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CN102038683A - Tablet containing amlodipine ester and candesartan ester and application thereof - Google Patents

Tablet containing amlodipine ester and candesartan ester and application thereof Download PDF

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CN102038683A
CN102038683A CN2010105943367A CN201010594336A CN102038683A CN 102038683 A CN102038683 A CN 102038683A CN 2010105943367 A CN2010105943367 A CN 2010105943367A CN 201010594336 A CN201010594336 A CN 201010594336A CN 102038683 A CN102038683 A CN 102038683A
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amlodipine
candesartan cilexetil
candesartan
ester
pharmaceutically acceptable
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王定豪
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Abstract

The invention relates to a novel tablet. The tablet comprises 2-64mg of candesartan or a pharmaceutically acceptable salt or ester of candesartan, 0.3-20mg of amlodipine or a pharmaceutically acceptable salt or ester of amlodipine and a pharmaceutically acceptable carrier, wherein the candesartan or a pharmaceutically acceptable salt or ester of candesartan is candesartan ester; and the amlodipine or a pharmaceutically acceptable salt or ester of amlodipine is amlodipine maleate, amlodipine mesylate, amlodipine L-aspartic acid, amlodipine camphorsulfonate, amlodipine camsylate, amlodipine nicotinate, amlodipine pyroglutamate, amlodipine gentisate, amlodipine lipoic acid or L-amlodipine besylate. The tablet is used for preventing and delaying the progress of hypertension or the diseases related to hypertension or treating hypertension or the diseases related to hypertension of the patients, reduces morbidity and/or mortality of cardio-cerebrovascular diseases, reduces adverse reactions of medicines and simultaneously improves the administration compliance of the patients.

Description

Comprise the tablet and the application thereof of amlodipine and candesartan Cilexetil
Technical field
The present invention relates to a kind of novel tablet, it is made up of the amlodipine of the Candesartan of 2～64mg or its pharmaceutically acceptable salt or ester and 0.3～20mg or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier, wherein said Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate or Levamlodipine besylate, be used for prevention, delay of progression or treatment patient's hypertension or its relevant disease belong to medical technical field.
Background technology
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, 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 (with reference to non-patent literature 1,2) such as heart and brain kidney that cause of alleviating hypertension.
Relevant literature research shows, 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's (with reference to non-patent literature 1) who recommends to adopt the compound preparation that comprises the dosage fixed mixing ratio.
Candesartan or its pharmaceutically acceptable salt or ester are selectivity angiotensin-ii receptor (AT1) antagonist, by the vasoconstriction effect of the nervous plain II of antagonizing vessel with vascular smooth muscle AT1 receptors bind, thereby reduce peripheral vascular resistance; Candesartan also can be brought into play certain hypotensive effect by suppressing the acth secretion aldosterone.Candesartan has than the more superior characteristics of angiotensin-convertion enzyme inhibitor (ACEI), does not increase Kallidin I effect due to the ACE enzyme, thereby can not cause the side effect of cough.
The mechanism of action of amlodipine or its pharmaceutically acceptable salt or ester 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.
The administering drug combinations of Candesartan and two kinds of antihypertensive drugs of amlodipine, can be used for prevention, delay of progression or treatment patient essential hypertension, secondary hypertension, angina pectoris, arteriosclerosis, myocardial infarction, cardiac insufficiency, dyslipidemia, diabetes, diabetic complication, apoplexy, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia, glaucoma or Alzheimer, reduce the sickness rate and/or the mortality rate of cardiovascular and cerebrovascular disease, reduce the untoward reaction of medicine, improve the compliance that the patient takes medicine simultaneously.
Amlodipine Besylate Tablet Candesartan Cilexetil sheet abroad goes on the market, is used for the treatment of the various hypertension of patient.
Patent documentation 1 discloses pharmaceutical composition and the medicine box that contains Amlodipine Besylate Tablet and candesartan Cilexetil, and the weight ratio of wherein said Amlodipine Besylate Tablet and candesartan Cilexetil is 1: 1～6.
Patent documentation 2 discloses the compositions that comprises amlodipine and angiotensin-ii receptor inhibitor, said composition has addition or synergism, be used for to suffer from the individual of angina pectoris, atherosclerosis, mixed type hypertension and hyperlipemia and exist the cardiac risk symptom individuality, comprise that the people treats.
Patent documentation 3 discloses the pharmaceutical composition of treatment hypertension and cardiovascular disease, and said composition only needs disposable the taking in back of waking up early morning every day, can prevent the blood pressure acute variation after wake up early morning effectively, makes blood pressure be in the comparison poised state; Eliminated the untoward reaction of original raceme simultaneously, as side effect such as acro-edema, headache, dizzinesses, patient's medication compliance is better.
It is the amlodipine crystal salt that is applicable to pharmaceutical composition that patent documentation 4 discloses amlodipine camsylate, and it is to use the hypotoxicity camphorsulfonic acid to prepare, and satisfies to be used for the treatment of the desired pharmaceutical properties of cardiovascular disease.
