CN1359294A - Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel - Google Patents

Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel Download PDF

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Publication number
CN1359294A
CN1359294A CN00807001A CN00807001A CN1359294A CN 1359294 A CN1359294 A CN 1359294A CN 00807001 A CN00807001 A CN 00807001A CN 00807001 A CN00807001 A CN 00807001A CN 1359294 A CN1359294 A CN 1359294A
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China
Prior art keywords
pharmaceutical composition
clopidogrel
aspirin
clopidogrel hydrogenesulphate
hydrogenesulphate
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CN00807001A
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B·阿布拉默维奇
J·莱里蒂尔
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Sanofi Aventis France
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Sanofi Synthelabo SA
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Publication of CN1359294A publication Critical patent/CN1359294A/en
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Abstract

The invention concerns a pharmaceutical composition containing in galenical unit form a combination of active principles with platelet antiaggregating activity consisting of acetylsalicylic acid and clopidogrel hydrogenosulphonate.

Description

The unit dosage forms shape pharmaceutical composition that contains aspirin and clopidogrel hydrogenesulphate
The present invention relates to have the pharmaceutical composition that covers the human relations unit dosage forms, it contains simultaneously and has active active component aspirin of anti-platelet aggregation (it is also known by people with the title aspirin) and clopidogrel (Clopidogrel) disulfate.
Lid human relations unit dosage forms type preferably includes tablet, capsule or bag agent by oral administration.
In compositions of the present invention, aspirin uses its sour form, and clopidogrel hydrogenesulphate can use one or another kind of in its polymorphic, is referred to as 1 type (F1) or 2 types (F2) at present.1 type clopidogrel hydrogenesulphate is the salt of narrating in patent EP-281459, and 2 type clopidogrel hydrogenesulphates are salts of narration in application for patent FR-98 07464.
In application for patent WO 97/29753, narrated especially and united the treatment meaning of using aspirin and clopidogrel.
But, above the pharmaceutical composition the mentioned officinal salt that never is described in detail use be the disulfate of clopidogrel.
This file often points out that said composition can or orally use by the outer approach of intestinal, can be according to four kinds of mode of administration with delivery of active ingredients, i.e. two kinds of oral patterns, two kinds of intestinal external schemas, being oral pattern on the one hand in other words, is the intestinal external schema on the other hand, or opposite.
But, have the dosage form of covering the human relations unit dosage forms without any a kind of pharmaceutical composition, and be suitable for the disulfate administration simultaneously of aspirin with the clopidogrel that does not have narration.
Owing to determine, the dosage of every kind of antiplatelet blood coagulation component of associating use can pre-determine, and need not judge according to the patient who is treated, and therefore uses and passes through oral administration, the single medicine type that contains these two kinds of active component is exactly useful, and is favourable.
Active component with aspirin and other carried out the research of many associatings, but ought use the galenic dosage form of the salt that contains aspirin and active component together, especially during tablet, confirmed to have many shortcomings.
Such as, in the article in " Inpharm magazine " (Internatioal Journal ofPharmaceutics) (Holland) 1984,18,287～298, shown the incompatibility between aspirin and other solid active agent.Use aspirin and maleic acid U.S. this model to be carried out affirmation experimentally than the Lamine.In aspirin, add maleic acid U.S. and reduced acetysalicylic fusing point, can exert an influence to acetysalicylic decomposition rate in this mixture simultaneously than the Lamine.Therefore confirmed that unite in the use in this class, the fusing point reduction can cause the decomposition of active component.
Therefore, known all these shortcomings of professional will can not impelled in same tablet, or in same capsule, or in the agent of same bag, unite salt such as the clopidogrel hydrogenesulphate that uses aspirin and alkali.
According to the present invention, use different manufacture method well known by persons skilled in the art and different technology, can be with a kind of complete accident and wonderful mode, produce and have the pharmaceutical composition that covers the human relations unit dosage forms, said composition is containing the acetysalicylic while, also contain another kind of salt, more specifically say the active component that constitutes by the clopidogrel sulfur hydrogen salt by alkali.
Therefore, can obtain by different manufacture methods according to tablet of the present invention, such as:
