CN102000075A - Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride - Google Patents
Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride Download PDFInfo
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- CN102000075A CN102000075A CN2010105854236A CN201010585423A CN102000075A CN 102000075 A CN102000075 A CN 102000075A CN 2010105854236 A CN2010105854236 A CN 2010105854236A CN 201010585423 A CN201010585423 A CN 201010585423A CN 102000075 A CN102000075 A CN 102000075A
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Abstract
The invention relates to a novel pharmaceutical composite containing the following components by weight: 5-160 mg of atorvastatin calcium anhydrides and 0.5-20 mg of amlodipine or pharmaceutically acceptable salts or esters and carriers thereof, wherein the amlodipine or the pharmaceutically acceptable salts or esters thereof are amlodipine besylate, amlodipine maleate, amlodipine mesylate, amlodipine L-aspartate, amlodipine camsilate, amlodipine camsylate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoate, levamlodipine besylate, levamlodipine maleate and levamlodipine mesylate or levamlodipine L-aspartate. The novel pharmaceutical composite is used for preventing or treating cardiovascular and cerebrovascular diseases, reducing the morbidity and/or mortality of the cardiovascular and cerebrovascular diseases and the adverse reaction of pharmaceuticals and also improving the compliance of patients on taking medicines.
Description
Technical field
The present invention relates to a kind of novel medicament compositions, it is made up of the amlodipine of the Atorvastatin calcium anhydride of 5～160mg and 0.5～20mg or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier, wherein said pharmaceutical composition is tablet, capsule, dispersible tablet, bilayer tablet, tri-layer tablets, slow releasing tablet, slow releasing capsule, granule, dry suspension, drop pill, pellet or chewable tablet, be used for prevention or treatment patient cardiovascular and cerebrovascular disease, 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, 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 shows that 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, accounts for 37% and 28% of dead formation respectively; Occupy cause of death first place.
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.
The cohort study of China shows that also it is one of independent hazard factor of coronary heart disease and cerebral infarction that serum total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) raise.For this reason, to the control of dyslipidemia must attach the importance early (non-patent literature 2).Though Chinese population blood lipid level and dyslipidemia prevalence still are lower than most western countries, along with The development in society and economy, the raising of living standards of the people and the variation of life style, the serum TC level of people's group mean just progressively raises.
The Atorvastatin calcium anhydride is a Statins blood lipid regulation medicine, belongs to the HMG-CoA reductase inhibitor.The itself non-activity, 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 cholesterolemia and low-density lipoprotein cholesterol level, moderate reduces serum triglyceride level and increases the blood hdl level, is mainly used in treatment or prevention hypercholesterolemia, combined hyperlipidemia familial, coronary heart disease or apoplexy.
The Atorvastatin calcium anhydride has identical pharmacological action with Atorvastatin calcium trihydrate, atorvastatin calcium solvate, and oral absorption is good, and bioavailability and stability are all higher.
The mechanism of action of amlodipine or its pharmaceutically acceptable salt enters in the cell for the retardance calcium ion, and the vascular smooth muscle that can relax effectively reduces peripheral vascular resistance, the expansion small artery alleviates cardiac afterload, the blood pressure that reduction has been increased; It also has good cardiovascular effect, such as reversing ventricular hypertrophy, improves the lax function of diastole; renal function protecting, slight diuresis, slight antiplatelet; resist myocardial ischemia, arrhythmia increases insulin sensitivity and certain effects such as atherosclerosis.The amlodipine oral absorption is good, and is not subjected to the influence of dietary intake.6～12 hours blood drug level reaches to the peak after the administration, and absolute bioavailability is about 64～80%, and apparent volume of distribution is about 21L/kg, and eventually the end is eliminated the half-life and is about 35～50 hours, once a day, successive administration after 7～8 days blood drug level reach to stable state.
Hypertension usually coexists with hyperlipemia, they the two all be considered to develop into heart disease, finally cause the main hazard factor of disadvantageous heart attack.These risk factors are mainly owing to common mechanism.In addition, the patient who carries out hypertension therapeutic generally is better than the patient who carries out the hyperlipemia treatment.Therefore, these two kinds of diseases being carried out single therapy is favourable to the patient.People such as Jukema are in " circulation ", and 1995 (Suppl.1) disclose calcium channel blocker and lipid lowerers (for example, the HMG-CoA reductase inhibitor) on the 1-197, particularly the evidence of Pravastatin combination and cooperation treatment.People such as Orkhov are at " cardiovascular drugs and treatment " (Cardiovascular Drug and therany), disclose amlodipine on 1997,11,350 and have cut down the atherosclerotic purposes of his spit of fland therapeutic alliance with drawing.
International publication application WO99/11259, U.S. Pat 6486182 (B1), US7129265 (B2), US7834195 (B2), Chinese patent CN1617717A, CN1351492A, CN1268053A, CN1352640A and CN101062035A disclose the combination that comprises amlodipine and atorvastatin, be mainly used in treatment or prevention of arterial and related heart disease, be selected from hypertension, myocardial infarction, hyperlipemia, atherosclerosis, arteriosclerosis, coronary artery disease, mental and physical efforts congestive heart failure, apoplexy or angina pectoris.Therefore, need the patient of double treatment can use this two kinds of medicines during expectation.Wish and to use this two kinds of medicines with the single dose form in addition, even more.
