis index CVF, the myocardial vascular, CVF and PVCA raise almost synchronous, show that myocardium interstitial fibrosis has participated in the pathological process of renal hypertension companion dyslipidemia rat heart reconstruct.Compare with model group, losartan and losartan+atorvastatin compound recipe group rat heart muscle CVF, PVCA all significantly reduces, losartan+atorvastatin+folic acid group rat heart muscle CVF, PVCA further reduces, and with losartan folk prescription and compound recipe group significant difference arranged relatively.See Table 4.
Table 4 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia rat cardiac function (X ± SD)
Annotate; Compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.5 losartan+atorvastatin+folic acid is to renal function and the arteriolar influence of kidney
Model group and normal rats compare, urine protein content and 24h α
1-microglobulin all obviously raises, clearance rate obviously descend (P＜0.01); Atorvastatin folk prescription group after the administration, losartan+atorvastatin compound recipe group and three joint group renal functioies all can effectively be regulated, and losartan+atorvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Losartan+atorvastatin+folic acid (5+1.0+0.08mg/kg) three joint group effects then not only are better than the folk prescription group, also are better than compound recipe group (p＜0.05 or 0.01), see Table 5.
Table 5 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia kidney of rats function (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
Model group animal kidney small artery pathological changes mainly shows as wall thickness to be increased, and internal diameter reduces, and wall thickness/internal diameter is than increasing.After the administration, losartan, losartan+atorvastatin compound recipe group kidney of rats small artery wall thickness reduces, internal diameter increases, wall thickness/internal diameter ratio reduces, losartan+atorvastatin+folic acid three joint group kidney of rats small artery wall thickness further reduce, internal diameter further increases, wall thickness/internal diameter reduces than further, with each folk prescription group and each compound recipe group significant difference (p＜0.05 or 0.01) is arranged relatively, see Table 6.
Table 6 amlodipine+atorvastatin+folic acid is to (the X ± SD) of arteriolar influence in the hypertension companion dyslipidemia kidney of rats
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.6 losartan+atorvastatin+folic acid is to the influence of medicated porridge sample atherosclerosis atheromatous plaque area
Model group and normal rats relatively, area of aorta atherosclerotic plaque obviously raise (P＜0.01); Each administration group and model group are relatively after the administration, atorvastatin folk prescription group, losartan+atorvastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively reduce the formation of aorta wall atheromatous plaque area, and losartan+atorvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Losartan+atorvastatin+folic acid (5+1.0+0.08mg/kg) three joint group effects then not only are better than the folk prescription group, also are better than compound recipe group (p＜0.05 or 0.01).See table 7 for details.
Table 7 losartan+atorvastatin+folic acid is to the influence of hypertension companion dyslipidemia rat artery atherosclerotic plaque area (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with losartan folk prescription group,
@P＜0.05; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
Embodiment 2: telmisartan+simvastatin+folic acid is to the protective effect of apoplexy susceptible type spontaneously hypertensive (SHR-SP) companion dyslipidemia rat target organ damage
Male SHR-SP rat is totally 80 about 8 ages in week, in conjunction with blood pressure values, is divided into model group, telmisartan+simvastatin (0.25+1mg/kg) group, telmisartan+simvastatin+folic acid (0.25+1+0.08mg/kg) group, and other establishes the WKY matched group, 20 every group.Gastric infusion is weighed weekly once every day 1 time, adjusts dose, continuous 8 weeks according to body weight.
Observation index:
(1) general state is observed: observe animal diet followed, survival condition and behavioral activity every day, compare between organizing.
(2) blood pressure: reach 4 weeks of administration before the administration, respectively measure blood pressure 8 weeks one time, observe the influence of medication to hypertension companion hyperlipemia rat blood pressure.
(3) after 8 weeks of pathological observation administration, all rats are all got cerebral tissue, section, HE dyeing, observe cerebral hemorrhage, cerebral infarction or Combination apoplexy, calculate and respectively organize the rat brain stroke incidence,, all get cerebral tissue and carry out pathological observation as in the experiment process animal dead taking place.
