CN103494788B - Pharmaceutical composition of rosuvastatin calcium tablets and preparation method thereof - Google Patents
Pharmaceutical composition of rosuvastatin calcium tablets and preparation method thereof Download PDFInfo
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- CN103494788B CN103494788B CN201310469441.1A CN201310469441A CN103494788B CN 103494788 B CN103494788 B CN 103494788B CN 201310469441 A CN201310469441 A CN 201310469441A CN 103494788 B CN103494788 B CN 103494788B
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Abstract
The invention belongs to field of pharmaceutical preparations, be specifically related to drug regimen of a kind of rosuvastatin calcium tablets and preparation method thereof, the present invention by active medicine label, be wrapped in the outer slow release layer of active medicine label and form, add alkaline matter calcium hydrogen phosphate in label, slow release layer is made up of ethyl cellulose, Polyethylene Glycol, polyacrylic resin Ⅲ; The present invention obtains a kind of stable, and the easypro of slow release cuts down statin calcium tablet.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to pharmaceutical composition of a kind of rosuvastatin calcium tablets and preparation method thereof
Background technology
Hyperlipemia is high morbidity in mid-aged population, and along with the raising of people's living standard, the change of living habit, the sickness rate of hyperlipemia increases year by year, and the age of patient is tending towards rejuvenation.There is hyperlipidemia patient 8,000 ten thousand in China, and every day increases with the quantity of ten thousand people, and hyperlipemia, as time bomb, threatens the health of people at any time.It is the arteriosclerosis causing whole body that hyperlipemia is the most directly damaged, and then causes the disease of being correlated with, and the arteriosclerosis as heart and brain can cause the diseases such as coronary heart diseases and angina pectoris, myocardial infarction and cerebrovas-cularaccident.
Rosuvastain calcium is blood lipid-lowering medicine, proves through clinical trial, and for the light moderate hyperlipidemia patient in Asia, no matter whether patient is first medication, and rosuvastain calcium all shows strong lipid-lowering effect and high safety.
Rosuvastain calcium is developed by AstraZeneca pharmaceutical Co. Ltd of Britain, and in November, 2002, first in Holland's listing, obtains U.S. FDA approval in August, 2003, food and medicine Surveillance Authority of China in 2006 approval of import.
Rosuvastain calcium chemistry is by name two-[(E)-7-[the fluorine-based phenyl of 4-(4-)-6-isopropyl-2-[methyl (mesyl) is amino]-pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy-6-heptenoic acid] and calcium salt.
Physicochemical property: soluble,very slightly in water, almost insoluble in methanol or ethanol.
Rosuvastain calcium is stablized in the basic conditions, unstable under high temperature and illumination, acid, oxidizing condition, produces a certain amount of impurity.Document money report rosuvastain calcium is easy to degraded in high temperature or higher levels of humidity environment, the primary product formed is (3R, 5S) lactone degradant and oxidative breakdown product, thus cause its stability test result of compositions adopting conventional fabrication process to obtain undesirable, this instability determined by its structure itself, β in rosuvastain calcium molecule on heptenoic acid chain, δ-hydroxyl is very unstable, and the hydroxyl that wherein carbon-to-carbon double bond is adjacent is easy to be oxidized to ketone.Also can there is molecule inner ring condensation, generate lactone.
Disclose the stabilization medicines compositions containing statins in Chinese patent CN93100650, said composition reaches stable object by adding a kind of alkaline medium that the pH value of the aqueous solution of said composition or dispersion liquid can be made at least to remain on 8.
Chinese patent CN200780034516 discloses at the relax magnesium hydroxide and/or calcium acetate or calcium gluconate or calcium glycerophosphate that cut down in the compositions of statin calcium and add alkalescence or aluminium hydroxide, the stable problem that can solve Rosuvastatin calcium composition.
Disclose the stabilization medicines compositions containing statins in Chinese patent CN93100650, said composition reaches stable object by adding a kind of alkaline medium that the pH value of the aqueous solution of said composition or dispersion liquid can be made at least to remain on 8.
Disclosing in Chinese patent CN00122484 relaxes cuts down the compositions of statin or its pharmaceutically useful salt, and said composition reaches stable object by the cationic three alkali valency phosphate added as stabilizing agent.
