CN107951847A - A kind of clopidogrel hydrogen sulfate tablet and its preparation method and application - Google Patents
A kind of clopidogrel hydrogen sulfate tablet and its preparation method and application Download PDFInfo
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- CN107951847A CN107951847A CN201711160319.0A CN201711160319A CN107951847A CN 107951847 A CN107951847 A CN 107951847A CN 201711160319 A CN201711160319 A CN 201711160319A CN 107951847 A CN107951847 A CN 107951847A
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- Prior art keywords
- hydrogen sulfate
- clopidogrel
- clopidogrel hydrogen
- sulfate tablet
- tablet
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- 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
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
Abstract
The invention discloses a kind of clopidogrel hydrogen sulfate tablet and its preparation method and application, the clopidogrel hydrogen sulfate tablet includes the raw material of following parts by weight：90~100 parts of bisulfate clopidogrel, 100~200 parts of filler, 5~30 parts of disintegrant, 5~30 parts of polyethylene glycol, 5~30 parts of antiplastering aid, the preparation method comprises the following steps：S1, prepare polyglycol solution；S2, after bisulfate clopidogrel, filler and disintegrant are mixed, addition polymerization ethylene glycol solution, softwood processed, then pelletize, dry, whole grain；S3 plus antiplastering aid mixing, tabletting, coating, to obtain the final product；The purposes is that can prevent and treat the circulation disorder of the heart, brain and other arteries caused by the high coherent condition of blood platelet.The advantage of the invention is that：Efficiently reduce sticking and tablet in tableting processes and be disintegrated slow situation, ensure that tableting processes are smooth, main ingredient dissolution is rapid, improve the bioavilability of medicine.
Description
Technical field
The present invention relates to medicament research and development technical field, more particularly to a kind of clopidogrel hydrogen sulfate tablet and preparation method thereof
And purposes.
Background technology
Bisulfate clopidogrel (CAS:135046-48-9), it is the sulfate of clopidogrel, English name Clopidogrel
Hydrogen Sulfate, chemistry are entitled：(s)-α-(2- chlorphenyls) -6,7- dihydro-thiophenes simultaneously [3,2-c] pyridine -5 (4H) second
Sour methyl esters disulfate.Bisulfate clopidogrel is a kind of anti-platelet aggregation agent.The product by French pharmacy corporation Sai Nuofei-
Sanofi-Aventis develops, and is listed first in Britain and the U.S. in 1998, and bisulfate clopidogrel entered China in 2001,
Bisulfate clopidogrel is clinically mainly used for treating acute myocardial infarction AMI, apoplexy and peripheral arterial disease, can reduce artery congee
The generation of sample firm time.
CN102485218A discloses a kind of clopidogrel bisulfate tablet dry granulation preparation method, compressing dry granulation
The shortcomings that：Large-scale production difficulty is larger, and sliver easily occurs for tabletting, and yield rate is low in manufacturing process.CN103284972A is draped over one's shoulders
A kind of clopidogrel hydrogen sulfate tablet and preparation method thereof is revealed, the tablet that this method is prepared by wet granulation technology is deposited
In following problems：3~4h, production time length is pre-dried in auxiliary material；Pelletized using 40% ethanol wet, 40 DEG C~45 DEG C low temperature dry
It is dry, drying time length, low production efficiency.CN105380916A discloses a kind of clopidogrel bisulfate tablet wet granulation preparation side
Method, this method are described as after bisulfate clopidogrel mixes with other auxiliary materials, using polyglycol solution as adhesive, put boiling
Rise spraying granulation in drying machine, reboiling drying, tabletting after mixing.This method is because spray time is longer, in boiling-bed drying
Obtained particle is crisp, and fine powder is more, causes material fluidity in tableting processes to reduce, the tabletting time is also easy to produce sticking feelings when long
Condition.