We find astoundingly and unexpectedly, amlodipine and atorvastatin can be mixed with the single dose form, it is stable and has and use the bioavailability of medicine equivalence separately with separate dosage forms, and contains very low-level impurity and/or catabolite.
By the listing of state approvals such as Germany, France, Australia's land productivity, specification is respectively 10mg, 20mg, 40mg and 80mg to Atorvastatin calcium anhydride sheet.
The amlodipine besylate and atorvastatin calcium sheet, in country's listings such as China, the U.S., France, Japan, Italy, Germany, Britain, Australia, Canada, Austria, specification is respectively 2.5mg/10mg, 2.5mg/20mg, 2.5mg/40mg, 5mg/10mg, 5mg/20mg, 5mg/40mg, 5mg/80mg, 10mg/10mg, 10mg/20mg, 10mg/40mg and 10mg/80mg.
Pharmaceutical composition of the present invention, administration every day 1～3 time is preferably once a day, and the patient is very easy to use like this, can prevent the acute variation of blood pressure effectively, makes blood pressure be in more equilibrated state, keeps the normal level of blood fat simultaneously effectively.
Patent documentation 1 discloses the preparation method and the character of Atorvastatin calcium new model, also has these new forms particularly useful in pharmaceutical compositions.
Non-patent literature 1: Chinese hypertension prevention and control guide revised edition in 2005,4-5,9,31-32
Non-patent literature 2: China adult dyslipidemia guideline of prevention and treatment is worked out joint committee. China adult dyslipidemia guideline of prevention and treatment. and Chinese cardiovascular diseases's magazine, 35 (5), in May, 2007,390-419
Patent documentation 1:US2009018182 (A1), JP2008007507 (A), EP1924556 (A2), CA2655881 (A1), KR20080031487 (A), MX2008002804 (A), WO2008002655 (A2)
Patent documentation 2:US6646133 (B1), JP2003512354 (T), CN1379760A
Summary of the invention
The object of the present invention is to provide a kind of novel medicament compositions, it is made up of the amlodipine of the Atorvastatin calcium anhydride of 5～160mg and 0.5～20mg or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier; Wherein said amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate, amlodipine niacin, the pyroglutamic acid amlodipine, amlodipine gentisate, the thioctic acid amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, the methanesulfonic acid Levamlodipine, L-Aspartic Acid Levamlodipine, the camphorsulfonic acid Levamlodipine, the d-camphorsulfonic acid Levamlodipine, the nicotinic acid Levamlodipine, the pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine or thioctic acid Levamlodipine.
Another object of the present invention is also to provide that aforementioned pharmaceutical compositions is used for preventing in preparation, the application of the medicine of delay of progression or treatment patient cardiovascular and cerebrovascular disease.
The technical scheme that the present invention solves is as follows:
(1) a kind of pharmaceutical composition is characterized in that, it consists of the following components:
(I) the Atorvastatin calcium anhydride of 5～160mg;
(II) amlodipine of 0.5～20mg or its pharmaceutically acceptable salt or ester; And
(III) at least a pharmaceutically acceptable carrier.
The pharmaceutical preparation of pharmaceutical composition of the present invention is pharmaceutically acceptable various dosage form, is selected to be non-controlled release agent type, controlled release agent type or injection;
Wherein non-controlled release agent type is selected from: tablet, capsule, bilayer tablet, multilayer tablet, enteric coatel tablets, enteric coated capsule, drop pill, pellet, pill, dispersible tablet, granule, dry suspension, effervescent tablet, powder, oral cavity disintegration tablet, chewable tablet, oral suspensions, oral solution, Orally taken emulsion, buccal tablet, Sublingual tablet, tincture, suppository, ointment, aerosol, spray, membrane, Emulsion, liniment, gel or the agent of transdermal card; The controlled release agent type is selected from: slow releasing tablet, slow releasing capsule, controlled release tablet or controlled release capsule; Injection is selected from: small-volume injection, aseptic freeze-dried powder pin, sterilized powder packing or bulk capacity injection;
Be preferably tablet, capsule, dispersible tablet, bilayer tablet, tri-layer tablets, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, granule, dry suspension, drop pill, pellet, chewable tablet or oral cavity disintegration tablet; More preferably tablet, capsule, dispersible tablet, bilayer tablet, slow releasing tablet, slow releasing capsule, granule, dry suspension, drop pill, pellet or chewable tablet; More preferably tablet, capsule, dispersible tablet, bilayer tablet or chewable tablet.
The Atorvastatin calcium anhydride of 5～160mg of the present invention is pressed atorvastatin and is calculated, and unit dose is 5～160mg, is preferably 5mg～80mg, more preferably 10mg～80mg, more preferably 5mg, 10mg, 20mg, 30mg, 40mg or 80mg.
