CN104434932B - Pharmaceutical composition of clopidogrel hydrogen sulfate and acetylsalicylic acid tablet and preparation method thereof - Google Patents
Pharmaceutical composition of clopidogrel hydrogen sulfate and acetylsalicylic acid tablet and preparation method thereof Download PDFInfo
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- CN104434932B CN104434932B CN201410797659.4A CN201410797659A CN104434932B CN 104434932 B CN104434932 B CN 104434932B CN 201410797659 A CN201410797659 A CN 201410797659A CN 104434932 B CN104434932 B CN 104434932B
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- bisulfate clopidogrel
- aspirin
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- clopidogrel
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960001138 acetylsalicylic acid Drugs 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical group OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 title abstract description 6
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 42
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims description 99
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims description 99
- 229960003009 clopidogrel Drugs 0.000 claims description 99
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 58
- 239000002245 particle Substances 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 3
- 235000020985 whole grains Nutrition 0.000 claims description 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 239000000463 material Substances 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 6
- 229960004889 salicylic acid Drugs 0.000 description 6
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 5
- 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 5
- 230000000694 effects Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000008859 change Effects 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000002775 capsule Substances 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960004274 stearic acid Drugs 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- USKPQBRNXDJQGX-CKUXDGONSA-N 2-acetyloxybenzoic acid;methyl (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate;sulfuric acid Chemical compound OS(O)(=O)=O.CC(=O)OC1=CC=CC=C1C(O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl USKPQBRNXDJQGX-CKUXDGONSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PZAGQUOSOTUKEC-UHFFFAOYSA-N acetic acid;sulfuric acid Chemical compound CC(O)=O.OS(O)(=O)=O PZAGQUOSOTUKEC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- -1 acyl salicylic acid Chemical compound 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940085350 aspirin 75 mg Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UXKUODQYLDZXDL-UHFFFAOYSA-N fulminic acid Chemical compound [O-][N+]#C UXKUODQYLDZXDL-UHFFFAOYSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000009363 superior mesenteric artery syndrome Diseases 0.000 description 1
Classifications
-
- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
Abstract
The invention provides a pharmaceutical composition of clopidogrel hydrogen sulfate and an acetylsalicylic acid tablet and a preparation method thereof, belonging to the field of pharmaceutical preparation. According to the pharmaceutical composition of clopidogrel hydrogen sulfate and the acetylsalicylic acid tablet provided by the invention, F-Melt is added into the formula, so that the flowability of materials is improved and the materials are uniformly mixed; and meanwhile, clopidogrel hydrogen sulfate and the acetylsalicylic acid tablet are respectively pressed into double-layer tablets, so that the two components are prevented from interacting, thereby benefiting the safety of clinical medication and the stability in the storage process.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of bisulfate clopidogrel aspirin tablet medicament composition
And preparation method thereof.
Background technology
Bisulfate clopidogrel, chemical entitled 2- (2- chlorphenyls) -2- (6,7- dihydro-thiophenes simultaneously [3,2-c] pyridine -5-
Base) acetate hydrogensulfate, chemical structural formula is：
Clopidogrel is a kind of RA233, optionally suppresses adenosine diphosphate (ADP) (ADP) small with its blood
The activation of the glycoprotein GPlllb/llla compounds of the combination of plate acceptor and secondary ADP mediations, therefore platelet aggregation can be suppressed
Collection.Other activators can also be blocked by discharging the platelet aggregation that ADP causes.
Aspirin and bisulfate clopidogrel all have the effect for suppressing platelet aggregation, Papillary, antiplatelet
Activity is significantly increased, and can be used to treat the disease that platelet aggregation causes, including stability or unstable angina pectoris, angiocarpy
With the disease of cerebrovascular system, its determined curative effect is confirmed in the clinical test in global multiregion, is the acute hat for the treatment of
The choice drug of shape superior mesenteric artery syndrome, the two is made compound preparation, beneficial to clinical practice, increases the compliance of patient.
The compound preparation listing of bisulfate clopidogrel and aspirin is had at present, but both compositions were being contacted
Exist in journey and interact.Aspirin facile hydrolysis generation salicylic acid, soda acid energy catalytic hydrolysis reaction, and hydrogen sulfate chlorine pyrrole lattice
Fulminic acid is stronger, and being contacted with aspirin can accelerate salicylic generation, the influence very big for Clinical practice security presence.Separately
Outward, bisulfate clopidogrel can be degraded into clopidogrel acid or laevoisomer so as to drop in placement process because of the moisture absorption
Low curative effect；Put into practice and also found, sticking is susceptible in preparation process, influence product quality and yield.
