CN106137994B - A kind of stable tablet of clopidogrel and preparation method thereof - Google Patents
A kind of stable tablet of clopidogrel and preparation method thereof Download PDFInfo
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- CN106137994B CN106137994B CN201610683734.3A CN201610683734A CN106137994B CN 106137994 B CN106137994 B CN 106137994B CN 201610683734 A CN201610683734 A CN 201610683734A CN 106137994 B CN106137994 B CN 106137994B
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- clopidogrel
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- gluten
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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 160
- 229960003009 clopidogrel Drugs 0.000 title claims abstract description 158
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title claims abstract description 153
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004080 punching Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- 239000000843 powder Substances 0.000 claims description 32
- 235000019441 ethanol Nutrition 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- 239000003513 alkali Substances 0.000 claims description 16
- 239000000945 filler Substances 0.000 claims description 16
- 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 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000003381 stabilizer Substances 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 13
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007884 disintegrant Substances 0.000 claims description 11
- 108010068370 Glutens Proteins 0.000 claims description 10
- 229920000881 Modified starch Polymers 0.000 claims description 10
- 235000021312 gluten Nutrition 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 9
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical group OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 7
- 239000012530 fluid Substances 0.000 claims description 7
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 claims description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical group [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- -1 polyethylene Polymers 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- XEENARPWPCQXST-DDJQTTAYSA-N C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl XEENARPWPCQXST-DDJQTTAYSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 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 4
- 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
- 229930195725 Mannitol Natural products 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 239000008118 PEG 6000 Substances 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 4
- 229950010560 clopidogrel hydrochloride Drugs 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- XIHVAFJSGWDBGA-RSAXXLAASA-N methyl (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate;hydrochloride Chemical compound Cl.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl XIHVAFJSGWDBGA-RSAXXLAASA-N 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 239000004964 aerogel Substances 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 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 claims description 2
- 239000004965 Silica aerogel Substances 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000018102 proteins Nutrition 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 235000013312 flour Nutrition 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 238000011105 stabilization Methods 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 10
- 230000015556 catabolic process Effects 0.000 abstract description 9
- 238000006731 degradation reaction Methods 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000007774 longterm Effects 0.000 abstract description 4
- QGQXAMBOYWULFX-LZWSPWQCSA-N 2-morpholin-4-ylethyl (e)-6-(4,6-dihydroxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound OC=1C=2C(=O)OCC=2C(C)=C(O)C=1C\C=C(/C)CCC(=O)OCCN1CCOCC1 QGQXAMBOYWULFX-LZWSPWQCSA-N 0.000 abstract description 3
- 238000007908 dry granulation Methods 0.000 abstract description 3
- 238000003860 storage Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 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 6
- 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 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- QSMTUAJDOTXEDZ-UHFFFAOYSA-N N1C=CC=C1.[Cl] Chemical class N1C=CC=C1.[Cl] QSMTUAJDOTXEDZ-UHFFFAOYSA-N 0.000 description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 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 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 229960005001 ticlopidine Drugs 0.000 description 3
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- 229940080313 sodium starch Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- ASJCVVGLGXVRGQ-UHFFFAOYSA-N 1-butyl-2-methoxybenzene Chemical compound CCCCC1=CC=CC=C1OC ASJCVVGLGXVRGQ-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 101710149643 Integrin alpha-IIb Proteins 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 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 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 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
- 238000011160 research Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Abstract
The present invention provides a kind of stable tablet of clopidogrel and preparation method thereof, it is used as the stable carrier of clopidogrel by aeroge-Gluten, flexible viscous-elastic behaviour and microcosmos network structure make clopidogrel in compressing dry granulation from clopidogrel chiral reversion and degradation caused by high pressure, fast ram, punch high temperature.Even if more than 15kg/mm2Pressure under, with the tabletting speed punching press of 130,000 tablets hs, punch friction temperature is more than 80 DEG C, clopidogrel piece is with good stability, clopidogrel acid Determination of Levo is 0.20% before pharmaceutical production, Determination of Levo is 0.22% after production, clopidogrel is not detected, apparent chiral inversion and degradation occurs.Particularly, it is used as the stable carrier of clopidogrel by aeroge-Gluten, in long-term storing process, clopidogrel acid content in clopidogrel stable tablet（Impurity A）, clopidogrel laevoisomer（Impurity C）It remains in stable range, the shelf-life can extend to 3 years or more.Greatly improve the safety of medication.
