CN101897710A - Medicament composition containing HMG-CoA reductase inhibitor, aspirin and folic acid and application thereof - Google Patents
Medicament composition containing HMG-CoA reductase inhibitor, aspirin and folic acid and application thereof Download PDFInfo
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Abstract
The invention relates to a fat-lowering medicament composition with synergy and application thereof. The fat-lowering medicament composition comprises an HMG-CoA reductase inhibitor with medicinal content, aspirin, folic acid or calcium folinate or levocalcium folinate and a pharmaceutically acceptable carrier. The medicament composition has pharmacological synergetic treatment effect which is shown in lowering blood fat, preventing and curing atherosclerosis and reducing a cardiovascular and cerebrovascular event risk. The invention also provides the application of the medicament composition to preparing a medicament for lowering the blood fat, preventing and curing the atherosclerosis and reducing the cardiovascular and cerebrovascular event risk. By applying the invention, the medicament composition with specific application, which is provided for a patient, can improve the compliance of the patient, is convenient for the patient to take medicines, reduces the medical expense and has more favorable market prospect.
Description
Technical field
The present invention relates to the medical composition and its use of a kind of 3-of containing hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, aspirin, folic acid.The invention belongs to pharmaceutical field.
Background technology
Cardiovascular disease is one of human main causes of death, comprising coronary heart disease (myocardial infarction) and apoplexy (being commonly called as apoplexy).The sickness rate of China's cardiovascular disease and case fatality rate were ascendant trend gradually in nearly 20 years, and its major reason is that the initiation potential factor is constantly increasing.These risk factors comprise dyslipidemia, atherosclerosis, hypertension, smoking, drink etc.Therefore, the rising that reduces various controllable risk factors or prevention risk factor is to prevent and reduce key such as cardiovascular disease such as coronary heart disease, apoplexy.
85% coronary heart disease is owing to coronary atherosclerosis causes, and atherosclerosis is directly related with dyslipidemia (lipidosis), even therefore effective blood fat reducing can delay the de-rotation pulse atherosclerosis.One or more levels that dyslipidemia shows as in triglyceride in the blood (TG), T-CHOL (TC), the low-density lipoprotein cholesterol (LDL-C) raise or HDL-C (HDL-C) level reduction (it is one of independent hazard factor of coronary heart disease that HDL-C reduces).Clinical research shows, reduce serum TC and LDL-C level with simvastatin or pravastatin, not only can reduce the coronary event incidence rate and reach 30%～40%, and reduce total case fatality rate and reach 22%～30%, and reduce and do the incidence rate that the coronary artery intracavity forms art and apoplexy.
Secular hyperlipidemia state also can produce induration to cells of vascular wall film and hemocyte film, mobility of erythrocyte membrance is reduced, erythrocyte deformability descends, thereby microcirculation blood stasis, slack-off, the blood viscosity increase (hemorheology is unusual) of blood flow, be easy to form thrombosis, the danger that embolic cardiovascular and cerebrovascular vessel incident is taken place increases.In addition, lipid components and content also influence the stability of speckle in the atheromatous plaque, and lipid also influences thrombin and fibrinolytic system.Therefore, use anticoagulant or other improves the generation that hemorheological measure helps preventing embolic diseases such as myocardial infarction, apoplexy.
Atorvastatin, pravastatin, statins antilipemic drugs such as simvastatin belong to the HMG-CoA reductase inhibitor, hydrolyzate after the oral absorption suppresses the rate-limiting enzyme hydroxyl first glutaryl CoA reductase in the cholesterol building-up process in vivo competitively, make the synthetic minimizing of cholesterol, also make the synthetic increase of low density lipoprotein receptor, main site of action is at liver, the result reduces blood TC and LDL-C level, moderate reduces blood TG level and increases the HDL-C level, be used for the treatment of hypercholesterolemia and combined hyperlipidemia familial clinically, also be used for the prevention of coronary heart disease and apoplexy.HMG-CoA reductase inhibitor class medicine can also reduce the LDL-C in the speckle, recovers inner skin cell function, promotes the stability of atheromatous plaque, so the benefit of its treatment is not detected in cholesterol rising patient, also sees the normal patients with coronary heart disease of cholesterol.
Thereby aspirin has anticoagulant suppresses thrombotic pharmacological action.It brings into play this effect by the generation that irreversibly suppresses hematoblastic epoxidase, minimizing prostaglandin.But a little less than the Cycloxygenase effect of aspirin to vascular endothelial cell, to prostacyclin I
2(PGI
2) almost not influence of generation.This is because platelet itself can not the synthesizing epoxy enzyme, and when the epoxidase activity was suppressed, must treat that newborn platelet enters could continue to synthesize thromboxane A in the blood circulation
2, and vascular endothelial cell has the ability of synthesizing epoxy enzyme, only suppresses the oxidasic activity of platelet internal ring so use the aspirin of low dosage, is used for prevention and treatment of diseases such as angina pectoris, myocardial infarction clinically.When aspirin was used for the secondary prevention of coronary heart disease, recommended dose is in 50mg～325mg scope, and was wherein comparatively commonly used with 50～150mg again.
