CN104688694B - A kind of pharmaceutical composition containing bisulfate clopidogrel - Google Patents
A kind of pharmaceutical composition containing bisulfate clopidogrel Download PDFInfo
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- CN104688694B CN104688694B CN201310639819.8A CN201310639819A CN104688694B CN 104688694 B CN104688694 B CN 104688694B CN 201310639819 A CN201310639819 A CN 201310639819A CN 104688694 B CN104688694 B CN 104688694B
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- China
- Prior art keywords
- clopidogrel
- pharmaceutical composition
- bisulfate clopidogrel
- vitamin
- powder
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- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 title claims abstract description 71
- 229960003009 clopidogrel Drugs 0.000 title claims abstract description 69
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title claims abstract description 65
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 title claims abstract description 55
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 45
- 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 45
- 229940046009 vitamin E Drugs 0.000 claims abstract description 45
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 45
- 239000011709 vitamin E Substances 0.000 claims abstract description 45
- -1 vitamin E succinic acid ester Chemical class 0.000 claims abstract description 37
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims abstract description 32
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 9
- 239000007884 disintegrant Substances 0.000 claims abstract description 6
- 239000000843 powder Substances 0.000 claims description 33
- 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
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000008107 starch Substances 0.000 claims description 18
- 235000019698 starch Nutrition 0.000 claims description 18
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 claims description 16
- 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 claims description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000000741 silica gel Substances 0.000 claims description 16
- 229910002027 silica gel Inorganic materials 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 14
- 238000007908 dry granulation Methods 0.000 claims description 11
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 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
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- 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
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims 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 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
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 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 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 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 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229940088594 vitamin Drugs 0.000 abstract description 2
- 229930003231 vitamin Natural products 0.000 abstract description 2
- 235000013343 vitamin Nutrition 0.000 abstract description 2
- 239000011782 vitamin Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- 238000000034 method Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000000052 vinegar Substances 0.000 description 10
- 235000021419 vinegar Nutrition 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 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
- 229920002785 Croscarmellose sodium Polymers 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- 229960001681 croscarmellose sodium Drugs 0.000 description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 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
- 239000007788 liquid Substances 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940066015 clopidogrel 75 mg 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
- 229960003511 macrogol Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- IQXJCCZJOIKIAD-UHFFFAOYSA-N 1-(2-methoxyethoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCOC IQXJCCZJOIKIAD-UHFFFAOYSA-N 0.000 description 1
- VYTNBPLMTVGIQZ-UHFFFAOYSA-N 2-(4-chlorophenyl)sulfanyl-n-(2-methoxy-5-methylphenyl)acetamide Chemical compound COC1=CC=C(C)C=C1NC(=O)CSC1=CC=C(Cl)C=C1 VYTNBPLMTVGIQZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 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
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- WKUVAEYSJGZGCX-UHFFFAOYSA-M N1C=CC=C1.[Cl+].S(=O)(=O)(O)[O-] Chemical compound N1C=CC=C1.[Cl+].S(=O)(=O)(O)[O-] WKUVAEYSJGZGCX-UHFFFAOYSA-M 0.000 description 1
- QSMTUAJDOTXEDZ-UHFFFAOYSA-N N1C=CC=C1.[Cl] Chemical compound N1C=CC=C1.[Cl] QSMTUAJDOTXEDZ-UHFFFAOYSA-N 0.000 description 1
- 108010064983 Ovomucin Proteins 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- XFKVHUONJVDEIW-UHFFFAOYSA-N [Cl].S(O)(O)(=O)=O Chemical compound [Cl].S(O)(O)(=O)=O XFKVHUONJVDEIW-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 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
- 238000004458 analytical method Methods 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229950009789 cetomacrogol 1000 Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960003958 clopidogrel bisulfate Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000004703 cross-linked polyethylene Substances 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber 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
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 239000000546 pharmaceutical excipient Substances 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
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 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
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 150000003900 succinic acid esters Chemical class 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
- 210000003462 vein Anatomy 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
Abstract
The invention belongs to pharmaceutical technology fields, more particularly to a kind of pharmaceutical composition containing bisulfate clopidogrel, the pharmaceutical composition contains bisulfate clopidogrel, filler, disintegrant and lubricant, also contains polyethylene glycol 1000 vitamin E succinic acid ester and vitamin acetate.The product stability of the present invention of the present invention is good, and dissolution is complete, has more outstanding product quality；Operation is simple for the production of the present invention, is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of pharmaceutical composition containing bisulfate clopidogrel and its
The preparation method of tablet.
