CN102657657A - Capsule containing valsartan, amlodipine and hydrochlorothiazide - Google Patents
Capsule containing valsartan, amlodipine and hydrochlorothiazide Download PDFInfo
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- CN102657657A CN102657657A CN2012101114119A CN201210111411A CN102657657A CN 102657657 A CN102657657 A CN 102657657A CN 2012101114119 A CN2012101114119 A CN 2012101114119A CN 201210111411 A CN201210111411 A CN 201210111411A CN 102657657 A CN102657657 A CN 102657657A
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Abstract
The invention relates to a capsule containing valsartan, amlodipine and hydrochlorothiazide, comprising 160 weight parts of valsartan, 2-20 weight parts of amlodipine, 5-50 weight parts of hydrochlorothiazide, 50-300 weight parts of microcrystalline cellulose, 20-200 weight parts of lactose and/or pregelatinized starch, and optional pharmaceutically acceptable carrier. The invention also relates to a preparation method of the capsule. The capsule provided by the invention can be used for treating hypertension with significant curative effect.
Description
Technical field
The invention belongs to medical technical field, more precisely, relate to a kind of capsule that contains active component valsartan, amlodipine, hydrochlorothiazide, and the method for preparing this medicament.
Background technology
According to statistics, the population in the whole world about 25% suffers from high blood pressure disease, and the control rate of blood pressure is not satisfactory, adopts folk prescription medicine controlling blood pressure compliance rate less than 50%.Clinical practice for many years proves that 50% hyperpietic needs drug combination or compound recipe.The U.S. healthy with nutrition inspection and audit committee report show only have 27% be diagnosed as the hyperpietic blood pressure can be controlled in and be lower than 140/90mmHg.The various places guide all recommends to use multiple medication combined scheme at present, and drug combination has become clinical antihypertensive common strategy.The hyperpietic of the high-risk or high danger factor of companion's cardiovascular mostly need be with drug combination as initial treatment.A kind of novel combination-ARB9 (angiotensin receptor inhibitor) of up-to-date listing and CCB (calcium channel blocker) are noticeable with the efficacy of antihypertensive treatment and the complementary mechanism of action of its optimization.Generally speaking, the high blood pressure disease patient adopts the compound medicine treatment, and compliance will be improved, and curative effect obviously is superior to the single medicine treatment.
Valsartan is a kind of special strong angiotensin (AT) II receptor antagonist; It optionally acts on the AT1 receptor subtype, and the AT1 receptor subtype produces reaction to the known action of Angiotensin II, and AT2 receptor subtype and cardiovascular effect are irrelevant; Valsartan has no the activity of partial agonist to the AT1 receptor; Valsartan is stronger 20000 times than AT2 receptor with the affinity of AT1, and peak time is 2-4 hour after the valsartan oral absorption, and absolute bioavailability is about 25%.
Amlodipine (Amlodipine) is a calcium ion antagonist of new generation, and by Pfizer's development, 1990 go on the market in Britain first; Be used to clinically treat hypertension and stable angina pectoris, be characterized in evident in efficacy, onset is steady; EDD long (24h long-acting), side effect is little.In addition, patient's taking convenience, once a day, patient's better tolerance.Being regarded as by U.S. FDA is safe and effective medicine, and is accepted by vast hyperpietic, is the hypertensive choice drug of treatment.
Amlodipine is dihydropyridine type calcium antagonists (calcium ion antagonist or a slow channel blocking agent), mainly uses its benzene sulfonate clinically.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.The contraction of cardiac muscle and smooth muscle depends on the extracellular Ca2 ion and gets into cell through the specificity ion.The amlodipine selectivity suppresses calcium ion strides film and gets into smooth muscle cell and myocardial cell, to the effect of smooth muscle greater than cardiac muscle.It is decided by that with the effect of calcium channel it and acceptor site combine and dissociated gradual speed, so pharmacological action produces gradually.Amlodipine is the peripheral arterial expander, directly acts on vascular smooth muscle, reduces peripheral vascular resistance, thereby brings high blood pressure down.Under the therapeutic dose, amlodipine does not influence plasma calcium concentration.
(Hydrochlorothiazide HCT) is piperazine class diuretic to hydrochlorothiazide.Its chemical name is: 6-chloro-3,4 dihydros-2H-1,2; 4-benzothiadiazine-7-sulfonamide-1, the 1-dioxide, experiment proof hydrochlorothiazide has direct effect to kidney; Phenothiazine drug acts on medullary loop and rises a branch butt end cortex part, suppresses this position and the active of chloride ion is absorbed with the passive of sodium ion again absorbs, causes sodium water negative balance in the body; Make extracellular fluid and hypovolemia, thereby play the initial stage hypotensive effect.But incomplete, feed can increase absorbtivity to the hydrochlorothiazide oral absorption rapidly, possibly prolong relevant in the holdup time of small intestinal with medicine.
Amlodipine and valsartan all are the leading kinds in the field of treating separately; Wherein, Valsartan (trade name:
) sales volume in 2006 has surpassed 6,000,000,000 dollars; And overdue amlodipine (trade name:
) in 2007; Sales volumes in 2006 was 5,000,000,000 dollars, was in the rising stage of growing up in China.
Valsartan amlodipine sheet is had identical ideas with the recommendation of the guide of U.S.'s treatment at present, promptly just should adopt drug combination to the patient who is fit to.Research points out that nearly 80% patient needs the multiple medicines therapeutic alliance, to help blood pressure up to standard.Along with the line medication approval of valsartan amlodipine sheet, the therapeutic strategy of doctor's controlling blood pressure can obtain simplifying.Need multiple treatment to realize the patient that blood pressure is up to standard for those, adopt the immobilised compound preparation to be superior to by a kind of medicine begin treatment, then increase dosage and add stepped care scheme then again with another kind of medicine as the first-line treatment scheme.
