HUP0202329A2 - Pharmaceutical composition in unit form containing acetylsalycilic acid and clopidogrel hydrogenosulphate - Google Patents

Description

PO202329

PUBLICATION COPY

Galenic pharmaceutical forms containing acetylsalicylic acid and clopidogrel hydrogen sulfate

Notifier: SANOFI-S YNTHEL AB O

174, avenue de France. F-75013 Paris France

Inventors:

- ABRAMOVICI, Bemard, F-34990 Juvignac (FR)

- LHERITIER, Jean, F-34090 Montpellier (FR)

EU priority: 30 April 1999 (1999.04.30.)

99/05497(FR)

International application: PCT/FR00/01086 (2000.04.25.) publication: WO/00/66130 (2000.11.09.)

Representative: Mrs. Tamás Mármarosi

CHINOIN Pharmaceutical and Chemical Products Factory Ltd., Budapest (pursuant to Section 12 (1) of the Patent Attorneys Act)

SSY-30/NEW

SSY-30

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

The present invention relates to a pharmaceutical composition in galenic unit form, which contains a combination of platelet aggregation inhibitory active ingredients and consists of acetylsalicylic acid and clopidogrel hydrogen sulfate.

The galenic unit form can be administered orally and preferably consists of a tablet or gelatin capsule.

In the composition according to the invention, acetylsalicylic acid is used in its acid form and clopidogrel hydrogen sulfate is used in one of the currently known polymorphic forms, which are called form 1 (F1) or form 2 (F2).

Clopidogrel hydrogen sulfate form 1 is described in European patent EP-281459 and clopidogrel hydrogen sulfate form 2 (F2) is described in patent application FR-98/07464.

The therapeutic need for combining acetylsalicylic acid and clopidogrel is described in patent application WO-97/29753, among others.

The pharmaceutical compositions mentioned therein never specify that the pharmaceutically acceptable salt used is clopidogrel hydrogen sulfate. This document does indicate that the composition can be administered parenterally or orally and that the active ingredients can be administered by four routes of administration, i.e. both orally, both parenterally or one orally and the other parenterally or vice versa.

In any case, a pharmaceutical preparation prepared in galenic unit form, which would be suitable for the combined administration of acetylsalicylic acid and clopidogrel hydrogen sulfate, has not been described.

Provided that it is clearly defined that the dosage of each platelet aggregation inhibitor component may be predetermined and does not require adjustment to the patient to be treated, it has been found useful and advantageous to have a single dosage form which can be administered orally and which contains these two active ingredients.

Several combination studies have been conducted with acetylsalicylic acid and other active ingredients, but many disadvantages have been encountered in the preparation of galenic forms, especially in the case of tablets containing acetylsalicylic acid and salts of an active ingredient.

Thus, the publication in the Int. Journal of Pharmaceutics (Netherlands) /18 p 287-298(1984)/ shows the incompatibility between acetylsalicylic acid and other solid active ingredients. Experimental confirmation of these models was made using acetylsalicylic acid and mepyramine maleate. The addition of mepyramine maleate to acetylsalicylic acid lowered its melting point, which affects the decomposition rate of acetylsalicylic acid in this mixture. Thus, it was observed that the decrease in melting point leads to the decomposition of the active ingredients in this type of mixture.

All these disadvantages, which are well known to the skilled person, would not encourage the preparation of a combination of acetylsalicylic acid and a basic salt such as clopidogrel hydrogen sulfate in the same tablet or gelatin capsule or sachet.

It was completely unexpected and surprising that it was possible according to the invention to produce a pharmaceutical composition in galenic unit form, which contained acetylsalicylic acid in combination with another active ingredient, which is a basic salt, more precisely clopidogrel hydrogen sulfate, using various manufacturing methods and techniques well known to the person skilled in the art.

Thus, the tablets of the invention can be produced by various manufacturing processes, for example:

- Direct tableting method, in which the active ingredients and selected excipients are mixed. The resulting mixture is sieved through a sieve of a predetermined mesh value to homogenize the particle size of the components.

Mixing is carried out again to ensure good homogenization of the active ingredients, special flow agents and lubricants are added and mixed. The final mixture obtained is tableted.

- Pregranulation method, in which granulation, mixing and compacting of active ingredients and selected excipients (internal phase components) are carried out in order to obtain, by passing through a given sieve, a granule consisting of homogeneous active ingredient-containing particles and suitable for tablet compression after the addition of specific excipients (external phase components). Granulation allows improving the rheological properties of the mixture to be compressed and the physical properties of the tablets, especially in the case of active ingredients or their dosages. If two active ingredients are combined in the same tablet, it is possible to incorporate one of them into one of the external phases, depending on the case.

