CN106137994A - 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
- Publication number
- CN106137994A CN106137994A CN201610683734.3A CN201610683734A CN106137994A CN 106137994 A CN106137994 A CN 106137994A CN 201610683734 A CN201610683734 A CN 201610683734A CN 106137994 A CN106137994 A CN 106137994A
- Authority
- CN
- China
- Prior art keywords
- clopidogrel
- weight portion
- aeroge
- tablet
- gluten meal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 163
- 229960003009 clopidogrel Drugs 0.000 title claims abstract description 162
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title claims abstract description 158
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 235000012054 meals Nutrition 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 21
- 108010068370 Glutens Proteins 0.000 claims abstract description 8
- 235000021312 gluten Nutrition 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- 239000000843 powder Substances 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 239000000945 filler Substances 0.000 claims description 15
- 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
- 238000000034 method Methods 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
- 229920000881 Modified starch Polymers 0.000 claims description 10
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 9
- 239000008187 granular material Substances 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical group OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 7
- 238000003825 pressing Methods 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 229940049654 glyceryl behenate Drugs 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 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 5
- 229920000168 Microcrystalline cellulose Polymers 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
- 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
- 239000008118 PEG 6000 Substances 0.000 claims description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 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
- -1 clopidogrel oxalates Chemical class 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
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 229940084030 carboxymethylcellulose calcium Drugs 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
- 239000004964 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
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 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
- 239000002994 raw material Substances 0.000 claims description 2
- 241000209140 Triticum Species 0.000 claims 1
- 235000021307 Triticum Nutrition 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 238000011105 stabilization Methods 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 229950004288 tosilate Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 238000003860 storage Methods 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 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
- 238000004080 punching Methods 0.000 abstract description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 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
- QSMTUAJDOTXEDZ-UHFFFAOYSA-N N1C=CC=C1.[Cl] Chemical class N1C=CC=C1.[Cl] QSMTUAJDOTXEDZ-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 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
- 239000000377 silicon dioxide Substances 0.000 description 4
- 230000001629 suppression Effects 0.000 description 4
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 3
- 239000002585 base Substances 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
- 238000005516 engineering process Methods 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000008280 blood Substances 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
- 230000000284 resting effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 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
- 208000033386 Buerger disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010008132 Cerebral thrombosis 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
- 208000005189 Embolism Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 239000004698 Polyethylene Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010043540 Thromboangiitis obliterans Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108010046722 Thrombospondin 1 Proteins 0.000 description 1
- 102100036034 Thrombospondin-1 Human genes 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
- 239000002671 adjuvant Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000001014 amino acid Nutrition 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
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 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
- 238000000227 grinding Methods 0.000 description 1
- 210000004247 hand Anatomy 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
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- 125000004492 methyl ester group 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
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 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
- 238000002791 soaking 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
- 239000000126 substance 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Botany (AREA)
- Zoology (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides stable tablet of a kind of clopidogrel and preparation method thereof, by aeroge gluten meal as the stable carrier of clopidogrel, its whippy viscous-elastic behaviour and microcosmos network structure make clopidogrel from the clopidogrel chiral reversion caused because of high pressure, fast ram, drift high temperature and degraded in compressing dry granulation.Even if more than 15kg/mm2Pressure under, tabletting speed punching press with 130,000 tablets h, drift friction temperature is more than 80 DEG C, clopidogrel sheet has good stability, before pharmaceutical production, clopidogrel acid Determination of Levo is 0.20%, after production, Determination of Levo is 0.22%, is not detected by clopidogrel and obvious chiral inversion and degraded occur.Particularly, by aeroge gluten meal as the stable carrier of clopidogrel, during longer-term storage, in clopidogrel stable tablet, clopidogrel acid content (impurity A), clopidogrel laevoisomer (impurity C) remain in stable scope, and the shelf-life can extend to more than 3 years.Drastically increase the safety of medication.
Description
Technical field
The present invention relates to pharmaceutical preparations technology field, be specifically related to stable tablet and the preparation side thereof of a kind of clopidogrel
Method, this stable tablet efficiently solves the hydrolysis of current clopidogrel tablet easy deliquescence, overcomes during clopidogrel processing storage right
Rotation isomer is converted into laevoisomer, thus adds the stability of clopidogrel.