The two approved of atorvastatin and aspirin is used for the secondary prevention of heart disease.The result that the open data of issuing are carried out the meta analysis shows that pravastatin and aspirin have complementary enlarge-effect in the secondary prevention of cardiovascular disease.The use in conjunction that research worker is found above-mentioned two kinds of medicines and independent application aspirin with use pravastatin separately and compare, the danger of myocardial infarction reduces by 31% and 26% respectively, the danger of Ischemic Stroke correspondingly reduces by 29% and 31% respectively.
Folic acid belongs to vitamin B group, is nucleic acid, cell growth and the necessary element of tissue repair.Discovering in recent years, (homocysteine Hcy) reduces the cardiovascular event occurrence risk by reducing homocysteine in the blood for it.This R﹠D team has delivered clinical test results meta-analysis (the Wang X that existing 8 report folic acid is prevented cardiovascular events, reduction apoplexy risk at " The Lancet (lancet) " magazine in June, 2007, et al.Efficacy of folic acidsupplementation in stroke prevention:a meta-analysis.Lancet, 2007,369:1876).The result shows that Supplement of folic acid can reduce apoplexy risk 18% (p＜0.05).When being used for primary prevention, folic acid reduces apoplexy risk 25%; When being applied to not accept to add the crowd of folic acid in the food, Supplement of folic acid reduces apoplexy risk 25%; When Supplement of folic acid can reduce Plasma Hcy 20% when above, it reduces apoplexy risk and reaches 23%; And when the Supplement of folic acid curative effect surpassed 3 years, it reduced the apoplexy risk and reaches 29%.
The new drug development pattern that is combined as target with the research cooperative drug starts from 2000 in the world.The research and development company that a family specializes in " cooperative drug combination " has been set up in Harvard University and Massachusetts Institute of Technology's cooperation, and develops azithromycin+chloroquine treatment malaria, chlorpromazine+novel composing prescription medicines such as pentane miaow treatment pulmonary carcinoma, obtains very ten-strike.For remedying the deficiency of noval chemical compound research and development, the U.S., European Union, Japan and Australia have all put into effect the basic principle about the compound medicine research and development in succession, i.e. potentiation, and attenuation improves compliance.2003, professor Wald of London University also proposed the notion of multiple-effect pill (Polypill), promptly in a pill, mix three kinds or more the multiple medicines thing come angiocardiopathy preventing, it is evaluated as " one of most important discovery over 50 years " by BMJ.2004, compound drug " Caduet " was released in the Pfizer pharmaceutical factory, and it is to be combined by antihypertensive amlodipine and hypolipidemic atorvastatin.
The present invention is intended to exploitation at great public health problem---and cardiovascular and cerebrovascular disease has the compound medicine of better curative effect.The present invention is improved in that polypill is conceptive, forms compound medicine by a kind of HMG-CoA reductase inhibitor+aspirin+folic acid, and indication is a hyperlipemia, also as the primary prevention medication of cardiovascular disease.This three-in-one drug regimen possesses the effect for reducing blood fat of current clinical line medicine the best, and has the effect of anticoagulant, reduction Hcy, thus the treatment hyperlipemia, and reduce the risk that cardiovascular event (as myocardial infarction and apoplexy) takes place.
Scientific basis of the present invention based on following some:
(1) collaborative on the pharmacological mechanism: the HMG-CoA reductase inhibitor by effect for reducing blood fat to atherosclerosis; The aspirin anticoagulant, and platelet all plays an important role to atherosclerosis formation, thrombosis.Therefore, both share the coronary atherosclerotic score piece formed or formed on the basis at speckle has significantly collaborative antagonism to thrombophilia.Aspirin also has tangible antiinflammatory action, and inflammatory reaction also occupies critical role in acute coronary syndrome (being the coronary heart disease emergency case) morbidity.In addition, bibliographical information blood fat reducing treatment can significantly improve patient's aspirin resistance phenomenon [McKee SA, et al.Aspirin resistance in cardiovascular disease:a review of prevalence, mechanisms, and clinical significance.Thromb Haemost, 2002,88:711].In sum, HMG-CoA reductase inhibitor+aspirin prescription has splendid reasonability.Still do not have at present and studies have shown that other antiplatelet drug treatments obviously are better than aspirin.
(2) evidence-based medicine EBM evidence: carried out many famous extensive clinical trials abroad, as WOSCOPS, CARE and LIPID etc., the result proves, compare with independent use, HMG-CoA reductase inhibitor+aspirin can obviously reduce the generation of coronary heart disease clinical events (unstable angina pectoris, myocardial infarction).