Currently, three methods of granulation are used: Wet granulation, dry granulation (compaction) and “hot melt” granulation.

Dry granulation (compaction) involves ensuring that the active ingredients and selected excipients are mixed, “calibrated” (sifted to a given screen size) and the components are blended again. The mixture is forced through two counter-rotating rollers to obtain flakes with a given mechanical strength corresponding to the forces applied.

These plates are calibrated. The specified excipients are added and the final mixture is tableted.

“Hot melt” granulation is a granulation method that can be used when the active ingredient decomposes in the presence of water.

The active ingredients and selected excipients are calibrated and then mixed. The mixture is brought to a temperature slightly above the melting point of the excipient with slow stirring, mixed with rapid stirring, and then cooled to room temperature. The resulting granular material is calibrated. Specific excipients are added and the final mixture is tableted.

An example of “hot melt” granulation using a fluidized air bed granulator is described below. The entire mixture is fluidized by introducing hot air until the temperature of the mixture is slightly lower than the melting point of the granulating component. The molten granulating component is then sprayed onto the fluidized mixture. The temperature of the fluidizing air is reduced. The resulting granules are screened.

The specified components are mixed and the final mixture is tableted.

Gelatin capsules and single-dose sachets are prepared in a manner well known to those skilled in the art.

The pharmaceutical composition of the invention is used in the treatment of diseases related to platelet aggregation, including stable and unstable angina, disorders of the cardiovascular and cerebrovascular systems such as thromboembolic disorders related to atherosclerosis and diabetes, such as unstable angina, stroke, restenosis after angioplasty, endarterectomy, implantation of metallic endovascular prostheses, or thromboembolic disorders related to recurrent thrombosis, such as thrombosis after thrombus dissolution of infarction, dementia or ischemic origin, peripheral arterial disease, hemodialysis, atrial fibrillation, use of vascular prostheses or coronary artery bypass grafts or to reduce side effects during radiotherapy.

The pharmaceutical compositions of the invention are used for the preparation of pharmaceutical preparations aimed at and capable of treating the above-mentioned pathologies.

In the pharmaceutical compositions according to the invention, clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a clopidogrel hydrogen sulfate/acetylsalicylic acid ratio of between 2.5 and 11.5, preferably between 5 and 9.

In humans, 1-500 mg/day of clopidogrel hydrogen sulfate and 1-500 mg/day of acetylsalicylic acid are used; the doses are expressed as free clopidogrel.

Preferably, 97.875 mg of clopidogrel hydrogen sulfate and 75-325 mg of acetylsalicylic acid are used.

Compositions containing 97.875 mg of clopidogrel hydrogen sulfate and 75 mg of acetylsalicylic acid are particularly preferred.

A composition containing 97.875 mg of clopidogrel hydrogen sulfate and 375 mg of acetylsalicylic acid is also preferred.

Example 1: Tablet containing 100 mg of clopidogrel base and 75 mg of acetylsalicylic acid

Example: Granulation process by pressing

Unit composition

Components Amount in mg Clopidogrel hydrogen sulfate equivalent to 75 mg base 97,875 Acetylsalicylic acid 75 Pregelatinized corn starch 30 Anhydrous colloidal silica gel 2 Anhydrous β-lactose 324,625 Microcrystalline cellulose 90 pm 30 Low-Substitution Hydroxypropyl Cellulose 30 Hydrogenated castor oil 10.5 Total weight 600

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2 g of anhydrous colloidal silica gel.

b.) To a.) add 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose and mix.

c.) the mixture from b.) is sieved and mixed again.

d.) the mixture is pressed and then sieved again through a 1000 mesh sieve.

e.) 75 g of acetylsalicylic acid, 250 g of anhydrous lactose, 30 g of microcrystalline cellulose and g of low-substituted hydroxypropyl cellulose are mixed with the sieved granule.

f.) 10.5 g of hydrogenated castor oil are added before final mixing.

g.) the final mixture is tableted at a theoretical unit weight of 600 mg.