Background technology
Clopidogrel is a kind of anticoagulant, and it can optionally suppress adenosine diphosphate (ADP) (ADP) little with blood
The combination of plate receptor, suppression subsequently activates ADP and Glycoprotein G PIIb/IIIa complex, thus suppresses hematoblastic gathering.Remove
Outside ADP, clopidogrel can also suppress other to induce by blocking the amplification of the platelet activation caused by the ADP discharged
Platelet aggregation；Can be used for preventing and treating myocardial infarction, ischemic cerebral thrombosis, thromboangiitis obliterans and atherosclerosis and thrombosis
The complication that thromboembolism causes.Since 2005, chlorine pyrroles's thunder is used clinically for treating and preventing cardiac muscle as anticoagulation medicine
Infraction starts to widely apply in clinical heart disease patients, and taking chlorine pyrroles's thunder, can substantially to reduce the generation of myocardial infarction several
Rate, is applied to the patient of the apoplexy, myocardial infarction or the peripheral arterial disease that occur in the recent period, is effectively reduced tremulous pulse medicated porridge sample after treatment
The generation of hardening event.
Clopidogrel, chemistry entitled (S)-a-(2-chlorphenyl)-6,7-dichloro-thiophene also (3,2-c) pyridine-5 (4H)-
Methyl acetate, its structural formula is as follows:
Its chemical constitution is similar to Ticlopidine, only at the many carboxymethyls of side chain, but it
Curative effect far above Ticlopidine, its specific activity Ticlopidine is high 50 times, higher 110 times than aspirin, and gastrointestinal tract is not
Good reaction is less, and safety is greatly improved.But, due to containing ester bond and chiral carbon in clopidogrel molecule structure, thus right
Light, heat, pH value wet, high are the most sensitive, there are some researches show the clopidogrel of dextrorotatory configuration due to the existence of methyl ester group, meeting
Cause hydrolysis to form acid, become the factors of instability；Chiral inversion, clopidogrel is the most easily there is in preparation, storing process
Medicinal forms be mainly dextrorotatory configuration, its laevo-configuration is then isomer impurities, and the reversion of chiral carbon causes medicine by dextrorotation
The most rotary, on the one hand laevo-configuration lacks antithrombotic acitivity so that activity occurs notable change, on the other hand, left-handed structure
There is certain toxicity and easily cause human body to faint from fear in type, and its results of animal display laevo-configuration toxicity is significantly higher than chlorine pyrrole
Gray's dextrorotatory configuration.Particularly, clinically clopidogrel to be widely used in the anti-blood of percutaneous coronary intervention (pci) perioperative little
Plate is treated, and is mainly used in the excessive risk operation of heart and intravascular stent, and the content of clopidogrel laevoisomer increases, opponent
The success of art just has a great impact, and requires high to Drug safety.So strictly controlling the left-handed isomery of clopidogrel
The content of body and clopidogrel acid is the important indicator controlling the quality of production.Therefore, strictly to control during producing, storing
Its stability.
Chinese invention patent application number is 200610063151.7 solid preparations disclosing a kind of clopidogrel sulfate
With and preparation method thereof.This solid preparation adds glycerol palmitic, stearic fat and micropowder silica gel, effectively reduces chlorine
The dextroisomer of pyrrole Gray is converted into clopidogrel laevoisomer, adds stability and the safety of solid preparation.
Chinese invention patent application number is 201510102350.3 to disclose a kind of solid drugs group containing clopidogrel
Compound, by using aminoacid as stabilizer, makes the hydrolysis of crude drug be inhibited.
Chinese invention patent application number is the 200710129305.2 solid systems disclosing a kind of bisulfate clopidogrel
Agent, its granule and preparation method thereof, this patent uses bisulfate clopidogrel and cellulose family adjuvant and melted binding agent
It is mixed to form solid mixture and prepares granule.Owing to using melt granulation technology, preparation process requires heat to higher temperature,
Easily cause the degraded of medicine.
Chinese invention patent application number is 200810061954.8 to disclose a kind of clopidogrel hydrogen sulfate tablet and system thereof
Preparation Method, uses vitamin C, BHA to make lubricant, and suppression clopidogrel is converted into clopidogrel acid and chlorine pyrrole lattice
Thunder dextroisomer is converted into laevoisomer. and Chinese invention patent application number 201410796447.4 discloses a kind of hydrogen sulfate
Clopidogrel tablet medicament composition and preparation method thereof, uses Magnesiumaluminumsilicate, not only improves material fluidity in prescription, moreover it is possible to
Effectively prevent the deliquescence of medicine, reduce clopidogrel and be degraded into the risk of clopidogrel acid because of the moisture absorption.