Chinese patent (Application No. 00807001.6) discloses a kind of containing acetylsalicylic acid and clopidogrel hydrogensulfate
The unit dosage forms pharmaceutical composition of salt.Be made two kinds of active ingredients using direct compression method or advance comminution granulation by the patent
After grain, direct mixed pressuring plate.As can be seen here, bisulfate clopidogrel and acetylsalicylic acid two kinds of active components can in the presence of what is contacted
Can, impurity, reducing effect or increase side effect are easily produced, bring potential safety hazard to clinical application.
Chinese patent (Application No. 201410357824.4) discloses a kind of sulfated compound clopidogrel hydrogen and A Si
The controlled release preparation of woods, is three layers of osmotic pump controlled release tablet of compound, and label is made up of middle boosting layer and upper and lower two medicine layers, two
Individual medicine layer is respectively bisulfate clopidogrel layer and aspirin layer；Label outsourcing with pellicle, upper and lower two medicine layers position
There is small delivery aperture respectively on the pellicle at the place of putting, so that the speed of Drug controlled release.
Chinese patent (Application No. 200810097686.5) discloses a kind of containing clopidogrel hydrogen sulfate salt tablets and second
The tablet capsule of acyl salicylic acid tablets, by the way that bisulfate clopidogrel and aspirin to be prepared into the tablet of single component respectively,
It is filled in same capsule, then is separated by blank.But obtained capsule is larger, and patient takes compliance
It is poor.
The content of the invention
Regarding to the issue above, the present invention provides a kind of new bisulfate clopidogrel aspirin tablet medicament composition, together
When a kind of preparation method of bisulfate clopidogrel acetylsalicylic acid tablet is provided.
To achieve the above object, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided is double for compound
Synusia, upper and lower two medicine layers are respectively bisulfate clopidogrel layer and aspirin layer.
Further, in the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, hydrogen sulfate chlorine pyrrole
It is 75 that Gray is counted with the mass ratio of aspirin with clopidogrel：75 or 75：100.
Further, hydrogen sulfate chlorine pyrrole in the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided
Gray's layer is made up of bisulfate clopidogrel, mannitol, microcrystalline cellulose and F-Melt；Aspirin layer is by aspirin, micro-
Crystalline cellulose and stearic acid are constituted.
Further, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, per unit preparation
The quality of middle each component is：
Further, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, per unit preparation
The quality of middle each component is:
Preferably, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, it is each in per unit preparation
The quality of component is:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Or, the bisulfate clopidogrel aspirin tablet medicament composition that the present invention is provided, each group in per unit preparation
Point quality be:
Present invention also offers a kind of preparation method of above-mentioned bisulfate clopidogrel aspirin tablet medicament composition, bag
Include following steps：
(1) prepare bisulfate clopidogrel and always mix particle：The bisulfate clopidogrel of recipe quantity, mannitol, crystallite is fine
Dimension element is mixed in adding hopper with the F-Melt of 50% recipe quantity；Dry granulation；Whole grain, sieve number is 24 mesh；Will system
Standby bisulfate clopidogrel particle is added in mixer, adds the F-Melt mixing of surplus, and bisulfate clopidogrel is obtained
Always mix particle；
(2) prepare aspirin and always mix powder：The aspirin of recipe quantity, microcrystalline cellulose and stearic acid are added into hopper
In mixed, prepared aspirin always mix powder；
(3) bisulfate clopidogrel is always mixed particle and aspirin and always mixes two that powder is separately added into bi-layer tablet press
In hopper, compressing tablet.
Bisulfate clopidogrel aspirin tablet medicament composition prepared by the present invention has advantages below：
(1) F-Melt is added in prescription, improves the mobility of material, also can in the case where other lubricants are not used
Ensure the bisulfate clopidogrel well mixed steady quality of layer, and can be disintegrated rapidly, be conducive to the raising of bioavilability；
(2) bisulfate clopidogrel and aspirin are pressed into double-layer tablets respectively, it is to avoid bisulfate clopidogrel with
Aspirin interacts, and is conducive to the stability in the security and storage process of clinical application；
(3) technical scheme that the present invention is provided, efficiently solves the problem of bisulfate clopidogrel particle sticking, improves
Product appearance proterties, product yield is improve, can more meet industrialized production demand.
Specific embodiment
Below in conjunction with test example and embodiment, the present invention is described in further detail, but not to limit of the invention
System, the equivalent of all any this areas made according to the disclosure of invention belongs to protection scope of the present invention.
Embodiment 1：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：
(1) prepare bisulfate clopidogrel and always mix particle：By the bisulfate clopidogrel of 97.875g, 60g mannitol, 60g
Microcrystalline cellulose is mixed in adding hopper with the F-Melt of 2.5g；Dry granulation；Whole grain, sieve number is 24 mesh；Will system
The bisulfate clopidogrel particle for obtaining is added in mixer, adds the F-Melt mixing of 2.5g, bisulfate clopidogrel is obtained total
Mixed particle；
(2) prepare aspirin and always mix powder：By 75g aspirin, the microcrystalline cellulose of 55g and 1.0g stearic acid, plus
Mix in material bin, prepared aspirin always mixes powder；
(3) bisulfate clopidogrel is always mixed particle and aspirin, and always mixed powder is added separately to the two of bi-layer tablet press
In individual hopper, compressing tablet.