In conclusion current market sales of clopidogrel hydrogen sulfate tablet is primarily present following deficiency：
(1) poor fluidity：Direct compression of full-powder is difficult to control because of poor fluidity, tablet weight variation；
(2) easy sticking：Bisulfate clopidogrel in process of production, is extremely readily adsorbed in metal surface, is rubbed
Bonding, therefore the extruding of upper low punch and the extruding of punch and mould during tabletting are also easy to produce with extruding so that slice, thin piece bonds rapidly
On the punch and mould of tablet press machine, and it is increasingly severe；
(3) finished dosage form stability is there are problem, this product raw material are sensitive to damp and hot comparison, if production process control is improper,
Raw material is degradable.
Therefore, it is badly in need of providing a kind of efficient, high stability clopidogrel hydrogen sulfate tablet and preparation method thereof.
The content of the invention
The purpose of the present invention is to solve poor fluidity existing in the prior art, easy sticking, finished dosage form stability
The shortcomings that poor, and a kind of clopidogrel hydrogen sulfate tablet proposed and its preparation method and application.
A kind of clopidogrel hydrogen sulfate tablet, includes the raw material of following parts by weight：
Preferably, the clopidogrel hydrogen sulfate tablet includes the raw material of following parts by weight：
Preferably, the filler is at least one of lactose, macro crystalline cellulose, mannitol and starch.
Preferably, the disintegrant is at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
Preferably, the average molecular weight of the polyethylene glycol is 1500~8000, it is further preferred that the polyethylene glycol
Average molecular weight be 4000~6000.
Preferably, the antiplastering aid is any one or a few compounding in stearic acid, silica and rilanit special,
And the particle diameter of adhesive is 75~100 μm.
The invention also provides a kind of preparation method of clopidogrel hydrogen sulfate tablet, comprise the following steps：
S1, mix polyethylene glycol with solvent, obtains polyglycol solution；
Bisulfate clopidogrel, filler and disintegrant, be placed in wet mixing pelletizer by S2, after fully mixing, adds
Enter polyglycol solution, softwood processed, then bisulfate clopidogrel particle is obtained through oscillating granulation, wet granular drying, whole grain；
S3, the bisulfate clopidogrel particle after whole grain mixed with antiplastering aid, tabletting, coating, that is, obtain sulfuric acid
Clopidogrel hydrogen tablet.
Preferably, the solvent is water or ethanol, and the purity of the ethanol is 60%~80%, it is further preferred that institute
The purity for stating ethanol is 70%.
Preferably, the mass concentration of polyethylene glycol is 5%~15% in the polyglycol solution, it is further preferred that
The mass concentration of polyethylene glycol is 10% in the polyglycol solution.
A kind of purposes of clopidogrel hydrogen sulfate tablet proposed by the present invention is gathered for that can prevent and treat because blood platelet is high
The circulation disorder of the heart, brain and other arteries caused by collection state.
Compared with prior art, technical solution of the present invention has the beneficial effect that：
(1) softwood processed, oscillating granulator extruding granulation are first mixed using wet mixing pelletizer, the particle of gained relatively fluidizes
The particle of bed granulation is compact, and fine powder amount is few under same amount of binder, while improving particle flow sex chromosome mosaicism, reduces fine powder
Amount, avoids because of the sticking caused by more than fine powder amount and big friability the problems such as；
(2) present invention prepares solvent using 60~80% ethanol as adhesive, and concentration of alcohol is excessive, and the particle made is fluffy
Pine, fine powder amount is big in follow-up drying process, is unfavorable for tabletting；Concentration of alcohol is too low, and the viscosity of raw material in itself is induced, softwood
It is sticky big, oscillating granulation paste sieve, and low-concentration ethanol water content is big, drying time extends, and it is steady to raw material to increase hygrothermal environment
Qualitatively influence.
(3) present invention is dried using boiling drier, is accelerated drying process, is avoided unfavorable shadow of the hygrothermal environment to product
Ring, improve production efficiency and the stability of product.