US5520928, by using stearic acid to substitute magnesium stearate, overcomes magnesium stearate to accelerate clopidogrel and is degraded to chlorine
The problem of pyrrole Gray acid；WO2005/070464 uses hydrogenated vegetable oil and carboxymethyl starch as lubricant, it is possible to resolve tablet
The problem that middle clopidogrel is degraded to clopidogrel acid.
According to above-mentioned, the most by anti-deliquescence, the hydrolysis of selecting auxiliary agent AF panel clopidogrel.But also do not have
There is the dextrorotation of means suppression clopidogrel effectively to left-handed conversion.Therefore the clopidogrel storage time is short, and at storage period
Between impurity be stepped up.
Summary of the invention
Even if clopidogrel is in room temperature, however it remains signs of degradation, easily hydrolysis generates clopidogrel acid (general designation impurity
A), clopidogrel dextroisomer is unstable, is easily converted into not having the clopidogrel laevoisomer of pharmaceutical active (to be referred to as
Impurity C).In prior art, for ensureing the stability in clopidogrel tablet manufacturing and storing process, generally use hydrophobic skill
Art means process hydrolysis.But, the stability of clopidogrel tablet is by the shadow of the multiple factors such as moisture, temperature, tonnage, light
Ring, even if having employed hydrophobic treatment, it is impossible to effectively the dextrorotation of suppression clopidogrel is to left-handed conversion.It is an object of the invention to
There is provided a kind of have good stability, more than extended shelf-life to 3 year clopidogrel stable tablet, particularly this stable tablet can
Effectively suppress clopidogrel by dextrorotation to left-handed conversion.This stable tablet has good anti-hygroscopy and stripping property simultaneously.
Further, it is provided that the preparation method of this clopidogrel stable tablet.
For achieving the above object, the present invention is by the following technical solutions:
The stable tablet of a kind of clopidogrel, it is characterised in that using aeroge-gluten meal as stabilizer, comprise by weight
Following raw material:
Clopidogrel pharmaceutically acceptable salt 30-50 weight portion,
Filler 30-45 weight portion,
Disintegrating agent 10-15 weight portion,
Stabilizer 5-8 weight portion,
Lubricant 2-5 weight portion,
Wherein, the pharmaceutically acceptable salt of described clopidogrel is that clopidogrel free alkali is formed with organic acid or mineral acid
Salt, no matter clopidogrel with which kind of salt form exists, described weight portion is all with clopidogrel free alkali (C16H16ClNO2S)
Meter, when follow-up statement, the weight portion of the pharmaceutically acceptable salt of clopidogrel refers both to clopidogrel free alkali (C16H16ClNO2S)；
The most described pharmaceutically acceptable salt of clopidogrel is clopidogrel hydrochlorate, clopidogrel hydrobromate, chlorine pyrrole
Gray's sulfate, clopidogrel camphorsulfonate, clopidogrel naphthalene sulfonate, clopidogrel benzene sulfonate, clopidogrel are to first
Benzene sulfonate or clopidogrel oxalates,
Described filler is at least one in microcrystalline cellulose, mannitol, lactose, calcium hydrogen phosphate, pregelatinized Starch；The most micro-
Crystalline cellulose and pregelatinized Starch are combined, and preferably combination is microcrystalline cellulose and the mass ratio of pregelatinized Starch is 1:3；
Described disintegrating agent is that polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose are received, in carboxymethylcellulose calcium
At least one；
Described stabilizer is aeroge-gluten meal, and its aeroge-gluten meal is by aeroge forming process, adds ammonia
Water-soluble gluten meal is formed by connecting by the hydroxyl of aeroge and the amido of gluten meal in the way of grafting, and wherein aeroge is oxygen
Change at least one in aluminum aeroge, silica aerogel, titania aerogel；
Preferably aeroge-gluten meal is made up of with volume ratio 3:1 aeroge and gluten meal；
Described lubricant is PEG6000(polyethylene glycol 6000), Pulvis Talci, Tissuemat E, in Glyceryl Behenate at least
A kind of.