-direct compression process is in the method with the mixed with excipients of active component and selection.The mixture that obtains is sieved on the grid that pre-determines the mesh perforate (classification), make the size homogenization of each component particles.Again mix, better uniformity is arranged to guarantee active component.Add specific excipient (such as flowable) and lubricant and mix.At this moment the final mixture that obtains is carried out tabletting.
-comminution granulation in advance, process for granulating comprises that the excipient (inner component mutually) with active component and selection mixes and densification in the method, it is even to obtain active component content after carrying out classification on the grid of determining, is suitable for carrying out after adding specific excipient (component of inner phase) particle of the granulometric composition of tabletting.Pelletize can improve the rheological behavior of the mixture for the treatment of tabletting and the physical property of tablet, particularly under the very high dosage form situation of active component content.When in a tablet, using two kinds of active component simultaneously, according to circumstances differently can be externally add wherein a kind of in mutually.
Currently using three kinds of process for granulating: wet granulation, non-slurry pelletizing (compacting) and " hot melt " pelletize.
Non-slurry pelletizing (compacting) comprises allows mixed with excipients, the classification of active component and selection, mixes again then.Mixture is pulled between the active cylinder of two direction of rotation, with the difference according to the power that applies, obtains tolerating the small pieces of determining mechanical force.With these small pieces classifications.Add specific excipient also with final mixture tabletting.
" hot melt " pelletize is a kind of prilling process that can use when active component is met water decomposition.The excipient of active component and selection is carried out classification, mix then.Under stirring slowly, allow the temperature of mixture reach the temperature that the tip is higher than the excipient fusing point, under stirring fast, mix, be cooled to ambient temperature then.The granule that obtains is carried out classification.Add specific excipient and final mixture is carried out tabletting.
Be described in the example of " hot melt " method in the air fluidized bed pelletizer below.The excipient (except fusile excipient) of active component and selection is carried out classification, transfer to then in the air fluidized bed pelletizer.Mix whole material by providing hot-air to carry out fluidization, up to the temperature of mixture fusing point a shade below the pelletize excipient.At this moment fused excipient is sprayed on the fluidised mixture.Reduce the temperature of fluidizing air.The granule that obtains is carried out classification.Add specific excipient and final mixture is carried out tabletting.
Capsule and bag agent are all made according to technology well known by persons skilled in the art.
Pharmaceutical composition of the present invention is used for treating the disease that platelet aggregation is brought out, comprise stable or unsettled angina pectoris, the disease of cardiovascular and cerebrovascular system, as the thromboembolism illness relevant with atherosclerosis and diabetes, as unstable angina pectoris, the brain onste, angioplasty, endarterectomize or lay the restenosis (rest é nose) behind the metal rack in the blood vessel, perhaps with thromboembolism after thromboembolism again, myocardial infarction, ischemia causes dementia, peripheral arterial disease, hemodialysis, the thromboembolic disorders that the ear fibrillation is relevant, also be used in the use blood vessel graft, when coronary artery is built bridge, alleviate side effect when perhaps being used for radiotherapy.
Pharmaceutical composition of the present invention is used for preparing the medicine that is used for the treatment of and can treats above-mentioned disease.
In pharmaceutical composition of the present invention, clopidogrel hydrogenesulphate and acetysalicylic mol ratio are that clopidogrel hydrogenesulphate/aspirin is 2.5～11.5, are preferably 5～9.
To the people take be every day 1～500mg clopidogrel hydrogenesulphate and every day 1～500mg aspirin, this dosage is to represent according to a great deal of of the clopidogrel of free form.
Preferably take the clopidogrel hydrogenesulphate of 97.875mg and the aspirin of 75～325mg.
Especially preferably contain the acetysalicylic compositions of 97.875mg clopidogrel hydrogenesulphate and 75mg.
Also preferably contain the acetysalicylic compositions of 97.875mg clopidogrel hydrogenesulphate and 375mg.
Embodiment 1
Contain the acetysalicylic tablet of 75mg clopidogrel base and 75mg
Embodiment: tabletting comminution granulation
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????75
Pre-gelatinizing corn starch ????30
Colloidal silica anhydrous ????2
Anhydrous beta lactose ????324.625
Microcrystalline Cellulose (90 μ m) ????30
The hydroxypropyl cellulose of low degree of substitution ????30
Castor oil hydrogenated ????10.5
Amount to ????600