Patent documentation 5 discloses the stable amorphous amlodipine camsylate with high-dissolvability, and it can be used for the treatment of cardiovascular disease effectively.
Tablet of the present invention, administration every day 1～3 time is preferably once a day, 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, improve the compliance that the patient takes medicine simultaneously, improved patient's quality of life.
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, 15 (9), in JIUYUE, 2007,708-710
Patent documentation 1:CN101371834A
Patent documentation 2:CN1765362A, WO2006/034631
Patent documentation 3:CN1883478A
Patent documentation 4:CN1501916 (A), WO02079158 (A1), US2004116478 (A1)
Patent documentation 5:CN1777586A, US2006128763 (A1), WO2004067512 (A1)
Summary of the invention
The object of the present invention is to provide a kind of novel tablet, it is made up of the amlodipine of the Candesartan of 2～64mg or its pharmaceutically acceptable salt or ester and 0.3～20mg or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable carrier, wherein said Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, and described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate, amlodipine niacin, the pyroglutamic acid amlodipine, amlodipine gentisate, thioctic acid amlodipine or Levamlodipine besylate.
Another object of the present invention is also to provide that above-mentioned tablet is used for preventing in preparation, the application of the medicine of delay of progression or treatment patient's hypertension or its relevant disease.
The technical scheme that the present invention solves is as follows:
(1) a kind of tablet is characterized in that, it consists of the following components:
(A) Candesartan of 2～64mg or its pharmaceutically acceptable salt or ester;
(B) amlodipine of 0.3～20mg or its pharmaceutically acceptable salt or ester, wherein said amlodipine or its pharmaceutically acceptable salt or ester are not Amlodipine Besylate Tablets; And
(C) at least a pharmaceutically acceptable carrier.
Tablet of the present invention is selected from conventional tablet, enteric coatel tablets, slow releasing tablet or controlled release tablet, is preferably conventional tablet; Do not comprise dispersible tablet, bilayer tablet, oral cavity disintegration tablet or chewable tablet.
Candesartan of the present invention or its pharmaceutically acceptable salt or ester are selected from: Candesartan Cilexetil, Candesartan sodium salt, Candesartan potassium salt, Candesartan calcium salt, Candesartan magnesium salt or Candesartan amine salt are preferably Candesartan Cilexetil; Unit dose is calculated as 2mg～64mg by Candesartan Cilexetil, is preferably 2mg～32mg, 4mg～32mg more preferably, and 4mg～16mg more preferably, more preferably 2mg, 4mg, 8mg, 16mg or 32mg most preferably are 8mg or 16mg.
Candesartan 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 US5196444 (A), EP459136 (A1), EP0720982 (A1), JP4364171 (A), CN1147515A, CN1086998A, CN101781286A, CN1072338A, CN101516864A, CN101558061A, CN101679300A, CN1055927A, CN101715447A, CN1715278A, CN101646659A, CN101296923A, CN101633656A, CN1666989A, CN101584700A, CN101068807A, CN1534025A, CN1970554A, CN1902192A, CN101200464A, CN101171246A, CN1953973A, CN1800179A, those that CN101880241A announced are incorporated herein by reference this in full at this.
The chemical structural formula of Candesartan (Candesartan) is suc as formula shown in (A):
Figure BDA0000039262250000041
Amlodipine of the present invention or its pharmaceutically acceptable salt or ester are not Amlodipine Besylate Tablet (English names: Amlodipine besylate, molecular formula: C 20H 25ClN 2O 5.C 6H 5SO 3H, molecular weight: 567.05, see patent documentation EP89167A2 for details, US4572909A), but comprise Levamlodipine besylate, be selected from: 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 maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate or Levamlodipine besylate; Unit dose is calculated as 0.3mg～20mg by amlodipine, is preferably 0.625mg～20mg, more preferably 0.625mg～10mg, more preferably 1.25mg～10mg, more preferably 0.312mg, 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):
Figure BDA0000039262250000051
Described amlodipine or its pharmaceutically acceptable salt 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 CN1263525A, CN1263093A, CN101766582A, CN1267669A, CN101209991A, CN101805284A, CN1678583A, CN1609102A, CN1681786A, CN1882543A, CN1343663A, CN1495166A, CN1496353A, CN101528696A, CN1501916A, CN1915974A, CN1850801A, CN1927837A, CN1927836A, CN1678584A, CN101560181A CN1956956A, CN101812014A, CN101798280A, CN101307020A, CN101316820A, CN101481348A, CN101495451A, CN101648903A, CN101507715A, CN101528697A, CN101544597A, CN101530396A, CN101570506A, CN101611003A, CN101111478A, CN101654429A, EP89167 (A2), those that US4572909 (A) is 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.
