CN104644595A - Solid pharmaceutical composition with clopidogrel - Google Patents
Solid pharmaceutical composition with clopidogrel Download PDFInfo
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- CN104644595A CN104644595A CN201510102350.3A CN201510102350A CN104644595A CN 104644595 A CN104644595 A CN 104644595A CN 201510102350 A CN201510102350 A CN 201510102350A CN 104644595 A CN104644595 A CN 104644595A
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Abstract
In order to overcome shortcomings of material sticking of a clopidogrel crude drug and hydrolysis of the crude drug in a preparation thereof in storage, the invention designs a solid pharmaceutical composition with clopidogrel and provides a prescription and a process for further preparing the solid pharmaceutical composition into a tablet. The tablet has good forming property and is capable of inhibiting hydrolysis of the crude drug in the process of existence; and unexpectedly, the tablet also inhibits mutarotation of the crude drug. The tablet of the invention is simple in preparation method and can be manufactured by conventional preparation methods without special devices, so that the tablet has the advantages of easy industrialization, high production efficiency, good stability and controllable quality. Thus the solid pharmaceutical composition has outstanding substantive features and obvious inventive steps.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of solid composite medicament containing clopidogrel and its production and use.
Background technology
Cardiovascular and cerebrovascular vessel thrombotic disease is the commonly encountered diseases of China, is also the important cause of the death of our people.China's myocardial infarction average attack rate is about 42 people/100,000 people; And along with the improvement of nutriture, sickness rate shows a rising trend.China is also cerebral thrombosis patient hotspot, current number of patients more than 8,000,000, annual new cases about 1,500,000 people, annual died reaches more than 100 ten thousand, in survivor, the people disability to some extent of about 25%, wherein severe disables up to more than 40%.At present, clopidogrel, aspirin are the mainstream medicine of antithrombotic therapy in cardiovascular and cerebrovascular disease.
Bisulfate clopidogrel (Clopidogrel Bisulfate) is the new drug of French Sai Nuofei-Sheng Delabao company research and development, trade name: Plavix, Plavix.The chemical name of bisulfate clopidogrel is: S (+)-2-(2-chlorphenyl)-2-(4,5,6,7-Tetramethylene sulfide [3,2-c] and pyridine-5)-acetate hydrogensulfate, molecular formula: C16H16ClNO2SH2SO4, molecular weight: 419.90, structural formula is as follows:
Bisulfate clopidogrel is the inhibitor of the platelet aggregation of ADP induction, it passes through the activation of the Glycoprotein G PIIb/IIIa complex optionally suppressing the combination of adenosine diphosphate (ADP) (ADP) and its platelet receptor and ADP subsequently to mediate, thus anticoagulant.The biology of clopidogrel transforms and suppresses to be required for generation platelet.Isolate the active metabolite (Pereillo etc., Drug Metab.Disposition (2002), 30 (11), 1288-1295) of responsible pharmaceutically active.Clopidogrel also by blocking the amplification of the platelet activation caused by the ADP discharged, and suppresses the platelet aggregation of the agonist induction except ADP.Clopidogrel does not suppress the activity of phosphodiesterase.
Clopidogrel hydrogenesulphate is that white is to pale powder.It is water-soluble hardly when neutral pH, dissolves completely when pH is 1.United States Patent (USP) the 4th, 847, No. 265 clopidogrels disclosing dextrorotatory form.
United States Patent (USP) the 7th, 074, No. 928, the 6767th, No. 913, the 6th, 504, No. 030, the 6th, 429, No. 210 and the 6th, 504, No. 030 discloses polymorphic clopidogrel hydrogenesulphate.
United States Patent (USP) the 6th, 858, No. 734, the 6th, 800, No. 759 and the 6th, 737, No. 411 various methods disclosed for the preparation of clopidogrel.
