CN101966181A - Oral solid preparation containing candesartan and amlodipine and new application thereof - Google Patents
Oral solid preparation containing candesartan and amlodipine and new application thereof Download PDFInfo
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- CN101966181A CN101966181A CN 201010220491 CN201010220491A CN101966181A CN 101966181 A CN101966181 A CN 101966181A CN 201010220491 CN201010220491 CN 201010220491 CN 201010220491 A CN201010220491 A CN 201010220491A CN 101966181 A CN101966181 A CN 101966181A
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Abstract
The invention relates to a novel oral solid preparation containing 2-32 mg of candesartan or pharmaceutically acceptable salts or esters thereof, and 1.25-20 mg of amlodipine or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers thereof. The novel oral solid preparation can be a dispersible tablet, a capsule, a double-layer tablet, an orally disintegrating tablet, a chewable tablet, a dripping pill and a granular formulation or a dry-mixed suspension and used for preventing and deferring the progress or treating patients with hypertension accompanied with an Alzheimer disease, reducing the incidence rate and/or the death rate of cardiovascular and cerebrovascular diseases and the adverse reaction of drugs and also improving the compliance of the drug administration of the patients.
Description
Technical field
The present invention relates to a kind of novel oral solid formulation, it is made up of the amlodipine of the Candesartan of 2～32mg or its pharmaceutically acceptable salt or ester and 1.25～20mg or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, wherein said oral solid formulation is dispersible tablet, capsule, bilayer tablet, oral cavity disintegration tablet, chewable tablet, drop pill, granule or dry suspension, be used for prevention, delay of progression or treatment patient hypertension simultaneously with Alzheimer, 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.
Alzheimer (Alzheimer disease), being so-called senile dementia, is a kind of lethal neurodegenerative diseases that carries out sexual development, and clinical manifestation constantly worsens for cognitive and memory function, carrying out property of activity of daily living goes down, and various neural mental symptoms and behavior disorder are arranged.According to the advancing of disease and the damaged order of severity of cognitive function, can be divided into slight, moderate and severe.According to statistics, Alzheimer number of the infected speed increment often to double in per more than 20 years.The whole world has 1,700 ten thousand～3,500 ten thousand Alzheimer patients approximately; China's number of patients is 6,000,000～more than 8,000,000,4.8% old people suffers from Alzheimer, and constantly increasing.
In recent years, hypertension prevention and control guide both domestic and external shows (with reference to non-patent literature 1,2), strengthen the blood pressure lowering dynamics, make hyperpietic's blood pressure reduce to 140/90 millimetres of mercury following (it is following that the best should be reduced to 130/80 millimetres of mercury) actively, enduringly, effectively the target organ damages such as heart and brain kidney that cause of alleviating hypertension; The administering drug combinations of antihypertensive drugs, especially the oral solid formulation that comprises Candesartan and amlodipine, be used for prevention, delay of progression or treatment patient essential hypertension, secondary hypertension, angina pectoris, atherosclerosis, apoplexy, myocardial infarction, cardiac insufficiency, dyslipidemia, diabetes, diabetic complication, renal function injury, ventricular hypertrophy, aneurysm, myocardial ischemia, glaucoma or hypertension are simultaneously with Alzheimer (with reference to non-patent literature 3～10), reduce the incident rate of cardiovascular and cerebrovascular disease, mortality rate and disability rate, improve patients ' life quality, prolong patient's life-span.
Relevant document (with reference to non-patent literature 1) studies show that, in order to reach actively, strengthen the purpose of blood pressure lowering, and two or more antihypertensive drugs of the needs of patients coupling of 70%-100%.The benefit of drug combination is: the medicine hypotensive effect of different mechanism of action can add up, work in coordination with or be complementary, and the reverse adjusting of passivation is compensatory, improves efficacy of antihypertensive treatment; It is excessive and the adverse effect that causes increases drug safety to reduce single survival dose; Take into account multiple risk factor and relevant disease that the patient exists, help individualized treatment; Improve patient's quality of life, improve patient's compliance; Can work in coordination with the protection of reinforcement to organ.Therefore the current domestic and international consistent scheme of combination drug therapy treatment hyperpietic who recommends to adopt the compound preparation that comprises the dosage fixed mixing ratio.
The Candesartan Cilexetil amlodipine besylate tablets of Japan Takede Chemical Industries Ltd exploitation, commodity are by name
Submitted application for quotation to Japanese drug regulatory department in the past in 2007 08 month, and went through to be used for the treatment of patient's hypertension in Japan's listing in 2010 04 month, specification is two kinds of 8mg/5mg and 8mg/2.5mg.
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 2,3 discloses the compositions that comprises amlodipine and angiotensin-ii receptor inhibitor, this medicaments compound has addition and synergism, can 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 4 discloses the pharmaceutical composition of treatment hypertension and cardiovascular disease, and its active component comprises Levamlodipine officinal salt and angiotensin ii receptor antagonist.Medicine of the present invention back 1 property that only needs to wake up early morning every day is taken, and 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.
Oral solid formulation of the present invention, administration every day 1～2 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, the 15th the 9th phase of volume of JIUYUE in 2007,708-710
Non-patent literature 3: Dong Haoran. depressor helps avoid senile dementia. preventing and treating cardiovascular disease knowledge, 2007 12 phases, 27
Non-patent literature 4: Wang Huanrong, Yang Xiaopeng. the influence that valsartan is expressed the vascular dementia rats synaptophysin. medical information, the 19th the 2nd phase of volume of February in 2006,287-288
Non-patent literature 5: Wang Huanrong. valsartan is to the influence of vascular dementia rats microtubule-associated protein 1. and Chinese gerontology magazine, November the 26th in 2006 was rolled up 1549-1550
Non-patent literature 6: Zhang Juan, Zhang Jianying, Dong Shengshan, Yang Ping. the medicine of Alzheimer is used present situation. combination of Chinese and Western medicine cardiovascular and cerebrovascular disease magazine, 2005 04 month, 3 (4), 343-344
Non-patent literature 7: Shi Linrong summary. the Progress in Medication of Alzheimer. Nantong Medical College's journal,, 23 (2), 334-336 in 2003
Non-patent literature 8: Wang Hongquan. calcium insufficiency of accommodation in the Alzheimer. foreign medical science medical geography fascicle, 2008 03 month, 29 (1), 4-8,19
Non-patent literature 9: Liang Minwen, Xian Yingjie, Dai Yaozong, Li Liren. the magnesium calcium concentration changes in the patients of senile dementia blood plasma. medical forum magazine, in December, 2007,28 (23), 55-57
Non-patent literature 10: open gorgeous compiling. calcium deficiency and senile dementia and other nervous system disease. foreign medical science medical geography fascicle, 09 month calendar year 2001,22 (3), 106-107
Patent documentation 1: Chinese patent CN101371834A
Patent documentation 2: Chinese patent CN1765362A
Patent documentation 3: international monopoly WO2006/034631
Patent documentation 4: Chinese patent CN1883478A
Summary of the invention
The object of the present invention is to provide a kind of oral solid formulation that comprises Candesartan and amlodipine, wherein said oral solid formulation is dispersible tablet, capsule, bilayer tablet, oral cavity disintegration tablet, chewable tablet, drop pill, granule or dry suspension.
