CN104644633A - Preparation method of high-stability amlodipine atorvastatin calcium tablet - Google Patents
Preparation method of high-stability amlodipine atorvastatin calcium tablet Download PDFInfo
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- CN104644633A CN104644633A CN201510051390.XA CN201510051390A CN104644633A CN 104644633 A CN104644633 A CN 104644633A CN 201510051390 A CN201510051390 A CN 201510051390A CN 104644633 A CN104644633 A CN 104644633A
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Abstract
The invention relates to a preparation method of a high-stability amlodipine atorvastatin calcium tablet. The preparation method of the high-stability amlodipine atorvastatin calcium tablet is characterized in that the amount of peroxide in microcrystalline cellulose is controlled. The preparation method of the high-stability amlodipine atorvastatin calcium tablet comprises the following steps: A, granulating of atorvastatin calcium, concretely comprising the steps of firstly dissolving a surfactant in water, adding a binding agent, stirring and dissolving, secondly mixing atorvastatin calcium, calcium carbonate, other diluents and a disintegrant, thirdly, granulating, and fourthly, drying wet granules obtained in the step three, so that dry atorvastatin calcium granules are prepared; and B, preparing of finished granules, concretely comprising the steps of firstly adding amlodipine besylate, a disintegrant and a flow aid into the dry atorvastatin calcium granules, secondly, uniformly mixing powder obtained in the step one in a mixing machine, thirdly, adding a lubricating agent, and uniformly mixing, and fourthly, pressing the powder into tablets.
Description
Technical field
The present invention relates to pharmaceutical technology sectors, be specifically related to a kind of preparation method of high stability amlodipine besylate and atorvastatin calcium sheet.
Background technology
Hypertension and dyslipidemia are the important risk factor of atherosclerosis, coronary heart disease and other cardiovascular and cerebrovascular diseases.Cardiovascular disease has been one of common, the most serious disease of harm humans health.Investigation display China middle-aged and elderly people hyperlipidemia accounts for more than 50%, and the total incidence rate of population is 7 ~ 8%.It is reported that the hyperlipemic patients of 43% suffers from hypertension.Therefore the medicine of hypertension and hyperlipidemia while of developing a kind of, can be treated, there is very high social meaning and economic implications.Patent CN101185646A discloses the pharmaceutical composition of amlodipine and Atorvastatin calcium, is used for the treatment of angina pectoris, atherosclerosis, hypertension and hyperlipidemia complication and/or hypercholesterolemia and treatment cardiac risk sign.
Amlodipine Besylate Tablet and atorvastatin are that the medicine that current market sales volume is leading is divided into, and are respectively to have treatment hypertension and anginal effect, and the effect for the treatment of hyperlipidemia.Amlodipine Besylate Tablet be the mid-80 second filial generation 1,4 of coming out ?dihydropyridine calcium ion antagonist, belong to New-type long-acting calcium channel blocker, comparatively strong to cardioselective, can diastole coronary vasodilator and system vascular, increase coronary flow, reduce blood pressure.1987, in U.S.'s approval listing (trade name: Norvasc), this medicine onset was releived, and the persistent period is long, is used for the treatment of hypertension, also can be used for patients with stable angina pectoris.Its chemical name is: 3 ?Yi Ji ?5 ?Jia Ji ?2 ?(2 ?amino ethoxymethyl) ?4 ?(2 ?chlorphenyl) ?1,4 ?Er Qing ?6 ?Jia Ji ?3,5 ?pyridine dicarboxylate benzene sulfonate.Chemical structural formula is as follows:
