CN106176644B - A kind of clopidogrel sulfate solid tablet and preparation method thereof - Google Patents
A kind of clopidogrel sulfate solid tablet and preparation method thereof Download PDFInfo
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- CN106176644B CN106176644B CN201610681842.7A CN201610681842A CN106176644B CN 106176644 B CN106176644 B CN 106176644B CN 201610681842 A CN201610681842 A CN 201610681842A CN 106176644 B CN106176644 B CN 106176644B
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- China
- Prior art keywords
- clopidogrel
- silica gel
- gel powder
- superfine silica
- weight
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- 229960003009 clopidogrel Drugs 0.000 title claims abstract description 115
- 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 80
- 239000007787 solid Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 103
- 239000000843 powder Substances 0.000 claims abstract description 91
- 239000000741 silica gel Substances 0.000 claims abstract description 91
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 91
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims abstract description 61
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000011806 microball Substances 0.000 claims abstract description 31
- 239000000661 sodium alginate Substances 0.000 claims abstract description 31
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 31
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 31
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 30
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims abstract description 23
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 17
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 15
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000011709 vitamin E Substances 0.000 claims abstract description 15
- 229940046009 vitamin E Drugs 0.000 claims abstract description 15
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000000945 filler Substances 0.000 claims abstract description 10
- 239000000314 lubricant Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000002270 dispersing agent Substances 0.000 claims description 14
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000006185 dispersion Substances 0.000 claims description 10
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 8
- 238000000227 grinding Methods 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- 238000003723 Smelting Methods 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 239000008367 deionised water Substances 0.000 claims description 7
- 229910021641 deionized water Inorganic materials 0.000 claims description 7
- 235000019441 ethanol Nutrition 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000007873 sieving Methods 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 6
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 6
- 150000002194 fatty esters Chemical class 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 235000019890 Amylum Nutrition 0.000 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 238000003825 pressing Methods 0.000 claims description 4
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 4
- 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 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 3
- 229920000193 polymethacrylate Polymers 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 11
- 239000002253 acid Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 238000012545 processing Methods 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 239000002075 main ingredient Substances 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 description 36
- 230000000694 effects Effects 0.000 description 8
- 235000012054 meals Nutrition 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- QSMTUAJDOTXEDZ-UHFFFAOYSA-N N1C=CC=C1.[Cl] Chemical compound N1C=CC=C1.[Cl] QSMTUAJDOTXEDZ-UHFFFAOYSA-N 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 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 description 2
- 239000005046 Chlorosilane Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- -1 palmitic acid stearic acid ester Chemical class 0.000 description 2
- 238000004080 punching Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- WKUVAEYSJGZGCX-UHFFFAOYSA-M N1C=CC=C1.[Cl+].S(=O)(=O)(O)[O-] Chemical compound N1C=CC=C1.[Cl+].S(=O)(=O)(O)[O-] WKUVAEYSJGZGCX-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000000320 anti-stroke effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960003958 clopidogrel bisulfate Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention proposes a kind of clopidogrel sulfate solid tablet and preparation method thereof.It is characterized in that wrapping up clopidogrel sulfate, and the solid tablet stable equipped with the modified superfine silica gel powder of trim,ethylchlorosilane by sodium alginate micro ball.The clopidogrel sulfate solid tablet is equipped with microcrystalline cellulose, vitamin E, filler, disintegrating agent, lubricant, sodium alginate micro ball and modified superfine silica gel powder using bisulfate clopidogrel as main ingredient.By carrying out the surface modified processing of trim,ethylchlorosilane to the superfine silica gel powder with hollow meso-hole structure, clopidogrel sulfate is wrapped up using sodium alginate micro ball, it is mixed with modified superfine silica gel powder, solve the problems, such as that clopidogrel is degraded to clopidogrel acid in clopidogrel sulfate solid pharmaceutical preparation and clopidogrel dextroisomer is converted into laevoisomer, ensure safety of the clopidogrel tablet in the stability and medicine use process during storage, it is made more effectively to play therapeutic effect.Preparation process is simple, particularly suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of pharmaceutical preparation and preparation method thereof, more particularly to a kind of chlorine
Pyrrole Gray's sulfate solid tablet and preparation method thereof.