Another object of the present invention is also to provide that above-mentioned oral solid formulation is used for preventing in preparation, delay of progression or treatment patient hypertension is simultaneously with the application of the medicine of Alzheimer.
The technical scheme that the present invention solves is as follows:
(1) a kind of oral solid formulation that comprises Candesartan and amlodipine is characterized in that it consists of the following components:
(A) Candesartan of 2～32mg or its pharmaceutically acceptable salt or ester;
(B) amlodipine of 1.25～20mg or its pharmaceutically acceptable salt; And
(C) pharmaceutically acceptable carrier;
Wherein said oral solid formulation is dispersible tablet, capsule, bilayer tablet, oral cavity disintegration tablet, chewable tablet, drop pill, granule or dry suspension.
The pharmaceutically acceptable salt of Candesartan of the present invention is selected from sodium salt, potassium salt, calcium salt, magnesium salt or the amine salt of Candesartan, and every day, consumption was calculated as 2mg～32mg by Candesartan, was preferably 4mg～16mg.
The pharmaceutically acceptable ester of Candesartan of the present invention is preferably Candesartan Cilexetil, every day, consumption was calculated as 2mg～32mg by Candesartan Cilexetil, was preferably 4mg～32mg, more preferably 4mg～16mg, be preferably 4mg, 8mg, 16mg again, most preferably be 8mg, 16mg.
Candesartan salt or candesartan Cilexetil 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 EP459136, US5196444, CN1147515A, CN1086998A, CN1072338A, CN1055927A, CN1715278A, CN101516864A, CN101558061A, CN101679300A, CN101715447A, CN101646659A, CN101633656A, CN101584700A, CN101296923A, CN101068807A, CN1970554A, CN101200464A, CN101171246A, CN1666989A, CN1953973A, CN1902192A, CN1800179A, those that CN1534025A announced are incorporated herein by reference this in full at this.
Candesartan salt or candesartan Cilexetil are a kind of orally active specificity angiotensin (AT) II receptor antagonist, because of its specificity and selectivity that has increased blood circulation and organized the nervous plain II acceptor levels blocking-up of medium vessels, have than the more superior characteristics of angiotensin-convertion enzyme inhibitor (ACEI), do not increase Kallidin I effect due to the ACE enzyme, thereby can not cause the side effect of cough.The chemical structural formula of Candesartan is suc as formula shown in (I):
Formula (I)
Amlodipine of the present invention or its pharmaceutically acceptable salt are selected from: Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate, amlodipine camsylate, amlodipine niacin, the pyroglutamic acid amlodipine, amlodipine gentisate, the thioctic acid amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, L-Aspartic Acid Levamlodipine, the methanesulfonic acid Levamlodipine, the camphorsulfonic acid Levamlodipine, the nicotinic acid Levamlodipine, the pyroglutamic acid Levamlodipine, gentisic acid Levamlodipine or thioctic acid Levamlodipine; Be preferably Amlodipine Besylate Tablet, L-Aspartic Acid amlodipine, Amlodipine mesylate, amlodipine maleate, amlodipine camsylate, amlodipine niacin, pyroglutamic acid amlodipine, amlodipine gentisate or thioctic acid amlodipine; Most preferably be Amlodipine Besylate Tablet.The chemical structural formula of amlodipine is suc as formula shown in (II):
Formula (II)
Consumption every day of amlodipine of the present invention or its pharmaceutically acceptable salt is calculated as 1.25mg～20mg by amlodipine, is preferably 1.25mg～10mg, and more preferably 2.5mg～10mg is preferably 2.5mg～5mg again, most preferably is 2.5mg, 5mg.
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 EP89167, US4572909, CN1263525A, CN1267669A, CN1263093A, CN101209991A, CN1678583A, CN1678584A, CN1609102A, CN1681786A, CN1343663A, CN1495166A, CN1496353A, CN1501916A, CN1915974A, CN1850801A, CN1882543A, CN1927837A, CN1927836A, CN1956956A, CN101111478A, CN101307020A, CN101316820A, CN101481348A, CN101495451A, CN101507715A, CN101528696A, CN101528697A, CN101544597A, CN101560181A, CN101530396A, CN101570506A, CN101611003A, CN101654429A, those that CN101648903A announced are incorporated herein by reference this in full at this.
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.
One or both that pharmaceutically acceptable carrier of the present invention is pharmaceutically acceptable carrier or multiple combination, be 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 can be preferably from diluent, disintegrating agent, binding agent, lubricant, fluidizer, wetting agent, correctives, aromatic, coloring agent, dissolubility promoter or their combination.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, sodium bicarbonate, surfactant, calsium supplement, correctives, aromatic, coloring agent or their combination; Calsium supplement is selected from calcium carbonate, calcium phosphate, calcium hydrogen phosphate, Malic acid citric acid calcium, Citric acid calcium, calcium malate, calcium lactate or calcium acetate;
Suitable disintegrants can be selected from carboxymethylstach sodium, polyvinylpolypyrrolidone, primojel, L-hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, dried starch or their combination;
Suitable bonding can be selected from polyvidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, pre-paying starch, starch or their combination; Polyvidone is preferably 30 POVIDONE K 30 BP/USP 30;
Examples of suitable lubricants can be selected from magnesium stearate, calcium stearate, stearic acid, calcium silicates, Talcum or their combination;
Suitable fluidizer can be selected from micropowder silica gel, magnesium trisilicate, cellulose powder, starch, Talcum or their combination;
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 sucrose, Icing Sugar, sucralose, steviosin, saccharin sodium, aspartame, lactose or their combination;
Suitable aromatic is selected from water quality essence, emulsifying essence, Water/oil dual-purpose essence, panchromatic essence or their combination, and wherein water quality essence is selected from 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 their combination;
Suitable coloring agent be selected from carmine, lemon yellow, sunset yellow, amaranth, erythrosine, newly red, red pigment of cowberry, capsanthin of red, indigo, light blue, beet red, lac, red rice is red or their combination;
Suitable dissolubility promoter or dissolution promoter can be selected from polyvinylpolypyrrolidone, polyvidone, sodium lauryl sulphate, polyoxyethylene sorbitan monoleate or their combination.