A) 97.875g clopidogrel hydrogenesulphate and 2g colloidal silica anhydrous are mixed; B) in joining the pre-gelatinizing corn starch of 30g and 74.6g Lactis Anhydrous a) and mix; C) with mixture b) classification mixing again then; D) with this mixture tabletting, classification on the sieve aperture of 1.000mm then; E) the low hydroxypropyl cellulose that replaces of 75g aspirin, 250g Lactis Anhydrous, 30g microcrystalline Cellulose and 30g is mixed with granule after the classification; F) add the 10.5g castor oil hydrogenated, finally mix then; G) final mixture is carried out tabletting, making the theoretical unit dose quality is 600mg.β-Lactis Anhydrous can replace with the mannitol of a great deal of.
Embodiment 2
Contain the acetysalicylic tablet of 75mg clopidogrel base and 75mg
Embodiment: tabletting comminution granulation
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????200
Pre-gelatinizing corn starch ????30
Colloidal silica anhydrous ????2
Anhydrous beta lactose ????199.625
Microcrystalline Cellulose (90 μ m) ????30
The low hydroxypropyl cellulose that replaces ????30
Castor oil hydrogenated ????10.5
Amount to ????600
A) 97.875g clopidogrel hydrogenesulphate and 2g colloidal silica anhydrous are mixed; B) in joining the pre-gelatinizing corn starch of 30g and 74.6g Lactis Anhydrous a) and mix; C) with mixture b) classification mixing again then; D) with this mixture tabletting, classification on the sieve aperture of 1.000mm then; E) the low hydroxypropyl cellulose that replaces of 200g aspirin, 125g Lactis Anhydrous, 30g microcrystalline Cellulose and 30g is mixed with granule after the classification; F) add the 10.5g castor oil hydrogenated, finally mix then; G) final mixture is carried out tabletting, making the theoretical unit dose quality is 600mg.β-Lactis Anhydrous can replace with the mannitol of a great deal of.
Embodiment 3
Contain the acetysalicylic tablet of 75mg clopidogrel base and 325mg
Embodiment: tabletting comminution granulation
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????325
Pre-gelatinizing corn starch ????30
Colloidal silica anhydrous ????2
Anhydrous beta lactose ????74.625
Microcrystalline Cellulose (90 μ m) ????30
The low hydroxypropyl cellulose that replaces ????30
Castor oil hydrogenated ????10.5
Amount to ????600
A) 97.875g clopidogrel hydrogenesulphate and 2g colloidal silica anhydrous are mixed; B) in joining the pre-gelatinizing corn starch of 30g and 74.6g Lactis Anhydrous a) and mix; C) with mixture b) classification mixing again then; D) with this mixture tabletting, classification on the sieve aperture of 1.000mm then; E) the low hydroxypropyl cellulose that replaces of 325g aspirin, 30g microcrystalline Cellulose and 30g is mixed with granule after the classification; F) add the 10.5g castor oil hydrogenated, finally mix then; G) final mixture is carried out tabletting, making the theoretical unit dose quality is 600mg.β-Lactis Anhydrous can replace with the mannitol of a great deal of.
Embodiment 4
Contain the acetysalicylic tablet of 75mg clopidogrel base and 75mg
Embodiment: direct compression process
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????75
Corn starch ????30
Colloidal silica anhydrous ????2
Mannitol 300 DC ????324.625
Microcrystalline Cellulose (90 μ m) ????60
Castor oil hydrogenated ????10.5
Amount to ????600
A) 97.875g clopidogrel hydrogenesulphate and 2g colloidal silica anhydrous are mixed; B) in joining 75g aspirin, 30g corn starch, 324.6g mannitol and 60g microcrystalline Cellulose a), mix then; C) with mixture b) classification mixing again then; D) at c) in add the 10.5g castor oil hydrogenated, finally mix then; E) final mixture is carried out tabletting, making the theoretical unit dose quality is 600mg.Mannitol can replace with the β-Lactis Anhydrous of a great deal of.
Embodiment 5
Contain the acetysalicylic tablet of 75mg clopidogrel base and 325mg
Embodiment: direct compression process
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????325
Corn starch ????30
Colloidal silica anhydrous ????2
Mannitol 300 DC ????124.625
Microcrystalline Cellulose (90 μ m) ????60
Hydrogenated castor oil ????10.5
Amount to ????650
A) 97.875g clopidogrel hydrogenesulphate and 2g colloidal silica anhydrous are mixed; B) in joining 325g aspirin, 30g corn starch, 124.6g mannitol and 60g microcrystalline Cellulose a), mix then; C) with mixture b) classification mixing again then; D) at c) in add the 10.5g castor oil hydrogenated, finally mix then; E) final mixture is carried out tabletting, making the theoretical unit dose quality is 650mg.Mannitol can replace with the β-Lactis Anhydrous of a great deal of.
Embodiment 6
Contain the acetysalicylic capsule of 75mg clopidogrel base and 75mg
Embodiment: simple mixing method
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????75
Pre-gelatinizing corn starch ????50
Colloidal silica anhydrous ????2.5
Mannitol 300 DC ????265.875
Castor oil hydrogenated ????8.75
Amount to ????500
A) 97.875g clopidogrel hydrogenesulphate and 2.5g colloidal silica anhydrous are mixed; B) in joining 75g aspirin, the pre-gelatinizing corn starch of 50g, 265.9g mannitol a), mix then; C) with mixture b) classification mixing again then; D) at c) in add the 8.75g castor oil hydrogenated, finally mix then; E) final mixture is separated into capsule, making the theoretical unit dose quality is 500mg.Mannitol can replace with the β-Lactis Anhydrous of a great deal of.
Embodiment 7
Contain the acetysalicylic capsule of 75mg clopidogrel base and 325mg
Embodiment: simple mixing method
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????325