Background technique
Clopidogrel, its chemical name is (+)-(S)-α-(2- Chloro-O-Phenyl) -6,7- dihydro-thiophene simultaneously [3,2-c] pyrroles
Pyridine -5 (4H)-methyl acetate inhibits to the property of can choose the combination of adenosine diphosphate (ADP) (ADP) and its platelet receptor and secondary
The activation for the sugar-protein compound that ADP is mediated reaches inhibition blood by inhibiting platelet aggregation to reduce the chance of obstruction of artery
The effect of platelet aggregation plays pre- anti-stroke and heart attack curative effect, at present artery congee clinically mainly used for treating
Sample hardens disease, acute coronary artery syndrome, prevents restenosis and thrombotic complications etc. in coronary stenting after-poppet.
Clopidogrel is administered usually in the form of sulphate salt, i.e. bisulfate clopidogrel, but presently commercially available hydrogen sulfate
There are many problems for clopidogrel, and degradation and configuration transition problem such as easily occurs.In clopidogrel molecule structure containing ester bond and
Chiral carbon, it is clopidogrel acid that Degradation and Transformation is easy to happen under the influence ofs environmental factor such as illumination, pH, humidity etc., and is being prepared
In the process in clopidogrel sulfate tablet, the dextroisomer of clopidogrel is easier to be converted into laevoisomer.Existing report
Show the laevoisomer of clopidogrel almost without the effect of anti-platelet aggregation, and its toxicity is apparently higher than clopidogrel
Dextroisomer, therefore the content of clopidogrel laevoisomer has increased slightly, and just has a great impact to the success of operation, it is close
Cut the life and health for being associated with patient.So the content of laevoisomer and the clopidogrel acid of strict control clopidogrel is control
The important indicator of the quality of production processed.For the problem present on, the prior art uses a variety of methods and attempts to solve.
China Patent Publication No. CN101766573A discloses the preparation process of clopidogrel bisulfate solid preparation, the chlorine
Pyrrole Gray is pre-mixed particle and is made of the superfine silica gel powder of bisulfate clopidogrel and package bisulfate clopidogrel, wherein micro mist
The weight of silica gel is the 0.5-10% of bisulfate clopidogrel weight, and the average grain diameter of bisulfate clopidogrel is 10-100 μm.
Superfine silica gel powder is added in the invention can effectively reduce the bonding situation in punching course, improve final product quality.
The solid composite medicament of bisulfate clopidogrel is disclosed in Chinese patent application CN101721410A, is contained
I crystal bisulfate clopidogrel, Macrogol 6000 and superfine silica gel powder, and the disintegration selected from low-substituted hydroxypropyl cellulose
Agent and filler selected from one or more of microcrystalline cellulose, dextrin and pre-paying starch.Superfine silica gel powder can in the invention
To keep the stabilization of I crystal bisulfate clopidogrel jointly with polyethylene glycol, degradation is protected it from or to II transformation of crystal；Separately
On the one hand, superfine silica gel powder also acts as the effect of antiplastering aid, glidant in the present invention, has well solved viscous in tableting processes
Rush problem.
China Patent Publication No. 1935119 discloses solid pharmaceutical preparation of clopidogrel sulfate and preparation method thereof, this is solid
It joined palmitic acid stearic acid ester of glycerol and superfine silica gel powder in body preparation, be prepared for clopidogrel sulphur by grinding equal increments method
Hydrochlorate, the dextroisomer for being effectively reduced clopidogrel are converted into laevoisomer, with increasing solid pharmaceutical preparation stability
And safety.
In conclusion the technology for solving clopidogrel sulfate stability difference at present mainly adds lubricant or package
Superfine silica gel powder or the mixture with other auxiliary agents are such as added in agent, although can improve the stability of clopidogrel, without basic
Upper solution clopidogrel sulfate degradation and configuration transition problem.
Summary of the invention
In view of the deficiencies of the prior art, the present invention proposes a kind of clopidogrel sulfate solid tablets and preparation method thereof.