Pharmaceutically acceptable salt of the present invention refers to can be according to normally used nontoxic salt or ester 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.
Oral solid formulation of the present invention can prepare with the conventional method in the pharmaceuticals industry.
(2) as the described oral solid formulation of claim (1), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt are Amlodipine Besylate Tablet, wherein the weight ratio of Candesartan Cilexetil and Amlodipine Besylate Tablet is 1.6: 1, and the weight of described Amlodipine Besylate Tablet is pressed amlodipine and calculated.
Specifically, the weight ratio of Candesartan Cilexetil of the present invention and Amlodipine Besylate Tablet is 1.6: 1, be preferably 16mg/10mg, 8mg/5mg, 4mg/2.5mg, more preferably 16mg/10mg, 8mg/5mg, most preferably be 8mg/5mg, the weight of wherein said Amlodipine Besylate Tablet is pressed amlodipine and is calculated.
Candesartan Cilexetil of the present invention, its 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 Candesartan Cilexetil, and molecular formula is C
33H
34N
6O
6, molecular weight is 610.66, chemical structural formula is suc as formula shown in (III):
Formula (III)
Amlodipine Besylate Tablet of the present invention, its chemical name is: 3-ethyl-5-methyl-2-(the amino ethoxymethyl of 2-)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, English name is Amlodipine besylate, and molecular formula is C
20H
25ClN
2O
5.C
6H
5SO
3H, molecular weight are 567.05, and chemical structural formula is suc as formula shown in (IV):
(3) as the described oral solid formulation of claim (1), it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt are Amlodipine Besylate Tablet, wherein the weight ratio of Candesartan Cilexetil and Amlodipine Besylate Tablet is 3.2: 1, and the weight of described Amlodipine Besylate Tablet is pressed amlodipine and calculated.
Specifically, the weight ratio of Candesartan Cilexetil of the present invention and Amlodipine Besylate Tablet is 3.2: 1, be preferably 16mg/5mg, 8mg/2.5mg, 4mg/1.25mg, more preferably 16mg/5mg, 8mg/2.5mg, most preferably be 8mg/2.5mg, the weight of wherein said Amlodipine Besylate Tablet is pressed amlodipine and is calculated.
(4) as each described oral solid formulation of claim (1) to (3), it is characterized in that described oral solid formulation is a dispersible tablet.
(5) as each described oral solid formulation of claim (1) to (3), it is characterized in that described oral solid formulation is a capsule.
(6) as each described oral solid formulation of claim (1) to (3), it is characterized in that described oral solid formulation is oral cavity disintegration tablet, chewable tablet, drop pill, granule or dry suspension.
(7) as each described oral solid formulation of claim (1) to (3), it is characterized in that described oral solid formulation is a bilayer tablet.
Bilayer tablet of the present invention, can adopt Candesartan or its pharmaceutically acceptable salt or ester is ground floor, and be the second layer with amlodipine or its pharmaceutically acceptable salt, each layer of bilayer tablet can adopt wet granulation, dry granulation or direct powder compression; Also can adopt amlodipine or its pharmaceutically acceptable salt is ground floor, and is the second layer with Candesartan or its pharmaceutically acceptable salt or ester, and each layer of same bilayer tablet also can adopt wet granulation, dry granulation or direct powder compression.Be preferably first kind of situation.
Wherein said bilayer tablet can randomly carry out film coating; Can be the gastric solubleness coating, also can be enteric coating.
Because Candesartan and amlodipine are two kinds of active substances, separately granulate, be pressed into bilayer tablet, can well avoid the interaction of two kinds of medicines, strengthen stability of drug; In addition, layer tablets of the present invention has also solved layer tablets and has often existed and to place the problem that sliver took place after a period of time, has obvious superiority.
(8) a kind of method for preparing claim (1) to (6) each described oral solid formulation is characterized in that described preparation method comprises:
(A) Candesartan or its pharmaceutically acceptable salt or ester and amlodipine or its pharmaceutically acceptable salt are sieved respectively pulverizing, then in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(B) various pharmaceutically acceptable carriers are sieved respectively pulverizing is then with diluent, disintegrating agent and/or dissolubility promoter mix homogeneously in mixing apparatus;
(C) will be the above-mentioned raw materials medicine of mix homogeneously, with diluent, disintegrating agent and/or dissolubility promoter in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(D) take by weighing binding agent, make 2～15% adhesive solution in the water-soluble or ethanol-water solution, use as binding agent;
(E) will be the various supplementary materials of mix homogeneously and/or correctives, aromatic, coloring agent add and make soft material in the above-mentioned adhesive solution, granulations of sieving, oven dry, adding fluidizer and/or lubricant, disintegrating agent, granulate makes Candesartan amlodipine granule, and is standby;
(F) two drug contents in the mensuration Candesartan amlodipine granule calculate packing or tabletting weight;
(G) with granule packing of Candesartan amlodipine or tabletting, make the oral solid formulation that comprises Candesartan and amlodipine.
(9) a kind of method for preparing the described bilayer tablet of claim (7) is characterized in that described preparation method comprises:
(A) Candesartan or its pharmaceutically acceptable salt or ester are sieved pulverizing;
(B) various pharmaceutically acceptable carriers are sieved respectively pulverizing will prepare the needed diluent of Candesartan granule, disintegrating agent and/or dissolubility promoter mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer then;
(C) Candesartan that will sieve or its pharmaceutically acceptable salt or ester and (B) in the step diluent, disintegrating agent and/or the dissolubility promoter of mix homogeneously in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(D) take by weighing binding agent, make 2～15% adhesive solution in the water-soluble or ethanol-water solution, use as binding agent;
(E) incite somebody to action the various supplementary materials of mix homogeneously, add and make soft material in the above-mentioned adhesive solution, the granulation of sieving, oven dry adds lubricant, fluidizer and/or disintegrating agent, and granulate makes the Candesartan granule, and is standby;
(F) drug content in the mensuration Candesartan granule, it is heavy to calculate sheet;
(G) amlodipine or its pharmaceutically acceptable salt are sieved pulverizing;
(H) will prepare the needed diluent of amlodipine granule, disintegrating agent and/or dissolubility promoter mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer;
(I) amlodipine that will sieve or its pharmaceutically acceptable salt and (H) in the step diluent, disintegrating agent and/or the dissolubility promoter of mix homogeneously in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(J) take by weighing binding agent, make 2～15% adhesive solution in the water-soluble or ethanol-water solution, use as binding agent;
(K) will be the various supplementary materials of mix homogeneously add and make soft material in the above-mentioned adhesive solution, granulations of sieving, oven dry, adding lubricant, fluidizer and/or disintegrating agent, granulate makes the amlodipine granule, and is standby;
(L) drug content in the mensuration amlodipine granule, it is heavy to calculate sheet;
(M) use double-deck rotary tablet machine that the Candesartan granule is pressed into ground floor, subsequently the amlodipine granule is pressed into the second layer, promptly.