Background technology
Bisulfate clopidogrel, or be clopidogrel hydrogenesulphate, chemistry entitled (+)-(S)-α-(2- chlorphenyls)-
6,7- dihydro-thiophenes simultaneously [3,2-c] pyridine -5 (4H)-methyl acetate sulfate (1:1), molecular formula:C16H16ClNO2S·H2SO4,
Molecular weight 419.9, chemical constitution is as follows：
Bisulfate clopidogrel is a kind of platelet aggregation inhibitor of inductivity, selectively inhibits adenosine diphosphate (ADP)
(ADP) and the activation of glycoprotein GPIIb/IIIa compounds that mediates of the combination of its platelet receptor and secondary ADP, because
This can inhibit platelet aggregation.Atherosclerosis disease, acute coronary artery syndrome, prevention hat clinically mainly used for treating
Restenosis and thrombotic complications etc. in arteries and veins stent after-poppet.
Clopidogrel hydrogenesulphate is white to pale powder.It is practically insoluble in water in neutral pH, is 1 in pH
When be completely dissolved.However, the property of clopidogrel salt is unstable, under wet heat condition, clopidogrel dextroisomer is easy to turn
Become the laevoisomer of not bioactivity.
In the preparation technique of these existing clopidogrels, stearic acid, polyethylene glycol, hydrogenated vegetable oil, hard is mainly used
One or more of fatty acid magnesium, zinc stearate, rich horse odium stearate, palmitic acid stearic acid ester of glycerol lubricant and other figurations
The composition of agent composition is used for the preparation of clopidogrel solid pharmaceutical preparation.
Stearic acid is used to replace magnesium stearate as the prescription of lubricant to solve chlorine pyrrole lattice for example, US5520928 is disclosed
The problem of thunder is degraded.It is disclosed in CN1935119 using palmitic acid stearic acid ester of glycerol and superfine silica gel powder instead of magnesium stearate
Improve the stability of solid pharmaceutical preparation.CN101951891A, which is disclosed, disperses clopidogrel in the polymer by hot-melt technology
The technique for forming solid dispersion.CN101390856 wraps up the technique of clopidogrel sulfate using beta-cyclodextrin,
CN101766577 is by the technique of clopidogrel sulfate and other excipient wet granulations to improve clopidogrel sulfate system
The stability of agent.However, technology in the disclosure without fundamentally improve during compression molding existing sticking phenomenon and
The problem of clopidogrel sulfate configuration conversion degradation.Further, since clopidogrel hydrothermal stability is poor, using above-mentioned technique pair
The control of production equipment and production process requires high, and clopidogrel is heated in production process easily degrades.
Polyethylene glycol 1000 vitamin E succinic acid ester（TPGS）It is the soluble derivative of vitamin E, by vitamin E amber
The carboxyl of amber acid esters (vES) is esterified with polyethylene glycol (PEG) 1000, and relative molecular mass is about 1513, is ground for preparation
In studying carefully, the load as solubilizer, sorbefacient, emulsifier, plasticizer and slightly water-soluble and fat-soluble medicine transmission system
Body, such as the carrier of solid dispersions, ophthalmic administration, intranasal administration carrier.
Invention content
The object of the present invention is to provide a kind of new pharmaceutical compositions containing bisulfate clopidogrel, this contains hydrogen sulfate
The stability of the pharmaceutical composition of clopidogrel is good, dissolves out.
It is another object of the present invention to provide a kind of preparation sides of the pharmaceutical composition containing bisulfate clopidogrel
Method, this method are suitble to industrial production.
