CN101590239B - Pharmaceutical composition containing uretic, statin and folic acid as well as applications thereof - Google Patents
Pharmaceutical composition containing uretic, statin and folic acid as well as applications thereof Download PDFInfo
- Publication number
- CN101590239B CN101590239B CN 200810114222 CN200810114222A CN101590239B CN 101590239 B CN101590239 B CN 101590239B CN 200810114222 CN200810114222 CN 200810114222 CN 200810114222 A CN200810114222 A CN 200810114222A CN 101590239 B CN101590239 B CN 101590239B
- Authority
- CN
- China
- Prior art keywords
- folic acid
- group
- hydrochlorothiazide
- atorvastatin
- simvastatin
- 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.)
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- 239000011724 folic acid Substances 0.000 claims abstract description 182
- 235000019152 folic acid Nutrition 0.000 claims abstract description 182
- 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 claims abstract description 157
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a pharmaceutical composition containing uretic, statin lipid-lowering drugs and folic acid compound. The pharmaceutical composition contains medicinal dose of uretic, medicinal dose of statin lipid-lowering drugs, medicinal dose of folic acid compound and a carrier acceptable in pharmaceutics. The invention also relates to an application of the pharmaceutical composition in preparing medicines for preventing and treating or retarding high blood pressure accompanied by dyslipidemia and the application thereof in preparing medicines for treating target organ damage caused by the high blood pressure accompanied by dyslipidemia; in addition, the invention further relates to the application of the pharmaceutical composition in preparing medicines for lowering risk of cardiovascular and cerebrovascular events caused by high blood pressure accompanied by dyslipidemia. The invention belongs to the pharmaceutical field. With the implementation of the invention, the pharmaceutical composition with special usage, provided to the patients, can improve compliance of the patients, bring convenience to the patients to take medicines and reduce medical expenses, thus enjoying good market prospect.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains diuretic, stanin fat-reducing medicament and folic acid, and this pharmaceutical composition for the preparation of prevention, treat or delay the purposes in the medicine of the target organ damage that purposes in the medicine of hypertension complicated dyslipidemia and hypertension complicated dyslipidemia cause, the invention still further relates to this pharmaceutical composition for the preparation of the purposes in the medicine that reduces the cardiocerebrovasculaevents events danger that the hypertension complicated dyslipidemia causes.Belong to pharmaceutical field.
Background technology
Cardiovascular disease is one of human main causes of death, wherein mainly is coronary heart disease and apoplexy.The main hazard factor of attested cardiovascular disease has three: dyslipidemia comprises high/low density lipoprotein cholesterol (LDL-C), high triglyceride and low hdl cholesterol (HDL-C); Hypertension; Smoking.Studies show that, 80～90% patients with coronary heart disease has a kind of in these three kinds of risk factor at least.Other risk factor is has age (〉=55 years old) also, male, apoplexy history, peripheral arterial disease, diabetes, albuminuria, left ventricular hypertrophy and coronary heart disease family history.The risk factor of cardiovascular disease occurs seldom separately, is present in the patient body but usually jointly unite.Hypertension and dyslipidemia are two kinds of concurrent cardiovascular disease risk factor the most general, the hyperpietic greater than 50% be attended by dyslipidemia [O ' Meara JG, et al.Arch Intern Med.2004; 164:1313-1318].Studies show that recently, the adult of Britain 20% suffer from the hypertensive patients dyslipidemia [WilliamsB, et al.Eur Heart J.2004; 25:528-529].One of WHO analyzes and finds, approximately has 30% adult to suffer from hypertensive patients dyslipidemia [Tunstall-Pedoe H, et al.Pharmacoepidemiol Drug Saf.2004 in West Europe; 13 (Suppl 1): S307].Baseline blood pressure and serum cholesterol raise can sharply increase the incidence rate of cardiovascular disease and the danger of coronary heart disease, and clinical researches show in a large number, and the application of depressor and lipid lowerers can significantly reduce the M ﹠ M of cardiovascular disease.
Yet most of patients does not reach gratifying curative effect [Clinical reality of coronary preventionguidelines:a comparison of EUROASPIRE I and II in nine countries.EUROASPIRE I andII Group.European Action on Secondary Prevention by Intervention to Reduce Events.Lancet, 2001; 357:995-1001], one of its reason is degree of the adhering to problem of prescribed treatment, the patient more than 50% selects to stop treatment [the Insull WJ.Intern Med.1997 of this class multiple medicines ball; 241:317-325], the direct impact of this phenomenon be exactly the M ﹠ M of cardiovascular disease raise [Flack JM, et al.Eur Heart J.1996; 17 (SupplA): 16-20].Therefore, simplify prescription and can strengthen patient's degree of adhering to the minimizing pill burden.Retrospective review shows, just gives simultaneously blood pressure lowering and lipid-lowering therapy from starting stage for the treatment of, and in succession gives seldom again other medicines, just can improve patient's degree of adhering to [Chapman RH, et al.Arch Intern Med.2005; 165:1147-1152]; Especially for high-risk cardiovascular patient, its effect is more obvious, because they often are given the Various Complex medicine to treat different risk factors of cardiovascular diseases.Recently, the drug combination of fixed dosage is widely used.But unique compound medicines that goes on the market for hypertension complicated with hyperlipemia is that amlodipine and atorvastatin are combined into " Caduet ", clinical verified, both use in conjunction can obviously reduce blood pressure and blood cholesterol levels, can make the cardiovascular patient more than 80% reach target blood pressure and target LDL-C level [Dorval JF, et al.Am J Cardiol.2005; 95:249-253].Therefore, the more compound medicines that have simultaneously blood pressure lowering and an effect for reducing fat of exploitation have great clinical meaning for the treatment of cardiovascular disease.