Description
Technical field
Invention is related to pharmaceutical preparations technology field, and in particular to a kind of stable tablet of clopidogrel and preparation method thereof,
The stable tablet efficiently solves current clopidogrel tablet and easily deliquesces hydrolysis, and dextrorotation is different when overcoming clopidogrel processing storage
Structure body is converted into laevoisomer, to increase the stability of clopidogrel.
Background technology
Clopidogrel is a kind of platelet aggregation inhibitor, it can selectively inhibit adenosine diphosphate (ADP) (ADP) and blood small
The combination of plate receptor then inhibits activation ADP and glycoprotein GPIIb/IIIa compounds, to inhibit the aggregation of blood platelet.It removes
Outside ADP, clopidogrel can also inhibit other and can induce by blocking the amplification of the platelet activation caused by the ADP that discharges
Platelet aggregation；It can be used for preventing myocardial infarction, ischemic cerebral thrombus, obliterans and atherosclerosis and thrombus
Complication caused by embolism.Since 2005, chlorine pyrroles thunder is used clinically for treating and preventing cardiac muscle as anticoagulation medicine
Infraction start widely applied in clinical heart disease patients, take chlorine pyrroles thunder can be substantially reduced myocardial infarction generation it is several
It is athero- can to effectively reduce artery using the patient of the apoplexy, myocardial infarction or the peripheral arterial disease that occur in the near future, after treatment for rate
The generation of hardening event.
Clopidogrel, entitled (S)-a- (2- chlorphenyls) -6, the 7- dichloro-thiophenes of chemistry simultaneously (3,2-c) pyridine -5 (4H) -
Methyl acetate, structural formula are as follows：
Its chemical constitution is similar to Ticlopidine, a carboxymethyl only more than the side chain, but
Its effect of, is far above Ticlopidine, and activity is 50 times higher than Ticlopidine, 110 times higher than aspirin, and gastrointestinal tract
Adverse reaction is less, and safety greatly improves.However, due to containing ester bond and chiral carbon in clopidogrel molecule structure, to
To light, heat, wet, high pH values are more sensitive, and some researches show that the clopidogrels of dextrorotatory configuration due to the presence of methyl esters group,
It can cause to hydrolyze and form acid, become the factors of instability；It is preparing, chiral inversion, chlorine pyrrole lattice also easily occurs in storing process
The medicinal forms of thunder are mainly dextrorotatory configuration, and laevo-configuration is then isomer impurities, and the reversion of chiral carbon causes drug by the right side
The left-handed conversion of rotation direction, one side laevo-configuration lack antithrombotic acitivity to make activity that significant changes occur, and another aspect is left-handed
There are certain toxicity easily human body to be caused to be fainted from fear for configuration, and its results of animal shows that laevo-configuration toxicity is significantly higher than chlorine
Pyrrole Gray's dextrorotatory configuration.In particular, clinically clopidogrel is widely used in the anti-blood of percutaneous coronary intervention (pci) perioperative
Platelet is treated, and is mainly used in the high risk operation of heart and intravascular stent, the content of clopidogrel laevoisomer increases, right
The success of operation just has a great impact, and requires Drug safety high.So strictly controlling the left-handed different of clopidogrel
The content of structure body and clopidogrel acid is to control the important indicator of the quality of production.Therefore, it strictly to be controlled during production, storage
Make its stability.
Chinese invention patent application number discloses a kind of solid pharmaceutical preparation of clopidogrel sulfate for 200610063151.7
With and preparation method thereof.Glycerine palmitic, stearic fat and superfine silica gel powder are added in the solid pharmaceutical preparation, effectively reduce chlorine
The dextroisomer of pyrrole Gray is converted into clopidogrel laevoisomer, increases stability and the safety of solid pharmaceutical preparation.
