EP1178809A1

EP1178809A1 - Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel hydrogenosulphate

Info

Publication number: EP1178809A1
Application number: EP00922737A
Authority: EP
Inventors: Bernard Abramovici; Jean Lheritier
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1999-04-30
Filing date: 2000-04-25
Publication date: 2002-02-13
Also published as: JP2002543137A; TR200103039T2; SK15542001A3; HK1041823A1; WO2000066130A1; AU4303600A; CZ20013887A3; UY26131A1; BR0010194A; NZ514248A; MXPA01011071A; HUP0202329A2; EE200100559A; FR2792836B3; CN1359294A; IL145648A0; CA2371231A1; FR2792836A1; NO20015295L; EA200100959A1

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

Pharmaceutical composition in unit form containing acetylsalicylic acid and clopidogrel hydrogen sulfate

The present invention relates to a pharmaceutical composition in a unit dosage form containing an association of active principles with antiplatelet activity consisting of acetylsalicylic acid, also known under the brand name Aspirin, and clopidogrel hydrogen sulfate.

The unit dosage form can be administered orally and preferably consists of a tablet, a capsule or a dose sachet. In the compositions according to the invention acetylsalicylic acid is used in its acid form and clopidogrel hydrogen sulphate can be used in the form of one or other of its polymorphs known to date and called Form 1 (F1) or Form 2 (F2). Clopidogrel hydrogen sulfate Form 1 is the salt described in patent EP 281459 and clopidogrel hydrogen sulfate Form 2 is that described in patent application FR 98 07464. The therapeutic advantage of the combination of acetylsalicylic acid and of clopidogrel is among others described in patent application WO 97/29753.

Pharmaceutical compositions are mentioned there without ever specifying that the pharmaceutically acceptable salt used is clopidogrel hydrogen sulfate. This document always indicates that the composition can be used parenterally or orally and that it is possible to administer the active ingredients according to four modes of administration, namely, both orally, both parenterally or one orally and the other parenterally or vice versa.

However, no pharmaceutical composition in a unique dosage form suitable for the concomitant administration of acetylsalicylic acid and clopidogrel hydrogen sulfate is described.

Since it has been well determined that the doses of each of the antiplatelet agents constituting the association can be fixed beforehand and do not require adjustment according to the patients to be treated, it has proved useful and advantageous to have of a single drug form which can be administered orally and contains these two active ingredients.

Several association studies have been carried out with acetylsalicylic acid and other active principles, but numerous drawbacks have been highlighted during the production of the galenical forms, in particular tablets containing acetylsalicylic acid in combination with salts. active ingredient. Thus, the publication published in International Journal of Pharmaceutics (Netherlands) 1984, 18, 287-298, demonstrates the incompatibility between acetylsalicylic acid and other solid active ingredients. Experimental confirmation of these models has been demonstrated using acetylsalicylic acid and mepyramine maleate. The addition of mepyramine maleate to acetylsalicylic acid decreases its melting point, with an effect on the rate of decomposition of acetylsalicylic acid in this mixture. It has therefore been observed that a reduction in the melting point leads to the degradation of the active principles in this type of association.

All these drawbacks well known to those skilled in the art would therefore not have encouraged him to make an association between acetylsalicylic acid and a base salt such as clopidogrel hydrogen sulfate in the same tablet or the same capsule or in a same bag. Quite unexpectedly and surprisingly, it was possible, according to the invention, to produce a pharmaceutical composition in a unit dosage form containing acetylsalicylic acid in association with another active principle consisting of a basic salt more precisely clopidogrel hydrogen sulfate by implementing various manufacturing processes and various techniques well known to those skilled in the art.

Thus, the tablets according to the invention can be obtained by various manufacturing processes such as for example:

- the direct compression process in which the active ingredients and the selected excipients are mixed. The mixture obtained is sieved (calibrated) on a previously defined mesh opening grid, in order to homogenize the particle sizes of the constituents. A new mixing is carried out to ensure good homogeneity of the active ingredients. Specific excipients (example: a flow agent) as well as a lubricant are added and mixed. The final mixture obtained is then compressed. - the process with prior granulation in which the granulation consists in amalgamating and densifying the active principles and the selected excipients (constituents of internal phase), in order to obtain after calibration on a determined grid, a grain made up of homogeneous particles in content of principles active, suitable for compression, after adding specific excipients (external phase constituents). Granulation improves the rheological characteristics of the mixture to be compressed and the physical characteristics of the tablets, in particular in the case of dosages of high active ingredients. When combining two active ingredients in the same tablet, it is possible, depending on the case, to incorporate one of them in an external phase. Three granulation processes are commonly used: wet granulation, dry granulation (compaction), and “hot melt” granulation. Dry granulation (compaction) consists in ensuring that the active ingredients and the selected excipients are mixed, calibrated and then mixed again. The mixture is forced between two mobile cylinders, in opposite directions of rotation, in order to obtain, according to the forces exerted, plates of determined mechanical strengths. These plates are calibrated. The specific excipients are added and the final mixture compressed.