(4) row aorta intubate behind the rat anesthesia, behind the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, the perfusion of 2.5% glutaraldehyde is fixing, broken end is got brain, separates skull base arterial ring and intraparenchymatous small artery of brain and arteriole, and 2.5% glutaraldehyde is fixed, embedding, section, Toluidine blue staining.Computer pathology image analysis system is measured media thickness, the lumen diameter footpath of blood vessel, calculates the ratio of media thickness/lumen diameter, and 10 tremulous pulsies are surveyed in every section.
The result:
(1) overview: in this experimentation, obvious lethargy appears after the model group rat apoplexy, drowsiness, hair is fluffy, withered or come off, tarnish, weight loss, active movement obviously reduces, be slow in action, limbs are in various degree paralysis, and with symptoms such as tic, diarrhoea, urinary incontinence, eyeball are hemorrhage, the person of being in a bad way is dead in a few hours simultaneously for the morbidity of part rat.Most of animal nerve functional impairment of treatment group is slight than model group, and the mental status obviously is better than model group, and autonomic activities increases, and initiatively looks for food, drinks water, and weight loss is not obvious, and hair is also glossy along sliding than model group.
(2) blood pressure: model group and normal rats compare, and systolic pressure continues significantly to raise (P＜0.01); Each administration group and model group compare after the administration, telmisartan folk prescription group, and telmisartan+simvastatin compound recipe group and three joint group systolic pressures all can effectively descend, and telmisartan+simvastatin compound recipe group hypotensive effect is more obvious than the effect of folk prescription group; Telmisartan+simvastatin+folic acid (0.25+1.0+0.08mg/kg) three joint group hypotensive effects then not only are better than the folk prescription group, also are better than compound recipe group (p＜0.05 or 0.01).See table 6 for details.
Table 8 telmisartan+simvastatin+folic acid is to the influence (X ± SD n) of hypertension companion's dyslipidemia rat systolic pressure (mmHg)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲ ▲P＜0.01; Compare with telmisartan folk prescription group,
@P＜0.05; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
(3) pathological observation: have 16 apoplexy takes place in 20 rats of model group, wherein dead 5, except that 2 animals fail in time to obtain the tissue after death at night, other 18 animals have all carried out the histopathology observation, totally 16 have only the apoplexy pathological manifestations to take place, 5 of its midbrains hemorrhage, 6 of cerebral infarctions, 5 of Combination apoplexy.Apoplexy kitchen range and all visible on every side small artery hyaline degeneration or fibrinoid necrosis, tube wall thickens, and all oozings of blood are managed in visible microthrombusis in the luminal stenosis, the tube chamber that has.20 rats of telmisartan folk prescription group have 14 apoplexy takes place, and 20 rats of simvastatin group have 15 apoplexy takes place, and do not have the significance difference with model group comparison apoplexy incidence rate.In telmisartan+20 rats of simvastatin compound recipe group 12 generations are arranged, compare with model group, the apoplexy incidence rate obviously reduces (P＜0.05), telmisartan+simvastatin+folic acid three joint groups and model group, telmisartan, simvastatin folk prescription group and telmisartan+simvastatin compound recipe group more all has the significance difference opposite sex (P＜0.05), show three drug combinations, can obviously reduce the apoplexy incidence rate.See table 9 for details.
The influence that table 9 telmisartan+simvastatin+8 weeks of folic acid successive administration observe SHR-SP rat histopathology
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05; Compare with telmisartan folk prescription group,
@P＜0.05; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
(4) arteriae cerebri blood vessel thickness: compare with normal rats, model group rat brain tunica media of artery thickness increases, and lumen diameter reduces, and media thickness/lumen diameter is than increasing.Compare with model group, telmisartan+simvastatin group rat brain tunica media of artery thickness, media thickness/lumen diameter are than reducing, telmisartan+simvastatin+folic acid group cerebral arteries media thickness, media thickness/lumen diameter more all have significant difference than further reducing with folk prescription and compound recipe group.See Table 10.