Chinese invention patent application number discloses a kind of solid drugs group containing clopidogrel for 201510102350.3
Close object makes the hydrolysis of bulk pharmaceutical chemicals be inhibited by using amino acid as stabilizer.
Chinese invention patent application number discloses a kind of solid system of bisulfate clopidogrel for 200710129305.2
Agent, its particle and preparation method thereof, the patent are used the adhesive of bisulfate clopidogrel and cellulose family auxiliary material and melting
It is mixed to form solid mixture and prepares particle.Due to use melt granulation technology, higher temperature is required heat in preparation process,
Easily cause the degradation of drug.
Chinese invention patent application number is 200810061954.8 to disclose a kind of clopidogrel hydrogen sulfate tablet and its system
Preparation Method makees lubricant using vitamin C, butyl anisole, clopidogrel is inhibited to be converted into clopidogrel acid and chlorine pyrrole lattice
Thunder dextroisomer is converted into laevoisomer Chinese invention patent application numbers 201410796447.4 and discloses a kind of hydrogen sulfate
Clopidogrel tablet medicament composition and preparation method thereof uses aluminum magnesium silicate, not only improves material fluidity in prescription, moreover it is possible to
It is effectively prevent the deliquescence of drug, reduces the risk that clopidogrel is degraded into clopidogrel acid because of the moisture absorption.
US5520928 substitutes magnesium stearate by using stearic acid, overcomes magnesium stearate that clopidogrel is accelerated to be degraded to chlorine
The problem of pyrrole Gray's acid；WO2005/070464 uses hydrogenated vegetable oil and carboxymethyl starch as lubricant, can solve tablet
Middle clopidogrel is degraded to the problem of clopidogrel acid.
According to above-mentioned, the hydrolysis for passing through anti-deliquescence, selecting auxiliary agent AF panel clopidogrel existing at present.However do not have also
There are effectively means to inhibit the dextrorotation of clopidogrel to left-handed conversion.Therefore clopidogrel storage time is short, and in storage period
Between impurity be stepped up.
Invention content
Even if clopidogrel is in room temperature, however it remains signs of degradation is easy hydrolysis and generates clopidogrel acid（It is referred to as impurity
A）, clopidogrel dextroisomer is unstable, and the clopidogrel laevoisomer for being easy to be converted into not pharmaceutical active (is referred to as
Impurity C).In the prior art, it is the stability for ensureing in clopidogrel tablet manufacturing and storing process, the hydrophobic skill of generally use
The processing hydrolysis of art means.However, shadow of the stability of clopidogrel tablet by multiple factors such as moisture, temperature, tonnage, light
It rings, even if using hydrophobic treatment, can not effectively inhibit the dextrorotation of clopidogrel to left-handed conversion.It is an object of the invention to
There is provided it is a kind of have good stability, the clopidogrel stable tablet of extended shelf-life to 3 years or more, especially the stable tablet can
Effectively inhibit clopidogrel from dextrorotation to left-handed conversion.The stable tablet has good anti-hygroscopy and stripping property simultaneously.
Further, the preparation method of the clopidogrel stable tablet is provided.