(3) Supplement of folic acid reduces the apoplexy risk: the source of evidence is in 1) AHA and apoplexy joint committee common release " about in the ischemic cerebral apoplexy and transient ischemic attack prevention guide " (2006) suggestion patient should strict controlling blood pressure, recommend high Hcy mass formed by blood stasis (Hcy＞10 μ mol/L) patient to take vitamin B6 (1.7mg/d) every day simultaneously, vitamin B12 (2.4 μ g/d) and folic acid (400 μ g/d) are to reduce the Hcy level.2) this R﹠D team prevents the meta-analysis of cardiovascular event, apoplexy occurrence risk what " lancet " magazine was delivered to existing 8 folic acid.3) meet national conditions: increasing folic acid is China's characteristic, because for western-style food, the cooking custom of Chinese meal is destroyed the vitamin in the vegetable easily, the nutriture of rural area population has been compared certain gap with western countries in addition, therefore, there is the potential possibility of folic acid deficiency in China's a big chunk crowd.
(4) drug compliance: the compound recipe form can improve patient's drug compliance, avoids missing.Unite for a long time under the situation of use at the multiple medicine of needs, it is particularly necessary that this point just seems.
Summary of the invention
The deficiency that clinical application exists when the objective of the invention is to overcome at dyslipidemia provides a kind of Antilipidemic pharmaceutical compositions more efficiently, and this active isomer is prevented and treated atherosclerosis now and reduced cardiovascular and cerebrovascular vessel event risk aspect.For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) a kind of in the HMG-CoA reductase inhibitor of medicinal content;
(2) aspirin of medicinal content;
(3) folic acid of medicinal content or calcium folinate or levoleucovorin calcium; With
(4) acceptable carrier on the pharmaceutics.
Wherein " medicinal content " is meant the amount of pharmacological action with collaborative, prevention or treatment.
Further, preferred
(1) a kind of in the HMG-CoA reductase inhibitor of 0.1mg～100mg;
(2) aspirin of 50mg～325mg;
(3) folic acid of 0.1mg～2.0mg or calcium folinate or levoleucovorin calcium; With
(4) acceptable carrier on the pharmaceutics.
Be more preferably
(1) a kind of in the HMG-CoA reductase inhibitor of 1mg～80mg;
(2) aspirin of 50mg～150mg;
(3) folic acid of 0.2mg～2.0mg or calcium folinate or levoleucovorin calcium; With
(4) acceptable carrier on the pharmaceutics.
Wherein, the HMG-CoA reductase inhibitor medicaments is meant that (but being not limited to) atorvastatin (atorvastatin), simvastatin (simvastatin), Pitavastatin (pitavastatin), pravastatin (pravastatin), lovastatin (lovastatin), fluvastatin (fluvastatin), cerivastatin (cerivastatin), Rosuvastatin (rosuvastatin), itavastatin (itavastatin), Buddhist nun cut down a kind of in his spit of fland (nisvastatin), bervastatin (bervastatin), the mevastatin (mevastatin).
In the present invention, atorvastatin content is that 5mg～80mg, simvastatin content are that 5mg～80mg, Pitavastatin content are that 1mg～4mg, lovastatin content are that 5mg～80mg, fluvastatin content are that 5mg～80mg, pravastatin content are that 5mg～80mg, Rosuvastatin content are 5mg～80mg, and the active metabolite of above-mentioned substance or salt content are equal to corresponding above-mentioned substance content.
In the present invention, the content of folic acid or calcium folinate or levoleucovorin calcium more preferably: folic acid 0.4mg～1.6mg, or calcium folinate 0.5mg～2.0mg, or levoleucovorin calcium 0.25mg～1.0mg.
In the pharmaceutical composition provided by the invention, described HMG-CoA reductase inhibitor is an atorvastatin, and content is 5mg～80mg; Aspirin content is 50mg～325mg; Folate content is 0.1mg～2.0mg.
In the pharmaceutical composition provided by the invention, described HMG-CoA reductase inhibitor is a Pitavastatin, and content is 1mg～4mg; Aspirin content is 50mg～325mg; Folate content is 0.1mg～2.0mg.
In the pharmaceutical composition provided by the invention, described HMG-CoA reductase inhibitor is a simvastatin, and content is 5mg～80mg; Aspirin content is 50mg～325mg; Folate content is 0.1mg～2.0mg.
Pharmaceutical composition provided by the invention has the effect of blood fat reducing.
Pharmaceutical composition provided by the invention has the atherosclerotic effect of control, this atherosclerosis can cause the secondary lesion of organs such as the heart, brain, kidney, eye, comprises coronary heart disease, angina pectoris, myocardial infarction, acute coronary syndrome, apoplexy, arteriolar nephrosclerosis, peripheral arterial disease, retinal arteriosclerosis etc.