Specifically, the present invention provides：
A kind of pharmaceutical composition containing bisulfate clopidogrel, contains：Bisulfate clopidogrel, filler, disintegrant
And lubricant, also contain polyethylene glycol 1000 vitamin E succinic acid ester and vitamin acetate.
The pharmaceutical composition containing bisulfate clopidogrel is tablet.
The weight ratio of the polyethylene glycol 1000 vitamin E succinic acid ester and Vitwas E is 6: 3.
The pharmaceutical composition containing bisulfate clopidogrel, the weight ratio of each component are：
1 ~ 4 parts by weight of bisulfate clopidogrel
3 ~ 8 parts by weight of polyethylene glycol 1000 vitamin E succinic acid ester
1 ~ 5 parts by weight of Vitwas E
30 ~ 60 parts by weight of filler
4 ~ 20 parts by weight of disintegrant
1 ~ 5 parts by weight of lubricant.
One kind in starch, lactose, Icing Sugar, mannitol, microcrystalline cellulose, pregelatinized starch of the filler or
It is several.
The disintegrant is selected from dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrroles
One or more of alkanone, croscarmellose sodium.
The lubricant is selected from one or more of superfine silica gel powder, talcum powder, magnesium stearate.
The pharmaceutical composition containing bisulfate clopidogrel prepares piece agent, and preparation method includes following step
Suddenly：
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) to obtained by step (1) powder and filler, disintegrant and mix lubricant it is uniform, after dry granulation
Tabletting obtains clopidogrel hydrogen sulfate tablet.
Compared with the prior art, the present invention has the following advantages and good effect：
1, product stability of the invention is good, and dissolution is complete.
2, operation is simple for production of the invention, is suitable for industrial production.
Specific implementation mode
The following describes the present invention further through the description of specific embodiments, but this is not the limit to the present invention
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Test method
Related substance takes this product fine powder appropriate（It is approximately equivalent to clopidogrel 75mg）, set in 50ml measuring bottles, add mobile phase A
Scale is dissolved and be diluted to, is shaken up, filters, takes subsequent filtrate as test solution；Precision measures 1ml, sets in 100ml measuring bottles,
It is diluted to scale with mobile phase A, is shaken up, precision measures 1ml, sets in 10ml measuring bottles, is diluted to scale with mobile phase A, shakes up, and makees
For contrast solution.It is another to take bisulfate clopidogrel reference substance, impurity A reference substance and impurity B reference substance each appropriate, add methanol to make molten
The mixed solution of containing clopidogrel hydrogen sulfate 2mg in every 1ml, impurity A and each 20 μ g of impurity B is made of mobile phase A dilution for solution,
As system suitability solution.According to high effective liquid chromatography for measuring（Two V D of annex of Chinese Pharmacopoeia version in 2010）, use
Octadecylsilane chemically bonded silica is filler；With the pentanesulfonic acid sodium-hydrate solution of 0.96g/L（With phosphorus acid for adjusting pH value
To 2.5）Methanol（95:5）For mobile phase A, with acetonitrile-methanol（95:5）For Mobile phase B；Detection wavelength is 220nm.According to the form below
Carry out linear gradient elution.10 μ l injection liquid chromatographs of system suitability solution are taken, chromatogram, main chromatographic peak are recorded
Peak sequence be：Impurity A, clopidogrel and impurity B, clopidogrel peak and the separating degree at the peaks other impurities B should meet the requirements.
10 μ l injection liquid chromatographs of contrast solution are taken, adjust detection sensitivity, it is about full scale to make the peak height of principal component chromatographic peak
10%.Precision measures test solution and each 10 μ l of contrast solution, is injected separately into liquid chromatograph, records chromatogram.Test sample is molten
If any the chromatographic peak consistent with impurity A peak retention time in liquid chromatography figure, peak area is not greater than contrast solution main peak area
5 times（0.5%）；Other single impurity peak areas are not greater than 2 times of contrast solution main peak area（0.2%）；Each impurity peaks face
Long-pending sum（In addition to impurity B peak）It is not greater than 15 times of contrast solution main peak area（1.5%）.
