CN104644595B - A kind of solid composite medicament containing clopidogrel - Google Patents

Abstract

Shortcoming of the present invention for the contained bulk drug hydrolysis in storing process of clopidogrel bulk drug material sticking and its preparation, devise a kind of solid composite medicament containing clopidogrel, and provide prescription and technique is further prepared into tablet, the tablet compactibility is good, and bulk drug hydrolysis is inhibited during presence, surprisingly, the mutarotation of bulk drug is similarly obtained suppression.Method for preparing tablet thereof of the present invention is simple, can be using customary preparation methods production, without special installation, with easy industrialization, the remarkable advantage such as production efficiency is high, stability is good, quality controllable, with prominent substantive distinguishing features and significant progressive.

Description

A kind of solid composite medicament containing clopidogrel

Technical field

The invention belongs to pharmaceutical technology field, and in particular to a kind of solid composite medicament containing clopidogrel and its system Preparation Method and purposes.

Background technology

Cardiovascular and cerebrovascular thrombotic diseases are the common diseases of China, are also the important cause of the death of our people.China's miocardial infarction Average attack rate is about the people of 42 people/100,000；And with the improvement of nutrition condition, the incidence of disease shows a rising trend.China is also brain Thrombus patient hotspot, current number of patients is more than 8,000,000, and the people of annual new cases about 1,500,000, annual died reaches More than 100 ten thousand, in survivor, about 25% people disability to some extent, wherein severe disable up to more than 40%.Mesh Before, clopidogrel, aspirin are the mainstream medicines of curing thrombus in cardiovascular and cerebrovascular diseases.

Bisulfate clopidogrel (Clopidogrel Bisulfate), is that French Sai Nuofei-Sheng Delabao companies research is opened The new drug of hair, trade name：Plavix, Plavix.The chemical name of bisulfate clopidogrel is：S (+) -2- (2- chlorphenyls) -2- (4,5,6,7- thiophanes [3,2-c] and pyridine -5)-acetate hydrogensulfate, molecular formula：C16H16ClNO2S· H2SO4, molecular weight：419.90, structural formula is as follows：

Bisulfate clopidogrel is the inhibitor of the platelet aggregation of ADP inductions, and it is by optionally suppressing diphosphonic acid The activation of the glycoprotein GPIIb/IIIa compounds of the combination of adenosine (ADP) and its platelet receptor and subsequent ADP mediations, from And suppress platelet aggregation.The bioconversion of clopidogrel suppresses to be required for producing blood platelet.Isolate responsible Active metabolite (Pereillo etc., the Drug Metab.Disposition (2002), 30 (11), 1288- of pharmaceutical activity 1295).Clopidogrel suppresses the excitement in addition to ADP also by blocking the amplification of the platelet activation as caused by the ADP discharged The platelet aggregation of agent induction.Clopidogrel does not suppress the activity of phosphodiesterase.

Clopidogrel hydrogenesulphate is white to pale powder.It is practically insoluble in water in neutral pH, when pH is 1 It is completely dissolved.The clopidogrel that U.S. Patent No. 4,847,265 discloses dextrorotatory form.

U.S. Patent No. 7,074,928, No. 6767,913, No. 6,504,030, No. 6,429,210 and the 6th, No. 504,030 disclose polymorphic clopidogrel hydrogenesulphate.

U.S. Patent No. 6,858,734, No. 6,800,759 and No. 6,737,411 are disclosed for preparing chlorine pyrrole The various methods of Gray.

Disclosed before being authorized in the U.S. No. 20060154957, No. 20060100231, No. 20060074242, the No. 20060047121, No. 20060041136, No. 20050256152, No. 20050228012, the 20050203122nd Number, No. 20050143414, disclose in No. 20050049275 and No. 20050049226 clopidogrel salt form, The polymorph of clopidogrel and the method for preparing clopidogrel.

The clopidogrel and its preparation method of hydrochloride form are disclosed in international publication WO03/66637.

Clopidogrel hydrochloride is white to rice white or Light yellow crystals powder, especially water insoluble under pH neutral, But under strong acid environment, it is water-soluble.The Clopidogrel hydrochloride difference maximum with bisulfate clopidogrel is that it is not deposited In polymorphic problem.The same with bisulfate clopidogrel, S- isomers is its activity form, and it is hydrolyzed in the basic conditions, High temperature and hydrolyzed under acidic conditions.Toxicologic study shows that its security is not different with disulfate.