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

Example 2: Tablet containing mg of clopidogrel base and 200 mg of acetylsalicylic acid

Example: Granulation method by pressing

Unit formula

Ingredients Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 200 Pre-gelatinized corn starch 30 Anhydrous colloidal silica gel 2 Anhydrous β-lactose 199,625 Microcrystalline cellulose (90 pm) 30 Low-substituted hydroxypropyl cellulose 30

Ingredients Amount in mg Hydrogenated castor oil 10.5 Total weight 600

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2 g of anhydrous colloidal silica gel

b.) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a.) and mixed.

c.) ab.) mixture is sieved and mixed again

d.) the mixture is pressed and then sieved through a 1000 mm mesh sieve

e.) 200 g of acetylsalicylic acid, 125 g of anhydrous lactose, 30 g of microcrystalline cellulose and 100 g of low-substituted hydroxypropyl cellulose are mixed with the sieved granule.

f.) 10.5 g of hydrogenated castor oil is added before final mixing.

g.) the final mixture is tableted at a theoretical unit weight of 600 mg • Anhydrous β-lactose can be replaced with an equivalent amount of mannitol.

Example 3: Tablet containing 100 mg of clopidogrel base and 325 mg of acetylsalicylic acid

Example: granulation method by pressing

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate equivalent to 75 mg base 97,875 Acetylsalicylic acid 325 Pre-gelatinized cornbread seasoning 30 Anhydrous colloidal silica gel 2 Anhydrous β-lactose 74,625 Microcrystalline cellulose 90 pm 30 Low-Substitution Hydroxypropyl Cellulose 30 Hydrogenated castor oil 10.5 Total weight 600

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2 g of anhydrous colloidal silica gel.

b.) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a.) and mixed.

c.) the mixture from b.) is sieved and mixed again

d.) the mixture is pressed and sieved at 1000 mm mesh size

e.) 325 g of acetylsalicylic acid, 30 g of microcrystalline cellulose and 30 g of low-substituted hydroxypropyl cellulose are mixed with the sieved granule.

f.) 10.5 g of hydrogenated castor oil are added to the mixture before final mixing.

g.) The final mixture is tableted at a unit weight of 600 mg.

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

Example 4: Tablet containing 100 mg of clopidogrel and 75 mg of acetylsalicylic acid

Example: Direct tableting method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate equivalent to 75 mg base 97,875 Acetylsalicylic acid 75 Corn starch 30 Anhydrous colloidal silica gel 2 Mannitol 300 DC 324,625 Microcrystalline cellulose (90 pm) 60 Hydrogenated castor oil 10.5 Total weight 600

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2 g of anhydrous colloidal silica gel

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 from b.) is sieved and then mixed again

d.) 10.5 g of hydrogenated castor oil is added to c.) before final mixing

e.) the final mixture is tableted at a theoretical unit weight of 600 mg • Mannitol can be replaced with an equivalent amount of anhydrous β-lactose.

Example 5: Tablet containing 100 mg of clopidogrel base and 325 mg of acetylsalicylic acid

Example: Direct tableting method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate equivalent to 75 mg base 97,875 Acetylsalicylic acid 325 Corn cake maker 30 Anhydrous colloidal silica gel 2 Mannitol 300 DC 124,625 Microcrystalline cellulose 90 pm 60 Hydrogenated castor oil 10.5 Total mass 650

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2 g of anhydrous colloidal silica gel

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 from b.) is sieved and then mixed again

d.) 10.5 g of hydrogenated castor oil is added to c.) before final mixing

e.) the final mixture is tableted at a theoretical unit weight of 650 mg • Mannitol can be replaced with an equivalent amount of anhydrous β-lactose.

Example 6

Gelatin capsule containing 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example: Simple mixing method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 75 Pregelatinized cornstarch 50 Anhydrous colloidal silica gel 2.5 Mannitol 300 DC 265,875 Hydrogenated castor oil 8.75 Total weight 500

a.) 97.875 g of clopidogrel hydrogen sulfate and 2.5 g of anhydrous colloidal silica gel are mixed

b.) 75 g of acetylsalicylic acid, 50 g of pregelatinized corn starch and 265.9 g of mannitol are added to a.) and mixed

c.) the mixture from b.) is sieved and mixed again

d.) 8.75 g of hydrogenated castor oil are added to c.) before final mixing.

e.) The final mixture is distributed into gelatin capsules with a theoretical unit weight of 500 mg.

• Mannitol can be replaced with an equivalent amount of anhydrous β-lactose.