Pre-gelatinizing corn starch ????50
Colloidal silica anhydrous ????2.5
Mannitol 300 DC ????15.875
Castor oil hydrogenated ????8.75
Amount to ????500
A) 97.875g clopidogrel hydrogenesulphate and 2.5g colloidal silica anhydrous are mixed; B) in joining 325g aspirin, the pre-gelatinizing corn starch of 50g and 15.9g mannitol a) and mix; C) with mixture b) classification mixing again then; D) at c) in add the 8.75g castor oil hydrogenated, finally mix then; E) final mixture is advanced to be separated into capsule, making the theoretical unit dose quality is 500mg.Mannitol can replace with the β-Lactis Anhydrous of a great deal of.
Embodiment 8
Contain the agent of the acetysalicylic bag of 75mg clopidogrel base and 75mg
Embodiment: simple mixing method
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????75
Colloidal silica anhydrous ????2.5
Mannitol 300 DC ????824.625
Amount to ????1000
A) 97.875g clopidogrel hydrogenesulphate and 2.5g colloidal silica anhydrous are mixed; B) in joining 75g aspirin and 824.6g mannitol a) and mix; C) with mixture b) classification mixing again then; D) final mixture is distributed in the pouch, making the theoretical unit dose quality is 1g.The aromatic that can in mixture, add powdered.
Embodiment 9
Contain the agent of the acetysalicylic bag of 75mg clopidogrel base and 325mg
Embodiment: simple mixing method
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????325
Colloidal silica anhydrous ????2.5
Mannitol ????574.625
Amount to ????1000
A) 97.875g clopidogrel hydrogenesulphate and 2.5g colloidal silica anhydrous are mixed; B) in joining 325g aspirin and 574.6g mannitol a) and mix; C) with mixture b) classification mixing again then; D) final mixture is distributed in the pouch, making the theoretical unit dose quality is 1g.The aromatic that can in mixture, add powdered.
Embodiment 10
Contain the acetysalicylic tablet of 75mg clopidogrel base and 75mg
Embodiment: " hot melt " comminution granulation
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????75
Polyethylene Glycol (Macrogol) 6000 ????97.5
Corn starch ????32.5
Colloidal silica anhydrous ????2
Mannitol ????273.625
Microcrystalline Cellulose (50 μ m) ????65
Castor oil hydrogenated ????6.5
Amount to ????650
A) 97.875g clopidogrel hydrogenesulphate, 97.5g polyethylene glycol 6000,32.5g corn starch and 273.6g mannitol are mixed after classification; B) in stirring slowly down in temperature chamber with mixture heated to 65 ℃; C) stirring is cooled off up to ambient temperature classification then down with mixture pelleting rapidly; D) in fractionated granule, add 75g aspirin, 2g colloidal silica anhydrous, 65g microcrystalline Cellulose, and mix; E) at d) in add the 6.5g castor oil hydrogenated, finally mix then; F) final mixture is carried out tabletting, making the theoretical unit dose quality is 650mg.
Embodiment 11
Contain the acetysalicylic tablet of 75mg clopidogrel base and 325mg
Embodiment: " hot melt " comminution granulation
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????325
Polyethylene Glycol (Magrogol) 6000 ????97.5
Corn starch ????32.5
Colloidal silica anhydrous ????2
Mannitol ????23.625
Microcrystalline Cellulose (50 μ m) ????65
Castor oil hydrogenated ????6.5
Amount to ????650
A) 97.875g clopidogrel hydrogenesulphate, 97.5g polyethylene glycol 6000,32.5g corn starch and 23.6g mannitol are mixed after classification; B) in stirring slowly down in temperature chamber with mixture heated to 65 ℃; C) stirring is cooled to ambient temperature, then classification down with mixture pelleting always rapidly; D) in fractionated granule, add 325g aspirin, 2g colloidal silica anhydrous, 65g microcrystalline Cellulose, and mix; E) at d) in add the 6.5g castor oil hydrogenated, finally mix then; F) final mixture is carried out tabletting, making the theoretical unit dose quality is 650mg.
Embodiment 12
Contain the acetysalicylic tablet of 75mg clopidogrel base and 75mg
Embodiment: direct compression process
The unit dosage forms prescription
Component Quantity (mg)
Clopidogrel hydrogenesulphate (being equivalent to 75mg alkali) ????97.875
Aspirin ????75.00
Emdex ????136.605
Castor oil hydrogenated ????5.520
Amount to ????315
Embodiment 13
Component Quantity (mg)
2 type clopidogrels (being equivalent to 75mg alkali) ????97.875
Aspirin ????75.00
Cellactose?80 ????121.875
Castor oil hydrogenated ????5.25
Amount to ????300
Embodiment 12 and 13 operator scheme
In mini-rh n mixer, mixed 10 minutes with active component and diluent.
Add lubricant (castor oil hydrogenated), in mini-rh n mixer, mixed 5 minutes then.
Embodiment 14
Contain the acetysalicylic tablet of 75mg clopidogrel base and 75mg
Embodiment: direct compression process
The unit dosage forms prescription
Component Quantity (mg)
2 type clopidogrels (being equivalent to 75mg alkali) ????97.875
Aspirin ????75.00
Emdex ????10.00
Avicel?PH?112 ????21.125
Pearlitol?SD?200 ????24.00
Colloidal silica anhydrous ????2.00
Castor oil hydrogenated ????4.20
Amount to ????240
Operator scheme:
Active component was mixed 10 minutes in mini-rh n mixer with diluent.
Add colloidal silica anhydrous in the mixture in front, sieve by the graticule mesh of sieve aperture 0.315mm then.
In mini-rh n mixer, mixed 5 minutes.
Add lubricant (castor oil hydrogenated), in mini-rh n mixer, mixed 5 minutes.