"Hot melt" granulation is a granulation process that can be used when an active ingredient degrades in the presence of water. The active ingredients and the selected excipients are calibrated and then mixed. The mixture is brought under slow stirring to a temperature slightly higher than that of the melting point of the excipient, mixed under rapid stirring, then cooled to room temperature. The grain obtained is calibrated. The specific excipients are added and the final mixture compressed. An example of a "hot melt" process in a granulator with a fluidized air bed is described below. The active ingredients and the selected excipients, except the fusible excipient, are calibrated and then transferred to a granulator with a fluidized air bed. The whole is mixed by fluidization with supply of hot air, up to a temperature of the mixture slightly lower than that of the melting point of the granulation excipient. The molten excipient is then sprayed onto the fluidized mixture. The temperature of the fluidizing air is lowered. The grain obtained is calibrated. The specific excipients are added and the final mixture compressed.

The capsules and dose sachets are prepared according to techniques well known to those skilled in the art. The pharmaceutical compositions according to the invention are used for the treatment of a pathology induced by platelet aggregation including stable or unstable angina, disorders of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, cerebral attack, restenosis after angioplasty, endarterectomy or fitting of metal endovascular prostheses or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillation or even when using vascular prostheses, bypass surgery, or during radiotherapy to reduce side effects. The pharmaceutical compositions according to the invention are used for the preparation of a medicament intended for the treatment of the pathologies mentioned above and allow the treatment of these pathologies. In the pharmaceutical compositions according to the invention, clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a molar ratio of clopidogrel hydrogenosulfate / acetylsalicylic acid comprised between 2.5 and 11, preferably between 5 and 9.

1 to 500 mg per day of clopidogrel hydrogen sulfate and 1 to 500 mg per day of acetylsalicylic acid are administered to humans, the doses being expressed in equivalent amounts of clopidogrel in free form.

Preferably 97.875 mg of clopidogrel hydrogen sulfate is administered and 75 to

325 mg of acetylsalicylic acid.

Particularly preferred are compositions containing 97.875 mg of clopidogrel hydrogen sulfate and 75 mg of acetylsalicylic acid.

Preference is also given to compositions containing 97.875 mg of clopidogrel hydrogen sulfate and 375 mg of acetylsalicylic acid.

EXAMPLE 1

Tablet containing 75 mg of clopidogrel base and 75 mg of acetylsalicylic acid

Example: granulation process by compacting

Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2 g of anhydrous colloidal silica b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a) and mixed c) The mixture b) is calibrated then mixed again d) the mixture is compacted and then calibrated over 1,000 mm of mesh size e) 75 g of acetylsalicylic acid, 250 g of anhydrous lactose, 30 g of cellulose microcrystalline, and 30 g of weakly substituted hydroxypropylcellulose are mixed with the calibrated grain f) 10.5 g of hydrogenated castor oil are added before final mixing g) The final mixture is compressed to the theoretical unit mass of 600 mg

• Anhydrous lactose β can be replaced in an equivalent amount with mannitol.

EXAMPLE 2

Tablet containing 75 mg of clopidogrel base and 200 mg of acetylsalicylic acid

Example: granulation process by compacting

Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2 g of anhydrous colloidal silica b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a) and mixed c) The mixture b) is calibrated then mixed again d) the mixture is compacted and then calibrated over 1,000 mm of mesh opening e) 200 g of acetylsalicylic acid, 125 g of anhydrous lactose, 30 g of microcrystalline cellulose, and 30 g of weakly substituted hydroxypropylcellulose are mixed with the calibrated grain f) 10.5 g of hydrogenated castor oil are added before final mixing g) The final mixture is compressed to the theoretical unit mass of 600 mg

