CZ20013887A3 - Pharmaceutical preparation in unit form containing a combination of acetylsalicylic acid and clopidogrel-hydrogen sulfate - Google Patents

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

Technical field

The present invention relates to a pharmaceutical composition in unit galenical form comprising a combination of active substances with an anti-platelet aggregation action comprising aspirin and clopidogrel hydrogen sulphate. The unit galenic form can be administered orally and is preferably a tablet, a gelatin capsule or a single dose sachet.

BACKGROUND OF THE INVENTION

In the compositions of the invention, aspirin is used in its acid form, and clopidogrel hydrogensulfate can be used either in its polymorphic forms, which are heretofore known, and are called Form 1 (F1) or Form 2 (F2). Clopidogrel hydrogen sulfate form 1 is the salt described in ΞΡ 281459 and clopidogrel hydrogen sulfate form 2 is the salt described in patent application FR 98/07464

The therapeutic interest of combining aspirin and clopidogrel is described, inter alia, in WO 97/29 (753).

Pharmaceutical compositions are disclosed herein, but without any mention that the pharmaceutically acceptable salt used is clopidogrel hydrogensulfate. However, this document indicates that the composition may be used parenterally or orally and that the active compounds may be administered by four routes of administration, i.e. both orally and parenterally, or one orally and the other parenterally or vice versa.

However, no pharmaceutical composition is described which 4 4 44 44 4 4

Would be in unit galenic form and would be suitable for the simultaneous administration of aspirin and clopidogrel hydrogen sulphate.

Assuming that it has been clearly established that doses of each of the platelet combination antiagregating agents may be pre-associated and need not be adapted as a function of the patients to be treated, it has been found useful and advantageous to have a single therapeutic form that can be administered orally, and which comprises the two active ingredients.

Several combination studies have been performed with aspirin and other active substances, but many drawbacks have been found during the manufacture of galenic forms, especially in tablets containing aspirin combined with the active ingredient salts.

Thus, the publication, which appeared in the International Journal of Pharmaceutics (Netherlands) 1984, 18, 287-298, demonstrates the incompatibility between aspirin and other solid active ingredients. Experimental confirmation of these models was demonstrated using aspirin and mepyramine maleate. Addition of mepyramine maleate to aspirin lowers its melting point, resulting in an effect on aspirin decomposition rate in this mixture. Thus, it has been observed that lowering the melting point leads to degradation of the active ingredients in this type of combination.

Consequently, all of these drawbacks, which are well known to one skilled in the art, would not lead to the rapid preparation of a combination of aspirin and a basic salt such as clopidogrene hydrogen sulfate in the same tablet or in the same gelatin capsule or in the same sachet.

SUMMARY OF THE INVENTION

Unexpectedly and surprisingly, according to the invention, it was possible to prepare a pharmaceutical composition in unit galenic form comprising aspirin in combination with another active ingredient which is a basic salt, namely clopidogrel hydrogen.

By the use of various production methods and various techniques well known to those skilled in the art.

Thus, the tablets of the invention may be manufactured by a variety of manufacturing methods, such as:

- a direct tabletting method in which the active substances and the excipients selected are mixed. The resulting mixture is sieved (calibrated) on a screen of predetermined mesh size to equalize the particle size of the components. Mixing is again carried out to ensure good homogeneity of the active ingredients. Specific excipients (e.g., glidants) and lubricant may be added and mixed. The final mixture obtained is then tabletted.

- a pre-granulation method in which the granulation consists in combining and densifying the active substances and the excipients chosen (internal phase components) to obtain, after calibration on a given mesh, grain consisting of particles which are homogeneous with respect to the active substance content compression after the addition of specific excipients (external phase components). Granulation allows the rheological properties of the mixture to be compressed and the physical properties of the tablets to be improved, especially in the case of large doses of active substances. When two active substances are combined in the same tablet, one of them can be incorporated into the external phase, depending on the case.

Three granulation methods are commonly used: wet granulation, dry granulation (compacting) and hot melt granulation.