The chemical name of Atorvastatin calcium anhydride is: [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-Methylethyl)-3-phenyl-4-[(anilino-) carbonyl]-1H-pyrroles-1-Calcium salt enanthate (2: 1), English name is Atorvastatin Calcium anhydrous, and molecular formula is C
66H
68CaF
2N
40
10, molecular weight is 1155.33, its chemical structural formula is suc as formula shown in (A):
The Atorvastatin calcium anhydride can crystallization, partially crystallizable, amorphous forms or polycrystalline form exist, also can laevoisomer, dextroisomer, racemic modification or optical isomer exist.Patent documentation EP409281A1, US5273995A, US6486182 (B1), CN1352640A, US7129265 (B2), CN1351492A, CN1617717A, CN1268052A, US7834195 (B2), WO2008089557 (A1), CN1843357A, CN101433539A, CN1827104A, CN101199523A, CN101433539A, CN101468001A, CN101062035A, CN101185646A, EP459136, US5196444, CN101268047A, CN1157374C, CN1489463A, CN1260213C, CN101027282A, CN101048141A, CN101215253A, US5969156A, US6121461A, CN101370774A, CN1630510A, CN1423634A, CN101805279A, CN101613312A, CN1942439A, CN1997651A, CN101560176A, CN101437791A, CN101643443A, CN1351493A, CN1680315A, CN1960972A, CN101492406A, CN1379760A, CN1487921A, CN101684090A, CN101892276AA, CN101560177A, CN101124230A, CN101683333A, CN1543468A, CN101395132A, CN101437791A, CN101492406A, CN101600688A, CN101643443A, CN101862329A, CN101804029A, CN101684090, US6646133 (B1), JP2003512354 (T), those that CN1379760A announced are incorporated herein by reference this in full at this.
The amlodipine of 0.5～20mg of the present invention or its pharmaceutically acceptable salt or ester, comprise Levamlodipine or its pharmaceutically acceptable salt or ester, be selected from: Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate, amlodipine niacin, the pyroglutamic acid amlodipine, amlodipine gentisate, the thioctic acid amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, the methanesulfonic acid Levamlodipine, L-Aspartic Acid Levamlodipine, the camphorsulfonic acid Levamlodipine, the d-camphorsulfonic acid Levamlodipine, the nicotinic acid Levamlodipine, the pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine or thioctic acid Levamlodipine; Be preferably Amlodipine Besylate Tablet, Levamlodipine besylate, amlodipine maleate, maleic acid levo amido chloro diping, Amlodipine mesylate or L-Aspartic Acid amlodipine, more preferably Amlodipine Besylate Tablet or Levamlodipine besylate; Press amlodipine or Levamlodipine respectively and calculate, unit dose is 0.5～20mg, is preferably 1.25～10mg, more preferably 2.5～10mg, more preferably 0.625mg, 1.25mg, 2.5mg, 5mg or 10mg.
The chemical name of amlodipine is 3-ethyl-5-methyl-2-(the amino ethoxymethyl of 2-)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3, and 5-pyridine dicarboxylate, English name are Amlodipine, molecular formula is C
20H
25ClN
2O
5, molecular weight is 408.88, its chemical structural formula is suc as formula shown in (B):
Amlodipine or its pharmaceutically acceptable salt or ester can crystallizations, partially crystallizable or amorphous forms, solvate especially hydrate or polycrystalline form exist, also can laevoisomer, dextroisomer, raceme or optical isomer exist.Patent documentation US4572909A, EP0089167 (A2), CN1267669A, CN1263525A, CN1678583A, CN1263093A, CN101209991A, CN1678584A, CN1609102A, CN1681786A, CN1343663A, CN1695618A, CN1495166A, CN1496353A, CN1501916A, CN1915974A, CN1850801A, CN1882543A, CN1927837A, CN1927836A, CN1956956A, CN101111478A, CN101307020A, CN101495451A, CN1879621A, CN101316820A, CN1263093A, CN101481348A, CN101507715A, CN101528696A, CN101530396A, CN101528697A, CN1695617A, CN101544597A, CN101560181A, CN101570506A, CN101648903A, CN1370532A, CN101611003A, CN101654429A, CN101230035A, CN101798280A, CN101531629A, CN1505614A, CN1681785A, CN1608051A, CN101812014A, CN1352634A, those that CN1777586A announced are incorporated herein by reference this in full at this.
Pharmaceutically acceptable carrier of the present invention is art-recognized, and refer to participate in to deliver or transport any theme composition or its component pharmaceutically acceptable material, component or carrier from the part of an organ or health to the part of another organ or health, as liquid or solid filler, diluent, excipient, solvent or encapsulating material.With theme composition and the compatible meaning of component thereof on, every kind of carrier must be acceptable and be harmless to the patient.Some examples that can be used as the material of pharmaceutically acceptable excipient comprise: (a) saccharide, as lactose, dextrose plus saccharose; (b) starch based is as corn starch and potato starch; (c) cellulose and derivant thereof are as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (d) pulverous Tragacanth; (e) Fructus Hordei Germinatus; (f) gelatin; (g) Talcum; (h) excipient is as cupu oil and suppository wax; (i) oils is as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (j) glycols is as propylene glycol; (k) polyalcohols is as glycerol, Sorbitol, mannitol and Polyethylene Glycol; (l) esters is as ethyl oleate and ethyl laurate; (m) agar; (n) buffer agent class is as magnesium hydroxide and aluminium hydroxide; (o) alginic acid; (p) pyrogen-free water; (q) isotonic saline solution; (r) fluid used of intravenous includes but not limited to Ringer's mixture, contains the water of 5% glucose and manages saline half a lifetime; (s) ethanol; (t) phosphate buffer; (v) used nontoxic compatible material in the other drug preparation.