• Anhydrous lactose β can be replaced in an equivalent amount with mannitol. EXAMPLE 3 Tablet containing 75 mg of clopidogrel base and 325 mg of acetylsalicylic acid Example: granulation process by compacting Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2 g of anhydrous colloidal silica b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a) and mixed c) The mixture b) is calibrated then mixed again d) the mixture is compacted and then calibrated over 1,000 mm of mesh opening e) 325 g of acetylsalicylic acid, 30 g of microcrystalline cellulose and 30 g of weakly substituted hydroxypropylcellulose are mixed with the graded grain f) 10.5 g of hydrogenated castor oil are added before final mixing g) The final mixture is compressed to the theoretical unit mass of 600 mg

• Anhydrous lactose β can be replaced in an equivalent amount with mannitol. EXAMPLE 4 Tablet containing 75 mg of clopidogrel base and 75 mg of acetylsalicylic acid

Example: direct compression method Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2 g of anhydrous colloidal silica b) 75 g of acetylsalicylic acid, 30 g of corn starch, 324.6 g of mannitol and 60 g of microcrystalline cellulose are added to a) and mixed c) The mixture b) is calibrated and then mixed again d) 10.5 g of hydrogenated castor oil are added to c) before the final mixture e) The final mixture is compressed to the theoretical unit mass of 600 mg

• Mannitol can be replaced in an equivalent amount by anhydrous lactose β.

EXAMPLE 5

Tablet containing 75 mg of clopidogrel base and 325 mg of acetylsalicylic acid

Example: direct compression process

Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2 g of anhydrous colloidal silica b) 325 g of acetylsalicylic acid, 30 g of corn starch, 124.6 g of mannitol and 60 g of microcrystalline cellulose are added to a) and mixed c) The mixture b) is calibrated and then mixed again d) 10.5 g of hydrogenated castor oil are added to c) before the final mixture e) The final mixture is compressed to a theoretical unit mass of 650 mg

• Mannitol can be replaced in an equivalent amount by anhydrous lactose β. EXAMPLE 6

Capsule containing 75 mg of clopidogrel base and 75 mg of acetylsalicylic acid

Example: simple mixing process Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2.5 g of anhydrous colloidal silica b) 75 g of acetylsalicylic acid, 50 g of pregelatinized corn starch, 265.9 g of mannitol are added to a) and mixed c ) The mixture b) is calibrated and then mixed again d) 8.75 g of hydrogenated castor oil are added to c) before the final mixture e) The final mixture is divided into capsules with a theoretical unit mass of 500 mg • Mannitol can be replaced in an equivalent amount by anhydrous lactose β. EXAMPLE 7 Capsule containing 75 mg of clopidogrel base and 325 mg of acetylsalicylic acid Example: process by simple mixing Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2.5 g of silica anhydrous colloid b) 325 g of acetylsalicylic acid, 50 g of pregelatinized corn starch, 15.9 g of mannitol are added to a) and mixed c) The mixture b) is calibrated and then mixed again d) 8.75 g of hydrogenated castor oil are added to c) before the final mixture e) The final mixture is divided into capsules with a theoretical unit mass of 500 mg • The mannitol can be replaced in an equivalent amount by anhydrous lactose β. EXAMPLE 8

Bag containing 75 mg of clopidogrel base and 75 mg of acetylsalicylic acid Example: simple mixing method Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2.5 g of anhydrous colloidal silica b) 75 g of acetylsalicylic acid and 824.6 g of mannitol are added to a) and mixed. c) The mixture b) is calibrated and then mixed again d) The mixture is distributed in sachets with a theoretical mass of 1 g • A powdery aroma can be added to the mixture EXAMPLE 9 Bag containing 75 mg of clopidogrel base and 325 mg of acetylsalicylic acid Example: simple mixing process Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate are mixed with 2.5 g of anhydrous colloidal silica b) 325 g of acetylsalicylic acid and 574.6 g of mannitol are added to a) and mixed. c) The mixture b) is calibrated and then mixed again d) the mixture is distributed in sachets with a theoretical mass of 1 g • A powdery flavor can be added to the mixture EXAMPLE 10

Tablet containing 75 mg of clopidogrel base and 75 mg of acetylsalicylic acid Example: “hot melt” granulation process Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate, 97.5 g of macrogol 6000, 32.5 g of corn starch and 273.6 g of mannitol are mixed after calibration. b) The temperature of the mixture is brought to 65 ° C., in a thermostatically controlled tank, with slow stirring c) The mixture is granulated with rapid stirring, cooled to room temperature then calibrated d) 75 g of acetylsalicylic acid, 2 g of anhydrous colloidal silica, 65 g of microcrystalline cellulose are added to the calibrated grain and mixed e) 6.5 g of hydrogenated castor oil are added to d) before final mixing f) The final mixture is compressed to the theoretical unit mass of 650 mg EXAMPLE 11