Atorvastatin calcium is Statins blood lipid regulation medicine, 1997 first in listings such as Great Britain and America, belong to HMG ?CoA reductase inhibitor.Atorvastatin by suppress HMG in liver ?CoA reductase and cholesterol biosynthesis thus reduce cholesterolemia and low-density lipoprotein cholesterol, moderate reduces serum triglyceride level and increases blood hdl level.Medical circle is generally acknowledged than natural microbial fermentation, semisynthetic statins is good, and when patient uses, namely initial dose has excellent tune fat compliance rate.The atorvastatin (trade name: lipitor) of current Pfizer Inc. has been the best-selling medicine in the whole world, and the occupation rate on lipid lowering agent market, the world is 65%.Its chemical name is: 7 ?[2 ?(4 ?fluorophenyl) ?3 ?benzene base ?4 ?(anilino-formoxyl) ?5 ?(2 ?propyl group) pyrrole coughs up ?1 ?yl] ?3,5 ?dihydroxy enanthic acid calcium.Chemical structural formula is as follows:
Amlodipine Besylate Tablet crude drug less stable, meets the wet easy moisture absorption, needs lucifuge when preparing preparation, and also more responsive to temperature.Brand amlodipine besylate tablets (Norvasc) adopts the technique of direct powder compression to produce, and avoids in the damp and hot impact on principal agent Amlodipine Besylate Tablet stability of granulating and in dry run.Atorvastatin calcium hydrophobicity is strong, is all difficult to dissolve in water, in acid, needs in pelletization, to add certain surfactant as Tween80, and dry rear granulation of granulating, to improve the dissolution of principal agent.In order to overcome the above problems, patent CN20152341U adopts the mode preparing Amlodipine Besylate Tablet Atorvastatin calcium double-layer tablet (Amlodipine Besylate Tablet layer adopts direct powder compression, and Atorvastatin calcium granule adopts wet granulation) to address this problem; First patent CN101185646A prepares the granule of Atorvastatin calcium, then adds the instability that method that Amlodipine Besylate Tablet carries out direct compression avoids Amlodipine Besylate Tablet.
We find in the research process carrying out compound amlodipine atorvastatin formulation and technology, and Atorvastatin calcium not only exists the problem of dissolubility, go back the problem of existence and stability, easily under soda acid high temperature and oxidizing condition, produce degraded.Soda acid high temperature degradation mainly produces atorvastatin lactone and atorvastatin pyrroles piperazine impurity; Its oxidative degradation produces and mainly contains atorvastatin three ring impurity and atorvastatin epoxide impurity, and structural formula is as follows:
We buy the existing atorvastatin of compound amlodipine on the market, the formulation and technology repeating patent CN20152341U and CN101185646A is prepared compound amlodipine atorvastatin and carries out accelerated stability research, result all finds that its oxidative degradation impurity increase is violent especially, the results are shown in embodiment 5.Therefore, we consider may exist in adjuvant the material existence accelerating oxidation of drug degraded.We consider to adopt the method controlling peroxide value in adjuvant, and the generation of controlled oxidization degradation impurity, prepares the amlodipine besylate and atorvastatin calcium sheet of high stability.
Referenced patent CN101185646A and CN20152341U, and former description of grinding sheet FDA we determine that the pharmaceutic adjuvant preparing compound amlodipine atorvastatin is as follows: calcium carbonate, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, pregelatinized Starch, Tween80, hydroxypropyl cellulose, silicon dioxide, magnesium stearate and coating powder (polyvinyl alcohol, titanium dioxide, Macrogol 3000 and Pulvis Talci).Above adjuvant Tween80 controls peroxide value in quality standard, but the consumption of Tween80 is 0.4% in whole prescription (see embodiment 2), the consumption of Atorvastatin calcium is 10.8%, Comparatively speaking the consumption of Tween80 in whole prescription is low especially, even if there is the peroxide of 1%, to the influence amount of Atorvastatin calcium oxidative degradation in prescription namely (0.4/10.8 × 1% × 100%=0.037%).Therefore, we get rid of the impact of Tween80.Adopt peroxide assay method to measure (assay method is shown in embodiment 3) other adjuvants, our surprised discovery detects peroxide in microcrystalline Cellulose.In whole prescription, the consumption of (see embodiment 1) microcrystalline Cellulose is 16.35%, therefore has vital impact to the oxidative degradation of the oxidation statin calcium that atropic cuts down.