Dry granulation (compaction) consists in ensuring that the active substances and the selected excipients are mixed, calibrated and then mixed again. The mixture is compressed between two movable rollers rotating in opposite directions, thereby obtaining a given mechanical force according to the forces applied. These • · «· 9 9

9 9

9

9 9 • 9

9 plates are calibrated. Specific excipients are added and the final mixture is tabletted.

and then mix to the temperature,

Hot melt granulation is a granulation method that can be used when the active ingredient decomposes in the presence of water. Active ingredients and selected excipients are calibrated The mixture is introduced with slow stirring, which is slightly higher than the melting point of the excipient, mixed with rapid stirring, and then cooled to room temperature. The obtained grain is calibrated. Specific excipients are added and the final mixture is tabletted. An example of a hot melt method using a fluidized bed granulator is described below. The active ingredients and selected excipients in addition to the fusible excipient are calibrated and then transferred to a fluidized bed granulator. The mixture was stirred by fluidization with hot air until a mixture temperature of slightly below the melting point of the granulation aid was reached. The molten excipient is then sprayed onto the fluidized mixture. The temperature of the fluidizing air is reduced. The obtained grain is calibrated. Specific excipients are added and the final mixture is tabletted.

Gelatin capsules and single dose sachets are prepared according to techniques well known to those skilled in the art.

The pharmaceutical compositions of the invention are used to treat diseases caused by platelet aggregation including stable or unstable angina, cardiovascular and cerebrovascular disorders such as thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, sudden stroke, restenosis after angioplasty, endarterectomy or metallic endovascular prosthesis, or thromboembolic disorders associated with retrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral artery disease, hemodialysis, atrial fibrillation, or during use of vascular prostheses or coronary arterial

99 9

9 »1 99 <9 9 9 9 · · 9 ♦ 9 9 9 9

9 9 9

99 9 bypasses, or during radiotherapy to reduce its side effects.

The pharmaceutical compositions according to the invention are used for the preparation of a therapeutic product intended for the treatment of the above-mentioned pathological conditions and enable the treatment of these pathological conditions.

In the pharmaceutical compositions of the invention, clopidogrel hydrogensulfate and aspirin are present in a clopidogrel hydrogensulfate / aspirin molar ratio of between 2.5 and 11.5, preferably between 5 and 9.

In humans, 1 to 500 mg per day of clopidogrel hydrogensulfate and 1 to 500 mg per day of aspirin are administered, with doses being expressed in equivalent amounts of clopidogrel in free form.

Preferably, 97.875 mg of clopidogrel hydrogen sulfate and 75 to 325 mg of aspirin are administered.

Especially preferred are compositions comprising 97.875 mg of clopidogrel hydrogensulfate and 75 mg of aspirin.

Also preferred are compositions containing 97.875 mg of clopidogrel hydrogen sulfate and 375 mg of aspirin.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Tablet containing 75 mg clopidogrel base and 75 mg aspirin

Example: compaction granulation method

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875 Aspirin 75 Pregelatinised maize starch 30 Anhydrous colloidal silica 2 Anhydrous beta-lactose 324,625 Microcrystalline cellulose (90 µm) 30 Low grade hydroxypropylcellulose substitution 30 Hydrogenated castor oil 10.5 Total 600 (a) 97,875 g of clopidogrel hydrogen sulphate se Mix 2 g without

aqueous colloidal silica

(b) 30 g of pregelatinised maize starch and 74,6 g of anhydrous lactose are added to (a) and mixed

(c) mixture (b) is calibrated and then blended again

(d) The mixture is compacted and then calibrated to an ocularity of 1000 mm

(e) 75 g aspirin, 250 g anhydrous lactose, 30 g microcrystalline cellulose and 30 g hydroxypropylcellulose with a low degree of substitution shall be mixed with the calibrated grain.

(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 beta-lactose may be replaced by an equivalent amount of mannitol.

Example 2

Tablet containing 75 g of clopidogrel base and 200 mg aspirin

Example: compaction granulation method

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875 Aspirin 200 Pregelatinised maize starch 30 Anhydrous colloidal silica 2 Anhydrous beta-lactose 199,625 Microcrystalline cellulose (90 µm) 30 Low grade hydroxypropylcellulose substitution 30 Hydrogenated castor oil 10.5

Total

600

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2 g of anhydrous colloidal silica

(b) 30 g of pregelatinised maize starch and 74,6 g of anhydrous lactose are added to (a) and mixed

(c) mixture (b) is calibrated and then blended again

(d) The mixture is compacted and then calibrated to an ocularity of 1000 mm

(e) 200 g of aspirin, 125 g of anhydrous lactose, 30 g of microcrystalline cellulose and 30 g of low-substitution 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 tableted at a theoretical unit dose weight of 600 mg ⁺ Anhydrous beta-lactose may be replaced by an equivalent amount of mannitol.