To achieve the above object, the present invention uses following technical scheme：
A kind of stable tablet of clopidogrel, it is characterised in that using aeroge-Gluten as stabilizer, by weight
Including the following raw material：
The pharmaceutically acceptable salt 30-50 parts by weight of clopidogrel,
Filler 30-45 parts by weight,
Disintegrant 10-15 parts by weight,
Stabilizer 5-8 parts by weight,
Lubricant 2-5 parts by weight,
Wherein, the pharmaceutically acceptable salt of the clopidogrel is clopidogrel free alkali and organic acid or inorganic acid shape
At salt, though clopidogrel with which kind of salt form exist, the parts by weight are with clopidogrel free alkali
(C16H16ClNO2S it) counts, in follow-up statement, the parts by weight of the pharmaceutically acceptable salt of clopidogrel refer both to clopidogrel free alkali
(C16H16ClNO2S)；
The pharmaceutically acceptable salt of clopidogrel be clopidogrel hydrochloride, clopidogrel hydrobromate,
Clopidogrel sulfate, clopidogrel camphorsulfonate, clopidogrel naphthalene sulfonate, clopidogrel benzene sulfonate, clopidogrel
Tosilate or clopidogrel oxalates,
The filler is at least one of microcrystalline cellulose, mannitol, lactose, calcium monohydrogen phosphate, pregelatinized starch；
Preferably microcrystalline cellulose is combined with pregelatinized starch, and preferred combination is that the mass ratio of microcrystalline cellulose and pregelatinized starch is 1:
3；
The disintegrant is crospovidone, sodium carboxymethyl starch, cross-linked carboxymethyl cellulose are received, calcium carboxymethylcellulose
At least one of；
The stabilizer is aeroge-Gluten, and aeroge-Gluten is by aeroge forming process, adding
The Gluten for entering ammonia solvent is formed by connecting in a manner of being grafted by the amido of the hydroxyl of aeroge and Gluten, wherein aeroge
For at least one of alumina aerogels, silica aerogel, titania aerogel；
Preferred aeroge-Gluten is by aeroge and Gluten with volume ratio 3:1 composition；
The lubricant is PEG6000（Macrogol 6000）, talcum powder, polyethylene wax, in Compritol 888 ATO
It is at least one.
A kind of stable tablet of clopidogrel, is prepared by the following method：
(1) by stabilizer aeroge-paddy of the pharmaceutically acceptable salt of the clopidogrel of 30-50 parts by weight and 5-8 parts by weight
Protein powder is uniformly mixed, spare；
(2) filler of 30-45 parts by weight, the disintegrant of 10-15 parts by weight and ethanol in proper amount are soaked, with step（1）
Obtained mixture is added fluid bed and is wrapped up, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, package powder is finally made
50 mesh sieve is crossed completely, obtains the uniform powder of particle, and the mix lubricant that 2-5 parts by weight are then added uniformly is sent into the more punchings of rotation
The pressure of tablet press machine, control stamping machine is 10-15kg/mm2, tabletting speed in ten thousand tablets hs of 12-13, by powder pressing at
Surface smooth circular tablet, obtains the stable tablet of clopidogrel.
Above-mentioned steps（2）The ethanol in proper amount, taken amount is as few as possible, because different fillers and disintegrant are to ethyl alcohol
Sensibility is different, and the standard of taken amount can shape after being ground with hand, and preferred ethyl alcohol taken amount is filler and disintegrant gross mass
2-3%, the concentration of ethyl alcohol choose 85% or more refined ethyl alcohol.
Inventor has found that in conventional clopidogrel tablet manufacture, pressure and temperature can lead to clopidogrel dextrorotation
Configuration is to laevo-configuration instantaneous conversion, and inventor attempts by reducing pressure, control punch temperature is suppressed within 40 DEG C
Tablet, but not enough even there is air marks on surface to obtained tablet hardness, and i.e. fragmentation of gently being pressurizeed with thumb.Inventor is surprised
It was found that it is used as the stable carrier of clopidogrel by aeroge-Gluten, flexible viscous-elastic behaviour and microcosmos network knot
Structure make clopidogrel in compressing dry granulation from caused by high pressure, fast ram, punch high temperature clopidogrel chiral reversion and
Degradation.Even if more than 15kg/mm2Pressure under, with the tabletting speed punching press of 130,000 tablets hs, punch friction temperature is more than
80 DEG C, clopidogrel piece is with good stability, and clopidogrel acid Determination of Levo is 0.20% before pharmaceutical production, raw
Postpartum Determination of Levo is 0.22%, clopidogrel is not detected, apparent chiral inversion and degradation occurs.Particularly, lead to
Stable carrier of the aeroge-Gluten as clopidogrel is crossed, in clopidogrel tablet storing process, is not only able to prevent chlorine
The hydrolysis of pyrrole Gray, and the chiral inversion of clopidogrel can be inhibited, effectively extend the storage period of clopidogrel tablet.
