CN101637609A - Drug composition containing amlodipine, A II receptor antagonist and statins - Google Patents
Drug composition containing amlodipine, A II receptor antagonist and statins Download PDFInfo
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Abstract
The invention relates to a drug composition which contains: (1) any one of (a) l- amlodipine or acceptable salts thereof in pharmacy, or (b) amlodipine or acceptable salts thereof in pharmacy; (2) A II receptor antagonist (ARB) or acceptable salts or esters thereof in pharmacy; (3) statins or acceptable salts thereof in pharmacy; and (4) acceptable carriers in pharmacy; wherein the amlodipine is selected from benzenesulfonic acid l-amlodipine and benzenesulfonic acid amlodipine; the ARB is selected from micardis, losartan, olmesartan, or acceptable salts or esters thereof in pharmacy; and thestatin drugs are selected from atorvastatin, simvastatin, pravastatin, or acceptable salts on pharmacy. The composition is used for treating various hypertensions simultaneously with companion or without companion of hyperlipemia, angina and atherosclerosis, preventing or treating heart cerebrovascular diseases related to hypertensions and improving the drug taking compliance of a patient.
Description
Technical field
The present invention relates to a kind of novel medicament compositions, it specifically comprises:
(1) contain wherein any in following two kinds: (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) statins or its pharmaceutically acceptable salt and (4) pharmaceutically acceptable carrier belong to medical technical field.
Background technology
Because the change of The development in society and economy and people life style, population of China hypertension prevalence is sustainable growth trend, national resident's nutrition in 2002 and investigation of health conditions result show that China adult hypertension prevalence reaches 18.8%, estimates that there is hyperpietic 1.6 hundred million in the whole nation.At present, China just has a people to die from cardiovascular and cerebrovascular disease per 15 seconds, and the total incidence of cardiovascular and cerebrovascular disease and mortality rate are near level of developed countries.The Ministry of Public Health statistics showed in 2004, and China's urban population cardiovascular and cerebrovascular disease mortality rate is 2,00/,100,000 people, and the rural area is 1,42/,100,000 people, accounted for 37% and 28% of dead formation respectively; Occupy cause of death first place (with reference to non-patent literature 1).
Hypertension is a kind of commonly encountered diseases frequently-occurring disease, also is the most important risk factor of cardiovascular and cerebrovascular disease.Blood pressure level and cardiovascular diseases's sickness rate are continuous positive correlation.Hypertensive important complication apoplexy, heart disease and nephropathy serious harm China people ' s health, the disability rate height that causes death brings white elephant (with reference to non-patent literature 1) for individual, family and society.
In recent years, hypertension prevention and control guide both domestic and external shows (with reference to non-patent literature 1,2), strengthen the blood pressure lowering dynamics, make hyperpietic's blood pressure reduce to 140/90 millimetres of mercury following (it is following that the best should be reduced to 130/80 millimetres of mercury) actively, enduringly, effectively the target organ damages such as heart and brain kidney that cause of alleviating hypertension;
Antihypertensive medicine and antihyperlipidemics thing administering drug combinations, can treat all kinds hypertension simultaneously with or without all kinds hyperlipemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma cardiovascular and cerebrovascular diseases such as (with reference to patent documentations 1), reduce incident rate, mortality rate and the disability rate of cardiovascular and cerebrovascular disease, improve patients ' life quality, prolong patient's life-span.
Relevant document (with reference to non-patent literature 1,3, patent documentation 1) studies show that, in order to reach actively, strengthen the purpose of blood pressure lowering, and two or more antihypertensive drugs of the needs of patients coupling of 70%-100%.The benefit of drug combination is: the medicine hypotensive effect of different mechanism of action can add up, work in coordination with or be complementary, and the reverse adjusting of passivation is compensatory, improves efficacy of antihypertensive treatment; It is excessive and the adverse effect that causes increases drug safety to reduce single survival dose; Take into account multiple risk factor and relevant disease that the patient exists, help individualized treatment; Improve patient's quality of life, improve patient's compliance; Can work in coordination with the protection of reinforcement to organ.Therefore the current domestic and international consistent scheme of combination drug therapy treatment hyperpietic who recommends to adopt the compound preparation that comprises the dosage fixed mixing ratio.
China's hypertension magazine report (with reference to non-patent literature 4), in JIUYUE, 2005 have been announced the hypertension therapeutic research of European maximum on ESC: big belly Ge Lu-Si bears De Naweiya heart consequence research (Anglo-Scandinavian Cardiac OutcomesTrial, abbreviation ASCOT) result of study, the result shows (with reference to patent documentation 1): calcium ion antagonist (abbreviation calcium antagonist) adds angiotensin converting enzyme inhibitor (ACEI) and adds statins (statins, also claiming the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) three share, can reduce by 66% apoplexy incidence rate, can also reduce myocardial infarction, the incidence rate of coronary heart disease and New Development diabetes.ASCOT thinks also no matter the hypertensive patient has or not blood fat (T-CHOL) to increase, and in the calcium ion antagonist blood pressure lowering, all is useful with atorvastatin.What deserves to be explained is that the ASCOT therapeutic scheme does not adopt the composite antihypertensive preparation administration that comprises the dosage fixed mixing ratio just simply with above-mentioned three kinds of single medicine administering drug combinations.
China's hypertension magazine is also reported (with reference to non-patent literature 2), held the academic annual meeting of European hypertension association (ESH) and ESC (ESC) in 2007 at Milan, ITA in 2007 06 month, the guideline of prevention and treatment of ESH in 2007 and ESC Arterial Hypertention has been issued in meeting.This guide is pointed out, the hyperpietic that all are diagnosed as cardiovascular disease or suffer from type 2 diabetes mellitus, all should consider to accept the statins treatment, so that total cholesterol density of serum (TC) less than 4.5mmol/L, concentration of low density lipoprotein cholesterol (LDL-C) less than 2.5mmol/L, as might can also be lower.No obvious cardiovascular disease but cardiovascular risk higher (cardiovascular event was not less than 20% in 10 years) though hyperpietic's baseline TC, LDL-C not high, also should accept the statins treatment.
It needs to be noted that Angiotensin II (being called for short A II) receptor antagonist and angiotensin converting enzyme inhibitor all belong to two hypotensors that suppress renin-angiotensin system (RAS), hypotensive effect mechanism is same or similar.
Based on above-mentioned discovery, the invention provides a kind of pharmaceutical composition of novel dosage fixed mixing ratio, it comprises: (1) contains wherein any in following two kinds: (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) effective dose angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) effective dose statins or its pharmaceutically acceptable salt and (4) pharmaceutically acceptable carrier.Aforementioned pharmaceutical compositions is used for the treatment of various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma; Several effective ingredient all have synergism to hypertension and hyperlipemia.For the hypertensive patient, no matter have or not blood fat (T-CHOL) to increase, in with amlodipine or its pharmaceutically acceptable salt associating angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester blood pressure lowering, all be useful with statins; The hyperpietic that all are diagnosed as cardiovascular disease or suffer from type 2 diabetes mellitus all should consider to accept statins treatment so that TC less than 4.5mmol/L, LDL-C less than 2.5mmol/L, as might can also be lower.
The present invention contains wherein any in following two kinds with (1): (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) statins or its pharmaceutically acceptable salt, and (4) pharmaceutically acceptable carrier, make the composite antihypertensive preparation administration of dosage fixed mixing ratio, the patient is very easy to use, every day 1～2 time, be preferably and only need use once every day, can prevent the acute variation of blood pressure effectively, make blood pressure be in more equilibrated state, improve the compliance that the patient takes medicine simultaneously, improved patient's quality of life.