(10) as each described oral solid formulation of claim (1) to (7) be used for preventing in preparation, delay of progression or treatment patient hypertension is simultaneously with the application of the medicine of Alzheimer.
Term " patient " refers to animal, preferred mammal, and optimum is chosen, and comprises masculinity and femininity.
Dispersible tablet, bilayer tablet, oral cavity disintegration tablet and the capsule that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet of the present invention carried out the dissolution test, the dissolution of Candesartan Cilexetil and Amlodipine Besylate Tablet reaches more than 90% respectively, related substance is about 0.5%, illustrate that oral solid formulation of the present invention not only satisfies the Chinese Pharmacopoeia requirement, and have dissolution height, drug bioavailability raising, the stable advantage of medicine, brought benefit to clinical application.
Compare with prior art, oral solid formulation provided by the invention has following unforeseeable technique effect:
(1) oral solid formulation of the present invention, disintegrate is rapid, the dissolution height;
(2) oral solid formulation of the present invention, drug bioavailability improves 20% at least;
(3) oral solid formulation of the present invention, medicine is stable, and related substance changes less;
(4) adopt conventional process equipment, can extensive, the high efficiency production of industry, constant product quality is a kind of uniqueness and blanket, low-cost industrial preparation method.
The oral solid formulation that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet provided by the invention is carried out stability test to be investigated: placed respectively 10 days under high temperature is 60 ℃, high humility (relative humidity 90% scholar 5%), illumination 4500LX condition, every detection index has no significant change; Carried out accelerated test 6 months under temperature is 40 ℃, relative humidity 75% scholar 5% condition, every detection index does not all have significant change; In temperature is that 25 ℃, relative humidity are to carry out long term test 12 months under 60% scholar, 10% condition, and every detection index does not all have significant change.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment.
Embodiment 1: the dispersible tablet that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Candesartan Cilexetil | 4.00 | 8.00 | 16.00 |
| Amlodipine Besylate Tablet * | 1.73 | 3.47 | 6.93 |
| Mannitol | 26.27 | 52.54 | 105.08 |
| Polyvinylpolypyrrolidone | 5.00 | 10.00 | 20.00 |
| Polyethylene glycol 6000 | 4.00 | 8.00 | 16.00 |
| 30 POVIDONE K 30 BP/USP 30 | 5.00 | 10.00 | 20.00 |
| Carboxymethylstach sodium | 3.00 | 6.00 | 12.00 |
| Micropowder silica gel | 0.50 | 1.00 | 2.00 |
| Magnesium stearate | 0.50 | 1.00 | 2.00 |
| Sheet is heavy | 50.00 | 100.00 | 200.00 |
* Amlodipine Besylate Tablet 6.93mg is calculated as 5.00mg by amlodipine, down together.
Preparation method:
(A) Candesartan Cilexetil and Amlodipine Besylate Tablet are crossed 100 mesh sieves respectively and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) mannitol, polyvinylpolypyrrolidone, polyethylene glycol 6000, carboxymethylstach sodium, micropowder silica gel and magnesium stearate are crossed 80 mesh sieves respectively and pulverize, then with mannitol, polyvinylpolypyrrolidone and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(C) will be Candesartan Cilexetil, the Amlodipine Besylate Tablet of mix homogeneously, with mannitol, polyvinylpolypyrrolidone and the polyethylene glycol 6000 of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) take by weighing 30 POVIDONE K 30 BP/USP 30, be dissolved in and make 10% 30 POVIDONE K 30 BP/USP 30 solution in the purified water, make adhesive and use;
(E) with the various supplementary materials of above-mentioned mix homogeneously, add in 30 POVIDONE K 30 BP/USP 30 solution and make soft material, cross 30 mesh sieves and granulate, 60 ℃～80 ℃ oven dry add micropowder silica gel, carboxymethylstach sodium and magnesium stearate, cross 18 mesh sieve granulate, make Candesartan Cilexetil amlodipine granule, standby;
(F) two drug contents in the mensuration Candesartan amlodipine granule, it is heavy to calculate sheet;
(G) use the high speed rotating tablet machine that Candesartan Cilexetil amlodipine granule is pressed into dispersible tablet, make 10000, get final product.
Embodiment 2: the capsule that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Candesartan Cilexetil | 4.00 | 8.00 | 16.00 |
| Amlodipine Besylate Tablet | 3.47 | 6.93 | 13.86 |
| Microcrystalline Cellulose | 29.03 | 58.06 | 116.12 |
| Polyvinylpolypyrrolidone | 2.00 | 4.00 | 8.00 |
| Polyethylene glycol 6000 | 5.00 | 10.00 | 20.00 |
| 30 POVIDONE K 30 BP/USP 30 | 5.00 | 10.00 | 20.00 |
| Carboxymethylstach sodium | 1.00 | 2.00 | 4.00 |
| Micropowder silica gel | 0.50 | 1.00 | 2.00 |
| Capsule is heavy | 50.00 | 100.00 | 200.00 |
Preparation method:
(A) Candesartan Cilexetil and Amlodipine Besylate Tablet are crossed 100 mesh sieves respectively and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) 100 mesh sieves are crossed in microcrystalline Cellulose, polyvinylpolypyrrolidone, polyethylene glycol 6000, carboxymethylstach sodium and micropowder silica gel respectively and pulverized, then with microcrystalline Cellulose, polyvinylpolypyrrolidone and polyethylene glycol 6000 mix homogeneously in trough type mixing machine;
(C) will be mix homogeneously Candesartan Cilexetil, Amlodipine Besylate Tablet and the microcrystalline Cellulose, polyvinylpolypyrrolidone, polyethylene glycol 6000 of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) take by weighing 30 POVIDONE K 30 BP/USP 30, be dissolved in and make 10% 30 POVIDONE K 30 BP/USP 30 alcoholic solution in 30% ethanol water, make adhesive and use;
(E) 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, cross 24 mesh sieves and granulate, 60 ℃～80 ℃ oven dry add micropowder silica gel and carboxymethylstach sodium, cross 16 mesh sieve granulate, make Candesartan Cilexetil amlodipine granule, standby;
(F) two drug contents in the mensuration Candesartan Cilexetil amlodipine granule, it is heavy to calculate grain;
(G) use the capsule subpackage machine that Candesartan Cilexetil amlodipine granule is distributed into capsule, make 10000, promptly.