Wherein said pharmaceutically acceptable carrier is preferably from filler, disintegrating agent, binding agent, lubricant, fluidizer, wetting agent, correctives, 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 filler can be selected from microcrystalline Cellulose, optimize microcrystalline Cellulose, Powderd cellulose, saccharide, sugar derivatives, mannitol, lactose, sorbitol, Polyethylene Glycol, sodium bicarbonate, surfactant, calcium carbonate, calcium phosphate, calcium hydrogen phosphate 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, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pre-paying starch, starch 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 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 sucrose, Icing Sugar, sucralose, steviosin, saccharin sodium, aspartame, lactose or its mixture;
Suitable 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.
Tablet 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; Also can adopt the direct powder compression tabletting; Can randomly carry out film coating or sweet tablet; Also can be the gastric solubleness coating, also can be enteric coating.
The purposes of tablet of the present invention is preferred for prevention, delay of progression or treatment patient's hypertension or its relevant disease.
(2) as the described tablet of claim (1), it is characterized in that, the weight ratio of described Candesartan or its pharmaceutically acceptable salt or ester and amlodipine or its pharmaceutically acceptable salt or ester is 0.2～102.4: 1, be preferably 0.4～102.4: 1, more preferably 0.4～51.2: 1, more preferably 0.4～25.6: 1, more preferably 0.8～12.8: 1, more preferably 1.6～6.4: 1, more preferably 1.6: 1,3.2: 1 or 6.4: 1, the weight of wherein said amlodipine or its pharmaceutically acceptable salt or ester was pressed amlodipine and is calculated.
Amlodipine of the present invention or its pharmaceutically acceptable salt or ester are not Amlodipine Besylate Tablets, but comprise Levamlodipine besylate.
(3) as claim (1), (2) each described tablet, it is characterized in that described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil.
Candesartan Cilexetil of the present invention, also abbreviate candesartan Cilexetil as, chemical name is: (±)-1-(((hexamethylene oxo) carbonyl) oxo) ethyl-2-ethyoxyl-1-[[2 '-(1H-tetrazole base-5)-(1,1 '-xenyl)-and the 4-yl] methyl]-the 1H-benzimidazole-7-carboxylate, English name is CandesartanCilexetil, and molecular formula is C 33H 34N 6O 6, molecular weight is 610.66, its chemical structural formula is suc as formula shown in (C):
Figure BDA0000039262250000081
The weight ratio of Candesartan Cilexetil of the present invention and amlodipine or its pharmaceutically acceptable salt or ester is preferably 1.6: 1, more preferably 32mg/20mg, 16mg/10mg, 8mg/5mg, 4mg/2.5mg or 2mg/1.25mg, more preferably 16mg/10mg, 8mg/5mg or 4mg/2.5mg, the weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine or its pharmaceutically acceptable salt or ester is pressed amlodipine and calculated.
The weight ratio of Candesartan Cilexetil of the present invention and amlodipine or its pharmaceutically acceptable salt or ester is preferably 3.2: 1, more preferably 32mg/10mg, 16mg/5mg, 8mg/2.5mg, 4mg/1.25mg or 2mg/0.625mg, more preferably 16mg/5mg, 8mg/2.5mg or 4mg/1.25mg, the weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine or its pharmaceutically acceptable salt or ester is pressed amlodipine and calculated.
The weight ratio of Candesartan Cilexetil of the present invention and amlodipine or its pharmaceutically acceptable salt or ester is preferably 6.4: 1, more preferably 32mg/5mg, 16mg/2.5mg, 8mg/1.25mg, 4mg/0.625mg or 2mg/0.312mg, more preferably 16mg/2.5mg, 8mg/1.25mg or 4mg/0.625mg, the weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine or its pharmaceutically acceptable salt or ester is pressed amlodipine and calculated.
(4) as each described tablet of claim (1) to (3), it is characterized in that described amlodipine or its pharmaceutically acceptable salt or ester are 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 maleate, Amlodipine mesylate, L-Aspartic Acid amlodipine, amlodipine camsylate, amlodipine camsylate or Levamlodipine besylate.
(5) as each described tablet of claim (1) to (4), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine maleate, and Candesartan Cilexetil and amlodipine maleate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 4mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 4mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 4mg and amlodipine maleate 5mg; Candesartan Cilexetil 4mg and amlodipine maleate 10mg;
Candesartan Cilexetil 8mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 8mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 8mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 8mg and amlodipine maleate 5mg; Candesartan Cilexetil 8mg and amlodipine maleate 10mg;
Candesartan Cilexetil 16mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 16mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 16mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 16mg and amlodipine maleate 5mg; Candesartan Cilexetil 16mg and amlodipine maleate 10mg;
Candesartan Cilexetil 32mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 32mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 32mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 32mg and amlodipine maleate 5mg; Candesartan Cilexetil 32mg and amlodipine maleate 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine maleate is pressed amlodipine and calculated.