Example 3

Tablet containing 75 mg clopidogrel base and 325 mg aspirin

Example: compaction granulation method

Composition of the unit

Folders

Amount in mg

Clopidogrel hydrogen sulphate (equivalent to 75 mg base)

97,875 · • * f • f · ·

999 99

9 9

9

9 9

9

9

Folders Amount in mg Aspirin 325 Pregelatinised maize starch 30 Anhydrous colloidal silica 2 Anhydrous beta-lactose 74.625 Microcrystalline cellulose (90 µm) 30 Low grade hydroxypropylcellulose substitution 30 Hydrogenated castor oil 10.5 Total 600

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2 g of anhydrous colloidal silica

(b) 30 g of pregelatinised maize starch and 74,6 g of anhydrous lactose are added to (a) and mixed

(c) mixture (b) is calibrated and then blended again

(d) The mixture is compacted and then calibrated to an ocularity of 1000 mm

(e) 325 g of aspirin, 30 g of microcrystalline cellulose and 30 g of low-substitution hydroxypropylcellulose are mixed with the calibrated grain

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

44 44 44

4 4 4 44 4 · 444

444 444 44 «444 44 444444

4 4 4 4 4 5

4444 44 444 44 44

g) The final mixture is tableted at a theoretical unit dose weight of 600 mg ⁺ Anhydrous beta-lactose may be replaced by an equivalent amount of mannitol.

Example 4

Tablet containing 75 g of clopidogrel base and 75 mg aspirin

Example: direct tableting method

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulphate (equivalent to 75 mg base) 97,875 Aspirin 75 Cornstarch 30 Anhydrous colloidal silica 2 Mannitol 300 DC 324,625 Microcrystalline cellulose (90 vUm) 60 Hydrogenated castor oil 10.5 Total 600 (a) 97,875 g of clopidogrel hydrogen sulphate se Mix 2 g without

aqueous colloidal silica

(b) 75 g aspirin, 30 g maize starch, 324,6 g mannitol

9 9 9 9 9 9 9

9 9 9 9 9

999 · 99,999 9

9

999 99 99 and 60 g of microcrystalline cellulose are added to a) and mixed

(c) mixture (b) is calibrated and then blended again

d) to c) 10.5 g hydrogenated castor oil are added before final mixing

e) the final mixture is tableted at a theoretical unit dose weight of 600 mg ⁺ Mannitol may be replaced by an equivalent amount of anhydrous beta-lactose.

Example 5

Tablet containing 75 g of clopidogrel base and 325 mg of aspirin

Example: direct tableting method

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate 97,875 (equivalent to 75 mg of base) Aspirin 325 Cornstarch 30 Anhydrous colloidal silica 2 Mannitol 300 DC 124.625 Microcrystalline cellulose (90 Jhm) 60

····

5 · «·· ·

4 · ·· ·

4 ··

1 · · · · · · · · · · ·

** · · · ·

Folders Amount in mg Hydrogenated castor oil 10.5 Total 600

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2 g of anhydrous colloidal silica

(b) 325 g aspirin, 30 g maize starch, 124.6 g mannitol and 60 g microcrystalline cellulose are added to (a) and mixed

(c) mixture (b) is calibrated and then blended again

d) to c) 10.5 g hydrogenated castor oil are added before final mixing

e) the final mixture is tableted at a theoretical unit dose weight of 500 mg ⁺ Mannitol may be replaced by an equivalent amount of anhydrous beta-lactose.