The stable tablet of a kind of clopidogrel, is prepared from by the following method:
(1) by the pharmaceutically acceptable salt of clopidogrel and the stabilizer aeroge-gluten meal of 5-8 weight portion of 30-50 weight portion
Mix homogeneously, standby；
(2) filler of 30-45 weight portion, the disintegrating agent of 10-15 weight portion are soaked with ethanol in proper amount, obtain with step (1)
Compound add fluidized bed and wrap up, and make ethanol get rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the mix lubricant being subsequently adding 2-5 weight portion uniformly sends into the many stampings of rotation
Machine, the pressure controlling stamping machine is 10-15kg/mm2, powder pressing, in 12-13 ten thousand tablets h, is become surface by tabletting speed
Smooth circular tablet, obtains the stable tablet of clopidogrel.
Ethanol in proper amount described in above-mentioned steps (2), its taken amount is the fewest, because different filleies and disintegrating agent are to ethanol
Sensitivity is different, and the standard of taken amount can be shaped after grinding with hands, and preferred ethanol taken amount is filler and disintegrating agent gross mass
2-3%, the concentration of ethanol chooses 85% and above refined ethanol.
Inventor finds, in conventional clopidogrel tablet manufacture, pressure and temperature can cause clopidogrel dextrorotation
Configuration is to laevo-configuration instantaneous conversion, and inventor attempts by reducing pressure, control drift temperature is suppressed within 40 DEG C
Tablet, but there is an air marks on the tablet hardness obtained not the most even surface, and i.e. fragmentation of pressurizeing gently with thumb.Inventor is surprised
Find, by aeroge-gluten meal as the stable carrier of clopidogrel, its whippy viscous-elastic behaviour and microcosmos network knot
Structure make clopidogrel in compressing dry granulation from cause because of high pressure, fast ram, drift high temperature clopidogrel chiral reversion and
Degraded.Even if more than 15kg/mm2Pressure under, with the tabletting speed punching press of 130,000 tablets h, drift friction temperature exceedes
80 DEG C, clopidogrel sheet has good stability, and before pharmaceutical production, clopidogrel acid Determination of Levo is 0.20%, raw
Puerperal, Determination of Levo was 0.22%, is not detected by clopidogrel and obvious chiral inversion and degraded occur.Particularly, logical
Cross the aeroge-gluten meal stable carrier as clopidogrel, in clopidogrel tablet storing process, be not only able to prevent chlorine
The hydrolysis of pyrrole Gray, and the chiral inversion of clopidogrel can be suppressed, effectively extend the storage period of clopidogrel tablet.
The characteristic of another excellence is that in tableting processes, sticking phenomenon disappears, and the clopidogrel stable tablet obtained has smooth
Outward appearance and good hardness.
Further, by aeroge-gluten meal as the stable carrier of clopidogrel, after oral administration, aeroge-gluten meal
Network structure swelling, make clopidogrel stripping property improve.Its dissolution characteristic is not affected by gastric acid environment.Its pH2.0,
In the media environment of pH4.0, pH7.0, the dissolution of 20 minutes is above 90%.
The stability of clopidogrel tablet is mainly by clopidogrel acid content (impurity A), clopidogrel laevoisomer
The content of (impurity C) is weighed.With reference to " Chinese Pharmacopoeia 2005 version annex XIXC relevant stability test guideline requirement,
The clopidogrel stable tablet of gained of the present invention is carried out Accelerated stability test.Experiment condition is: 40 ± 2 DEG C, relative humidity
In the climatic chamber of 75% ± 5%, in hot and humid environment, there is hydrolysis and chiral inversion in clopidogrel stable tablet
Ratio is less.As shown in table 1:
| Resting period process | Clopidogrel acid acid content % | Clopidogrel acid Determination of Levo % |
| Produce day | 0.10 | 0.22 |
| 1 month | 0.10 | 0.22 |
| 3 months | 0.10 | 0.23 |
| 6 months | 0.12 | 0.25 |
With reference to " Chinese Pharmacopoeia 2005 version annex XIXC relevant stability test guideline requirement, the chlorine to gained of the present invention
Pyrrole Gray's stable tablet carries out stability long term test.Experiment condition is: 25 ± 2 DEG C, the constant temperature of relative humidity 60% ± 10%
In constant humidity cabinet, the environment that simulation nature is placed, during longer-term storage, clopidogrel acid content in clopidogrel stable tablet
(impurity A), clopidogrel laevoisomer (impurity C) remain in stable scope, the shelf-life can extend to 3 years with
On.As shown in table 2:
| Resting period process | Clopidogrel acid acid content % | Clopidogrel acid Determination of Levo % |
| Produce 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 |
Thus, the present invention as the stable carrier of clopidogrel, makes clopidogrel in longer-term storage mistake by aeroge-gluten meal
The ratio that degraded and chiral inversion occur in journey reduces, and extends storage period.Even if in high temperature, high humidity environment, depositing one
Fix time, also do not detect clopidogrel acid and the sharply increasing of clopidogrel laevoisomer, drastically increase medication
Safety.