Clopidogrel is sold in the U.S. with trade name PLAVIX (Sanofi-Aventis) at present.It is to contain 75mg chlorine pyrroles The tablet form of Gray's alkali equivalent is provided, and medicine exists in disulfate form.It is to be ratified by FDA (Food and Drug Adminstration) Antiplatelet drug, for reducing the atherosclerotic Cardioversion in following patient：

1) there is recent myocardial infarction (MI), recent cerebral apoplexy or peripheral arterial disease (PAD) medical history made a definite diagnosis with oneself Patient；

2) there is the patient of acute coronary syndrome (unstable angina pectoris/non-Q ripple MI), including medicine will be received The patient for the treatment of, and will to receive percutaneous coronary intervention (pci) (percutaneous transluminal coronary angioplasty (PTCA), support, dynamic Pulse atherosclerosis resection etc.) or coronary artery bypass grafting (CABG) those patients.

PLAVIX is prescription medicine, and it takes the risk that can help to reduce heart disease from now on or cerebral apoplexy daily.

U.S. Patent No. 5,576,328 is disclosed after the ischemic events breaking-out of primary by giving clopidogrel Method to prevent secondary ischemic events.

U.S. Patent No. 6,071,514 discloses by giving clopidogrel to patient in need to treat thrombus The method of sexual dysfunction.

Carboxylate methyl ester group and chiral carbon therein in bisulfate clopidogrel structure are known destabilizing factors, Carboxylate methyl ester may hydrolyze and form free acid (impurity A), and the chiral inversion of chiral centre also results in the bioactivity of medicine Generation significant changes.Known clopidogrel has the chemical stability of difference in the solution.Its degraded is entered typically via hydrolysis pathway OK, ester-formin is thus converted into carboxylic acid derivates.

Clopidogrel for hydrolysis stability dependency in pH, when being stored in 0.1M phosphate-buffereds at a temperature of 37 DEG C When in agent, the t90 under pH5.6 is about 52.7 days (Drug Metab.Disposition (2000), 28 (12), 1405-1410).

(the R)-enantiomter formed after clopidogrel chiral reversion lacks antithrombotic acitivity and can triggered in animal Faint from fear.

U.S. FDA approval listing clopidogrel bisulfate tablet use auxiliary material be respectively：Microcrystalline cellulose, mannitol, Hydroxypropyl cellulose, Macrogol 6000, rilanit special.The prescription employs the poly- second two being of little use in tablet manufacture Alcohol 6000 and rilanit special are used as lubricant.

But found during practical study, sulfuric acid is prepared as lubricant using Macrogol 6000 and rilanit special During clopidogrel hydrogen piece, rilanit special tack is not good, it is impossible to and the other compositions in preparation are well mixed, so as to cause each Composition skewness in piece, influences final quality.

A kind of solid pharmaceutical preparation of bisulfate clopidogrel, particle are refer in the patent of Publication No. 200710129305 And preparation method thereof.The particle contained in the solid pharmaceutical preparation is bisulfate clopidogrel and cellulose family auxiliary material and the fusing point of melting For the solid mixture of 50~86 DEG C of adhesive formation；The additional auxiliary material of particle contains alkalescent lubricant and crosslinked polyethylene Pyrrolidones.But the solid pharmaceutical preparation and its particle are prepared by melt granulation, this method preparation process is complicated, is not solid The customary preparation methods of preparation particularly tablet.

Suitable diluent is selected when thinking to prepare clopidogrel bisulfate tablet in Application No. EP1970054 European patents Also it is critically important, thus disclose and prepare tablet together using lactose, stearic acid and other one or more kinds of auxiliary materials, and employ The method of dry granulation, the sticking in formulation manufacturing processes is solved the problems, such as with this.

A kind of clopidogrel bisulfate solid preparation is described in Application No. 201010106188.X Chinese patent Preparation technology：Bisulfate clopidogrel and superfine silica gel powder are mixed to form premixing particle, superfine silica gel powder is regard as antiplastering aid/cover Lid agent with this to solve sticking in preparation process the problem of.