Because valsartan, amlodipine have the different mechanism of action with hydrochlorothiazide; Three medicines associating back valsartan is through keeping nervous plain II receptors bind; Suppressed this strong endogenous vasoconstrictor; Amlodipine reduces total peripheral vascular resistance through stoping in the calcium ion intravasation wall, and hydrochlorothiazide is received and the outer mechanism of action blood pressure lowering of kidney through diuresis row.These three kinds of mechanism of action complementations, three medicine therapeutic alliances are more satisfactory combinations, have the curative effect of 1+1+1＞3, and side effect cancels out each other, can be used for treating single therapy after blood pressure can not get the fully hypertension of control.
At present, (trade name: listing Exforge HCT) is used to treat hypertension to the amlodipine and valsartan hydrochlorothiazide tablet compound preparation of drugs approved by FDA Novartis Co.,Ltd.Exforge HCT provides the combination (mg) of the valsartan/amlodipine/hydrochlorothiazide of five kinds of fixed dosages: 160/5/12.5 and 320/10/25,160/10/12.5,160/5/25,160/10/25.These make up poor effect patient after two types of antihypertensive drug therapeutic alliances of those application is a kind of important new selection.
Still need the compound medicine combination of for example forming by above-mentioned three types of drug regimens clinically by valsartan, amlodipine and hydrochlorothiazide; The capsule that for example has fixed dosage; Treat hypertension, capsule is shorter relatively in trouble and the production cycle that can avoid many preparations to make owing to need not carry out tabletting on the preparation process.
Summary of the invention
The object of the present invention is to provide the compound medicine combination of being made up of valsartan, amlodipine and hydrochlorothiazide, this drug regimen is the capsule with fixed dosage, is provided for treating hypertensive effective healing potion for clinical.It is the capsule with special formulation that active component is mixed with that the inventor finds with valsartan, amlodipine and hydrochlorothiazide three, has good pharmaceutics character.The present invention is based on this discovery and be accomplished.
First aspect present invention relates to the pharmaceutical composition that dosage form is a capsule, that is, this capsule is a hard capsule, and it comprises capsule shells and is wrapped in the inner content of this capsule shells.Under situation about not explaining especially in addition, when the present invention mentions capsule, when particularly mentioning the prescription composition of capsule of the present invention, all be meant the prescription composition that is wrapped in the inner content of capsule shells.
Therefore, first aspect present invention relates to a kind of capsule, and it comprises:
Valsartan 160 weight portions,
Amlodipine 2-20 weight portion,
Hydrochlorothiazide 5-50 weight portion,
Microcrystalline Cellulose 50-300 weight portion,
Lactose and/or pregelatinized Starch 20-200 weight portion and
Optional pharmaceutically acceptable carrier.
According to the capsule of first aspect present invention, wherein the amount of amlodipine is the 4-16 weight portion.In one embodiment, the amount of amlodipine is the 4-12 weight portion.In one embodiment, the amount of amlodipine is the 5-10 weight portion.
According to the capsule of first aspect present invention, wherein the amount of hydrochlorothiazide is the 10-40 weight portion.In one embodiment, the amount of hydrochlorothiazide is the 12-30 weight portion.In one embodiment, the amount of hydrochlorothiazide is the 12.5-25 weight portion.
According to the capsule of first aspect present invention, wherein the amount of microcrystalline Cellulose is the 75-250 weight portion.In one embodiment, the amount of microcrystalline Cellulose is the 90-225 weight portion.In one embodiment, the amount of microcrystalline Cellulose is the 100-210 weight portion.
According to the capsule of first aspect present invention, wherein the amount of lactose and/or pregelatinized Starch is the 25-175 weight portion.In one embodiment, the amount of lactose and/or pregelatinized Starch is the 40-150 weight portion.In one embodiment, the amount of lactose and/or pregelatinized Starch is the 50-120 weight portion.
According to the capsule of first aspect present invention, it comprises:
Valsartan 160 weight portions,
Amlodipine 4-12 weight portion,
Hydrochlorothiazide 12-30 weight portion,
Microcrystalline Cellulose 90-225 weight portion,
Lactose and/or pregelatinized Starch 40-150 weight portion and
Optional pharmaceutically acceptable carrier.
According to the capsule of first aspect present invention, it comprises:
Valsartan 160 weight portions,
Amlodipine 5-10 weight portion,
Hydrochlorothiazide 12.5-25 weight portion,
Microcrystalline Cellulose 100-210 weight portion,
Lactose and/or pregelatinized Starch 50-120 weight portion and
Optional pharmaceutically acceptable carrier.
According to the capsule of first aspect present invention, it has the described prescription like arbitrary embodiment basically.
According to the capsule of first aspect present invention, wherein in each preparation unit, in promptly every capsules, the amount that contains the active component valsartan can be 20～400mg, for example about 40mg, about 80mg, about 160mg or about 320mg.According to the capsule of first aspect present invention, the amount that wherein contains the active component amlodipine in each preparation unit can be 1～20mg, for example about 2.5, about 5mg or about 10mg.According to the capsule of first aspect present invention, the amount that wherein contains the active component hydrochlorothiazide in each preparation unit can be 2～50mg, for example about 6.25mg, about 12.5mg or about 25mg.
According to the capsule of first aspect present invention, wherein said valsartan is valsartan or its pharmaceutically acceptable salt.