The International Society of Hypertension (ISH) that holds in February, 2004 the 20th Annual Conference reported a multicenter that carries out at north America region, random, double blinding, placebo short-term clinical trial AVALON research, this research purpose be by with amlodipine or atorvastatin single therapy relatively, the therapeutic alliance of observing amlodipine (5mg/d) and atorvastatin (10mg/d) makes the situation up to standard of hypertensive patients patients with dyslipidemia blood pressure and blood fat; Patient's 847 examples of hypertensive patients dyslipidemia are included in this research in, through the treatment of 8 weeks, each group reaches u.s. national cholesterol education program (NCEP) adult treatment group and reports that for the third time LDL-C control target in (ATPIII) and the Proportion of patients of the controlling of blood pressure target among the U.S. hypertension prevention and control guide JNC-6 are respectively: drug combination group 82.1% and 51.1%, amlodipine group 12.4% and 54.0%, atorvastatin group 78.2% and 32.3%, placebo group 6.6% and 29.7%; In the drug combination group, compliance rate in the time of LDL-C and blood pressure (45.5%) is significantly higher than amlodipine group (8.3%), atorvastatin group (28.6%) and placebo group (3.5%).Another is for the clinical trial of multicenter, random, double blinding, selected 1220 routine hyperpietics (51.9% merges the LDL-C horizontal abnormality), baseline mean blood pressure 146.6/87.9mmHg, average LDL-C level is 152.9mg/dl, except recommending to adjust the life style, selection gives the amlodipine/atorvastatin (5/10,5/20,5/40 of different proportionings, 5/80,10/10,10/20,10/40, and 10/80mg) carries out the hypertension and hyperlipemia treatment, after 14 weeks, 57.7% patient reaches the control target .[Blank of LDL-C and blood pressure ,-R simultaneously; Et al.Single-pill therapy in the treatment of concomitant hypertension anddyslipidemia (the amlodipine/ atorvastatin gemini study) .J Clin Hypertens (Greenwich), 2005; 7 (5): 264-273].As seen, only amlodipine and the atorvastatin cardiovascular patient of uniting for the hypertensive patients dyslipidemia still has certain limitation.Patient's target organ damage also needs further control and intervenes, the prevention of cardiovascular event or treatment do not obtain the checking [Wilson of clinical data yet, et al.Amlodipine/ Atorvastatin (Caduet) for Preventing Heart Disease.American Family Physician, 2006; 73 (6): 1067-1068].
Because it is to reduce to greatest extent cardiovascular diseases's death and invalid total danger 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 cardiocerebrovasculaevents events danger of exploitation has great clinical meaning for the treatment of cardiovascular disease.
The line antihypertensive drug that WHO and China Treatment Guidelines for Hypertension are recommended is respectively: diuretic, beta-adrenoceptor antagonists, calcium antagonist, angiotensin converting enzyme inhibitor, angiotensin ii receptor antagonist, the composite antihypertensive preparation of the fixed dosage that perhaps is comprised of said medicine.
As far back as 1978, diuretic was namely classified as a line depressor by World Health Organization (WHO), often was applied to separately treat light, moderate hypertension.In the research (ALLHAT) of an extensive hypertension and hyperlipemia prevention of cardiac outbreak, have 33000 hypertensive patients, patient has another cardiovascular risk factor at least.Study the curative effect that prevents from having a heart attack of three kinds of antihypertensive drugs (amlodipine, lisinopril and doxazosin), do than effect with a kind of thiazide diuretic chlortalidone.This group of doxazosin finishes ahead of time, because the cardiovascular event that should organize is than chlortalidone group showed increased.Whole research was on average visited 4.9 years, to cause death with the non-lethality heart infarction as observing terminal point, found that the terminal point incidence rate of amlodipine and lisinopril group is as broad as long; Heart failure is more in the amlodipine group; Total cardiovascular event is more in the lisinopril group.Conclusion: the thiazide diuretic agent is poor unlike any other expensive medicine antihypertensive effect.Any drug combination blood pressure lowering all be should first-selected thiazide diuretic as one of drug combination.Among the U.S. hypertension prevention and control guide JNC-7, strengthened the critical role of thiazide diuretic as resisting hypertension first-line treatment medicine, in 6 stiffness of the nape indications, had 4 (heart failure, coronary heart disease are high-risk, diabetes and preventing brain stroke recurrence) to show thiazide diuretic; And from the cost-benefit angle analysis, thiazide diuretic is classified the antihypertensive drug of worth selection as.
Existing fat-reducing medicament mainly comprises 3-hydroxy-3-methyl glutaryl base-CoA-reductase inhibitors (HMG-CoA reductase inhibitor) class, fibrate and nicotinic acid class fat-reducing medicament.Stanin fat-reducing medicament is the general name of limit element enzyme hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor of liver synthesis cholesterol, effectively hypercholesterolemia reducing and low-density lipoprotein cholesterol, slight high density lipoprotein increasing cholesterol, be used for the treatment of clinically hypercholesterolemia and combined hyperlipidemia familial, and the control of coronary heart disease and apoplexy.The stanin fat-reducing medicament of commonly using both at home and abroad at present has atorvastatin (atorvastatin), simvastatin (simvastatin), Pitavastatin (pitavastatin), pravastatin (pravastatin), lovastatin (lovastatin), fluvastatin (fluvatin) etc.
Still do not find the report that diuretic, stanin fat-reducing medicament and folate coupling are used in the clinical and existing research, based on above many-sided consideration, we are studied the use in conjunction of diuretic, 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 cardiocerebrovasculaevents events danger.The present invention also provide this pharmaceutical composition for the preparation of prevention, treat or delay the purposes in the medicine of the target organ damage that purposes in the medicine of hypertension complicated dyslipidemia and hypertension complicated dyslipidemia cause, the present invention also provides this pharmaceutical composition for the preparation of the purposes in the medicine that reduces the cardiocerebrovasculaevents events danger that the hypertension complicated dyslipidemia causes.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) diuretic 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 diuretic of above-mentioned pharmaceutical dosage is selected from a kind of in hydrochlorothiazide, indopamide, eplerenone or the spironolactone, and content is 2.5～50mg.
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), itavastatin (nisvastatin), bervastatin (bervastatin), mevastatin (mevastatin), or a kind of in the cerivastatin (cerivastatin).
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 diuretic of described pharmaceutical dosage is hydrochlorothiazide, and content is 12.5～25mg; The stanin fat-reducing medicament of described pharmaceutical dosage is 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 diuretic of described pharmaceutical dosage is hydrochlorothiazide, and content is 12.5～25mg; The stanin fat-reducing medicament of described pharmaceutical dosage is 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 diuretic of described pharmaceutical dosage is hydrochlorothiazide, and content is 12.5～25mg; The stanin fat-reducing medicament of described pharmaceutical dosage is 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 diuretic of described pharmaceutical dosage is indopamide, and content is 2.5～5mg; The stanin fat-reducing medicament of described pharmaceutical dosage is 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 diuretic of described pharmaceutical dosage is indopamide, and content is 2.5～5mg; The stanin fat-reducing medicament of described pharmaceutical dosage is 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 diuretic of described pharmaceutical dosage is indopamide, and content is 2.5～5mg; The stanin fat-reducing medicament of described pharmaceutical dosage is 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 diuretic of described pharmaceutical dosage is spironolactone, and content is 20～80mg; The stanin fat-reducing medicament of described pharmaceutical dosage is atorvastatin, and content is 10～80mg; Described folacin compound is folic acid, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the diuretic of described pharmaceutical dosage is spironolactone, and content is 20～80mg; The stanin fat-reducing medicament of described pharmaceutical dosage is simvastatin, and content is 5～40mg; Described folacin compound is folic acid, and content is 0.2～1.6mg, preferred 0.2～1.0mg.