WO2005070464 is disclosed to be shared by using rilanit special and sodium carboxymethyl starch and used as lubricant Direct compression method overcomes the clopidogrel in tablet to be degraded to the problem of clopidogrel is sour；CN1935119A, which is disclosed, uses micro mist Silica gel and glycerine palmitic, stearic fat can reduce the left-handed isomery of clopidogrel as lubricant by grinding the equivalent method of progressively increasing The generation of body, increases the stability and security of solid pharmaceutical preparation using direct compression method；More also as EP1310245 is disclosed Lubricant replaces magnesium stearate to carry out tabletting using zinc stearate, sodium stearyl fumarate, prevents clopidogrel from degrading.

In fact, the method for above-mentioned patent can not all be fully solved bisulfate clopidogrel degraded and occur in production Active laevoisomer can be converted into bisulfate clopidogrel dextroisomer in problem, the tablet of bisulfate clopidogrel (impurity C) and clopidogrel acid (impurity A), the two nearly all effect without anti-platelet aggregation, and its zoopery knot Fruit shows that toxicity is significantly higher than bisulfate clopidogrel laevoisomer.Clinically bisulfate clopidogrel be mainly used in heart and In the excessive risk operation of intravascular stent, i.e. the content increase of clopidogrel dextroisomer just has very big to the success of operation Influence, close association the life and health of patient.So strictly control clopidogrel dextroisomer and clopidogrel acid Content is the important indicator for controlling the quality of production, stability and the clinically security of medication to improve medicine.

As can be seen here, the problem of preparing sticking during clopidogrel hydrogen sulfate tablet for solution, and preparation were stored Degraded and mutarotation problem in journey, there has been proposed many solutions, but have certain defect, are such as unable to wet method Granulation, complex operation, production cost height etc..

This area approach new in the urgent need to opening up is asked to solve the sticking occurred in clopidogrel hydrogen tablet manufacture Topic, and the degraded in preparation storing process and mutarotation problem, to improve finished product stability, it is ensured that product final mass.

Accompanying drawing 1：Clopidogrel hydrolyzes to form sour (impurity A) schematic diagram of clopidogrel.

Accompanying drawing 2：Clopidogrel impurity C (isomers) formation schematic diagrames.

The content of the invention

As described above, in order to solve the problems, such as the sticking occurred in clopidogrel hydrogen tablet manufacture, and preparation storage During degraded and mutarotation problem, inventor by further investigation, find moisture and alkaline matter presence be to cause chlorine pyrrole The principal element of Gray's degraded.And a kind of solid composite medicament containing clopidogrel is obtained by further research, should Composition is using clopidogrel as main component, including filler, disintegrant, and neutral lubricant, acid stabilizer, coating agent is beaten Photo etching.Said composition can be further prepared into tablet as follows：

1) operating space is dehumidified with dehumidifier；

2) clopidogrel bulk drug is taken, ultramicro grinding makes particle diameter less than 25 microns, standby；

3) clopidogrel is taken, filler, acid stabilizer is well mixed, dry granulation；

4) step 3 is taken) gained dry particl, disintegrant and neutral lubricant are added, is well mixed, tabletting；

5) by step 4) gained tablet, it is coated, polishing；

Characterized in that, the clopidogrel is clopidogrel hydrochloride, the acid stabilizer is acidic amino acid, institute Neutral lubricant is stated for Compritol 888 ATO.

The thinking of this patent is by adding in the composition in acid stabilizer, and control operation environment and composition Ester bond in the mode of moisture, stable clopidogrel chemical constitution, makes it from hydrolysis, forms the sour (clopidogrel of clopidogrel Impurity A).Degradation pathway is shown in accompanying drawing 1.

Therefore filler used be maximum water content be only 0.3% mannitol.Disintegrant used is only for maximum water content 5% PVPP.

Based on the reason for same, alkaline lubricants cannot be used in the composition, magnesium stearate, and with water imbibition The glidant silica of matter, but neutral lubricant Compritol 888 ATO is used, solve in clopidogrel granulation, tableting processes Sticking problem.

In order to further control influence of the moisture to the composition in storing process, plain piece coating, babassu have been used Wax polishing, and double aluminium pack three kinds of technological means.