(6) as each described tablet of claim (1) to (4), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine mesylate, and Candesartan Cilexetil and Amlodipine mesylate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 10mg;
Candesartan Cilexetil 8mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 10mg;
Candesartan Cilexetil 16mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 10mg;
Candesartan Cilexetil 32mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described Amlodipine mesylate is pressed amlodipine and calculated.
(7) as each described tablet of claim (1) to (4), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are L-Aspartic Acid amlodipine, and Candesartan Cilexetil and L-Aspartic Acid amlodipine are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 10mg;
Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 10mg;
Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 10mg;
Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described L-Aspartic Acid amlodipine is pressed amlodipine and calculated.
(8) as each described tablet of claim (1) to (4), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine camsylate, and Candesartan Cilexetil and amlodipine camsylate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 4mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 4mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 4mg and amlodipine camsylate 5mg; Candesartan Cilexetil 4mg and amlodipine camsylate 10mg;
Candesartan Cilexetil 8mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 8mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 8mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 8mg and amlodipine camsylate 5mg; Candesartan Cilexetil 8mg and amlodipine camsylate 10mg;
Candesartan Cilexetil 16mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 16mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 16mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 16mg and amlodipine camsylate 5mg; Candesartan Cilexetil 16mg and amlodipine camsylate 10mg;
Candesartan Cilexetil 32mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 32mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 32mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 32mg and amlodipine camsylate 5mg; Candesartan Cilexetil 32mg and amlodipine camsylate 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine camsylate is pressed amlodipine and calculated.
(9) as each described tablet of claim (1) to (4), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are Levamlodipine besylate, and Candesartan Cilexetil and Levamlodipine besylate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 5mg;
Candesartan Cilexetil 8mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 5mg;
Candesartan Cilexetil 16mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 5mg;
Candesartan Cilexetil 32mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 5mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described Levamlodipine besylate is pressed amlodipine and calculated.
(10) as each described tablet of claim (1) to (9) be used for preventing in preparation, the application of the medicine of delay of progression or treatment patient's hypertension or its relevant disease.
Term " patient " refers to animal, preferred mammal, and optimum is chosen, and comprises masculinity and femininity.
Term " hypertension or its relevant disease " is selected from but is not limited to following disease or disease: essential hypertension, secondary hypertension, atherosclerosis, arteriosclerosis, coronary artery disease, angina pectoris, myocardial infarction, congestive heart failure or apoplexy.
Description of drawings
Below will be by invention being described in conjunction with following accompanying drawing, therefore above-mentioned and other purpose of the present invention and feature will become apparent; These accompanying drawings are respectively:
Fig. 1: Candesartan Cilexetil accumulation dissolution rate curve;
Fig. 2: amlodipine accumulation dissolution rate curve.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment.
Embodiment 1: the tablet that comprises Candesartan Cilexetil and amlodipine maleate
The supplementary material title Dosage 1 (mg) Dosage 2 (mg) Dosage 3 (mg) Dosage 4 (mg)
Candesartan Cilexetil 4.00 8.00 16.00 32.00
Amlodipine maleate 1.60 3.20※ 6.40 12.80
Mannitol 16.65 33.30 66.60 133.20
Microcrystalline Cellulose 16.30 32.60 65.20 130.40
The fine little plain sodium of cross-linked carboxymethyl 4.00 8.00 16.00 32.00
Polyethylene glycol 6000 4.20 8.40 16.80 33.60
Hydroxypropyl cellulose 2.50 5.00 10.00 20.00
Magnesium stearate 0.75 1.50 3.00 6.00
Purified water In right amount In right amount In right amount In right amount
Sheet is heavy 50.00 100.00 200.00 400.00
※ amlodipine maleate 3.20mg is equivalent to amlodipine 2.50mg.
Preparation method:
(A) various supplementary materials are crossed 80 mesh sieves respectively and pulverize, standby;
(B) with Candesartan Cilexetil and amlodipine maleate in V-Mixer by the equivalent method mixing that progressively increases;
(C) with mannitol, microcrystalline Cellulose, the fine little plain sodium of 2/3 cross-linked carboxymethyl, polyethylene glycol 6000 and hydroxypropyl cellulose mix homogeneously in trough type mixing machine;
(D) will be the Candesartan Cilexetil and the amlodipine maleate of mixing, with the fine little plain sodium of mannitol, microcrystalline Cellulose, 2/3 cross-linked carboxymethyl, polyethylene glycol 6000 and the hydroxypropyl cellulose of mixing in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(E) with the various supplementary materials of above-mentioned mix homogeneously, add in the purified water and make soft material, cross 30 mesh sieves and granulate, 18 mesh sieve granulate are crossed in 60 ℃～80 ℃ oven dry, add 1/3 carboxymethylstach sodium and magnesium stearate, mix homogeneously makes Candesartan Cilexetil amlodipine granule, and is standby;
(F) two drug contents in the mensuration Candesartan amlodipine granule, it is heavy to calculate sheet;
(G) use sheeting equipment that Candesartan Cilexetil amlodipine granule is pressed into tablet, make 1000.