Pharmaceutical composition provided by the invention also has the effect that reduces the cardiovascular and cerebrovascular vessel event risk, wherein reduces the cardiovascular and cerebrovascular vessel event risk and is meant disease or the high-risk incidence rates of coronary heart disease such as reducing acute coronary syndrome, angina pectoris, myocardial infarction, apoplexy.
● pharmacological evaluation one: atorvastatin+aspirin+folic acid is to blood fat reducing, the antiplatelet aggregative activity of rat
Modeling: 100 of SD rats, male and female half and half, body weight 150～180g sets up rat high blood lipid model [Chen Yuyao by the bibliographical information method, Deng. the foundation of rat hyperlipidemia and fatty liver model. Pharmacology and Clinics of Chinese Materia Medica, 2007,23 (4): 64], promptly feed high fat diet (prescription: cholesterol 2.0% to rat every day, propylthiouracil 0.2%, sodium cholate 0.5%, Adeps Sus domestica 12.0%, common mixed feed meal 85.3%).After 6 weeks, rat tail hematometry blood fat (following) is adopted in sampling, to confirm the modeling success.
Grouping and administration: get 90 of above-mentioned hyperlipemia rats, be divided into 6 groups (15 every group) at random, be divided into model control group (not administration), atorvastatin+aspirin+folic acid (1.0+7.5+0.08mg/kg) group, atorvastatin+aspirin+folic acid (1.0+15+0.08mg/kg) group, atorvastatin+aspirin+folic acid (2.0+7.5+0.08mg/kg) group, atorvastatin+folic acid (1.0+0.08mg/kg) group, aspirin (7.5mg/kg) group by the administration difference, other gets 15 normal rats as the normal control group.When other group gastric infusion, normal group and model group rat wait capacity 0.5% sodium carboxymethyl cellulose (CMC) solution to irritate stomach.In the experimentation, except that normal rats was fed normal diet, all the other were respectively organized rat and continue to feed high lipid food.Each group is weighed weekly once, adjusts dosage, 12 weeks of successive administration according to body weight.
Detect index: get blood after 12 weeks of (1) lipid determination, measure according to the test kit description and survey serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C).(2) platelet aggregation rate, Determination of Blood Rheology are that platelet aggregation derivant (turbidimetry) is measured platelet maximum agglutination rate (PARmax) with ADP with platelet aggregation instrument, measure parameters such as whole blood viscosity, blood plasma viscosity with fully automatic blood rheology instrument.
Statistical method: measurement data is used
Expression, data statistics are handled and are adopted SPSS10.0 statistical package, two means relatively to adopt the t check, relatively adopt variance analysis between many groups.
The result:
(1) atorvastatin+aspirin+folic acid compared with normal rats the 12nd weekend that influenced of rat fat, and model group rat TC, TG, LDL-C significantly raise; With model group relatively, the variant dosage ratio group of atorvastatin+aspirin+folic acid, atorvastatin+folic acid group rat TC, TG, LDL-C all significantly reduce, especially reduction is more remarkable when atorvastatin high dose (2mg/kg); And aspirin group rat TC, TG, LDL-C level do not have significant change.See Table 1.
Table 1 atorvastatin+aspirin+folic acid to the influence of hyperlipemia rat blood fat (X ± SD, n=15)
Annotate: model group and normal group compare, * * P＜0.01; Medication group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01;
(2) atorvastatin+aspirin+folic acid compares rat platelet aggregation, hemorheological influence and normal rats, and model group rat whole blood viscosity, plasma viscosity all significantly raise, and show: hyperlipemia rat presents the change that hemorheological property reduces.Compare with model group, the variant dosage ratio group of atorvastatin+aspirin+folic acid, atorvastatin+folic acid or aspirin group rat whole blood and plasma viscosity all have reduction (seeing Table 2) in various degree, prompting atorvastatin and aspirin all have the effect of the hemorheology of improvement, and effect strengthened when both share.On the other hand, compare with normal rats, model group rat platelet aggregation rate increases; Compare with model group, the variant dosage ratio group of atorvastatin+aspirin+folic acid, single with all reductions in various degree of aspirin group rat platelet aggregation rate, especially this antiplatelet aggregative activity is more remarkable when aspirin high dose (15mg/kg), sees Table 2.