It is characterized in that wrapping up clopidogrel sulfate by sodium alginate micro ball, and stable equipped with the modified superfine silica gel powder of trim,ethylchlorosilane
Solid tablet.The clopidogrel sulfate solid tablet is equipped with microcrystalline cellulose, dimension life using bisulfate clopidogrel as main ingredient
Plain E, filler, disintegrating agent, lubricant, sodium alginate micro ball and modified superfine silica gel powder.By to hollow meso-hole structure
Superfine silica gel powder carries out the surface modified processing of trim,ethylchlorosilane, wraps up clopidogrel sulfate using sodium alginate micro ball,
It is mixed with modified superfine silica gel powder, solves clopidogrel in clopidogrel sulfate solid pharmaceutical preparation and be degraded to clopidogrel acid and chlorine
The problem of pyrrole Gray's dextroisomer is converted into laevoisomer, it is ensured that stability of clopidogrel tablet during storage and
Safety in medicine use process makes it more effectively play therapeutic effect；The modification superfine silica gel powder of addition can be with simultaneously
The processing fluidity for increasing substantially clopidogrel sulfate solves the problems, such as the sticking in preparation process, is suitble to industrialized production.
To solve the above problems, the invention adopts the following technical scheme:
A kind of clopidogrel sulfate solid tablet, it is characterized in that clopidogrel sulfate is wrapped up by sodium alginate micro ball,
And the solid tablet stable equipped with the modified superfine silica gel powder of trim,ethylchlorosilane, raw material composition includes: 75 weight of clopidogrel sulfate
Measure part, 20 ~ 50 parts by weight of microcrystalline cellulose, 0.1 ~ 5 parts by weight of vitamin E, 10 ~ 40 parts by weight of filler, sodium alginate micro ball 5
~ 15 parts by weight, trim,ethylchlorosilane modified 1 ~ 10 parts by weight of superfine silica gel powder, 1 ~ 10 parts by weight of disintegrating agent, 1 ~ 10 weight of lubricant
Part, wherein the modified superfine silica gel powder of the trim,ethylchlorosilane is handled by trim,ethylchlorosilane surface modification superfine silica gel powder
Superfine silica gel powder.
The modified superfine silica gel powder of the trim,ethylchlorosilane is hollow meso-hole structure, and partial size is 50 ~ 200nm, aperture is 5 ~
30nm, hollow volume are 70 ~ 80%.
The clopidogrel sulfate is I type bisulfate clopidogrel or II type bisulfate clopidogrel.
The filler is one of fatty ester of maltose, hydroxypropyl-β-cyclodextrin, amylum pregelatinisatum, lactose
Or two kinds of mixture.
The disintegrating agent is that 1:1 ~ 3 form by low-substituted hydroxypropyl cellulose and diatomite in mass ratio.
The lubricant is talcum powder, polyethylene glycol, any one in magnesium stearate.
The present invention further provides a kind of preparation method of clopidogrel sulfate solid tablet, specific preparation steps
Are as follows:
(1) will with the superfine silica gel powder of hollow meso-hole structure be sieved choose 100 ~ 200 mesh, with dispersing agent 1000r/min ~
It is added in dimethylbenzene organic solvent under the mixing speed of 5000r/ min, the mass volume ratio of superfine silica gel powder and organic solvent
For 1:40~80, it is dispersed with stirring 1 ~ 2h, obtains superfine silica gel powder dispersion liquid；80 ~ 120 DEG C are warming up to, trim,ethylchlorosilane is added dropwise,
Continue to stir 2 ~ 4h of meal, filters, cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified superfine silica gel powder；
(2) it weighs clopidogrel sulfate and sodium alginate micro ball crosses 100 ~ 200 meshes, then mixing is stirred in high speed mixing smelting machine
Dispersion is mixed, makes clopidogrel sulfate uniform load in sodium alginate micro ball；
(3) it is proportionally added into microcrystalline cellulose, vitamin E and filler in step (2) to be uniformly mixed, step is added
(1) modified superfine silica gel powder obtained in is uniformly mixed tabletting, and gained tablet grinding and sieving is pelletized；
(4) particle for obtaining step (3) and disintegrating agent and mix lubricant uniformly after direct pressing to get a kind of chlorine pyrrole
Gray's sulfate solid tablet.