Embodiment 2: the tablet that comprises Candesartan Cilexetil and Amlodipine mesylate
The supplementary material title Dosage 1 (mg) Dosage 2 (mg) Dosage 3 (mg) Dosage 4 (mg)
Candesartan Cilexetil 4.00 8.00 16.00 32.00
Amlodipine mesylate 1.60 3.21 6.42※ 12.84
Mannitol 15.90 31.80 63.60 127.20
Microcrystalline Cellulose 16.80 33.6 67.20 134.40
Polyvinylpolypyrrolidone 3.60 7.20 14.40 28.80
Polyethylene glycol 6000 4.20 8.40 16.80 33.60
30 POVIDONE K 30 BP/USP 30 2.50 5.00 10.00 20.00
Micropowder silica gel 0.65 1.30 2.60 5.20
Magnesium stearate 0.75 1.50 3.00 6.00
30% ethanol water In right amount In right amount In right amount In right amount
Sheet is heavy 50.00 100.00 200.00 400.00
※ Amlodipine mesylate 6.42mg is equivalent to amlodipine 5.00mg.
Preparation method:
(A) various supplementary materials are crossed 80 mesh sieves respectively and pulverize, standby;
(B) with Candesartan Cilexetil and Amlodipine mesylate in V-Mixer by the equivalent method mixing that progressively increases;
(C) with mannitol, microcrystalline Cellulose, 2/3 polyvinylpolypyrrolidone and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(D) will be the Candesartan Cilexetil of mixing and Amlodipine mesylate and mannitol, microcrystalline Cellulose, 2/3 polyvinylpolypyrrolidone and the polyethylene glycol 6000 of mixing in V-Mixer by the equivalent method mixing that progressively increases;
(E) take by weighing 30 POVIDONE K 30 BP/USP 30, be dissolved in and make 5% 30 POVIDONE K 30 BP/USP 30 alcoholic solution in 30% ethanol water, make adhesive and use;
(F) incite somebody to action the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 ethanol waters and make soft material, crossing 24 mesh sieves granulates, 60 ℃～80 ℃ oven dry, cross 18 mesh sieve granulate, add micropowder silica gel, magnesium stearate and 1/3 polyvinylpolypyrrolidone, mix homogeneously, make Candesartan Cilexetil amlodipine granule, standby;
(G) two drug contents in the mensuration Candesartan Cilexetil amlodipine granule, it is heavy to calculate grain;
(H) use sheeting equipment that Candesartan Cilexetil amlodipine granule is pressed into tablet, make 1000.
Embodiment 3: the tablet that comprises Candesartan Cilexetil and L-Aspartic Acid amlodipine
The supplementary material title Dosage 1 (mg) Dosage 2 (mg) Dosage 3 (mg) Dosage 4 (mg)
Candesartan Cilexetil 4.00 8.00 16.00 32.00
L-Aspartic Acid amlodipine 1.66 3.32 6.64※ 13.28
Mannitol 14.76 29.52 59.04 118.08
Microcrystalline Cellulose 15.60 31.20 62.40 124.80
Carboxymethylstach sodium 4.00 8.00 16.00 32.00
Polyethylene glycol 6000 4.80 9.60 19.20 38.40
30 POVIDONE K 30 BP/USP 30 2.50 5.00 10.00 20.00
Micropowder silica gel 0.68 1.36 2.72 5.44
Magnesium stearate 1.00 2.00 4.00 8.00
30% ethanol water In right amount In right amount In right amount In right amount
Sheet is heavy 50.00 100.00 200.00 400.00
※ L-Aspartic Acid amlodipine 6.64mg is equivalent to amlodipine 5.00mg.
Preparation method:
(A) various supplementary materials are crossed 80 mesh sieves respectively and pulverize, standby;
(B) with Candesartan Cilexetil and L-Aspartic Acid amlodipine in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(C) with mannitol, microcrystalline Cellulose, 2/3 carboxymethylstach sodium and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(D) will be the Candesartan Cilexetil of mixing and L-Aspartic Acid amlodipine and mannitol, microcrystalline Cellulose, 2/3 carboxymethylstach sodium and the polyethylene glycol 6000 of mixing in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(E) take by weighing 30 POVIDONE K 30 BP/USP 30, be dissolved in and make 5% 30 POVIDONE K 30 BP/USP 30 alcoholic solution in 30% ethanol water, make adhesive and use;
(F) incite somebody to action the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 ethanol waters and make soft material, crossing 24 mesh sieves granulates, 60 ℃～80 ℃ oven dry, cross 18 mesh sieve granulate, add micropowder silica gel, magnesium stearate and 1/3 carboxymethylstach sodium, mix homogeneously, make Candesartan Cilexetil amlodipine granule, standby;
(G) two drug contents in the mensuration Candesartan Cilexetil amlodipine granule, it is heavy to calculate grain;
(H) use sheeting equipment that Candesartan Cilexetil amlodipine granule is pressed into tablet, make 1000.