Brazil wax is to be formed by the leaf of babassu with leaf bud Hydrolysis kinetics, also referred to as Ka Naba waxes.Bar wax can float In vain, matter is hard and crisp, water insoluble, is a kind of hard, dystectic (82-86 DEG C), glossiness wax.Main component is palmitic acid Beeswax ester, fatty acid ester, cerinic acid and hydro carbons composition, are constituted by hexadecanoic acid spermaceti alcohol ester and (are accounted for 84-85%), and also a small amount of is double Ester and hydroxy fatty acid.Saturated hydroxy ester is that Brazil wax has offered as a tribute ultimate hardness, makes babassu without saturated hydroxy ester Wax has particularly preferred gloss in terms of glazing polishing.Its main component is hydrophobic combination, and tablet is thrown by Brazil wax After light, appearance formation coating of wax matter hydrophobic layer has effectively prevented influence of the moisture in storing process in environment to tablet.

Coating agent used is the common stomach dissolution type coating powder by filmogen of hydroxypropyl methyl cellulose, in order to reduce bag Influence of the clothing agent to clopidogrel bulk drug in plain piece, the Pidolidone that addition mass fraction is 0.5% wherein is used as stable Agent.

Pidolidone, is a kind of acidic amino acid.Intramolecular is containing two carboxyls, and chemical name is alpha-amido glutaric acid.L- Glutamic acid is a kind of flakey or powdered crystal, nontoxic in subacidity.Because Pidolidone sheet is as flakey or powdered Crystal, thus have it is certain help stream to act on, can be used for increasing the mobility of material.

Therefore acidic amino acid used is Pidolidone in the present invention, as stabilizer, to chlorine pyrrole lattice in composite inhibiting Thunder raw material is hydrolyzed in storing process, forms clopidogrel acid, and material fluidity is increased as glidant.

The composition of the further present composition is as follows：

Constituent	(the unit of specification 1：g)	(the unit of specification 2：g)
			Clopidogrel hydrochloride (in terms of clopidogrel)	25	75
Mannitol	70	135
			PVPP	6	13.5
Pidolidone	12	27
			Compritol 888 ATO	2.4	5.4
Coating agent	In right amount	In right amount
			Brazil wax	In right amount	In right amount
It is made altogether	1000	1000

Preparation technology is as follows：

1) operating space is dehumidified with dehumidifier, control ambient humidity is less than 20%；

2) clopidogrel bulk drug is taken, ultramicro grinding makes particle diameter less than 25 microns, standby；

3) clopidogrel bulk drug after recipe quantity crushing is taken, mannitol, Pidolidone is well mixed, dry granulation, 24 mesh Screen cloth whole grain, is obtained containing clopidogrel dry particle；

4) step 3 is taken) gained dry particle, PVPP is added, Compritol 888 ATO is well mixed, tabletting obtains chlorine Pyrrole Gray's plain piece；

5) appropriate Pidolidone is taken, preparation mass fraction is 0.5% aqueous solution, and common stomach dissolution type coating powder is added thereto In right amount, coating solution is prepared；

6) with step 5) gained coating solution to step 4) gained clopidogrel plain piece be coated, obtain coating tablet；

7) with carnauba wax powder foot couple step 6) gained coating tablet progress polishing；

8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminium/polyvinyl chloride and aluminium foil (i.e. double aluminium are packed) to step Rapid 7) gained tablet is packed, and obtains finished product.

Beneficial effects of the present invention are further illustrated by following experiment.

Test an auxiliary material compatibility experiments

By Clopidogrel hydrochloride bulk drug；Clopidogrel hydrochloride respectively with mannitol, pregelatinized starch, disintegrant crosslinking is poly- Ketone is tieed up, Ac-Di-Sol is well mixed (mass ratio 1:5), respectively with magnesium stearate lubricant, Compritol 888 ATO, Acid stabilizer Pidolidone, citric acid and coating agent, well mixed (weight compares 20:1), put in culture dish and spread out into respectively< Thin layer thick 5mm, sample number into spectrum is respectively A, B, C, D, E, F, G, H, I, J.

