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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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical group [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 title claims abstract description 21
- 229960004796 rosuvastatin calcium Drugs 0.000 title claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000011575 calcium Substances 0.000 claims abstract description 38
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 38
- 239000003814 drug Substances 0.000 claims abstract description 31
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims abstract description 13
- 235000019700 dicalcium phosphate Nutrition 0.000 claims abstract description 13
- 239000004925 Acrylic resin Substances 0.000 claims abstract description 12
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 12
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 12
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 12
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 21
- 239000011248 coating agent Substances 0.000 claims description 15
- 238000000576 coating method Methods 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 15
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 13
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 13
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 13
- 238000013268 sustained release Methods 0.000 claims description 13
- 239000012730 sustained-release form Substances 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 11
- 229960001021 lactose monohydrate Drugs 0.000 claims description 11
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 11
- 206010013786 Dry skin Diseases 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000004806 packaging method and process Methods 0.000 claims description 5
- 239000007779 soft material Substances 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 10
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229960005069 calcium Drugs 0.000 description 35
- 239000000523 sample Substances 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 229960000672 rosuvastatin Drugs 0.000 description 5
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 201000005577 familial hyperlipidemia Diseases 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 3
- 239000001639 calcium acetate Substances 0.000 description 3
- 229960005147 calcium acetate Drugs 0.000 description 3
- 235000011092 calcium acetate Nutrition 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002040 relaxant effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000006101 laboratory sample Substances 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- BPRHUIZQVSMCRT-YXWZHEERSA-N (e,3r,5r)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-YXWZHEERSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 239000001736 Calcium glycerylphosphate Substances 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 description 1
- 229940095618 calcium glycerophosphate Drugs 0.000 description 1
- 235000019299 calcium glycerylphosphate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- YURNCBVQZBJDAJ-UHFFFAOYSA-N heptenoic acid group Chemical group C(C=CCCCC)(=O)O YURNCBVQZBJDAJ-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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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| 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 |
| BR112019009709A2 (en) * | 2016-11-15 | 2019-08-13 | Lg Chemical Ltd | combination preparation. |
| 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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| 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 |
|---|
| 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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