CN117503720A - Clopidogrel bisulfate tablet and preparation method thereof - Google Patents
Clopidogrel bisulfate tablet and preparation method thereof Download PDFInfo
- Publication number
- CN117503720A CN117503720A CN202410002278.6A CN202410002278A CN117503720A CN 117503720 A CN117503720 A CN 117503720A CN 202410002278 A CN202410002278 A CN 202410002278A CN 117503720 A CN117503720 A CN 117503720A
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- China
- Prior art keywords
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- clopidogrel bisulfate
- clopidogrel
- carboxymethyl starch
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- 229960003958 clopidogrel bisulfate Drugs 0.000 title claims abstract description 106
- 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 58
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 229920002472 Starch Polymers 0.000 claims abstract description 123
- 235000019698 starch Nutrition 0.000 claims abstract description 123
- 239000008107 starch Substances 0.000 claims abstract description 123
- 239000011734 sodium Substances 0.000 claims abstract description 83
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 83
- 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 abstract description 80
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 60
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 42
- 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 abstract description 33
- 229930195725 Mannitol Natural products 0.000 claims abstract description 33
- 239000000594 mannitol Substances 0.000 claims abstract description 33
- 235000010355 mannitol Nutrition 0.000 claims abstract description 33
- 239000000126 substance Substances 0.000 claims abstract description 31
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 30
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims abstract description 28
- 229930002330 retinoic acid Natural products 0.000 claims abstract description 28
- 229960001727 tretinoin Drugs 0.000 claims abstract description 28
- 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 claims description 98
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims description 51
- 229960003009 clopidogrel Drugs 0.000 claims description 51
- 238000002156 mixing Methods 0.000 claims description 40
- 239000000203 mixture Substances 0.000 claims description 36
- 238000007873 sieving Methods 0.000 claims description 21
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 claims description 14
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 claims description 14
- 238000000227 grinding Methods 0.000 claims description 12
- 235000015424 sodium Nutrition 0.000 claims description 10
- 238000010298 pulverizing process Methods 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000004584 weight gain Effects 0.000 claims description 2
- 235000019786 weight gain Nutrition 0.000 claims description 2
- 230000007547 defect Effects 0.000 abstract description 5
- 238000004220 aggregation Methods 0.000 abstract description 2
- 230000002776 aggregation Effects 0.000 abstract description 2
- 210000004556 brain Anatomy 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000013543 active substance Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000012535 impurity Substances 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 8
- 238000007865 diluting Methods 0.000 description 7
- 201000001320 Atherosclerosis Diseases 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 6
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- 238000005286 illumination Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
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- 230000002490 cerebral effect Effects 0.000 description 3
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- 238000010812 external standard method Methods 0.000 description 3
- 210000003141 lower extremity Anatomy 0.000 description 3
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- 239000000047 product Substances 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- 108010068370 Glutens Proteins 0.000 description 2
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- 238000003556 assay Methods 0.000 description 2
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- 230000000747 cardiac effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000021312 gluten Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 229960003471 retinol Drugs 0.000 description 2
- 235000020944 retinol Nutrition 0.000 description 2
- 239000011607 retinol Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 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 description 1
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010057469 Vascular stenosis Diseases 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- -1 clopidogrel hydrogen Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- SOJSYOXMFGDLHY-UHFFFAOYSA-N methyl acetate;hydrochloride Chemical compound Cl.COC(C)=O SOJSYOXMFGDLHY-UHFFFAOYSA-N 0.000 description 1
- QYSXFLDJHDDOLS-UHFFFAOYSA-N methyl acetate;sulfuric acid Chemical compound COC(C)=O.OS(O)(=O)=O QYSXFLDJHDDOLS-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 208000031225 myocardial ischemia 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