Claims (14)

1. pharmaceutical composition, it is the lid human relations unit dosage forms that can be taken orally, and contains active component clopidogrel hydrogenesulphate and aspirin.
2. the pharmaceutical composition that contains active component as claimed in claim 1, itself and drug excipient are united use.
3. as the pharmaceutical composition that contains active component of claim 1 or 2, it is characterized in that the clopidogrel sulfur hydrogen salt uses the polymorphic form of 1 type.
4. as the pharmaceutical composition that contains active component of claim 1 or 2, it is characterized in that the clopidogrel sulfur hydrogen salt uses the polymorphic form of 2 types.
5. as any one pharmaceutical composition in claim 1 or 4, it is tablet form.
6. as any one pharmaceutical composition in claim 1 or 4, it is capsule form.
7. as any one pharmaceutical composition in claim 1 or 4, it is a bag agent form.
8. as any one pharmaceutical composition in the claim 1～7, it is characterized in that clopidogrel hydrogenesulphate and acetysalicylic mol ratio are that clopidogrel hydrogenesulphate/aspirin equals 2.5～11.5.
9. as any one pharmaceutical composition in the claim 1～8, it is characterized in that clopidogrel hydrogenesulphate and acetysalicylic mol ratio are that clopidogrel hydrogenesulphate/aspirin equals 5～9.
10. as any one pharmaceutical composition in the claim 1～9, it is characterized in that clopidogrel hydrogenesulphate and acetysalicylic content are clopidogrel hydrogenesulphate 97.875mg, aspirin 75mg.
11., it is characterized in that clopidogrel hydrogenesulphate and acetysalicylic content are clopidogrel hydrogenesulphate 97.875mg, aspirin 375mg as any one pharmaceutical composition in the claim 1～10.
12. as any one pharmaceutical composition in the claim 1～11, said composition is used for the treatment of the disease that platelet aggregation causes, comprise stable or unsettled angina pectoris, the disease of cardiovascular and cerebrovascular system, as the thromboembolism illness relevant with atherosclerosis and diabetes, as unstable angina pectoris, the brain onste, angiopoiesis, endarterectomize or lay the restenosis behind the metal rack in the blood vessel, perhaps with thromboembolism after thromboembolism again, myocardial infarction, ischemia causes dementia, peripheral arterial disease, hemodialysis, the thromboembolic disorders that the ear fibrillation is relevant, also be used in the use blood vessel graft, when coronary artery is built bridge, alleviate side effect when perhaps being used for radiotherapy.
13. be used for treating the application on the medicine of the disease that platelet aggregation brings out in manufacturing as the compositions of any one in the every claim in front.
14. be used for treating the application on the medicine of the disease that platelet aggregation brings out in manufacturing as the compositions of any one in the every claim in front, these diseases comprise stable or unsettled angina pectoris, the disease of cardiovascular and cerebrovascular system, as the thromboembolism illness relevant with atherosclerosis and diabetes, as unstable angina pectoris, the brain onste, angiopoiesis, endarterectomize or lay the restenosis behind the metal rack in the blood vessel, perhaps with thromboembolism after thromboembolism again, myocardial infarction, ischemia causes dementia, peripheral arterial disease, hemodialysis, the thromboembolic disorders that the ear fibrillation is relevant, also be used in the use blood vessel graft, when coronary artery is built bridge, alleviate side effect when perhaps being used for radiotherapy.
CN00807001A 1999-04-30 2000-04-25 Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel Pending CN1359294A (en)