Above-mentioned patent, all by adding alkaline matter, making to relax and cutting down statin calcium and stablize in the basic conditions, decreasing the generation of impurity.But above-mentioned patent does not all solve to relax cuts down the problem of statin calcium drug release, relaxing, to cut down statin calcium be blood lipid-lowering medicine, and need long-term taking, stable drug release contributes to reducing drug side effect.
So Chinese patent CN201010237681 discloses a kind of relaxing and cuts down slow releasing preparation of statin calcium and preparation method thereof, cut down statin calcium, sustained-release matrix material and other pharmaceutic adjuvants by relaxing and prepare burden in proportion, by conventional tablet, granule, capsule preparation method thereof preparation.The slow releasing preparation according to said method prepared, avoids the excessive untoward reaction such as striped muscle hemolytic disease, albuminuria, nephropathy caused of drug dose.After making drug administration simultaneously, can the due blood drug level of maintaining treatment disease and time, effectively prevent the peak valley phenomenon of blood drug level.
But CN201010237681 uses sustained-release matrix material, prepare by conventional tablet preparation method, the active pharmaceutical ingredient of tablet surface easily makes moist, oxidation, in addition basic auxiliary is not used, tablet active pharmaceutical ingredient relaxes and cuts down statin calcium and play pendulum, and very easily produces impurity after placement.
Therefore, prepare a kind of stable, the easypro of slow release cuts down statin calcium tablet, is the problem that we should solve.
Summary of the invention
Object preparation of the present invention is a kind of stable, and the easypro of slow release cuts down statin calcium tablet.
We find: a kind of pharmaceutical composition of rosuvastatin calcium tablets, comprise active medicine label, be wrapped in the outer slow release layer composition of active medicine label: can obtain a kind of stable, the easypro of slow release cuts down statin calcium tablet.
This is because: add alkaline matter calcium hydrogen phosphate in active medicine label, ensure that in label, active medicine rosuvastain calcium is in alkaline environment, more stable, simultaneously, label outsourcing one deck slow release layer, not only makes active medicine sheet slow releasing, and label and moisture, oxygen-barrier, more avoids the generation of impurity.
We find: active medicine label forms better by rosuvastain calcium, low-substituted hydroxypropyl cellulose, magnesium stearate, polyvinylpolypyrrolidone, lactose monohydrate, calcium hydrogen phosphate, and the weight percent content of its composition is:
| The name of an article | Percentage ratio |
| Rosuvastain calcium | 6～10％ |
| Low-substituted hydroxypropyl cellulose | 10％ |
| Magnesium stearate | 0.7％ |
| Polyvinylpolypyrrolidone | 7～9％ |
| Lactose monohydrate | 50％ |
| Calcium hydrogen phosphate | 22～26％ |
It is good that above-mentioned composition can obtain molding, the label of disintegrate effect.
We find: the outer slow release layer of label forms better by ethyl cellulose, Polyethylene Glycol, polyacrylic resin Ⅲ, and the weight percent content of outer its composition of slow release layer of label is:
| The name of an article | Percentage ratio |
| Ethyl cellulose | 80～85％ |
| Polyethylene Glycol | 8～12％ |
| Polyacrylic resin Ⅲ | 5～8％ |
Its preparation method comprises:
(1) label is prepared: the supplementary material rosuvastain calcium of composition active medicine label, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, lactose monohydrate, calcium hydrogen phosphate are pulverized, cross 80 mesh sieves, 80% ethanol is added, soft material processed, crosses 40 mesh sieves and granulates, 50 DEG C of dryings, 40 mesh sieve granulate, add magnesium stearate, mixing, tabletting;
(2) bag slow release layer: after ethyl cellulose, polyacrylic resin Ⅲ are added dissolve with ethanol respectively, mixing, mixed liquor adds Polyethylene Glycol again, mixing, obtains sustained release coating liquid, puts in coating pan by label prepared by (1), spray into quantitative sustained release coating liquid, label weightening finish 3-5%, dry;
(3) coated tablet (3) prepared is detected, after qualified, packaging.
The beneficial effect of the pharmaceutical composition of rosuvastatin calcium tablets of the present invention is shown in experiment 1,2.