Above-mentioned sample is put into 40 DEG C, RH≤20% respectively；Illumination 4500Lx ± 500Lx, RH≤20%, intense light conditions decentralization Put 10 days, sampled in the 0th day, the 5th day and the 10th day, detection clopidogrel, impurity A, impurity C and other impurities content.Inspection Survey data as shown in the table：

The clopidogrel of table 1 and auxiliary material compatibility experiments result to be selected (40 DEG C, RH≤20%)

From above experimental result can be seen that selected auxiliary material, compared with pregelatinized starch, mannitol can preferably and Clopidogrel compatibility (mannitol water content is less than pregelatinized starch), compared with Ac-Di-Sol, PVPP Can preferably and clopidogrel compatibility (PVPP water content be less than Ac-Di-Sol), with citric acid phase Can preferably and clopidogrel compatibility, compared with magnesium stearate than, Pidolidone, Compritol 888 ATO can preferably and chlorine Pyrrole Gray compatibility (magnesium stearate for alkalescence, and Compritol 888 ATO for neutrality), be embodied in its above-mentioned two influence because Under the conditions of element, produced impurity A, total impurities and other maximum lists are miscellaneous smaller.

Clopidogrel and disintegrant PVPP, lubricant Compritol 888 ATO, filler mannitol, acid stabilizer Pidolidone and coating agent compatibility are good, compound can be grouped under solid states with above-mentioned auxiliary material, and further make It is standby into solid pharmaceutical preparation.

By the further research of experiment two, it is determined that the preparation work of each component consumption in the composition and final tablet Skill, as shown in embodiment 1 and embodiment 2.

Experiment two：Prescription screening is tested

Clopidogrel and disintegrant PVPP are obtained by experiment one, lubricant Compritol 888 ATO, filler is sweet Reveal alcohol, acid stabilizer Pidolidone and coating agent compatibility are good, can be grouped with above-mentioned auxiliary material under solid states Compound, and it is further prepared into solid pharmaceutical preparation.

Each supplementary product consumption in this experiment screening composition prescription, for determining the final prescription of tablet, due to being coated and beating Light operation is routine operation, and tablet hardness can be completed enough, therefore this experiment is only screened to plain piece prescription.By screening The prescription gone out finally confirms the reasonability of prescription by coating and polishing again.

Screen prescription as follows：

Technique is as follows：

1) operating space is dehumidified with dehumidifier, control ambient humidity is less than 20%；

2) clopidogrel bulk drug is taken, ultramicro grinding makes particle diameter less than 25 microns, standby；

3) clopidogrel bulk drug after recipe quantity crushing is taken, mannitol, Pidolidone is well mixed, dry granulation, 24 mesh Screen cloth whole grain, is obtained containing clopidogrel dry particle；

4) step 3 is taken) gained dry particle, PVPP is added, Compritol 888 ATO is well mixed, tabletting obtains chlorine Pyrrole Gray's plain piece.

Analysis of experimental results：

Pidolidone is added to the effect for being primarily served in prescription and suppressing clopidogrel hydrolysis as acid stabilizer, simultaneously Due to its laminated structure, it can be used for increasing material fluidity, improve the Electrostatic Absorption characteristic of Clopidogrel hydrochloride bulk drug, make It is from adhesion and vessel surface.

Compritol 888 ATO, as neutral lubricant, is added in tablet formulation, is mainly used as tablet compression lubricant, Avoid the generation of the puckery punching in tableting processes.Simultaneously because it is neutral substance, it is to avoid Clopidogrel hydrochloride bulk drug is adding Enter to commonly use the hydrolysis after alkalescence magnesium stearate lubricant.

Prescription 1 and prescription 2, very few due to adding Pidolidone and Compritol 888 ATO, its material sticks chamber wall is serious, Also, even if sheeting operation can be carried out reluctantly, can also occur puckery punching.

Prescription 3 and prescription 4 increase the consumption of Pidolidone and Compritol 888 ATO, and tablet shaping is good, while material No longer adhere to chamber wall.

In order to increase the mobility of mixed material, 25mg gauge sheets are used as from the more prescription 4 of Pidolidone addition The final prescription of agent.

Prescription 5 adds PVPP according to the ratio similar to prescription 4, and Pidolidone and Compritol 888 ATO are obtained The result similar to prescription 4.

Prescription 6 increases the consumption of disintegrant PVPP, to obtain preferably disintegration effect.But tied from experiment Seen on fruit, complete disintegration time improves unobvious, while this prescription formability is good.

Prescription 7 and prescription 8 further increase the consumption of Pidolidone and Compritol 888 ATO on the basis of prescription 5, But it is due to that Compritol 888 ATO addition is excessive, causes sliver.