Embodiment 3: the bilayer tablet that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
Preparation method:
(I) the particulate granulation of Candesartan Cilexetil
(A) Candesartan Cilexetil being crossed 100 mesh sieves pulverizes;
(B) microcrystalline Cellulose, polyethylene glycol 6000, polyvinylpolypyrrolidone, micropowder silica gel, magnesium stearate, carboxymethylstach sodium are crossed 100 mesh sieves respectively and pulverize, will prepare the needed microcrystalline Cellulose of Candesartan Cilexetil granule, polyethylene glycol 6000 and polyvinylpolypyrrolidone mix homogeneously in trough type mixing machine then;
(C) Candesartan Cilexetil that will sieve and (B) in the step microcrystalline Cellulose, polyethylene glycol 6000 and the polyvinylpolypyrrolidone of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) get 30 POVIDONE K 30 BP/USP 30, be dissolved in an amount of purified water, make 10% 30 POVIDONE K 30 BP/USP, 30 solution, as binding agent;
(E) with the various supplementary materials of above-mentioned mix homogeneously, add in the above-mentioned adhesive solution and make soft material, to cross 24 mesh sieves and granulate, 80 ℃ of oven dry add carboxymethylstach sodium, magnesium stearate and micropowder silica gel, cross 18 mesh sieve granulate, make the Candesartan Cilexetil granule, and are standby;
(F) drug content in the mensuration Candesartan Cilexetil granule, it is heavy to calculate sheet;
(II) the particulate granulation of Amlodipine Besylate Tablet
(G) Amlodipine Besylate Tablet being crossed 100 mesh sieves pulverizes;
(H) remaining microcrystalline Cellulose and polyvinylpolypyrrolidone mix homogeneously in trough type mixing machine of 100 mesh sieves will be crossed in (A) step;
(I) Amlodipine Besylate Tablet that will sieve and (H) in the step the microcrystalline Cellulose of mix homogeneously and polyvinylpolypyrrolidone in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(J) get 30 POVIDONE K 30 BP/USP 30, be dissolved in an amount of purified water, make 10% 30 POVIDONE K 30 BP/USP, 30 solution, as binding agent;
(K) with in (I) step the various supplementary materials of mix homogeneously add and make soft material in the above-mentioned adhesive solution, cross 24 mesh sieves and granulate 80 ℃ of oven dry, add carboxymethylstach sodium, magnesium stearate and micropowder silica gel, cross 18 mesh sieve granulate, make the Amlodipine Besylate Tablet granule, standby;
(L) drug content in the mensuration Amlodipine Besylate Tablet granule, it is heavy to calculate sheet;
(III) be pressed into bilayer tablet:
(M) use double-deck rotary tablet machine that the Candesartan Cilexetil granule is pressed into ground floor, subsequently the Amlodipine Besylate Tablet granule is pressed into the second layer, promptly get the bilayer tablet that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet.
Embodiment 4: the oral cavity disintegration tablet that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| 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 Besylate Tablet | 1.73 | 3.47 | 6.93 | 13.86 |
| Mannitol | 32.52 | 65.04 | 130.08 | 260.16 |
| Polyethylene glycol 6000 | 5.00 | 10.00 | 20.00 | 40.00 |
| 30 POVIDONE K 30 BP/USP 30 | 5.00 | 10.00 | 20.00 | 40.00 |
| Sodium bicarbonate | 0.50 | 1.00 | 2.00 | 4.00 |
| Sucralose | 1.25 | 2.50 | 5.00 | 10.00 |
| 30% ethanol | In right amount | In right amount | In right amount | In right amount |
| Sheet is heavy | 50.00 | 100.00 | 200.00 | 400.00 |
Preparation method:
(A) Candesartan Cilexetil and Amlodipine Besylate Tablet are crossed 100 mesh sieves respectively and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) mannitol, polyethylene glycol 6000, sodium bicarbonate, sucralose are crossed 100 mesh sieves respectively and pulverize, then mix homogeneously in trough type mixing machine;
(C) will be the Candesartan Cilexetil and the Amlodipine Besylate Tablet of mix homogeneously, with mannitol, polyethylene glycol 6000, sodium bicarbonate and the sucralose of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) get the 30 POVIDONE K 30 BP/USP 30 of recipe quantity, be dissolved in the 30% an amount of alcoholic solution, make 30% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30, as binding agent;
(E) will be the various supplementary materials of mix homogeneously, add in 30% alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 and make soft material, cross 24 mesh sieves and granulate, 60 ℃ of oven dry, 18 order granulate make Candesartan Cilexetil amlodipine granule;
(F) measure Candesartan Cilexetil amlodipine granule content, it is heavy to calculate sheet according to assay;
(G) with rotary tablet machine Candesartan Cilexetil amlodipine granule is pressed into oral cavity disintegration tablet, makes 10000, promptly.
Embodiment 5: the chewable tablet that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Candesartan Cilexetil | 4.00 | 8.00 | 16.00 |
| Amlodipine Besylate Tablet | 1.73 | 3.47 | 6.93 |
| Microcrystalline Cellulose | 22.77 | 45.54 | 91.08 |
| Polyethylene glycol 6000 | 5.00 | 10.00 | 20.00 |
| 30 POVIDONE K 30 BP/USP 30 | 4.50 | 9.00 | 18.00 |
| 0.25% cochineal solution | 0.40 | 0.80 | 1.60 |
| 0.25% lemon yellow solution | 0.40 | 0.80 | 1.60 |
| Sucralose | 0.50 | 1.00 | 2.00 |
| Mannitol | 10.50 | 21.00 | 42.00 |
| The Fructus Fragariae Ananssae powdered flavor | 0.20 | 0.40 | 0.80 |
| Purified water | In right amount | In right amount | In right amount |
| Sheet is heavy | 50.00 | 100.00 | 200.00 |
Preparation method:
(A) Candesartan Cilexetil and Amlodipine Besylate Tablet are crossed 80 mesh sieves respectively and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) microcrystalline Cellulose, polyethylene glycol 6000, sucralose and mannitol are crossed 80 mesh sieves respectively and pulverize, then mix homogeneously in trough type mixing machine;
(C) will be mix homogeneously Candesartan Cilexetil, Amlodipine Besylate Tablet and the sucralose, polyethylene glycol 6000, mannitol, microcrystalline Cellulose of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in an amount of purified water, makes 10% 30 POVIDONE K 30 BP/USP, 30 solution, as binding agent;
(E) will be the various supplementary materials of mix homogeneously and 0.25% cochineal solution, 0.25% lemon yellow solution, Fructus Fragariae Ananssae powdered flavor, add and make soft material in 10% 30 POVIDONE K 30 BP/USP, 30 solution, cross 30 mesh sieves and granulate, 80 ℃ of oven dry, 16 order granulate make Candesartan Cilexetil amlodipine granule, and are standby;
(F) measure Candesartan Cilexetil amlodipine granule content, it is heavy to calculate sheet according to assay;
(G) use rotary tablet machine that amlodipine Candesartan Cilexetil granule is pressed into chewable tablet, make 10000, promptly.