Microcrystalline Cellulose brand more common on current market is German JRS, Japanese Asahi Chemical Industry, FMC; We select the microcrystalline Cellulose of three to carry out determination of POV, and have found lipid peroxidation has the microcrystalline Cellulose of larger difference to carry out the research of prescription.We carry out formula preparation with reference to patent CN101185646A, and place accelerated stability test, and result Atorvastatin calcium oxidative degradation impurity obviously reduces, and the results are shown in embodiment 4.Show the amount effectively controlling peroxide in microcrystalline Cellulose, the compound recipe Amlodipine Besylate Tablet atorvastatin of high stability can be prepared.
Summary of the invention
The object of this invention is to provide a kind of preparation method of compound amlodipine atorvastatin of high stability.The present invention is mainly through controlling the amount of peroxide in microcrystalline Cellulose, and the generation of controlled oxidization degradation impurity, prepares the amlodipine besylate and atorvastatin calcium sheet of high stability.
The preparation method of compound amlodipine atorvastatin of the present invention, comprises the following steps:
A: the granulation of Atorvastatin calcium
Step 1 ?surfactant dissolves is added binding agent stirring and dissolving in water;
Step 2 ?in facility for granulating, mix Atorvastatin calcium, calcium carbonate and other diluent and disintegrating agent;
Mixture of powders from step 2 and the solution from step 1 are granulated by step 3 ?in granulator equipment;
Step 4 ?, by the wet grain drying from step 3, is prepared into atorvastatin calcium dried granule;
B: the configuration of final granule
Step 1 ?add Amlodipine Besylate Tablet, disintegrating agent, fluidizer to atorvastatin calcium dried granule;
Step 2 ?is by the mix homogeneously in mixer of the powder from step 1;
Step 3 ?in the powder of step 2, add lubricant, mix homogeneously.
Powder compaction from step 3 is become tablet by step 4 ?.
Of the present invention, the adjuvant of amlodipine besylate and atorvastatin calcium sheet controls peroxide, can be the diluent in prescription, disintegrating agent or binding agent.
Of the present invention, the adjuvant of amlodipine besylate and atorvastatin calcium sheet controls peroxide, especially will control the amount of peroxide in diluent.
Wherein, diluent can be starch, lactose, microcrystalline Cellulose, pregelatinized Starch etc., the amount of the peroxide especially in microcrystalline Cellulose.
The microcrystalline Cellulose amount of peroxides of the compound amlodipine atorvastatin that the present invention adopts as above method to prepare is less than 400ppm amount of hydrogen peroxide, preferably be less than 289ppm, preferably be less than 124ppm further, be preferably less than 50ppm further, be further preferably less than 35ppm.Wherein amount of peroxides statement is converted into the amount being equivalent to hydrogen peroxide to carry out stating.
Compound amlodipine atorvastatin of the present invention needs to carry out coating, and coating material can be but not be defined as following material: polyvinyl alcohol, titanium dioxide, Macrogol 3000 and Pulvis Talci.
Compound amlodipine atorvastatin of the present invention, its supplementary material consumption proportion is as follows:
Wherein, described binding agent is selected from: hypromellose (HPMC), hydroxypropyl cellulose (HPC), polyvidone (PVP) and carmethose (CMS ?Na), be preferable over hypromellose and hydroxypropyl cellulose, most preferably in hypromellose E5 (HPMC E5), hydroxypropyl cellulose LF (HPC LF) and hydroxypropyl cellulose (HPMC JF).
Wherein, described disintegrating agent is selected from: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, and carboxymethyl starch is received, polyvinylpolypyrrolidone, preferred cross-linking sodium carboxymethyl cellulose.
Wherein, described diluent is selected from: microcrystalline Cellulose (MCC), lactose, pregelatinized Starch, mannitol, calcium hydrogen phosphate, preferably microcrystalline cellulose and pregelatinized Starch, most preferably microcrystalline Cellulose PH101 (MCC PH101), microcrystalline Cellulose PH102 (MCC PH102), microcrystalline Cellulose PH302 (MCC PH302) and pregelatinized Starch.