According to the capsule of first aspect present invention, wherein said amlodipine is other pharmaceutical salts of amlodipine benzenesulphonate or maleate or amlodipine, is preferably Amlodipine Besylate Tablet.In the present invention, when mentioning the amount of amlodipine,, all be meant the amount of amlodipine free base, as feeding intake with its pharmaceutical salts or when handling, the amount of sign all is equivalent to the amount of amlodipine free base as clearly not indicating in addition.According to the capsule of first aspect present invention, wherein said amlodipine is the raceme of amlodipine.
Capsule according to first aspect present invention; Wherein said optional pharmaceutically acceptable carrier is meant that this carrier is selected from: filler, binding agent, disintegrating agent, antiplastering aid, lubricant, fluidizer, coloring agent, coating powder and combination thereof except microcrystalline Cellulose, lactose, other pharmaceutically acceptable carrier the pregelatinized Starch.Need to prove that it will be appreciated by those skilled in the art that the used microcrystalline Cellulose of the present invention, lactose, pregelatinized Starch, they have functions such as filler, diluent, disintegrating agent in medicament manufacturing field.
According to the present invention, wherein said filler is selected from: one or more of mannitol, sorbitol, starch, dextrin, sucrose, calcium hydrogen phosphate etc.
According to the present invention, wherein said binding agent is selected from: one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, copolyvidone, carboxymethyl cellulose, methylcellulose etc.; Can also be as the water of wetting agent and the medicinal alcohol solution of suitable concn.
According to the present invention, wherein said disintegrating agent is selected from: one or more of carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose etc.
According to the present invention, wherein said fluidizer is selected from: micropowder silica gel etc.
According to the present invention, wherein said lubricant is selected from: one or more of Pulvis Talci, stearic acid, magnesium stearate, Polyethylene Glycol etc.Need to prove that the two can exchange use to it will be appreciated by those skilled in the art that fluidizer and lubricant.
According to the present invention, wherein said coloring agent is selected from iron oxide red, iron oxide yellow etc.
According to the present invention, wherein said coating material comprises: one or more of Opadry, polyvinyl alcohol, hydroxypropyl cellulose, Polyethylene Glycol etc.
According to the present invention, the medicinal alcohol solution of the preferred hydroxypropyl methylcellulose of wherein said binding agent, copolyvidone, medicinal water and suitable concn.
According to the present invention, the preferred polyvinylpolypyrrolidone of wherein said disintegrating agent, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or its combination.
According to the present invention, the preferred micropowder silica gel of wherein said fluidizer.
According to the present invention, wherein said lubricant preferably talc powder, magnesium stearate or its combination.
In the present invention, the consumption of said filler, binding agent, disintegrating agent, antiplastering aid, lubricant, fluidizer, coloring agent, coating powder can be selected according to the general consumption of each excipient in solid preparation by those skilled in the art.When for example diluent was present in the pharmaceutical composition of capsule of the present invention, it accounted for about 0.5 to about 60%, preferred 2% to 50%, preferred 5 to 30% of composition total weight.When for example disintegrating agent was present in the pharmaceutical composition of capsule of the present invention again, it accounted for about 0.5 to about 50%, preferred 2% to 25%, preferred 5 to 15%, preferred 5 to 10% of composition total weight.When for example binding agent was present in the pharmaceutical composition of capsule of the present invention again, it accounted for about 0.5 to about 50%, preferred 2% to 25%, preferred 5 to 15%, preferred 5 to 10% of composition total weight.When for example lubricant and/or fluidizer were present in the pharmaceutical composition of capsule of the present invention again, it accounted for about 0.5 to about 20%, preferred 0.5% to 10%, preferred 0.5 to 5%, preferred 0.5 to 2.5% of composition total weight.
In the pharmaceutical composition of capsule of the present invention, the weight of said microcrystalline Cellulose is 0.5～5 times of weight of lactose and/or pregelatinized Starch, preferred 0.75～4 times, and preferred 0.8～3 times, also preferred 1.5～3 times.
In the present invention, valsartan, amlodipine, hydrochlorothiazide can prepare according to known technology, perhaps can directly buy from market.
Second aspect present invention provides the method for preparing the first aspect present invention capsule; It comprises the steps: each active component and ingredient powder are broken into can be through the aperture less than 60 purpose fine powders (for example each active component and adjuvant can pass through 60-120 purpose sieve, for example can pass through 80-100 purpose sieve); Adopt dry granulation method or wet granulation process, each active component is processed granule with adjuvant respectively or together, randomly granule is carried out drying; The gained granule is packed in the hollow capsule shells, promptly get.
According to the method for second aspect present invention, it adopts the dry granulation method, may further comprise the steps:
A) with valsartan, amlodipine, hydrochlorothiazide and microcrystalline Cellulose, lactose and/or pregelatinized Starch, and other optional pharmaceutically acceptable carrier crosses the 80-100 mesh sieve respectively, and is subsequent use;
B) with valsartan, amlodipine, hydrochlorothiazide three and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with valsartan, amlodipine, hydrochlorothiazide respectively with microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with any two kinds and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously in three kinds of active component, and with another kind and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; In the process that obtains above-mentioned variety of way gained mixture, randomly add pharmaceutically acceptable carrier (especially filler, disintegrating agent, binding agent, antiplastering aid);
C) mixture compacted that step b is obtained (can use any suitable means to realize compacting; Usually use the lift-over compacting machine at about 20-60kn; Also can be through being that sheet reduces its size then and realizes compacting with the mixed-powder precompressed) obtain compact; Again this compact is milled (can use any form to grind), with 16-20 mesh sieve granulate, subsequent use;
D) granule and optional lubricant and/or fluidizer and optional disintegrating agent mix homogeneously that step c are obtained promptly get capsule medicine compositions of the present invention, and said composition can be filled in the capsule shells of suitable size, becomes the medicament of capsule form.