Disclose in No. 20060154957, No. 20060100231, No. 20060074242, No. 20060047121, No. 20060041136, No. 20050256152, No. 20050228012, No. 20050203122, No. 20050143414, No. 20050049275 and No. 20050049226 before the U.S. is authorized and disclose the salt form of clopidogrel, the polymorph of clopidogrel and the method for the preparation of clopidogrel.
Clopidogrel and its preparation method of hydrochloride form is disclosed in No. WO03/66637, international publication.
Clopidogrel hydrochloride is white to rice white or Light yellow crystals powder, especially water insoluble under pH neutral, but under strong acid environment, water soluble.Clopidogrel hydrochloride and the maximum difference of bisulfate clopidogrel are that it does not exist polymorphic problem.The same with bisulfate clopidogrel, S-isomer is its activity form, and it is hydrolyzed in the basic conditions, at high temperature and hydrolyzed under acidic conditions.Toxicologic study show, its safety and disulfate as broad as long.
Clopidogrel is sold with trade name PLAVIX (Sanofi-Aventis) in the U.S. at present.It provides with the tablet form containing 75mg clopidogrel base equivalent, and medicine exists with disulfate form.The antiplatelet drug ratified by FDA (Food and Drug Adminstration), for reducing the atherosclerotic Cardioversion in following patient:
1) there is recent myocardial infarction (MI), in the recent period apoplexy or suffer from the patient of peripheral arterial disease (PAD) medical history that oneself makes a definite diagnosis;
2) there is the patient of acute coronary syndrome (unstable angina pectoris/non-Q ripple MI), comprise and will accept the patient of Drug therapy, and those patients of percutaneous coronary intervention (pci) (percutaneous transluminal coronary angioplasty (PTCA), support, Atherectomy etc.) or coronary bypass grafting (CABG) will be accepted.
PLAVIX is prescription drugs, takes the risk that can contribute to reducing heart disease or apoplexy from now on its every day.
United States Patent (USP) the 5th, 576, No. 328 disclose the method for preventing the ischemic events of secondary after idiopathic ischemic events outbreak by giving clopidogrel.
United States Patent (USP) the 6th, 071, No. 514 disclose the method for the treatment of thrombotic disorders by giving clopidogrel to the patient having this to need.
Carboxylate methyl ester group in bisulfate clopidogrel structure and chiral carbon are wherein known unstable factors, carboxylate methyl ester may be hydrolyzed and form free acid (impurity A), and the chiral inversion of chiral centre also can cause the biological activity generation significant change of medicine.Known clopidogrel has poor chemical stability in the solution.Its degraded is carried out typically via hydrolysis pathway, thus ester-formin is converted into carboxylic acid derivates.
Clopidogrel for hydrolysis stability dependency in pH, when being stored at the temperature of 37 DEG C in 0.1M phosphate buffer, t90 under pH5.6 is about 52.7 days (Drug Metab.Disposition (2000), 28 (12), 1405-1410).
(the R)-enantiomer formed after clopidogrel chiral reversion lacks antithrombotic acitivity and can cause convulsions in animal.
The adjuvant that the clopidogrel bisulfate tablet of U.S. FDA approval listing adopts is respectively: microcrystalline Cellulose, mannitol, hydroxypropyl cellulose, polyethylene glycol 6000, castor oil hydrogenated.This prescription have employed the polyethylene glycol 6000 and castor oil hydrogenated that are of little use in tablet manufacture as lubricant.
But find in practical study process, when application polyethylene glycol 6000 and castor oil hydrogenated prepare clopidogrel bisulfate tablet as lubricant, castor oil hydrogenated tack is not good, can not with other composition mix homogeneously in preparation, thus cause each composition skewness in sheet, affect final quality.
Be the solid preparation, granule and preparation method thereof that refer to a kind of bisulfate clopidogrel in the patent of 200710129305 at publication number.The granule contained in this solid preparation to be the fusing point of bisulfate clopidogrel and cellulose family adjuvant and melting be solid mixture that the binding agent of 50 ~ 86 DEG C formed; The additional adjuvant of granule contains alkalescence lubricant and crospolyvinylpyrrolidone.But this solid preparation and granule thereof are prepared by melt granulation, the method preparation process is complicated, is not the customary preparation methods of solid preparation particularly tablet.