Dissolution rate takes this product, according to dissolution method（Chinese Pharmacopoeia two annex X the second methods of C of version in 2010）, with
PH2.0 buffer solutions（Potassium chloride 6.57g, adds appropriate amount of water to make dissolving, adds 0.1mol/L hydrochloric acid solution 119.0ml, adds water to
1000ml）1000ml is dissolution medium, and rotating speed is 50 turns per minute, operates in accordance with the law, when through 30 minutes, takes solution 10ml, is filtered,
Precision measures subsequent filtrate 3ml, sets in 10ml measuring bottles, is diluted to scale with dissolution medium, shakes up, as test solution；Separately take
Bisulfate clopidogrel reference substance about 12mg, it is accurately weighed, it sets in 50ml measuring bottles, adds methanol to dissolve and be diluted to scale, shake up,
Precision measures 5ml, sets in 50ml measuring bottles, is diluted to scale with dissolution medium, shakes up, as a contrast product solution.Take above two
Solution, according to UV-VIS spectrophotometry（Two annex IV A of Chinese Pharmacopoeia version in 2010）, distinguish at the wavelength of 240nm
Absorbance is measured, every stripping quantity is calculated, result is multiplied by 0.7664, limit is the 80% of labelled amount, should meet regulation.
【Assay】According to high performance liquid chromatography（Two annex V D of Chinese Pharmacopoeia version in 2010）It measures.
It is filler that chromatographic condition is bonded spherical silica gel with system suitability with ovomucoid（UltronES-
OVM）；With phosphate buffer（Potassium dihydrogen phosphate 1.36g is taken, water 1000ml is added to make dissolving, mixing）Acetonitrile（75：25）For stream
Dynamic phase；Detection wavelength is 220nm.It takes bisulfate clopidogrel reference substance and impurity B reference substance each appropriate, adds methanol in right amount and make and is molten
Solution, the solution of 2.5 μ g of containing clopidogrel hydrogen sulfate and 5 μ g of impurity B in every 1ml are made of flowing phase dilution, take 10 μ l injection liquid
Chromatography, records chromatogram, and clopidogrel peak and the separating degree at first isomers peak of impurity B should be greater than 2.0.
Measuring method takes this product 20, accurately weighed, and finely ground, precision weighs in right amount（It is approximately equivalent to clopidogrel 75mg）, set
In 100ml measuring bottles, adding methanol to dissolve and be diluted to scale, shake up, filters, precision measures subsequent filtrate 5ml, sets in 50ml measuring bottles,
It is diluted to scale with mobile phase, is shaken up, precision measures 10 μ l, injects liquid chromatograph, records chromatogram；Separately take hydrogen sulfate chlorine pyrrole
Gray's reference substance about 20mg, it is accurately weighed, it sets in 20ml measuring bottles, adds methanol to dissolve and be diluted to scale, shake up, precision measures
5ml, sets in 50ml measuring bottles, is diluted to scale with mobile phase, shakes up, is measured in the same method, by external standard method with calculated by peak area, and will knot
Fruit be multiplied by 0.7664 to get.
Test example 1：Prescription screening is tested
Bisulfate clopidogrel 3g is taken respectively（Content 99.9%, total miscellaneous 0.09%）, it is made by following prescriptions and contains sulfuric acid chlorine
The pulverulent solids of pyrrole Gray detect related substance, the results are shown in Table 1：
Prescription I：Bisulfate clopidogrel is dissolved in Vitwas E and is stirred evenly, cetomacrogol 1000 dimension is added
After raw element E succinates mixing, pulverulent solids are obtained.
Prescription II：Vitamin E is dissolved in after bisulfate clopidogrel is mixed with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acetate, pulverulent solids are obtained；:
Prescription III：Hydrogen sulfate is added after Vitwas E is mixed with polyethylene glycol 1000 vitamin E succinic acid ester
Clopidogrel obtains pulverulent solids；
Prescription IV：Bisulfate clopidogrel is dissolved in the Macrogol 6000 of heat and is stirred with after, it is cooling, crush to obtain powder
Last shape solid.