According to the method for second aspect present invention, it adopts wet granulation process, may further comprise the steps:
A) with valsartan, amlodipine, hydrochlorothiazide and microcrystalline Cellulose, lactose and/or pregelatinized Starch, and other optional pharmaceutically acceptable carrier crosses the 80-100 mesh sieve respectively, and is subsequent use;
B) with valsartan, amlodipine, hydrochlorothiazide three and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with valsartan, amlodipine, hydrochlorothiazide respectively with microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with any two kinds and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously in three kinds of active component, and with another kind and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; In the process that obtains above-mentioned variety of way gained mixture, randomly add pharmaceutically acceptable carrier (especially filler, disintegrating agent, binding agent, antiplastering aid);
C) mixture that step b is obtained with binding agent or wetting agent system soft material, is granulated drying, granulate with the 16-20 mesh sieve;
D) granule and optional lubricant and/or fluidizer and optional disintegrating agent mix homogeneously that step c are obtained promptly get capsule medicine compositions of the present invention, and said composition can be filled in the capsule shells of suitable size, becomes the medicament of capsule form.
According to the method for second aspect present invention, wherein said optional disintegrating agent can adopt the mode of interior addition, outer addition or its combination to join in the hybrid particles.That is, said optional disintegrating agent can add in the mixed process of step b, can also in the mixed process of steps d, add.
Arbitrary technical characterictic that arbitrary embodiment had of the arbitrary aspect of the present invention or this arbitrary aspect is suitable for arbitrary embodiment of other arbitrary embodiment or other arbitrary aspect equally; As long as they can be not conflicting; Certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Do further to describe with characteristics to various aspects of the present invention below.
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition; Various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art; Nonetheless; The present invention still hopes at this more detailed explanation and explanation to be done in these terms and phrase, and term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
A kind of capsule is provided in the present invention, has specifically provided a kind of pharmaceutical composition with special formulation, this pharmaceutical composition is wrapped in the capsule shells, and said capsule shells does not have special qualification.
When the inventor found to prepare the capsule that comprises valsartan, amlodipine and hydrochlorothiazide, the capsule that has like specific prescription according to the invention had good dissolving out capability.
The specific embodiment
Further specify the present invention through concrete embodiment/experimental example below, still, be to be understood that into, these embodiment and experimental example are only used for the usefulness of explanation more in detail particularly, are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and operational approach are well known in the art.
In following examples, like not explanation in addition, used amlodipine is its benzene sulfonate.
Embodiment 1: valsartan amlodipine hydrochlorothiazide capsule (160/5/12.5mg)
| Amlodipine | 5 |
| Hydrochlorothiazide | 12.5 |
| Valsartan | 160 |
| Microcrystalline Cellulose | 130 |
| Lactose | 50 |
| Polyvinylpolypyrrolidone | 25 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and valsartan, hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases, then repress behind the polyvinylpolypyrrolidone mix homogeneously of the principal agent of mix homogeneously and microcrystalline Cellulose, lactose and 75% is processed compact; Compact is ground; With 20 mesh sieve granulate, add the polyvinylpolypyrrolidone of recipe quantity magnesium stearate and surplus, mix homogeneously; Survey the content of active component in the granule, encapsulated.
Embodiment 2: valsartan amlodipine hydrochlorothiazide capsule (160/10/12.5mg)
| Composition | Weight (g) |
| Amlodipine | 10 |
| Hydrochlorothiazide | 12.5 |
| Valsartan | 160 |
| Microcrystalline Cellulose | 135 |
| Lactose | 60 |
| Polyvinylpolypyrrolidone | 30 |
| Magnesium stearate | 6 |
| Process altogether | 1000 |
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and valsartan, hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases, then repress behind the polyvinylpolypyrrolidone mix homogeneously of the principal agent of mix homogeneously and microcrystalline Cellulose, lactose and 75% is processed compact; Compact is ground; With 20 mesh sieve granulate, add the polyvinylpolypyrrolidone of recipe quantity magnesium stearate and surplus, mix homogeneously; Survey granule content, encapsulated.
Embodiment 3: valsartan amlodipine hydrochlorothiazide capsule (160/10/25mg)
| Composition | Weight (g) |
| Amlodipine | 10 |
| Hydrochlorothiazide | 25 |
| Valsartan | 160 |
| Microcrystalline Cellulose | 150 |
| Pregelatinized Starch | 60 |
| Polyvinylpolypyrrolidone | 25 |
| Magnesium stearate | 8 |
| Process altogether | 1000 |
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and valsartan, hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases, then repress behind the polyvinylpolypyrrolidone mix homogeneously of the principal agent of mix homogeneously and microcrystalline Cellulose, pregelatinized Starch and 75% is processed compact; Compact is ground; With 20 mesh sieve granulate, add the polyvinylpolypyrrolidone of recipe quantity magnesium stearate and surplus, mix homogeneously; Survey granule content, encapsulated.
Embodiment 4: valsartan amlodipine hydrochlorothiazide capsule (160/10/25mg)
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively.
In part 1; With the amlodipine of recipe quantity and hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases; Then repress behind the principal agent of mix homogeneously and microcrystalline Cellulose, pregelatinized Starch and the polyvinylpolypyrrolidone mix homogeneously is processed compact, compact is ground, with 20 mesh sieve granulate; Make amlodipine hydrochlorothiazide granule, subsequent use;
In part 2, with recipe quantity valsartan and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone mix homogeneously, be pressed into compact then, compact is ground, with 20 mesh sieve granulate, make the valsartan granule, subsequent use;
Take by weighing above two kinds of granules respectively in proportion, add recipe quantity differential silica gel, magnesium stearate and Pulvis Talci mix homogeneously, encapsulated, get finished product.
