CN104688694A - Pharmaceutical composition containing clopidogrel hydrogen sulfate - Google Patents
Pharmaceutical composition containing clopidogrel hydrogen sulfate Download PDFInfo
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- CN104688694A CN104688694A CN201310639819.8A CN201310639819A CN104688694A CN 104688694 A CN104688694 A CN 104688694A CN 201310639819 A CN201310639819 A CN 201310639819A CN 104688694 A CN104688694 A CN 104688694A
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- CN
- China
- Prior art keywords
- vitamin
- pharmaceutical composition
- clopidogrel
- bisulfate clopidogrel
- polyethylene glycol
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 26
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 title claims abstract description 20
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 title claims abstract description 20
- -1 vitamin acetate Chemical class 0.000 claims abstract description 40
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 36
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims abstract description 36
- 229940046009 vitamin E Drugs 0.000 claims abstract description 36
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 36
- 239000011709 vitamin E Substances 0.000 claims abstract description 36
- 239000000945 filler Substances 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 229940088594 vitamin Drugs 0.000 claims abstract description 3
- 229930003231 vitamin Natural products 0.000 claims abstract description 3
- 235000013343 vitamin Nutrition 0.000 claims abstract description 3
- 239000011782 vitamin Substances 0.000 claims abstract description 3
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims description 75
- 229960003009 clopidogrel Drugs 0.000 claims description 73
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims description 69
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 58
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims description 32
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 claims description 32
- 229940042585 tocopherol acetate Drugs 0.000 claims description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 229920002472 Starch Polymers 0.000 claims description 18
- 239000008107 starch Substances 0.000 claims description 18
- 235000019698 starch Nutrition 0.000 claims description 18
- 239000000843 powder Substances 0.000 claims description 17
- 239000000741 silica gel Substances 0.000 claims description 16
- 229910002027 silica gel Inorganic materials 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- 238000007908 dry granulation Methods 0.000 claims description 12
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 8
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 8
- 238000004132 cross linking Methods 0.000 claims description 8
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 8
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 8
- 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 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000003900 succinic acid esters Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 238000012360 testing method Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 238000004811 liquid chromatography Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 229940066015 clopidogrel 75 mg Drugs 0.000 description 2
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 108010046722 Thrombospondin 1 Proteins 0.000 description 1
- 102100036034 Thrombospondin-1 Human genes 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960003958 clopidogrel bisulfate Drugs 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- YIPQMWQDUUCXLX-UHFFFAOYSA-N pentane-1-sulfonic acid;sodium;hydrate Chemical compound O.[Na].CCCCCS(O)(=O)=O YIPQMWQDUUCXLX-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicine, and specifically relates to a pharmaceutical composition containing clopidogrel hydrogen sulfate. The pharmaceutical composition contains clopidogrel hydrogen sulfate, a filler, a disintegrating agent, a lubricant, polyethylene glycol 1000, vitamin E, succinic acid ester, and vitamin acetate. The pharmaceutical composition is high in product stability; complete dissolving can be realized; product quality is excellent; production of the pharmaceutical composition is simple and convenient; and the pharmaceutical composition is suitable for industrial production.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of containing the pharmaceutical composition of bisulfate clopidogrel and the preparation method of tablet thereof.
Background technology
Bisulfate clopidogrel, or be called clopidogrel hydrogenesulphate, chemistry (+)-(S)-α-(2-chlorphenyl)-6,7-dihydro-thiophenes by name also [3,2-c] pyridine-5 (4H)-methyl acetate sulfate (1:1), molecular formula: C
16h
16clNO
2sH
2sO
4, molecular weight 419.9, its chemical constitution is as follows:
Bisulfate clopidogrel is a kind of epigamic anticoagulant, the activation of the Glycoprotein G PIIb/IIIa complex optionally suppressing adenosine diphosphate (ADP) (ADP) to mediate with the combination of its platelet receptor and the ADP of secondary, therefore can anticoagulant.Be mainly used in restenosis and thrombotic complications etc. in treatment atheromatosis, acute coronary artery syndrome, prevention coronary stenting after-poppet clinically.
Clopidogrel hydrogenesulphate is that white is to pale powder.It is water-soluble hardly when neutral pH, dissolves completely when pH is 1.But the character of clopidogrel salt is unstable, and under wet heat condition, clopidogrel dextroisomer easily changes into does not have bioactive laevoisomer.