The composite antihypertensive preparation of the dosage fixed mixing ratio of China's listing at present is a lot, wherein amlodipine besylate and atorvastatin calcium sheet (reaching) was got permission listing by Pfizer on 04 03rd, 2008, and specification is respectively: three kinds of 5mg/10mg, 5mg/20mg and 5mg/40mg.Nearly one development is based on such fact: simple blood pressure lowering treatment does not but reach expection to the amount of decrease of coronary event when significantly reducing heart failure and stroke event; And studies show that even hyperpietic's blood pressure is reduced to normal range, its risk that coronary heart disease takes place still is significantly higher than ordinary person.This may be because, had the atherosclerotic lesion of progressivity at hypertensive commitment.The individual postmortem result that dies unexpectedly is confirmed that also even young hyperpietic, atherosclerotic incidence rate is up to 50%.Past treats the statins blood fat reducing, total some misgivings of doctor and patient, in fact statins blood fat reducing treatment is quite safe, and the benefit of its blood fat reducing treatment firsts and seconds prevention is considerably beyond its risk (someone thinks that he treats risk even littler than aspirin at the spit of fland blood fat reducing).Based on the above fact, multi-faceted transformation is taking place for the theory of cardiovascular disease prevention in people.Recognize that at first hypertensive main therapeutic goal is to reduce coronary heart disease and apoplexy risk, and statins is the strongest the replenishing of realizing this goal.Observe the patient who statins is widely used for cardiovascular risk in the research, and make it adhere to treating extremely important." reaching one " is the compound preparation of western medicine of depressurization and non-depressor coupling, just hypertensive cross-domain treatment.
In recent years, the composite antihypertensive preparation of U.S.'s listing dosage fixed mixing ratio is quite a few, but contains the composite antihypertensive preparation of amlodipine and angiotensin ii receptor antagonist or statins, mainly contains following 3 kinds:
Caduet (Amlodipine Besylate Tablet+atorvastatin calcium), Exforge (Amlodipine Besylate Tablet+valsartan) and Azor (Amlodipine Besylate Tablet+olmesartan medoxomil); Wherein the Caduet specification has 11 kinds, and specification commonly used is five kinds of 2.5mg/10mg, 5mg/20mg, 5mg/40mg, 10mg/40mg, 10mg/80mg; The specification of Exforge is respectively: 5mg/160mg, 5mg/320mg, 10mg/160mg, 10mg/320mg; The specification of Azor has: four kinds of 5mg/20mg, 5mg/40mg, 10mg/20mg and 10mg/40mg.
CADUET is used for treating simultaneously hypertension and hypercholesterolemia, and indication comprises hypertension, chronic stable angina pectoris, vasospasm angina pectoris (or claiming ariant angina), various familial or non-familial dyslipidemia.But hypertension prevention and control guide both domestic and external shows (non-patent literature 1,2), wants to obtain satisfied antihypertensive effect, generally needs two or more antihypertensive drugs administration of associating, so that the CADUET antihypertensive effect still is difficult to is satisfactory.
Exforge and Azor also are used for the treatment of all kinds hypertension, antihypertensive effect is obvious, but for the hyperlipemia that causes because of hypertension, apoplexy, coronary heart disease, diabetes, angina pectoris, myocardial infarction, diabetic complication, cardiac insufficiency, renal function injury, atherosclerosis, ventricular hypertrophy, aneurysm and myocardial ischemia, prevention or therapeutic effect still are difficult to satisfactory.
Patent documentation 1 discloses the pharmaceutical composition of calcium ion antagonist or its mixture, angiotensin ii receptor antagonist or its mixture and statins or its mixture, be used for the treatment of all kinds hypertension, and prevention or the treatment cardiovascular and cerebrovascular disease relevant with hypertension, reduce the sickness rate and/or the mortality rate of cardiovascular and cerebrovascular disease, improve the compliance that the patient takes medicine simultaneously.The said composition antihypertensive effect is obvious, and the sickness rate and/or the mortality rate of cardiovascular and cerebrovascular disease obviously reduce, and the result is very satisfactory.
Patent documentation 2 discloses the pharmaceutical composition of valsartan and amlodipine, is used for the treatment of hypertension, congestive heart failure, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal insufficiency, apoplexy, left ventricular hypertrophy, cognitive dysfunction, headache and chronic heart failure.Though this compound preparation can be treated the cardiovascular and cerebrovascular disease relevant with hypertension, reduces its sickness rate and/or mortality rate, antihypertensive effect still is difficult to satisfactory.
Pharmaceutical composition of the present invention, it comprises: (1) contains wherein any in following two kinds: (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) statins or its pharmaceutically acceptable salt, and (4) pharmaceutically acceptable carrier, be made into the compound preparation administering drug combinations of dosage fixed mixing ratio, can not only strengthen the hypertension and hyperlipemia effect, produce collaborative decompression lipid-lowering effect, can also prevent or treat diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma; Reduce the sickness rate and/or the mortality rate of the cardiovascular and cerebrovascular disease relevant with hypertension; It is excessive and the adverse effect that causes increases drug safety to reduce the single medicine consumption; Having improved the compliance that the patient takes medicine simultaneously, had good practicality, is pressing for of countries in the world clinical application from now on.
Non-patent literature 1: Chinese hypertension prevention and control guide revised edition in 2005,4-5,9,31-32
Non-patent literature 2:2007 Europe hypertension association and ESC's hypertension guide new highlight. Chinese hypertension magazine, the 15th the 9th phase of volume of JIUYUE in 2007,708-710
Non-patent literature 3: Du Yueling, Chen Shaohang. the use in conjunction of antihypertensive drugs. world's clinical medicine, 2005 the 26th the 10th phases of volume, 592-595,602
Non-patent literature 4: the scheme of treatment hypertension " ASCOT ". Chinese hypertension magazine, the 15th the 4th phase of volume of April in 2007,265-267
Patent documentation 1: Chinese patent CN2009103056493
Patent documentation 2: Chinese patent CN200680028935.4
Summary of the invention
The purpose of this invention is to provide a kind of novel medicament compositions, it comprises: (1) contains wherein any in following two kinds: (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) statins or its pharmaceutically acceptable salt and (4) pharmaceutically acceptable carrier.Aforementioned pharmaceutical compositions is used for the treatment of various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma; Several effective ingredient all have synergism to hypertension and hyperlipemia.It has the hypertension and hyperlipemia effect obviously, the sickness rate and/or the mortality rate of the cardiovascular and cerebrovascular disease relevant with hypertension obviously reduce, improve compliance that the patient takes medicine, minimizing because of advantages such as the excessive adverse effect that causes of single medicine consumption, prolongation patient life.
In a first aspect of the present invention, a kind of novel medicament compositions is provided, it is characterized in that it comprises:
(1) contain wherein any in following two kinds:
(a) Levamlodipine or its pharmaceutically acceptable salt, or
(b) amlodipine or its pharmaceutically acceptable salt;
(2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester;
(3) statins or its pharmaceutically acceptable salt; And
(4) pharmaceutically acceptable carrier.