Table 10 telmisartan+simvastatin+folic acid is to the arteriocerebral influence of SHR-SP companion dyslipidemia rat (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05; Compare with telmisartan folk prescription group,
@P＜0.05; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
Embodiment 3: irbesartan+Pitavastatin+folic acid is to the target organ protection function of hypertension companion dyslipidemia rat
Preparation 2K1C hypertension companion dyslipidemia composite model animal, method be with embodiment 1, chooses the administration of dividing into groups of hypertension companion dyslipidemia animal, 16 weeks of administration time.
Observation index
(1) blood pressure: reach 8 weeks of administration before the administration, respectively measure blood pressure 16 weeks one time, observe the influence of medication to 2K1C hypertension companion hyperlipemia rat blood pressure.
(2) blood glucose and blood fat: administration is got blood and is measured plasma cholesterol (using kit measurement) and blood sugar level with biochemical process after finishing.
(3) endotheliocyte and anti-oxidation function: the same blood of getting, serum NO level, ET-1, SOD, the horizontal biochemical process of MDA are measured.
(4) cardiorenal function: myocardium hydroxyproline determination is got left ventricular free wall cardiac muscular tissue, be prepared into cardiac muscular tissue's homogenate of 10%, press hydroxyproline testing cassete description, digestion method is measured myocardium hydroxyproline content, press collagen content=hydroxyproline content * 7.46, be converted into collagen content.Small artery is observed through abdominal aortic cannulation in the kidney, and behind the abundant blood vessel dilating of 0.1mg/ml sodium nitroprusside, the formalin with 10% is poured into fixing under 10～12kPa, separate left kidney, the place cuts kidney from the hilus renalis, places 4% formaldehyde fixing, conventional dehydration, paraffin embedding, transverse section, HE dyeing.Choosing external diameter under the optical microscope is the interior small artery of kidney of 50～100 μ m, measures small artery internal diameter, wall thickness in the kidney, calculated wall thickness internal diameter ratio.Each specimen is measured 4 and is small artery in the cross section wall, gets its meansigma methods.
(5) atheromatous plaque area: gather the aorta sample, detect aorta lipid plaque area with image analytical method.
Measurement data represents that with x ± s data statistics is handled and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
Experimental result:
Model group and normal rats compare, and systolic pressure continues significantly to raise; Administration is preceding except that the normal control group, other respectively organize the blood pressure level zero difference, each administration group and model group are relatively after the administration, irbesartan folk prescription group, irbesartan+Pitavastatin compound recipe group and three joint group systolic pressures all can effectively descend, and irbesartan+Pitavastatin compound recipe group hypotensive effect is more obvious than the effect of folk prescription group; Irbesartan+Pitavastatin+folic acid (1.5+0.4+0.08mg/kg) three joint group hypotensive effects then not only are better than the folk prescription group, also are better than the compound recipe group.
Model group and normal rats compare, and blood glucose and blood fat all obviously raise; Each administration group and model group compare after the administration, Pitavastatin folk prescription group, and irbesartan+Pitavastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively descend, and irbesartan+Pitavastatin compound recipe group hypoglycemic lipid-lowering effect is more obvious than the effect of folk prescription group; Irbesartan+Pitavastatin+folic acid (1.5+1.0+0.08mg/kg) three joint group effect for reducing fat then not only are better than the folk prescription group, also are better than the compound recipe group.
Model group and normal rats compare, and ET-1 and MDA level obviously raise, and NO and SOD level then obviously reduce; Each administration group and model group compare after the administration, Pitavastatin folk prescription group, and irbesartan+Pitavastatin compound recipe group and three joint group index of correlation levels all can effectively be adjusted, and irbesartan+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group; Irbesartan+Pitavastatin+folic acid (1.5+1.0+0.08mg/kg) three joint group effects then not only are better than the folk prescription group, also are better than the compound recipe group.