Described pharmaceutically acceptable carrier is selected from diluent, disintegrating agent, binding agent, lubricant, fluidizer, wetting agent, correctives, aromatic, coloring agent, dissolubility promoter or its mixture.The amount of pharmaceutically acceptable every kind of carrier in pharmaceutical composition can change in the normal ranges of this area.
Suitable diluent can be selected from microcrystalline Cellulose, optimize microcrystalline Cellulose, Powderd cellulose, saccharide, sugar derivatives, mannitol, lactose, sorbitol, Polyethylene Glycol, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, sodium bicarbonate, surfactant, correctives, aromatic, coloring agent or its mixture; Suitable disintegrants can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, L-hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, dried starch or its mixture;
Suitable bonding can be selected from polyvidone, 30 POVIDONE K 30 BP/USP 30, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, Cellulose ethyl hydroxypropyl ether, pre-paying starch, Icing Sugar, starch, syrup, starch slurry, gelatin, mannitol, sorbitol, N-vinyl pyrrolidone or its mixture;
Examples of suitable lubricants can be selected from magnesium stearate, calcium stearate, stearic acid, calcium silicates, Pulvis Talci or its mixture;
Suitable fluidizer can be selected from micropowder silica gel, magnesium trisilicate, cellulose powder, starch, Pulvis Talci or its mixture;
Suitable wetting agent or solvent can be selected from water, ethanol, Polyethylene Glycol or ethanol water; Be preferably water or ethanol water; Ethanol water is preferably 30%～90% ethanol water;
Suitable correctives is selected from cane sugar powder, sucralose, steviosin, saccharin sodium, aspartame, lactose or its mixture;
Suitable aromatic is selected from water quality essence, emulsifying essence, Water/oil dual-purpose essence, panchromatic essence or its mixture, preferably from fresh milk powder essence, strawberry essence, apple essence, flavoring banana essence, flavoring pineapple essence, flavoring orange essence, honey peach essence, Fructus Citri Limoniae essence, fragrant citrus essence, hami melon essence, Fructus Fragariae Ananssae powdered flavor, Fructus Ananadis comosi powdered flavor or its mixture;
Suitable coloring agent be selected from carmine, lemon yellow, sunset yellow, amaranth, erythrosine, newly red, the red pigment of cowberry of red, indigo, light blue, capsanthin, beet red, lac, red rice is red or its mixture;
Suitable dissolubility promoter or dissolution promoter can be selected from polyvinylpolypyrrolidone, polyvidone, sodium lauryl sulphate, polyoxyethylene sorbitan monoleate or its mixture.
Pharmaceutically acceptable salt of the present invention or ester refer to can be according to normally used nontoxic salt or ester or derivatives thereof in the pharmaceutical industries of method preparation well known in the art.On the one hand, based on inorganic acid salts such as the halogen acid salt of the preferred hydrofluoride of the salt of basic group, hydrochlorate, hydrobromate, hydriodate and so on, nitrate, perchlorate, sulfate, phosphate; Acylates such as the aromatic sulfonic acid salt of the lower alkane sulfonate of mesylate, fluoroform sulphonate, esilate and so on, benzene sulfonate, tosilate and so on, maleate, acetate, malate, fumarate, hemifumarate, succinate, citrate, succinate, Ascorbate, tartrate, acetate, trifluoroacetate, lactate, malonate, tosilate, oxalates; And the amino acid salts of glycinate, lysinate, arginine salt, ornithine salt, glutamate, Glu, aspartate and so on; On the other hand, based on alkali salt, the aluminum salt of the alkali metal salt of the salt particular certain cancers of acidic-group, potassium salt, lithium salts and so on, calcium salt, magnesium salt and so on, slaines such as iron salt; The inorganic salt of ammonium salt and so on, t-octanylamine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucosamine salt, guanidinesalt, diethyl amine salt, triethylamine salt, hexanamine salt, N, the amine salt such as organic salt of N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-1-phenylethylamine salt, piperazine salt, tetramethyl ammonium, three (methylol) aminomethane salt and so on; And the amino acid salts of glycinate, lysinate, arginine salt, ornithine salt, glutamate, Glu, aspartate and so on.Should be understood that described nontoxic salt or ester comprise pharmaceutically acceptable pharmacological activity derivant, or with the chemical compound of its significant correlation, include but not limited to mixture, crystallization, partially crystallizable, amorphous forms or polycrystalline form, solvate, hydrate, oxide, fragment or the radiosiotope of any ratio of salt or ester, pharmaceutically acceptable salt or ester, prodrug, active metabolite, various isomer or these isomers.
Pharmaceutical composition of the present invention can prepare with the conventional method in the pharmaceuticals industry; Can adopt wet granulation, dry granulation, fluidized bed granulation, spray-drying process, wet-mixed granulation, spherocrystal pelletize or solid dispersion to granulate; Can adopt the direct powder compression tabletting; Also can adopt bilayer or multilamellar tabletting; Can randomly carry out film coating or sweet tablet; Can be the gastric solubleness coating, also can be enteric coating.
