CN103006599A - Anticoagulant tablet containing sodium chloride medicine carrier and preparation method thereof - Google Patents
Anticoagulant tablet containing sodium chloride medicine carrier and preparation method thereof Download PDFInfo
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- CN103006599A CN103006599A CN2012105878579A CN201210587857A CN103006599A CN 103006599 A CN103006599 A CN 103006599A CN 2012105878579 A CN2012105878579 A CN 2012105878579A CN 201210587857 A CN201210587857 A CN 201210587857A CN 103006599 A CN103006599 A CN 103006599A
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- sodium chloride
- clopidogrel
- tablet
- salt
- clopidogre
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Abstract
The invention relates to an anticoagulant tablet containing a sodium chloride medicine carrier and a preparation method for the tablet, which are suitable for a pharmaceutical enterprise. The disclosed tablet comprises the sodium chloride, clopidogre salt and pharmaceutically acceptable adjuvants. The sodium chloride is stable in property and good in water solubility and compressibility, and is well compatible with the clopidogre salt. The sodium chloride is taken as the carrier for the clopidogre salt; by injecting polyethylene glycol 6000 solution or polyethylene glycol 8000 solution, a medicine is loaded on the sodium chloride and the mixed carrier containing other pharmaceutically acceptable adjuvants of the medicine; the adjuvants, such as a lubricant, are added to mix uniformly, and the mixture is subjected to tabletting and can be molded by compression under a pretty low pressure; by reducing the pressure in the tabletting process, the crystal transformation of the clopidogre, the reduction of the clopidogre content, and the increase of the impurity content can be prevented; and simultaneously, the sticking problem in the tabletting process can be better solved. The tablet prepared by the invention has good stability and is released quickly.
Description
Technical field
The present invention relates to the medical solid tablet, be specifically related to the anticoagulation tablet of sodium chloride-containing pharmaceutical carrier, belong to medical technical field.
Background technology
Clopidogrel (Clopidogrel), chemistry S (+) by name-2-(2-chlorphenyl)-2-(6,7-dihydro-thiophene is [3,2-c] pyridine-5-yl also) methyl acetate, this medicine has significant antiplatelet aggregation and anti-thrombosis function.Clopidogrel is a kind of prodrug of non-activity, becomes active metabolite performance drug effect through liver cell pigment P450 metabolic conversion, combines with its receptor by the inhibition adenosine phosphate and works.At present, the clopidogrel formulations that uses clinically is the tablet of the preparations such as its disulfate, hydrochlorate.France Sai Nuofei (Sanofi) company researched and developed successful bisulfate clopidogrel early than 1986, and commodity are called Plavix (Plavix).This medicine has gone on the market for many years, has obtained preferably clinical evaluation, is widely used at present treating restenosis and thrombotic complications etc. in atheromatosis, acute coronary artery syndrome, the prevention coronary stenting after-poppet.
So far, for the existing more widely research of the preparation of clopidogrel salt, documents and materials disclose the difficulty that mainly there is following three aspects: in preparation clopidogrel oral formulations:
(1) less stable of clopidogrel salt, all responsive to water, acid, alkali and heat, poor with many adjuvant compatibilitys, cause that related substance obviously raises in the preparation storage;
(2) clopidogrel salt easy sticking in pressing process, but raising pressure can improve sticking can cause the transformation of crystal formation and the increase of impurity;
(3) clopidogrel salt dissolubility in water is less, and bad with the compatibility of multiple disintegrating agent, thereby the raising of preparation dissolution rate is limited.