In another preference, it is characterized in that:
(1) described Levamlodipine is selected from Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine, methanesulfonic acid Levamlodipine, d-camphorsulfonic acid Levamlodipine, nicotinic acid Levamlodipine, pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine, thioctic acid Levamlodipine or its pharmaceutically acceptable salt;
Described amlodipine is selected from Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate, amlodipine camsylate, amlodipine niacin, pyroglutamic acid amlodipine, amlodipine gentisate, thioctic acid amlodipine or its pharmaceutically acceptable salt;
(2) described angiotensin ii receptor antagonist is selected from: telmisartan, losartan, valsartan, Olmesartan, irbesartan, Candesartan, eprosartan, Tasosartan, Irb, Ai Lishatan, Abitesartan, Elisartan, Embusartan, Forasartan, milfasartan, Pomisaratan, Pratosartan, Ripisartan, saprisartan, zolasartan or its pharmaceutically acceptable salt or ester;
(3) described statins is selected from: atorvastatin, simvastatin, Pitavastatin, pravastatin, Rosuvastatin, fluvastatin, lovastatin, rosuvastatin, bervastatin, crilvastatin, dalvastatin, lattice logical sequence cut down his spit of fland, mevastatin, for cut down his spit of fland, the Buddhist nun cuts down his spit of fland or its pharmaceutically acceptable salt;
And (4) pharmaceutically acceptable carrier.
In another preference, it is characterized in that:
(1) those medicines of preferably having gone on the market of described Levamlodipine or its pharmaceutically acceptable salt, most preferably Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine and methanesulfonic acid Levamlodipine;
Those medicines that described amlodipine or its pharmaceutically acceptable salt have preferably gone on the market, most preferably Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate and amlodipine maleate;
(2) those medicines of preferably having gone on the market of described angiotensin ii receptor antagonist, most preferably telmisartan, losartan, valsartan, Olmesartan or its pharmaceutically acceptable salt or ester;
(3) those medicines of preferably having gone on the market of described statins, most preferably atorvastatin, simvastatin, Pitavastatin, pravastatin or its pharmaceutically acceptable salt.
In another preference, wherein Levamlodipine is selected from Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine and methanesulfonic acid Levamlodipine, and amlodipine is selected from Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate and amlodipine maleate; Angiotensin ii receptor antagonist is selected from telmisartan, Losartan Potassium, valsartan and olmesartan medoxomil; Statins is selected from Atorvastatin calcium, simvastatin, Pitavastatin Calcium and pravastatin sodium.
In another preference, it is characterized in that:
(1) the effective amount of Levamlodipine besylate is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of maleic acid levo amido chloro diping is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of L-Aspartic Acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of methanesulfonic acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg;
The effective amount of Amlodipine Besylate Tablet is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of L-Aspartic Acid amlodipine is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine mesylate is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of amlodipine maleate is 2.5mg～20mg, more preferably is 2.5mg～10mg;
(2) the effective amount of telmisartan is 20mg～160mg, more preferably is 20mg～80mg; The effective amount of Losartan Potassium is 25mg～200mg, more preferably is 25mg～100mg; The effective amount of valsartan is 20mg～640mg, more preferably is 40mg～320mg; The effective amount of olmesartan medoxomil is 2.5mg～160mg, more preferably is 5mg～40mg;
(3) the effective amount of Atorvastatin calcium is 5mg～160mg, more preferably is 10mg～80mg; The effective amount of simvastatin is 2.5mg～160mg, more preferably is 5mg～80mg; The effective amount of Pitavastatin Calcium is 0.5mg～16mg, more preferably is 1mg～4mg; The effective amount of pravastatin sodium is 2.5mg～160mg, more preferably is 5mg～80mg.
A second aspect of the present invention, provide and used medicine composite for curing of the present invention to treat various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or the treatment cardiovascular and cerebrovascular disease relevant with hypertension, reduce the sickness rate and/or the mortality rate of cardiovascular and cerebrovascular disease, improve the compliance that the patient takes medicine simultaneously, minimizing increases the safety of medication because of the excessive adverse effect that causes of single medicine consumption.
In another preference, described pharmaceutical composition be used for the treatment of all kinds hypertension simultaneously with or without all kinds hyperlipemia, angina pectoris, atherosclerosis, and prevention or the treatment cardiovascular and cerebrovascular disease relevant with hypertension, the sickness rate and/or the mortality rate of minimizing cardiovascular and cerebrovascular disease.
In another preference, described pharmaceutical composition be used for the treatment of various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma, reduce its sickness rate and/or mortality rate.
A third aspect of the present invention provides preparation of drug combination method of the present invention, and every day access times.
In another preference, the dosage form of described pharmaceutical composition is non-controlled release agent type, controlled release agent type or injection.
In another preference, the dosage form of described pharmaceutical composition is tablet, capsule, dispersible tablet, oral cavity disintegration tablet, chewable tablet, drop pill or injection.
In another preference, described pharmaceutical composition can be a compound injection, and it consists of the following components:
(1) contain wherein any in following two kinds:
(a) Levamlodipine or its pharmaceutically acceptable salt, be preferably nicotinic acid Levamlodipine, pyroglutamic acid Levamlodipine, methanesulfonic acid Levamlodipine and Levamlodipine besylate, wherein the effective amount of nicotinic acid Levamlodipine is 0.625mg～20mg, more preferably is 1.25mg～5mg; The effective amount of pyroglutamic acid Levamlodipine is 0.625mg～20mg, more preferably is 1.25mg～5mg; The effective amount of methanesulfonic acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of Levamlodipine besylate is 1.25mg～10mg, more preferably is 1.25mg～5mg; Or
(b) amlodipine or its pharmaceutically acceptable salt, be preferably amlodipine niacin, pyroglutamic acid amlodipine, Amlodipine mesylate and Amlodipine Besylate Tablet, wherein the effective amount of amlodipine niacin is 1.25mg～40mg, more preferably is 2.5mg～10mg; The effective amount of pyroglutamic acid amlodipine is 1.25mg～40mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine mesylate is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine Besylate Tablet is 2.5mg～20mg, more preferably is 2.5mg～10mg;
(2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester are preferably Losartan Potassium, and wherein the effective amount of Losartan Potassium is 25mg～200mg, more preferably are 25mg～100mg;
(3) statins or its pharmaceutically acceptable salt are preferably pravastatin sodium, fluvastatin sodium, sodium atorvastatin and Pitavastatin sodium, and wherein the effective amount of pravastatin sodium is 2.5mg～160mg, more preferably are 5mg～80mg; The effective amount of fluvastatin sodium is 10mg～160mg, more preferably is 20mg～80mg; The effective amount of sodium atorvastatin is 5mg～160mg, more preferably is 10mg～80mg; The effective amount of Pitavastatin sodium is 0.5mg～16mg, more preferably is 1mg～4mg;
And (4) pharmaceutically acceptable carrier;
Described compound injection can be an injection with small volume, and conventional specification is respectively 1ml, 2ml, 5ml, 10ml and 20ml; Also can high-capacity injection, conventional specification is respectively 50ml, 100ml, 250ml and 500ml; Can also be aseptic freeze-dried powder or sterilized powder packing.
In another preference, described pharmaceutical composition uses once or twice every day, is preferably and only need uses once every day, can prevent the acute variation of blood pressure effectively, makes blood pressure be in more equilibrated state.
The specific embodiment
The result of study of ASCOT shows, calcium ion antagonist adds the angiotensin converting enzyme inhibitor adds the statins three and share, and can reduce by 66% stroke onset rate, can also reduce the sickness rate of myocardial infarction, coronary heart disease and New Development diabetes.ASCOT thinks also no matter the hypertensive patient has or not blood fat (T-CHOL) to increase, and in the calcium ion antagonist blood pressure lowering, all is useful with atorvastatin.But the ASCOT therapeutic scheme does not adopt the compound preparation administration that comprises the dosage fixed mixing ratio just simply with above-mentioned three kinds of single medicine administering drug combinations.