Stable tablet of a kind of clopidogrel of the present invention and preparation method thereof, compared with prior art, its prominent feature
It is with excellent effect:
1, by aeroge-gluten meal as the stable carrier of clopidogrel, its whippy viscous-elastic behaviour and microcosmos network
Structure makes clopidogrel from the clopidogrel chiral reversion caused because of high pressure, fast ram, drift high temperature in compressing dry granulation
And degraded.
2, by aeroge-gluten meal as the stable carrier of clopidogrel, make clopidogrel during longer-term storage
The ratio that degraded and chiral inversion occur reduces, and extends storage period, drastically increases the safety of medication..
3, solve sticking phenomenon in clopidogrel tableting processes, the clopidogrel stable tablet obtained have smooth outward appearance and
Good hardness, can high speed tabletting.
4, by aeroge-gluten meal as the stable carrier of clopidogrel, after oral administration, the net of aeroge-gluten meal
Network structure swells, makes clopidogrel stripping property improve.
Detailed description of the invention
Below by way of detailed description of the invention, the present invention is described in further detail, but this should be interpreted as the present invention
Scope be only limitted to Examples below.In the case of without departing from said method thought of the present invention, according to ordinary skill
Various replacements that knowledge and customary means are made or change, 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:
Clopidogrel hydrochlorate 30 weight portion is (with clopidogrel free alkali (C16H16ClNO2S) meter),
Calcium hydrogen phosphate 35 weight portion,
Polyvinylpolypyrrolidone 10 weight portion,
Alumina aerogels-gluten meal 8 weight portion,
Tissuemat E 2 weight portion；
Preparation method:
(1) by the clopidogrel hydrochlorate of 30 weight portions (with clopidogrel free alkali (C16H16ClNO2S) meter), and 8 weight portions
Stabilizer alumina aerogels-gluten meal mix homogeneously, standby；
(2) the disintegrating agent polyvinylpolypyrrolidone of the filler calcium hydrogen phosphate of 35 weight portions, 10 weight portions is soaked with ethanol in proper amount, with
The compound that step (1) obtains adds fluidized bed and wraps up, and makes ethanol get rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the lubricant polyethylene wax mix homogeneously feeding being subsequently adding 2 weight portions rotates many
Stamping machine, the pressure controlling stamping machine is 15kg/mm2, powder pressing, in 12-13 ten thousand tablets h, is become table by tabletting speed
Face smooth circular tablet, obtains the stable tablet of clopidogrel.
Embodiment 2
The composition of the stable tablet of clopidogrel is calculated as by weight:
Clopidogrel hydrobromate 35 weight portion is (with clopidogrel free alkali
(C16H16ClNO2S) meter),
Microcrystalline cellulose and pregelatinized Starch compositions 30 weight portion with mass ratio as 1:3,
Carboxymethyl starch sodium 12 weight portion,
Silica aerogel-gluten meal 5 weight portion,
Glyceryl Behenate 3 weight portion；
Preparation method:
(1) by the clopidogrel hydrobromate of 35 weight portions (with clopidogrel free alkali (C16H16ClNO2S) meter), and 5 weight portions
Stabilizer silica aerogel-gluten meal mix homogeneously, standby；
(2) by the filler microcrystalline cellulose of 30 weight portions and pregelatinized Starch compositions with mass ratio as 1:3,12 weight portions
Disintegrating agent carboxymethyl base Starch Sodium is soaked with ethanol in proper amount, and the compound obtained with step (1) adds fluidized bed and wraps up, and makes
Ethanol is got rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the lubricant Glyceryl Behenate mix homogeneously being subsequently adding 3 weight portions sends into rotation
Turning many stampings machine, the pressure controlling stamping machine is 12kg/mm2, tabletting speed is in 12-13 ten thousand tablets h, by powder pressing
Become smooth surface circular tablet, obtain the stable tablet of clopidogrel.