Select suitable diluent also very important when application number is and thinks and prepare clopidogrel bisulfate tablet in EP1970054 European patent, thus disclose and adopt lactose, prepare tablet together with other adjuvants of stearic acid and one or more, and have employed the method for dry granulation, the sticking problem in formulation manufacturing processes is solved with this.
Application number is the preparation technology describing a kind of clopidogrel bisulfate solid preparation in the Chinese patent of 201010106188.X: bisulfate clopidogrel and micropowder silica gel are mixed to form premixing granule, micropowder silica gel is solved the problem of sticking in preparation process with this as antiplastering aid/coverture.
WO2005070464 discloses and adopts the direct compression process clopidogrel overcome in tablet to be degraded to the problem of clopidogrel acid by using castor oil hydrogenated and carboxymethyl starch sodium to share as lubricant; CN1935119A discloses and uses micropowder silica gel and glycerol palmitic, stearic fat as lubricant, can be reduced the generation of clopidogrel laevoisomer by the grinding equivalent method of progressively increasing, and adopts direct compression process to increase stability and the safety of solid preparation; Also have some to adopt zinc stearate, sodium stearyl fumarate to replace magnesium stearate to carry out tabletting as EP1310245 discloses lubricant, prevent clopidogrel from degrading.
In fact, the method of above-mentioned patent all can not solve bisulfate clopidogrel degraded and produced problem aborning completely, in the tablet of bisulfate clopidogrel, activated laevoisomer can be converted into bisulfate clopidogrel dextroisomer (impurity C) and clopidogrel acid (impurity A), the two does not nearly all have the effect of anti-platelet aggregation, and its results of animal display toxicity is significantly higher than bisulfate clopidogrel laevoisomer.Bisulfate clopidogrel is mainly used in the excessive risk operation of heart and intravascular stent clinically, and namely the content of clopidogrel dextroisomer increases, and just have a great impact the success of operation, close association the life and health of patient.The important indicator that the dextroisomer of clopidogrel and the content of clopidogrel acid are production control quality is controlled, in order to the safety of the stability and medication clinically that improve medicine so strict.
As can be seen here, the problem of sticking in clopidogrel hydrogen sulfate tablet process is prepared for solving, and degraded in preparation storing process and mutarotation problem, there has been proposed a lot of solutions, but all there is certain defect, as can not wet granulation, complicated operation, production cost high.
The sticking problem occurred in clopidogrel hydrogen tablet manufacture is solved in the urgent need to opening up new approach in this area, and degraded in preparation storing process and mutarotation problem, to improve finished product stability, ensures product final mass.
Accompanying drawing 1: clopidogrel hydrolysis forms clopidogrel acid (impurity A) schematic diagram.
Accompanying drawing 2: clopidogrel impurity C (isomer) forms schematic diagram.
Summary of the invention
As mentioned above, in order to solve the sticking problem occurred in clopidogrel hydrogen tablet manufacture, and degraded in preparation storing process and mutarotation problem, inventor, through further investigation, finds that the existence of moisture and alkaline matter is the principal element causing clopidogrel to degrade.And obtaining a kind of solid composite medicament containing clopidogrel through further studying, said composition is main component with clopidogrel, comprises filler, disintegrating agent, neutral lubricant, acid stabilizer, coating materials, polishing agent.Said composition can be prepared into tablet as follows further:
1) with dehumidifier, dehumidified in working place;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) clopidogrel is got, filler, acid stabilizer, mix homogeneously, dry granulation;
4) step 3 is got) the dry granule of gained, add disintegrating agent and neutral lubricant, mix homogeneously, tabletting;
5) by step 4) gained tablet, carries out coating, polishing;
It is characterized in that, described clopidogrel is clopidogrel hydrochlorate, and described acid stabilizer is acidic amino acid, and described neutral lubricant is Glyceryl Behenate.