Example 7: Gelatin capsule containing 100 mg of clopidogrel base and 325 mg of acetylsalicylic acid

Example: Simple mixing method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 325 Pre-gelatinized corn starch 50 Anhydrous colloidal silica gel 2.5 Mannitol 300 DC 15,875 Hydrogenated castor oil 8.75 Total weight 500

a.) 97.875 g of clopidogrel hydrogen sulfate and 2.5 g of anhydrous colloidal silica gel are mixed

b.) 325 g of acetylsalicylic acid, 50 g of pregelatinized corn starch and 15.9 g of mannitol are added to a.) and mixed

c.) the mixture from b.) is sieved and mixed again

d.) 8.75 g of hydrogenated castor oil are added to c.) before final mixing.

e.) The final mixture is distributed into gelatin capsules with a theoretical unit weight of 500 mg.

• Mannitol can be replaced with an equivalent amount of anhydrous β-lactose.

Example 8: Sachet containing 100 mg of clopidogrel base and 75 mg of acetylsalicylic acid

Example: Simple mixing method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 75 Anhydrous colloidal silica gel 2.5 Mannitol 300 DC 824,625 Total weight 1000

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2.5 g of anhydrous colloidal silica gel

b.) add 75 g of acetylsalicylic acid and 824.6 g of mannitol to a.) and mix

c.) the mixture is sieved and then mixed again

d.) the mixture is distributed into sachets with a theoretical weight of 1 g.

• Powdered flavoring may be added to the mixture.

Example 9: Sachet containing 100 mg of clopidogrel base and 325 mg of acetylsalicylic acid

Example: Simple mixing method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 325 Anhydrous colloidal silica gel 2.5 Mannitol 300 DC 574,625 Total weight 1000

a.) 97.875 g of clopidogrel hydrogen sulfate are mixed with 2.5 g of anhydrous colloidal silica gel

b.) add 325 g of acetylsalicylic acid and 574.6 g of mannitol to a.) and mix

c.) the mixture is sieved and then mixed again

d.) the mixture is distributed into sachets with a theoretical mass of 1 g.

• A powdered thickener can be added to the mixture.

Example 10: Tablet containing 100 mg of clopidogrel base and 75 mg of acetylsalicylic acid

Example: Hot melt method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 75

Ingredients Amount in mg Macrogol 6000 97.5 Cornstarch 32.5 Anhydrous colloidal silica gel 2 Mannitol 273,625 Microcrystalline cellulose (50 pm) 65 Hydrogenated castor oil 6.5 Total weight 650

a.) 97.875 g clopidogrel hydrogen sulfate, 97.5 g Macrogol 6000, 32.5 g corn starch and 273.6 g mannitol mixture after sieving

b.) the temperature of the mixture is raised to 65 °C in a thermostated incubator with slow stirring

c.) granulate the mixture with rapid stirring, cool to room temperature and sieve

d.) 75 g of acetylsalicylic acid, 2 g of anhydrous colloidal silica gel and 65 g of microcrystalline cellulose are added to the sieved granules and mixed

e.) 6.5 g of hydrogenated castor oil is added before final mixing

f.) the final mixture is tableted at a theoretical weight of 650 mg.

Example 11: Tablet containing 11 mg of clopidogrel base and 325 mg of acetylsalicylic acid

Example: Hot melt method

Unit formula

Components Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 325 Macrogol 6000 97.5 Corn stalks 32.5 Anhydrous colloidal silica gel 2 Mannitol 23,625 Microcrystalline cellulose (50 pm) 65 Hydrogenated castor oil 6.5 Total weight 650

a.) 97.875 g clopidogrel hydrogen sulfate, 97.5 g Macrogol 6000, 32.5 g corn starch and 23.6 g mannitol mixture after sieving

b.) the temperature of the mixture is raised to 65 °C in a thermostated incubator with slow stirring

c.) granulate the mixture with rapid stirring, cool to room temperature and sieve

d.) 325 g of acetylsalicylic acid, 2 g of anhydrous colloidal silica gel and 65 g of microcrystalline cellulose are added to the sieved granules and mixed

e.) 6.5 g of hydrogenated castor oil is added before final mixing

f.) the final mixture is tableted at a theoretical weight of 650 mg.

Example 12. Tablets containing mg ciopidogrel base and 75 g acetylsalicylic acid

Example: Direct tableting method

Unit formula

Components Amount in mg Clopidogrel Form 2 (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 75 Emdex® 136,605 Hydrogenated castor oil 5.520 Total weight 315

Example 13

Components Amount in mg Clopidogrel Form 2 (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 75 Cellactose 80. 121875 Hydrogenated castor oil 5.52 Total mass 300

Procedure for Examples 12 and 13

The active ingredients and diluents are mixed for 10 minutes in a mini-rhön apparatus.