Another excellent characteristic is that sticking phenomenon disappears in tableting processes, and obtained clopidogrel stable tablet has smooth
Appearance and good hardness.
Further, the stable carrier of clopidogrel is used as by aeroge-Gluten, after oral administration, aeroge-Gluten
Network structure swelling, make clopidogrel stripping property improve.Its dissolution characteristic is not influenced by gastric acid environment.Its pH2.0,
20 minutes dissolution rates are above 90% in the media environment of pH4.0, pH7.0.
The stability of clopidogrel tablet mainly passes through clopidogrel acid content（Impurity A）, clopidogrel laevoisomer
（Impurity C）Content weigh.Reference《Chinese Pharmacopoeia》The related stability test guideline requirements of version annex XIXC in 2005,
Accelerated stability test is carried out to the clopidogrel stable tablet obtained by the present invention.Experiment condition is：40 ± 2 DEG C, relative humidity
In 75% ± 5% climatic chamber, in hot and humid environment, hydrolysis and chiral inversion occur for clopidogrel stable tablet
Ratio is smaller.As shown in table 1：
| Resting period process | Clopidogrel acid acid content % | Clopidogrel acid Determination of Levo % |
| Produces day | 0.10 | 0.22 |
| 1 month | 0.10 | 0.22 |
| 3 months | 0.10 | 0.23 |
| 6 months | 0.12 | 0.25 |
Reference《Chinese Pharmacopoeia》The related stability test guideline requirements of version annex XIXC in 2005, obtained by the present invention
Clopidogrel stable tablet carry out stability long term test.Experiment condition is：25 ± 2 DEG C, relative humidity 60% ± 10%
In climatic chamber, the environment that simulation nature is placed, in long-term storing process, clopidogrel acid in clopidogrel stable tablet
Content（Impurity A）, clopidogrel laevoisomer（Impurity C）It remains in stable range, the shelf-life can extend to 3
Year or more.As shown in table 2：
| Resting period process | Clopidogrel acid acid content % | Clopidogrel acid Determination of Levo % |
| Produces day | 0.10 | 0.22 |
| 1 month | 0.10 | 0.22 |
| 3 months | 0.10 | 0.22 |
| 6 months | 0.10 | 0.23 |
| 24 months | 0.11 | 0.26 |
| 36 months | 0.12 | 0.33 |
The present invention is used as the stable carrier of clopidogrel by aeroge-Gluten as a result, and clopidogrel is made to be deposited for a long time
The ratio of degradation and chiral inversion occurs during storage to be reduced, and storage period is extended.Even in high temperature, high humidity environment, deposit
It puts certain time, does not also detect sharply increasing for clopidogrel acid and clopidogrel laevoisomer, greatly improve use
The safety of medicine.
A kind of stable tablet of clopidogrel of the present invention and preparation method thereof, compared with prior art, the feature protruded
It is with excellent effect：
1, it is used as the stable carrier of clopidogrel by aeroge-Gluten, flexible viscous-elastic behaviour and microcosmic
Network structure makes clopidogrel in compressing dry granulation from the clopidogrel chiral caused by high pressure, fast ram, punch high temperature
Reversion and degradation.
2, it is used as the stable carrier of clopidogrel by aeroge-Gluten, makes clopidogrel in long-term storing process
The ratio of degradation and chiral inversion, which occurs, to be reduced, and is extended storage period, is greatly improved the safety of medication.
3, sticking phenomenon in clopidogrel tableting processes is solved, obtained clopidogrel stable tablet has smooth outer
Sight and good hardness, can high speed tabletting.
4, it is used as the stable carrier of clopidogrel by aeroge-Gluten, after oral administration, the net of aeroge-Gluten
Network structure swells make clopidogrel stripping property improve.