Embodiment 5: valsartan amlodipine hydrochlorothiazide capsule (160/10/12.5mg)
Method for preparing:
Amlodipine is its maleate.
In 1 part; The amlodipine and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone that take by weighing recipe quantity are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone by the equivalent method mix homogeneously that progressively increases, repress is processed compact; Compact is ground; With 20 mesh sieve granulate, make the amlodipine granule, subsequent use;
In 2 parts; The hydrochlorothiazide and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone that take by weighing recipe quantity are crossed 80 mesh sieves respectively, again with the hydrochlorothiazide of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone by the equivalent method mix homogeneously that progressively increases, and then be pressed into compact; Compact is ground; With 20 mesh sieve granulate, make the hydrochlorothiazide granule, subsequent use;
In 3 parts; Valsartan and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone of recipe quantity are crossed 80 mesh sieves respectively; Again the valsartan of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone are processed compact by the equivalent repress that progressively increases behind the method mix homogeneously; Compact is ground with 20 mesh sieve granulate, make the valsartan granule, subsequent use;
Take by weighing above three kinds of granules respectively in proportion, the Pulvis Talci and the magnesium stearate mix homogeneously that add recipe quantity are encapsulated, get finished product.
Embodiment 6: valsartan amlodipine hydrochlorothiazide capsule (160/5/12.5mg)
| Composition | Weight (g) |
| Amlodipine | 5 |
| Hydrochlorothiazide | 12.5 |
| Valsartan | 160 |
| Microcrystalline Cellulose | 130 |
| Lactose | 50 |
| Polyvinylpolypyrrolidone | 25 |
| 1.8% hydroxypropyl emthylcellulose aqueous solution | In right amount |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and valsartan, hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously, reuse 1.8% hydroxypropyl emthylcellulose aqueous solution system soft material; Cross 18 mesh sieves, granulate, 40-60 ℃ is dried to moisture and is lower than 5%; With 20 mesh sieve granulate, add the recipe quantity magnesium stearate, mix homogeneously; Survey granule content, encapsulated, get finished product.
Embodiment 7: valsartan amlodipine hydrochlorothiazide capsule (160/10/12.5mg)
| Composition | Weight (g) |
| Amlodipine | 10 |
| Hydrochlorothiazide | 12.5 |
| Valsartan | 160 |
| Microcrystalline Cellulose | 135 |
| Lactose | 60 |
| Polyvinylpolypyrrolidone | 30 |
| 95% ethanol | In right amount |
| Magnesium stearate | 6 |
| Process altogether | 1000 |
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and valsartan, hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously; 95% ethanol system soft material is crossed 18 mesh sieves and is granulated, and 40-60 ℃ is dried to moisture and is lower than 5%; With 20 mesh sieve granulate, add the recipe quantity magnesium stearate, mix homogeneously; Survey granule content, encapsulated, get finished product.
Embodiment 8: valsartan amlodipine hydrochlorothiazide capsule (160/10/25mg)
| Composition | Weight (g) |
| Amlodipine | 10 |
| Hydrochlorothiazide | 25 |
| Valsartan | 160 |
| Microcrystalline Cellulose | 150 |
| Pregelatinized Starch | 60 |
| Polyvinylpolypyrrolidone | 25 |
| Water | In right amount |
| Magnesium stearate | 8 |
| Process altogether | 1000 |
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and valsartan, hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases.With principal agent and microcrystalline Cellulose, pregelatinized Starch and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously, water system soft material is crossed 18 mesh sieves and is granulated then; 40-60 ℃ is dried to moisture and is lower than 5%, with 20 mesh sieve granulate, adds the recipe quantity magnesium stearate; Mix homogeneously; Survey granule content, encapsulated, get finished product.
Embodiment 9: valsartan amlodipine hydrochlorothiazide capsule (160/10/25mg)
Method for preparing:
Above recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively.
For part 1, with the amlodipine of recipe quantity and hydrochlorothiazide by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, pregelatinized Starch and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously; 95% ethanol system soft material; Cross 18 mesh sieves and granulate, 40-60 ℃ is dried to moisture for being lower than 5%, with 20 mesh sieve granulate; Make amlodipine hydrochlorothiazide granule, subsequent use.
For part 2, with recipe quantity valsartan and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone mix homogeneously, 95% ethanol system soft material is crossed 18 mesh sieves and is granulated, and 40-60 ℃ is dried to moisture and is lower than 5%, with 20 mesh sieve granulate, makes the valsartan granule, subsequent use.
Take by weighing above two kinds of granules respectively in proportion, add recipe quantity differential silica gel, magnesium stearate and Pulvis Talci mix homogeneously, encapsulated, get finished product.
Embodiment 10: valsartan amlodipine hydrochlorothiazide capsule (160/5/12.5mg)
Method for preparing:
For part 1, the amlodipine and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone that take by weighing recipe quantity are crossed 80 mesh sieves respectively, again with the amlodipine of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone by the equivalent method mix homogeneously that progressively increases; Water system soft material; Cross 18 mesh sieves and granulate, 40-60 ℃ is dried to moisture and is lower than 5%, with 20 mesh sieve granulate; Make the amlodipine granule, subsequent use;
For part 2, the hydrochlorothiazide and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone that take by weighing recipe quantity are crossed 80 mesh sieves respectively, again with the hydrochlorothiazide of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone by the equivalent method mix homogeneously that progressively increases; With 1.8% hydroxypropyl emthylcellulose aqueous solution system soft material; Cross 18 mesh sieves and granulate, 40-60 ℃ is dried to moisture and is lower than 5%, with 20 mesh sieve granulate; Make the hydrochlorothiazide granule, subsequent use;
For the 3rd part, the valsartan of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone are crossed 80 mesh sieves respectively, again with the valsartan of recipe quantity and microcrystalline Cellulose, lactose and polyvinylpolypyrrolidone by the equivalent method mix homogeneously that progressively increases; With 1.8% hydroxypropyl emthylcellulose aqueous solution system soft material; Cross 18 mesh sieves and granulate, 40-60 ℃ is dried to moisture and is lower than 5%, with 20 mesh sieve granulate; Make the valsartan granule, subsequent use;
Take by weighing above three kinds of granules respectively in proportion, adding recipe quantity Pulvis Talci and magnesium stearate mix homogeneously are encapsulated, get finished product.