(4) particle diameter (D90 of the invention by controlling antiplastering aid：75~100 microns), while anti-adhesion effectiveness is ensured,
Influence of the hydrophobic lubricant to product dissolution is taken into account, the bisulfate clopidogrel particle of not sticking has been prepared.
Using method provided by the invention be made bisulfate clopidogrel particle carry out tabletting, during do not find that sticking is asked
Topic, stability test is carried out to it, the results showed that, degradation material will no more than limit in accelerated stability experiment for the tablet
Ask.
Embodiment
Embodiments of the present invention are illustrated by particular specific embodiment below, those skilled in the art can be by this explanation
Content disclosed by book understands other advantages and effect of the present invention easily.
Before the specific embodiment of the invention is further described, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that the term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, the protection domain being not intended to be limiting of the invention.The test method of actual conditions is not specified in the following example,
Usually according to normal condition, or the condition proposed by according to each manufacturer.
When embodiment provides number range, it should be appreciated that except non-invention is otherwise noted, two ends of each number range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, in the present invention all technologies for using and
Scientific terminology is identical with the normally understood meaning of those skilled in the art of the present technique.Except used in embodiment specific method, equipment,
Outside material, according to grasp of the those skilled in the art to the prior art and the record of the present invention, it can also use and this
Any method, equipment and the material of the similar or equivalent prior art of method, equipment described in inventive embodiments, material come real
The existing present invention.
Embodiment one
Preparation method comprises the following steps：
S1, Macrogol 6000 are mixed with the ethanol that purity is 70%, obtain 10% polyglycol solution；
S2, put bisulfate clopidogrel, microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, Macrogol 6000
In wet granulator, mixing adds 10% polyglycol solution, softwood processed 1 minute, through waving in 5 minutes to after fully mixing
Granulator (20 mesh stainless steels sieve) is pelletized；
S3, wet granular put boiling drier drying, and inlet air temperature is arranged to 60 DEG C, and drying stops to temperature of charge to 40 DEG C
Only heat, discharge, 18 mesh sieve whole grains；
S4, mixed the rilanit special that the bisulfate clopidogrel particle after whole grain and particle diameter are 75 microns, is mixed
Close product and carry out tabletting；
S5, coating, that is, obtain clopidogrel hydrogen sulfate tablet.
Embodiment two
Preparation method comprises the following steps：
S1, Macrogol 4000 are mixed with the ethanol that purity is 60%, obtain 10% polyglycol solution；
S2, put bisulfate clopidogrel, microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, Macrogol 4000
In wet granulator, mixing mixes for 5 minutes to abundant, adds 10% polyglycol solution, softwood processed 1 minute, through waving
Grain machine (20 mesh stainless steels sieve) granulation；
S3, wet granular put boiling drier drying, and inlet air temperature is arranged to 60 DEG C, and drying stops to temperature of charge to 40 DEG C
Only heat, discharge, 18 mesh sieve whole grains；
S4, mixed the rilanit special that the bisulfate clopidogrel particle after whole grain and particle diameter are 100 microns, is mixed
Close product and carry out tabletting；
S5, coating, that is, obtain clopidogrel hydrogen sulfate tablet.
Embodiment three
Preparation method comprises the following steps：
S1, polyethylene glycol 5000 are mixed with the ethanol that purity is 80%, obtain 10% polyglycol solution；
S2, put bisulfate clopidogrel, microcrystalline cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyethylene glycol 5000
In wet granulator, mixing mixes for 5 minutes to abundant, adds 10% polyglycol solution, softwood processed 1 minute, through waving
Grain machine (20 mesh stainless steels sieve) granulation；
S3, wet granular put boiling drier drying, and inlet air temperature is arranged to 60 DEG C, and drying stops to temperature of charge to 40 DEG C
Only heat, discharge, 18 mesh sieve whole grains；
S4, mixed the rilanit special that the bisulfate clopidogrel particle after whole grain and particle diameter are 90 microns, is mixed
Close product and carry out tabletting；
S5, coating, that is, obtain clopidogrel hydrogen sulfate tablet.