Table 2 atorvastatin+aspirin+folic acid to the influence of hemorheology of rat, platelet aggregation rate (X ± SD, n=15)
Annotate: model group with normal group relatively, * P＜0.05, * * P＜0.01; Medication group and model group compare,
▲P＜0.05,
▲ ▲P＜0.01;
● pharmacological evaluation two: atorvastatin+aspirin+folic acid is to the protective effect of atherosclerotic rat
Modeling: SD rat, male and female half and half, body weight 150～180g, set up rat hyperlipidemia companion Atherosclerosis Model [Wen Jinkun by literature method, Deng. a kind of experimental technique of setting up the atherosis model of rat artery fast. Chinese gerontology magazine, 2001,21 (1): 50], be to feed high lipid food (prescription: cholesterol 1.0% every day, propylthiouracil 0.2%, sodium cholate 0.5%, Adeps Sus domestica 5.0%, methionine 1.0%, normal feedstuff 92.3%).After 12 weeks, rat tail hematometry blood fat is adopted in sampling, kidney small artery pathology is observed, and confirms the modeling success.
Grouping administration: get 90 of hyperlipidemia companion atherosclerotic rat, be divided into 6 groups (15 every group) at random, be divided into model control group (not administration), atorvastatin+aspirin (1.0+7.5mg/kg) group, atorvastatin+aspirin+folic acid (1.0+7.5+0.04mg/kg) group, atorvastatin+aspirin+folic acid (1.0+7.5+0.08mg/kg) group, atorvastatin (1.0mg/kg) group, folic acid (0.08mg/kg) group by the administration difference, other gets 15 normal rats as the normal control group.When other group gastric infusion, normal group and model group rat wait capacity 0.5%CMC solution to irritate stomach.In the experimentation, except that normal rats was fed normal diet, all the other were respectively organized rat and continue to feed high lipid food.Each group is weighed weekly once, adjusts dosage, 20 weeks of successive administration according to body weight.
Detect index: small artery is observed through abdominal aortic cannulation in (1) kidney, 0.1mg/ml behind the abundant blood vessel dilating of sodium nitroprusside, formalin with 10% is poured into fixing under 10～12kPa, separate left kidney, the place cuts kidney from the hilus renalis, place 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) gather the aorta sample, detect aorta lipid plaque area with image analytical method.
Statistical method: measurement data is used
Expression, data statistics are handled and are adopted SPSS10.0 statistical package, two means relatively to adopt the t check, relatively adopt variance analysis between many groups.
The result:
(1) atorvastatin+aspirin+folic acid influences the blood vessel that hyperlipidemia causes rat and changes arteriolar in the kidney of rats, mainly show as the fibrosis of blood vessel wall adventitia, the tube wall middle level thickens (due to being increased by smooth muscle cell proliferation, plumpness and intercellular substance); Inner membrance vitreous degeneration, endotheli ocytosis, above-mentioned variation reduce blood vessel wall thickness/tube chamber ratio.Compare with normal rats, model group kidney of rats small artery wall thickness increases, and internal diameter reduces, and wall thickness/internal diameter is than increasing.Compare with model group, atorvastatin+aspirin group kidney of rats small artery wall thickness reduces, wall thickness/internal diameter ratio reduces, atorvastatin+aspirin+folic acid group kidney of rats small artery wall thickness further reduces, wall thickness/internal diameter reduces than further, with atorvastatin+aspirin group significant difference is arranged relatively.See Table 3.
Table 3 atorvastatin+aspirin+folic acid to arteriolar influence in the hyperlipemia rat kidney (X ± SD, n=15)
Annotate: model group and normal group compare, * * P＜0.01; Each administration group and model group compare,
▲ ▲P＜0.01;
▲P＜0.05
(2) atorvastatin+aspirin+folic acid influences model group aorta wall plaque area average out to 10.2% to what the rat artery atherosclerotic plaque formed; Compare with model group, atorvastatin+aspirin group rat aorta wall plaque area significantly reduces; The aorta plaque area of folic acid group has reduction trend than model group aorta wall plaque area, but there was no significant difference; Compare with atorvastatin+aspirin group, (0.04～0.08mg/kg) group rat aorta wall plaque area has further reduction trend to atorvastatin+aspirin+various dose folic acid.See Table 4.
Table 4 atorvastatin+aspirin+folic acid to the atherosclerotic influence of hyperlipemia rat (X ± SD, n=15)
Annotate: compare * * P＜0.01 with normal group; Compare with model group,
▲P＜0.05,
▲ ▲P＜0.01;
● pharmacological evaluation three: atorvastatin+aspirin+folic acid is to the protective effect of apoplexy susceptible type dyslipidemia rat
Modeling: 8～10 all apoplexy susceptible type spontaneous hypertensive rats in age (SHRsp), respectively available from Shanghai City hypertension institute, Fuwai Hospital's Experimental Animal Center, raising is in room temperature (23 ± 2) ℃, relative humidity (50 ± 10) %, each 12h of illumination light and shade, feed 12 weeks of high lipid food (prescription is with pharmacological evaluation 2).