To sum up selection prescription 5 is used as the final prescription of 75mg specification tablets.

5 two specification tablets of prescription 4 and prescription are coated respectively, polishing and packaging operation, that is, obtain the He of embodiment 1 2 two specification Clopidogrel hydrochloride tablet agent of embodiment.

Experiment two：Clopidogrel tablet dissolution test

By 2010 editions enlarged editions of II portions second of Chinese Pharmacopoeia, the dissolution method of clopidogrel tablet takes tablet samples, According to the regulation of dissolution method (methods of annex XC second, paddle method), take and take 6 two specification embodiments 1 and the sample of embodiment 2 respectively Product and commercial sulfuric acid clopidogrel hydrogen tablet samples, under conditions of 37 ± 0.5 DEG C, with 1000ml pH2.0 hydrochloride buffers (taking 0.2mol/L Klorvess Liquid 250ml, plus 0.2mol/L hydrochloric acid solution 65.0mL, be diluted with water to 1000ml) is situated between for dissolution Matter, rotating speed 50rpm, respectively at bulk drug clopidogrel in 5min, 10min, 15min, 30min, 60min sampling, determination sample Content, it is as shown in the table：

The dissolution data of 1 two specification clopidogrel tablets of table

Sample	5min	10min	15min	30min	60min
						The sample of 25mg specifications embodiment 1	9.95%	37.41%	68.02%	90.94%	93.32%
The sample of 75mg specifications embodiment 1	7.39%	39.90%	64.49%	85.60%	93.29%
						75mg specification marketed tablet samples	6.62%	33.78%	66.37%	86.98%	94.12%

Above-mentioned experiment proves, the clopidogrel tablet prepared according to prescription of the present invention and technique, its Dissolution behaviours with it is commercially available Clopidogrel tablet is similar, and strong material base is provided for the body absorption and biological utilisation of clopidogrel medicine.

Experiment three：Clopidogrel tablet and marketed tablet accelerated stability contrast test

Two specification clopidogrel tablet samples (containing packaging) and commercial sulfuric acid hydrogen chlorine in Example 1 and embodiment 2 Pyrrole Gray tablet (Plavix) (containing packaging) puts 40 DEG C ± 2 DEG C respectively, is stored 24 months under the conditions of 75% ± 5%RH, respectively at 0 Month, in January, in March, in June, in December, relevant nature is measured by sampling within 24 months, obtains corresponding data, it is as shown in the table：

According to the hydrochloric acid prepared by embodiment 1 of the present invention and the prescription of embodiment 2 and technique it can be seen from upper table data Clopidogrel tablet, under acceleration conditions, after storage in 24 months, its content, relevant material is varied from, but content surpasses 99% is crossed, impurity A % generation is effectively suppressed, maximum only 0.059%, unexpectedly impurity C content It is similarly obtained suppression, maximum only 0.064%.

Clopidogrel tablet is made in storing process by the prescription and technique of the present invention, impurity A and impurity C production It is effectively suppressed, so that the drug quality improved.Simultaneously in the preparation process of tablet, by adding neutral lubricant behenyl Acid glyceride, and acid stabilizer Pidolidone, efficiently solve the problems, such as bulk drug adhesion and sticking.So that of the invention With prominent substantive distinguishing features and marked improvement, and with practicality.

Clopidogrel tablet as described above, often releases oral formulations as clopidogrel, can be used for preventing acute hat Arteries and veins syndrome and apoplexy patient atherothrombosis.

Embodiment

Beneficial effects of the present invention are further illustrated by following experiment.But it is not limited to following embodiments, this area Technical staff made on the basis of the present invention, equivalent substitute or the conversion of substantive content of the present invention are not departed from, also at this Within the protection domain of invention.