Preferably, the preparation method of compound amlodipine atorvastatin of the present invention, comprises the following steps:
Preparation technology:
1. supplementary material burden process:
A. after accurately taking cross-linking sodium carboxymethyl cellulose (inside adding part), microcrystalline Cellulose, pregelatinized Starch, hyprolose according to recipe quantity, for subsequent use.
B. be: sieve first respectively, then weigh respectively according to recipe quantity that mixing is as joining powder one for Atorvastatin calcium, calcium carbonate handling procedure.
C. for Amlodipine Besylate Tablet, silicon dioxide, cross-linked carboxymethyl cellulose sodium (additional) and magnesium stearate, title is joined rear for subsequent use:
2. granule operation:
D. the preparation of binding agent: adopt Subtraction method to add in the pony mixer of purified water by polyoxyethylene sorbitan monoleate, be stirred to dissolve, gradation adds hydroxypropyl cellulose on a small quantity, and constantly stirs to clarify.
E. premix: in the following order successively by microcrystalline Cellulose, joins powder (), pregelatinized Starch, and cross-linking sodium carboxymethyl cellulose (inside adding) is added in high-speed mixing granulating machine material trough, premix;
F. spray: by peristaltic pump and compressed air by binding agent injectant hopper;
G. granulate;
H. wet granulate;
I. drying obtains the dry granulate of atorvastatin calcium dried granule;
3. mixed processes
J. main mixed: after having arranged, first the Atorvastatin calcium granule of 1/2 amount to be added in material bin mixer, mixing; Add Amlodipine Besylate Tablet, silicon dioxide, cross-linked carboxymethyl cellulose sodium (additional) more successively, mixing; Add residue Atorvastatin calcium granule again, mixing.
K. always mix: add magnesium stearate in the material after main mixing, mixing.
4. tabletting
5. coating: pressed plain sheet is added to coating pan, coating.
Beneficial effect of the present invention is as follows:
In the research of compound amlodipine atorvastatin, often notice that Amlodipine Besylate Tablet is unstable, avoided its wet granulation.But in this process for Atorvastatin calcium stability we in prescription, often add calcium carbonate avoid acid degradation, but our method of the control of oxidative breakdown product is little.So to the oxidative degradation that solid is granulated, be often add antioxidant or adopt the packaged form of inflated with nitrogen to process.Because the great majority of antioxidant have uv absorption, there is larger interference in the detection for preparation related substance, especially inapplicable for the material that degradation impurity is many; The form industrialization production requirements of inflated with nitrogen packaging is higher, needs special equipment, and it is also comparatively difficult for realizing.We pass through to find adjuvant and the amount controlling the peroxide in adjuvant, find one control mode simply and easily.
Detailed description of the invention
By following specific embodiment, the present invention is further illustrated, but not as restriction of the present invention.
Embodiment 1
The preparation of the description prescription of patent CN101185646A (prescription 1) and CN20152341U (prescription 2), is used from the stable research of acceleration environment (40 DEG C/75%) with the former sheet one that grinds.Investigate conventional microcrystalline cellulose, the impact of different process.Prescription list is as follows:
Preparation technology:
The preparation technology of prescription 1 is with embodiment 2.
The preparation technology of prescription 2, the preparation of Atorvastatin calcium granule is with embodiment 2, and Amlodipine Besylate Tablet adopts the mode tabletting that directly mixes of powder.
Stability Determination the results are shown in embodiment 5.
Embodiment 2
The present invention is also not limited to this embodiment for the prescription of compound amlodipine atorvastatin and technique.We prepare amlodipine besylate and atorvastatin calcium sheet from the microcrystalline Cellulose that have chosen different peroxide content on the market; Relatively three kinds of microcrystalline Cellulose stability related substance results, result shows that microcrystalline Cellulose peroxide value is the prescription of 35ppm, and oxidative degradation impurity obviously reduces.Prescription list is as follows:
Preparation technology:
1. supplementary material burden process:
A. put into plastic bag separately after accurately taking cross-linking sodium carboxymethyl cellulose (inside adding part), microcrystalline Cellulose, pregelatinized Starch, hyprolose according to recipe quantity, carry out mark.