According to the present invention, the diuretic of described pharmaceutical dosage is spironolactone, and content is 20～80mg; The stanin fat-reducing medicament of described pharmaceutical dosage is Pitavastatin, and content is 1～4mg; Described folacin compound is 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 complicated dyslipidemia, emphatically for target-organ protection and the dangerous aspect of reduction cardiocerebrovasculaevents events.The target organ damage that the hypertension complicated dyslipidemia causes comprises left ventricular hypertrophy, benign arteriolar nephrosclerosis disease, 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 cardiocerebrovasculaevents events, cardiocerebrovasculaevents events 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 complicated dyslipidemia patient's main purpose is to reduce to greatest extent the death of cardiovascular and cerebrovascular disease and invalid total danger, and target-organ protection and blood pressure lowering develop simultaneously, and are the cores of hypertension complicated dyslipidemia treatment.
The research discovery, pharmaceutical composition provided by the invention not only has decompression lipid-lowering effect and also has target organ protection function; When diuretic, 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 diuretic/folic acid bigeminy compound hypertension medicine, also be better than alone diuretic, difference all has statistical significance.When diuretic, stanin fat-reducing medicament and folacin compound are share, can work in coordination with blood fat reducing, and its synergism is better than only uses stanin fat-reducing medicament/folic acid bigeminy compound hypertension medicine, also is better than alone stanin fat-reducing medicament, and difference all has statistical significance.
When diuretic, 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 diuretic/stanin fat-reducing medicament bigeminy compound hypertension medicine, also is better than alone folacin compound, and difference all has statistical significance.
Further, in experiment, we find, when diuretic, stanin fat-reducing medicament and folacin compound are share, can collaboratively reduce cardiocerebrovasculaevents events dangerous, and effect is better than only uses diuretic/stanin fat-reducing medicament bigeminy compound hypertension medicine, also is better than alone 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 diuretic, pharmaceutical dosage of above-mentioned pharmaceutical dosage and pharmaceutical dosage forms for the preparation of prevention, treat or delay purposes in the medicine of hypertension complicated dyslipidemia.
The present invention also provide aforementioned pharmaceutical compositions for the preparation of prevention, treat or delay the purposes in the medicine of the target organ damage that the hypertension complicated dyslipidemia causes.The target organ damage that the hypertension complicated dyslipidemia causes, refer to because the secondary lesion of the organs such as the heart that hypertension and/or dyslipidemia cause, brain, kidney, eye comprises apoplexy, atherosclerosis, coronary heart disease, left ventricular hypertrophy, angina pectoris, myocardial infarction, acute coronary syndrome, Heart function fails, benign arteriolar nephrosclerosis disease, heart failure, arrhythmia, primary cardiac all standing, renal hypofunction, pernicious arteriolar nephrosclerosis, peripheral arterial disease, retinal arteriosclerosis or hypertension retinopathy.
The present invention also provides the purposes of aforementioned pharmaceutical compositions in the medicine of the cardiocerebrovasculaevents events danger that causes for the preparation of reduction hypertension complicated dyslipidemia.Wherein reduce cardiocerebrovasculaevents events danger and refer to reduce 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 such 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, the dosage form such as membrane or patch, wherein preferred tablet, capsule or granule.
According to the present invention, pharmaceutical composition also can refer to contain the medicine box of two or three independent medicines.When " pharmaceutical composition " referred to contain the medicine box of 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 diuretic and stanin fat-reducing medicament in first medicine, contain folacin compound in second medicine.When " pharmaceutical composition " referred to contain the medicine box of 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 diuretic 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 same 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 Human Umbilical Vein Endothelial Cells function that the folacin compound of the stanin fat-reducing medicament of diuretic, pharmaceutical dosage of pharmaceutical dosage and pharmaceutical dosage forms has protective effect and lipoid peroxidization resistant, and effect is better than diuretic/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 diuretic/stanin fat-reducing medicament bigeminy medication; Aspect the target organ heart, myocardial collagen fraction by volume (CVF) and collagen volume fraction (PVCA) represent respectively two kinds of principal modes---the lesion degree of interstitial fibrosis and perivascular fibrosis of myocardial fibrosis pathological changes, 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 such 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 diuretic/stanin fat-reducing medicament bigeminy medication; Aspect the target organ kidney, the curative effect of pharmaceutical composition provided by the invention is better than diuretic/stanin fat-reducing medicament bigeminy medication 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 continuous, and is consistent, and is independent of other risk factor, and blood pressure is higher, and the danger of occurrence of stroke, heart failure, myocardial infarction and nephropathy is just larger; Dyslipidemia also has the similar feature of this class.Therefore reduce cardiocerebrovasculaevents events danger, have important clinical significance for the treatment of hypertension complicated dyslipidemia.The treatment of the diseases such as " cardiocerebrovasculaevents events is dangerous " and above-mentioned target organ damage is distinguishing.So-called " cardiocerebrovasculaevents events is dangerous " refers to that an individual patients is with respect to the risk of whole crowd's generation cardiovascular and cerebrovascular disease.Nearly more than ten years, in the cardiovascular and cerebrovascular disease research field, " reducing cardiocerebrovasculaevents events dangerous " 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 diuretic of pharmaceutical dosage provided by the invention, the stanin fat-reducing medicament of pharmaceutical dosage and pharmaceutical dosage forms has obvious synergism aspect the reduction incidence of stroke, and its effect significantly is better than the effect that diuretic/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 incidence of stroke 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 diuretic and stanin fat-reducing medicament.Therefore, be significantly improved meaning for prior art.