Embodiment 4: the tablet that comprises Candesartan Cilexetil and Levamlodipine besylate
The supplementary material title Dosage 1 (mg) Dosage 2 (mg) Dosage 3 (mg) Dosage 4 (mg)
Candesartan Cilexetil 4.00 8.00 16.00 32.00
Levamlodipine besylate 0.87 1.74 3.47※ 6.93
Lactose monohydrate 20.01 40.02 80.04 160.08
Microcrystalline Cellulose 12.80 25.60 51.20 102.40
Carboxymethylstach sodium 4.00 8.00 16.00 32.00
Polyethylene glycol 6000 4.20 8.40 16.80 33.60
30 POVIDONE K 30 BP/USP 30 2.50 5.00 10.00 20.00
Micropowder silica gel 0.62 1.24 2.48 4.96
Magnesium stearate 1.00 2.00 4.00 8.00
30% ethanol water In right amount In right amount In right amount In right amount
Sheet is heavy 50.00 100.00 200.00 400.00
※ Levamlodipine besylate 3.47mg is equivalent to amlodipine 2.50mg.
Preparation method:
(A) various supplementary materials are crossed 80 mesh sieves respectively and pulverize, standby;
(B) with Candesartan Cilexetil and Levamlodipine besylate in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(C) with lactose monohydrate, microcrystalline Cellulose, 2/3 carboxymethylstach sodium and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(D) will be the Candesartan Cilexetil and the Levamlodipine besylate of mixing, with lactose monohydrate, microcrystalline Cellulose, 2/3 carboxymethylstach sodium and the polyethylene glycol 6000 of mixing in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(E) take by weighing 30 POVIDONE K 30 BP/USP 30, be dissolved in and make 5% 30 POVIDONE K 30 BP/USP 30 alcoholic solution in 30% ethanol water, make adhesive and use;
(F) incite somebody to action the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 ethanol waters and make soft material, crossing 30 mesh sieves granulates, 60 ℃～80 ℃ oven dry, cross 16 mesh sieve granulate, add micropowder silica gel, magnesium stearate and 1/3 carboxymethylstach sodium, mix homogeneously, make Candesartan Cilexetil amlodipine granule, standby;
(G) two drug contents in the mensuration Candesartan Cilexetil amlodipine granule, it is heavy to calculate grain;
(H) use sheeting equipment that Candesartan Cilexetil amlodipine granule is pressed into tablet, make 1000.
Embodiment 5: the tablet that comprises Candesartan Cilexetil and amlodipine camsylate
The supplementary material title Dosage 1 (mg) Dosage 2 (mg) Dosage 3 (mg) Dosage 4 (mg)
Candesartan Cilexetil 4.00 8.00 16.00 32.00
Amlodipine camsylate 1.96 3.92 7.84※ 15.68
Mannitol 12.27 24.54 49.08 98.16
Microcrystalline Cellulose 18.40 36.80 73.60 147.20
Cross-linking sodium carboxymethyl cellulose 5.00 10.00 20.00 40.00
Polyethylene glycol 6000 4.30 8.60 17.20 34.40
30 POVIDONE K 30 BP/USP 30 2.50 5.00 10.00 20.00
Micropowder silica gel 0.72 1.44 2.88 5.76
Magnesium stearate 0.85 1.70 3.40 6.80
30% ethanol water In right amount In right amount In right amount In right amount
Sheet is heavy 50.00 100.00 200.00 400.00
※ amlodipine camsylate 7.84mg is equivalent to amlodipine 5.00mg.
Preparation method:
(A) various supplementary materials are crossed 80 mesh sieves respectively and pulverize, standby;
(B) with candesartan Cilexetil and amlodipine camsylate in V-Mixer by the equivalent method mixing that progressively increases;
(C) with mannitol, microcrystalline Cellulose, 2/3 cross-linking sodium carboxymethyl cellulose and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(D) will be the Candesartan Cilexetil and the amlodipine camsylate of mixing, with mannitol, microcrystalline Cellulose, 2/3 carboxymethylstach sodium and the polyethylene glycol 6000 of mixing in V-Mixer by the equivalent method mixing that progressively increases;
(E) take by weighing 30 POVIDONE K 30 BP/USP 30, be dissolved in and make 5% 30 POVIDONE K 30 BP/USP 30 alcoholic solution in 30% ethanol water, make adhesive and use;
(F) incite somebody to action the various supplementary materials of mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 ethanol waters and make soft material, crossing 30 mesh sieves granulates, 60 ℃～80 ℃ oven dry, cross 18 mesh sieve granulate, add micropowder silica gel, magnesium stearate and 1/3 cross-linking sodium carboxymethyl cellulose, mix homogeneously, make Candesartan Cilexetil amlodipine granule, standby;
(G) two drug contents in the mensuration Candesartan Cilexetil amlodipine granule, it is heavy to calculate grain;
(H) use sheeting equipment that Candesartan Cilexetil amlodipine granule is pressed into tablet, make 1000.