Specific implementation mode
In the following, the present invention will be further described in detail by way of specific embodiments, but this should not be interpreted as to the present invention
Range be only limitted to example below.Without departing from the idea of the above method of the present invention, according to ordinary skill
The various replacements or change that knowledge and customary means are made, should be included in the scope of the present invention.
Embodiment 1
The composition of the stable tablet of clopidogrel is calculated as by weight：
30 parts by weight of clopidogrel hydrochloride（With clopidogrel free alkali (C16H16ClNO2S it) counts）,
35 parts by weight of calcium monohydrogen phosphate,
10 parts by weight of crospovidone,
8 parts by weight of alumina aerogels-Gluten,
2 parts by weight of polyethylene wax；
Preparation method：
(1) by the clopidogrel hydrochloride of 30 parts by weight（With clopidogrel free alkali (C16H16ClNO2S it) counts）And 8 weight
Stabilizer alumina aerogels-the Gluten of part is uniformly mixed, spare；
(2) the filler calcium monohydrogen phosphate of 35 parts by weight, the disintegrant crospovidone of 10 parts by weight and ethanol in proper amount are soaked
It is wet, with step（1）Obtained mixture is added fluid bed and is wrapped up, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, package powder is finally made
50 mesh sieve is crossed completely, obtains the uniform powder of particle, and the lubricant polyethylene wax that 2 parts by weight are then added is uniformly mixed feeding rotation
Turn more stamping machines, the pressure of control stamping machine is 15kg/mm2, tabletting speed is in ten thousand tablets hs of 12-13, by powder pressing
At surface smooth circular tablet, the stable tablet of clopidogrel is obtained.
Embodiment 2
The composition of the stable tablet of clopidogrel is calculated as by weight：
35 parts by weight of clopidogrel hydrobromate（With clopidogrel free alkali
(C16H16ClNO2S it) counts）,
Microcrystalline cellulose is with pregelatinized starch with mass ratio for 1:3 30 parts by weight of composition,
12 parts by weight of sodium carboxymethyl starch,
5 parts by weight of silica aerogel-Gluten,
3 parts by weight of Compritol 888 ATO；
Preparation method：
(1) by the clopidogrel hydrobromate of 35 parts by weight（With clopidogrel free alkali (C16H16ClNO2S it) counts）And 5 weight
Stabilizer silica aerogel-the Gluten for measuring part is uniformly mixed, spare；
(2) by the filler microcrystalline cellulose of 30 parts by weight and pregelatinized starch with mass ratio for 1:3 composition, 12 weights
The disintegrating agent carboxymethyl base sodium starch of amount part is soaked with ethanol in proper amount, with step（1）Obtained mixture is added fluid bed and is wrapped
It wraps up in, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, package powder is finally made
Completely cross 50 mesh sieve, obtain the uniform powder of particle, be then added 3 parts by weight lubricant Compritol 888 ATO be uniformly mixed give
Enter to rotate more stamping machines, the pressure of control stamping machine is 12kg/mm2, tabletting speed is in ten thousand tablets hs of 12-13, by powder
It is pressed into surface smooth circular tablet, obtains the stable tablet of clopidogrel.
Embodiment 3
The composition of the stable tablet of clopidogrel is calculated as by weight：
45 parts by weight of clopidogrel sulfate（With clopidogrel free alkali (C16H16ClNO2S it) counts）,
40 parts by weight of lactose,
Cross-linked carboxymethyl cellulose receives 12 parts by weight,
6 parts by weight of titania aerogel-Gluten,
3 parts by weight of PEG6000；
Preparation method：
(1) by the clopidogrel sulfate of 45 parts by weight（With clopidogrel free alkali (C16H16ClNO2S it) counts）And 6 weight
Stabilizer titania aerogel-the Gluten of part is uniformly mixed, spare；
(2) the disintegrant cross-linked carboxymethyl cellulose of the filler lactose of 40 parts by weight, 12 parts by weight is received and appropriate second
Alcohol soaks, with step（1）Obtained mixture is added fluid bed and is wrapped up, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, package powder is finally made
50 mesh sieve is crossed completely, obtains the uniform powder of particle, and the lubricant PEG6000 that 3 parts by weight are then added is uniformly mixed feeding rotation
Turn more stamping machines, the pressure of control stamping machine is 14kg/mm2, tabletting speed is in ten thousand tablets hs of 12-13, by powder pressing
At surface smooth circular tablet, the stable tablet of clopidogrel is obtained.