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to clopidogrel bisulfate tablets and a preparation method thereof. The clopidogrel bisulfate tablet consists of clopidogrel bisulfate, starch, mannitol, carboxymethyl starch sodium, magnesium stearate and retinoic acid. The improved clopidogrel bisulfate tablet has the advantages of greatly improving active substances and being used for preventing and treating heart, brain and other arterial circulatory disorders caused by platelet high aggregation in clinic. Meanwhile, the product overcomes the defect that clopidogrel bisulfate is easy to decompose by visible light, solves the problem of unstable content of clopidogrel bisulfate tablets, improves the stability of clopidogrel bisulfate tablets and reduces the content of related substances.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to clopidogrel bisulfate tablets and a preparation method thereof.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Atherosclerotic thrombi are mixtures of aggregated platelets, erythrocytes, leukocytes, and low density lipoproteins, cholesterol, and triglycerides due to rupture of unstable plaques within the blood vessel. Atherosclerosis is at great risk and needs to be prevented and treated early, and the risk is mainly expressed in the following aspects: 1. thrombosis: atherosclerosis causes damage to vascular endothelial cells, which causes platelet aggregation and activation of clotting factors, forming thrombi. After thrombosis, the blood vessels are blocked, resulting in ischemia and dysfunction of the tissue and organs. 2. Stenosis of blood vessels: atherosclerosis causes thickening, hardening and calcification of the vessel wall, narrowing the vessel lumen and impeding blood flow. This reduces blood supply and affects the functioning of the tissue and organs. 3. Acute myocardial infarction: if atherosclerosis occurs in coronary arteries, myocardial ischemia and hypoxia can be caused, and myocardial infarction can be caused in severe cases. 4. Cerebral apoplexy: if atherosclerosis occurs in cerebral arteries, cerebral vascular stenosis or blockage may occur, causing cerebral stroke. 5. Ischemia of lower limbs: atherosclerosis of the lower extremities can lead to ischemia of the lower extremities, and may cause intermittent claudication, pain, ulcers and the like.
Clopidogrel bisulfate is a platelet aggregation inhibitor, can inhibit platelet aggregation, and is clinically used for mainly preventing and treating heart, brain and other arterial circulatory disorders caused by platelet aggregation. Its effect is mainly expressed in the following aspects: 1. preventing thrombosis: clopidogrel bisulfate can inhibit aggregation of platelets, thereby preventing thrombosis. This is important for preventing the formation of atherosclerotic thrombi. 2. Improving blood circulation: clopidogrel bisulfate can also help to improve blood circulation, as it can prevent thrombosis. This helps to ensure blood supply to the individual organs, preventing the occurrence of ischemia. 3. Reducing the risk of cardiac events: clopidogrel bisulfate can reduce the risk of cardiac events such as myocardial infarction and cerebral apoplexy. This is because it can prevent thrombosis, thereby reducing the likelihood of vessel occlusion.
The original grinding medicine of clopidogrel bisulfate is developed and produced by the Sainofil and has the trade name of 'Brillouin vitamin'. The first time in 1997, bortezomib was marketed in france, and later in europe, asia and multiple countries in north america. In China, boliwei was approved in 1999 and formally marketed in 2001. In addition to the original ground medicine, the Boliwei, there are also a plurality of imitation pharmaceutical brands on the market, such as "Shuaitai" of Le Pu pharmaceutical industry, and "Taijia" of Xindonggang. These simulated drugs are similar to the original drugs in clinical use, but they may differ in terms of production process, impurity content, stability, etc.
The Chinese patent with publication number of CN106137994A discloses a clopidogrel stable tablet and a preparation method thereof, and the clopidogrel is prevented from chiral inversion and degradation caused by high pressure, rapid stamping and high temperature of a punch in dry tabletting by taking aerogel-wheat gluten as a stable carrier of clopidogrel, and the clopidogrel chiral inversion and degradation caused by high pressure, rapid stamping and high temperature of a punch are prevented by virtue of the elastic viscoelastic property and a micro-network structure of the aerogel-wheat gluten, so that the clopidogrel acid content (impurity A) and clopidogrel left-handed isomer (impurity C) in the clopidogrel stable tablet are always kept in a stable range, but the defect that active ingredients are easy to decompose by visible light is not solved.
Chinese patent publication No. CN116115608A discloses a solid preparation containing clopidogrel and a preparation method, the solid preparation comprises a tablet core and a coating layer, the tablet core comprises clopidogrel, an antioxidant, a surfactant, a filler, an adhesive and a disintegrating agent, and the coating layer auxiliary material comprises methacrylic acid-methyl methacrylate copolymer and/or methacrylic acid-ethyl acrylate copolymer. Although it was confirmed in the acceleration test that the impurity A, B, C was controlled, the problem of poor photostability of the solid preparation of clopidogrel was not solved.
Disclosure of Invention
The clopidogrel bisulfate tablet is prepared by optimizing auxiliary materials in the clopidogrel bisulfate tablet, improving the preparation process, overcoming the defect that clopidogrel bisulfate is easy to decompose in the prior art, and providing the clopidogrel bisulfate tablet with stable content and low content of related substances.