The purposes of pharmaceutical composition of the present invention is preferred for prevention, delay of progression or treatment patient cardiovascular and cerebrovascular disease.
(2) as the described pharmaceutical composition of claim (1), it is characterized in that, the weight ratio of described Atorvastatin calcium anhydride and amlodipine or its pharmaceutically acceptable salt or ester is 0.5～128: 1, be preferably 0.5～64: 1, more preferably 1～64: 1, more preferably 1～32: 1, the weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described amlodipine or its pharmaceutically acceptable salt or ester press amlodipine calculating.
Term " weight of described amlodipine or its pharmaceutically acceptable salt or ester press amlodipine calculate " means if amlodipine or its pharmaceutically acceptable salt or ester, and then weight press amlodipine calculating; If Levamlodipine or its pharmaceutically acceptable salt or ester, then weight is pressed Levamlodipine calculating.
(3) as claim (1), (2) each described pharmaceutical composition, it is characterized in that described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate, amlodipine niacin, the pyroglutamic acid amlodipine, amlodipine gentisate, the thioctic acid amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, the methanesulfonic acid Levamlodipine, L-Aspartic Acid Levamlodipine, the camphorsulfonic acid Levamlodipine, the d-camphorsulfonic acid Levamlodipine, the nicotinic acid Levamlodipine, the pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine or thioctic acid Levamlodipine;
Be preferably Amlodipine Besylate Tablet, Levamlodipine besylate, amlodipine maleate, maleic acid levo amido chloro diping, Amlodipine mesylate or L-Aspartic Acid amlodipine; More preferably Amlodipine Besylate Tablet or Levamlodipine besylate.
(4) as each described pharmaceutical composition of claim (1) to (3), it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine Besylate Tablet, and Atorvastatin calcium anhydride and Amlodipine Besylate Tablet are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described Amlodipine Besylate Tablet is pressed amlodipine and calculated.
(5) as each described pharmaceutical composition of claim (1) to (3), it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine maleate, and Atorvastatin calcium anhydride and amlodipine maleate are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 5mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 5mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 5mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 10mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 10mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 10mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 10mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 20mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 20mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 20mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 20mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 40mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 40mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 40mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 40mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 80mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 80mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 80mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 80mg and amlodipine maleate 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described amlodipine maleate is pressed amlodipine and calculated.
(6) as each described pharmaceutical composition of claim (1) to (3), it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine mesylate, and Atorvastatin calcium anhydride and Amlodipine mesylate are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described Amlodipine mesylate is pressed amlodipine and calculated.
(7) as each described pharmaceutical composition of claim (1) to (3), it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are L-Aspartic Acid amlodipine, and Atorvastatin calcium anhydride and L-Aspartic Acid amlodipine are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described L-Aspartic Acid amlodipine is pressed amlodipine and calculated.
(8) as each described pharmaceutical composition of claim (1) to (3), it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are Levamlodipine besylate, and Atorvastatin calcium anhydride and Levamlodipine besylate are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 5mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described Levamlodipine besylate is pressed Levamlodipine and calculated.
(9) as each described pharmaceutical composition of claim (1) to (8), it is characterized in that described pharmaceutical composition is tablet, capsule, dispersible tablet, bilayer tablet, tri-layer tablets, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, granule, dry suspension, drop pill, pellet, chewable tablet or oral cavity disintegration tablet; Be preferably tablet, capsule, dispersible tablet, bilayer tablet, slow releasing tablet, slow releasing capsule, granule, dry suspension, drop pill, pellet or chewable tablet; More preferably tablet, capsule, dispersible tablet, bilayer tablet or chewable tablet.
(10) as each described pharmaceutical composition of claim (1) to (9) be used for preventing in preparation, the application of the medicine of delay of progression or treatment patient cardiovascular and cerebrovascular disease.
Term " patient " refers to animal, preferred mammal, and optimum is chosen, and comprises masculinity and femininity.
Term " cardiovascular and cerebrovascular disease " is selected from but is not limited to following disease or disease: hypertension, dyslipidemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, apoplexy, angina pectoris, hypertension or angina pectoris merge hypercholesterolemia or combined hyperlipidemia familial; Be preferably hypertension or angina pectoris and merge hypercholesterolemia or combined hyperlipidemia familial.
Term " dyslipidemia " be often referred in the blood plasma cholesterol and (or) the sweet ester of glycerol (TG) raises, and is commonly called as hyperlipemia.In fact hyperlipemia is also made a general reference the various dyslipidemia that comprise the low hdl mass formed by blood stasis.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment.
Embodiment 1: the tablet that comprises Atorvastatin calcium anhydride and Amlodipine Besylate Tablet
※ Atorvastatin calcium anhydride 10.36mg is equivalent to atorvastatin 10.00mg; Amlodipine Besylate Tablet 6.93mg is equivalent to amlodipine 5.00mg, down together.