B. be: sieve first respectively, then weigh respectively according to recipe quantity that mixing is as joining powder one for Atorvastatin calcium, calcium carbonate handling procedure.
C. for Amlodipine Besylate Tablet, silicon dioxide, cross-linked carboxymethyl cellulose sodium (additional) and magnesium stearate, should be weighed again after being calculated as follows according to gained grain amount after drying, claim to join rear leaving in separately in respective plastic bag, carry out mark for subsequent use:
2. granule operation:
D. the preparation of binding agent: adopt Subtraction method to add in the pony mixer of purified water by polyoxyethylene sorbitan monoleate, be stirred to dissolve, gradation adds hydroxypropyl cellulose on a small quantity, and constantly stirs to clarify.
E. premix: in the following order successively by microcrystalline Cellulose, joins powder (), pregelatinized Starch, cross-linking sodium carboxymethyl cellulose (inside adding) is added in high-speed mixing granulating machine material trough, arranging rotating speed of agitator is 300rpm, and cutter rotating velocity is 1500rpm, premix 5min;
F. spray: by peristaltic pump and compressed air by binding agent injectant hopper, arranging rotating speed of agitator is 150rpm, and cutter rotating velocity is 600rpm.
G. granulate: arranging rotating speed of agitator is 250rpm, and cutter rotating velocity is 1500rpm, has obvious granule to soft material, granulate and terminate.
H. wet granulate: screen cloth specification 3mm;
I. dry: being dried to product temperature is 50 DEG C;
J. dry granulate: 1.0mm screen cloth carries out dry granulate.
3. mixed processes
K. main mixed: after having arranged, first the Atorvastatin calcium granule of 1/2 amount to be added in material bin mixer, mix about 2min; Add Amlodipine Besylate Tablet, silicon dioxide, cross-linked carboxymethyl cellulose sodium (additional) more successively, mix about 5min; Add residue Atorvastatin calcium granule again, rotating speed is that 12rpm (clockwise) remixes 15min.
L. always mix: add magnesium stearate in the material after main mixing, rotating speed is that 12rpm (clockwise) mixes 5min.
4. sheeting process
Adopt the shallow round punch of Φ 6.0mm.
5. enrobing processes
Preparation coating solution solid content is 15%; Pressed plain sheet is added to coating pan, and inlet temperature is 40 ± 10 DEG C, controls temperature of outgoing air 35 ± 5 DEG C of ★, makes coating weight gain in 1 ~ 3% scope.
6. Nei Bao and outsourcing operation
Adopt Lv ?aluminum packaging (drug packaging aluminium foil/cold stamping forming solid body medicinal composite plate negative is immediate packaging materials), every plate 15.
Peroxide assay method in embodiment 3, microcrystalline Cellulose
A. titanous chloride .-sulphuric acid test solution: get 15% titanium trichloride solution 20ml, mix homogeneously with sulphuric acid 13ml is careful under ice bath, add appropriate strong hydrogen peroxide solution to occurring yellow, be heated to emit white cigarette, let cool, repeatedly dilute with water to be evaporated to solution closely colourless, add water to obtain colourless solution, and add water to 100ml, filter, to obtain final product.
B. operate at 20 ~ 25 DEG C, get microcrystalline Cellulose 4.0g, put in 100ml measuring bottle, add water about 80ml, jolting 10 minutes, add water to scale, shake up, filter, get subsequent filtrate 25ml, add titanous chloride .-sulphuric acid test solution 2.0ml, shake up, place 30 minutes, as need testing solution; Separately get above-mentioned subsequent filtrate 25ml, add 13% (V/V) sulfuric acid solution 2.0ml, shake up, place 30 minutes, as blank solution, measure absorbance in 405nm place.
C. absorbance 0.35 (is equivalent to 400ppmH
2o
2)
The measurement result of embodiment 4, different microcrystalline Cellulose peroxide
The microcrystalline Cellulose measurement result used in embodiment 1 and embodiment 2.