The technical scheme of the invention is as follows:
the first object of the invention is to provide a clopidogrel bisulfate tablet which consists of the following components:
25-75 parts of clopidogrel bisulfate,
120-320 parts by weight of starch,
10-25 parts by weight of mannitol,
12-30 parts by weight of carboxymethyl starch sodium,
0.5 to 3 parts by weight of magnesium stearate,
5-8 parts of retinoic acid.
In one embodiment, the clopidogrel hydrogen sulfate tablet consists of the following components:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate,
retinoic acid 7 weight portions.
In one embodiment, the clopidogrel hydrogen sulfate tablet consists of the following components:
75 parts by weight of clopidogrel bisulfate,
240 parts by weight of starch, wherein the starch comprises,
15 parts by weight of mannitol,
20 parts by weight of carboxymethyl starch sodium,
2 parts by weight of magnesium stearate,
retinoic acid 6 weight portions.
In one embodiment, the clopidogrel hydrogen sulfate tablet consists of the following components:
25 parts by weight of clopidogrel bisulfate,
120 parts by weight of starch,
10 parts by weight of mannitol, based on the total weight of the mannitol,
12 parts by weight of carboxymethyl starch sodium,
0.5 part by weight of magnesium stearate,
retinoic acid 5 weight portions.
In one embodiment, the clopidogrel hydrogen sulfate tablet consists of the following components:
75 parts by weight of clopidogrel bisulfate,
320 parts by weight of starch,
25 parts by weight of mannitol,
30 parts by weight of carboxymethyl starch sodium,
3 parts by weight of magnesium stearate,
retinoic acid 8 weight portions.
Furthermore, the clopidogrel bisulfate tablet can be coated, the coating material is opard, and the coating weight gain is 1.5% -3.5%.
A second object of the present invention is to provide a method for preparing the clopidogrel hydrogen sulfate tablet, which comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/4-1/2, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain a retinoic acid-carboxymethyl starch sodium mixture for later use;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
Further, the weight of the carboxymethyl starch sodium in the step (1) is 1/3 of the prescription amount.
Compared with the prior art, the invention has the beneficial effects that:
the invention improves the formula of clopidogrel bisulfate tablet, optimizes auxiliary materials, adds retinoic acid in a certain proportion in the formula, improves the preparation method, firstly mixes part of disintegrant sodium carboxymethyl starch with retinoic acid, and then co-grinds the sodium carboxymethyl starch with active ingredient clopidogrel bisulfate, overcomes the defect that clopidogrel bisulfate is easy to decompose in visible light, solves the problem of unstable content of clopidogrel bisulfate, improves the stability of clopidogrel bisulfate tablet and reduces the content of related substances of clopidogrel bisulfate.
Drawings
Fig. 1: clopidogrel bisulfate tablet of examples 1 to 4, clopidogrel bisulfate tablet of comparative examples 1 to 4, and commercially available (national standard words HJ 20171237) are shown in the content change chart of clopidogrel bisulfate in the light test.
Fig. 2: the total content change charts of substances related to the accelerator test of the clopidogrel bisulfate tablet of example 1, the clopidogrel bisulfate tablet of example 2, the clopidogrel bisulfate tablet of comparative example 5 and the clopidogrel bisulfate tablet of comparative example 2.
Fig. 3: examples 3, 4, 8, 3, 4 and 4, and the total content of the substances for the accelerator test.
Fig. 4: structure of clopidogrel impurity I ((+) 2- [ S- (2-aminophenyl) S]-2- (4,5.6.7-tetrahydrothieno [3, 2-c)]Pyridin-5-yl) acetic acid hydrochloride of the formula: c (C) 15 H 15 Cl 2 NO 2 S, molecular weight: 344.26).
Fig. 5: structure of clopidogrel impurity II (±) 2- [ (2-aminophenyl)]-2- (4, 5,6, 7-tetrahydrothieno [2, 3-c)]Pyridin-6-yl) acetic acid methyl ester hydrochloride having the formula: c (C) 16 H 17 Cl 2 NO 2 S, molecular weight: 385.28, R is cis and S is the inverse).
Fig. 6: structure of clopidogrel impurity III ((-) -R-2- [ (2-chlorophenyl)]-2- (4, 5,6, 7-tetrahydrothieno [3, 2-c)]Pyridin-5-yl) acetic acid methyl ester sulfate, formula: c (C) 16 H 18 ClNO 6 S 2 Molecular weight: 419.9).