In view of the beneficial effect of above-mentioned cooperative effect in clinical, the present invention also provide pharmaceutical composition that the folacin compound of the stanin fat-reducing medicament of diuretic, pharmaceutical dosage of above-mentioned pharmaceutical dosage and pharmaceutical dosage forms for the preparation of prevention, treat or delay purposes in the medicine of hypertension complicated dyslipidemia, target organ damage that the hypertension complicated dyslipidemia causes or hypertension complicated dyslipidemia relevant disease; The present invention also provides aforementioned pharmaceutical compositions for the preparation of the purposes in the medicine that reduces cardiocerebrovasculaevents events danger.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient 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: hydrochlorothiazide+atorvastatin+folic acid is to the target organ protection function of hypertension complicated dyslipidemia rat
1. prepare the composite model animal
SD rat, adaptability are fed and begin test after 5 days.Carry out the antioxidant operation, preparation 2K1C hypertension model animal.After raising for 6 weeks, measure rat blood pressure (measuring three times averages), be considered as the model success such as blood pressure＞140mmHg, model group begins gavage fat milk (cholesterol 10g every day, propylene glycol 20ml, cholate 2g, tween 80 20ml, propylthiouracil 1g, Oleum Arachidis hypogaeae semen 20ml, sucrose 20g, adding distil water is to 200ml after the dissolving) 10ml/kg and freely drink water (containing 1% methionine), the gavage fat milk after 4 weeks (filling with rear blood pressures of repetition measurement of 2 weeks of fat milk) rat fasting 10h eye socket is taken a blood sample places the EDTA anticoagulant tube, 4000prm, centrifugal 10 minutes, separated plasma was measured TC (T-CHOL) and TG (triglyceride).
In above-mentioned animal pattern, choose the administration of dividing into groups of hypertension complicated dyslipidemia animal, 16 weeks of administration time.
2. observation index
2.1 blood pressure: reach 8 weeks of administration before the administration, respectively measure blood pressure 16 weeks one time, observe medication to the impact of 2K1C hypertension complicated 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.Intrarenal small artery is observed through abdominal aortic cannulation, 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.Choose the intrarenal small artery that external diameter is 50～100 μ m under the optical microscope, measure intrarenal small artery internal diameter, wall thickness, 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 atherosclerotic plaques with image analytical method.
Measurement data represents with x ± s, and data statistics is processed and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
3. experimental result
3.1 hydrochlorothiazide+atorvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat blood pressure
Model group and normal rats compare, and systolic pressure continues significantly to raise (P＜0.01); Administration is front except Normal group, other respectively organize the blood pressure level zero difference, each administration group and model group are relatively after the administration, hydrochlorothiazide folk prescription group, hydrochlorothiazide+atorvastatin compound recipe group and three joint group systolic pressures all can effectively descend, and hydrochlorothiazide+atorvastatin compound recipe group hypotensive effect is more obvious than the effect of folk prescription group; Hydrochlorothiazide+atorvastatin+folic acid (1.25+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 1 for details.
Table 1 hydrochlorothiazide+atorvastatin+folic acid is on the impact (X ± SD n) of hypertension complicated dyslipidemia rat systolic pressure (mmHg)
Annotate: compare with matched group,
*P＜001; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with hydrochlorothiazide 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 hydrochlorothiazide+atorvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat on 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 are relatively after the administration, atorvastatin folk prescription group, hydrochlorothiazide+atorvastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively descend, and hydrochlorothiazide+atorvastatin compound recipe group hypoglycemic lipid-lowering effect is more obvious than the effect of folk prescription group; Hydrochlorothiazide+atorvastatin+folic acid (1.25+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 hydrochlorothiazide+atorvastatin+folic acid is on the impact of hypertension complicated 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 hydrochlorothiazide 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 hydrochlorothiazide+atorvastatin+folic acid is on hypertension complicated dyslipidemia rat endotheliocyte and anti-oxidation function impact
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 are relatively, hydrochlorothiazide folk prescription group, atorvastatin folk prescription group, hydrochlorothiazide+atorvastatin compound recipe group and three joint group index of correlation levels all can effectively be regulated, and hydrochlorothiazide+atorvastatin compound recipe group regulating action is more obvious than the effect of folk prescription group; Hydrochlorothiazide+atorvastatin+folic acid (1.25+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 hydrochlorothiazide+atorvastatin+folic acid is on the impact of hypertension complicated 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 hydrochlorothiazide folk prescription group,
@P＜0.05,
@@P＜0.01; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.4 hydrochlorothiazide+atorvastatin+folic acid is on the impact of cardiorenal function
Model group and normal rats compare, collagen content, 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, hydrochlorothiazide+atorvastatin compound recipe group and three joint group cardiorenal functions all can effectively be regulated, and hydrochlorothiazide+atorvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Hydrochlorothiazide+atorvastatin+folic acid (1.25+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 4 for details.
Table 4 hydrochlorothiazide+atorvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat heart renal 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 hydrochlorothiazide folk prescription group,
@P＜0.05,
@@P＜0.01; Compare with atorvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.5 hydrochlorothiazide+atorvastatin+folic acid is on the impact of 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, hydrochlorothiazide+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 hydrochlorothiazide+atorvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Hydrochlorothiazide+atorvastatin+folic acid (1.25+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 for details.
Table 5 hydrochlorothiazide+atorvastatin+folic acid is on the impact of hypertension complicated dyslipidemia atherosclerosis plaque in rat area (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
*P＜0.01; Compare with hydrochlorothiazide 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: indopamide+simvastatin+folic acid is to the target organ protection function of hypertension complicated dyslipidemia rat
1. prepare the composite model animal
SD rat, adaptability are fed and begin test after 5 days.Carry out the antioxidant operation, preparation 2K1C hypertension model animal.After raising for 6 weeks, measure rat blood pressure (measuring three times averages), be considered as the model success such as blood pressure＞140mmHg, model group begins gavage fat milk (cholesterol 10g every day, propylene glycol 20ml, cholate 2g, tween 80 20ml, propylthiouracil 1g, Oleum Arachidis hypogaeae semen 20ml, sucrose 20g, adding distil water is to 200ml after the dissolving) 10ml/kg and freely drink water (containing 1% methionine), the gavage fat milk after 4 weeks (filling with rear blood pressures of repetition measurement of 2 weeks of fat milk) rat fasting 10h eye socket is taken a blood sample places the EDTA anticoagulant tube, 4000prm, centrifugal 10 minutes, separated plasma was measured TC (T-CHOL) and TG (triglyceride).
In above-mentioned animal pattern, choose the administration of dividing into groups of hypertension complicated dyslipidemia animal, 16 weeks of administration time.
2. observation index
2.1 blood pressure: reach 8 weeks of administration before the administration, respectively measure blood pressure 16 weeks one time, observe medication to the impact of 2K1C hypertension complicated 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.Intrarenal small artery is observed through abdominal aortic cannulation, 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.Choose the intrarenal small artery that external diameter is 50～100 μ m under the optical microscope, measure intrarenal small artery internal diameter, wall thickness, 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 atherosclerotic plaques with image analytical method.