In the preparation technique of these existing clopidogrels, the compositions mainly adopting one or more lubricants in stearic acid, Polyethylene Glycol, hydrogenated vegetable oil, magnesium stearate, zinc stearate, rich horse sodium stearate, palmitic acid stearic acid ester of glycerol and other excipient to form is for the preparation of clopidogrel solid preparation.
Such as, US5520928 discloses and replaces magnesium stearate as the prescription of lubricant to solve the problem of clopidogrel degraded with stearic acid.Disclose in CN1935119 and use palmitic acid stearic acid ester of glycerol and micropowder silica gel to replace magnesium stearate to improve the stability of solid preparation.CN101951891A discloses the technique disperseing clopidogrel to be formed in the polymer by hot-melt technology solid dispersion.CN101390856 adopts the technique of beta-schardinger dextrin-parcel clopidogrel sulfate, CN101766577 by the technique of clopidogrel sulfate and other excipient wet granulations to improve the stability of clopidogrel sulfate preparation.But, described open in technology fundamentally do not improve the problem of sticking phenomenon in compression molding process and the degraded of clopidogrel sulfate configuration conversion.In addition, because clopidogrel hydrothermal stability is poor, adopt the control overflow of above-mentioned technique to production equipment and production process high, and in production process, clopidogrel is heated and easily degrade.
Polyethylene glycol 1000 vitamin E succinic acid ester (TPGS) is the soluble derivative of vitamin E, formed by the carboxyl of vitamin e succinate (vES) and Polyethylene Glycol (PEG) 1000 esterification, relative molecular mass is about 1513, for in preparation research, as the carrier of solubilizing agent, absorption enhancer, emulsifying agent, plasticizer and slightly water-soluble and fat-soluble medicine transmission system, as the carrier of solid dispersion, dosing eyes, the carrier etc. of intranasal administration.
Summary of the invention
The object of this invention is to provide a kind of pharmaceutical composition containing bisulfate clopidogrel newly, should contain the good stability of the pharmaceutical composition of bisulfate clopidogrel, stripping is good.
Another object of the present invention is the preparation method providing a kind of pharmaceutical composition containing bisulfate clopidogrel, and the method is applicable to commercial production.
Specifically, the invention provides:
A pharmaceutical composition containing bisulfate clopidogrel, contains: bisulfate clopidogrel, filler, disintegrating agent and lubricant, also containing polyethylene glycol 1000 vitamin E succinic acid ester and vitamin acetate.
The described pharmaceutical composition containing bisulfate clopidogrel is tablet.
The weight ratio of described polyethylene glycol 1000 vitamin E succinic acid ester and Vitamin E acetate is 6:3.
The described pharmaceutical composition containing bisulfate clopidogrel, the weight ratio of each component is:
Bisulfate clopidogrel 1 ~ 4 weight portion
Polyethylene glycol 1000 vitamin E succinic acid ester 3 ~ 8 weight portion
Vitamin E acetate 1 ~ 5 weight portion
Filler 30 ~ 60 weight portion
Disintegrating agent 4 ~ 20 weight portion
Lubricant 1 ~ 5 weight portion.
Described filler is selected from one or more in starch, lactose, Icing Sugar, mannitol, microcrystalline Cellulose, pregelatinized Starch.
Described disintegrating agent is selected from one or more in dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose.
Described lubricant is selected from one or more in micropowder silica gel, Pulvis Talci, magnesium stearate.
The described pharmaceutical composition containing bisulfate clopidogrel is prepared into tablet, and its preparation method comprises the following steps:
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) to the powder of step (1) gained and filler, disintegrating agent and mix lubricant even, adopt tabletting after dry granulation, obtain clopidogrel hydrogen sulfate tablet.
The present invention compared with prior art has the following advantages and good effect:
1, product stability of the present invention is good, and stripping is complete.