Model group and normal rats compare, collagen content, urine protein content and 24h α
1-microglobulin all obviously raises, and clearance rate obviously descends; Pitavastatin folk prescription group after the administration, irbesartan+Pitavastatin compound recipe group and three joint group cardiorenal functions all can effectively be regulated, and irbesartan+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group; Irbesartan+Pitavastatin+folic acid (1.5+1.0+0.08mg/kg) three joint group effects then not only are better than the folk prescription group, also are better than the compound recipe group.
Model group and normal rats compare, and area of aorta atherosclerotic plaque obviously raises; Each administration group and model group are relatively after the administration, Pitavastatin folk prescription group, irbesartan+Pitavastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively reduce the formation of aorta wall atheromatous plaque area, and irbesartan+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group.
Model group and normal rats compare, and area of aorta atherosclerotic plaque obviously raises; Each administration group and model group are relatively after the administration, Pitavastatin folk prescription group, irbesartan+Pitavastatin compound recipe group and three joint groups all can effectively reduce the formation of aorta wall atheromatous plaque area, and irbesartan+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group; Irbesartan+Pitavastatin+folic acid (1.5+1.0+0.08mg/kg) three joint group effects then not only are better than the folk prescription group, also are better than the compound recipe group.
Embodiment 4: the preparation of losartan 50mg/ atorvastatin 10.0mg/ folic acid 0.2mg sheet
Prescription
Losartan 50g
Atorvastatin 10.0g
Folic acid 0.2g
Carboxymethyl starch sodium 20.0g
Calcium hydrogen phosphate 150.0g
10% polyvidone aqueous solution is an amount of
Magnesium stearate 1%
Make 1000
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get losartan 50g, atorvastatin 10g and folic acid 0.2g according to equivalent incremental method mix homogeneously, add carboxymethyl starch sodium 20g, calcium hydrogen phosphate 180g, according to equivalent incremental method uniform mixing, folic acid is dissolved in the binding agent 10% polyvidone aqueous solution, add binding agent and make soft material in right amount, 30 orders are granulated, 40～45 ℃ of dry 3h; 30 order granulate add an amount of magnesium stearate mixing, behind the assay, and tabletting, packing.Note lucifuge in the preparation process, after product inspection was qualified, aluminium-plastic bubble plate packing kept in Dark Place.Every contains losartan 50mg, atorvastatin 10mg, folic acid 0.2mg in the compound tablet of making.
Embodiment 5～10: the preparation of the losartan atorvastatin YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 11 obtains.
Embodiment 11: the preparation of losartan 50mg/ atorvastatin 10.0mg/ calcium folinate 0.4mg sheet
Embodiment 12: the preparation of losartan 50mg/ atorvastatin 10.0mg/ levoleucovorin calcium 0.2mg sheet
The preparation method of embodiment 11～12 is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 11 obtains.
Table 11 embodiment 5～15 tablet formulations are formed
Every contains losartan 50mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid tablet that embodiment 5 makes.
Every contains losartan 50mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe losartan atorvastatin folic acid tablet that embodiment 6 makes.
Every contains losartan 12.5mg, atorvastatin 10mg, folic acid 1.0mg in the compound recipe losartan atorvastatin folic acid tablet that embodiment 7 makes.
Every contains losartan 50mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid tablet that embodiment 8 makes.
Every contains losartan 100mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid tablet that embodiment 9 makes.
Every contains losartan 100mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid tablet that embodiment 10 makes.
Every contains losartan 50mg, atorvastatin 10mg, calcium folinate 0.4mg in the compound recipe losartan atorvastatin calcium folinate tablet that embodiment 11 makes.
Every contains losartan 50mg, atorvastatin 10mg, levoleucovorin calcium 0.2mg in the compound recipe losartan atorvastatin levo leucovorin calcium tablet that embodiment 12 makes.
Embodiment 13～19: the preparation of the losartan simvastatin YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 12 obtains.
Embodiment 20: the preparation of losartan 50mg/ simvastatin 10.0mg/ calcium folinate 0.4mg sheet
Embodiment 21: the preparation of losartan 50mg/ simvastatin 10.0mg/ levoleucovorin calcium 0.2mg sheet
The preparation method of embodiment 20～21 is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 12 obtains.