Preparation method:
(I) the particulate granulation of Atorvastatin calcium anhydride:
(A) various solid supplementary materials are crossed 80 mesh sieves, standby;
(B) 30 POVIDONE K 30 BP/USP 30 is dissolved in the purified water, mix homogeneously is done binding agent and is used;
(C) in granulator, mix Atorvastatin calcium anhydride, lactose monohydrate, magnesium carbonate and polyvinylpolypyrrolidone;
(D) will mix from the mixture of powders of step (C) with from the solution of step (B) in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 6.0～9.0, makes wet granular with 24 mesh sieves;
(E) dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 3.0% with 18 mesh sieve granulate at last;
(II), preparation at last
(F) in the Atorvastatin calcium anhydride granule that step (I) obtains, add Amlodipine Besylate Tablet, microcrystalline Cellulose, polyvinylpolypyrrolidone and micropowder silica gel;
(G) with the mill mixture of powders of milling, make it become satisfactory thin sprills;
(H) in the mixture of powders of milling, add magnesium stearate, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step (G);
(I) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into tablet with sheeting equipment, makes 1000, promptly.
Embodiment 2: the capsule that comprises Atorvastatin calcium anhydride and amlodipine maleate
※ amlodipine maleate 6.40mg is equivalent to amlodipine 5.00mg.
Preparation method:
(I) the particulate granulation of Atorvastatin calcium anhydride:
(A) various solid supplementary materials are crossed 80 mesh sieves, standby;
(B) be dissolved in polyoxyethylene sorbitan monoleate in the purified water and add 30 POVIDONE K 30 BP/USP 30, mixing;
(C) in granulator, mix Atorvastatin calcium anhydride, microcrystalline Cellulose, magnesium carbonate and carboxymethylstach sodium;
(D) will mix from the mixture of powders of step (C) with from the solution of step (B) in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 6.0～9.0, makes wet granular with 30 mesh sieves;
(E) dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 3.0% with 18 mesh sieve granulate at last;
(II), preparation at last
(F) in the Atorvastatin calcium anhydride granule that step (I) obtains, add amlodipine maleate, microcrystalline Cellulose, carboxymethylstach sodium and micropowder silica gel;
(G) with the mill mixture of powders of milling, make it become satisfactory thin sprills;
(H) in the mixture of powders of milling, add magnesium stearate, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step (G);
(I) measure intermediate content, it is heavy to calculate sheet according to assay, is distributed into capsule with the granule dispensing apparatus, makes 1000, promptly.
Embodiment 3: the dispersible tablet that comprises Atorvastatin calcium anhydride and Amlodipine mesylate
※ Amlodipine mesylate 6.42mg is equivalent to amlodipine 5.00mg.
Preparation method:
(I) the particulate granulation of Atorvastatin calcium anhydride:
(A) various solid supplementary materials are crossed 80 mesh sieves, standby;
(B) be dissolved in polyoxyethylene sorbitan monoleate and fresh milk powder essence in 30% alcoholic solution and add 30 POVIDONE K 30 BP/USP 30, mix homogeneously;
(C) in granulator, mix Atorvastatin calcium anhydride, lactose monohydrate, calcium carbonate, sucralose and carboxymethylstach sodium;
(D) will mix from the mixture of powders of step (C) with from the solution of step (B) in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 6.0～9.0, makes wet granular with 24 mesh sieves;
(E) dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 3.0% with 18 mesh sieve granulate at last;
(II), preparation at last
(F) in the Atorvastatin calcium anhydride granule that step (I) obtains, add Amlodipine mesylate, microcrystalline Cellulose, carboxymethylstach sodium and micropowder silica gel;
(G) with the mill mixture of powders of milling, make it become satisfactory thin sprills;
(H) in the mixture of powders of milling, add magnesium stearate, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step (G);
(I) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into dispersible tablet with sheeting equipment, makes 1000, promptly.
Embodiment 4: the bilayer tablet that comprises Atorvastatin calcium anhydride and Levamlodipine besylate
※ Levamlodipine besylate 3.47mg is equivalent to amlodipine 2.50mg.
Preparation method:
(I) the particulate granulation of Atorvastatin calcium anhydride:
(A) various solid supplementary materials are crossed 80 mesh sieves, standby;
(B) be dissolved in polyoxyethylene sorbitan monoleate in the purified water and add 30 POVIDONE K 30 BP/USP 30, mix homogeneously;
(C) in granulator, mix Atorvastatin calcium anhydride, lactose monohydrate, magnesium carbonate and polyvinylpolypyrrolidone;
(D) will mix from the mixture of powders of step (C) with from the solution of step (B) in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 6.0～9.0, makes wet granular with 24 mesh sieves;
(E) dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 3.0% with 18 mesh sieve granulate at last;
(F) in from the granule of step (E), add magnesium stearate and micropowder silica gel, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix, make Atorvastatin calcium anhydride granule, standby;
(G) drug content in the mensuration Atorvastatin calcium anhydride granule, it is heavy to calculate sheet;
(II) the particulate granulation of Levamlodipine besylate
(H) 30 POVIDONE K 30 BP/USP 30 is dissolved in the purified water, does binding agent and use;
(I) in granulator, mix Atorvastatin calcium anhydride, lactose monohydrate and carboxymethylstach sodium;
(J) will mix from the mixture of powders of step (I) with from the solution of step (H) in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 6.0～9.0, makes wet granular with 24 mesh sieves;
(L) dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 3.0% with 18 mesh sieve granulate at last;
(M) in from the granule of step (L), add magnesium stearate and micropowder silica gel, and in mixing apparatus such as V-Mixer or three-dimensional movement mixer, mix, make the Levamlodipine besylate granule, standby;
(N) drug content in the mensuration Levamlodipine besylate granule, it is heavy to calculate sheet;
(III) be pressed into bilayer tablet:
(O) use double-deck rotary tablet machine that Atorvastatin calcium anhydride granule is pressed into ground floor, subsequently the Levamlodipine besylate granule is pressed into the second layer, promptly get the bilayer tablet that comprises Atorvastatin calcium anhydride and Levamlodipine besylate, make 1000.