2, operation is simple for production of the present invention, is suitable for commercial production.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
Test method
Related substance gets this product fine powder appropriate (being about equivalent to clopidogrel 75mg), puts in 50ml measuring bottle, adds mobile phase A and dissolve and be diluted to scale, shake up, and filters, gets subsequent filtrate as need testing solution; Precision measures 1ml, and put in 100ml measuring bottle, be diluted to scale by mobile phase A, shake up, precision measures 1ml, puts in 10ml measuring bottle, is diluted to scale by mobile phase A, shake up, in contrast solution.Separately get bisulfate clopidogrel reference substance, impurity A reference substance and impurity B reference substance in right amount each, add methanol and make dissolving, the mixed solution of each 20 μ g of containing clopidogrel hydrogen sulfate 2mg, impurity A and impurity B in every 1ml is made, as system suitability solution with mobile phase A dilution.According to high effective liquid chromatography for measuring (Chinese Pharmacopoeia version in 2010 two annex V D), be filler with octadecylsilane chemically bonded silica; With the pentanesulfonic acid sodium-hydrate solution of 0.96g/L (by phosphoric acid adjust ph to 2.5)-methanol (95:5) for mobile phase A, with acetonitrile-methanol (95:5) for Mobile phase B; Determined wavelength is 220nm.According to the form below carries out linear gradient elution.Get system suitability solution 10 μ l injection liquid chromatography, record chromatogram, the peak sequence of main chromatographic peak is: impurity A, clopidogrel and impurity B, and the separating degree at clopidogrel peak and other impurities B peak should meet the requirements.Get contrast solution 10 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% of full scale.Precision measures need testing solution and each 10 μ l of contrast solution, respectively injection liquid chromatography, record chromatogram.If any the chromatographic peak consistent with impurity A peak retention time in need testing solution chromatogram, its peak area must not be greater than 5 times (0.5%) of contrast solution main peak area; Other single impurity peak area must not be greater than 2 times (0.2%) of contrast solution main peak area; Each impurity peak area and (outside removal of impurity B peak) 15 times (1.5%) of contrast solution main peak area must not be greater than.
Dissolution gets this product, according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex X C second methods), with pH2.0 buffer (potassium chloride 6.57g, adding water and make dissolving in right amount, add 0.1mol/L hydrochloric acid solution 119.0ml, add water to 1000ml) 1000ml is dissolution medium, rotating speed is 50 turns per minute, operates in accordance with the law, through 30 minutes time, get solution 10ml, filter, precision measures subsequent filtrate 3ml, put in 10ml measuring bottle, be diluted to scale with dissolution medium, shake up, as need testing solution; Separately get bisulfate clopidogrel reference substance and be about 12mg, accurately weighed, put in 50ml measuring bottle, add dissolve with methanol and be diluted to scale, shaking up, precision measures 5ml, puts in 50ml measuring bottle, is diluted to scale with dissolution medium, shake up, in contrast product solution.Get above-mentioned two kinds of solution, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia version in 2010 two annex IV A), measure absorbance respectively at the wavelength place of 240nm, calculate the stripping quantity of every sheet, result is multiplied by 0.7664, and limit is 80% of labelled amount, should conform with the regulations.
[assay] measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability ovomucoid bonding spherical silica gel are filler (UltronES-OVM); Be mobile phase with phosphate buffer (get potassium dihydrogen phosphate 1.36g, the 1000ml that adds water makes dissolving, mixing)-acetonitrile (75:25); Determined wavelength is 220nm.Get bisulfate clopidogrel reference substance and impurity B reference substance is in right amount each, add methanol and make dissolving in right amount, the solution of containing clopidogrel hydrogen sulfate 2.5 μ g and impurity B 5 μ g in every 1ml is made with mobile phase dilution, get 10 μ l injection liquid chromatographies, record chromatogram, the separating degree at clopidogrel peak and impurity B first isomer peak should be greater than 2.0.
Algoscopy gets this product 20, accurately weighed, porphyrize, precision takes in right amount (being about equivalent to clopidogrel 75mg), puts in 100ml measuring bottle, adds dissolve with methanol and be diluted to scale, shake up, filter, precision measures subsequent filtrate 5ml, put in 50ml measuring bottle, be diluted to scale with mobile phase, shake up, precision measures 10 μ l, injection liquid chromatography, record chromatogram; Separately get bisulfate clopidogrel reference substance and be about 20mg, accurately weighed, put in 20ml measuring bottle, add dissolve with methanol and be diluted to scale, shake up, precision measures 5ml, puts in 50ml measuring bottle, scale is diluted to mobile phase, shake up, be measured in the same method, by external standard method with calculated by peak area, and result is multiplied by 0.7664, to obtain final product.