Comprise the ester bond that is easy to be hydrolyzed in the structure of clopidogrel salt, therefore all bad with the high adjuvant compatibility of water content, the acid compatibility strong and adjuvant commonly used of the disulfate of clopidogrel etc. itself is also bad.Tablet ingredients includes clopidogrel or its salt, lactose (Lactis Anhydrous or lactose monohydrate), stearic acid and one or more other pharmaceutically acceptable adjuvant among the EP1970054A2, method is direct powder compression, but ambient humidity must be controlled at below the 30%RH.Also point out to use mannitol or microcrystalline Cellulose can cause sticking in the tabletting process as filler in this patent.The saccharide adjuvant is because containing aldehyde radical, and is unstable under acidic condition, and easily the clopidogrel salt with acidity reacts, thereby makes acidic drug that the medicine color change occur in depositing process, causes content decrease.Point out among the WO2005070464 that clopidogrel and magnesium stearate, polyvinylpyrrolidone or colloid coexistence are easy to degrade.It is better than the thermodynamic stability of crystalline form I to propose crystal form II among the US6429210, and powder is tightr, and a little less than the electrostatic interaction, so the preparation processing performance is good.US6914141B2 screens different lubricants, and result of study shows, replaces with the inconsistent magnesium stearate of clopidogrel better as the clopidogrel tablet stability of lubricant with zinc stearate, stearyl alcohol fumaric acid sodium or stearic acid.WO2005048992 is by adopting hydrophobic auxiliary (such as hydrogenated vegetable oil); and with dry pressing granulate or first dry-pressing again with the polymer coating granule processed method of tabletting then; obtain a kind of stable preparation of tide of meeting, can solve the problem of clopidogrel formulations sticking and poor stability.In fact, this method is owing to adopted the dry pressing granulation, medicine is subject to the elevated pressures extruding, easily turn brilliant, impurity increase, the mixture that EP2359810A2 and CN101690719A propose medicine and pharmacy can be accepted adjuvant mixes with the PEG fused solution, and then cooling curing becomes agglomerate, again fragmentation acquisition granule, and point out that the method can improve the stability of tablet, to solving sticking certain help is arranged also.The shortcoming of the method is in medicine and adjuvant and process that the PEG fused solution mixes, medicine all is in higher temperature (fusing point of PEG) in longer a period of time, the stability of medicine for a long time is influenced by heat, and after the mixed material that contains the PEG fused solution solidifies, needing further brokenly or grind, complicated operation in the actual production, production cycle are long.Although preparation performance, dissolution rate, stability that researcher is all adopted various measures from different perspectives and improved medicine, the problem that can not solve comprehensively all so far that when compacting sticking, preparation dissolution rate are slow, stability and dissolution rate descends in the storage.
Summary of the invention
The purpose of this invention is to provide anticoagulation tablet of a kind of sodium chloride-containing pharmaceutical carrier and preparation method thereof, it can be so that tablet stability be good, it is rapid to discharge.
Technical solution of the present invention is that every chloride pyrrole Gray or its salt 25 ~ 150mg(are in clopidogrel), the weight ratio of sodium chloride is 25%～75%.
More than tablet of the present invention, every preferred weight ratio that contains sodium chloride is 30%～70%.
Tablet of the present invention, clopidogrel pharmaceutically acceptable salt are clopidogrel hydrogenesulphate, clopidogrel hydrochlorate, clopidogrel hydrobromate, clopidogrel benzene sulfonate, clopidogrel Salicylate; But the upper acceptable adjuvant of drug of choice comprises polyethylene glycol 6000, PEG 8000, low-substituted hydroxypropyl cellulose, castor oil hydrogenated, stearic acid.
The preparation method of tablet of the present invention comprises the steps: the polyethylene glycol 6000 of melting or PEG 8000 liquid are sprayed into temperature on the material that 45 ℃ and the following and clopidogrel salt that is kept in motion and sodium chloride and pharmaceutically acceptable adjuvant form by aerodynamic atomization, polyethylene glycol 6000 or PEG 8000 solidify rapidly clopidogrel salt appendix granulation on the carrier of sodium chloride and pharmaceutically acceptable adjuvant composition, then it is even to add mix lubricant, tabletting.
The tablet of the present invention preparation accelerated test under 40 ℃ of RH75% conditions is investigated 6 months, and the result shows that the tablet related substance that the present invention prepares is few, and stripping is rapid.