A thickener (hydrogenated castor oil) is added and mixed in a mini-rhön device for 5 minutes.

Example 14. Tablets containing mg clopidogrel base and 75 mg acetylsalicylic acid

Example: Direct tableting method

Unit formula

Components Amount in mg Clopidogrel Form 2 (equivalent to 75 mg base) 97,875 Acetylsalicylic acid 75 Emdex® 10 Avicel PH 112 21.125 Pearlitol SD 200 24 Anhydrous silica gel 2 Hydrogenated castor oil 4.2 Total weight 240

Proceedings:

The active ingredients are mixed with the diluents for 10 minutes in a mini-rhön apparatus.

Anhydrous silica gel is added to the above mixture and then sieved through a 0:315 mm mesh sieve.

The mixture is mixed in a mini-rhön device.

The lubricant (hydrogenated castor oil) is added and mixed for 5 minutes in a mini rhön apparatus.

Claims (14)

Patent claims 1. Pharmaceutical composition, which is implemented in galenic form, can be administered orally and contains a combination of the active ingredients clopidogrel hydrogen sulfate and acetylsalicylic acid. 2. A pharmaceutical composition comprising the active ingredient combination according to claim 1 together with a pharmaceutical excipient. 3. Pharmaceutical composition comprising a combination of pharmaceutical active ingredients according to claim 1 or 2, characterized in that clopidogrel hydrogen sulfate is used in polymorphic form 1. 4. A pharmaceutical composition comprising a combination of active pharmaceutical ingredients according to claim 1 or 2, characterized in that clopidogrel hydrogen sulfate is used in polymorphic form 2. 5. A pharmaceutical composition according to any one of claims 1-4 in tablet form. 6. The pharmaceutical composition according to any one of claims 1-4 in the form of a gelatin capsule. 7. A single dose sachet of the pharmaceutical composition according to any one of claims 1-4. 8. Pharmaceutical composition according to any one of claims 1-7, characterized in that the clopidogrel hydrogen sulfate and the acetylsalicylic acid are present in a molar ratio of clopidogrel hydrogen sulfate/acetylsalicylic acid between 2.5 and 11.5. 22 .......... 9. The composition according to any one of claims 1-8, characterized in that the clopidogrel hydrogen sulfate and the acetylsalicylic acid are present in a molar ratio of clopidogrel hydrogen sulfate/acetylsalicylic acid of between 5 and 9. 10. Pharmaceutical composition according to any one of claims 1-9, characterized in that the clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a ratio of 97.875 mg of clopidogrel hydrogen sulfate to acetylsalicylic acid. 11. Pharmaceutical composition according to any one of claims 1-10, characterized in that the clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a ratio of 97.875 mg of clopidogrel hydrogen sulfate and 375 mg of acetylsalicylic acid. 12. A pharmaceutical composition according to any one of claims 1-11 for the treatment of diseases caused 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 metal endovascular prosthesis implantation or thromboembolic disorders associated with rethrombosis after thrombosis, infarction, ischemic dementia, peripheral arterial disease, hemodialysis, atrial fibrillation or the use of vascular prostheses or coronary artery bypass grafts or to reduce side effects during radiotherapy. 13. Use of a pharmaceutical composition according to any one of the preceding claims for the preparation of a pharmaceutical composition for the treatment of a disease caused by platelet aggregation. 23 ......... 14. Use of a pharmaceutical composition according to any one of the preceding claims for the preparation of a medicament for the treatment of diseases caused by platelet aggregation, including stable or unstable angina, disorders of the cardiovascular and cerebrovascular systems such as thromboembolic disorders associated with atherosclerosis and diabetes, such as unstable angina, stroke, restenosis after angioplasty, endarterectomy or metal endovascular prosthesis implantation or thromboembolic disorders associated with rethrombosis after thrombosis, infarction, ischemic dementia, peripheral arterial disease, hemodialysis, atrial fibrillation or the use of vascular prostheses or coronary artery bypass grafts or to reduce side effects during radiotherapy. Instead of the notifier, the authorized person: sanoFi-syhtheiabo 78. (^CHINOIN CHINOIN Rt. ^Member of the Sanofi-Syr^thelabo group of companies ' ( i -· '...... / (y Old/New