Table 12 embodiment 13～21 tablet formulations are formed
Every contains losartan 50mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 13 makes.
Every contains losartan 50mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 14 makes.
Every contains losartan 50mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 15 makes.
Every contains losartan 50mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 16 makes.
Every contains losartan 50mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 17 makes.
Every contains losartan 100mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 18 makes.
Every contains losartan 100mg, simvastatin 20mg, folic acid 0.8mg in the compound recipe losartan simvastatin folic acid tablet that embodiment 19 makes.
Every contains losartan 50mg, simvastatin 10mg, calcium folinate 0.4mg in the compound recipe losartan simvastatin calcium folinate tablet that embodiment 20 makes.
Every contains losartan 50mg, simvastatin 10mg, levoleucovorin calcium 0.2mg in the compound recipe losartan simvastatin levo leucovorin calcium tablet that embodiment 21 makes.
Embodiment 22～26: the preparation of the losartan Pitavastatin YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 13 obtains.
Embodiment 27: the preparation of losartan 50mg/ Pitavastatin 1.0mg/ calcium folinate 0.4mg sheet
Embodiment 28: the preparation of losartan 50mg/ Pitavastatin 2.0mg/ levoleucovorin calcium 0.2mg sheet
The preparation method of embodiment 27～28 is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 13 obtains.
Table 13 embodiment 22～28 tablet formulations are formed
Every contains losartan 50mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid tablet that embodiment 22 makes.
Every contains losartan 50mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe losartan Pitavastatin folic acid tablet that embodiment 23 makes.
Every contains losartan 50mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid tablet that embodiment 24 makes.
Every contains losartan 100mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid tablet that embodiment 25 makes.
Every contains losartan 100mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid tablet that embodiment 26 makes.
Every contains losartan 50mg, Pitavastatin 1mg, calcium folinate 0.4mg in the compound recipe losartan Pitavastatin calcium folinate tablet that embodiment 27 makes.
Every contains losartan 50mg, Pitavastatin 2mg, levoleucovorin calcium 0.2mg in the compound recipe losartan Pitavastatin levo leucovorin calcium tablet that embodiment 28 makes.
Embodiment 29～33: the preparation of the telmisartan atorvastatin YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 14 obtains.
Embodiment 34～38: the preparation of the telmisartan simvastatin YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 14 obtains.
Embodiment 39～43: the preparation of the telmisartan Pitavastatin YESUAN PIAN of different content proportioning
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 14 obtains.
Table 14 embodiment 29～43 tablet formulations are formed
Every contains telmisartan 40mg, atorvastatin 10mg, folic acid 0.2mg in the compound recipe telmisartan atorvastatin folic acid tablet that embodiment 29 makes.
Every contains telmisartan 40mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe telmisartan atorvastatin folic acid tablet that embodiment 30 makes.
Every contains telmisartan 40mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe telmisartan atorvastatin folic acid tablet that embodiment 31 makes.
Every contains telmisartan 40mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe telmisartan atorvastatin folic acid tablet that embodiment 32 makes.
Every contains telmisartan 40mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe telmisartan atorvastatin folic acid tablet that embodiment 33 makes.
Every contains telmisartan 40mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe telmisartan simvastatin folic acid tablet that embodiment 34 makes.
Every contains telmisartan 40mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe telmisartan simvastatin folic acid tablet that embodiment 35 makes.
Every contains telmisartan 40mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe telmisartan simvastatin folic acid tablet that embodiment 36 makes.
Every contains telmisartan 40mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe telmisartan simvastatin folic acid tablet that embodiment 37 makes.
Every contains telmisartan 40mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe telmisartan simvastatin folic acid tablet that embodiment 38 makes.
Every contains telmisartan 40mg, Pitavastatin 1mg, folic acid 0.2mg in the compound recipe telmisartan Pitavastatin folic acid tablet that embodiment 39 makes.
Every contains telmisartan 40mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe telmisartan Pitavastatin folic acid tablet that embodiment 40 makes.