Test example 1: prescription screening is tested
Get bisulfate clopidogrel 3g(content 99.9% respectively, always mix 0.09%), obtain the pulverulent solids containing Clopidogrel Hydrogensulfate by following prescription, detect related substance, the results are shown in Table 1:
Prescription I: be dissolved in Vitamin E acetate by bisulfate clopidogrel and stir, after adding polyethylene glycol 1000 vitamin E succinic acid ester mixing, obtains pulverulent solids.
Prescription II: be dissolved in after bisulfate clopidogrel is mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids; :
Prescription III: add bisulfate clopidogrel after being mixed with polyethylene glycol 1000 vitamin E succinic acid ester by Vitamin E acetate, obtain pulverulent solids;
Prescription IV: bisulfate clopidogrel is dissolved in heat polyethylene glycol 6000 in stir all with after, cool, pulverize to obtain pulverulent solids.
Table 1 related substance result of the test
Result of the test shows:
1. the related substance in powder bisulfate clopidogrel and Vitamin E acetate and polyethylene glycol 1000 vitamin E succinic acid ester are mixed to get is lower than mixing obtained powder with polyethylene glycol 6000, analysis reason is as follows: be solid under polyethylene glycol 6000 room temperature, hot body is become after heating, but bisulfate clopidogrel is to thermally labile, the pH of PEG6000 is 4 ~ 7 in addition, unstable to Clopidogrel Hydrogensulfate
2. related substance bisulfate clopidogrel and polyethylene glycol 1000 vitamin E succinic acid ester being dissolved in the powder that Vitamin E acetate obtains is better than additive method.
Test example 2: influence factor tests
Get bisulfate clopidogrel 3g(content 99.9% respectively, total assorted 0.09%), mannitol 8g, microcrystalline Cellulose 25g, low-substituted hydroxypropyl cellulose 8.3g, Vitamin E acetate 3g, polyethylene glycol 1000 vitamin E succinic acid ester 6g, by following formula preparation clopidogrel hydrogen sulfate tablet and press Chinese patent 201210185355(embodiment A 8) obtained product (comparative example).
Result is investigated in the factorial experiments of table 2 sample effects
Conclusion: road as seen from the above table, the product prepared by the inventive method, the stability under high temperature and high humidity is better than comparative example.
Test example 3: accelerated test
Example 3,5,6,8 product and by CN102309462A(embodiment A 8) obtained product carries out accelerated test, the results are shown in Table 3.
Table 3 clopidogrel bisulfate tablet accelerated test data
Packaging: commercially available back, investigates condition: temperature 40 DEG C, humidity 75%
Conclusion: road as seen from the above table, the product prepared by the inventive method, the stability under high temperature and illumination is better than comparative example.
Preparation example
Embodiment 1
Prescription
Bisulfate clopidogrel 1.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 5g
Vitamin E acetate 3.6g
Starch 35g
Dried starch 4g
Micropowder silica gel 1.8g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with starch, dried starch and micropowder silica gel, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 2
Prescription
Bisulfate clopidogrel 1.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 4.5g
Vitamin E acetate 2.0g
Lactose 38g
Carboxymethyl starch sodium 8g
Pulvis Talci 2.8g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with lactose, carboxymethyl starch sodium and Pulvis Talci, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 3
Prescription
Bisulfate clopidogrel 2.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 4.0g
Vitamin E acetate 2.8g
Icing Sugar 45g
Low-substituted hydroxypropyl cellulose 12g
Micropowder silica gel 2.5g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with Icing Sugar, low-substituted hydroxypropyl cellulose and micropowder silica gel, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 4
Prescription
Bisulfate clopidogrel 2.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 7.5g
Vitamin E acetate 4.3g
Mannitol 54g
Crospolyvinylpyrrolidone 15g
Magnesium stearate 2.5g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with mannitol, crospolyvinylpyrrolidone and magnesium stearate, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 5
Prescription
Bisulfate clopidogrel 3.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 6.0g
Vitamin E acetate 3.0g
Microcrystalline Cellulose 37g
Cross-linking sodium carboxymethyl cellulose 16g
Micropowder silica gel 1.2g
Magnesium stearate 0.5g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, micropowder silica gel and magnesium stearate, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 6
Prescription
Bisulfate clopidogrel 3.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 4g
Vitamin E acetate 5.0g
Microcrystalline Cellulose 85g
Dried starch 6g
Carboxymethyl starch sodium 4g
Pulvis Talci 0.8g