Detailed Description
The present invention will be further described with reference to examples for the purpose of making the objects and technical aspects of the present invention more apparent, but the scope of the present invention is not limited to these examples, which are only for explaining the present invention. It will be understood by those skilled in the art that variations or equivalent substitutions that do not depart from the spirit of the invention are intended to be included within the scope of the invention. It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
EXAMPLE 1 clopidogrel bisulfate tablet
Prescription:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate,
retinoic acid 7 weight portions.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/3, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain retinoic acid-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
EXAMPLE 2 clopidogrel bisulfate tablet
Prescription:
75 parts by weight of clopidogrel bisulfate,
240 parts by weight of starch, wherein the starch comprises,
15 parts by weight of mannitol,
20 parts by weight of carboxymethyl starch sodium,
2 parts by weight of magnesium stearate,
retinoic acid 6 weight portions.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/3, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain retinoic acid-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
EXAMPLE 3 clopidogrel bisulfate tablet
Prescription:
25 parts by weight of clopidogrel bisulfate,
120 parts by weight of starch,
10 parts by weight of mannitol, based on the total weight of the mannitol,
12 parts by weight of carboxymethyl starch sodium,
0.5 part by weight of magnesium stearate,
retinoic acid 5 weight portions.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/2, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain a retinoic acid-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
EXAMPLE 4 clopidogrel bisulfate tablet
Prescription:
75 parts by weight of clopidogrel bisulfate,
320 parts by weight of starch,
25 parts by weight of mannitol,
30 parts by weight of carboxymethyl starch sodium,
3 parts by weight of magnesium stearate,
retinoic acid 8 weight portions.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/4, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain retinoic acid-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
Examples 5 to 8 clopidogrel bisulfate tablet
Prescription:
the preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/3, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain retinoic acid-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively crushing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with a 80-mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in the step (2), and tabletting to obtain a plain tablet;
(4) Coating the tablet obtained in the step (3) by using an opadry coating material.
Comparative example 1 clopidogrel bisulfate tablet
Prescription:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/3, and sieving with a 80-mesh sieve for standby;
(2) Mixing clopidogrel bisulfate with the carboxymethyl starch sodium in the step (1), and grinding the mixture together to obtain clopidogrel bisulfate-carboxymethyl starch sodium co-ground matter; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel hydrogen sulfate-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
Comparative example 2 clopidogrel bisulfate tablet
Prescription:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate,
7 parts of retinol.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/3, sieving with a 80-mesh sieve, and mixing with retinol to obtain a retinol-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain clopidogrel bisulfate-retinol-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinol-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
Comparative example 3 clopidogrel bisulfate tablet
Prescription:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate,
10 parts by weight of retinoic acid.
The preparation method comprises the following steps:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/3, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain retinoic acid-carboxymethyl starch sodium mixture for standby;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
Comparative example 4 clopidogrel bisulfate tablet
Prescription:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate,
retinoic acid 7 weight portions.
The preparation method comprises the following steps:
mixing clopidogrel bisulfate, carboxymethyl starch sodium, retinoic acid, magnesium stearate, mannitol and starch according to the prescription amount, sieving with a 80-mesh sieve, and tabletting.
Clopidogrel bisulfate tablet quality inspection
The clopidogrel bisulfate tablets of examples 1 to 8 and the clopidogrel bisulfate tablets of comparative examples 1 to 4 were subjected to quality inspection for hardness, friability, appearance and the like, and the results were as follows:
TABLE 1 clopidogrel bisulfate tablet quality inspection
Table 1 shows that the basic quality inspection of clopidogrel bisulfate tablets of examples 1-8 and clopidogrel bisulfate tablets of comparative examples 1-4 is qualified.