Tablet containing 75 mg of clopidogrel base and 325 mg of acetylsalicylic acid Example: "hot melt" granulation process Unit formula

a) 97.875 g of clopidogrel hydrogenosulfate, 97.5 g of macrogol 6000, 32.5 g of corn starch and 23.6 g of mannitol are mixed after calibration. b) The temperature of the mixture is brought to 65 ° C., in a thermostatically controlled tank, with slow stirring c) The mixture is granulated with rapid stirring, cooled to room temperature then calibrated d) 325 g of acetylsalicylic acid, 2 g of anhydrous colloidal silica, 65 g of microcrystalline cellulose are added to the calibrated grain and mixed e) 6.5 g of hydrogenated castor oil are added to d) before final mixing f) The final mixture is compressed to the theoretical unit mass of 650 mg EXAMPLE 12

Tablets containing 75 mg of clopidogrel base and 75 mg of acetylsalicylic acid Example: direct compression method Unit formula

EXAMPLE 13

Procedure for EXAMPLES 12 and 13

The mixture is made in mini-rhôn for 10 minutes between the active ingredients and the diluents.

Lubricant (hydrogenated castor oil) is added and then mixed with mini-rhôn for 5 minutes. EXAMPLE 14

Procedure:

The active ingredients are mixed with the mini-rhôn for 10 minutes with the diluents. Anhydrous colloidal silica is added to the above mixture and then sieved through a grid of 0.315 mm mesh opening.

Mix with mini-rhôn for 5 minutes.

Add lubricant (hydrogenated castor oil) and mix with mini-rhôn for

5 minutes.

Claims

1. Pharmaceutical composition in unit dosage form which can be administered orally and containing a combination of active principles of clopidogrel hydrogen sulfate and acetylsalicylic acid.

2. Pharmaceutical composition containing a combination of active principles according to claim 1 in association with a pharmaceutical excipient.

3. Pharmaceutical composition containing an association of active principles according to claim 1 or 2 characterized in that clopidogrel hydrogen sulfate is used in polymorphic form 1.

4. Pharmaceutical composition containing an association of active principles according to claim 1 or 2 characterized in that clopidogrel hydrogen sulfate is used in polymorphic form 2.

5. Pharmaceutical composition according to any one of claims 1 or 4 in tablet form.

6. Pharmaceutical composition according to any one of claims 1 or 4 in the form of a capsule.

7. Pharmaceutical composition according to any one of claims 1 or 4 in the form of a dose sachet.

8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a molar ratio of clopidogrel hydrogenosulfate / acetylsalicylic acid of between 2.5 and 11.5.

9. Pharmaceutical composition according to any one of claims 1 to 8, characterized in that the clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a molar ratio of clopidogrel hydrogenosulfate / acetylsalicylic acid of between 5 and 9.

10. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that the clopidogrel hydrogen sulfate and acetylsalicylic acid are present in an amount of 97.875 mg of clopidogrel hydrogen sulfate and 75 mg of acetylsalicylic acid.

11. Pharmaceutical composition according to any one of claims 1 to 10, characterized in that the clopidogrel hydrogen sulfate and acetylsalicylic acid are present in an amount of 97.875 mg of clopidogrel hydrogen sulfate and 375 mg of acetylsalicylic acid.

12. Pharmaceutical composition according to any one of claims 1 to 11 for the treatment of a pathology induced by platelet aggregation including stable or unstable angina, disorders of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, stroke, restenosis after angioplasty, endarterectomy or insertion of metal endovascular prostheses or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillations or even when using vascular prostheses, coronary bypass grafts, or even during radiotherapy to reduce side effects.

13. Use of a composition according to any one of the preceding claims for the preparation of a medicament intended for the treatment of a pathology induced by platelet aggregation.

14. Use of a composition according to any one of the preceding claims for the preparation of a medicament intended for the treatment of a pathology induced by platelet aggregation including stable or unstable angina, disorders of the cardiovascular system and cerebrovascular like thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, cerebral attack, restenosis after angioplasty, endarterectomy or fitting of metal endovascular prostheses or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillation or even when using vascular prostheses, bypass surgery, or even during radiotherapy for reduce side effects.