The thinking of this patent is by adding acid stabilizer in the composition, and the mode of moisture in control operation environment and compositions, stablize the ester bond in clopidogrel chemical constitution, make it avoid hydrolysis, form clopidogrel acid (clopidogrel impurity A).Degradation pathway is shown in accompanying drawing 1.
Therefore filler used is the mannitol that maximum water content is only 0.3%.Disintegrating agent used is the polyvinylpolypyrrolidone that maximum water content is only 5%.
Based on same reason, cannot alkaline lubricants be used in the composition, magnesium stearate, and there is the fluidizer silicon dioxide of water suction character, but adopt neutral lubricant Glyceryl Behenate, solve clopidogrel and granulate, the sticking problem in tableting processes.
In order to control the impact of moisture on the compositions in storing process further, employ plain coating tablets, Brazil wax polishing, and two aluminum packs three kinds of technological means.
Brazil wax is formed by the leaf of babassu and leaf bud Hydrolysis kinetics, also claims Ka Naba wax.Bar wax can bleach, matter is hard and crisp, water insoluble, be a kind of firmly, dystectic (82-86 DEG C), glossiness wax.Main component is Palmic acid Cera Flava ester, fatty acid ester, cerinic acid and hydro carbons composition, is made up of (accounting for 84-85%) hexadecanoic acid spermaceti alcohol ester, also has a small amount of dibasic acid esters and hydroxy fatty acid.Saturated hydroxy ester is that ultimate hardness offered as a tribute by Brazil wax, and unsaturated hydroxy ester makes Brazil wax have particularly preferred gloss in glazing polishing.Its main component is hydrophobic combination, and tablet is after carnauba wax polish, and appearance forms one deck waxiness hydrophobic layer, has effectively stopped the impact of the moisture in storing process in environment on tablet.
Coating materials used is take hydroxypropyl emthylcellulose as the common stomach dissolution type coating powder of filmogen, and in order to reduce the impact of coating materials on clopidogrel crude drug in plain sheet, adding mass fraction is wherein that the Pidolidone of 0.5% is as stabilizing agent.
Pidolidone is a kind of acidic amino acid.Molecule includes two carboxyls, and chemical name is alpha-amido 1,3-propanedicarboxylic acid.Pidolidone is a kind of flakey or Powdered crystal, in subacidity, nontoxic.Because Pidolidone is originally as flakey or Powdered crystal, therefore there is certain fluidizer effect, may be used for the mobility increasing material.
Therefore acidic amino acid used is Pidolidone in the present invention, as stabilizing agent, be hydrolyzed in storing process in order to clopidogrel raw material in composite inhibiting, form clopidogrel acid, increase material fluidity as fluidizer.
The further present composition composed as follows:
| Constituent | Specification 1 (unit: g) | Specification 2 (unit: g) |
| Clopidogrel hydrochloride (in clopidogrel) | 25 | 75 |
| Mannitol | 70 | 135 |
| Polyvinylpolypyrrolidone | 6 | 13.5 |
| Pidolidone | 12 | 27 |
| Glyceryl Behenate | 2.4 | 5.4 |
| Coating materials | In right amount | In right amount |
| Brazil wax | In right amount | In right amount |
| Make altogether | 1000 | 1000 |
Preparation technology is as follows:
1) dehumidify to working place with dehumidifier, the humidity that controls environment is less than 20%;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) get recipe quantity and pulverize rear clopidogrel crude drug, mannitol, Pidolidone mix homogeneously, dry granulation, 24 eye mesh screen granulate, must contain clopidogrel dried particles;
4) step 3 is got) gained dried particles, add polyvinylpolypyrrolidone, Glyceryl Behenate, mix homogeneously, tabletting, obtain clopidogrel element sheet;
5) get appropriate Pidolidone, preparation mass fraction is 0.5% aqueous solution, adds common stomach dissolution type coating powder wherein in right amount, preparation coating solution;
6) with step 5) gained coating solution is to step 4) gained clopidogrel element sheet carries out coating, obtains coated tablet;
7) with Brazil wax powder to step 6) gained coated tablet carries out polishing;
8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminum/polrvinyl chloride and aluminium foil (i.e. two aluminum packaging) to step 7) gained tablet packs, and obtains finished product.