Every contains telmisartan 40mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe telmisartan Pitavastatin folic acid tablet that embodiment 41 makes.
Every contains telmisartan 40mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe telmisartan Pitavastatin folic acid tablet that embodiment 42 makes.
Every contains telmisartan 40mg, Pitavastatin 2mg, folic acid 0.8mg in the compound recipe telmisartan Pitavastatin folic acid tablet that embodiment 43 makes.
Embodiment 44～52: the preparation of the irbesartan atorvastatin/simvastatin of different content proportioning/Pitavastatin YESUAN PIAN
Preparation method is identical with embodiment 4, makes tablet according to the granule that prescription shown in the table 15 obtains.
Table 15 embodiment 44～52 tablet formulations are formed
Every contains irbesartan 150mg, atorvastatin 5mg, folic acid 0.4mg in the compound recipe irbesartan atorvastatin folic acid tablet that embodiment 44 makes.
Every contains irbesartan 150mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe irbesartan atorvastatin folic acid tablet that embodiment 45 makes.
Every contains irbesartan 150mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe irbesartan atorvastatin folic acid tablet that embodiment 46 makes.
Every contains irbesartan 150mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe irbesartan atorvastatin folic acid tablet that embodiment 47 makes.
Every contains irbesartan 150mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe irbesartan simvastatin folic acid tablet that embodiment 48 makes.
Every contains irbesartan 150mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe irbesartan simvastatin folic acid tablet that embodiment 49 makes.
Every contains irbesartan 150mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe irbesartan simvastatin folic acid tablet that embodiment 50 makes.
Every contains irbesartan 150mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe irbesartan Pitavastatin folic acid tablet that embodiment 51 makes.
Every contains irbesartan 150mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe irbesartan Pitavastatin folic acid tablet that embodiment 52 makes.
Embodiment 53: the capsular preparation of losartan 50mg/ atorvastatin 10.0mg/ folic acid 0.2mg
Prescription
Losartan 50g
Atorvastatin 10.0g
Folic acid 0.2g
Starch 60.0g
Microcrystalline Cellulose 20.0g
Carboxymethyl starch sodium 20.0g
5% polyvidone k-30 aqueous solution is an amount of
1% magnesium stearate is an amount of
Make 1000
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get losartan 50g, atorvastatin 10g, folic acid 0.2g according to equivalent incremental method mix homogeneously, add 60g starch, 20g microcrystalline Cellulose, 20g carboxymethyl starch sodium, according to equivalent incremental method uniform mixing, make soft material with 5% polyvidone k-30 aqueous solution, 20 mesh sieves are granulated, 60 ℃ of dry about 2h, 20 mesh sieve granulate, controlling particulate water content is 2-3%, with 1% magnesium stearate mix homogeneously of dried granule and recipe quantity, semi-finished product detect, and measure content, the Capsules of packing into promptly gets 1000 capsules.Note lucifuge in the preparation process.The qualified back of product inspection aluminium-plastic bubble plate packing keeps in Dark Place.Every contains losartan 50mg, atorvastatin 10mg, folic acid 0.2mg in the compound capsule of making.
Embodiment 54～95: the diuretic+stanin fat-reducing medicament+folacin compound capsule of preparation different content proportioning
Preparation method is identical with embodiment 53, makes capsule according to the granule that prescription shown in the table 16 obtains.
Table 16 embodiment 54～95 capsule prescriptions are formed (unit: gram)
Every contains losartan 50mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid capsule that embodiment 54 makes.
Every contains losartan 50mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe losartan atorvastatin folic acid capsule that embodiment 55 makes.
Every contains losartan 50mg, atorvastatin 10mg, folic acid 1.0mg in the compound recipe losartan atorvastatin folic acid capsule that embodiment 56 makes.
Every contains losartan 50mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid capsule that embodiment 57 makes.
Every contains losartan 100mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid capsule that embodiment 58 makes.
Every contains losartan 100mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe losartan atorvastatin folic acid capsule that embodiment 59 makes.
Every contains losartan 50mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 60 makes.