Embodiment 11: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 8 |
| Hydrochlorothiazide | 20 |
| Microcrystalline Cellulose | 150 |
| Lactose | 80 |
| Polyvinylpolypyrrolidone | 25 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously; Repress is processed compact; Compact is ground,, add the magnesium stearate mix homogeneously with 20 mesh sieve granulate; Survey the content of active component in the granule, encapsulated.
Embodiment 12: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 4 |
| Hydrochlorothiazide | 30 |
| Microcrystalline Cellulose | 225 |
| Lactose | 50 |
| Starch | 40 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the starch mix homogeneously of mix homogeneously; Repress is processed compact; Compact is ground,, add the magnesium stearate mix homogeneously with 20 mesh sieve granulate; Survey the content of active component in the granule, encapsulated.
Embodiment 13: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 12 |
| Hydrochlorothiazide | 12 |
| Microcrystalline Cellulose | 90 |
| Lactose | 80 |
| Sodium carboxymethyl cellulose | 10 |
| Polyvinylpolypyrrolidone | 20 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose, sodium carboxymethyl cellulose and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously; Repress is processed compact; Compact is ground,, add the magnesium stearate mix homogeneously with 20 mesh sieve granulate; Survey the content of active component in the granule, encapsulated.
Embodiment 14: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 12 |
| Hydrochlorothiazide | 12 |
| Microcrystalline Cellulose | 90 |
| Lactose | 20 |
| Pregelatinized Starch | 20 |
| Sodium carboxymethyl cellulose | 5 |
| Polyvinylpolypyrrolidone | 15 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose, pregelatinized Starch, sodium carboxymethyl cellulose and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously; Repress is processed compact; Compact is ground,, add the magnesium stearate mix homogeneously with 20 mesh sieve granulate; Survey the content of active component in the granule, encapsulated.
Embodiment 15: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 8 |
| Hydrochlorothiazide | 20 |
| Microcrystalline Cellulose | 180 |
| Pregelatinized Starch | 150 |
| Polyvinylpolypyrrolidone | 25 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, pregelatinized Starch and the polyvinylpolypyrrolidone mix homogeneously of mix homogeneously; Repress is processed compact; Compact is ground,, add the magnesium stearate mix homogeneously with 20 mesh sieve granulate; Survey the content of active component in the granule, encapsulated.
Embodiment 16: valsartan amlodipine hydrochlorothiazide capsule
| Valsartan | 160 |
| Amlodipine | 8 |
| Hydrochlorothiazide | 20 |
| Microcrystalline Cellulose | 180 |
| Lactose | 150 |
| Low-substituted hydroxypropyl cellulose | 28 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the low-substituted hydroxypropyl cellulose mix homogeneously of mix homogeneously; Water is made soft material in right amount, granulates, and 40-60 ℃ is dried to moisture and is lower than 5%; With 20 mesh sieve granulate; Add the magnesium stearate mix homogeneously, encapsulated, get finished product.
Embodiment 17: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 4 |
| Hydrochlorothiazide | 30 |
| Microcrystalline Cellulose | 90 |
| Lactose | 40 |
| Low-substituted hydroxypropyl cellulose | 30 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the low-substituted hydroxypropyl cellulose mix homogeneously of mix homogeneously; Water is made soft material in right amount, granulates, and 40-60 ℃ is dried to moisture and is lower than 5%; With 20 mesh sieve granulate; Add the magnesium stearate mix homogeneously, encapsulated, get finished product.
Embodiment 18: valsartan amlodipine hydrochlorothiazide capsule
| Composition | Weight (g) |
| Valsartan | 160 |
| Amlodipine | 12 |
| Hydrochlorothiazide | 12 |
| Microcrystalline Cellulose | 225 |
| Lactose | 150 |
| Low-substituted hydroxypropyl cellulose | 30 |
| Magnesium stearate | 5 |
| Process altogether | 1000 |
Method for preparing:
Recipe quantity principal agent and adjuvant are crossed 80 mesh sieves respectively, again with the principal agent of recipe quantity by the equivalent method mix homogeneously that progressively increases, then with principal agent and microcrystalline Cellulose, lactose and the low-substituted hydroxypropyl cellulose mix homogeneously of mix homogeneously; Water is made soft material in right amount, granulates, and 40-60 ℃ is dried to moisture and is lower than 5%; With 20 mesh sieve granulate; Add the magnesium stearate mix homogeneously, encapsulated, get finished product.
Reference examples 1: reference implementation example 11, different is that used microcrystalline Cellulose amount is respectively 275mg, 300mg, 350mg and 400mg, obtains the capsule of four kinds of prescriptions.
Reference examples 2: reference implementation example 11, different is that used microcrystalline Cellulose amount is respectively 80mg, 60mg, 40mg and 20mg, obtains the capsule of four kinds of prescriptions.
Reference examples 3: reference implementation example 11, different is that used lactose yield is respectively 175mg, 200mg, 225mg and 250mg, obtains the capsule of four kinds of prescriptions.
Reference examples 4: reference implementation example 11, different is that used lactose yield is respectively 30mg, 25mg, 20mg and 10mg, obtains the capsule of four kinds of prescriptions.