ESH and ESC guideline of prevention and treatment are also pointed out, the hyperpietic that all are diagnosed as cardiovascular disease or suffer from type 2 diabetes mellitus all should consider to accept statins treatment so that TC less than 4.5mmol/L, LDL-C less than 2.5mmol/L, as might can also be lower.No obvious cardiovascular disease but cardiovascular risk higher (cardiovascular event was not less than 20% in 10 years) though hyperpietic's baseline TC, LDL-C not high, also should accept the statins treatment.
It needs to be noted that angiotensin ii receptor antagonist and angiotensin converting enzyme inhibitor all belong to two hypotensors that suppress renin-angiotensin system (RAS), hypotensive effect mechanism is same or similar.
Based on above-mentioned discovery, the invention provides a kind of pharmaceutical composition of novel dosage fixed mixing ratio, it comprises: (1) contains wherein any in following two kinds: (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) effective dose angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) effective dose statins or its pharmaceutically acceptable salt and (4) pharmaceutically acceptable carrier.Aforementioned pharmaceutical compositions is used for the treatment of various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma; Several effective ingredient all have synergism to hypertension and hyperlipemia.For the hypertensive patient, no matter have or not blood fat (T-CHOL) to increase, in with amlodipine or its pharmaceutically acceptable salt associating angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester blood pressure lowering, all be useful with statins; The hyperpietic that all are diagnosed as cardiovascular disease or suffer from type 2 diabetes mellitus all should consider to accept statins treatment so that TC less than 4.5mmol/L, LDL-C less than 2.5mmol/L, as might can also be lower.
Can be used for Levamlodipine of the present invention or amlodipine or its pharmaceutically acceptable salt has no particular limits.Representational Levamlodipine or its pharmaceutically acceptable salt example are selected from (but being not limited to): Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine, methanesulfonic acid Levamlodipine, d-camphorsulfonic acid Levamlodipine, nicotinic acid Levamlodipine, pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine and thioctic acid Levamlodipine; Representational amlodipine or its pharmaceutically acceptable salt example are selected from (but being not limited to): Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate, amlodipine niacin, pyroglutamic acid amlodipine, amlodipine camsylate, amlodipine gentisate and thioctic acid amlodipine.
Dihydropyridine calcium channel blockers such as Levamlodipine besylate, maleic acid levo amido chloro diping or Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine retardance calcium ion enters in the cell, vascular smooth muscle effectively can relax, reduce peripheral vascular resistance, the expansion small artery, alleviate cardiac afterload, reduce the blood pressure increased.
Dihydropyridine calcium channel blockers such as Levamlodipine besylate, maleic acid levo amido chloro diping or Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine also have good cardiovascular effect; such as reversing ventricular hypertrophy; improve the lax function of diastole; renal function protecting; slight diuresis, slight antiplatelet resists myocardial ischemia; arrhythmia increases insulin sensitivity and certain effects such as atherosclerosis.
Can be used for the angiotensin ii receptor antagonist of the present invention restriction that has nothing special.Representational angiotensin ii receptor antagonist example is selected from (but being not limited to): telmisartan, losartan, valsartan, Olmesartan, irbesartan, Candesartan, eprosartan, Tasosartan, Irb, Ai Lishatan, Abitesartan, Elisartan, Embusartan, Forasartan, milfasartan, Pomisaratan, Pratosartan, Ripisartan, saprisartan, zolasartan or its pharmaceutically acceptable salt or ester;
Angiotensin ii receptor antagonist such as telmisartan, losartan, valsartan or Olmesartan are nervous plain II receptor 1 hypotype (AT1) of vasoactive optionally, combine AT1 with aii receptor competitiveness, lax vascular smooth muscle, reduce peripheral vascular resistance, blood vessel dilating obviously descends systolic arterial pressure and diastolic pressure, chamber, left side diastasis pressure descends, increase the drainage of kidney salt and water simultaneously, reduce plasma volume, thereby play the effect of blood pressure lowering and protection target organ; Such drug half-life is all longer, and steadily and lasting, drug effect can be kept more than 24 hours in effect.
Angiotensin ii receptor antagonist such as telmisartan, losartan, valsartan or Olmesartan are after eliminating the AII effect, can also alleviate afterload, improve myocardial contraction, alleviate the clinical symptoms of heart failure, can be used for prevention or treatment heart failure, coronary heart disease, angina pectoris and myocardial infarction.
Can be used for the statins of the present invention restriction that has nothing special.Representational statins example is selected from (but being not limited to): atorvastatin, simvastatin, Pitavastatin, pravastatin, Rosuvastatin, fluvastatin, lovastatin, rosuvastatin, bervastatin, crilvastatin, dalvastatin, lattice logical sequence cut down his spit of fland, mevastatin, for cut down his spit of fland, the Buddhist nun cuts down his spit of fland or its pharmaceutically acceptable salt.
Statinses such as atorvastatin, simvastatin, Pitavastatin or pravastatin reduce the cholesterol levels in the blood plasma by suppressing HMG-CoA reductase (also claiming the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a kind of biosynthetic enzyme of cholesterol that involves).Usually, statins is to cause circulation LDL-C level reduction in the blood plasma by the generation synthetic and promotion LDL-bind receptor of multiple inhibition liver inner cholesterol, and HDL-C level then appropriateness raises.
Clinical and the pathological study of statinses such as atorvastatin, simvastatin, Pitavastatin or pravastatin also shows, T-CHOL in the blood plasma, LDL-C and apolipoprotein B level raise, promoting human atherosclerosis, also is the risk factor that develops into cardiovascular disease; And when the HDL-C level raise, the M ﹠ M of cardiovascular disease just reduced.Epidemiological study also shows that cardiovascular morbidity is directly relevant with the LDL-C level with different T-CHOLs with mortality rate, and is then opposite with HDL-C.
Being used for Levamlodipine besylate of the present invention, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine, methanesulfonic acid Levamlodipine, Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate and telmisartan, losartan, valsartan and olmesartan medoxomil, all is one of first-selected best antihypertensive drugs that meets hypertension prevention and control guide (non-patent literature 1) recommendation.Statins atorvastatin, simvastatin, Pitavastatin and pravastatin also are the choice drugs of treatment hyperlipidemia commonly used.
In pharmaceutical composition of the present invention, wherein Levamlodipine is selected from Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine and methanesulfonic acid Levamlodipine, and amlodipine is selected from Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate and amlodipine maleate; Angiotensin ii receptor antagonist is selected from telmisartan, Losartan Potassium, valsartan and olmesartan medoxomil; Statins is selected from Atorvastatin calcium, simvastatin, Pitavastatin Calcium and pravastatin sodium.