Every contains losartan 50mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 61 makes.
Every contains losartan 50mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 62 makes.
Every contains losartan 50mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 63 makes.
Every contains losartan 50mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 64 makes.
Every contains losartan 100mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 65 makes.
Every contains losartan 100mg, simvastatin 20mg, folic acid 0.8mg in the compound recipe losartan simvastatin folic acid capsule that embodiment 66 makes.
Every contains losartan 50mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid capsule that embodiment 67 makes.
Every contains losartan 50mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe losartan Pitavastatin folic acid capsule that embodiment 68 makes.
Every contains losartan 50mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid capsule that embodiment 69 makes.
Every contains losartan 100mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid capsule that embodiment 70 makes.
Every contains losartan 100mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe losartan Pitavastatin folic acid capsule that embodiment 71 makes.
Every contains telmisartan 40mg, atorvastatin 10mg, folic acid 0.2mg in the compound recipe telmisartan atorvastatin folic acid capsule that embodiment 72 makes.
Every contains telmisartan 40mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe telmisartan atorvastatin folic acid capsule that embodiment 73 makes.
Every contains telmisartan 40mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe telmisartan atorvastatin folic acid capsule that embodiment 74 makes.
Every contains telmisartan 40mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe telmisartan atorvastatin folic acid capsule that embodiment 75 makes.
Every contains telmisartan 40mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe telmisartan atorvastatin folic acid capsule that embodiment 76 makes.
Every contains telmisartan 40mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe telmisartan simvastatin folic acid capsule that embodiment 77 makes.
Every contains telmisartan 40mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe telmisartan simvastatin folic acid capsule that embodiment 78 makes.
Every contains telmisartan 40mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe telmisartan simvastatin folic acid capsule that embodiment 79 makes.
Every contains telmisartan 40mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe telmisartan simvastatin folic acid capsule that embodiment 80 makes.
Every contains telmisartan 40mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe telmisartan simvastatin folic acid capsule that embodiment 81 makes.
Every contains telmisartan 40mg, Pitavastatin 1mg, folic acid 0.2mg in the compound recipe telmisartan Pitavastatin folic acid capsule that embodiment 82 makes.
Every contains telmisartan 40mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe telmisartan Pitavastatin folic acid capsule that embodiment 83 makes.
Every contains telmisartan 40mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe telmisartan Pitavastatin folic acid capsule that embodiment 84 makes.
Every contains telmisartan 40mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe telmisartan Pitavastatin folic acid capsule that embodiment 85 makes.
Every contains telmisartan 40mg, Pitavastatin 2mg, folic acid 0.8mg in the compound recipe telmisartan Pitavastatin folic acid capsule that embodiment 86 makes.
Every contains irbesartan 150mg, atorvastatin 5mg, folic acid 0.4mg in the compound recipe irbesartan atorvastatin folic acid capsule that embodiment 87 makes.
Every contains irbesartan 150mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe irbesartan atorvastatin folic acid capsule that embodiment 88 makes.
Every contains irbesartan 150mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe irbesartan atorvastatin folic acid capsule that embodiment 89 makes.
Every contains irbesartan 150mg, atorvastatin 150mg, folic acid 0.4mg in the compound recipe irbesartan atorvastatin folic acid capsule that embodiment 90 makes.
Every contains irbesartan 150mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe irbesartan simvastatin folic acid capsule that embodiment 91 makes.
Every contains irbesartan 150mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe irbesartan simvastatin folic acid capsule that embodiment 92 makes.
Every contains irbesartan 150mg, simvastatin 150mg, folic acid 0.4mg in the compound recipe irbesartan simvastatin folic acid capsule that embodiment 93 makes.
Every contains irbesartan 150mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe irbesartan Pitavastatin folic acid capsule that embodiment 94 makes.
Every contains irbesartan 150mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe irbesartan Pitavastatin folic acid capsule that embodiment 95 makes.