Reference examples 5: reference implementation example 11, different is that used pregelatinized Starch amount is respectively 30mg, 20mg, 175mg and 225mg, obtains the capsule of four kinds of prescriptions.
Reference examples 6: reference implementation example 11, different is that the amount that does not wherein add microcrystalline Cellulose and lactose is respectively 40mg, 80mg, 120mg and 150mg, obtains the capsule of four kinds of prescriptions.
Reference examples 7: reference implementation example 11, different is that the amount that does not wherein add lactose and microcrystalline Cellulose is respectively 90mg, 120mg, 180mg and 225mg, obtains the capsule of four kinds of prescriptions.
Reference examples 8: reference implementation example 11, different is wherein microcrystalline Cellulose to be replaced with starch, sucrose, mannitol, dextrin respectively, obtains the capsule of four kinds of prescriptions.
Reference examples 9: reference implementation example 11, different is wherein lactose to be replaced with starch, sucrose, mannitol, dextrin respectively, obtains the capsule of four kinds of prescriptions.
Reference examples 10: reference implementation example 6, different is that used microcrystalline Cellulose amount is respectively 40mg, 80mg, 275mg, 350mg, obtains the capsule of four kinds of prescriptions.
Reference examples 11: reference implementation example 6, different is that used lactose yield is respectively 10mg, 30mg, 175mg, 225mg, obtains the capsule of four kinds of prescriptions.
Reference examples 12: reference implementation example 16, different is that used microcrystalline Cellulose amount is respectively 40mg, 80mg, 275mg, 350mg, obtains the capsule of four kinds of prescriptions.
Reference examples 13: reference implementation example 16, different is that used lactose yield is respectively 10mg, 30mg, 175mg, 225mg, obtains the capsule of four kinds of prescriptions.
Reference examples 14: reference implementation example 16, different is not use microcrystalline Cellulose or do not use lactose, obtains the capsule of two kinds of prescriptions.
Test Example 1: the dissolution of measuring capsule of the present invention
Dissolution is got the capsule of the present invention of preceding text preparation and the capsule of reference examples preparation, according to dissolution method (two appendix XC first methods of Pharmacopoeia of People's Republic of China version in 2010), (gets potassium dihydrogen phosphate 6.80g and sodium hydroxide 0.90g with phosphate buffer; Being dissolved in water into 1000ml, regulating pH value to 6.8) 1000ml is dissolution medium, rotating speed is that per minute 100 changes; Operation in accordance with the law, in the time of 30 minutes, it is an amount of to get solution; Filter; It is an amount of that precision is measured subsequent filtrate, quantitatively dilutes with dissolution medium and process the solution that contains valsartan 1-10ug among every 1ml approximately, measures.
Measure the result: for each capsule of embodiment 1-18; In the time of 30 minutes; The dissolution of amlodipine all reaches 82～94% of labelled amount, and the dissolution of valsartan all reaches 85～93% of labelled amount, and the dissolution of hydrochlorothiazide all reaches 74～87% of labelled amount.In the time of 45 minutes, the dissolution of three kinds of active component all reaches more than 90% of labelled amount.For each capsule of reference examples 1-14 preparation, in the time of 30 minutes, the dissolution of amlodipine all reaches 58～73% of labelled amount, and the dissolution of valsartan all reaches 63～79% of labelled amount, and the dissolution of hydrochlorothiazide all reaches 44～67% of labelled amount.In the time of 45 minutes, the dissolution of three kinds of active component all is lower than 85% of labelled amount.Four kinds of capsules of reference examples 1 preparation for example, the dissolution of three kinds of active component all was lower than the corresponding composition of embodiment 11 samples more than 20% in the time of 30 minutes, also low more than 10% in the time of 45 minutes.Other reference examples also shows the situation that is similar to reference examples 1.
Wherein, the stripping quantity of amlodipine and valsartan adopts document (the HPLC method is measured Amlodipine Besylate Tablet and valsartan content in the FUFANG LIXUEPING PIAN simultaneously, and the Chinese Hospitals medication is estimated and analyzed 2011 the 8th phases) method of Zhang Fang to measure; The stripping quantity of hydrochlorothiazide adopts fur coat one blue document (the HPLC method is measured the content and the related substance of hydrochlorothiazide tablet, Chinese drug standard, 2006 the 3rd phases) method to measure.
Claims (10)
1. capsule, it comprises:
Valsartan 160 weight portions,
Amlodipine 2-20 weight portion,
Hydrochlorothiazide 5-50 weight portion,
Microcrystalline Cellulose 50-300 weight portion,
Lactose and/or pregelatinized Starch 20-200 weight portion and
Optional pharmaceutically acceptable carrier.
2. according to the capsule of claim 1, wherein
The amount of amlodipine is the 4-16 weight portion;
The amount of hydrochlorothiazide is the 10-40 weight portion;
The amount of microcrystalline Cellulose is the 75-250 weight portion; And/or
The amount of lactose and/or pregelatinized Starch is the 25-175 weight portion.
3. according to the capsule of claim 1, it comprises:
Valsartan 160 weight portions,
Amlodipine 4-12 weight portion,
Hydrochlorothiazide 12-30 weight portion,
Microcrystalline Cellulose 90-225 weight portion,
Lactose and/or pregelatinized Starch 40-150 weight portion and
Optional pharmaceutically acceptable carrier.
4. according to the capsule of claim 1, it comprises:
Valsartan 160 weight portions,
Amlodipine 5-10 weight portion,
Hydrochlorothiazide 12.5-25 weight portion,
Microcrystalline Cellulose 100-210 weight portion,
Lactose and/or pregelatinized Starch 50-120 weight portion and
Optional pharmaceutically acceptable carrier.