Dispersing agent described in above-mentioned steps (1) is selected from sodium polymethacrylate, dodecanol, triethanolamine or nonionic
Any one in type hyper-dispersant YRC；The dosage of dispersing agent is the 0.5 ~ 5% of superfine silica gel powder weight.
The additive amount of trim,ethylchlorosilane described in above-mentioned steps (1) is the 5 ~ 20% of superfine silica gel powder weight.
A kind of clopidogrel sulfate solid tablet of the present invention and preparation method thereof, it is compared with prior art, outstanding
Feature and excellent effect are:
1, the superfine silica gel powder of the surface modified processing of trim,ethylchlorosilane is added in the present invention as clopidogrel sulfuric acid
The stabilizer of salt, it is effective inhibit clopidogrel be degraded to clopidogrel acid and clopidogrel dextroisomer be converted into it is left-handed different
Structure body, it is ensured that the stability of clopidogrel tablet makes it more effectively play therapeutic effect.
2, the modification superfine silica gel powder added in the present invention can increase substantially the processing fluidity of clopidogrel sulfate,
It solves the problems, such as the sticking in preparation process, is suitble to industrialized production.
3, clopidogrel sulfate solid tablet formula of the present invention is reasonable, using sodium alginate micro ball as hydrogen sulfate chlorine pyrrole
The coating agent of Gray, the problem of effectively preventing clopidogrel sulfate from degrading, obtained tablet quality are stablized, reproducibility
It is good.
4, the present invention uses direct tablet compressing method, and simple process is easy to industrialized production, prepared clopidogrel sulfuric acid
Salt solid tablet stability is good.
Specific embodiment
The present invention is explained in detail below in conjunction with specific embodiment, is not restricted to the present invention.It is not departing from
In the case where above method thought of the present invention, the various replacements made according to ordinary skill knowledge and customary means or change
Into should all be included in the protection scope of the present invention.
Embodiment 1
Component proportion:
| Material name | Dosage |
| I type bisulfate clopidogrel | 75 parts by weight (in terms of clopidogrel free alkali) |
| Microcrystalline cellulose | 20 parts by weight |
| Vitamin E | 0.1 parts by weight |
| Fatty ester of maltose | 10 parts by weight |
| Low-substituted hydroxypropyl cellulose | 1 parts by weight |
| Diatomite | 1 parts by weight |
| Talcum powder | 1 parts by weight |
| Sodium alginate micro ball | 5 parts by weight |
| Modified superfine silica gel powder | 1 parts by weight |
Preparation method:
(1) it will be sieved with the superfine silica gel powder of hollow meso-hole structure and choose 100 ~ 200 mesh, disperse with sodium polymethacrylate
Agent is added in dimethylbenzene organic solvent under the mixing speed of 1000r/min ~ 5000r/ min, superfine silica gel powder with it is organic molten
The mass volume ratio of agent is 1:40, is dispersed with stirring 1 ~ 2h, obtains superfine silica gel powder dispersion liquid；120 DEG C are warming up to, trimethyl is added dropwise
Chlorosilane continues to stir meal 2h, filters, cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified superfine silica gel powder；Its
The dosage of middle dispersing agent is the 0.5% of superfine silica gel powder weight, and the additive amount of trim,ethylchlorosilane is the 5% of superfine silica gel powder weight.
(2) it weighs I type bisulfate clopidogrel and sodium alginate micro ball crosses 100 ~ 200 meshes, then mixed in high speed mixing smelting machine
Conjunction is dispersed with stirring, and makes clopidogrel sulfate uniform load in sodium alginate micro ball.
(3) it is proportionally added into microcrystalline cellulose, vitamin E and fatty ester of maltose in step (2) to be uniformly mixed, adds
Enter modified superfine silica gel powder obtained in step (1) and be uniformly mixed tabletting, gained tablet grinding and sieving is pelletized.