In pharmaceutical composition of the present invention, it is characterized in that:
(1) the effective amount of Levamlodipine besylate is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of maleic acid levo amido chloro diping is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of L Aspartic Acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of methanesulfonic acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg;
The effective amount of Amlodipine Besylate Tablet is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of L-Aspartic Acid amlodipine is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine mesylate is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of amlodipine maleate is 2.5mg～20mg, more preferably is 2.5mg～10mg;
(2) the effective amount of telmisartan is 20mg～160mg, more preferably is 20mg～80mg; The effective amount of Losartan Potassium is 25mg～200mg, more preferably is 25mg～100mg; The effective amount of valsartan is 20mg～640mg, more preferably is 40mg～320mg; The effective amount of olmesartan medoxomil is 2.5mg～160mg, more preferably is 5mg～40mg;
(3) the effective amount of Atorvastatin calcium is 5mg～160mg, more preferably is 10mg～80mg; The effective amount of simvastatin is 2.5mg～160mg, more preferably is 5mg～80mg; The effective amount of Pitavastatin Calcium is 0.5mg～16mg, more preferably is 1mg～4mg; The effective amount of pravastatin sodium is 2.5mg～160mg, more preferably is 5mg～80mg.
Pharmaceutical composition of the present invention, be used for the treatment of mammal (comprising the mankind) all kinds hypertension simultaneously with or without all kinds hyperlipemia, angina pectoris, atherosclerosis, and prevention or the treatment cardiovascular and cerebrovascular disease relevant with hypertension, the sickness rate and/or the mortality rate of minimizing cardiovascular and cerebrovascular disease.
Pharmaceutical composition of the present invention, be used for the treatment of various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma, reduce its sickness rate and/or mortality rate.
The dosage form and the preparation method of pharmaceutical composition of the present invention are not particularly limited, and the conventional general method for making in available this area is made the pharmaceutically various non-controlled release agent types of acceptable, controlled release agent type or injection; Preferred dosage form is tablet, capsule, dispersible tablet, oral cavity disintegration tablet, chewable tablet, drop pill or injection.
The dosage form of pharmaceutical composition of the present invention can be compound injection, and it consists of the following components:
(1) contain wherein any in following two kinds:
(a) Levamlodipine or its pharmaceutically acceptable salt, be preferably nicotinic acid Levamlodipine, pyroglutamic acid Levamlodipine, methanesulfonic acid Levamlodipine and Levamlodipine besylate, wherein the effective amount of nicotinic acid Levamlodipine is 0.625mg～20mg, more preferably is 1.25mg～5mg; The effective amount of pyroglutamic acid Levamlodipine is 0.625mg～20mg, more preferably is 1.25mg～5mg; The effective amount of methanesulfonic acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of Levamlodipine besylate is 1.25mg～10mg, more preferably is 1.25mg～5mg; Or
(b) amlodipine or its pharmaceutically acceptable salt, be preferably amlodipine niacin, pyroglutamic acid amlodipine, Amlodipine mesylate and Amlodipine Besylate Tablet, wherein the effective amount of amlodipine niacin is 1.25mg～40mg, more preferably is 2.5mg～10mg; The effective amount of pyroglutamic acid amlodipine is 1.25mg～40mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine mesylate is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine Besylate Tablet is 2.5mg～20mg, more preferably is 2.5mg～10mg;
(2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester are preferably Losartan Potassium, and wherein the effective amount of Losartan Potassium is 25mg～200mg, more preferably are 25mg～100mg;
(3) statins or its pharmaceutically acceptable salt are preferably pravastatin sodium, fluvastatin sodium, sodium atorvastatin and Pitavastatin sodium, and wherein the effective amount of pravastatin sodium is 2.5mg～160mg, more preferably are 5mg～80mg; The effective amount of fluvastatin sodium is 10mg～160mg, more preferably is 20mg～80mg; The effective amount of sodium atorvastatin is 5mg～160mg, more preferably is 10mg～80mg; The effective amount of Pitavastatin sodium is 0.5mg～16mg, more preferably is 1mg～4mg;
And (4) pharmaceutically acceptable carrier;
Described compound injection can be an injection with small volume, and conventional specification is respectively 1ml, 2ml, 5ml, 10ml and 20ml; Also can high-capacity injection, conventional specification is respectively 50ml, 100ml, 250ml and 500ml; Can also be aseptic freeze-dried powder or sterilized powder packing.
In pharmaceutical composition of the present invention, use once or twice every day; Preferred mode is only need use once every day, can prevent the acute variation of blood pressure effectively, makes blood pressure be in more equilibrated state; Simultaneously can reduce medicining times like this, be convenient to patient and adhere to, improve the compliance that the patient takes medicine.
In pharmaceutical composition of the present invention, adopt will: (1) contains wherein any in following two kinds: (a) Levamlodipine or its pharmaceutically acceptable salt or (b) amlodipine or its pharmaceutically acceptable salt, (2) effective dose angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester, (3) effective dose statins or its pharmaceutically acceptable salt and (4) pharmaceutically acceptable carrier, make the pharmaceutical composition administration of dosage fixed mixing ratio, improve the hypertension and hyperlipemia effect; Several effective ingredient all have synergism to hypertension and hyperlipemia.Above-mentioned composition is used for the treatment of various essential hypertensions, secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma, the sickness rate and/or the mortality rate of minimizing cardiovascular and cerebrovascular disease; Improved the compliance that the patient takes medicine, reduced, increased drug safety, improved patient's quality of life because of the excessive adverse effect that causes of single medicine consumption.
Pharmaceutical composition of the present invention also is applicable to through non-medicine measures such as positive change bad life style still fails controlling blood pressure satisfactorily to the hypertension patient in early stage of ideal value more than 6 months, promptly systolic pressure continues to continue patient at the 80-90 millimetres of mercury at 120-139 millimetres of mercury or diastolic pressure.No matter the hypertensive patient has or not blood fat (T-CHOL) to increase, in wherein a kind of and angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester associating blood pressure lowering, all be useful with statins with Levamlodipine or amlodipine or its pharmaceutically acceptable salt.
Hypertension is a kind of multi-factor disease, often needs the blood pressure lowering of two or more antihypertensive drugs ability up to standard, and generally all needs lifelong monitoring, takes medicine for a long time.New pharmaceutical composition of the present invention has utilized the synergism between the medicine, improve the hypertension and hyperlipemia effect, be used for the treatment of the various essential hypertensions of mammal (comprising the people), secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or the treatment cardiovascular and cerebrovascular disease relevant with hypertension, the sickness rate and/or the mortality rate of cardiovascular and cerebrovascular disease have been reduced, improved the compliance that the patient takes medicine simultaneously, minimizing is because of the excessive adverse effect that causes of single medicine consumption, increase drug safety, be convenient in a large amount of crowds, promote the popularization use.
According to the present invention, be example with the Atorvastatin calcium, triple therapeutic doses combinations (but being not limited to) of the fixed mixing ratio that following is uses in the preferred pharmaceutical composition:
Describe the present invention in detail below in conjunction with embodiment, these embodiment are presented for purposes of illustration, do not limit the scope of the invention.
Embodiment 1: Levamlodipine besylate, telmisartan and atorvastatin calcium tablet
Preparation method:
(I) the particulate granulation of Atorvastatin calcium
Step 1, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
Step 2, polyoxyethylene sorbitan monoleate is dissolved in 45 ℃～60 ℃ purified water and adds hydroxypropyl cellulose, make solution be cooled to room temperature;
Step 3, in granulator, mix Atorvastatin calcium, calcium carbonate, microcrystalline Cellulose, pre-paying starch, polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose;
Step 4, will mix from the mixture of powders of step 3 with from the solution of step 2 in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 5.5～10.0, becomes wet granular with No. 2 sieve series;
Step 5, in drying equipment dried particles, granulate are sieved with No. 2 in dry back, make moisture (loss on drying) be less than or equal to 2.0% at last;
(II), preparation at last
Step 1, in the Atorvastatin calcium granule that step (I) obtains, add Levamlodipine besylate, telmisartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and micropowder silica gel;
Step 2, with the mill mixture of powders of milling, make it become satisfactory thin sprills;
Step 3, in the mixture of powders of milling, add magnesium stearate, carboxymethylstach sodium, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step 2;
Step 4, use sheeting equipment are made 1000 with finally mixed granule compacting in flakes, get final product.