The present invention uses sodium chloride as major auxiliary burden and the pharmaceutical carrier of this product.Sodium chloride is the highly stable neutral compound of physicochemical property, chemical reaction can not occur with clopidogrel or its salt, and the compatibility is very good; Sodium chloride water content very low (pharmacopeia regulation loss on drying is no more than 0.5%), and at relative humidity under the production environment below 70%, it draws moist also very low, is conducive to keep the stability of clopidogrel formulations.And sodium chloride is soluble in water, is conducive to stripping and the release of clopidogrel or its salt.Sodium chloride is cubic crystal, have very good can molded property, can compression molding under lower pressure, can avoid high pressure to cause the crystal conversion of clopidogrel and the stability decreases that causes thus.The tablet stability that adopts sodium chloride to make as the pharmaceutical carrier of clopidogrel or its salt is very good, does not have the sticking phenomenon in the tabletting process, and preparation discharges very fast.The report that does not prepare at present its tablet to contain sodium chloride as the pharmaceutical carrier of clopidogrel or its salt.
Method of granulating of the present invention does not contact clopidogrel salt with water, organic solvent, all the time be in lower temperature (45 ℃ and following), medicine stability decline, crystal conversion, the sticking of having avoided the factors such as wet, heat, organic solvent, high pressure to cause, and method is simple, the granulating energy consumption is low, pollution-free.
Advantage of the present invention is the characteristic that the clopidogrel salt tablets has good stability and discharges fast, and preparation method is simple to operate, energy consumption is low, and is pollution-free.
The specific embodiment
Below be specific embodiments of the invention, but do not represent that the present invention only limits to following examples.
Embodiment 1
Prescription (in 1000, unit: gram):
Annotate: * bisulfate clopidogrel 33g, 98g, 196g are equivalent to clopidogrel 25g, 75g, 150g.
* Clopidogrel hydrochloride 27.8g is equivalent to clopidogrel 25g.
1. preparation method:
(1) take by weighing polyethylene glycol 6000 by formula ratio, be heated to 68 ~ 72 ℃, be fused into liquid (
).
(2) take by weighing bisulfate clopidogrel, sodium chloride, polyvinylpolypyrrolidone (or polyvinylpolypyrrolidone and hyprolose) mix homogeneously by formula ratio; add in the turbine granulator; open turbine granulator; the control inlet temperature makes the material boiling; temperature also remains on 20 ~ 45 ℃, will (
) slowly be sprayed onto on the material by aerodynamic atomization, sprayed rear discharging, granulate, obtain the clopidogrel granule (
).
(3) take by weighing stearic acid (or castor oil hydrogenated, stearyl alcohol fumaric acid sodium) by formula ratio, with (
) mix homogeneously, tabletting.
Embodiment 2
1. fill a prescription by (1000 meters):
Annotate: * bisulfate clopidogrel 33g, 98g are equivalent to clopidogrel 25g, 75g;
* Clopidogrel hydrochloride 83.5g is equivalent to clopidogrel 75g;
* * benzenesulfonic acid clopidogrel 112.0g is equivalent to clopidogrel 75g.
2. preparation method:
(1) take by weighing PEG 8000 by formula ratio, be heated to 70 ~ 80 ℃, be fused into liquid (
).
(2) take by weighing clopidogrel raw material, sodium chloride, hyprolose, polyvinylpolypyrrolidone mix homogeneously by formula ratio; add in the turbine granulator, open turbine granulator, the control inlet temperature makes the material boiling; temperature also remains on 30 ~ 45 ℃, will (
) slowly be sprayed onto on the material by aerodynamic atomization, sprayed rear discharging granulate, obtain the clopidogrel granule (
).
(3) take by weighing stearic acid (or castor oil hydrogenated, stearyl alcohol fumaric acid sodium) by formula ratio, with (
) mix homogeneously, tabletting.
Embodiment 3The clopidogrel tablet stability is investigated
The tablet of embodiment of the invention prescription 1～8 preparation and listing product P lavix under being 40 ℃, the condition of RH75%, temperature were placed 6 months, carry out accelerated test, that measures clopidogrel mainly contains related substance (hydrolyzate clopidogrel related substance A and laevoisomer clopidogrel related substance C), the results are shown in Table 1.
The related substance of table 1 clopidogrel sheet in 40 ℃ of accelerated tests changes
Annotate: the clopidogrel bisulfate tablet (chloride pyrrole Gray 75mg) that * France Sai Nuofei (Sanofi) company produces
The study on the stability result who placed 6 months under the condition of 40 ℃ of accelerated tests, RH75% shows, formerly grind sheet and in the growth that clopidogrel mainly contains related substance (clopidogrel related substance A and clopidogrel related substance C) obvious difference is arranged from grinding sheet, the more former sheet that grinds of related substance increment of embodiment of the invention prescription 1 ~ 8 tablet significantly reduces, and shows the stability that it is good.