Embodiment 6: the drop pill that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Candesartan Cilexetil | 0.400 | 0.800 | 1.600 |
| Amlodipine Besylate Tablet | 0.173 | 0.347 | 0.693 |
| Polyethylene glycol 6000 | 6.327 | 12.654 | 25.307 |
| Polyoxyethylene sorbitan monoleate | 0.100 | 0.200 | 0.400 |
| Ball is heavy | 7.000 | 14.000 | 28.000 |
Preparation method:
(A) with Candesartan Cilexetil and Amlodipine Besylate Tablet respectively at 80 ℃ of dryings 8 hours, cross 80 mesh sieves and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) PEG6000 and polyoxyethylene sorbitan monoleate mixing post-heating to 55 ℃～60 ℃ are made fusion;
(C) will be the Candesartan Cilexetil of mix homogeneously and Amlodipine Besylate Tablet add to and stir in the fused solution, move in the funnel, 55 ℃～60 ℃ insulations, adjusting dropping funnel size, dimethicone with-20～-5 or liquid paraffin are the cooling phase, and the system of dripping is made 10000 balls, filter, wash, select ball, get final product.Once oral 10 balls, once-a-day.
Embodiment 7: the granule that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) | Dosage 4 (mg) |
| Candesartan Cilexetil | 2.00 | 4.00 | 8.00 | 16.00 |
| Amlodipine Besylate Tablet | 1.73 | 3.47 | 6.93 | 13.86 |
| Mannitol | 11.17 | 22.34 | 44.68 | 89.36 |
| 30 POVIDONE K 30 BP/USP 30 | 5.00 | 10.00 | 20.00 | 40.00 |
| Sucralose | 0.05 | 0.10 | 0.20 | 0.40 |
| Polyethylene glycol 6000 | 5.00 | 10.00 | 20.00 | 40.00 |
| The Fructus Fragariae Ananssae powdered flavor | 0.05 | 0.10 | 0.20 | 0.40 |
| Purified water | In right amount | In right amount | In right amount | Purified water |
| Bag is heavy | 25.00 | 50.00 | 100.00 | 200.00 |
Preparation method:
(A) Candesartan Cilexetil and Amlodipine Besylate Tablet are crossed 80 mesh sieves respectively and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) mannitol, sucralose and polyethylene glycol 6000 are crossed 80 mesh sieves respectively and pulverize, then mix homogeneously in trough type mixing machine;
(C) will be mix homogeneously Candesartan Cilexetil, Amlodipine Besylate Tablet and the mannitol, sucralose, polyethylene glycol 6000 of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in an amount of purified water, makes 10% 30 POVIDONE K 30 BP/USP, 30 solution, as binding agent;
(E) incite somebody to action the various supplementary materials and the Fructus Fragariae Ananssae powdered flavor of mix homogeneously, add and make soft material in 10% 30 POVIDONE K 30 BP/USP, 30 solution, cross 24 mesh sieves and granulate, 16 order granulate are crossed in 80 ℃ of oven dry, make Candesartan Cilexetil amlodipine granule;
(F) two drug contents in the mensuration Candesartan amlodipine granule, it is heavy to calculate bag;
(G) use the granule racking machine to be distributed into granule Candesartan Cilexetil amlodipine granule, make 10000 bags, promptly.
Embodiment 8: the dry suspension that comprises Candesartan Cilexetil and Amlodipine Besylate Tablet
| The supplementary material title | Dosage 1 (mg) | Dosage 2 (mg) | Dosage 3 (mg) |
| Candesartan Cilexetil | 2.00 | 4.00 | 8.00 |
| Amlodipine Besylate Tablet | 1.73 | 3.47 | 6.93 |
| Sodium citrate | 17.00 | 34.00 | 68.00 |
| The fine little plain sodium of carboxymethyl | 18.50 | 37.00 | 74.00 |
| Polyethylene glycol 6000 | 3.00 | 6.00 | 12.00 |
| Sucralose | 0.25 | 0.50 | 1.00 |
| 30 POVIDONE K 30 BP/USP 30 | 7.50 | 15.00 | 30.00 |
| The Fructus Fragariae Ananssae powdered flavor | 0.02 | 0.04 | 0.08 |
| Purified water | In right amount | In right amount | In right amount |
| Bag is heavy | 50.00 | 100.00 | 200.00 |
Preparation method:
Preparation method:
(A) Candesartan Cilexetil and Amlodipine Besylate Tablet are crossed 80 mesh sieves respectively and pulverize, then in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(B) sodium citrate, the fine little plain sodium of carboxymethyl, sucralose and polyethylene glycol 6000 are crossed 80 mesh sieves respectively and pulverize, then mix homogeneously in trough type mixing machine;
(C) will be mix homogeneously Candesartan Cilexetil, Amlodipine Besylate Tablet and the fine little plain sodium of sodium citrate, carboxymethyl, sucralose, polyethylene glycol 6000 of mix homogeneously in V-Mixer by the equivalent method mix homogeneously that progressively increases;
(D) 30 POVIDONE K 30 BP/USP 30 of getting recipe quantity is dissolved in an amount of purified water, makes 10% 30 POVIDONE K 30 BP/USP, 30 solution, as binding agent;
(E) incite somebody to action the various supplementary materials and the Fructus Fragariae Ananssae powdered flavor of mix homogeneously, add and make soft material in 10% 30 POVIDONE K 30 BP/USP, 30 solution, cross 30 mesh sieves and granulate, 18 order granulate are crossed in 80 ℃ of oven dry, make Candesartan Cilexetil amlodipine granule;
(F) two drug contents in the mensuration Candesartan amlodipine granule, it is heavy to calculate bag;
(G) use the granule racking machine to be distributed into dry suspension Candesartan Cilexetil amlodipine granule, make 10000 bags, promptly.
Embodiment 9: study on the stability
The sample (in the same old way 1～5) of getting embodiment 1～5 preparation among the oral solid formulation of the embodiment of the invention 1～8 preparation and the patent documentation CN1013171834A 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 by the high spot reviews project, the results are shown in following table:
* supplemental instruction: 88.5/92.2 represents Candesartan Cilexetil 89.5/ Amlodipine Besylate Tablet 92.2, down together.