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FR99/05497 1999-04-30
FR9905497A FR2792836B3 (en) 1999-04-30 1999-04-30 PHARMACEUTICAL COMPOSITION IN UNIT FORM CONTAINING ASPIRIN AND CLOPIDOGREL HYDROGENOSULFATE

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AR (1) AR023789A1 (en)
AU (1) AU4303600A (en)
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CA (1) CA2371231A1 (en)
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HK (1) HK1041823A1 (en)
HU (1) HUP0202329A2 (en)
IL (1) IL145648A0 (en)
IS (1) IS6084A (en)
MX (1) MXPA01011071A (en)
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PL (1) PL351923A1 (en)
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CN105407877A (en) * 2013-08-02 2016-03-16 赛诺菲 Pharmaceutical tablet comprising acetylsalicylic acid and clopidogrel
CN115737578A (en) * 2022-11-23 2023-03-07 石家庄四药有限公司 Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof

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CN105407877A (en) * 2013-08-02 2016-03-16 赛诺菲 Pharmaceutical tablet comprising acetylsalicylic acid and clopidogrel
CN105407877B (en) * 2013-08-02 2019-05-07 赛诺菲 Medicinal tablet comprising acetylsalicylic acid and clopidogrel
CN104434932A (en) * 2014-12-18 2015-03-25 成都苑东药业有限公司 Pharmaceutical composition of clopidogrel hydrogen sulfate and acetylsalicylic acid tablet and preparation method thereof
CN104434932B (en) * 2014-12-18 2017-05-24 成都苑东生物制药股份有限公司 Pharmaceutical composition of clopidogrel hydrogen sulfate and acetylsalicylic acid tablet and preparation method thereof
CN115737578A (en) * 2022-11-23 2023-03-07 石家庄四药有限公司 Clopidogrel hydrogen sulfate and aspirin compound tablet and preparation method thereof

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TR200103039T2 (en) 2002-01-21
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WO2000066130A1 (en) 2000-11-09
AU4303600A (en) 2000-11-17
CZ20013887A3 (en) 2002-02-13
UY26131A1 (en) 2000-12-29
BR0010194A (en) 2002-02-13
NZ514248A (en) 2003-06-30
MXPA01011071A (en) 2002-07-22
HUP0202329A2 (en) 2002-10-28
EE200100559A (en) 2003-02-17
FR2792836B3 (en) 2001-07-27
IL145648A0 (en) 2002-06-30
CA2371231A1 (en) 2000-11-09
FR2792836A1 (en) 2000-11-03
NO20015295L (en) 2001-12-21
EA200100959A1 (en) 2002-06-27
KR20020005735A (en) 2002-01-17
EP1178809A1 (en) 2002-02-13
NO20015295D0 (en) 2001-10-29
IS6084A (en) 2001-09-25
AR023789A1 (en) 2002-09-04
PL351923A1 (en) 2003-06-30

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