Embodiment 6: the tablet that comprises Candesartan Cilexetil and amlodipine camsylate
The supplementary material title Dosage 1 (mg) Dosage 2 (mg) Dosage 3 (mg) Dosage 4 (mg)
Candesartan Cilexetil 4.00 8.00 16.00 32.00
Amlodipine camsylate 0.98 1.96※ 3.92 7.84
Mannitol 20.36 40.72 81.44 162.88
Microcrystalline Cellulose 13.80 27.60 55.20 110.40
Carboxymethylstach sodium 4.00 8.00 16.00 32.00
Polyethylene glycol 6000 4.10 8.20 16.40 32.80
Hydroxypropyl methylcellulose 1.25 2.50 5.00 10.00
Micropowder silica gel 0.76 1.52 3.04 6.08
Magnesium stearate 0.75 1.50 3.00 6.00
Purified water In right amount In right amount In right amount In right amount
Sheet is heavy 50.00 100.00 200.00 400.00
※ amlodipine camsylate 1.96mg is equivalent to amlodipine 1.25mg.
Preparation method:
(A) various supplementary materials are crossed 80 mesh sieves respectively and pulverize, standby;
(B) with Candesartan Cilexetil and amlodipine camsylate in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(C) with mannitol, microcrystalline Cellulose, 2/3 carboxymethylstach sodium, hydroxypropyl methylcellulose and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(D) will be the Candesartan Cilexetil and the amlodipine camsylate of mixing, with mannitol, microcrystalline Cellulose, 2/3 carboxymethylstach sodium, hydroxypropyl methylcellulose and the polyethylene glycol 6000 of mixing in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(E) incite somebody to action the various supplementary materials of mix homogeneously, add in the purified water and make soft material, cross 24 mesh sieves and granulate, 16 mesh sieve granulate are crossed in 60 ℃～80 ℃ oven dry, add micropowder silica gel, magnesium stearate and 1/3 carboxymethylstach sodium, mix homogeneously makes Candesartan Cilexetil amlodipine granule, and is standby;
(F) two drug contents in the mensuration Candesartan Cilexetil amlodipine granule, it is heavy to calculate grain;
(G) use sheeting equipment that Candesartan Cilexetil amlodipine granule is pressed into tablet, make 1000.
Embodiment 7: study on the stability
The tablet of getting the embodiment of the invention 1～6 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:
Figure BDA0000039262250000191
Figure BDA0000039262250000201
※ 91.3/95.6 represents Candesartan Cilexetil 91.3/ amlodipine 95.6, down together.
Result of the test shows, the total impurities of two kinds of principal agents of sample of the embodiment of the invention 1～6 preparation is about 0.6%, dissolution is about 90%/95%, every testing result does not all have obvious variation, illustrate by the tablet that comprises candesartan Cilexetil and amlodipine of the present invention preparation improve bioavailability and stable aspect its superiority is arranged.
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. tablet is characterized in that it consists of the following components:
(A) Candesartan of 2～64mg or its pharmaceutically acceptable salt or ester;
(B) amlodipine of 0.3～20mg or its pharmaceutically acceptable salt or ester, wherein said amlodipine or its pharmaceutically acceptable salt or ester are not Amlodipine Besylate Tablets; And
(C) at least a pharmaceutically acceptable carrier.
2. tablet as claimed in claim 1, it is characterized in that, the weight ratio of described Candesartan or its pharmaceutically acceptable salt or ester and amlodipine or its pharmaceutically acceptable salt or ester is 0.2～102.4: 1, and the weight of wherein said amlodipine or its pharmaceutically acceptable salt or ester is pressed amlodipine and calculated.
3. as claim 1,2 each described tablets, it is characterized in that described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil.
4. as each described tablet of claim 1 to 3, it is characterized in that described amlodipine or its pharmaceutically acceptable salt or ester are 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.
5. as each described tablet of claim 1 to 4, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine maleate, and Candesartan Cilexetil and amlodipine maleate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 4mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 4mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 4mg and amlodipine maleate 5mg; Candesartan Cilexetil 4mg and amlodipine maleate 10mg;
Candesartan Cilexetil 8mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 8mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 8mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 8mg and amlodipine maleate 5mg; Candesartan Cilexetil 8mg and amlodipine maleate 10mg;
Candesartan Cilexetil 16mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 16mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 16mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 16mg and amlodipine maleate 5mg; Candesartan Cilexetil 16mg and amlodipine maleate 10mg;
Candesartan Cilexetil 32mg and amlodipine maleate 0.625mg; Candesartan Cilexetil 32mg and amlodipine maleate 1.25mg; Candesartan Cilexetil 32mg and amlodipine maleate 2.5mg; Candesartan Cilexetil 32mg and amlodipine maleate 5mg; Candesartan Cilexetil 32mg and amlodipine maleate 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine maleate is pressed amlodipine and calculated.