Table 1 is in relation to substances test result
Test result shows：
1. bisulfate clopidogrel is mixed with Vitwas E with polyethylene glycol 1000 vitamin E succinic acid ester
To powder in related substance be less than the powder that is mixed to prepare with Macrogol 6000, analysis the reason is as follows that：Polyethylene glycol
6000 be at room temperature solid, and at hot body after heating, but bisulfate clopidogrel is to thermally labile, in addition the pH of PEG6000 be 4 ~
7, it is unstable to Clopidogrel Hydrogensulfate
2. bisulfate clopidogrel is dissolved in Vitwas E with polyethylene glycol 1000 vitamin E succinic acid ester to be made
Powder related substance be better than other methods.
Test example 2：Influence factor is tested
Bisulfate clopidogrel 3g is taken respectively（Content 99.9%, total miscellaneous 0.09%）, mannitol 8g, microcrystalline cellulose 25g, low
Replace hydroxypropyl cellulose 8.3g, Vitwas E 3g, polyethylene glycol 1000 vitamin E succinic acid ester 6g, by following prescriptions
Prepare clopidogrel hydrogen sulfate tablet and by Chinese patent 201210185355（Embodiment A8）Product obtained（Comparative example）.
Result is investigated in 2 sample effects factorial experiments of table
Conclusion：Road as seen from the above table, by product prepared by the method for the present invention, stability under high temperature and high humidity better than pair
Ratio.
Test example 3：Accelerated test
3,5,6,8 product of Example and press CN102309462A（Embodiment A8）Product obtained carries out accelerated test,
It the results are shown in Table 3.
3 clopidogrel bisulfate tablet accelerated test data of table
Packaging：Commercially available back investigates condition：40 DEG C of temperature, humidity 75%
Conclusion：Road as seen from the above table, by product prepared by the method for the present invention, stability under high temperature and illumination better than pair
Ratio.
Preparation example
Embodiment 1
Prescription
Bisulfate clopidogrel 1.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 5g
Vitwas E 3.6g
Starch 35g
Dried starch 4g
Superfine silica gel powder 1.8g.
Preparation method
(1) vitamin E acetic acid is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in ester, pulverulent solids are obtained；
(2) it is uniformly mixed to the powder obtained by step (1) with starch, dried starch and superfine silica gel powder, after dry granulation
Tabletting obtains clopidogrel hydrogen sulfate tablet.
Embodiment 2
Prescription
Bisulfate clopidogrel 1.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 4.5g
Vitwas E 2.0g
Lactose 38g
Sodium carboxymethyl starch 8g
Talcum powder 2.8g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) it is uniformly mixed to the powder obtained by step (1) with lactose, sodium carboxymethyl starch and talcum powder, using dry method system
Tabletting after grain, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 3
Prescription
Bisulfate clopidogrel 2.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 4.0g
Vitwas E 2.8g
Icing Sugar 45g
Low-substituted hydroxypropyl cellulose 12g
Superfine silica gel powder 2.5g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) it is uniformly mixed, adopts with Icing Sugar, low-substituted hydroxypropyl cellulose and superfine silica gel powder to the powder obtained by step (1)
With tabletting after dry granulation, clopidogrel hydrogen sulfate tablet is obtained.
Embodiment 4
Prescription
Bisulfate clopidogrel 2.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 7.5g
Vitwas E 4.3g
Mannitol 54g
Crosslinked polyvinylpyrrolidone 15g
Magnesium stearate 2.5g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) it is uniformly mixed to the powder obtained by step (1) with mannitol, crosslinked polyvinylpyrrolidone and magnesium stearate,
Using tabletting after dry granulation, clopidogrel hydrogen sulfate tablet is obtained.