Embodiment 5, formerly grind sheet, prescription 1 and prescription 2 accelerated stability (40 DEG C/75%) result
The former sheet accelerated stability (related substance %) that grinds investigates result
Prescription 1 accelerated stability (related substance %) investigates result
Prescription 2 accelerated stability (related substance %) investigates result
Embodiment 6, prescription 3, prescription 4 and prescription 5 accelerated stability (40 DEG C/75%) result
Prescription 3 accelerated stability (related substance %) investigates result
Prescription 4 accelerated stability (related substance %) investigates result
Prescription 5 accelerated stability (related substance %) investigates result
Claims (10)
1. a preparation method for high stability amlodipine besylate and atorvastatin calcium sheet, comprises the following steps:
A: the granulation of Atorvastatin calcium
Step 1 ?surfactant dissolves is added binding agent stirring and dissolving in water;
Step 2 ?in facility for granulating, mix Atorvastatin calcium, calcium carbonate and other diluent and disintegrating agent;
Mixture of powders from step 2 and the solution from step 1 are granulated by step 3 ?in granulator equipment;
Step 4 ?, by the wet grain drying from step 3, is prepared into atorvastatin calcium dried granule;
B: the configuration of final granule
Step 1 ?add Amlodipine Besylate Tablet, disintegrating agent, fluidizer to atorvastatin calcium dried granule;
Step 2 ?is by the mix homogeneously in mixer of the powder from step 1;
Step 3 ?in the powder of step 2, add lubricant, mix homogeneously;
Powder compaction from step 3 is become tablet by step 4 ?.
2., according to claims 1, the adjuvant of amlodipine besylate and atorvastatin calcium sheet controls peroxide, can be the diluent in prescription, disintegrating agent or binding agent.
3., according to claims 2, the adjuvant of amlodipine besylate and atorvastatin calcium sheet controls peroxide, especially will control the amount of peroxide in diluent.
4. preparation method according to claim 1, is characterized in that, diluent can be starch, lactose, microcrystalline Cellulose, pregelatinized Starch etc., and wherein microcrystalline Cellulose amount of peroxides is less than 400ppm amount of hydrogen peroxide.
5. preparation method according to claim 4, is characterized in that, microcrystalline Cellulose amount of peroxides is less than 289ppm.
6. preparation method according to claim 4, is characterized in that, microcrystalline Cellulose amount of peroxides is less than 124ppm.
7. preparation method according to claim 4, is characterized in that, microcrystalline Cellulose amount of peroxides is less than 50ppm amount of hydrogen peroxide.
8. preparation method according to claim 4, is characterized in that, microcrystalline Cellulose amount of peroxides is less than 35ppm amount of hydrogen peroxide.
9. preparation method according to claim 1, is characterized in that, described amlodipine besylate and atorvastatin calcium sheet, is made up of following Raw material processing:
Wherein, described binding agent is selected from: hypromellose (HPMC), hydroxypropyl cellulose (HPC), polyvidone (PVP) and carmethose (CMS ?Na), be preferable over hypromellose and hydroxypropyl cellulose, most preferably in hypromellose E5 (HPMC E5), hydroxypropyl cellulose LF (HPC LF) and hydroxypropyl cellulose (HPMC JF).
Wherein, described disintegrating agent is selected from: low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, and carboxymethyl starch is received, polyvinylpolypyrrolidone, preferred cross-linking sodium carboxymethyl cellulose.
Wherein, described diluent is selected from: microcrystalline Cellulose (MCC), lactose, pregelatinized Starch, mannitol, calcium hydrogen phosphate, preferably microcrystalline cellulose and pregelatinized Starch, most preferably microcrystalline Cellulose PH101 (MCCPH101), microcrystalline Cellulose PH102 (MCC PH102), microcrystalline Cellulose PH302 (MCC PH302) and pregelatinized Starch.