Beneficial effect of the present invention is further illustrated by following experiment.
Test an adjuvant compatibility experiments
By Clopidogrel hydrochloride crude drug; Clopidogrel hydrochloride respectively with mannitol, pregelatinized Starch, disintegrating agent polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose mix homogeneously (mass ratio 1:5), respectively with magnesium stearate lubricant, Glyceryl Behenate, acid stabilizer Pidolidone, citric acid and coating materials, mix homogeneously (weight ratio 20:1), put respectively in culture dish and spread out into the thick thin layer of <5mm, sample number into spectrum is respectively A, B, C, D, E, F, G, H, I, J.
Above-mentioned sample is put 40 DEG C respectively, RH≤20%; Illumination 4500Lx ± 500Lx, RH≤20%, places 10 days under intense light conditions, and in the 0th day, the 5th day and sampling in the 10th day, detected clopidogrel, impurity A, impurity C and other impurity contents.Detection data are as shown in the table:
Table 1 clopidogrel and adjuvant compatibility experiments result to be selected (40 DEG C, RH≤20%)
As can be seen from above experimental result, in selected adjuvant, compared with pregelatinized Starch, mannitol can better and clopidogrel compatibility (mannitol water content is less than pregelatinized Starch), compared with cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone can better and clopidogrel compatibility (polyvinylpolypyrrolidone water content is less than cross-linking sodium carboxymethyl cellulose), compared with citric acid, Pidolidone can better and clopidogrel compatibility, compared with magnesium stearate, Glyceryl Behenate can better and clopidogrel compatibility (magnesium stearate be alkalescence, and Glyceryl Behenate is neutral), be embodied in it under above-mentioned two influence factor's conditions, the impurity A produced, total impurities and other maximum lists are mixed all less.
Clopidogrel and disintegrating agent polyvinylpolypyrrolidone, lubricant Glyceryl Behenate, filler mannitol, acid stabilizer Pidolidone and the coating materials compatibility well, can form compositions with above-mentioned adjuvant, and be prepared into solid preparation further under solid states.
Study further through experiment two, determine each component consumption in the composition and the preparation technology of final tablet, as shown in embodiment 1 and embodiment 2.
Experiment two: prescription screening is tested
One obtain clopidogrel and disintegrating agent polyvinylpolypyrrolidone by experiment, lubricant Glyceryl Behenate, filler mannitol, acid stabilizer Pidolidone and the coating materials compatibility good, compositions can be formed with above-mentioned adjuvant under solid states, and be prepared into solid preparation further.
Each supplementary product consumption in this experiment screening composition prescription, for determining the final prescription of tablet, because coating and polishing are operating as routine operation, tablet hardness enough can complete, therefore this experiment is only screened plain tablet recipe.Finally confirmed the reasonability of prescription again by coating and polishing by screening the prescription drawn.
Screening prescription is as follows:
Technique is as follows:
1) dehumidify to working place with dehumidifier, the humidity that controls environment is less than 20%;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) get recipe quantity and pulverize rear clopidogrel crude drug, mannitol, Pidolidone mix homogeneously, dry granulation, 24 eye mesh screen granulate, must contain clopidogrel dried particles;
4) step 3 is got) gained dried particles, add polyvinylpolypyrrolidone, Glyceryl Behenate, mix homogeneously, tabletting, obtain clopidogrel element sheet.
Interpretation:
Pidolidone joins in prescription the effect mainly played and suppress clopidogrel hydrolysis as acid stabilizer, simultaneously due to its laminated structure, may be used for increasing material fluidity, improve the Electrostatic Absorption characteristic of Clopidogrel hydrochloride crude drug, make it avoid adhering to and vessel surface.