The grouping administration: SHRsp is divided into model group, atorvastatin+aspirin group (0.5+1mg/kg), atorvastatin+aspirin+folic acid group (0.04mg/kg), and other establishes the normal control group, 28 every group.Gastric infusion is weighed weekly once every day 1 time, adjusts dose, 24 weeks of successive administration according to body weight.
Detect index: observe animal diet followed, survival condition and behavioral activity (1) every day, writes down each treated animal cerebral seizure number.(2) all rats of pathological observation are all got cerebral tissue, and cerebral hemorrhage, cerebral infarction or Combination apoplexy are observed in section, HE dyeing, calculate and respectively organize the rat brain stroke incidence.(3) 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 blood vessels are surveyed in every section.
Statistical method: measurement data is used
Expression, data statistics are handled and are adopted SPSS10.0 statistical package, two means relatively to adopt the t check, relatively adopt variance analysis between many groups.
The result:
(1) in the phase, the model group rat amounts to, and 15 of apoplexy take place the influence that apoplexy susceptible type rat brain apoplexy is taken place of atorvastatin+aspirin+folic acid at experimental observation, and histopathology is observed, amount to 25 of apoplexy take place, 9 of its midbrains hemorrhage, 11 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.Compare with model group, atorvastatin+aspirin group, atorvastatin+aspirin+folic acid group rat brain stroke incidence all significantly reduce.Compare with atorvastatin+aspirin group, atorvastatin+aspirin+folic acid group apoplexy incidence rate further reduces, and prompting folic acid has remarkable effect in the prevention of brain apoplexy.See Table 5.
Table 5 atorvastatin+aspirin+folic acid to the influence of apoplexy susceptible type rat brain apoplexy (X ± SD, n=28)
Annotate: compare * * P＜0.01 with normal group; Compare with model group,
▲ ▲P＜0.01;
Compare #P＜0.05 with atorvastatin+aspirin group
(2) atorvastatin+aspirin+folic acid compares arteriosclerotic influence of apoplexy susceptible type rat brain and normal rats, and 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, atorvastatin+aspirin group rat brain tunica media of artery thickness, media thickness/lumen diameter are than reducing, atorvastatin+aspirin+folic acid group cerebral arteries media thickness, media thickness/lumen diameter relatively have significant difference than further reducing with atorvastatin+aspirin group.See Table 6.
Table 6 amlodipine+atorvastatin+folic acid to the arteriosclerotic influence of apoplexy susceptible type rat brain (X ± SD, n=15)
Annotate: compare * * P＜0.01 with normal group; Compare with model group,
▲P＜0.05,
▲ ▲P＜0.01;
Compare #P＜0.05 with atorvastatin+aspirin group
The dosage form of this pharmaceutical composition 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.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional 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 invention has the beneficial effects as follows:
HMG-CoA reductase inhibitor/aspirin provided by the invention/folic acid three pharmaceutical compositions have the synergism on tangible pharmacology, the pharmacodynamics---blood fat reducing, the danger of preventing and treating atherosclerosis, the generation of reduction cardiovascular and cerebrovascular vessel incident.Above-mentioned pharmacological experiment study shows, during HMG-CoA reductase inhibitor/aspirin/folic acid drug combination, and its blood fat reducing, anticoagulant and improve the hemorheology effect and be better than single HMG-CoA reductase inhibitor medicaments of using; And HMG-CoA reductase inhibitor/aspirin/folic acid three pharmaceutical compositions at atherosclerosis, reduce aspect the apoplexy incidence rate, its effect also is better than HMG-CoA reductase inhibitor/aspirin bigeminy and uses.Therefore, the present invention has the significant meaning of improving for existing Drug therapy technology.
Dyslipidemia is successive, consistent with the relation of cardiovascular event danger, and is independent of other risk factor, and blood fat is high more, and the danger that apoplexy, myocardial infarction take place is just big more.Therefore reduce the cardiovascular and cerebrovascular vessel event risk, accompany atherosclerotic's treatment to have important clinical significance for dyslipidemia.Treatment of diseases such as " cardiovascular and cerebrovascular vessel event risk " and above-mentioned target organ damage are distinguishing.So-called " cardiovascular and cerebrovascular vessel event risk " 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 the cardiovascular and cerebrovascular vessel event risk " 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.HMG-CoA reductase inhibitor/aspirin provided by the invention/folic acid three pharmaceutical compositions have obviously collaborative preventive effect aspect the causing danger property of reduction apoplexy.
In view of the beneficial effect of above-mentioned cooperative effect in clinical, the present invention also provides the pharmaceutical composition of HMG-CoA reductase inhibitor, aspirin and the folic acid of above-mentioned pharmaceutical dosage to be used for the application of blood fat reducing, the atherosclerotic medicine of control in preparation; The present invention also provides aforementioned pharmaceutical compositions to be used for reducing the application of the medicine of cardiovascular and cerebrovascular vessel event risk in preparation.In addition,, offer the pharmaceutical composition of this special-purpose of patient, can improve patient's compliance, the patient is taken medicine conveniently, reduce medical expense, therefore have better market prospect by enforcement of the present invention.