10. preparation method according to claim 1, is characterized in that, described amlodipine besylate and atorvastatin calcium sheet, is made up of following Raw material processing:
Preparation technology:
1. supplementary material burden process:
A. after accurately taking cross-linking sodium carboxymethyl cellulose (inside adding part), microcrystalline Cellulose, pregelatinized Starch, hyprolose according to recipe quantity, for subsequent use;
B. be: sieve first respectively, then weigh respectively according to recipe quantity that mixing is as joining powder one for Atorvastatin calcium, calcium carbonate handling procedure;
C. for Amlodipine Besylate Tablet, silicon dioxide, cross-linked carboxymethyl cellulose sodium (additional) and magnesium stearate, title is joined rear for subsequent use:
2. granule operation:
A. the preparation of binding agent: adopt Subtraction method to add in the pony mixer of purified water by polyoxyethylene sorbitan monoleate, be stirred to dissolve, gradation adds hydroxypropyl cellulose on a small quantity, and constantly stirs to clarify;
B. premix: in the following order successively by microcrystalline Cellulose, joins powder (), pregelatinized Starch, and cross-linking sodium carboxymethyl cellulose (inside adding) is added in high-speed mixing granulating machine material trough, premix;
C. spray: by peristaltic pump and compressed air by binding agent injectant hopper;
D. granulate;
E. wet granulate;
F. drying obtains the dry granulate of atorvastatin calcium dried granule;
3. mixed processes
A. main mixed: after having arranged, first the Atorvastatin calcium granule of 1/2 amount to be added in material bin mixer, mixing; Add Amlodipine Besylate Tablet, silicon dioxide, cross-linked carboxymethyl cellulose sodium (additional) more successively, mixing; Add residue Atorvastatin calcium granule again, mixing;
B. always mix: add magnesium stearate in the material after main mixing, mixing;
4. tabletting
5. coating: pressed plain sheet is added to coating pan, coating.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055357A (en) * | 2015-09-25 | 2015-11-18 | 青岛华之草医药科技有限公司 | Atorvastatin calcium composition tablet for treating hypercholesteremia |
| CN106174593A (en) * | 2016-08-16 | 2016-12-07 | 珠海同源药业有限公司 | A kind of calcium carbonate tablet and preparation technology thereof |
| CN109010298A (en) * | 2018-08-31 | 2018-12-18 | 迪沙药业集团有限公司 | A kind of melbine glipizide compound and preparation method thereof |
| CN110063944A (en) * | 2018-01-24 | 2019-07-30 | 北京红太阳药业有限公司 | A kind of Levamlodipine besylate atorvastatin and preparation method thereof |
| CN111467317A (en) * | 2020-05-22 | 2020-07-31 | 福建海西新药创制有限公司 | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof |
| CN112022824A (en) * | 2020-09-30 | 2020-12-04 | 天地恒一制药股份有限公司 | Preparation method of atorvastatin calcium tablet |
-
2015
- 2015-01-30 CN CN201510051390.XA patent/CN104644633A/en active Pending
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055357A (en) * | 2015-09-25 | 2015-11-18 | 青岛华之草医药科技有限公司 | Atorvastatin calcium composition tablet for treating hypercholesteremia |
| CN106174593A (en) * | 2016-08-16 | 2016-12-07 | 珠海同源药业有限公司 | A kind of calcium carbonate tablet and preparation technology thereof |
| CN110063944A (en) * | 2018-01-24 | 2019-07-30 | 北京红太阳药业有限公司 | A kind of Levamlodipine besylate atorvastatin and preparation method thereof |
| CN110063944B (en) * | 2018-01-24 | 2021-07-16 | 北京红太阳药业有限公司 | Levamlodipine besylate atorvastatin calcium tablet and preparation method thereof |
| CN109010298A (en) * | 2018-08-31 | 2018-12-18 | 迪沙药业集团有限公司 | A kind of melbine glipizide compound and preparation method thereof |
| CN111467317A (en) * | 2020-05-22 | 2020-07-31 | 福建海西新药创制有限公司 | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof |
| CN111467317B (en) * | 2020-05-22 | 2022-03-15 | 福建海西新药创制有限公司 | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof |
| CN112022824A (en) * | 2020-09-30 | 2020-12-04 | 天地恒一制药股份有限公司 | Preparation method of atorvastatin calcium tablet |
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Application publication date: 20150527 |