Clopidogrel bisulfate tablet content determination in illumination test
Clopidogrel bisulfate content is measured by high performance liquid chromatography (general rule 0512) according to Chinese pharmacopoeia 2020 edition. The specific method comprises the following steps: test solution: taking 20 tablets of the product, precisely weighing, grinding, precisely weighing a proper amount (about 75mg equivalent to clopidogrel), placing into a 100ml measuring flask, adding 50ml of methanol, carrying out ultrasound for about 5 minutes to dissolve clopidogrel bisulfate, cooling, diluting to a scale with methanol, shaking uniformly, filtering, precisely weighing 5ml of continuous filtrate, placing into a 50ml measuring flask, diluting to the scale with a mobile phase, and shaking uniformly. Control solution: taking clopidogrel bisulfate reference substance, precisely weighing, adding a proper amount of methanol to dissolve, and quantitatively diluting with a mobile phase to prepare a solution containing about 0.1mg per 1 ml. The system applicability solution, chromatographic conditions and system applicability requirements are presented in the relevant material section. Assay: precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. Calculated as peak area by the external standard method and multiplied by 0.7660.
Illumination test conditions: clopidogrel bisulfate tablet of examples 1 to 4, clopidogrel bisulfate tablet of comparative examples 1 to 4 and commercially available (national standard character HJ 20171237) are used as test substances, placed in an illumination box with fluorescent lamps, placed under the condition of illumination of 4500 lx.+ -. 500lx for 60 days, sampled on the 0 th day, 10 th day, 20 th day, 30 th day and 60 th day, and the content of clopidogrel bisulfate is detected according to the above method.
Fig. 1 is a graph showing the content change of clopidogrel bisulfate in an illumination test of examples 1-4 clopidogrel bisulfate, comparative examples 1-4 clopidogrel bisulfate and commercial products (national standard words of medicine HJ 20171237), and the results show that the clopidogrel bisulfate tablet disclosed by the invention has stable content, overcomes the defect that clopidogrel bisulfate is easy to decompose in visible light, and still has stable content in the clopidogrel bisulfate in 60 days of the illumination test.
Content determination of clopidogrel bisulfate tablet related substances in acceleration test
The clopidogrel bisulfate related substances are measured by high performance liquid chromatography (general rule 0512) according to Chinese pharmacopoeia 2020 edition. The specific method comprises the following steps: test solution: taking a proper amount of fine powder (about 75mg equivalent to clopidogrel) under the content measurement item, precisely weighing, placing into a 200ml measuring flask, adding 5ml of methanol, ultrasonically dissolving clopidogrel bisulfate, diluting to a scale with a mobile phase, shaking uniformly, filtering, and taking a subsequent filtrate. Control solution: taking clopidogrel hydrogen sulfate reference substance 10mg, clopidogrel impurity I reference substance 20mg and clopidogrel impurity III reference substance 40mg, precisely weighing, placing into a same 100ml measuring flask, adding methanol for dissolving and diluting to scale, shaking uniformly, precisely measuring 1ml, placing into a 100ml measuring flask, diluting to scale with mobile phase, shaking uniformly. System applicability solution: taking a proper amount of clopidogrel hydrogen sulfate reference substance and clopidogrel impurity II reference substance, adding a proper amount of methanol to dissolve, diluting with a mobile phase to prepare a mixed solution containing 2.5 mug of clopidogrel hydrogen sulfate and 5 mug of clopidogrel impurity II in each 1ml, and shaking uniformly. Chromatographic conditions: chiral chromatographic column (ULTRONES-OVM) with ovomucin-bonded silica gel as filler; acetonitrile-0.01 mol/L potassium dihydrogen phosphate solution (20:80) is taken as a mobile phase; the detection wavelength is 220nm; the sample volume was 10. Mu.l. System applicability requirements: in the system applicability solution chromatogram, the relative retention time of the two optical isomer peaks of clopidogrel impurity II and clopidogrel Lei Feng is about 0.8 and 1.2 respectively; the degree of separation between clopidogrel Lei Feng and the first optical isomer peak of clopidogrel impurity II should be greater than 2.0. Assay: precisely measuring the sample solution and the reference substance solution, respectively injecting into a liquid chromatograph, and recording the chromatograms. Limit: the chromatogram of the sample solution has impurity peaks, the peak area is calculated according to an external standard method, the clopidogrel impurity I is not more than 0.5% of the clopidogrel mark amount, and the clopidogrel impurity III is not more than 1.0% of the clopidogrel mark amount; calculating other single impurities according to a main component external standard method and the peak area, and multiplying the result by 0.766 to obtain 0.2% of the marked quantity of clopidogrel; the sum of the impurities is not 1.5% of the marked amount of clopidogrel (all except clopidogrel impurity II).