Embodiment 2: Levamlodipine besylate, valsartan and suffering are cut down his spit of fland capsule
Preparation method:
(I) suffering is cut down the particulate granulation in his spit of fland
Step 1, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
Step 2, be dissolved in polyoxyethylene sorbitan monoleate in 50 ℃ of purified water and add hydroxypropyl cellulose, make solution be cooled to room temperature;
Step 3, in granulator, mix suffering and cut down his spit of fland, calcium carbonate, microcrystalline Cellulose, pre-paying starch, sodium lauryl sulphate and cross-linking sodium carboxymethyl cellulose;
Step 4, will mix from the mixture of powders of step 3 with from the solution of step 2 in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 5.5～10.0; Become wet granular with No. 2 sieve series;
Step 5, in drying equipment dried particles, granulate are sieved with No. 2 in dry back, make moisture (loss on drying) be less than or equal to 2.0% at last;
(II), preparation at last
Step 1, cut down in his the spit of fland granule to the suffering that step (I) obtains and to add Levamlodipine besylate, valsartan, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and micropowder silica gel;
Step 2, with the mill mixture of powders of milling, make it become satisfactory thin sprills;
Step 3, in the mixture of powders of milling, add magnesium stearate, carboxymethylstach sodium, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step 2;
Behind step 4, the above-mentioned mixture of powders mix homogeneously, it is heavy to calculate grain, surveys intermediate content, qualified after, be distributed into 1000 capsules, get final product.
Embodiment 3: Amlodipine Besylate Tablet, olmesartan medoxomil and Pitavastatin calcium dispersible tablet
Preparation method:
(I) preparation of Pitavastatin Calcium microcapsule
Steps A, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
Step B, getting gelatin and Radix Acaciae senegalis respectively is dissolved in the purified water separately, stirring is fully dissolved it, in Radix Acaciae senegalis, add Pitavastatin Calcium, cross-linking sodium carboxymethyl cellulose, ultrasonic emulsification 45 minutes, gelatin solution and gum arabic solution are mixed in the adding there-necked flask, the control mixing speed is 200-400rpm, heating in water bath, temperature remains on 45 ℃-50 ℃, the pH value 3.5-4.0 of regulation system, aggregation 55 minutes is reduced to 2 ℃-8 ℃ with the temperature of system, adding mass concentration is that 25% formaldehyde and mass concentration are 8% glutaraldehyde solution, the pH value of regulation system is 8.0-9.5 then, and crosslinking curing 3 hours is used distilled water flushing product 3 times, remove remaining formaldehyde and glutaraldehyde, microcapsules and microsphere after the washing is placed there-necked flask, and bath temperature remains on 20 ℃-25 ℃, drips mass concentration then and be 6% tannic acid solution, post processing 8～10 hours will be dried under the room temperature of end product washing back naturally.
(II), mix at last
The dry fine powder of above-mentioned exsiccant Pitavastatin Calcium microcapsule is crossed 80 mesh sieves, with Amlodipine Besylate Tablet, olmesartan medoxomil and magnesium stearate, carboxymethylstach sodium, lactose, microcrystalline Cellulose, 0.5% cochineal solution and 0.25% lemon yellow solution mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer; Use sheeting equipment in flakes, make 1000, get final product finally mixed granule compacting.
Embodiment 4: maleic acid levo amido chloro diping, olmesartan medoxomil and atorvastatin Biocal
Preparation method:
(I) preparation of Atorvastatin calcium microcapsule
Steps A, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
Step B, getting gelatin and Radix Acaciae senegalis respectively is dissolved in the purified water separately, stirring is fully dissolved it, in Radix Acaciae senegalis, add Atorvastatin calcium, hydroxypropyl cellulose, ultrasonic emulsification 45 minutes, gelatin solution and gum arabic solution are mixed in the adding there-necked flask, the control mixing speed is 200-400rpm, heating in water bath, temperature remains on 45 ℃-50 ℃, the pH value 3.5-4.0 of regulation system, aggregation 55 minutes is reduced to 2 ℃-8 ℃ with the temperature of system, adding mass concentration is that 25% formaldehyde and mass concentration are 8% glutaraldehyde solution, the pH value of regulation system is 8.0-9.5 then, and crosslinking curing 3 hours is used distilled water flushing product 3 times, remove remaining formaldehyde and glutaraldehyde, microcapsules and microsphere after the washing is placed there-necked flask, and bath temperature remains on 20 ℃-25 ℃, drips mass concentration then and be 6% tannic acid solution, post processing 8～10 hours will be dried under the room temperature of end product washing back naturally.
(II), mix at last
The dry fine powder of above-mentioned exsiccant Atorvastatin calcium microcapsule is crossed 80 mesh sieves, with maleic acid levo amido chloro diping, olmesartan medoxomil and magnesium stearate, sucralose, mannitol, strawberry essence, 0.5% cochineal solution, 0.25% lemon yellow solution and microcrystalline Cellulose mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer; Use sheeting equipment in flakes, make 1000, get final product finally mixed granule compacting.
Embodiment 5:L-Aspartic Acid amlodipine, telmisartan and Pitavastatin Calcium oral cavity disintegration tablet
Preparation method:
(I) preparation of Pitavastatin Calcium clathrate:
Steps A, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
Step B, taking by weighing beta-schardinger dextrin-, is that saturated solution is made in 50 ℃～60 ℃ purified water dissolving with an amount of temperature; Other takes by weighing Pitavastatin Calcium, and it is an amount of to add purified water, under agitation adds above-mentioned beta-schardinger dextrin-aqueous solution, and supersound process 30 minutes, filter, a solution; The solution of gained is carried out lyophilization in freeze drying equipment, get white or off-white powder.
(II) white powder of above-mentioned exsiccant Pitavastatin Calcium clathrate is crossed No. 5 sieve, with L Aspartic Acid amlodipine, telmisartan and microcrystalline Cellulose, mannitol, crospolyvinylpyrrolidone, sucralose and magnesium stearate mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer; Use sheeting equipment in flakes, make 1000, get final product finally mixed granule compacting.
Embodiment 6: amlodipine maleate, olmesartan medoxomil and Atorvastatin calcium drop pill
Preparation method:
(I) preparation of Atorvastatin calcium clathrate:
Steps A, various solid supplementary materials are crossed sieve respectively 5～No. 6, standby;
Step B, taking by weighing beta-schardinger dextrin-, is that saturated solution is made in 50 ℃～60 ℃ purified water dissolving with an amount of temperature; Other takes by weighing Atorvastatin calcium, and it is an amount of to add purified water, under agitation adds above-mentioned beta-schardinger dextrin-aqueous solution, and supersound process 30 minutes, filter, a solution; The solution of gained is carried out lyophilization in freeze drying equipment, get white or off-white powder.
(II) PEG6000 and polyoxyethylene sorbitan monoleate mixing post-heating to 55 ℃～60 ℃ are made fusion; Again amlodipine maleate and olmesartan medoxomil are added in the fused solution and stir, move in the funnel 55 ℃～60 ℃ insulations, adjusting dropping funnel size serves as the cooling phase with the dimethicone of-20～5-or liquid paraffin, the system of dripping, make 1000 balls, filter, wash, select ball, get final product.