Embodiment 5: the chewable tablet that comprises Atorvastatin calcium anhydride and L-Aspartic Acid amlodipine
※ L-Aspartic Acid amlodipine 6.64mg is equivalent to amlodipine 5.00mg.
Preparation method:
(I) the particulate granulation of Atorvastatin calcium anhydride:
(A) various solid supplementary materials are crossed 80 mesh sieves, standby;
(B) be dissolved in polyoxyethylene sorbitan monoleate, 0.5% cochineal solution, 0.25% lemon yellow solution and fresh milk powder essence in 30% alcoholic solution and add 30 POVIDONE K 30 BP/USP 30, mix homogeneously;
(C) in granulator, mix Atorvastatin calcium anhydride, calcium carbonate, lactose monohydrate, sucralose and carboxymethylstach sodium;
(D) will mix from the mixture of powders of step (C) with from the solution of step (B) in granulator, the limit edged stirs, and makes suitable soft material, and regulating its pH value in case of necessity is 6.0～9.0, makes wet granular with 24 mesh sieves;
(E) dried particles in drying equipment, dry back makes moisture (loss on drying) be less than or equal to 3.0% with 18 mesh sieve granulate at last;
(II), preparation at last
(F) in the Atorvastatin calcium anhydride granule that step (I) obtains, add L-Aspartic Acid amlodipine, lactose monohydrate, carboxymethylstach sodium and micropowder silica gel;
(G) with the mill mixture of powders of milling, make it become satisfactory thin sprills;
(H) in the mixture of powders of milling, add magnesium stearate, and in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer, mix from step (G);
(I) measure intermediate content, it is heavy to calculate sheet according to assay, is pressed into chewable tablet with sheeting equipment, makes 1000, promptly.
Embodiment 6: study on the stability
The pharmaceutical composition of getting the embodiment of the invention 1～5 preparation is that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% the condition in temperature, carry out accelerated test, respectively at sampling at 0,1,2,3,6 the end of month once, measure, the results are shown in following table by the high spot reviews project:
※ 96.2/91.3 represents amlodipine 96.2/ atorvastatin 91.3.
Result of the test shows, the total impurities of two kinds of principal agents of sample of the embodiment of the invention 1～5 preparation is about 0.5%, dissolution is about 97%/90%, every testing result does not all have obvious variation, illustrate by the pharmaceutical composition that comprises amlodipine and Atorvastatin calcium anhydride of the present invention preparation improve dissolution and stable aspect its superiority is arranged.
The accumulation dissolution rate curve of the embodiment of the invention 1～4 is seen accompanying drawing 1,2.
Testing instruments model and producer:
(A), LC-20A/SPD-20AV type high performance liquid chromatograph (day island proper Tianjin company)
(B), ZRS-8G type intelligence dissolution test instrument (Tianjin was sent out company in huge day)
(C), BSA124S type ten thousand/electronic balance (Beijing Sai Duolisi company)
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.In addition, patent documentation that the present invention quoted and non-patent literature are incorporated herein by reference this in full at this.
Claims (10)
1. pharmaceutical composition is characterized in that it consists of the following components:
(I) the Atorvastatin calcium anhydride of 5～160mg;
(II) amlodipine of 0.5～20mg or its pharmaceutically acceptable salt or ester; And
(III) pharmaceutically acceptable carrier.
2. pharmaceutical composition as claimed in claim 1, it is characterized in that, the weight ratio of described Atorvastatin calcium anhydride and amlodipine or its pharmaceutically acceptable salt or ester is 0.5～128: 1, the weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described amlodipine or its pharmaceutically acceptable salt or ester is pressed amlodipine and calculated.
3. as claim 1,2 each described pharmaceutical compositions, it is characterized in that described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine Besylate Tablet, amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate, amlodipine niacin, the pyroglutamic acid amlodipine, amlodipine gentisate, the thioctic acid amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, the methanesulfonic acid Levamlodipine, L-Aspartic Acid Levamlodipine, the camphorsulfonic acid Levamlodipine, the d-camphorsulfonic acid Levamlodipine, the nicotinic acid Levamlodipine, the pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine or thioctic acid Levamlodipine.
4. as each described pharmaceutical composition of claim 1 to 3, it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine Besylate Tablet, and Atorvastatin calcium anhydride and Amlodipine Besylate Tablet are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 5mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 10mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 20mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 40mg and Amlodipine Besylate Tablet 10mg;
Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 1.25mg; Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 2.5mg; Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 5mg; Atorvastatin calcium anhydride 80mg and Amlodipine Besylate Tablet 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described Amlodipine Besylate Tablet is pressed amlodipine and calculated.