It is prepared by embodiment 125mg specification clopidogrels tablet

Constituent	Consumption (unit：g)
		Clopidogrel hydrochloride (in terms of clopidogrel)	25
Mannitol	70
		PVPP	6
Pidolidone	12
		Compritol 888 ATO	2.4
Coating agent	In right amount
		Brazil wax	In right amount
Piece is weighed about	120mg
		It is made altogether	1000

Preparation technology is as follows：

1) operating space is dehumidified with dehumidifier, control ambient humidity is less than 20%；

2) clopidogrel bulk drug is taken, ultramicro grinding makes particle diameter less than 25 microns, standby；

3) clopidogrel bulk drug after recipe quantity crushing is taken, mannitol, Pidolidone is well mixed, dry granulation, 24 mesh Screen cloth whole grain, is obtained containing clopidogrel dry particle；

4) step 3 is taken) gained dry particle, PVPP is added, Compritol 888 ATO is well mixed, tabletting obtains chlorine Pyrrole Gray's plain piece；

5) appropriate Pidolidone is taken, preparation mass fraction is 0.5% aqueous solution, and common stomach dissolution type coating powder is added thereto In right amount, coating solution is prepared；

6) with step 5) gained coating solution is to step 4) gained clopidogrel plain piece is coated, obtains coating tablet, be coated and increase Weight 2%-4%；

7) with carnauba wax powder foot couple step 6) gained coating tablet progress polishing, polishing weightening 1%-3%；

8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminium/polyvinyl chloride and aluminium foil (i.e. double aluminium are packed) to step Rapid 7) gained tablet is packed, and obtains finished product.

It is prepared by embodiment 275mg specification clopidogrels tablet

Constituent	Consumption (unit：g)
		Clopidogrel hydrochloride (in terms of clopidogrel)	75
Mannitol	135
		PVPP	13.5
Pidolidone	27
		Compritol 888 ATO	5.4
Coating agent	In right amount
		Brazil wax	In right amount
Piece is weighed about	270
		It is made altogether	1000

Preparation technology is as follows：

1) operating space is dehumidified with dehumidifier, control ambient humidity is less than 20%；

2) clopidogrel bulk drug is taken, ultramicro grinding makes particle diameter less than 25 microns, standby；

3) clopidogrel bulk drug after recipe quantity crushing is taken, mannitol, Pidolidone is well mixed, dry granulation, 24 mesh Screen cloth whole grain, is obtained containing clopidogrel dry particle；

4) step 3 is taken) gained dry particle, PVPP is added, Compritol 888 ATO is well mixed, tabletting obtains chlorine Pyrrole Gray's plain piece；

5) appropriate Pidolidone is taken, preparation mass fraction is 0.5% aqueous solution, and common stomach dissolution type coating powder is added thereto In right amount, coating solution is prepared；

6) with step 5) gained coating solution is to step 4) gained clopidogrel plain piece is coated, obtains coating tablet, be coated and increase Weight 2%-4%；

7) with carnauba wax powder foot couple step 6) gained coating tablet progress polishing, polishing weightening 1%-3%；

8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminium/polyvinyl chloride and aluminium foil (i.e. double aluminium are packed) to step Rapid 7) gained tablet is packed, and obtains finished product.

Claims (3)

1. a kind of solid composite medicament containing clopidogrel, it is characterised in that piece agent is prepared by following prescription：

2. a kind of solid composite medicament containing clopidogrel, it is characterised in that piece agent is prepared by following prescription:

3. the solid composite medicament containing clopidogrel as described in claim any one of 1-2, it is characterised in that by such as Lower step piece agent：

1) operating space is dehumidified with dehumidifier, control ambient humidity is less than 20%；

2) clopidogrel bulk drug is taken, ultramicro grinding makes particle diameter less than 25 microns, standby；

3) clopidogrel bulk drug after recipe quantity crushing is taken, mannitol, Pidolidone is well mixed, dry granulation, 24 eye mesh screens Whole grain, is obtained containing clopidogrel dry particle；

4) step 3 is taken) gained dry particle, PVPP is added, Compritol 888 ATO is well mixed, tabletting obtains chlorine pyrrole lattice Thunder plain piece；

5) appropriate Pidolidone is taken, preparation mass fraction is 0.5% aqueous solution, common stomach dissolution type coating powder is added thereto and is fitted Amount, prepares coating agent；

6) with step 5) gained coating agent to step 4) gained clopidogrel plain piece be coated, obtain coating tablet, coating weight gain 2%-4%；

7) with carnauba wax powder foot couple step 6) gained coating tablet progress polishing, polishing weightening 1%-3%；

8) with polyamide/cold stamping shaped medicinal composite hard sheet of aluminium/polyvinyl chloride and polyvinyl chloride composite hard sheet, i.e., double aluminium bags Dress, to step 7) gained tablet packs, and obtains finished product.