(4) particle and low-substituted hydroxypropyl cellulose, diatomite and talcum powder obtained step (3) is straight after mixing
Compacting is connect to get a kind of clopidogrel sulfate solid tablet.
Embodiment 2
Component proportion:
| Material name | Dosage |
| II type bisulfate clopidogrel | 75 parts by weight (in terms of clopidogrel free alkali) |
| Microcrystalline cellulose | 30 parts by weight |
| Vitamin E | 1 parts by weight |
| Hydroxypropyl-β-cyclodextrin | 20 parts by weight |
| Low-substituted hydroxypropyl cellulose | 1 parts by weight |
| Diatomite | 3 parts by weight |
| Polyethylene glycol | 4 parts by weight |
| Sodium alginate micro ball | 8 parts by weight |
| Modified superfine silica gel powder | 3 parts by weight |
Preparation method:
(1) it will be sieved with the superfine silica gel powder of hollow meso-hole structure and choose 100 ~ 200 mesh, exist with dodecanol dispersing agent
It is added in dimethylbenzene organic solvent under the mixing speed of 1000r/min ~ 5000r/ min, superfine silica gel powder and organic solvent
Mass volume ratio is 1:50, is dispersed with stirring 1 ~ 2h, obtains superfine silica gel powder dispersion liquid；100 DEG C are warming up to, trimethylchloro-silicane is added dropwise
Alkane continues to stir meal 3h, filters, cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified superfine silica gel powder；Wherein divide
The dosage of powder is the 2% of superfine silica gel powder weight, and the additive amount of trim,ethylchlorosilane is the 8% of superfine silica gel powder weight.
(2) it weighs II type bisulfate clopidogrel and sodium alginate micro ball crosses 100 ~ 200 meshes, then mixed in high speed mixing smelting machine
Conjunction is dispersed with stirring, and makes clopidogrel sulfate uniform load in sodium alginate micro ball.
(3) microcrystalline cellulose, vitamin E and hydroxypropyl-β-cyclodextrin is proportionally added into in step (2) to be uniformly mixed,
Modified superfine silica gel powder obtained in step (1) is added and is uniformly mixed tabletting, gained tablet grinding and sieving is pelletized.
(4) particle for obtaining step (3) and low-substituted hydroxypropyl cellulose, diatomite and polyethylene glycol be after mixing
Direct pressing is to get a kind of clopidogrel sulfate solid tablet.
Embodiment 3
Component proportion (clopidogrel content 75mg/ piece):
| Material name | Dosage |
| I type bisulfate clopidogrel | 75 parts by weight (in terms of clopidogrel free alkali) |
| Microcrystalline cellulose | 40 parts by weight |
| Vitamin E | 2 parts by weight |
| Amylum pregelatinisatum | 30 parts by weight |
| Low-substituted hydroxypropyl cellulose | 2 parts by weight |
| Diatomite | 3 parts by weight |
| Magnesium stearate | 6 parts by weight |
| Sodium alginate micro ball | 10 parts by weight |
| Modified superfine silica gel powder | 6 parts by weight |
Preparation method:
(1) it will be sieved with the superfine silica gel powder of hollow meso-hole structure and choose 100 ~ 200 mesh, exist with triethanolamine dispersant
It is added in dimethylbenzene organic solvent under the mixing speed of 1000r/min ~ 5000r/ min, superfine silica gel powder and organic solvent
Mass volume ratio is 1:60, is dispersed with stirring 1 ~ 2h, obtains superfine silica gel powder dispersion liquid；80 DEG C are warming up to, trimethylchloro-silicane is added dropwise
Alkane continues to stir meal 4h, filters, cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified superfine silica gel powder；Wherein divide
The dosage of powder is the 3% of superfine silica gel powder weight, and the additive amount of trim,ethylchlorosilane is the 12% of superfine silica gel powder weight.
(2) it weighs I type bisulfate clopidogrel and sodium alginate micro ball crosses 100 ~ 200 meshes, then mixed in high speed mixing smelting machine
Conjunction is dispersed with stirring, and makes clopidogrel sulfate uniform load in sodium alginate micro ball.