5. according to each capsule of claim 1 to 4, wherein in each preparation unit, the amount that contains the active component valsartan can be 20～400mg, for example about 40mg, about 80mg, about 160mg or about 320mg.
6. according to each capsule of claim 1 to 5, wherein
Described valsartan is valsartan or its pharmaceutically acceptable salt; And/or
Described amlodipine is other pharmaceutical salts of amlodipine benzenesulphonate or maleate or amlodipine.
7. according to each capsule of claim 1 to 6; Wherein said optional pharmaceutically acceptable carrier is meant that this carrier is selected from: filler, binding agent, disintegrating agent, antiplastering aid, lubricant, fluidizer, coloring agent, coating powder and combination thereof except microcrystalline Cellulose, lactose, other pharmaceutically acceptable carrier the pregelatinized Starch.
8. according to the capsule of claim 7, wherein
Said filler is selected from: one or more of mannitol, sorbitol, starch, dextrin, sucrose, calcium hydrogen phosphate etc.;
Said binding agent and/or wetting agent are selected from: the medicinal alcohol solution of hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch, copolyvidone, carboxymethyl cellulose, methylcellulose, water, suitable concn;
Said disintegrating agent is selected from: one or more of carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose etc.;
Fluidizer and/or lubricant are selected from: one or more of micropowder silica gel, Pulvis Talci, stearic acid, magnesium stearate, Polyethylene Glycol etc.
9. each the method for capsule of preparation claim 1 to 8, it comprises the steps: each active component and ingredient powder be broken into and can pass through the aperture less than 60 purpose fine powders; Adopt dry granulation method or wet granulation process, each active component is processed granule with adjuvant respectively or together, randomly granule is carried out drying; The gained granule is packed in the hollow capsule shells, promptly get.
10. according to the method for claim 9,
When adopting the dry granulation method, may further comprise the steps:
A) with valsartan, amlodipine, hydrochlorothiazide and microcrystalline Cellulose, lactose and/or pregelatinized Starch, and other optional pharmaceutically acceptable carrier crosses the 80-100 mesh sieve respectively, and is subsequent use;
B) with valsartan, amlodipine, hydrochlorothiazide three and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with valsartan, amlodipine, hydrochlorothiazide respectively with microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with any two kinds and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously in three kinds of active component, and with another kind and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; In the process that obtains above-mentioned variety of way gained mixture, randomly add pharmaceutically acceptable carrier (especially filler, disintegrating agent, binding agent, antiplastering aid);
C) mixture compacted that step b is obtained (can use any suitable means to realize compacting; Usually use the lift-over compacting machine at about 20-60kn; Also can be through being that sheet reduces its size then and realizes compacting with the mixed-powder precompressed) obtain compact; Again this compact is milled (can use any form to grind), with 16-20 mesh sieve granulate, subsequent use;
D) granule and optional lubricant and/or fluidizer and optional disintegrating agent mix homogeneously that step c are obtained promptly get capsule medicine compositions of the present invention, and said composition can be filled in the capsule shells of suitable size, becomes the medicament of capsule form;
When adopting wet granulation process, may further comprise the steps:
A) with valsartan, amlodipine, hydrochlorothiazide and microcrystalline Cellulose, lactose and/or pregelatinized Starch, and other optional pharmaceutically acceptable carrier crosses the 80-100 mesh sieve respectively, and is subsequent use;
B) with valsartan, amlodipine, hydrochlorothiazide three and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with valsartan, amlodipine, hydrochlorothiazide respectively with microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; Perhaps with any two kinds and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously in three kinds of active component, and with another kind and microcrystalline Cellulose, lactose and/or pregelatinized Starch mix homogeneously; In the process that obtains above-mentioned variety of way gained mixture, randomly add pharmaceutically acceptable carrier (especially filler, disintegrating agent, binding agent, antiplastering aid);
C) mixture that step b is obtained with binding agent or wetting agent system soft material, is granulated drying, granulate with the 16-20 mesh sieve;
D) granule and optional lubricant and/or fluidizer and optional disintegrating agent mix homogeneously that step c are obtained promptly get capsule medicine compositions of the present invention, and said composition can be filled in the capsule shells of suitable size, becomes the medicament of capsule form.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012101114119A CN102657657A (en) | 2012-04-17 | 2012-04-17 | Capsule containing valsartan, amlodipine and hydrochlorothiazide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113171352A (en) * | 2021-04-15 | 2021-07-27 | 海南锦瑞制药有限公司 | Preparation method of sartan antihypertensive compound preparation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829111A (en) * | 2010-05-23 | 2010-09-15 | 浙江华海药业股份有限公司 | Valsartan-containing solid preparation and preparation method thereof |
| CN102008482A (en) * | 2009-07-11 | 2011-04-13 | 邬林祥 | Compound preparation containing valsartan for treating hypertension |
| CN102335176A (en) * | 2011-07-14 | 2012-02-01 | 海南锦瑞制药股份有限公司 | Brand-new oral solid medicinal composition and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008482A (en) * | 2009-07-11 | 2011-04-13 | 邬林祥 | Compound preparation containing valsartan for treating hypertension |
| CN101829111A (en) * | 2010-05-23 | 2010-09-15 | 浙江华海药业股份有限公司 | Valsartan-containing solid preparation and preparation method thereof |
| CN102335176A (en) * | 2011-07-14 | 2012-02-01 | 海南锦瑞制药股份有限公司 | Brand-new oral solid medicinal composition and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113171352A (en) * | 2021-04-15 | 2021-07-27 | 海南锦瑞制药有限公司 | Preparation method of sartan antihypertensive compound preparation |
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