Magnesium stearate 0.5g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with microcrystalline Cellulose, dried starch, carboxymethyl starch sodium, Pulvis Talci, magnesium stearate, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 7
Prescription
Bisulfate clopidogrel 4.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 6.1g
Vitamin E acetate 4.2g
Pregelatinized Starch 53g
Low-substituted hydroxypropyl cellulose 7g
Cross-linking sodium carboxymethyl cellulose 5g
Micropowder silica gel 4g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with pregelatinized Starch, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, micropowder silica gel, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 8
Prescription
Bisulfate clopidogrel 1.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 3.5g
Vitamin E acetate 2.3g
Microcrystalline Cellulose 48g
Carboxymethyl starch sodium 5g
Low-substituted hydroxypropyl cellulose 9.2g
Micropowder silica gel 1.5g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with microcrystalline Cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, micropowder silica gel, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 9
Prescription
Bisulfate clopidogrel 2.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 3.5g
Vitamin E acetate 1.2g
Mannitol 60g
Cross-linking sodium carboxymethyl cellulose 3g
Pulvis Talci 3g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with mannitol, cross-linking sodium carboxymethyl cellulose, Pulvis Talci, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 10
Prescription
Bisulfate clopidogrel 4.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 7.1g
Vitamin E acetate 2.1g
Mannitol 10g
Low-substituted hydroxypropyl cellulose 19g
Micropowder silica gel 5g.
Preparation method
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) powder to step (1) gained is mixed homogeneously with mannitol, low-substituted hydroxypropyl cellulose, micropowder silica gel, and tabletting after employing dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Claims (8)
1. the pharmaceutical composition containing bisulfate clopidogrel, pharmaceutical composition contains bisulfate clopidogrel, filler, disintegrating agent and lubricant, and its feature pharmaceutical composition contains polyethylene glycol 1000 vitamin E succinic acid ester and vitamin acetate.
2., according to the pharmaceutical composition containing bisulfate clopidogrel described in claim 1, it is characterized in that pharmaceutical composition is prepared into tablet.
3., according to the pharmaceutical composition containing bisulfate clopidogrel described in claim 1, it is characterized in that the weight ratio of each component is:
Bisulfate clopidogrel 1 ~ 4 weight portion
Polyethylene glycol 1000 vitamin E succinic acid ester 3 ~ 8 weight portion
Vitamin E acetate 1 ~ 5 weight portion
Filler 30 ~ 60 weight portion
Disintegrating agent 4 ~ 20 weight portion
Lubricant 1 ~ 5 weight portion.
4., according to the pharmaceutical composition containing bisulfate clopidogrel described in claim 1, it is characterized in that: the weight ratio of described polyethylene glycol 1000 vitamin E succinic acid ester and Vitamin E acetate is 6:3.
5. according to described in claim 1 containing the pharmaceutical composition of bisulfate clopidogrel, it is characterized in that one or more that described filler is selected from starch, lactose, Icing Sugar, mannitol, microcrystalline Cellulose, pregelatinized Starch.
6. according to described in claim 1 containing the pharmaceutical composition of bisulfate clopidogrel, it is characterized in that one or more that described disintegrating agent is selected from dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose.
7. according to described in claim 1 containing the pharmaceutical composition of bisulfate clopidogrel, it is characterized in that one or more that described lubricant is selected from micropowder silica gel, Pulvis Talci, magnesium stearate.
8. the preparation method of the pharmaceutical composition containing bisulfate clopidogrel according to claim 1, comprises the following steps:
(1) be dissolved in after bisulfate clopidogrel being mixed with polyethylene glycol 1000 vitamin E succinic acid ester after stirring in Vitamin E acetate, obtain pulverulent solids;
(2) to the powder of step (1) gained and filler, disintegrating agent and mix lubricant even, adopt tabletting after dry granulation, obtain clopidogrel hydrogen sulfate tablet.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106913539A (en) * | 2015-12-25 | 2017-07-04 | 山东新时代药业有限公司 | A kind of Abiraterone acetate sublingual tablets and preparation method thereof |
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| CN104688694B (en) | 2018-09-11 |
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Denomination of invention: A drug combination containing clopidogrel bisulfate Effective date of registration: 20231226 Granted publication date: 20180911 Pledgee: China Construction Bank Co.,Ltd. Changchun Science and Technology Sub branch Pledgor: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Registration number: Y2023220000149 |