(3) it is proportionally added into microcrystalline cellulose, vitamin E and amylum pregelatinisatum in step (2) to be uniformly mixed, step is added
Suddenly modified superfine silica gel powder obtained in (1) is uniformly mixed tabletting, and gained tablet grinding and sieving is pelletized.
(4) particle for obtaining step (3) and low-substituted hydroxypropyl cellulose, diatomite and magnesium stearate be after mixing
Direct pressing is to get a kind of clopidogrel sulfate solid tablet.
Embodiment 4
Component proportion (clopidogrel content 75mg/ piece):
| Material name | Dosage |
| I type bisulfate clopidogrel | 75 parts by weight (in terms of clopidogrel free alkali) |
| Microcrystalline cellulose | 50 parts by weight |
| Vitamin E | 3 parts by weight |
| Lactose | 40 parts by weight |
| Low-substituted hydroxypropyl cellulose | 2 parts by weight |
| Diatomite | 4 parts by weight |
| Talcum powder | 10 parts by weight |
| Sodium alginate micro ball | 12 parts by weight |
| Modified superfine silica gel powder | 8 parts by weight |
Preparation method:
(1) it will be sieved with the superfine silica gel powder of hollow meso-hole structure and choose 100 ~ 200 mesh, with Non-ionic dispersant
YRC dispersing agent is added in dimethylbenzene organic solvent under the mixing speed of 1000r/min ~ 5000r/ min, superfine silica gel powder with
The mass volume ratio of organic solvent is 1:60, is dispersed with stirring 1 ~ 2h, obtains superfine silica gel powder dispersion liquid；100 DEG C are warming up to, is added dropwise
Trim,ethylchlorosilane continues to stir meal 3h, filters, cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified micro mist
Silica gel；Wherein the dosage of dispersing agent is the 4% of superfine silica gel powder weight, and the additive amount of trim,ethylchlorosilane is superfine silica gel powder weight
15%。
(2) it weighs clopidogrel sulfate and sodium alginate micro ball crosses 100 ~ 200 meshes, then mixing is stirred in high speed mixing smelting machine
Dispersion is mixed, makes clopidogrel sulfate uniform load in sodium alginate micro ball.
(3) it is proportionally added into microcrystalline cellulose, vitamin E and lactose in step (2) to be uniformly mixed, is added step (1)
Obtained in modified superfine silica gel powder be uniformly mixed tabletting, gained tablet grinding and sieving is pelletized.
(4) particle and low-substituted hydroxypropyl cellulose, diatomite and talcum powder obtained step (3) is straight after mixing
Compacting is connect to get a kind of clopidogrel sulfate solid tablet.
Embodiment 5
Component proportion:
| Material name | Dosage |
| II type bisulfate clopidogrel | 75 parts by weight (in terms of clopidogrel free alkali) |
| Microcrystalline cellulose | 50 parts by weight |
| Vitamin E | 5 parts by weight |
| Fatty ester of maltose | 20 parts by weight |
| Lactose | 20 parts by weight |
| Low-substituted hydroxypropyl cellulose | 5 parts by weight |
| Diatomite | 5 parts by weight |
| Talcum powder | 8 parts by weight |
| Sodium alginate micro ball | 15 parts by weight |
| Modified superfine silica gel powder | 10 parts by weight |
Preparation method:
(1) it will be sieved with the superfine silica gel powder of hollow meso-hole structure and choose 100 ~ 200 mesh, exist with triethanolamine dispersant
It is added in dimethylbenzene organic solvent under the mixing speed of 1000r/min ~ 5000r/ min, superfine silica gel powder and organic solvent
Mass volume ratio is 1:80, is dispersed with stirring 1 ~ 2h, obtains superfine silica gel powder dispersion liquid；120 DEG C are warming up to, trimethylchloro-silicane is added dropwise
Alkane continues to stir meal 2h, filters, cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified superfine silica gel powder；Wherein divide
The dosage of powder is the 5% of superfine silica gel powder weight, and the additive amount of trim,ethylchlorosilane is the 20% of superfine silica gel powder weight.