Experiment 1, the pharmaceutical composition of rosuvastatin calcium tablets of the present invention are compared with the release of other rosuvastatin calcium tablets:
(1) sample: sample A: the rosuvastatin calcium tablets prepared by the embodiment of the present invention 1;
Sample B: tablet prepared by the sustained-release matrix material used by CN201010237681 embodiment 1:
Its preparation method:
Prescription: rosuvastain calcium 5.2mg, HPMC K4M 72mg,
Lactose 82mg, 10% polyvinylpyrrolidone is appropriate, 60% appropriate amount of ethanol, magnesium stearate 1.6mg,
Preparation technology; Rosuvastain calcium was pulverized 80 mesh sieves, and mixed with HPMC K4M, lactose, with 10% polyvinylpyrrolidone, the moistening rear granulation of 60% ethanol, granulate after 50 DEG C of dryings, adds magnesium stearate mix homogeneously, tabletting, to obtain final product.
Sample C: the rosuvastatin calcium tablets prepared by CN200780034516 embodiment 10:
Prescription (weight percent content of its composition):
| The name of an article | Percentage ratio |
| Rosuvastain calcium | 6.93％ |
| Lactose | 55.00％ |
| Magnesium stearate | 1.00％ |
| Polyvinylpolypyrrolidone | 5.00％ |
| Microcrystalline Cellulose | 27.07％ |
| Calcium acetate | 5.00％ |
Preparation technology; Rosuvastain calcium was pulverized 80 mesh sieves, with polyvinylpolypyrrolidone, lactose,
Microcrystalline Cellulose, calcium acetate mix, and then add magnesium stearate mix homogeneously, dry powder sheeting, to obtain final product.
(2) carry out release to 3 samples to compare:
Experimental technique: according to Chinese Pharmacopoeia two annex XC in 2010, first method (blue laws), with water 900ml for dissolution medium, rotating speed was 100 turns per minute, operates in accordance with the law, respectively at sampling in 0.5,1,2,6,12,16,20,24 hour, filter with organic filter membrane, getting subsequent filtrate is need testing solution
With high performance liquid chromatography (Chinese Pharmacopoeia two annex VD in 2010), detect in 242nm place,
The release of calculation sample.3 sample releases see the following form 1:
(3) experiment conclusion: sample C does not have slow releasing function, sample B had slow releasing function in 24 hours, the rosuvastatin calcium tablets sample A prepared by the embodiment of the present invention 1 had slow releasing function in 24 hours, compare with sample B, release amount of medicine in 2 hours is greater than sample B, is conducive to the blood drug level reaching treatment after patient takes as early as possible.
Experiment 2, the pharmaceutical composition of rosuvastatin calcium tablets of the present invention are compared with the stability of other rosuvastatin calcium tablets:
(1) laboratory sample: laboratory sample is with experiment 1.
(2) carry out stability to 3 samples to compare:
Experimental technique: accelerated test:
3 samples are carried out aluminium-plastic bubble plate packing respectively, place under 40 DEG C ± 2 DEG C relative humidity 75% ± 5% constant temperature and humidity conditions, respectively at 0,1,2,3, sampling in June detects, testing result sees the following form 2:
(3) experiment conclusion: sample C is more stable, sample B is very unstable, and the rosuvastatin calcium tablets sample A prepared by the embodiment of the present invention 1 is highly stable, describes rosuvastatin calcium tablets prepared by the present invention very well stable.
Attached: rosuvastatin calcium tablets assay:
According to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; With water-acetonitrile-1% trifluoroacetic acid solution (62:37:1) for mobile phase; Determined wavelength is 242nm.Get rosuvastain calcium reference substance 20mg, put in 200ml measuring bottle, the 100ml jolting that adds water makes dissolving, add the hydrochloric acid solution 20ml of 1mol/L, shake up, put in 60 DEG C of water-baths and heat 2 hours, add the sodium hydroxide solution 20ml of 1mol/L, shake up, let cool, add acetonitrile 50ml, be diluted with water to scale, shake up, as diastereomer test stock solution.Measure this solution 5ml, put in 10ml measuring bottle, add acetonitrile-aqueous solution (25:75) and be diluted to scale, shake up, be diastereo-isomerism liquid solution, as system suitability solution, get 20 μ l injection liquid chromatographies, record chromatogram, the separating degree at Rosuvastatin peak and Rosuvastatin diastereomer peak should meet the requirements, and number of theoretical plate calculates by Rosuvastatin peak and is not less than 2000.