Embodiment 4
The composition of the stable tablet of clopidogrel is calculated as by weight：
50 parts by weight of clopidogrel camphorsulfonate（With clopidogrel free alkali (C16H16ClNO2S it) counts）,
45 parts by weight of mannitol,
10 parts by weight of sodium carboxymethyl starch,
8 parts by weight of titania aerogel-Gluten,
5 parts by weight of talcum powder；
Preparation method：
(1) by the clopidogrel camphorsulfonate of 50 parts by weight（With clopidogrel free alkali (C16H16ClNO2S it) counts）And 8
Stabilizer titania aerogel-Gluten of parts by weight is uniformly mixed, spare；
(2) the filler mannitol of 45 parts by weight, the disintegrating agent carboxymethyl base sodium starch of 10 parts by weight and ethanol in proper amount are soaked
It is wet, with step（1）Obtained mixture is added fluid bed and is wrapped up, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, package powder is finally made
50 mesh sieve is crossed completely, obtains the uniform powder of particle, and the lubricant talcum powder that 5 parts by weight are then added is uniformly mixed feeding rotation
The pressure of more stamping machines, control stamping machine is 12kg/mm2, tabletting speed in ten thousand tablets hs of 12-13, by powder pressing at
Surface smooth circular tablet, obtains the stable tablet of clopidogrel.
Embodiment 5
The composition of the stable tablet of clopidogrel is calculated as by weight：
50 parts by weight of clopidogrel benzene sulfonate（With clopidogrel free alkali (C16H16ClNO2S it) counts）,
35 parts by weight of pregelatinized starch,
15 parts by weight of calcium carboxymethylcellulose,
5 parts by weight of silica aerogel-Gluten,
4 parts by weight of Compritol 888 ATO；
Preparation method：
(1) by the clopidogrel benzene sulfonate of 50 parts by weight（With clopidogrel free alkali (C16H16ClNO2S it) counts）And 5 weight
Stabilizer silica aerogel-the Gluten for measuring part is uniformly mixed, spare；
(2) by the filler pregelatinized starch of 35 parts by weight, 15 parts by weight disintegrating agent carboxymethyl base cellulose calcium with it is appropriate
Ethyl alcohol soaks, with step（1）Obtained mixture is added fluid bed and is wrapped up, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, package powder is finally made
Completely cross 50 mesh sieve, obtain the uniform powder of particle, be then added 4 parts by weight lubricant Compritol 888 ATO be uniformly mixed give
Enter to rotate more stamping machines, the pressure of control stamping machine is 15kg/mm2, tabletting speed is in ten thousand tablets hs of 12-13, by powder
It is pressed into surface smooth circular tablet, obtains the stable tablet of clopidogrel.
Claims (8)
1. a kind of stable tablet of clopidogrel, it is characterised in that using aeroge-Gluten as stabilizer, wrap by weight
Containing the following raw material：
The pharmaceutically acceptable salt 30-50 parts by weight of clopidogrel,
Filler 30-45 parts by weight,
Disintegrant 10-15 parts by weight,
Stabilizer 5-8 parts by weight,
Lubricant 2-5 parts by weight,
Wherein, the pharmaceutically acceptable salt of the clopidogrel is clopidogrel free alkali and organic acid or inorganic acid formation
Salt, no matter clopidogrel exists with which kind of salt form, the parts by weight are with clopidogrel free alkali (C16H16ClNO2S it) counts,
In follow-up statement, the parts by weight of the pharmaceutically acceptable salt of clopidogrel refer both to clopidogrel free alkali (C16H16ClNO2S)；Institute
The filler stated is at least one of microcrystalline cellulose, mannitol, lactose, calcium monohydrogen phosphate, pregelatinized starch；The disintegrant
It is received for crospovidone, sodium carboxymethyl starch, cross-linked carboxymethyl cellulose, at least one of calcium carboxymethylcellulose；It is described
Stabilizer be aeroge-Gluten, aeroge-Gluten is that the paddy of ammonia solvent is added in aeroge forming process
Protein powder is formed by connecting in a manner of being grafted by the amido of the hydroxyl of aeroge and Gluten；The lubricant is PEG6000, cunning
At least one of mountain flour, polyethylene wax, Compritol 888 ATO.