6. as each described tablet of claim 1 to 4, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are Amlodipine mesylate, and Candesartan Cilexetil and Amlodipine mesylate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 4mg and Amlodipine mesylate 10mg;
Candesartan Cilexetil 8mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 8mg and Amlodipine mesylate 10mg;
Candesartan Cilexetil 16mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 16mg and Amlodipine mesylate 10mg;
Candesartan Cilexetil 32mg and Amlodipine mesylate 0.625mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 1.25mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 2.5mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 5mg; Candesartan Cilexetil 32mg and Amlodipine mesylate 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described Amlodipine mesylate is pressed amlodipine and calculated.
7. as each described tablet of claim 1 to 4, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are L-Aspartic Acid amlodipine, and Candesartan Cilexetil and L-Aspartic Acid amlodipine are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 4mg and L-Aspartic Acid amlodipine 10mg;
Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 8mg and L-Aspartic Acid amlodipine 10mg;
Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 16mg and L-Aspartic Acid amlodipine 10mg;
Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 0.625mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 1.25mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 2.5mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 5mg; Candesartan Cilexetil 32mg and L-Aspartic Acid amlodipine 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described L-Aspartic Acid amlodipine is pressed amlodipine and calculated.
8. as each described tablet of claim 1 to 4, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are amlodipine camsylate, and Candesartan Cilexetil and amlodipine camsylate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 4mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 4mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 4mg and amlodipine camsylate 5mg; Candesartan Cilexetil 4mg and amlodipine camsylate 10mg;
Candesartan Cilexetil 8mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 8mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 8mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 8mg and amlodipine camsylate 5mg; Candesartan Cilexetil 8mg and amlodipine camsylate 10mg;
Candesartan Cilexetil 16mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 16mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 16mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 16mg and amlodipine camsylate 5mg; Candesartan Cilexetil 16mg and amlodipine camsylate 10mg;
Candesartan Cilexetil 32mg and amlodipine camsylate 0.625mg; Candesartan Cilexetil 32mg and amlodipine camsylate 1.25mg; Candesartan Cilexetil 32mg and amlodipine camsylate 2.5mg; Candesartan Cilexetil 32mg and amlodipine camsylate 5mg; Candesartan Cilexetil 32mg and amlodipine camsylate 10mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described amlodipine camsylate is pressed amlodipine and calculated.
9. as each described tablet of claim 1 to 4, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt or ester are Levamlodipine besylate, and Candesartan Cilexetil and Levamlodipine besylate are selected from the combination of following fixed dosage:
Candesartan Cilexetil 4mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 4mg and Levamlodipine besylate 5mg;
Candesartan Cilexetil 8mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 8mg and Levamlodipine besylate 5mg;
Candesartan Cilexetil 16mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 16mg and Levamlodipine besylate 5mg;
Candesartan Cilexetil 32mg and Levamlodipine besylate 0.312mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 0.625mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 1.25mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 2.5mg; Candesartan Cilexetil 32mg and Levamlodipine besylate 5mg;
The weight of wherein said Candesartan Cilexetil is pressed Candesartan Cilexetil and is calculated, and the weight of described Levamlodipine besylate is pressed amlodipine and calculated.
As each described tablet of claim 1 to 9 be used for preventing in preparation, the application of the medicine of delay of progression or treatment patient's hypertension or its relevant disease.
CN2010105943367A 2010-12-19 2010-12-19 Tablet containing amlodipine ester and candesartan ester and application thereof Pending CN102038683A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102342937A (en) * 2011-07-20 2012-02-08 海南锦瑞制药股份有限公司 Amlodipine and candesartan pharmaceutical composition and preparation method thereof
CN102670604A (en) * 2012-05-18 2012-09-19 四川升和药业股份有限公司 Composition containing candesartan and amlodipine, preparation process, testing process and application thereof
CN114539135A (en) * 2022-02-23 2022-05-27 复旦大学 Novel salt form of levamlodipine, and preparation method and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102342937A (en) * 2011-07-20 2012-02-08 海南锦瑞制药股份有限公司 Amlodipine and candesartan pharmaceutical composition and preparation method thereof
CN102670604A (en) * 2012-05-18 2012-09-19 四川升和药业股份有限公司 Composition containing candesartan and amlodipine, preparation process, testing process and application thereof
CN102670604B (en) * 2012-05-18 2014-11-19 四川升和药业股份有限公司 Composition containing candesartan and amlodipine, preparation process, testing process and application thereof
CN114539135A (en) * 2022-02-23 2022-05-27 复旦大学 Novel salt form of levamlodipine, and preparation method and application thereof

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