Glyceryl Behenate, as neutral lubricant, joins in tablet formulation, main as tablet compression lubricant, avoids the generation of puckery punching in tableting processes.Be simultaneously neutral substance due to it, avoid Clopidogrel hydrochloride crude drug adding the hydrolysis after conventional alkaline magnesium stearate lubricant.
Prescription 1 and prescription 2, owing to adding Pidolidone and Glyceryl Behenate is very few, its material sticks chamber wall is serious, and, even if can sheeting operation be carried out reluctantly, also puckery punching can be there is.
Prescription 3 and prescription 4 increase the consumption of Pidolidone and Glyceryl Behenate, and tablet molding is good, and material no longer adheres to chamber wall simultaneously.
In order to increase the mobility of mixed material, the prescription 4 selecting Pidolidone addition more is as the final prescription of 25mg specification tablet.
Prescription 5 adds polyvinylpolypyrrolidone according to the ratio similar to prescription 4, and Pidolidone and Glyceryl Behenate obtain the result similar to prescription 4.
Prescription 6 increases the consumption of disintegrating agent polyvinylpolypyrrolidone, to obtaining better disintegrate effect.But from experimental result, complete disintegration time improvement is also not obvious, and this prescription formability is good simultaneously.
Prescription 7 and prescription 8 increase the consumption of Pidolidone and Glyceryl Behenate further on the basis of prescription 5, but due to Glyceryl Behenate addition excessive, cause sliver.
To sum up select prescription 5 as the final prescription of 75mg specification tablet.
Respectively coating, polishing and packaging operation are carried out to prescription 4 and prescription 5 two specification tablets, namely obtain embodiment 1 and the agent of embodiment 2 two specification Clopidogrel hydrochloride tablet.
Experiment two: clopidogrel tablet dissolution test
By Chinese Pharmacopoeia 2010 editions II portion second enlarged editions, the dissolution method of clopidogrel tablet, get tablet samples, according to dissolution method (annex XC second method, paddle method) regulation, get and get 6 two specification embodiments 1 and embodiment 2 sample and commercial sulfuric acid clopidogrel hydrogen tablet samples respectively, under the condition of 37 ± 0.5 DEG C, (0.2mol/L Klorvess Liquid 250ml is got with 1000ml pH2.0 hydrochloride buffer, add 0.2mol/L hydrochloric acid solution 65.0mL, be diluted with water to 1000ml) be dissolution medium, rotating speed 50rpm, respectively at 5min, 10min, 15min, 30min, 60min samples, the content of working sample Raw medicine clopidogrel, as shown in the table:
The stripping data of table 1 two specification clopidogrel tablets
| Sample | 5min | 10min | 15min | 30min | 60min |
| 25mg specification embodiment 1 sample | 9.95％ | 37.41％ | 68.02％ | 90.94％ | 93.32％ |
| 75mg specification embodiment 1 sample | 7.39％ | 39.90％ | 64.49％ | 85.60％ | 93.29％ |
| 75mg specification marketed tablet sample | 6.62％ | 33.78％ | 66.37％ | 86.98％ | 94.12％ |
Above-mentioned test proves, the clopidogrel tablet prepared according to prescription of the present invention and technique, and its Dissolution behaviours is similar to commercially available clopidogrel tablet, for the body absorption of clopidogrel medicine and biological utilisation provide strong material base.
Test three: clopidogrel tablet and marketed tablet accelerated stability contrast test
In Example 1 and embodiment 2, two specification clopidogrel tablet samples (containing packaging) and commercial sulfuric acid clopidogrel hydrogen tablet (Plavix) (containing packaging) put 40 DEG C ± 2 DEG C respectively, 24 months are stored under 75% ± 5%RH condition, respectively at 0 month, January, March, June, December, 24 months sampling and measuring relevant natures, obtain corresponding data, as shown in the table:
As can be seen from upper table data, according to the Clopidogrel hydrochloride tablet agent prepared by embodiment 1 of the present invention and embodiment 2 prescription and technique, under acceleration conditions, after within 24 months, storing, its content, related substance changes all to some extent, but content is all more than 99%, the generation of impurity A % is effectively suppressed, maximum only 0.059%, unexpectedly the content of impurity C is inhibited equally, and maximum only 0.064%.