Result of the test shows that the related substance of two kinds of principal agents of sample of the embodiment of the invention 1～8 preparation is about 0.55%/0.55%, and dissolution is about 88.5%/92.2%, and content is about 100%/100%, and every testing result does not all have obvious variation; And the related substance of 1～5, two kinds of principal agents in the same old way is about 1%/1%, and dissolution is about 76.5%/82.2%, and content is about 100%, and every testing result all has obvious variation.Explanation has its superiority aspect stable by the oral solid formulation that comprises candesartan Cilexetil and amlodipine of the present invention preparation improving.
Embodiment 10: the Combined with Oral administration of Candesartan Cilexetil and Amlodipine Besylate Tablet
(I) trial drug: Candesartan Cilexetil is must Loews, and military field, Tianjin drug company is produced specification: 8mg/ sheet; Amlodipine Besylate Tablet is a Norvasc, pfizer inc production, specification: 5mg/ sheet.
(II) case is selected: MethodsThe cases enrolled 123 examples, hypertension is simultaneously with patients with Alzheimer disease, without serious target organ damage.Patient age is 55～75 years old, male 62 examples, and women 64 examples, hypertension and Alzheimer diagnosis meet WHO standard; Hyperkalemia, serious habits of smoking and alcohol drinking, bilateral renal arteries are narrow, except severe renal functional lesion and the activeness hepatopath.
(III) test method: all stop using other 5 of medicines that influence blood pressure before all patient more than the half-life, detailed medical history-taking and every inspection.Employing establish matched group, multi-center clinical trial MethodsThe cases enrolled is divided at random must Loews preparation group (abbreviating 1. group as), Norvasc preparation group (abbreviating 2. group as) and must Loews associating Norvasc compound preparation group (abbreviating 3. group as), the treatment of the observation in 8 weeks by a definite date.
(IV) row electrocardiogram, hematuria routine, hepatic and renal function, blood glucose, blood fat and blood electrolyte inspection before and after the whole patients of lab testing test.
(V) result of the test sees Table 1 and table 2:
1. table 1 is organized, is 2. organized and 3. organize antihypertensive therapy relatively
(1) dosage:
1. organize therapeutic dose: must the Loews oral administration, each 1, once a day;
2. organize therapeutic dose: the Norvasc oral administration, each 1, once a day;
3. organize therapeutic dose: must Loews and Norvasc Combined with Oral administration simultaneously, at every turn must Loews and each 1 of Norvasc, once a day.
(2) blood pressure is up to standard: refer to treat the bleeding from anus pressure drop and be low to moderate≤135/85mn1Hg.
(3) blood pressure lowering is effective:
Refer to preceding reduction 〉=20mmHg of treatment after-contraction pressure ratio treatment or diastolic pressure reduction 〉=10mmHg; Or systolic pressure reduction 〉=10mmHg while diastolic pressure reduction 〉=5mmHg.
(4) P value: refer to t test value between two groups.
The blood pressure lowering result is as shown in table 1.
1. organize the average 161.7 ± 16.2/91.8 ± 7.3mmHg of blood pressure before treatment and reduce to 141.1 ± 16.2/84.4 ± 7.5 (P＜0.05).
2. organize the average 161.6 ± 16.5/91.4 ± 7.6mmHg of blood pressure before treatment and reduce to 140.7 ± 16.4/84.5 ± 7.6mmHg (P＜0.05).
3. the average 162.5 ± 15.6/91.3 ± 7.5mmHg of Zu blood pressure before treatment reduces to 128.4 ± 15.3/80.4 ± 7.5mmHg (P＜0.05).
1. group and 2. blood pressure lowering amplitude there was no significant difference (P＞0.05) between group; 1. group and 3. between group or group 2. and 3. between group the blood pressure lowering amplitude significant difference (P＜0.05) is all arranged; In addition, 1. blood pressure compliance rate, the effective percentage of group are respectively 67.5%, 76.9%; 2. Zu blood pressure compliance rate, effective percentage is respectively 48.5%, 69.1%; 3. Zu compliance rate, effective percentage are respectively 48.6%, 68.7%, thereby 3. compliance rate, the effective percentage of group all are better than 1. organizing or 2. (P＜0.05) (the results are shown in Table 1).
1. table 2 is organized, is 2. organized and 3. organize treatment of alzheimer relatively
Disease takes a turn for the better and to be meant by severe and to become moderate or become slightly by moderate; Be meant that effectively Sx partly improves.
Result of the test shows, 1. group and 2. there was no significant difference (P＞0.05) between group; 1. between organizing and 3. organizing significant difference (P＜0.05) is arranged; 2. between organizing and 3. organizing significant difference (P＜0.05) (the results are shown in Table 2) is also arranged.Each group does not all have death, may be short relevant with the investigation time.
(VI) untoward reaction: must single the using of Loews organize headache, nauseating, poor appetite 3 examples; The Norvasc list is dizzy with organizing, headache 2 examples, belong to slightly, can alleviate in 72 hours more; Tangible untoward reaction does not all appear in the drug combination group.Treat 8 weekend three groups of patient's lab testings result and electrocardiogram change no marked difference.
(VII) discuss: compare with independent medication group, drug combination group blood pressure lowering effective percentage and treatment of alzheimer effective percentage all are significantly higher than must single group or the Norvasc list group used of Loews.The incidence rate of adverse events significantly reduces in the therapeutic alliance group, and patient tolerability is good.Therefore, use in conjunction must Loews and Norvasc treat middle and high degree hypertension and accompany the patient of Alzheimer simultaneously, have and can improve curative effect of medication, increase the indication scope, reduce drug-induced untoward reaction, be rational medication combined scheme, be worthy to be popularized.
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.
Claims (10)
1. oral solid formulation that comprises Candesartan and amlodipine is characterized in that it consists of the following components:
(A) Candesartan of 2～32mg or its pharmaceutically acceptable salt or ester;
(B) amlodipine of 1.25～20mg or its pharmaceutically acceptable salt; And
(C) pharmaceutically acceptable carrier;
Wherein said oral solid formulation is dispersible tablet, capsule, bilayer tablet, oral cavity disintegration tablet, chewable tablet, drop pill, granule or dry suspension.
2. oral solid formulation as claimed in claim 1, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt are Amlodipine Besylate Tablet, wherein the weight ratio of Candesartan Cilexetil and Amlodipine Besylate Tablet is 1.6: 1, and the weight of described Amlodipine Besylate Tablet is pressed amlodipine and calculated.
3. oral solid formulation as claimed in claim 1, it is characterized in that, described Candesartan or its pharmaceutically acceptable salt or ester are Candesartan Cilexetil, described amlodipine or its pharmaceutically acceptable salt are Amlodipine Besylate Tablet, wherein the weight ratio of Candesartan Cilexetil and Amlodipine Besylate Tablet is 3.2: 1, and the weight of described Amlodipine Besylate Tablet is pressed amlodipine and calculated.