The following specific embodiment is to further specify of the present invention.
The specific embodiment
Embodiment 1: compound recipe atorvastatin/aspirin/folic acid preparation tablets
Following (1000) write out a prescription:
Atorvastatin 10g
Aspirin 75g
Folic acid 0.4g
Carboxymethyl starch sodium 20g
Calcium hydrogen phosphate 180g
10% polyvidone aqueous solution is an amount of
Magnesium stearate 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get atorvastatin 10g, aspirin 75g and folic acid 0.4g 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 with No. 8 drifts, tabletting, promptly.Note lucifuge in the preparation process, after product inspection was qualified, aluminium-plastic bubble plate packing kept in Dark Place.Every contains atorvastatin 10mg, aspirin 75mg, folic acid 0.4mg in the compound tablet of making.
Embodiment 2: the preparation compound tablet
Preparation method: with embodiment 1.The constituent and the content of 15 kinds of compound recipes see Table 7.
15 kinds of compound active pharmaceutical formulations of table 7 are formed
| The compound recipe kind | Atorvastatin | Aspirin | Folic acid | Calcium folinate | Levoleucovorin calcium |
| 1 | 10mg | 50mg | 0.2mg | - | - |
| 2 | 10mg | 100mg | 0.8mg | - | - |
| 3 | 80mg | 150mg | 1.6mg | - | - |
| 4 | 10mg | 50mg | 0.4mg | - | - |
| 5 | 80mg | 100mg | - | 0.5mg | - |
| 6 | 10mg | 100mg | - | 1.0mg | - |
| 7 | 40mg | 150mg | - | - | 0.125mg |
| 8 | 10mg | 100mg | - | - | 0.25mg |
| 9 | 20mg | 50mg | 0.8mg | - | - |
| 10 | 10mg | 100mg | 0.6mg | - | - |
| 11 | 20mg | 100mg | - | 1.0mg | - |
| 12 | 10mg | 100mg | - | 0.5mg | - |
| 13 | 20mg | 150mg | - | - | 0.75mg |
| 14 | 10mg | 100mg | - | - | 0.25mg |
| 15 | 10mg | 100mg | - | - | 0.125mg |
Embodiment 3: compound recipe atorvastatin/aspirin/folic acid capsule preparation
Following (1000) write out a prescription:
Atorvastatin 10g
Aspirin 75g
Folic acid 0.4g
Lactose 100～200g
Carboxymethyl starch sodium 15～25g
10% polyvidone aqueous solution is an amount of
Magnesium stearate 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get atorvastatin 10g, aspirin 75g and folic acid 0.4g according to equivalent incremental method mix homogeneously, add 100～200g lactose, 15～25g carboxymethyl starch sodium (the definite consumption of adjuvant is adjusted according to the active medicine consumption), according to equivalent incremental method uniform mixing, make soft material with 10% polyvidone alcoholic solution, 20 mesh sieves are granulated, 60 ℃ of dry about 2h, 20 mesh sieve granulate, controlling particulate water content is 2-3%, with dried granule and recipe quantity magnesium stearate mix homogeneously, 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 atorvastatin 10mg, aspirin 75mg, folic acid 0.4mg in the compound capsule of making.
Embodiment 4: the preparation compound capsule
Preparation method: with embodiment 3.The constituent and the content of 15 kinds of compound recipes see Table 7.
Embodiment 5: compound recipe atorvastatin/aspirin/folic acid granule preparation
Write out a prescription following (1000 bags):
Atorvastatin 10g
Aspirin 75g
Folic acid 0.4g
Lactose 850～950g
Carboxymethyl starch sodium 10～20g
Arabic gum 2g
10% polyvidone aqueous solution is an amount of
Orange flavor 2g
Aspartame 5g
Polyethylene Glycol 1%
Preparation method: supplementary material was pulverized 80 mesh sieves, drying for standby.Get atorvastatin 10g, aspirin 75g and folic acid 0.4g are according to equivalent incremental method mix homogeneously, add 850～950g lactose, 10～20g carboxymethyl starch sodium (the definite consumption of adjuvant is adjusted according to the active medicine consumption), according to equivalent incremental method uniform mixing, make soft material with 10% polyvidone alcoholic solution, 18 mesh sieves are granulated, 60 ℃ of dry about 2h, 16 mesh sieve granulate, controlling particulate water content is below 2%, with dried granule and recipe quantity orange flavor, aspartame, the magnesium stearate mix homogeneously, semi-finished product detect, and measure content, and the aluminum bag of packing into promptly gets 1000 bags.Note lucifuge in the preparation process.Every bag contains atorvastatin 10mg, aspirin 75mg and folic acid 0.4mg in the compound granular agent of making.