2. a kind of stable tablet of clopidogrel according to claim 1, it is characterised in that：The clopidogrel pharmacy can
The salt of receiving be clopidogrel hydrochloride, clopidogrel hydrobromate, clopidogrel sulfate, clopidogrel camphorsulfonate,
Clopidogrel naphthalene sulfonate, clopidogrel benzene sulfonate, clopidogrel tosilate or clopidogrel oxalates.
3. a kind of stable tablet of clopidogrel according to claim 1, it is characterised in that：The filler is that crystallite is fine
Dimension element is combined with pregelatinized starch.
4. a kind of stable tablet of clopidogrel according to claim 1, it is characterised in that：The filler is that crystallite is fine
Dimension element is with pregelatinized starch with mass ratio for 1:3 are composed.
5. a kind of stable tablet of clopidogrel according to claim 1, it is characterised in that：The aeroge is aluminium oxide
At least one of aeroge, silica aerogel, titania aerogel.
6. a kind of stable tablet of clopidogrel according to claim 1, it is characterised in that：Aeroge-the Gluten by
Aeroge and Gluten are with volume ratio 3:1 composition.
7. a kind of stable tablet of clopidogrel according to claim 1, it is characterised in that：The stabilization of the clopidogrel
Agent is prepared by the following method：
(1) by stabilizer aeroge-glutelin of the pharmaceutically acceptable salt of the clopidogrel of 30-50 parts by weight and 5-8 parts by weight
Powder is uniformly mixed, spare；
(2) filler of 30-45 parts by weight, the disintegrant of 10-15 parts by weight and ethanol in proper amount are soaked, with step（1）?
To mixture fluid bed be added wrapped up, and ethyl alcohol is made to exclude；
(3) by step（2）Obtained package powder crosses 50 mesh sieve, and residue on sieve is further pulverized, finally makes package powder complete
It is complete to cross 50 mesh sieve, the uniform powder of particle is obtained, the mix lubricant that 2-5 parts by weight are then added uniformly is sent into the more punching presses of rotation
The pressure of piece machine, control stamping machine is 10-15kg/mm2, and tabletting speed is in ten thousand tablets hs of 12-13, by powder pressing at table
Face smooth circular tablet, obtains the stable tablet of clopidogrel.
8. a kind of stable tablet of clopidogrel according to claim 7, it is characterised in that：Step（2）The appropriate second
Alcohol, taken amount are the 2-3% of filler and disintegrant gross mass, and the concentration of ethyl alcohol chooses 85% or more refined ethyl alcohol.
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|---|---|---|---|---|
| CN101092512A (en) * | 2007-07-20 | 2007-12-26 | 浙江大学 | Gluten powder / Nano silicon dioxide composite material in situ, and preparation method |
| CN101590023A (en) * | 2008-05-30 | 2009-12-02 | 浙江京新药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN104644595A (en) * | 2015-03-09 | 2015-05-27 | 杨玉廷 | Solid pharmaceutical composition with clopidogrel |
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2016
- 2016-08-18 CN CN201610683734.3A patent/CN106137994B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101092512A (en) * | 2007-07-20 | 2007-12-26 | 浙江大学 | Gluten powder / Nano silicon dioxide composite material in situ, and preparation method |
| CN101590023A (en) * | 2008-05-30 | 2009-12-02 | 浙江京新药业股份有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
| CN104644595A (en) * | 2015-03-09 | 2015-05-27 | 杨玉廷 | Solid pharmaceutical composition with clopidogrel |
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