(2) it weighs clopidogrel sulfate and sodium alginate micro ball crosses 100 ~ 200 meshes, then mixing is stirred in high speed mixing smelting machine
Dispersion is mixed, makes clopidogrel sulfate uniform load in sodium alginate micro ball.
(3) microcrystalline cellulose, vitamin E and fatty ester of maltose, lactose mixing are proportionally added into in step (2)
It is even, modified superfine silica gel powder obtained in step (1) is added and is uniformly mixed tabletting, gained tablet grinding and sieving is pelletized.
(4) particle and low-substituted hydroxypropyl cellulose, diatomite and talcum powder obtained step (3) is straight after mixing
Compacting is connect to get a kind of clopidogrel sulfate solid tablet.
Beneficial effects of the present invention are illustrated below by detection.
One, anti-stick to rush effect test
| Tabletting effect | Qualification rate % | |
| Embodiment 1 | Phenomenon is rushed again without viscous, it is unilateral bright and clean | Greater than 98% |
| Embodiment 2 | Phenomenon is rushed again without viscous, it is unilateral bright and clean | Greater than 98% |
| Embodiment 3 | Phenomenon is rushed again without viscous, it is unilateral bright and clean | Greater than 99% |
| Embodiment 4 | Phenomenon is rushed again without viscous, it is unilateral bright and clean | Greater than 99% |
| Embodiment 5 | Phenomenon is rushed again without viscous, it is unilateral bright and clean | Greater than 99% |
| Comparative example | There is sticking phenomenon more than 100 | 95% |
Modified superfine silica gel powder is changed to common superfine silica gel powder in above-mentioned comparative example.By the above test result as it can be seen that the present invention
Formula, which adds modified superfine silica gel powder, can have the function that fine anti-stick punching, and than common superfine silica gel powder anti-stick, to rush effect good.
Two, accelerated stability test
1, Testing index and method
Using ovomucoid bonding spherical silica gel as filler, with acetonitrile -0.01mol/L potassium dihydrogen phosphate (25:
75) be mobile phase, under conditions of 220nm Detection wavelength, carry out accelerate and long-term stable experiment, detection clopidogrel acid and
The content of clopidogrel laevoisomer.The content difference of national regulation, clopidogrel acid and clopidogrel laevoisomer is not
More than 0.2% and 1%.
2, embodiment sample and prior art reference substance testing result
The above test results show that the present invention wraps up clopidogrel sulfate by sodium alginate micro ball, and it is furnished with trimethyl
The modified superfine silica gel powder of chlorosilane can effectively inhibit clopidogrel dextroisomer to be converted into laevoisomer, improve chlorine pyrrole lattice
The stability of thunder, while improving clinical safety.
Claims (8)
1. a kind of clopidogrel sulfate solid tablet, it is characterized in that clopidogrel sulfate is wrapped up by sodium alginate micro ball, and
Equipped with the solid tablet that the modified superfine silica gel powder of trim,ethylchlorosilane is stable, raw material composition includes: 75 weight of clopidogrel sulfate
Part, 20 ~ 50 parts by weight of microcrystalline cellulose, 0.1 ~ 5 parts by weight of vitamin E, 10 ~ 40 parts by weight of filler, sodium alginate micro ball 5 ~
15 parts by weight, trim,ethylchlorosilane modified 1 ~ 10 parts by weight of superfine silica gel powder, 1 ~ 10 parts by weight of disintegrating agent, 1 ~ 10 weight of lubricant
Part, wherein the modified superfine silica gel powder of the trim,ethylchlorosilane is handled by trim,ethylchlorosilane surface modification superfine silica gel powder
Superfine silica gel powder；The modified superfine silica gel powder of the trim,ethylchlorosilane is hollow meso-hole structure, and partial size is 50 ~ 200nm, aperture is 5 ~
30nm, hollow volume are 70 ~ 80%.
2. a kind of clopidogrel sulfate solid tablet according to claim 1, it is characterised in that the clopidogrel
Sulfate is I type bisulfate clopidogrel or II type bisulfate clopidogrel.