Embodiment 6: the agent of preparation compound granular
Preparation method: with embodiment 5.The constituent and the content of 15 kinds of compound recipes see Table 7.
Claims (9)
1. pharmaceutical composition comprises:
(1) a kind of in the HMG-CoA reductase inhibitor of medicinal content;
(2) aspirin of medicinal content;
(3) folic acid of medicinal content or calcium folinate or levoleucovorin calcium; With
(4) acceptable carrier on the pharmaceutics.
2. the described pharmaceutical composition of claim 1, it is characterized in that: described HMG-CoA reductase inhibitor comprises atorvastatin, simvastatin, Pitavastatin, pravastatin, lovastatin, fluvastatin, cerivastatin, Rosuvastatin, itavastatin, the Buddhist nun cuts down his spit of fland, bervastatin, mevastatin, wherein, atorvastatin content is 5mg～80mg, simvastatin content is 5mg～80mg, Pitavastatin content is 1mg～4mg, lovastatin content is 5mg～80mg, fluvastatin content is 5mg～80mg, pravastatin content is 5mg～80mg, Rosuvastatin content is 5mg～80mg.
3. the described pharmaceutical composition of claim 1, it is characterized in that: the medicinal content of described aspirin is 50mg～325mg, the medicinal content of folic acid or calcium folinate or levoleucovorin calcium is 0.1mg～2.0mg.
4. the described pharmaceutical composition of claim 3, it is characterized in that: the medicinal content of folic acid is 0.4mg～1.6mg; The medicinal content of calcium folinate is 0.5mg～2.0mg; The medicinal content of levoleucovorin calcium is 0.25mg～1.0mg.
5. each described pharmaceutical composition in the claim 1～4, it is characterized in that: the pharmacy dosage form of described pharmaceutical composition is tablet, capsule or granule.
6. each described pharmaceutical composition is used for the purposes of the medicine of blood fat reducing in the claim 1～5 in preparation.
7. each described pharmaceutical composition is used for preventing, treating the purposes of atherosclerotic medicine in the claim 1～5 in preparation.
8. purposes according to claim 7, it is characterized in that: the target organ damage that described atherosclerosis causes comprises cerebral arteriosclerosis, apoplexy, coronary heart disease, angina pectoris, myocardial infarction, acute coronary syndrome, arteriolar nephrosclerosis, peripheral arterial disease etc.
9. each described pharmaceutical composition is used for reducing the purposes of the medicine of cardiovascular and cerebrovascular vessel event risk in the claim 1～5 in preparation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100862731A CN101897710A (en) | 2009-05-27 | 2009-05-27 | Medicament composition containing HMG-CoA reductase inhibitor, aspirin and folic acid and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100862731A CN101897710A (en) | 2009-05-27 | 2009-05-27 | Medicament composition containing HMG-CoA reductase inhibitor, aspirin and folic acid and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106310276A (en) * | 2016-07-06 | 2017-01-11 | 深圳奥萨制药有限公司 | Pharmaceutical composition containing sugar and lipid reducing medicine and aspirin and folic acid |
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|---|---|---|---|---|
| CN1185952A (en) * | 1996-12-24 | 1998-07-01 | 张善 | Medicine for angiocardiopathy |
| US6235311B1 (en) * | 1998-03-18 | 2001-05-22 | Bristol-Myers Squibb Company | Pharmaceutical composition containing a combination of a statin and aspirin and method |
| US20050026992A1 (en) * | 2003-07-28 | 2005-02-03 | Sasmal Badal Kumar | Treatment and prevention of cardiovascular events |
| CN1785196A (en) * | 2004-12-10 | 2006-06-14 | 张鹏 | Compounding prepn. for treating and preventing cardiovascular or cerebrovascular diseases |
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2009
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185952A (en) * | 1996-12-24 | 1998-07-01 | 张善 | Medicine for angiocardiopathy |
| US6235311B1 (en) * | 1998-03-18 | 2001-05-22 | Bristol-Myers Squibb Company | Pharmaceutical composition containing a combination of a statin and aspirin and method |
| US20050026992A1 (en) * | 2003-07-28 | 2005-02-03 | Sasmal Badal Kumar | Treatment and prevention of cardiovascular events |
| CN1785196A (en) * | 2004-12-10 | 2006-06-14 | 张鹏 | Compounding prepn. for treating and preventing cardiovascular or cerebrovascular diseases |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106310276A (en) * | 2016-07-06 | 2017-01-11 | 深圳奥萨制药有限公司 | Pharmaceutical composition containing sugar and lipid reducing medicine and aspirin and folic acid |
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