Namely make clopidogrel tablet in storing process by prescription of the present invention and technique, the production of impurity A and impurity C is effectively suppressed, thus the drug quality improved.Simultaneously in the preparation process of tablet, by adding neutral lubricant Glyceryl Behenate, and acid stabilizer Pidolidone, efficiently solve crude drug and adhere to and sticking problem.Thus make the present invention have outstanding substantive distinguishing features and marked improvement, and there is practicality.
Clopidogrel tablet as above, often releases oral formulations as clopidogrel, may be used for prevention acute coronary artery syndrome and apoplexy patient atherothrombosis.
Detailed description of the invention
Beneficial effect of the present invention is further illustrated by following experiment.But be not limited to following embodiment, those skilled in the art does on basis of the present invention, do not depart from the equivalent of flesh and blood of the present invention and substitute or conversion, also all within protection scope of the present invention.
Prepared by embodiment 125mg specification clopidogrel tablet
| Constituent | Consumption (unit: g) |
| Clopidogrel hydrochloride (in clopidogrel) | 25 |
| Mannitol | 70 |
| Polyvinylpolypyrrolidone | 6 |
| Pidolidone | 12 |
| Glyceryl Behenate | 2.4 |
| Coating materials | In right amount |
| Brazil wax | In right amount |
| Sheet heavily about | 120mg |
| Make altogether | 1000 |
Preparation technology is as follows:
1) dehumidify to working place with dehumidifier, the humidity that controls environment is less than 20%;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) get recipe quantity and pulverize rear clopidogrel crude drug, mannitol, Pidolidone mix homogeneously, dry granulation, 24 eye mesh screen granulate, must contain clopidogrel dried particles;
4) step 3 is got) gained dried particles, add polyvinylpolypyrrolidone, Glyceryl Behenate, mix homogeneously, tabletting, obtain clopidogrel element sheet;
5) get appropriate Pidolidone, preparation mass fraction is 0.5% aqueous solution, adds common stomach dissolution type coating powder wherein in right amount, preparation coating solution;
6) with step 5) gained coating solution is to step 4) gained clopidogrel element sheet carries out coating, obtains coated tablet, coating weight gain 2%-4%;
7) with Brazil wax powder to step 6) gained coated tablet carries out polishing, polishing weightening finish 1%-3%;
8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminum/polrvinyl chloride and aluminium foil (i.e. two aluminum packaging) to step 7) gained tablet packs, and obtains finished product.
Prepared by embodiment 275mg specification clopidogrel tablet
| Constituent | Consumption (unit: g) |
| Clopidogrel hydrochloride (in clopidogrel) | 75 |
| Mannitol | 135 |
| Polyvinylpolypyrrolidone | 13.5 |
| Pidolidone | 27 |
| Glyceryl Behenate | 5.4 |
| Coating materials | In right amount |
| Brazil wax | In right amount |
| Sheet heavily about | 270 |
| Make altogether | 1000 |
Preparation technology is as follows:
1) dehumidify to working place with dehumidifier, the humidity that controls environment is less than 20%;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) get recipe quantity and pulverize rear clopidogrel crude drug, mannitol, Pidolidone mix homogeneously, dry granulation, 24 eye mesh screen granulate, must contain clopidogrel dried particles;
4) step 3 is got) gained dried particles, add polyvinylpolypyrrolidone, Glyceryl Behenate, mix homogeneously, tabletting, obtain clopidogrel element sheet;
5) get appropriate Pidolidone, preparation mass fraction is 0.5% aqueous solution, adds common stomach dissolution type coating powder wherein in right amount, preparation coating solution;
6) with step 5) gained coating solution is to step 4) gained clopidogrel element sheet carries out coating, obtains coated tablet, coating weight gain 2%-4%;
7) with Brazil wax powder to step 6) gained coated tablet carries out polishing, polishing weightening finish 1%-3%;
8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminum/polrvinyl chloride and aluminium foil (i.e. two aluminum packaging) to step 7) gained tablet packs, and obtains finished product.