Claims (10)
1. pharmaceutical composition comprises:
(1) angiotensin ii receptor antagonist of pharmaceutical dosage;
(2) stanin fat-reducing medicament of pharmaceutical dosage;
(3) folacin compound of pharmaceutical dosage; And
(4) acceptable carrier on the pharmaceutics;
Wherein, described angiotensin ii receptor antagonist is selected from a kind of in losartan, telmisartan, Candesartan, irbesartan, eprosartan, valsartan or the Olmesartan; Described stanin fat-reducing medicament is selected from atorvastatin, simvastatin, Pitavastatin, lovastatin, fluvastatin, pravastatin, Rosuvastatin, itavastatin, Buddhist nun and cuts down a kind of in his spit of fland, bervastatin, mevastatin or the cerivastatin; The folacin compound of described pharmaceutical dosage is selected from a kind of in folic acid, calcium folinate or the levoleucovorin calcium.
2. the described pharmaceutical composition of claim 1, it is characterized in that: described angiotensin ii receptor antagonist is selected from a kind of in losartan, telmisartan or the irbesartan, and wherein losartan content is that 50～100mg, telmisartan content are that 40～80mg, irbesartan content are 150～300mg; Described stanin fat-reducing medicament is selected from a kind of in atorvastatin, simvastatin, the Pitavastatin, and wherein atorvastatin content is that 10～80mg, simvastatin content are that 5～40mg, Pitavastatin content are 1～4mg; The folacin compound of described pharmaceutical dosage is selected from a kind of in folic acid, calcium folinate or the levoleucovorin calcium, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
3. the described pharmaceutical composition of claim 1, it is characterized in that: the angiotensin ii receptor antagonist of described pharmaceutical dosage is a losartan, content is 50～100mg; The stanin fat-reducing medicament of described pharmaceutical dosage is an atorvastatin, and content is 10～80mg; Described folacin compound is a folic acid, and content is 0.2～1.0mg.
4. the described pharmaceutical composition of claim 1, it is characterized in that: the angiotensin ii receptor antagonist of described pharmaceutical dosage is a losartan, content is 50～100mg; The stanin fat-reducing medicament of described pharmaceutical dosage is a simvastatin, and content is 5～40mg; Described folacin compound is a folic acid, and content is 0.2～1.0mg.
5. each described pharmaceutical composition in the claim 1～4 is characterized in that the pharmacy dosage form of described pharmaceutical composition is an oral formulations, comprises tablet, capsule or granule.
6. each described pharmaceutical composition is used for preventing, treat or delays the purposes of the medicine of hypertension companion dyslipidemia in the claim 1～4 in preparation.
7. each described pharmaceutical composition is used for preventing, treat or delays the purposes of the medicine of the target organ damage that hypertension companion dyslipidemia causes in the claim 1～5 in preparation.
8. the described purposes of claim 7 is characterized in that: the target organ damage that described hypertension companion dyslipidemia causes is an apoplexy.
9. each described pharmaceutical composition is used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension companion dyslipidemia causes in the claim 1～5 in preparation.
10. the described purposes of claim 9 is characterized in that: the cardiovascular and cerebrovascular vessel incident danger that described reduction hypertension companion dyslipidemia causes is meant the incidence rate that reduces apoplexy.
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| CN110237070A (en) * | 2019-05-10 | 2019-09-17 | 辽宁大学 | Irbesartan is preparing the application in blood lipid-lowering medicine |
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| CA2406077C (en) * | 2000-04-10 | 2010-07-20 | Nicholas J. Wald | Formulation for the prevention of cardiovascular disease |
| US6669955B2 (en) * | 2001-08-28 | 2003-12-30 | Longwood Pharmaceutical Research, Inc. | Combination dosage form containing individual dosage units of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin |
| US20050054731A1 (en) * | 2003-09-08 | 2005-03-10 | Franco Folli | Multi-system therapy for diabetes, the metabolic syndrome and obesity |
| CN1602960A (en) * | 2004-07-23 | 2005-04-06 | 海南国栋药物研究所有限公司 | Mixture for preventing and treating metabolic syndrome like cerebrovascular and cardiovascular disease |
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