Embodiment 3
The composition of the stable tablet of clopidogrel is calculated as by weight:
Clopidogrel sulfate 45 weight portion is (with clopidogrel free alkali (C16H16ClNO2S) meter),
Lactose 40 weight portion,
Cross-linked carboxymethyl cellulose receives 12 weight portions,
Titania aerogel-gluten meal 6 weight portion,
PEG6000 3 weight portion；
Preparation method:
(1) by the clopidogrel sulfate of 45 weight portions (with clopidogrel free alkali (C16H16ClNO2S) meter), and 6 weight portions
Stabilizer titania aerogel-gluten meal mix homogeneously, standby；
(2) the disintegrating agent cross-linked carboxymethyl cellulose of the filler lactose of 40 weight portions, 12 weight portions is received and soak with ethanol in proper amount
Wet, the compound obtained with step (1) adds fluidized bed and wraps up, and makes ethanol get rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the lubricant PEG6000 mix homogeneously feeding being subsequently adding 3 weight portions rotates many
Stamping machine, the pressure controlling stamping machine is 14kg/mm2, powder pressing, in 12-13 ten thousand tablets h, is become table by tabletting speed
Face smooth circular tablet, obtains the stable tablet of clopidogrel.
Embodiment 4
The composition of the stable tablet of clopidogrel is calculated as by weight:
Clopidogrel camphorsulfonate 50 weight portion is (with clopidogrel free alkali (C16H16ClNO2S) meter),
Mannitol 45 weight portion,
Carboxymethyl starch sodium 10 weight portion,
Titania aerogel-gluten meal 8 weight portion,
Pulvis Talci 5 weight portion；
Preparation method:
(1) by the clopidogrel camphorsulfonate of 50 weight portions (with clopidogrel free alkali (C16H16ClNO2S) meter), and 8 weight
Stabilizer titania aerogel-gluten meal the mix homogeneously of part, standby；
(2) the disintegrating agent carboxymethyl base Starch Sodium of the filler mannitol of 45 weight portions, 10 weight portions is soaked with ethanol in proper amount, with
The compound that step (1) obtains adds fluidized bed and wraps up, and makes ethanol get rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the lubricant Pulvis Talci mix homogeneously being subsequently adding 5 weight portions sends into the many punchings of rotation
Tablet machine, the pressure controlling stamping machine is 12kg/mm2, powder pressing, in 12-13 ten thousand tablets h, is become surface by tabletting speed
Smooth circular tablet, obtains the stable tablet of clopidogrel.
Embodiment 5
The composition of the stable tablet of clopidogrel is calculated as by weight:
Clopidogrel benzene sulfonate 50 weight portion is (with clopidogrel free alkali (C16H16ClNO2S) meter),
Pregelatinized Starch 35 weight portion,
Carboxymethylcellulose calcium 15 weight portion,
Silica aerogel-gluten meal 5 weight portion,
Glyceryl Behenate 4 weight portion；
Preparation method:
(1) by the clopidogrel benzene sulfonate of 50 weight portions (with clopidogrel free alkali (C16H16ClNO2S) meter), and 5 weight portions
Stabilizer silica aerogel-gluten meal mix homogeneously, standby；
(2) by the filler pregelatinized Starch of 35 weight portions, the disintegrating agent carboxymethyl base cellulose calcium of 15 weight portions and ethanol in proper amount
Soaking, the compound obtained with step (1) adds fluidized bed and wraps up, and makes ethanol get rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the lubricant Glyceryl Behenate mix homogeneously being subsequently adding 4 weight portions sends into rotation
Turning many stampings machine, the pressure controlling stamping machine is 15kg/mm2, tabletting speed is in 12-13 ten thousand tablets h, by powder pressing
Become smooth surface circular tablet, obtain the stable tablet of clopidogrel.