Embodiment 2：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 3：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 4：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 5：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 6：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 7：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 8：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 9：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 10：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 11：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 12：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 13：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 14：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 15：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Embodiment 16：Bisulfate clopidogrel aspirin tablet recipe (in terms of 1000)
Preparation method：With embodiment 1.
Comparative formulation：Prepared with reference to the prescription and technique of Chinese patent (Application No. 00807001.6) embodiment 1
Comparative formulation, specification：Bisulfate clopidogrel/aspirin 75mg/75mg.
Test example 1：Quality research is tested
Take the sample of the embodiment of the present invention 1,2,6,7, investigate respectively bisulfate clopidogrel in each embodiment always mix particle with
Aspirin always mixes the mixing uniformity of powder and observes the appearance character and yield situation of tablet, result of the test such as table 1 and table
Shown in 2.
Mixing uniformity investigates method：The upper left corner, the lower right corner and intermediate point in mixer upper surface, the centre in intermediate layer
Point, the lower left corner of lower surface, the upper right corner and intermediate point sampling, determines each sample point bisulfate clopidogrel and A Si respectively
The content of woods, calculates 7 groups of RSD% of assay result.
The embodiment of the present invention of table 1 is investigated with Comparative formulation mixing uniformity
The embodiment of the present invention sample appearance proterties of table 2 is investigated with yield
Yield computing formula：Yield=total tablet weight/inventory × 100%
Result shows, in various embodiments of the present invention sample, bisulfate clopidogrel particle mixes with aspirin granule
Even property investigates RSD% no more than 0.2%, far smaller than the limit of the 2.0% of standard regulation, is well mixed.In tableting processes
In, embodiment of the present invention sample does not occur sticking phenomenon, plain piece complete appearance, any surface finish, and yield more than 85%,
Meet industrialized production requirement.
The influence factor of test example 2 is tested
Take the sample of the embodiment of the present invention 1,2,6,7 and Comparative formulation sample, high temperature (60 DEG C), high humidity (25 DEG C,
RH92.5%), placed 10 days under the conditions of illumination (4500 ± 500LX), carry out relevant material, contain respectively at the 0th day, sampling in 10 days
Amount, dissolution determination, investigate sample quality change situation under these conditions, and result of the test is referring to table 3.
Dissolution rate investigates method：With pH2.0 buffer solutions 1000ml as dissolution medium, according to《Chinese Pharmacopoeia》Version two in 2010
Portion's the second method of annex X C dissolution methods is determined, and when 15 minutes, takes solution in right amount, and sulfuric acid is determined respectively using HPLC methods
The content of clopidogrel hydrogen and aspirin.
The embodiment of the present invention of table 3 compares with Comparative formulation influence factor test mass
Result shows, at 0 day, embodiment of the present invention sample was with Comparative formulation sample size without significant difference, but contrast
The dissolution rate of formulation samples is significantly lower than the present embodiment sample, about material apparently higher than embodiment of the present invention sample.
After placing 10 days under the conditions of the high temperature (60 DEG C), embodiment of the present invention sample dissolution rate, content compared with 0 day,
Generation significant change, clopidogrel acid, laevoisomer and total impurities amount are increased slightly；And Comparative formulation sample salicylic acid,
Clopidogrel acid, laevoisomer and total impurities amount substantially increase, and embodiment of the present invention sample noticeably greater than under the same terms
Relevant amount of substance；Comparative formulation content is decreased obviously, and dissolution rate substantially slows down.
After placing 10 days under the conditions of the high humidity (25 DEG C, RH92.5%), embodiment of the present invention sample size compared with 0 day,
There is no significant change, salicylic acid, clopidogrel acid, laevoisomer and total impurities amount are increased slightly；And Comparative formulation sample
Product salicylic acid, clopidogrel acid, laevoisomer and total impurities amount substantially increase, and the present invention is real noticeably greater than under the same terms
Apply the relevant amount of substance of a sample；Comparative formulation content is decreased obviously, and dissolution rate substantially slows down.
After being placed 10 days under the conditions of illumination (4500 ± 500LX), the embodiment of the present invention is compared with 0 day, and indices are equal
Generation significant change；And Comparative formulation sample salicylic acid, clopidogrel be sour, laevoisomer and total impurities amount substantially increase,
And noticeably greater than under the same terms embodiment of the present invention sample relevant amount of substance；Comparative formulation content is declined slightly.