5. as each described pharmaceutical composition of claim 1 to 3, it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine maleate, and Atorvastatin calcium anhydride and amlodipine maleate are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 5mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 5mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 5mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 10mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 10mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 10mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 10mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 20mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 20mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 20mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 20mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 40mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 40mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 40mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 40mg and amlodipine maleate 10mg;
Atorvastatin calcium anhydride 80mg and amlodipine maleate 1.25mg; Atorvastatin calcium anhydride 80mg and amlodipine maleate 2.5mg; Atorvastatin calcium anhydride 80mg and amlodipine maleate 5mg; Atorvastatin calcium anhydride 80mg and amlodipine maleate 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described amlodipine maleate is pressed amlodipine and calculated.
6. as each described pharmaceutical composition of claim 1 to 3, it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine mesylate, and Atorvastatin calcium anhydride and Amlodipine mesylate are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 5mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 10mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 20mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 40mg and Amlodipine mesylate 10mg;
Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 1.25mg; Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 2.5mg; Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 5mg; Atorvastatin calcium anhydride 80mg and Amlodipine mesylate 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described Amlodipine mesylate is pressed amlodipine and calculated.
7. as each described pharmaceutical composition of claim 1 to 3, it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are L-Aspartic Acid amlodipine, and Atorvastatin calcium anhydride and L-Aspartic Acid amlodipine are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 5mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 10mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 20mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 40mg and L-Aspartic Acid amlodipine 10mg;
Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 1.25mg; Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 2.5mg; Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 5mg; Atorvastatin calcium anhydride 80mg and L-Aspartic Acid amlodipine 10mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described L-Aspartic Acid amlodipine is pressed amlodipine and calculated.
8. as each described pharmaceutical composition of claim 1 to 3, it is characterized in that, described amlodipine or its pharmaceutically acceptable salt or ester are Levamlodipine besylate, and Atorvastatin calcium anhydride and Levamlodipine besylate are selected from the combination of following fixed dosage:
Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 5mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 10mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 20mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 40mg and Levamlodipine besylate 5mg;
Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 0.625mg; Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 1.25mg; Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 2.5mg; Atorvastatin calcium anhydride 80mg and Levamlodipine besylate 5mg;
The weight of wherein said Atorvastatin calcium anhydride is pressed atorvastatin and is calculated, and the weight of described Levamlodipine besylate is pressed Levamlodipine and calculated.
9. as each described pharmaceutical composition of claim 1 to 8, it is characterized in that described pharmaceutical composition is tablet, capsule, dispersible tablet, bilayer tablet, tri-layer tablets, slow releasing tablet, slow releasing capsule, controlled release tablet, controlled release capsule, granule, dry suspension, drop pill, pellet, chewable tablet or oral cavity disintegration tablet.
As each described pharmaceutical composition of claim 1 to 9 be used for preventing in preparation, the application of the medicine of delay of progression or treatment patient cardiovascular and cerebrovascular disease.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105854236A CN102000075A (en) | 2010-12-11 | 2010-12-11 | Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105854236A CN102000075A (en) | 2010-12-11 | 2010-12-11 | Novel pharmaceutical composite containing amlodipine and atorvastatin calcium anhydride |
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| CN102000075A true CN102000075A (en) | 2011-04-06 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102342936A (en) * | 2011-07-20 | 2012-02-08 | 海南锦瑞制药股份有限公司 | Medicinal composition of amlodipine and atorvastatin calcium and its preparation method |
| CN104825449A (en) * | 2014-02-12 | 2015-08-12 | 天津药物研究院 | Compound composition containing atorvastatin calcium and amlodipine and preparation method of same |
| CN105012257A (en) * | 2015-08-06 | 2015-11-04 | 北京嘉林药业股份有限公司 | Method for preparing amlodipine atorvastatin calcium tablets |
| CN105012258A (en) * | 2015-08-06 | 2015-11-04 | 北京嘉林药业股份有限公司 | Preparation method of atorvastatin calcium and amlodipine tablets |
-
2010
- 2010-12-11 CN CN2010105854236A patent/CN102000075A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102342936A (en) * | 2011-07-20 | 2012-02-08 | 海南锦瑞制药股份有限公司 | Medicinal composition of amlodipine and atorvastatin calcium and its preparation method |
| CN102342936B (en) * | 2011-07-20 | 2014-12-24 | 海南锦瑞制药有限公司 | Medicinal composition of amlodipine and atorvastatin calcium and its preparation method |
| CN104825449A (en) * | 2014-02-12 | 2015-08-12 | 天津药物研究院 | Compound composition containing atorvastatin calcium and amlodipine and preparation method of same |
| CN105012257A (en) * | 2015-08-06 | 2015-11-04 | 北京嘉林药业股份有限公司 | Method for preparing amlodipine atorvastatin calcium tablets |
| CN105012258A (en) * | 2015-08-06 | 2015-11-04 | 北京嘉林药业股份有限公司 | Preparation method of atorvastatin calcium and amlodipine tablets |
| CN105012258B (en) * | 2015-08-06 | 2017-11-03 | 北京嘉林药业股份有限公司 | The preparation method of Atorvastatin calcium and Amlodipine tablet |
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Application publication date: 20110406 |