Claims (7)
1. the solid composite medicament containing clopidogrel, said composition is main component with clopidogrel, comprises filler, disintegrating agent, neutral lubricant, acid stabilizer, coating materials, polishing agent.Said composition can be prepared into tablet as follows further:
1) with dehumidifier, dehumidified in working place;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) clopidogrel is got, filler, acid stabilizer, mix homogeneously, dry granulation;
4) step 3 is got) the dry granule of gained, add disintegrating agent and neutral lubricant, mix homogeneously, tabletting;
5) by step 4) gained tablet, carries out coating, polishing;
It is characterized in that, described clopidogrel is clopidogrel hydrochlorate, and described acid stabilizer is acidic amino acid, and described neutral lubricant is Glyceryl Behenate.
2. the solid composite medicament as claimed in claim 1 containing clopidogrel, it is characterized in that described filler is mannitol, disintegrating agent is polyvinylpolypyrrolidone, and described acidic amino acid is Pidolidone, and described polishing agent is Brazil wax.
3. as described in claims 1 containing the solid composite medicament of clopidogrel, it is characterized in that described coating materials is that what add mass fraction 0.5%L-glutamic acid take hydroxypropyl emthylcellulose as the common stomach dissolution type coating powder of filmogen.
4. the solid composite medicament containing clopidogrel as described in claims 1, dehumidify to working place with dehumidifier described in it is characterized in that, its final moisture content is lower than 20%.
5. the solid composite medicament containing clopidogrel as described in claim 1-4, is characterized in that becoming tablet by following formula preparation.
6. the solid composite medicament containing clopidogrel as described in claim 1-4, is characterized in that becoming tablet by following formula preparation.
7. the solid composite medicament containing clopidogrel as described in claim 1-4, is characterized in that becoming tablet by following recipe step.
1) dehumidify to working place with dehumidifier, the humidity that controls environment is less than 20%;
2) get clopidogrel crude drug, micronizing, make particle diameter be less than 25 microns, for subsequent use;
3) get recipe quantity and pulverize rear clopidogrel crude drug, mannitol, Pidolidone mix homogeneously, dry granulation, 24 eye mesh screen granulate, must contain clopidogrel dried particles;
4) step 3 is got) gained dried particles, add polyvinylpolypyrrolidone, Glyceryl Behenate, mix homogeneously, tabletting, obtain clopidogrel element sheet;
5) get appropriate Pidolidone, preparation mass fraction is 0.5% aqueous solution, adds common stomach dissolution type coating powder wherein in right amount, preparation coating solution;
6) with step 5) gained coating solution is to step 4) gained clopidogrel element sheet carries out coating, obtains coated tablet, coating weight gain 2%-4%;
7) with Brazil wax powder to step 6) gained coated tablet carries out polishing, polishing weightening finish 1%-3%;
8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminum/polrvinyl chloride and polrvinyl chloride composite hard sheet (i.e. two aluminum packaging) to step 7) gained tablet packs, and obtains finished product.
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| US11478432B2 (en) | 2018-04-16 | 2022-10-25 | Jiangsu Vcare Pharma Tech Co., Ltd. | Instant release pharmaceutical preparation of anticoagulant and preparation method therefor |
| US11878078B2 (en) | 2018-04-16 | 2024-01-23 | Jiangsu Vcare Pharmatech Co., Ltd. | Instant release pharmaceutical preparation of anticoagulant and preparation method therefor |
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| CN104644595B (en) | 2017-10-24 |
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