It can be seen from the results above that embodiment of the present invention sample is significantly better than at aspects such as relevant material, dissolution rates
Comparative formulation sample, stability is significantly improved compared with prior art.
By above-mentioned result of the test, the bisulfate clopidogrel Ah prepared using prescription of the invention and technique
Department's forest tract pharmaceutical composition, adds F-Melt in prescription, improve the mobility of material, is not using the feelings of other lubricants
Also the bisulfate clopidogrel well mixed steady quality of layer is can guarantee that under condition, and can be disintegrated rapidly, be conducive to bioavilability
Raising；Double-layer tablets will be respectively pressed into aspirin powder again after bisulfate clopidogrel granule coating, effectively completely cut off
Contact of the bisulfate clopidogrel with aspirin, it is to avoid interacted between medicine, be conducive to the peace of clinical application
Stability in full property and storage process；And, bisulfate clopidogrel acetylsalicylic acid tablet is prepared using this technique, effectively solve
The problem of clopidogrel sticking, improves product appearance proterties, improves product yield, and can more meet industrialized production will
Ask.
Claims (6)
1. a kind of bisulfate clopidogrel aspirin tablet medicament composition, it is characterised in that the pharmaceutical composition is double compound
Synusia, upper and lower two medicine layers are respectively bisulfate clopidogrel layer and aspirin layer, wherein, bisulfate clopidogrel is with chlorine
It is 75 that pyrrole Gray is counted with the mass ratio of aspirin：75 or 75：100, the quality of each component is in per unit preparation：
Wherein, the preparation method of the bisulfate clopidogrel aspirin tablet medicament composition, comprises the following steps：
(1) prepare bisulfate clopidogrel and always mix particle：By the bisulfate clopidogrel of recipe quantity, mannitol, microcrystalline cellulose
Mixed in adding hopper with the F-Melt of 50% recipe quantity；Dry granulation；Whole grain, sieve number is 24 mesh；By what is prepared
Bisulfate clopidogrel particle is added in mixer, adds the F-Melt mixing of surplus, and prepared bisulfate clopidogrel is always mixed
Particle；
(2) prepare aspirin and always mix powder：Enter during the aspirin of recipe quantity, microcrystalline cellulose and stearic acid are added into hopper
Row mixing, prepared aspirin always mixes powder；
(3) bisulfate clopidogrel is always mixed particle and aspirin and always mixes two hoppers that powder is separately added into bi-layer tablet press
In, compressing tablet.
2. bisulfate clopidogrel aspirin tablet medicament composition according to claim 1, it is characterised in that per unit
The quality of each component is in preparation：
3. bisulfate clopidogrel aspirin tablet medicament composition according to claim 1, it is characterised in that per unit
The quality of each component is in preparation：
4. bisulfate clopidogrel aspirin tablet medicament composition according to claim 1, it is characterised in that per unit
The quality of each component is in preparation：
5. bisulfate clopidogrel aspirin tablet medicament composition according to claim 1, it is characterised in that per unit
The quality of each component is in preparation：
6. bisulfate clopidogrel aspirin tablet medicament composition according to claim 1, it is characterised in that per unit
The quality of each component is in preparation：
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| CN201410797659.4A CN104434932B (en) | 2014-12-18 | 2014-12-18 | Pharmaceutical composition of clopidogrel hydrogen sulfate and acetylsalicylic acid tablet and preparation method thereof |
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| CN201410797659.4A CN104434932B (en) | 2014-12-18 | 2014-12-18 | Pharmaceutical composition of clopidogrel hydrogen sulfate and acetylsalicylic acid tablet and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1359294A (en) * | 1999-04-30 | 2002-07-17 | 圣诺菲-合成实验室公司 | Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel |
| CN101632647A (en) * | 2008-07-21 | 2010-01-27 | 北京迈劲医药科技有限公司 | Preparation method for compound preparation comprising aspirin and alkaline drugs |
| CN201426858Y (en) * | 2009-07-06 | 2010-03-24 | 沈阳亿灵医药科技有限公司 | Clopidogrel hydrogen shlfate and aspirin double-layer tablet |
-
2014
- 2014-12-18 CN CN201410797659.4A patent/CN104434932B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1359294A (en) * | 1999-04-30 | 2002-07-17 | 圣诺菲-合成实验室公司 | Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel |
| CN101632647A (en) * | 2008-07-21 | 2010-01-27 | 北京迈劲医药科技有限公司 | Preparation method for compound preparation comprising aspirin and alkaline drugs |
| CN201426858Y (en) * | 2009-07-06 | 2010-03-24 | 沈阳亿灵医药科技有限公司 | Clopidogrel hydrogen shlfate and aspirin double-layer tablet |
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| CN104434932A (en) | 2015-03-25 |
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