Embodiment 7: the injection with small volume that contains amlodipine niacin, Losartan Potassium and pravastatin sodium
| The supplementary material title | Dosage 1 | Dosage 2 | Dosage 3 |
| Pravastatin sodium | ??10.00g | ??20.00g | ??80.00g |
| Sodium glutamate | ??50.00g | ??100.00g | ??400.00g |
| Amlodipine niacin | ??3.25g | ??6.50g | ??13.00g |
| Losartan Potassium | ??25.00g | ??50.00g | ??100.00g |
| Water for injection | In right amount | In right amount | In right amount |
| Gross weight | ??5000ml | ??10000ml | ??40000ml |
Preparation method:
Take by weighing amlodipine niacin, add an amount of water for injection stirring it is dissolved fully, as solution A; Other takes by weighing pravastatin sodium and sodium glutamate, adds an amount of water for injection stirring and makes its dissolving, as solution B; With solution B and Losartan Potassium, all pour in the solution A then, stir and make its dissolving, add 0.5%～1.0% active carbon and remove pyrogen, add water and be settled to full dose, stirred 20～30 minutes, earlier with 0.45um filter membrane coarse filtration, reuse 0.22um filter membrane fine straining; Be distributed into 1000 with 7ml or 10ml cillin bottle (having removed pyrogen) at last, immediately in 45 minutes (F0 〉=8) of 121 ℃ of sterilizations, get final product after packing finishes.
Embodiment 8: the aseptic freeze-dried powder pin that contains pyroglutamic acid amlodipine, Losartan Potassium and fluvastatin sodium
| The supplementary material title | Dosage 1 | Dosage 2 | Dosage 3 |
| Fluvastatin sodium | ??10.00g | ??20.00g | ??80.00g |
| Sodium glutamate | ??50.00g | ??100.00g | ??400.00g |
| The pyroglutamic acid amlodipine | ??3.29g | ??6.58g | ??13.16g |
| Losartan Potassium | ??25.00g | ??50.00g | ??100.00g |
| Water for injection | In right amount | In right amount | In right amount |
| Gross weight | ??5000ml | ??10000ml | ??40000ml |
Preparation method:
Take by weighing the pyroglutamic acid amlodipine, add an amount of water for injection stirring it is dissolved fully, as solution A; Other takes by weighing fluvastatin sodium and sodium glutamate, adds an amount of water for injection stirring and makes its dissolving, as solution B; With solution B and Losartan Potassium, all pour in the solution A then, stir and make its dissolving, add 0.5%～1.0% active carbon and remove pyrogen, add water and be settled to full dose, stirred 20～30 minutes, earlier with 0.45um filter membrane coarse filtration, reuse 0.22um filter membrane fine straining; Be distributed into 1000 with 7ml or 10ml cillin bottle (having removed pyrogen) at last, carry out lyophilization by the pharmaceuticals industry conventional method in freeze drying equipment, moisture is controlled at below 3.0%, gets final product.
Embodiment 9: the high-capacity injection that contains Levamlodipine besylate, Losartan Potassium and sodium atorvastatin
| The supplementary material title | Dosage 1 | Dosage 2 | Dosage 3 |
| Sodium atorvastatin | ??10.41g | ??20.82g | ??83.28g |
| Lysine hydrochloride | ??2500.00g | ??5000.00g | ??12500.00g |
| Levamlodipine besylate | ??1.74g | ??3.48g | ??6.96g |
| Losartan Potassium | ??25.00g | ??50.00g | ??100.00g |
| Sodium chloride | In right amount | In right amount | In right amount |
| Water for injection | In right amount | In right amount | In right amount |
| Gross weight | ??50000ml | ??100000ml | ??250000ml |
Preparation method:
Take by weighing Levamlodipine besylate, add an amount of water for injection stirring it is dissolved fully, as solution A; Other takes by weighing sodium atorvastatin and lysine hydrochloride, adds an amount of water for injection stirring and makes its dissolving, as solution B; With solution B, Losartan Potassium and sodium chloride, all pour in the solution A then, stir and make its dissolving, add 0.02%～0.03% active carbon and remove pyrogen, add water and be settled to full dose, stirred 20～30 minutes, earlier with 0.45um filter membrane coarse filtration, reuse 0.22um filter membrane fine straining; Use infusion bottle (having removed pyrogen) to be distributed into 1000 at last, immediately in 45 minutes (F0 〉=8) of 121 ℃ of sterilizations, get final product after packing finishes.
Claims (10)
1. pharmaceutical composition is characterized in that it comprises:
(1) contain wherein any in following two kinds:
(a) Levamlodipine or its pharmaceutically acceptable salt, or
(b) amlodipine or its pharmaceutically acceptable salt;
(2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester;
(3) statins or its pharmaceutically acceptable salt; And
(4) pharmaceutically acceptable carrier.
2. pharmaceutical composition as claimed in claim 1 is characterized in that:
(1) described Levamlodipine is selected from Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine, methanesulfonic acid Levamlodipine, d-camphorsulfonic acid Levamlodipine, nicotinic acid Levamlodipine, pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine, thioctic acid Levamlodipine or its pharmaceutically acceptable salt
Described amlodipine is selected from Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate, amlodipine camsylate, amlodipine niacin, pyroglutamic acid amlodipine, amlodipine gentisate, thioctic acid amlodipine or its pharmaceutically acceptable salt;
(2) described angiotensin ii receptor antagonist is selected from: telmisartan, losartan, valsartan, Olmesartan, irbesartan, Candesartan, eprosartan, Tasosartan, Irb, Ai Lishatan, Abitesartan, Elisartan, Embusartan, Forasartan, milfasartan, Pomisaratan, Pratosartan, Ripisartan, saprisartan, zolasartan or its pharmaceutically acceptable salt or ester;
(3) described statins is selected from: atorvastatin, simvastatin, Pitavastatin, pravastatin, Rosuvastatin, fluvastatin, lovastatin, rosuvastatin, bervastatin, crilvastatin, dalvastatin, lattice logical sequence cut down his spit of fland, mevastatin, for cut down his spit of fland, the Buddhist nun cuts down his spit of fland or its pharmaceutically acceptable salt; And
(4) pharmaceutically acceptable carrier.
3. pharmaceutical composition as claimed in claim 1 is characterized in that:
(1) those medicines of preferably having gone on the market of described Levamlodipine or its pharmaceutically acceptable salt, most preferably Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine and methanesulfonic acid Levamlodipine;
Those medicines that described amlodipine or its pharmaceutically acceptable salt have preferably gone on the market, most preferably Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate and amlodipine maleate;
(2) those medicines of preferably having gone on the market of described angiotensin ii receptor antagonist, most preferably telmisartan, losartan, valsartan, Olmesartan or its pharmaceutically acceptable salt or ester;
(3) those medicines of preferably having gone on the market of described statins, most preferably atorvastatin, simvastatin, Pitavastatin, pravastatin or its pharmaceutically acceptable salt.
4. pharmaceutical composition as claimed in claim 1, it is characterized in that, wherein Levamlodipine is selected from Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine and methanesulfonic acid Levamlodipine, and amlodipine is selected from Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate and amlodipine maleate; Angiotensin ii receptor antagonist is selected from telmisartan, Losartan Potassium, valsartan and olmesartan medoxomil; Statins is selected from Atorvastatin calcium, simvastatin, Pitavastatin Calcium and pravastatin sodium.