Embodiment 5
Prescription
Bisulfate clopidogrel 3.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 6.0g
Vitwas E 3.0g
Microcrystalline cellulose 37g
Croscarmellose sodium 16g
Superfine silica gel powder 1.2g
Magnesium stearate 0.5g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) to the powder and microcrystalline cellulose, croscarmellose sodium, superfine silica gel powder and tristearin obtained by step (1)
Sour magnesium is uniformly mixed, and using tabletting after dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 6
Prescription
Bisulfate clopidogrel 3.5g
Polyethylene glycol 1000 vitamin E succinic acid ester 4g
Vitwas E 5.0g
Microcrystalline cellulose 85g
Dried starch 6g
Sodium carboxymethyl starch 4g
Talcum powder 0.8g
Magnesium stearate 0.5g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) to the powder and microcrystalline cellulose, dried starch, sodium carboxymethyl starch, talcum powder, stearic acid obtained by step (1)
Magnesium is uniformly mixed, and using tabletting after dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 7
Prescription
Bisulfate clopidogrel 4.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 6.1g
Vitwas E 4.2g
Pregelatinized starch 53g
Low-substituted hydroxypropyl cellulose 7g
Croscarmellose sodium 5g
Superfine silica gel powder 4g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) to the powder and pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl fiber obtained by step (1)
Plain sodium, superfine silica gel powder are uniformly mixed, and using tabletting after dry granulation, obtain clopidogrel hydrogen sulfate tablet.
Embodiment 8
Prescription
Bisulfate clopidogrel 1.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 3.5g
Vitwas E 2.3g
Microcrystalline cellulose 48g
Sodium carboxymethyl starch 5g
Low-substituted hydroxypropyl cellulose 9.2g
Superfine silica gel powder 1.5g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) to powder and the microcrystalline cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, micro- obtained by step (1)
Powder silica gel is uniformly mixed, and using tabletting after dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 9
Prescription
Bisulfate clopidogrel 2.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 3.5g
Vitwas E 1.2g
Mannitol 60g
Croscarmellose sodium 3g
Talcum powder 3g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) it is uniformly mixed, uses with mannitol, croscarmellose sodium, talcum powder to the powder obtained by step (1)
Tabletting after dry granulation, obtains clopidogrel hydrogen sulfate tablet.
Embodiment 10
Prescription
Bisulfate clopidogrel 4.0g
Polyethylene glycol 1000 vitamin E succinic acid ester 7.1g
Vitwas E 2.1g
Mannitol 10g
Low-substituted hydroxypropyl cellulose 19g
Superfine silica gel powder 5g.
Preparation method
(1) vitamin E vinegar is dissolved in after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After being stirred in acid esters, pulverulent solids are obtained；
(2) it is uniformly mixed to the powder obtained by step (1) with mannitol, low-substituted hydroxypropyl cellulose, superfine silica gel powder,
Using tabletting after dry granulation, clopidogrel hydrogen sulfate tablet is obtained.
Claims (5)
1. a kind of pharmaceutical composition containing bisulfate clopidogrel, it is characterised in that the weight ratio of pharmaceutical composition each component
For：
Pharmaceutical composition prepares piece agent, and preparation method is：
(1) it is dissolved in Vitwas E after mixing bisulfate clopidogrel with polyethylene glycol 1000 vitamin E succinic acid ester
After stirring, pulverulent solids are obtained；
(2) to obtained by step (1) powder and filler, disintegrant and mix lubricant it is uniform, using tabletting after dry granulation,
Obtain clopidogrel hydrogen sulfate tablet.
2. the pharmaceutical composition according to claim 1 containing bisulfate clopidogrel, it is characterised in that：The poly- second two
1000 Vitamin E succinate of alcohol and the weight ratio of Vitwas E are 6:3.
3. the pharmaceutical composition according to claim 1 containing bisulfate clopidogrel, it is characterised in that the filling
Agent is selected from one or more of starch, lactose, Icing Sugar, mannitol, microcrystalline cellulose, pregelatinized starch.
4. the pharmaceutical composition according to claim 1 containing bisulfate clopidogrel, it is characterised in that the disintegration
It is fine that agent is selected from dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, cross-linked carboxymethyl
One or more of plain sodium of dimension.
5. the pharmaceutical composition according to claim 1 containing bisulfate clopidogrel, it is characterised in that the lubrication
Agent is selected from one or more of superfine silica gel powder, talcum powder, magnesium stearate.
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