(1) it is anti-stick to rush contrast experiment and stripping curve data
In example IV, embodiment five, embodiment six, comparative example one and comparative example two amount of weighing of raw material according to table 1 into
OK, and according to the preparation method identical with embodiment one carry out the preparation of clopidogrel hydrogen sulfate tablet, and record example IV,
The phenomenon of embodiment five, embodiment six, comparative example one and comparative example two in preparation process, the results are shown in Table 1.
Table 1：
The result shows that, when selecting the rilanit special of 75~100 μm of particle diameter as antiplastering aid, it can effectively solve to make by table 1
Sticking problem during standby.
Stripping curve test, specific behaviour are carried out to the clopidogrel hydrogen sulfate tablet prepared in example IV and comparative example one
It is as follows to make step：Tablet samples are taken, according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method, slurry processes)
Regulation, take the tablet and commercial sulfuric acid clopidogrel hydrogen tablet (Plavix) of 6 example IVs and contrast test one respectively,
Under conditions of 37 ± 0.5 DEG C, with 1000ml pH2.0 hydrochloride buffers, (0.2mol/L Klorvess Liquid 250ml, add
0.2mol/L hydrochloric acid solution 65.0ml, are diluted with water to 1000ml) be dissolution medium, rotating speed 50rpm, respectively at 5,10,15,
20th, 30,45,60min samplings, measure absorbance, calculate the stripping quantity of every, be averaged, tie respectively under the wavelength of 240nm
Fruit is shown in Table 2.
Table 2：
| Sample tablet | Example IV | Comparative example one | Plavix |
| 5min | 27.51 | 20.26 | 25.69 |
| 10min | 47.91 | 33.95 | 50.78 |
| 15min | 67.88 | 50.07 | 72.54 |
| 20min | 82.93 | 64.10 | 86.82 |
| 30min | 99.40 | 91.31 | 96.50 |
| 45min | 101.72 | 100.50 | 100.05 |
| 60min | 102.38 | 100.98 | 98.78 |
| F2 values | 74 | 42 |
2 the results show of table：The tablet of example IV is compared with Plavix, and F2 similar factors are up to 74；Contrast test one
Tablet is compared with Plavix, F2 similar factors only 42.Therefore 75 μm of rilanit special is used effectively to be solved as antiplastering aid
Certainly in tableting processes the problem of sticking, and dissolution data and the former similar factors for grinding piece Plavix are preferable, imply that the tablet energy
Reach and the original bioavilability that to grind piece Plavix similar.
(2) accelerated stability test
Comparative example three is pelletized for the ethanol for the use of purity being 40% as adhesive, other raw materials and preparation method are same
Example IV.
The tablet for choosing example IV, embodiment five, embodiment six and comparative example three carries out contrasting detection, reference《China
Pharmacopeia version pharmacopeia two in 2015》The related material detection of clopidogrel bisulfate tablet quality standard, with ovomucin bonded silica
Glue is the chiral chromatographic column (ULTRONES-OVM) of filler；With the potassium dihydrogen phosphate (20 of acetonitrile -0.01mol/L:80)
For mobile phase；Detection wavelength 220nm, carries out accelerated stability test (40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%), point
Not in accelerating impurity content in 1,2,3,6 month sampling detection clopidogrel hydrogen sulfate tablet, clopidogrel impurity I (chlorine is detected
Pyrrole Gray's acid degradation impurity) and the content of clopidogrel impurity III (clopidogrel laevoisomer) must not exceed 0.5% He
1.0%, it the results are shown in Table 3.