Algoscopy gets this product 20, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to Rosuvastatin 25mg), puts in 100ml measuring bottle, and solubilizer [acetonitrile-aqueous solution (25:75)] is appropriate, jolting makes rosuvastain calcium dissolve, and is diluted to scale, shakes up, filter, precision measures subsequent filtrate 10ml, puts in 100ml measuring bottle, with solvent dilution to scale, shake up, filter, precision measures subsequent filtrate 20 μ l injection liquid chromatography, record chromatogram; Separately get rosuvastain calcium reference substance appropriate, accurately weighed, solubilizer dissolves, and makes every 1ml about containing the solution of Rosuvastatin 25 μ g, is measured in the same method.By external standard method with calculated by peak area (for 1001.14, Rosuvastatin molecular weight is 481.54 to rosuvastain calcium molecular weight), to obtain final product.
Detailed description of the invention
Embodiment is used for describing the present invention further below, but does not impose any restrictions.
The preparation of embodiment 1 rosuvastatin calcium tablets
1, prescription:
Active medicine ball core:
| The name of an article | Percentage ratio | True weight (kilogram) |
| Rosuvastain calcium | 7％ | 1.00 |
| Low-substituted hydroxypropyl cellulose | 10％ | 1.43 |
| Magnesium stearate | 0.7％ | 0.10 |
| Polyvinylpolypyrrolidone | 7％ | 1.00 |
| Lactose monohydrate | 50％ | 7.14 |
| Calcium hydrogen phosphate | 25.3％ | 3.61 |
Slow release layer:
| The name of an article | Percentage ratio | True weight (kilogram) |
| Ethyl cellulose | 80％ | 0.80 |
| Polyethylene Glycol | 12％ | 0.12 |
| Polyacrylic resin Ⅲ | 8％ | 0.08 |
Preparation technology:
(1) label is prepared: the supplementary material rosuvastain calcium of recipe quantity, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, lactose monohydrate, calcium hydrogen phosphate are pulverized, cross 80 mesh sieves, 80% appropriate amount of ethanol is added, the soft material of obtained suitable stiff, crosses 40 mesh sieves and granulates, 50 DEG C of dryings, 40 mesh sieve granulate, add magnesium stearate, mixing, tabletting;
(2) bag slow release layer: after the ethyl cellulose of recipe quantity, polyacrylic resin Ⅲ are added 10L80% dissolve with ethanol, mixing, mixed liquor adds Polyethylene Glycol again, mixing, obtain sustained release coating liquid, label prepared by (1) is put in coating pan, spray into quantitative sustained release coating liquid, label weightening finish 4%, dry;
(3) coated tablet (3) prepared is detected, after qualified, packaging.
The preparation of embodiment 2 rosuvastatin calcium tablets
1, prescription:
Active medicine ball core:
| The name of an article | Percentage ratio | True weight (kilogram) |
| Rosuvastain calcium | 10％ | 1.43 |
| Low-substituted hydroxypropyl cellulose | 10％ | 1.43 |
| Magnesium stearate | 0.7％ | 0.10 |
| Polyvinylpolypyrrolidone | 7％ | 1.00 |
| Lactose monohydrate | 50％ | 7.14 |
| Calcium hydrogen phosphate | 22.3％ | 3.18 |
Slow release layer:
| The name of an article | Percentage ratio | True weight (kilogram) |
| Ethyl cellulose | 85％ | 0.85 |
| Polyethylene Glycol | 10％ | 0.10 |
| Polyacrylic resin Ⅲ | 5％ | 0.05 |
Preparation technology:
1) label is prepared: the supplementary material rosuvastain calcium of recipe quantity, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, lactose monohydrate, calcium hydrogen phosphate are pulverized, cross 80 mesh sieves, 80% appropriate amount of ethanol is added, the soft material of obtained suitable stiff, crosses 40 mesh sieves and granulates, 50 DEG C of dryings, 40 mesh sieve granulate, add magnesium stearate, mixing, tabletting;
(2) bag slow release layer: after the ethyl cellulose of recipe quantity, polyacrylic resin Ⅲ are added 10L80% dissolve with ethanol, mixing, mixed liquor adds Polyethylene Glycol again, mixing, obtain sustained release coating liquid, label prepared by (1) is put in coating pan, spray into quantitative sustained release coating liquid, label weightening finish 5%, dry;
(3) coated tablet (3) prepared is detected, after qualified, packaging.