Measurement data represents with x ± s, and data statistics is processed and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
3. experimental result
3.1 indopamide+simvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat blood pressure
Model group and normal rats compare, and systolic pressure continues significantly to raise (P＜0.01); Administration is front except Normal group, other respectively organize the blood pressure level zero difference, each administration group and model group are relatively after the administration, indopamide folk prescription group, indopamide+simvastatin compound recipe group and three joint group systolic pressures all can effectively descend, and indopamide+simvastatin compound recipe group hypotensive effect is more obvious than the effect of folk prescription group; Indopamide+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 6 indopamide+simvastatin+folic acid is to hypertension complicated dyslipidemia rat
The impact of systolic pressure (mmHg) (X ± SD n)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲ ▲P＜0.01; Compare with indopamide folk prescription group,
@P＜0.05; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.2 indopamide+simvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat on 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, simvastatin folk prescription group, and indopamide+simvastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively descend, and indopamide+simvastatin compound recipe group hypoglycemic lipid-lowering effect is more obvious than the effect of folk prescription group; Indopamide+simvastatin+folic acid (0.25+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).See table 7 for details.
Table 7 indopamide+simvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat blood sugar and blood fat (X ± SD)
Annotate: compare with matched group,
*P＜0.05,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with indopamide folk prescription group,
@P＜0.05; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.3 indopamide+simvastatin+folic acid is on hypertension complicated dyslipidemia rat endotheliocyte and anti-oxidation function impact
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, simvastatin folk prescription group, and indopamide+simvastatin compound recipe group and three joint group index of correlation levels all can effectively be adjusted, and indopamide+simvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Indopamide+simvastatin+folic acid (0.25+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 8 for details.
Table 8 indopamide+simvastatin+folic acid is on the impact of hypertension complicated 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 indopamide folk prescription group,
@P＜0.05,
@@P＜0.01; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.4 indopamide+simvastatin+folic acid is on the impact of cardiorenal function
Model group and normal rats compare, collagen content, urine protein content and 24h α
1-microglobulin all obviously raises, clearance rate obviously descend (P＜0.01); Indopamide folk prescription group after the administration, simvastatin folk prescription group, indopamide+simvastatin compound recipe group and three joint group cardiorenal functions all can effectively be regulated, and indopamide+simvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Indopamide+simvastatin+folic acid (0.25+1.0+0.0gmg/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 9 for details.
Table 9 indopamide+simvastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat heart renal 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 indopamide folk prescription group,
@P＜0.05; Compare with simvastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.5 indopamide+simvastatin+folic acid is on the impact 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, simvastatin folk prescription group, indopamide+simvastatin 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 indopamide+simvastatin compound recipe group effect is more obvious than the effect of folk prescription group; Indopamide+simvastatin+folic acid (0.25+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).See table 10 for details.
Table 10 indopamide+simvastatin+folic acid is on the impact of hypertension complicated dyslipidemia atherosclerosis plaque in rat area (X ± SD)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
*P＜0.01; Compare with indopamide folk prescription group,
@@P＜0.01; With simvastatin folk prescription group
Relatively,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
Embodiment 3: spironolactone+Pitavastatin+folic acid is to the target organ protection function of hypertension complicated dyslipidemia rat
1. prepare the composite model animal
SD rat, adaptability are fed and begin test after 5 days.Carry out the antioxidant operation, preparation 2K1C hypertension model animal.After raising for 6 weeks, measure rat blood pressure (measuring three times averages), be considered as the model success such as blood pressure＞140mmHg, model group begins gavage fat milk (cholesterol 10g every day, propylene glycol 20ml, cholate 2g, tween 80 20ml, propylthiouracil 1g, Oleum Arachidis hypogaeae semen 20ml, sucrose 20g, adding distil water is to 200ml after the dissolving) 10ml/kg and freely drink water (containing 1% methionine), the gavage fat milk after 4 weeks (filling with rear blood pressures of repetition measurement of 2 weeks of fat milk) rat fasting 10h eye socket is taken a blood sample places the EDTA anticoagulant tube, 4000prm, centrifugal 10 minutes, separated plasma was measured TC (T-CHOL) and TG (triglyceride).
In above-mentioned animal pattern, choose the administration of dividing into groups of hypertension complicated dyslipidemia animal, 16 weeks of administration time.
2. observation index
2.1 blood pressure: reach 8 weeks of administration before the administration, respectively measure blood pressure 16 weeks one time, observe medication to the impact of 2K1C hypertension complicated 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.Intrarenal small artery is observed through abdominal aortic cannulation, 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.Choose the intrarenal small artery that external diameter is 50～100 μ m under the optical microscope, measure intrarenal small artery internal diameter, wall thickness, 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 atherosclerotic plaques with image analytical method.
Measurement data represents with x ± s, and data statistics is processed and adopted the SPSS10.0 statistical package, relatively adopts the t check between two groups.
3. experimental result
3.1 spironolactone+Pitavastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat blood pressure
Model group and normal rats compare, and systolic pressure continues significantly to raise (P＜0.01); Administration is front except Normal group, other respectively organize the blood pressure level zero difference, each administration group and model group are relatively after the administration, spironolactone folk prescription group, spironolactone+Pitavastatin compound recipe group and three joint group systolic pressures all can effectively descend, and spironolactone+Pitavastatin compound recipe group hypotensive effect is more obvious than the effect of folk prescription group; Spironolactone+Pitavastatin+folic acid (2+0.4+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 11 for details.
Table 11 spironolactone+Pitavastatin+folic acid is to hypertension complicated dyslipidemia rat
The impact of systolic pressure (mmHg) (X ± SD n)
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01; Compare with spironolactone folk prescription group,
@P＜0.05; Compare with Pitavastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.2 spironolactone+Pitavastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat on 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, Pitavastatin folk prescription group, and spironolactone+Pitavastatin compound recipe group and three joint group blood glucose and blood lipid level all can effectively descend, and spironolactone+Pitavastatin compound recipe group hypoglycemic lipid-lowering effect is more obvious than the effect of folk prescription group; Spironolactone+Pitavastatin+folic acid (1.25+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 12 for details.
Table 12 spironolactone+Pitavastatin+folic acid is on the impact of hypertension complicated 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 spironolactone folk prescription group,
@P＜0.05; Compare with Pitavastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.3 spironolactone+Pitavastatin+folic acid is on hypertension complicated dyslipidemia rat endotheliocyte and anti-oxidation function impact
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, Pitavastatin folk prescription group, and spironolactone+Pitavastatin compound recipe group and three joint group index of correlation levels all can effectively be adjusted, and spironolactone+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group; Spironolactone+Pitavastatin+folic acid (1.25+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 13 for details.