5. pharmaceutical composition as claimed in claim 1 is characterized in that:
(1) the effective amount of Levamlodipine besylate is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of maleic acid levo amido chloro diping is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of L-Aspartic Acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of methanesulfonic acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg;
The effective amount of Amlodipine Besylate Tablet is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of L-Aspartic Acid amlodipine is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine mesylate is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of amlodipine maleate is 2.5mg～20mg, more preferably is 2.5mg～10mg;
(2) the effective amount of telmisartan is 20mg～160mg, more preferably is 20mg～80mg; The effective amount of Losartan Potassium is 25mg～200mg, more preferably is 25mg～100mg; The effective amount of valsartan is 20mg～640mg, more preferably is 40mg～320mg; The effective amount of olmesartan medoxomil is 2.5mg～160mg, more preferably is 5mg～40mg;
(3) the effective amount of Atorvastatin calcium is 5mg～160mg, more preferably is 10mg～80mg; The effective amount of simvastatin is 2.5mg～160mg, more preferably is 5mg～80mg; The effective amount of Pitavastatin Calcium is 0.5mg～16mg, more preferably is 1mg～4mg; The effective amount of pravastatin sodium is 2.5mg～160mg, more preferably is 5mg～80mg.
6. pharmaceutical composition as claimed in claim 1 is characterized in that, the dosage form of described pharmaceutical composition is non-controlled release agent type, controlled release agent type or injection; Preferred dosage form is tablet, capsule, dispersible tablet, oral cavity disintegration tablet, chewable tablet, drop pill or injection.
7. pharmaceutical composition as claimed in claim 1 is characterized in that, it can be a compound injection, consists of the following components:
(1) contain wherein any in following two kinds:
(a) Levamlodipine or its pharmaceutically acceptable salt, be preferably nicotinic acid Levamlodipine, pyroglutamic acid Levamlodipine, methanesulfonic acid Levamlodipine and Levamlodipine besylate, wherein the effective amount of nicotinic acid Levamlodipine is 0.625mg～20mg, more preferably is 1.25mg～5mg; The effective amount of pyroglutamic acid Levamlodipine is 0.625mg～20mg, more preferably is 1.25mg～5mg; The effective amount of methanesulfonic acid Levamlodipine is 1.25mg～10mg, more preferably is 1.25mg～5mg; The effective amount of Levamlodipine besylate is 1.25mg～10mg, more preferably is 1.25mg～5mg; Or
(b) amlodipine or its pharmaceutically acceptable salt, be preferably amlodipine niacin, pyroglutamic acid amlodipine, Amlodipine mesylate and Amlodipine Besylate Tablet, wherein the effective amount of amlodipine niacin is 1.25mg～40mg, more preferably is 2.5mg～10mg; The effective amount of pyroglutamic acid amlodipine is 1.25mg～40mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine mesylate is 2.5mg～20mg, more preferably is 2.5mg～10mg; The effective amount of Amlodipine Besylate Tablet is 2.5mg～20mg, more preferably is 2.5mg～10mg;
(2) angiotensin ii receptor antagonist or its pharmaceutically acceptable salt or ester are preferably Losartan Potassium, and wherein the effective amount of Losartan Potassium is 25mg～200mg, more preferably are 25mg～100mg;
(3) statins or its pharmaceutically acceptable salt are preferably pravastatin sodium, fluvastatin sodium, sodium atorvastatin and Pitavastatin sodium, and wherein the effective amount of pravastatin sodium is 2.5mg～160mg, more preferably are 5mg～80mg; The effective amount of fluvastatin sodium is 10mg～160mg, more preferably is 20mg～80mg; The effective amount of sodium atorvastatin is 5mg～160mg, more preferably is 10mg～80mg; The effective amount of Pitavastatin sodium is 0.5mg～16mg, more preferably is 1mg～4mg; And
(4) pharmaceutically acceptable carrier;
Described compound injection can be an injection with small volume, and conventional specification is respectively 1ml, 2ml, 5ml, 10ml and 20ml; Also can high-capacity injection, conventional specification is respectively 50ml, 100ml, 250ml and 500ml; Can also be aseptic freeze-dried powder or sterilized powder packing.
8. pharmaceutical composition as claimed in claim 1, it is characterized in that, described pharmaceutical composition be used for the treatment of mammal (comprising the mankind) all kinds hypertension simultaneously with or without all kinds hyperlipemia, angina pectoris, atherosclerosis, and prevention or the treatment cardiovascular and cerebrovascular disease relevant with hypertension, the sickness rate and/or the mortality rate of minimizing cardiovascular and cerebrovascular disease.
9. pharmaceutical composition as claimed in claim 1, it is characterized in that, described pharmaceutical composition be used for the treatment of the various essential hypertensions of mammal (comprising the people), secondary hypertension, simultaneously with or without all kinds familial or non-familial hyperlipidemia, angina pectoris, atherosclerosis, and prevention or treatment diabetes, diabetic complication, apoplexy, myocardial infarction, cardiac insufficiency, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia and glaucoma, reduce its sickness rate and/or mortality rate.
10. pharmaceutical composition as claimed in claim 1 is characterized in that, described pharmaceutical composition uses once or twice every day, is preferably and only uses once every day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910306617A CN101637609A (en) | 2009-09-06 | 2009-09-06 | Drug composition containing amlodipine, A II receptor antagonist and statins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910306617A CN101637609A (en) | 2009-09-06 | 2009-09-06 | Drug composition containing amlodipine, A II receptor antagonist and statins |
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| Publication Number | Publication Date |
|---|---|
| CN101637609A true CN101637609A (en) | 2010-02-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910306617A Pending CN101637609A (en) | 2009-09-06 | 2009-09-06 | Drug composition containing amlodipine, A II receptor antagonist and statins |
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| CN (1) | CN101637609A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101804055A (en) * | 2010-04-27 | 2010-08-18 | 施慧达药业集团(吉林)有限公司 | Compound medicinal preparation |
| CN103142596A (en) * | 2012-02-21 | 2013-06-12 | 四川大学 | Medicinal composition containing telmisartan and pitavastatin |
| WO2017007287A1 (en) * | 2015-07-08 | 2017-01-12 | 씨제이헬스케어 주식회사 | Pharmaceutical composition containing amlodipine, valsartan, and rosuvastatin |
| JP2017501126A (en) * | 2013-11-29 | 2017-01-12 | ハンミ ファーム． シーオー．， エルティーディー． | Pharmaceutical combination preparation containing amlodipine, losartan and rosuvastatin |
-
2009
- 2009-09-06 CN CN200910306617A patent/CN101637609A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101804055A (en) * | 2010-04-27 | 2010-08-18 | 施慧达药业集团(吉林)有限公司 | Compound medicinal preparation |
| CN103142596A (en) * | 2012-02-21 | 2013-06-12 | 四川大学 | Medicinal composition containing telmisartan and pitavastatin |
| CN103142596B (en) * | 2012-02-21 | 2015-05-06 | 四川大学 | Medicinal composition containing telmisartan and pitavastatin |
| JP2017501126A (en) * | 2013-11-29 | 2017-01-12 | ハンミ ファーム． シーオー．， エルティーディー． | Pharmaceutical combination preparation containing amlodipine, losartan and rosuvastatin |
| WO2017007287A1 (en) * | 2015-07-08 | 2017-01-12 | 씨제이헬스케어 주식회사 | Pharmaceutical composition containing amlodipine, valsartan, and rosuvastatin |
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