4. as each described oral solid formulation of claim 1 to 3, it is characterized in that described oral solid formulation is a dispersible tablet.
5. as each described oral solid formulation of claim 1 to 3, it is characterized in that described oral solid formulation is a capsule.
6. as each described oral solid formulation of claim 1 to 3, it is characterized in that described oral solid formulation is oral cavity disintegration tablet, chewable tablet, drop pill, granule or dry suspension.
7. as each described oral solid formulation of claim 1 to 3, it is characterized in that described oral solid formulation is a bilayer tablet.
8. a method for preparing each described oral solid formulation of claim 1 to 6 is characterized in that, described preparation method comprises:
(A) Candesartan or its pharmaceutically acceptable salt or ester and amlodipine or its pharmaceutically acceptable salt are sieved respectively pulverizing, then in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer by the equivalent method mix homogeneously that progressively increases;
(B) various pharmaceutically acceptable carriers are sieved respectively pulverizing is then with diluent, disintegrating agent and/or dissolubility promoter mix homogeneously in mixing apparatus;
(C) will be the above-mentioned raw materials medicine of mix homogeneously, with diluent, disintegrating agent and/or dissolubility promoter in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(D) take by weighing binding agent, make 2～15% adhesive solution in the water-soluble or ethanol-water solution, use as binding agent;
(E) will be the various supplementary materials of mix homogeneously and/or correctives, aromatic, coloring agent add and make soft material in the above-mentioned adhesive solution, granulations of sieving, oven dry, adding fluidizer and/or lubricant, disintegrating agent, granulate makes Candesartan amlodipine granule, and is standby;
(F) two drug contents in the mensuration Candesartan amlodipine granule calculate packing or tabletting weight;
(G) with granule packing of Candesartan amlodipine or tabletting, make the oral solid formulation that comprises Candesartan and amlodipine.
9. a method for preparing the described bilayer tablet of claim 7 is characterized in that, described preparation method comprises:
(A) Candesartan or its pharmaceutically acceptable salt or ester are sieved pulverizing;
(B) various pharmaceutically acceptable carriers are sieved respectively pulverizing will prepare the needed diluent of Candesartan granule, disintegrating agent and/or dissolubility promoter mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer then;
(C) Candesartan that will sieve or its pharmaceutically acceptable salt or ester and (B) in the step diluent, disintegrating agent and/or the dissolubility promoter of mix homogeneously in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(D) take by weighing binding agent, make 2～15% adhesive solution in the water-soluble or ethanol-water solution, use as binding agent;
(E) incite somebody to action the various supplementary materials of mix homogeneously, add and make soft material in the above-mentioned adhesive solution, the granulation of sieving, oven dry adds lubricant, fluidizer and/or disintegrating agent, and granulate makes the Candesartan granule, and is standby;
(F) drug content in the mensuration Candesartan granule, it is heavy to calculate sheet;
(G) amlodipine or its pharmaceutically acceptable salt are sieved pulverizing;
(H) will prepare the needed diluent of amlodipine granule, disintegrating agent and/or dissolubility promoter mix homogeneously in mixing apparatus such as V-Mixer, trough type mixing machine or three-dimensional movement mixer;
(I) amlodipine that will sieve or its pharmaceutically acceptable salt and (H) in the step diluent, disintegrating agent and/or the dissolubility promoter of mix homogeneously in mixing apparatus by the equivalent method mix homogeneously that progressively increases;
(J) take by weighing binding agent, make 2～15% adhesive solution in the water-soluble or ethanol-water solution, use as binding agent;
(K) will be the various supplementary materials of mix homogeneously add and make soft material in the above-mentioned adhesive solution, granulations of sieving, oven dry, adding lubricant, fluidizer and/or disintegrating agent, granulate makes the amlodipine granule, and is standby;
(L) drug content in the mensuration amlodipine granule, it is heavy to calculate sheet;
(M) use double-deck rotary tablet machine that the Candesartan granule is pressed into ground floor, subsequently the amlodipine granule is pressed into the second layer, promptly.
As each described oral solid formulation of claim 1 to 7 be used for preventing in preparation, delay of progression or treatment patient hypertension is simultaneously with the application of the medicine of Alzheimer.
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| CN 201010220491 CN101966181A (en) | 2010-07-08 | 2010-07-08 | Oral solid preparation containing candesartan and amlodipine and new application thereof |
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| CN 201010220491 CN101966181A (en) | 2010-07-08 | 2010-07-08 | Oral solid preparation containing candesartan and amlodipine and new application thereof |
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| CN103027895A (en) * | 2011-12-31 | 2013-04-10 | 山西振东泰盛制药有限公司 | Sugar-free cilnidipine dry-blend suspension and preparation method thereof |
| WO2014097209A1 (en) * | 2012-12-21 | 2014-06-26 | Adamed Sp. Z O.O. | A pharmaceutical composition containing candesartan cilexetil and amlodipine |
| CN105919947A (en) * | 2016-06-13 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Compound candesartan amlodipine granules and preparation method thereof |
| CN108472257A (en) * | 2015-12-28 | 2018-08-31 | 新丰制药株式会社 | Medicine composition |
| CN112716903A (en) * | 2021-01-18 | 2021-04-30 | 广州一品红制药有限公司 | Amlodipine dry suspension and preparation method thereof |
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| CN103027895B (en) * | 2011-12-31 | 2015-01-14 | 山西振东泰盛制药有限公司 | Sugar-free cilnidipine dry-blend suspension and preparation method thereof |
| CN103027895A (en) * | 2011-12-31 | 2013-04-10 | 山西振东泰盛制药有限公司 | Sugar-free cilnidipine dry-blend suspension and preparation method thereof |
| WO2014097209A1 (en) * | 2012-12-21 | 2014-06-26 | Adamed Sp. Z O.O. | A pharmaceutical composition containing candesartan cilexetil and amlodipine |
| AU2013365715B2 (en) * | 2012-12-21 | 2017-10-05 | Adamed Pharma S.A | A pharmaceutical composition containing candesartan cilexetil and amlodipine |
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| CN108472257A (en) * | 2015-12-28 | 2018-08-31 | 新丰制药株式会社 | Medicine composition |
| CN108472257B (en) * | 2015-12-28 | 2020-12-04 | 新丰制药株式会社 | Pharmaceutical combination preparation |
| CN105919947A (en) * | 2016-06-13 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Compound candesartan amlodipine granules and preparation method thereof |
| CN112716903A (en) * | 2021-01-18 | 2021-04-30 | 广州一品红制药有限公司 | Amlodipine dry suspension and preparation method thereof |
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