Acceleration test conditions: the clopidogrel bisulfate tablets of examples 1 to 4,5 and 8, the clopidogrel bisulfate tablets of comparative examples 1 to 4 and commercially available (national standard code HJ 20171237) are used as test products, and are packaged on the market, and are left for 6 months under the conditions of a temperature of 40+ -2 ℃ and a relative humidity of 75% + -5%, and are sampled at the end of the 0 th month, 1 st month, 3 rd month and 6 th month of the test period, for examination of the content of the related substances.
The term "month 0" in the present invention refers to the day when clopidogrel bisulfate tablet is prepared.
Fig. 2 is a graph showing the total content of the substances involved in the acceleration test of clopidogrel bisulfate, comparative example 1, and comparative example 2 in example 1, example 2, and example 5. Fig. 3 is a graph showing the total content of substances involved in the acceleration test of clopidogrel bisulfate, comparative clopidogrel 4, and commercially available clopidogrel bisulfate in example 3, example 4, example 8. The results show that the clopidogrel hydrogen sulfate tablet has low impurity content, basically does not increase the impurity content in an acceleration test, and has high stability. The results of the accelerated test changes in the content of the clopidogrel bisulfate related substances in example 6 and example 7 of the present invention were similar to those in example 5 and example 8, and the stability was good.
Claims (10)
1. The clopidogrel bisulfate tablet is characterized by comprising the following components:
25-75 parts of clopidogrel bisulfate,
120-320 parts by weight of starch,
10-25 parts by weight of mannitol,
12-30 parts by weight of carboxymethyl starch sodium,
0.5 to 3 parts by weight of magnesium stearate,
5-8 parts of retinoic acid.
2. Clopidogrel hydrogen sulfate tablet according to claim 1, characterized in that it consists of the following components:
25 parts by weight of clopidogrel bisulfate,
260 parts by weight of starch, based on the total weight of the starch,
18 parts by weight of mannitol, based on the total weight of the composition,
22 parts by weight of carboxymethyl starch sodium,
1.5 parts by weight of magnesium stearate,
retinoic acid 7 weight portions.
3. Clopidogrel hydrogen sulfate tablet according to claim 1, characterized in that it consists of the following components:
75 parts by weight of clopidogrel bisulfate,
240 parts by weight of starch, wherein the starch comprises,
15 parts by weight of mannitol,
20 parts by weight of carboxymethyl starch sodium,
2 parts by weight of magnesium stearate,
retinoic acid 6 weight portions.
4. Clopidogrel hydrogen sulfate tablet according to claim 1, characterized in that it consists of the following components:
25 parts by weight of clopidogrel bisulfate,
120 parts by weight of starch,
10 parts by weight of mannitol, based on the total weight of the mannitol,
12 parts by weight of carboxymethyl starch sodium,
0.5 part by weight of magnesium stearate,
retinoic acid 5 weight portions.
5. Clopidogrel hydrogen sulfate tablet according to claim 1, characterized in that it consists of the following components:
75 parts by weight of clopidogrel bisulfate,
320 parts by weight of starch,
25 parts by weight of mannitol,
30 parts by weight of carboxymethyl starch sodium,
3 parts by weight of magnesium stearate,
retinoic acid 8 weight portions.
6. Clopidogrel bisulfate tablet according to claim 1, wherein the clopidogrel bisulfate tablet is further coated.
7. Clopidogrel bisulfate tablet according to claim 6, wherein the coating material is opadry.
8. Clopidogrel bisulfate tablet according to claim 6 or 7, wherein the weight gain of the coating is 1.5% -3.5%.
9. A process for preparing clopidogrel hydrogen sulfate tablet of claim 1, comprising the steps of:
(1) Crushing carboxymethyl starch sodium with the prescription amount of 1/4-1/2, sieving with a 80-mesh sieve, and mixing with retinoic acid to obtain a retinoic acid-carboxymethyl starch sodium mixture for later use;
(2) Mixing clopidogrel bisulfate with the retinoic acid-carboxymethyl starch sodium mixture in the step (1), and grinding the mixture together to obtain a clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance; standby;
(3) Respectively pulverizing the rest carboxymethyl starch sodium, magnesium stearate, mannitol and starch, mixing, sieving with 80 mesh sieve, mixing with clopidogrel bisulfate-retinoic acid-carboxymethyl starch sodium co-ground substance in step (2), and tabletting.
10. The method of claim 9, wherein the weight of sodium carboxymethyl starch in step (1) is 1/3 of the prescribed amount.
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