Claims (8)
1. the stable tablet of a clopidogrel, it is characterised in that using aeroge-gluten meal as stabilizer, wrap by weight
Containing following raw material:
Clopidogrel pharmaceutically acceptable salt 30-50 weight portion,
Filler 30-45 weight portion,
Disintegrating agent 10-15 weight portion,
Stabilizer 5-8 weight portion,
Lubricant 2-5 weight portion,
Wherein, the pharmaceutically acceptable salt of described clopidogrel is that clopidogrel free alkali is formed with organic acid or mineral acid
Salt, no matter clopidogrel with which kind of salt form exists, described weight portion is all with clopidogrel free alkali (C16H16ClNO2S) meter,
When follow-up statement, the weight portion of the pharmaceutically acceptable salt of clopidogrel refers both to clopidogrel free alkali (C16H16ClNO2S)；Institute
The filler stated is at least one in microcrystalline cellulose, mannitol, lactose, calcium hydrogen phosphate, pregelatinized Starch；Described disintegrating agent is
Polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose are received, at least one in carboxymethylcellulose calcium；Described
Stabilizer is aeroge-gluten meal, and its aeroge-gluten meal is in aeroge forming process, adds the Wheat Gluten of ammonia solvent
Powder is formed by connecting by the hydroxyl of aeroge and the amido of gluten meal in the way of grafting；Described lubricant is PEG6000, Talcum
At least one in powder, Tissuemat E, Glyceryl Behenate.
A kind of stable tablet of clopidogrel, it is characterised in that: described clopidogrel pharmacy can
Accept salt be clopidogrel hydrochlorate, clopidogrel hydrobromate, clopidogrel sulfate, clopidogrel camphorsulfonate,
Clopidogrel naphthalene sulfonate, clopidogrel benzene sulfonate, clopidogrel tosilate or clopidogrel oxalates.
A kind of stable tablet of clopidogrel, it is characterised in that: described filler is that crystallite is fine
Dimension combines with pregelatinized Starch.
A kind of stable tablet of clopidogrel, it is characterised in that: described filler is that crystallite is fine
Dimension combines for 1:3 with mass ratio with pregelatinized Starch.
A kind of stable tablet of clopidogrel, it is characterised in that: described aeroge is aluminium oxide
At least one in aeroge, silica aerogel, titania aerogel.
A kind of stable tablet of clopidogrel, it is characterised in that: described aeroge-gluten meal by
Aeroge and gluten meal form with volume ratio 3:1.
A kind of stable tablet of clopidogrel, it is characterised in that: the stabilization of described clopidogrel
Agent is prepared from by the following method:
(1) by the pharmaceutically acceptable salt of clopidogrel and the stabilizer aeroge-gluten meal of 5-8 weight portion of 30-50 weight portion
Mix homogeneously, standby；
(2) filler of 30-45 weight portion, the disintegrating agent of 10-15 weight portion are soaked with ethanol in proper amount, obtain with step (1)
Compound add fluidized bed and wrap up, and make ethanol get rid of；
(3) the parcel powder that step (2) obtains is crossed 50 mesh sieves, residue on sieve is pulverized further, finally make parcel powder complete
Crossing 50 mesh sieves, obtain the powder that granule is homogeneous, the mix lubricant being subsequently adding 2-5 weight portion uniformly sends into the many stampings of rotation
Machine, the pressure controlling stamping machine is 10-15kg/mm2, powder pressing, in 12-13 ten thousand tablets h, is become surface by tabletting speed
Smooth circular tablet, obtains the stable tablet of clopidogrel.
A kind of stable tablet of clopidogrel, it is characterised in that: the appropriate second described in step (2)
Alcohol, its taken amount is filler and the 2-3% of disintegrating agent gross mass, and the concentration of ethanol chooses 85% and above refined ethanol.
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Cited By (1)
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| CN109528669A (en) * | 2018-12-25 | 2019-03-29 | 哈尔滨珍宝制药有限公司 | Bisulfate clopidogrel composition, clopidogrel hydrogen sulfate tablet and preparation method thereof |
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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 |
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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 |
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| CN109528669A (en) * | 2018-12-25 | 2019-03-29 | 哈尔滨珍宝制药有限公司 | Bisulfate clopidogrel composition, clopidogrel hydrogen sulfate tablet and preparation method thereof |
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