Table 13 spironolactone+Pitavastatin+folic acid is on the impact of hypertension complicated 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 spironolactone folk prescription group,
@P＜0.05,
@@P＜0.05; Compare with Pitavastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.4 spironolactone+Pitavastatin+folic acid is on the impact of cardiorenal function
Model group and normal rats compare, collagen content, urine protein content and 24h α
1-microglobulin all obviously raises, clearance rate obviously descend (P＜0.01); Pitavastatin folk prescription group after the administration, spironolactone+Pitavastatin compound recipe group and three joint group cardiorenal functions all can effectively be regulated, and spironolactone+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group; Spironolactone+Pitavastatin+folic acid (1.25+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 14 for details.
Table 14 spironolactone+Pitavastatin+folic acid is on the impact of hypertension complicated dyslipidemia rat heart renal 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 spironolactone folk prescription group,
@P＜0.05; Compare with Pitavastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
3.5 spironolactone+Pitavastatin+folic acid is on the impact 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, Pitavastatin folk prescription group, spironolactone+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 spironolactone+Pitavastatin compound recipe group effect is more obvious than the effect of folk prescription group; Spironolactone+Pitavastatin+folic acid (1.25+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 15 for details.
Table 15 spironolactone+Pitavastatin+folic acid is on the impact (X ± SD n) of hypertension complicated dyslipidemia atherosclerosis plaque in rat area
Annotate: compare with matched group,
*P＜0.01; Administration group and model group compare,
▲ ▲P＜0.01; Compare with spironolactone folk prescription group,
@P＜0.05; Compare with Pitavastatin folk prescription group,
$P＜0.05; Compare with the compound recipe group,
#P＜0.05.
Embodiment 4: the preparation of hydrochlorothiazide 12.5mg/ atorvastatin 10.0mg/ folic acid 0.2mg sheet
Prescription
Hydrochlorothiazide 12.5g
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 hydrochlorothiazide 12.5g, atorvastatin 10g and folic acid 0.2g according to equivalent incremental method mix homogeneously, add carboxymethyl starch sodium 20g, calcium hydrogen phosphate 180g, evenly mix according to the equivalent incremental method, folic acid is dissolved in the binding agent 10% polyvidone aqueous solution, add in right amount soft material processed of binding agent, 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 hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 0.2mg in the compound tablet of making.
Embodiment 5～10: the preparation of the hydrochlorothiazide 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 16 obtains.
Embodiment 11: the preparation of hydrochlorothiazide 12.5mg/ atorvastatin 10.0mg/ calcium folinate 0.4mg sheet
Embodiment 12: the preparation of hydrochlorothiazide 12.5mg/ 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 16 obtains.
Table 16 embodiment 5～15 tablet formulations form
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid tablet that embodiment 5 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide atorvastatin folic acid tablet that embodiment 6 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 1.0mg in the compound recipe hydrochlorothiazide atorvastatin folic acid tablet that embodiment 7 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid tablet that embodiment 8 makes.
Every contains hydrochlorothiazide 25mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid tablet that embodiment 9 makes.
Every contains hydrochlorothiazide 25mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid tablet that embodiment 10 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, calcium folinate 0.4mg in the compound recipe hydrochlorothiazide atorvastatin calcium folinate tablets that embodiment 11 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, levoleucovorin calcium 0.2mg in the compound recipe hydrochlorothiazide atorvastatin levo leucovorin calcium tablet that embodiment 12 makes.
Embodiment 13～19: the preparation of the hydrochlorothiazide 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 17 obtains.
Embodiment 20: the preparation of hydrochlorothiazide 12.5mg/ simvastatin 10.0mg/ calcium folinate 0.4mg sheet
Embodiment 21: the preparation of hydrochlorothiazide 12.5mg/ 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 17 obtains.
Table 17 embodiment 13～21 tablet formulations form
Every contains hydrochlorothiazide 12.5mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 13 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 14 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 15 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 16 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 17 makes.
Every contains hydrochlorothiazide 25mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 18 makes.
Every contains hydrochlorothiazide 25mg, simvastatin 20mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide simvastatin folic acid tablet that embodiment 19 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, calcium folinate 0.4mg in the compound recipe hydrochlorothiazide simvastatin calcium folinate tablets that embodiment 20 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, levoleucovorin calcium 0.2mg in the compound recipe hydrochlorothiazide simvastatin levo leucovorin calcium tablet that embodiment 21 makes.
Embodiment 22～26: the preparation of the hydrochlorothiazide 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 18 obtains.
Embodiment 27: the preparation of hydrochlorothiazide 12.5mg/ Pitavastatin 1.0mg/ calcium folinate 0.4mg sheet
Embodiment 28: the preparation of hydrochlorothiazide 12.5mg/ 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 18 obtains.
Table 18 embodiment 22～28 tablet formulations form
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid tablet that embodiment 22 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid tablet that embodiment 23 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid tablet that embodiment 24 makes.
Every contains hydrochlorothiazide 25mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid tablet that embodiment 25 makes.
Every contains hydrochlorothiazide 25mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid tablet that embodiment 26 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 1mg, calcium folinate 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin calcium folinate tablets that embodiment 27 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 2mg, levoleucovorin calcium 0.2mg in the compound recipe hydrochlorothiazide Pitavastatin levo leucovorin calcium tablet that embodiment 28 makes.
Embodiment 29～33: the preparation of the indopamide 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 19 obtains.
Embodiment 34～38: the preparation of the indopamide 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 19 obtains.
Embodiment 39～43: the preparation of the indopamide 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 19 obtains.
Table 19 embodiment 29～43 tablet formulations form
Every contains indopamide 2.5mg, atorvastatin 10mg, folic acid 0.2mg in the compound recipe indopamide atorvastatin folic acid tablet that embodiment 29 makes.
Every contains indopamide 2.5mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe indopamide atorvastatin folic acid tablet that embodiment 30 makes.
Every contains indopamide 2.5mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe indopamide atorvastatin folic acid tablet that embodiment 31 makes.
Every contains indopamide 2.5mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe indopamide atorvastatin folic acid tablet that embodiment 32 makes.
Every contains indopamide 2.5mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe indopamide atorvastatin folic acid tablet that embodiment 33 makes.
Every contains indopamide 2.5mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe indopamide simvastatin folic acid tablet that embodiment 34 makes.