Table 3：
3 the results show of table：Clopidogrel bisulfate tablet prepared by example IV, embodiment five and embodiment six accelerates 1 to 6
Impurity I and impurity III are tested within a month in limits, and it is smaller than comparative example three, show：Hydrogen sulfate provided by the invention
Clopidogrel tablet stability is good.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of clopidogrel hydrogen sulfate tablet, it is characterised in that include the raw material of following parts by weight：
A kind of 2. clopidogrel hydrogen sulfate tablet according to claim 1, it is characterised in that the bisulfate clopidogrel
Tablet includes the raw material of following parts by weight：
A kind of 3. clopidogrel hydrogen sulfate tablet according to claim 1, it is characterised in that the filler for lactose,
At least one of macro crystalline cellulose, mannitol and starch.
4. a kind of clopidogrel hydrogen sulfate tablet according to claim 1, it is characterised in that the disintegrant is carboxymethyl
At least one of sodium starch and low-substituted hydroxypropyl cellulose.
5. a kind of clopidogrel hydrogen sulfate tablet according to claim 1, it is characterised in that the polyethylene glycol is averaged
Molecular weight is 1500~8000.
6. a kind of clopidogrel hydrogen sulfate tablet according to claim 1, it is characterised in that the antiplastering aid is tristearin
Any one or a few compounding in acid, silica and rilanit special, and the particle diameter of adhesive is 75~100 μm.
7. a kind of preparation method of clopidogrel hydrogen sulfate tablet, it is characterised in that comprise the following steps：
S1, mix polyethylene glycol with solvent, obtains polyglycol solution；
Bisulfate clopidogrel, filler and disintegrant, be placed in wet mixing pelletizer by S2, after fully mixing, adds poly-
Ethylene glycol solution, softwood processed, then obtain bisulfate clopidogrel particle through oscillating granulation, wet granular drying, whole grain；
S3, the bisulfate clopidogrel particle after whole grain mixed with antiplastering aid, tabletting, coating, that is, obtain hydrogen sulfate chlorine
Pyrrole Gray's tablet.
A kind of 8. preparation method of clopidogrel hydrogen sulfate tablet according to claim 7, it is characterised in that the solvent
For water or ethanol, the purity of the ethanol is 60%~80%.
A kind of 9. preparation method of clopidogrel hydrogen sulfate tablet according to claim 7, it is characterised in that the poly- second
The mass concentration of polyethylene glycol is 5%~15% in glycol solution.
10. a kind of purposes of clopidogrel hydrogen sulfate tablet, it is characterised in that can prevent and treat because of the high aggregation shape of blood platelet
The circulation disorder of the heart, brain and other arteries caused by state.
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| CN201711160319.0A CN107951847A (en) | 2017-11-20 | 2017-11-20 | A kind of clopidogrel hydrogen sulfate tablet and its preparation method and application |
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| CN201711160319.0A CN107951847A (en) | 2017-11-20 | 2017-11-20 | A kind of clopidogrel hydrogen sulfate tablet and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114767642A (en) * | 2022-03-25 | 2022-07-22 | 扬子江药业集团广州海瑞药业有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766573A (en) * | 2010-02-05 | 2010-07-07 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN104490874A (en) * | 2014-12-23 | 2015-04-08 | 北京科莱博医药开发有限责任公司 | I type clopidogrel hydrogen sulfate particles and preparation method thereof as well as I type clopidogrel hydrogen sulfate solid preparation and preparation method thereof |
-
2017
- 2017-11-20 CN CN201711160319.0A patent/CN107951847A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766573A (en) * | 2010-02-05 | 2010-07-07 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN104490874A (en) * | 2014-12-23 | 2015-04-08 | 北京科莱博医药开发有限责任公司 | I type clopidogrel hydrogen sulfate particles and preparation method thereof as well as I type clopidogrel hydrogen sulfate solid preparation and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 孟胜男、胡容峰: "《药剂学》", 31 January 2016, 中国医药科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114767642A (en) * | 2022-03-25 | 2022-07-22 | 扬子江药业集团广州海瑞药业有限公司 | Clopidogrel hydrogen sulfate tablet and preparation method thereof |
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Application publication date: 20180424 |