The preparation of embodiment 3 rosuvastatin calcium tablets
1, prescription:
Active medicine ball core:
| The name of an article | Percentage ratio | True weight (kilogram) |
| Rosuvastain calcium | 8％ | 1.14 |
| Low-substituted hydroxypropyl cellulose | 10％ | 1.43 |
| Magnesium stearate | 0.7％ | 0.10 |
| Polyvinylpolypyrrolidone | 9％ | 1.29 |
| Lactose monohydrate | 50％ | 7.14 |
| Calcium hydrogen phosphate | 22.3％ | 3.18 |
Slow release layer:
| Name of an article percentage ratio true weight (kilogram) ethyl cellulose 82%0.82 Polyethylene Glycol 12%0.12 polyacrylic resin Ⅲ 6%0.06 |
Preparation technology:
1) label is prepared: the supplementary material rosuvastain calcium of recipe quantity, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, lactose monohydrate, calcium hydrogen phosphate are pulverized, cross 80 mesh sieves, 80% appropriate amount of ethanol is added, the soft material of obtained suitable stiff, crosses 40 mesh sieves and granulates, 50 DEG C of dryings, 40 mesh sieve granulate, add magnesium stearate, mixing, tabletting;
(2) bag slow release layer: after the ethyl cellulose of recipe quantity, polyacrylic resin Ⅲ are added 10L80% dissolve with ethanol, mixing, mixed liquor adds Polyethylene Glycol again, mixing, obtain sustained release coating liquid, label prepared by (1) is put in coating pan, spray into quantitative sustained release coating liquid, label weightening finish 3%, dry;
(3) coated tablet (3) prepared is detected, after qualified, packaging.
Claims (1)
1. a pharmaceutical composition for rosuvastatin calcium tablets, is characterized in that: by active medicine label and be wrapped in the outer slow release layer of active medicine label and form;
Each component weight percent content of described active medicine label is:
Each component weight percent content of described slow release layer is:
The preparation method of described pharmaceutical composition comprises:
(1) active medicine label is prepared: the supplementary material rosuvastain calcium of composition active medicine label, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, lactose monohydrate, calcium hydrogen phosphate are pulverized, cross 80 mesh sieves, 80% ethanol is added, soft material processed, crosses 40 mesh sieves and granulates, 50 DEG C of dryings, 40 mesh sieve granulate, add magnesium stearate, mixing, tabletting;
(2) bag slow release layer: after ethyl cellulose, polyacrylic resin Ⅲ are added 80% dissolve with ethanol, mixing, mixed liquor adds Polyethylene Glycol again, mixing, obtain sustained release coating liquid, label prepared by (1) is put in coating pan, spray into quantitative sustained release coating liquid, label weightening finish 3-5% is dry;
(3) coated tablet (2) prepared is detected, after qualified, packaging.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104739833A (en) * | 2015-02-16 | 2015-07-01 | 江苏欧信医药化工有限公司 | Compound double-layer tablet with Telmisartan and Rosuvastatin calcium and preparation method of compound double-layer tablet with Telmisartan and Rosuvastatin calcium |
| KR102055894B1 (en) * | 2016-11-15 | 2019-12-13 | 주식회사 엘지화학 | Combination preparation for treating type 2 diabetes mellitus and diabetic dyslipidemia |
| TWI749204B (en) * | 2018-04-02 | 2021-12-11 | 強生化學製藥廠股份有限公司 | A pharmaceutical composition capable of improving the bioavailability of oral statins and its use |
| CN111135149B (en) * | 2018-11-04 | 2021-05-11 | 张家港市中医医院 | Rosuvastatin calcium tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516349A (en) * | 2006-09-18 | 2009-08-26 | 里克特格登有限公司 | Pharmaceutical compositions containing rosuvastatin calcium |
| CN101889975A (en) * | 2010-07-27 | 2010-11-24 | 北京虹湾医药技术有限公司 | Rosuvastatin calcium sustained-release preparation and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516349A (en) * | 2006-09-18 | 2009-08-26 | 里克特格登有限公司 | Pharmaceutical compositions containing rosuvastatin calcium |
| CN101889975A (en) * | 2010-07-27 | 2010-11-24 | 北京虹湾医药技术有限公司 | Rosuvastatin calcium sustained-release preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 瑞舒伐他汀钙肠溶缓释微球的制备及影响因素考察;高萍等;《沈阳药科大学学报》;20120930;第29卷(第9期);661－666 * |
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