Every contains indopamide 2.5mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe indopamide simvastatin folic acid tablet that embodiment 35 makes.
Every contains indopamide 2.5mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe indopamide simvastatin folic acid tablet that embodiment 36 makes.
Every contains indopamide 2.5mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe indopamide simvastatin folic acid tablet that embodiment 37 makes.
Every contains indopamide 2.5mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe indopamide simvastatin folic acid tablet that embodiment 38 makes.
Every contains indopamide 2.5mg, Pitavastatin 1mg, folic acid 0.2mg in the compound recipe indopamide Pitavastatin folic acid tablet that embodiment 39 makes.
Every contains indopamide 2.5mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe indopamide Pitavastatin folic acid tablet that embodiment 40 makes.
Every contains indopamide 2.5mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe indopamide Pitavastatin folic acid tablet that embodiment 41 makes.
Every contains indopamide 2.5mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe indopamide Pitavastatin folic acid tablet that embodiment 42 makes.
Every contains indopamide 2.5mg, Pitavastatin 2mg, folic acid 0.8mg in the compound recipe indopamide Pitavastatin folic acid tablet that embodiment 43 makes.
Embodiment 44～52: the preparation of the spironolactone 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 20 obtains.
Table 20 embodiment 44～52 tablet formulations form
Every contains spironolactone 20mg, atorvastatin 5mg, folic acid 0.4mg in the Compound Spironolactone atorvastatin folic acid tablet that embodiment 44 makes.
Every contains spironolactone 20mg, atorvastatin 10mg, folic acid 0.4mg in the Compound Spironolactone atorvastatin folic acid tablet that embodiment 45 makes.
Every contains spironolactone 20mg, atorvastatin 10mg, folic acid 0.8mg in the Compound Spironolactone atorvastatin folic acid tablet that embodiment 46 makes.
Every contains spironolactone 20mg, atorvastatin 20mg, folic acid 0.4mg in the Compound Spironolactone atorvastatin folic acid tablet that embodiment 47 makes.
Every contains spironolactone 20mg, simvastatin 5mg, folic acid 0.4mg in the Compound Spironolactone simvastatin folic acid tablet that embodiment 48 makes.
Every contains spironolactone 20mg, simvastatin 10mg, folic acid 0.4mg in the Compound Spironolactone simvastatin folic acid tablet that embodiment 49 makes.
Every contains spironolactone 20mg, simvastatin 20mg, folic acid 0.4mg in the Compound Spironolactone simvastatin folic acid tablet that embodiment 50 makes.
Every contains spironolactone 20mg, Pitavastatin 1mg, folic acid 0.4mg in the Compound Spironolactone Pitavastatin folic acid tablet that embodiment 51 makes.
Every contains spironolactone 20mg, Pitavastatin 2mg, folic acid 0.4mg in the Compound Spironolactone Pitavastatin folic acid tablet that embodiment 52 makes.
Embodiment 53: the preparation of hydrochlorothiazide 12.5mg/ atorvastatin 10.0mg/ folic acid 0.2mg capsule
Prescription
Hydrochlorothiazide 12.5g
Atorvastatin 10.0g
Folic acid 0.2g
Starch 60.0g
Microcrystalline Cellulose 20.0g
Carboxymethyl starch sodium 20.0g
5% PVPk-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 hydrochlorothiazide 12.5g, atorvastatin 10g, folic acid 0.2g according to equivalent incremental method mix homogeneously, add 60g starch, 20g microcrystalline Cellulose, 20g carboxymethyl starch sodium, evenly mix according to the equivalent incremental method, make soft material with 5% PVPk-30 aqueous solution, 20 mesh sieves are granulated, 60 ℃ of dryings are 2h approximately, 20 mesh sieve granulate, the water content of control granule 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 namely gets 1000 capsules.Note lucifuge in the preparation process.The qualified rear aluminium-plastic bubble plate packing of product inspection keeps in Dark Place.Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 0.2mg in the compound capsule of making.
Embodiment 54～95: the diuretic+stanin fat-reducing medicament of preparation different content proportioning+folacin compound capsule
Preparation method is identical with embodiment 53, makes capsule according to the granule that prescription shown in the table 21 obtains.
Table 21 embodiment 54～95 capsule prescriptions form (unit: gram)
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid capsule that embodiment 54 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide atorvastatin folic acid capsule that embodiment 55 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 10mg, folic acid 1.0mg in the compound recipe hydrochlorothiazide atorvastatin folic acid capsule that embodiment 56 makes.
Every contains hydrochlorothiazide 12.5mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid capsule that embodiment 57 makes.
Every contains hydrochlorothiazide 25mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid capsule that embodiment 58 makes.
Every contains hydrochlorothiazide 25mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide atorvastatin folic acid capsule that embodiment 59 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 60 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 61 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 62 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 63 makes.
Every contains hydrochlorothiazide 12.5mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 64 makes.
Every contains hydrochlorothiazide 25mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 65 makes.
Every contains hydrochlorothiazide 25mg, simvastatin 20mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide simvastatin folic acid capsule that embodiment 66 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid capsule that embodiment 67 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid capsule that embodiment 68 makes.
Every contains hydrochlorothiazide 12.5mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid capsule that embodiment 69 makes.
Every contains hydrochlorothiazide 25mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid capsule that embodiment 70 makes.
Every contains hydrochlorothiazide 25mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe hydrochlorothiazide Pitavastatin folic acid capsule that embodiment 71 makes.
Every contains indopamide 2.5mg, atorvastatin 10mg, folic acid 0.2mg in the compound recipe indopamide atorvastatin folic acid capsule that embodiment 72 makes.
Every contains indopamide 2.5mg, atorvastatin 10mg, folic acid 0.4mg in the compound recipe indopamide atorvastatin folic acid capsule that embodiment 73 makes.
Every contains indopamide 2.5mg, atorvastatin 10mg, folic acid 0.8mg in the compound recipe indopamide atorvastatin folic acid capsule that embodiment 74 makes.
Every contains indopamide 2.5mg, atorvastatin 20mg, folic acid 0.4mg in the compound recipe indopamide atorvastatin folic acid capsule that embodiment 75 makes.
Every contains indopamide 2.5mg, atorvastatin 40mg, folic acid 0.4mg in the compound recipe indopamide atorvastatin folic acid capsule that embodiment 76 makes.
Every contains indopamide 2.5mg, simvastatin 5mg, folic acid 0.4mg in the compound recipe indopamide simvastatin folic acid capsule that embodiment 77 makes.
Every contains indopamide 2.5mg, simvastatin 10mg, folic acid 0.2mg in the compound recipe indopamide simvastatin folic acid capsule that embodiment 78 makes.