3. a kind of clopidogrel sulfate solid tablet according to claim 1, it is characterised in that the filler is
The mixture of one or both of fatty ester of maltose, hydroxypropyl-β-cyclodextrin, amylum pregelatinisatum, lactose.
4. a kind of clopidogrel sulfate solid tablet according to claim 1, it is characterised in that the disintegrating agent by
Low-substituted hydroxypropyl cellulose and diatomite are that 1:1 ~ 3 is formed in mass ratio.
5. a kind of clopidogrel sulfate solid tablet according to claim 1, it is characterised in that the lubricant is
Talcum powder, polyethylene glycol, any one in magnesium stearate.
6. a kind of preparation method of clopidogrel sulfate solid tablet described in claim 1, it is characterised in that specific preparation
Method is as follows:
(1) will with the superfine silica gel powder of hollow meso-hole structure be sieved choose 100 ~ 200 mesh, with dispersing agent 1000r/min ~
It is added in dimethylbenzene organic solvent under the mixing speed of 5000r/min, the mass volume ratio of superfine silica gel powder and organic solvent is
1:40~80 are dispersed with stirring 1 ~ 2h, obtain superfine silica gel powder dispersion liquid；80 ~ 120 DEG C are warming up to, trim,ethylchlorosilane is added dropwise, is continued
2 ~ 4h is stirred, is filtered, is cleaned respectively with acetone, ethyl alcohol, deionized water, be dried to obtain modified superfine silica gel powder；
(2) it weighs clopidogrel sulfate and sodium alginate micro ball crosses 100 ~ 200 meshes, be mixed and divide in high speed mixing smelting machine
It dissipates, makes clopidogrel sulfate uniform load in sodium alginate micro ball；
(3) it is proportionally added into microcrystalline cellulose, vitamin E and filler in step (2) to be uniformly mixed, is added in step (1)
Obtained modification superfine silica gel powder is uniformly mixed tabletting, and gained tablet grinding and sieving is pelletized；
(4) particle for obtaining step (3) and disintegrating agent and mix lubricant uniformly after direct pressing to get a kind of clopidogrel
Sulfate solid tablet.
7. a kind of preparation method of clopidogrel sulfate solid tablet according to claim 6, it is characterised in that step
(1) dispersing agent described in is in sodium polymethacrylate, dodecanol, triethanolamine or Non-ionic dispersant YRC
Any one, dosage is the 0.5 ~ 5% of superfine silica gel powder weight.
8. a kind of preparation method of clopidogrel sulfate solid tablet according to claim 6, it is characterised in that step
(1) additive amount of the trim,ethylchlorosilane described in is the 5 ~ 20% of superfine silica gel powder weight.
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|---|---|---|---|---|
| US6914141B2 (en) * | 2001-11-09 | 2005-07-05 | Bernard Charles Sherman | Clopidogrel bisulfate tablet formulation |
| CN103340834A (en) * | 2013-07-02 | 2013-10-09 | 山东罗欣药业股份有限公司 | Clopidogrel bisulfate composition tablet and preparation method thereof |
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| US6914141B2 (en) * | 2001-11-09 | 2005-07-05 | Bernard Charles Sherman | Clopidogrel bisulfate tablet formulation |
| CN103340834A (en) * | 2013-07-02 | 2013-10-09 | 山东罗欣药业股份有限公司 | Clopidogrel bisulfate composition tablet and preparation method thereof |
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Effective date of registration: 20240416 Address after: 310000, Room 101, Building 20, Yinhai Science and Technology Innovation Center, Xiasha Street, Qiantang District, Hangzhou City, Zhejiang Province Patentee after: Zhejiang Gaozhi Pharmaceutical Technology Co.,Ltd. Country or region after: China Address before: No.1, 12 / F, unit 1, building 1, No.12, Fengcheng 2nd Road, Xi'an Economic and Technological Development Zone, Shaanxi 710000 Patentee before: Xi'an mairuigao Biotechnology Co.,Ltd. Country or region before: China |
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