Embodiment 4The dissolution test of clopidogrel sheet
According to dissolution method (2010 editions two appendix X C of Chinese Pharmacopoeia the second method), hydrochloride buffer with pH2.0 (is got 0.2mol/L Klorvess Liquid 250ml, add 0.2mol/L hydrochloric acid solution 65ml, thin up is to 1000ml) 1000ml is dissolution medium, rotating speed is that per minute 50 turns, estimate the dissolving out capability of active component, the results are shown in Table 2.
The dissolution of clopidogrel in the table 2 clopidogrel sheet
Annotate: the clopidogrel bisulfate tablet (chloride pyrrole Gray 75mg) that * France Sai Nuofei (Sanofi) company produces
The dissolution testing result shows that the present invention 1～8 tablet clopidogrel 10min that makes that fills a prescription is leachable more than 70%, and the former Plavix 10min that grinds can only stripping 57.6%, rapidly stripping of clopidogrel in grinding sheet, dissolution rate are obviously faster than listing product P lavix.
Claims (5)
1. the anticoagulation tablet of sodium chloride-containing pharmaceutical carrier is characterized in that containing sodium chloride, clopidogrel salt and pharmaceutically acceptable adjuvant.
2. the anticoagulation tablet of sodium chloride-containing pharmaceutical carrier according to claim 1 is characterized in that containing clopidogrel salt 25 ~ 150mg in every of clopidogrel, and the weight ratio of sodium chloride is 25%～75%.
3. the anticoagulation tablet of sodium chloride-containing pharmaceutical carrier according to claim 2 is characterized in that every weight ratio that contains sodium chloride is 30%～70%.
4. the anticoagulation tablet of sodium chloride-containing pharmaceutical carrier according to claim 1 is characterized in that described clopidogrel salt is bisulfate clopidogrel, Clopidogrel hydrochloride, hydrobromic acid clopidogrel, benzenesulfonic acid clopidogrel, salicylic acid clopidogrel.
5. the preparation method of the anticoagulation tablet of described sodium chloride-containing pharmaceutical carrier according to claim 1, comprise the steps: the polyethylene glycol 6000 of melting or PEG 8000 liquid are sprayed into temperature at 45 ℃ and following and be on the material that dynamic clopidogrel salt and sodium chloride and pharmaceutically acceptable adjuvant form by aerodynamic atomization, polyethylene glycol 6000 or PEG 8000 solidify rapidly clopidogrel salt appendix granulation on the carrier of sodium chloride and pharmaceutically acceptable adjuvant composition, then it is even to add mix lubricant, tabletting.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105878579A CN103006599A (en) | 2012-12-31 | 2012-12-31 | Anticoagulant tablet containing sodium chloride medicine carrier and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105878579A CN103006599A (en) | 2012-12-31 | 2012-12-31 | Anticoagulant tablet containing sodium chloride medicine carrier and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105380916A (en) * | 2015-12-18 | 2016-03-09 | 北京华禧联合科技发展有限公司 | Tablets containing clopidogrel hydrogen sulfate and preparation method thereof |
| CN105616407A (en) * | 2015-12-04 | 2016-06-01 | 深圳信立泰药业股份有限公司 | Clopidogrel hydrogen sulfate solid preparation and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
-
2012
- 2012-12-31 CN CN2012105878579A patent/CN103006599A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105616407A (en) * | 2015-12-04 | 2016-06-01 | 深圳信立泰药业股份有限公司 | Clopidogrel hydrogen sulfate solid preparation and preparation method thereof |
| CN105616407B (en) * | 2015-12-04 | 2016-12-28 | 深圳信立泰药业股份有限公司 | A kind of clopidogrel bisulfate solid preparation and preparation method thereof |
| CN105380916A (en) * | 2015-12-18 | 2016-03-09 | 北京华禧联合科技发展有限公司 | Tablets containing clopidogrel hydrogen sulfate and preparation method thereof |
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Application publication date: 20130403 |