Every contains indopamide 2.5mg, simvastatin 10mg, folic acid 0.4mg in the compound recipe indopamide simvastatin folic acid capsule that embodiment 79 makes.
Every contains indopamide 2.5mg, simvastatin 10mg, folic acid 0.8mg in the compound recipe indopamide simvastatin folic acid capsule that embodiment 80 makes.
Every contains indopamide 2.5mg, simvastatin 20mg, folic acid 0.4mg in the compound recipe indopamide simvastatin folic acid capsule that embodiment 81 makes.
Every contains indopamide 2.5mg, Pitavastatin 1mg, folic acid 0.2mg in the compound recipe indopamide Pitavastatin folic acid capsule that embodiment 82 makes.
Every contains indopamide 2.5mg, Pitavastatin 1mg, folic acid 0.4mg in the compound recipe indopamide Pitavastatin folic acid capsule that embodiment 83 makes.
Every contains indopamide 2.5mg, Pitavastatin 1mg, folic acid 0.8mg in the compound recipe indopamide Pitavastatin folic acid capsule that embodiment 84 makes.
Every contains indopamide 2.5mg, Pitavastatin 2mg, folic acid 0.4mg in the compound recipe indopamide Pitavastatin folic acid capsule that embodiment 85 makes.
Every contains indopamide 2.5mg, Pitavastatin 2mg, folic acid 0.8mg in the compound recipe indopamide Pitavastatin folic acid capsule that embodiment 86 makes.
Every contains spironolactone 20mg, atorvastatin 5mg, folic acid 0.4mg in the Compound Spironolactone atorvastatin folic acid capsule that embodiment 87 makes.
Every contains spironolactone 20mg, atorvastatin 10mg, folic acid 0.4mg in the Compound Spironolactone atorvastatin folic acid capsule that embodiment 88 makes.
Every contains spironolactone 20mg, atorvastatin 10mg, folic acid 0.8mg in the Compound Spironolactone atorvastatin folic acid capsule that embodiment 89 makes.
Every contains spironolactone 20mg, atorvastatin 20mg, folic acid 0.4mg in the Compound Spironolactone atorvastatin folic acid capsule that embodiment 90 makes.
Every contains spironolactone 20mg, simvastatin 5mg, folic acid 0.4mg in the Compound Spironolactone simvastatin folic acid capsule that embodiment 91 makes.
Every contains spironolactone 20mg, simvastatin 10mg, folic acid 0.4mg in the Compound Spironolactone simvastatin folic acid capsule that embodiment 92 makes.
Every contains spironolactone 20mg, simvastatin 20mg, folic acid 0.4mg in the Compound Spironolactone simvastatin folic acid capsule that embodiment 93 makes.
Every contains spironolactone 20mg, Pitavastatin 1mg, folic acid 0.4mg in the Compound Spironolactone Pitavastatin folic acid capsule that embodiment 94 makes.
Every contains spironolactone 20mg, Pitavastatin 2mg, folic acid 0.4mg in the Compound Spironolactone Pitavastatin folic acid capsule that embodiment 95 makes.
Claims (6)
1. pharmaceutical composition, constituent is:
The indopamide of (1) 2.5～5mg;
The simvastatin of (2) 5～40mg;
The folic acid of (3) 0.2～1.0mg; And
(4) acceptable carrier on the pharmaceutics.
2. the pharmaceutical composition described in the claim 1 is characterized in that the pharmacy dosage form of described pharmaceutical composition is oral formulations, comprises tablet, capsule or granule.
Pharmaceutical composition described in the claim 1 for the preparation of prevention, treat or delay purposes in the medicine of hypertension complicated dyslipidemia.
Pharmaceutical composition described in the claim 1 for the preparation of prevention, treat or delay the purposes in the medicine of the target organ damage that the hypertension complicated dyslipidemia causes.
5. purposes claimed in claim 4, it is characterized in that: the target organ damage that described hypertension complicated dyslipidemia causes is apoplexy.
6. the pharmaceutical composition described in the claim 1 is for the preparation of the purposes in the medicine of the incidence rate that reduces low apoplexy.
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| CN103599537A (en) * | 2013-11-15 | 2014-02-26 | 深圳奥萨医药有限公司 | Pharmaceutical composition of calcium channel blocker/thiazide diuretic/5-methyltetrahydrofolate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001076632A1 (en) * | 2000-04-10 | 2001-10-18 | Wald Nicholas J | Formulation for the prevention of cardiovascular disease |
| US20050008970A1 (en) * | 2003-07-07 | 2005-01-13 | Yasuhito Oshima | Lithographic printing plate precursor and lithographic printing method using the same |
| WO2005011586A2 (en) * | 2003-07-28 | 2005-02-10 | Dr. Reddy's Laboratories, Inc. | Treatment and preventi0n of cardiovascular events |
| WO2005063761A1 (en) * | 2003-12-19 | 2005-07-14 | Bristol-Myers Squibb Company | Azabicyclic heterocycles as cannabinoid receptor modulators |
| WO2006135480A2 (en) * | 2005-04-08 | 2006-12-21 | Abbott Laboratories | Oral pharmaceutical formulations comprising fenofibric acid and/or its salts |
| WO2007004236A2 (en) * | 2005-07-04 | 2007-01-11 | Ramu Krishnan | Improved drug or pharmaceutical compounds and a preparation thereof |
-
2008
- 2008-05-30 CN CN 200810114222 patent/CN101590239B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001076632A1 (en) * | 2000-04-10 | 2001-10-18 | Wald Nicholas J | Formulation for the prevention of cardiovascular disease |
| US20050008970A1 (en) * | 2003-07-07 | 2005-01-13 | Yasuhito Oshima | Lithographic printing plate precursor and lithographic printing method using the same |
| WO2005011586A2 (en) * | 2003-07-28 | 2005-02-10 | Dr. Reddy's Laboratories, Inc. | Treatment and preventi0n of cardiovascular events |
| WO2005063761A1 (en) * | 2003-12-19 | 2005-07-14 | Bristol-Myers Squibb Company | Azabicyclic heterocycles as cannabinoid receptor modulators |
| WO2006135480A2 (en) * | 2005-04-08 | 2006-12-21 | Abbott Laboratories | Oral pharmaceutical formulations comprising fenofibric acid and/or its salts |
| WO2007004236A2 (en) * | 2005-07-04 | 2007-01-11 | Ramu Krishnan | Improved drug or pharmaceutical compounds and a preparation thereof |
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