Example 6

Gelatin capsule containing 75 g of clopidogrel base and 75 mg of aspirin

Example: method using simple mixing

- 13 - ····················· ··· · · ··· · · · · · ··· · • · · · · · · · · · · · ·

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875

Aspirin 75 Pregelatinised maize starch 5 0 Anhydrous colloidal silica 2.5 Mannitol 300 DC 265,875 Hydrogenated castor oil 8.75 Total 500

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2,5 g of anhydrous colloidal silica

(b) 75 g of aspirin, 50 g of pregelatinised maize starch and 265.9 g of mannitol are added to (a) and mixed

(c) mixture (b) is calibrated and then blended again

d) 8.75 g hydrogenated are added to c) before final mixing

castor oil e) the final mixture is divided into gelatinous weight per unit dose of 500 mg capsules

⁺ Mannitol can be replaced by equivalent beta-lactose. amount of anhydrous

Example 7

A gelatin capsule containing 75 g of clopidogrel base and 325 mg of aspirin

Example: method using simple mixing

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875 Aspirin 325 Pregelatinised maize starch 50 Anhydrous colloidal silica 2.5 Mannitol 300 DC 15,875 Hydrogenated castor oil 8.75 Total 500

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2,5 g of anhydrous colloidal silica

(b) 325 g of aspirin, 50 g of pregelatinised maize starch and 15.9 g of mannitol are added to (a) and mixed

(c) mixture (b) is calibrated and then blended again

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

e) The final mixture is dispensed into gelatin capsules at a theoretical unit dose weight of 500 mg ⁺ Mannitol may be replaced by an equivalent amount of anhydrous beta-lactose.

Example 8

A sachet containing 75 g of clopidogrel base and 75 mg of aspirin

Example: method using simple mixing

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875 Aspirin 75 Anhydrous colloidal silica 2.5 Mannitol 300 DC 824,625 Total 1000

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2,5 g of anhydrous colloidal silica

b) 75 g of aspirin and 824.6 g of mannitol are added to a) and mixed

c) The mixture b) is calibrated and then blended again.

d) The mixture is dispensed into sachets at a theoretical unit dose weight of 1 g ⁺ . A powdered flavoring may be added to the mixture.

Example 9

A sachet containing 75 g of clopidogrel base and 325 mg of aspirin

Example: method using simple mixing

Composition of the unit

Folders Amount in mg Copidogrel hydrogen sulphate (equivalent to 75 mg of base) 97,875 Aspirin 325 Anhydrous colloidal silica 2.5 Mannitol 300 DC 574,625 Total 1000 (a) 97,875 g of clopidogrel hydrogen sulphate is mixed with 2.5 without

aqueous colloidal silica

b) 325 g of aspirin and 574.6 g of mannitol are added to a) and mixed

(c) mixture (b) is calibrated and then blended again

(d) The mixture is divided into sachets at a theoretical unit dose weight of 1 g

^A powdered flavoring may be added to the mixture.

Example 10

Tablet containing 75 g of clopidogrel base and 75 mg aspirin

Example: hot-melt granulation method

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875 Aspirin 75 Makrogol 6000 97.5 Cornstarch 32.5 Anhydrous colloidal silica 2 Mannitol 300 DC 273,625 Microcrystalline cellulose (50 µm) 65 Hydrogenated castor oil 6.5 Total 650

(a) 97,875 g clopidogrel hydrogen sulphate, 97,5 g macrogol 6000, 32,5 g maize starch and 273,6 g mannitol shall be mixed after calibration

(b) bring the temperature of the mixture in a thermostatic incubator at a temperature of.

with gentle stirring at 65 ° C

c) the mixture is granulated with vigorous stirring, cooled to room temperature and then calibrated

(d) 75 g of aspirin, 2 g of anhydrous silica and 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) tableting the final mixture to a theoretical unit dose weight of 650 mg

Example 11

Tablet containing 75 g of clopidogrel base and 325 mg of aspirin

Example: hot-melt granulation method

Composition of the unit

Folders Amount in mg Clopidogrel hydrogen sulfate (equivalent to 75 mg of base) 97,875 Aspirin 325 Macrogol 6000 97.5 Cornstarch 32.5 Anhydrous colloidal silica 2

Folders Amount in mg Mannitol 23,625 Microcrystalline cellulose (50jim) 65 Hydrogenated castor oil 6.5 Total 650

(a) 97,875 g clopidogrel hydrogen sulphate, 97,5 g macrogol 6000, 32,5 g maize starch and 23,6 mannitol shall be mixed after calibration

(b) bring the temperature of the mixture in a thermostatic incubator with gentle stirring to 65 ° C

c) granulated with vigorous stirring, cooled to room temperature and then calibrated

(d) 325 g of aspirin, 2 g of anhydrous silica and 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) tableting the final mixture to a theoretical unit dose weight of 650 mg

Example 12

Tablets containing 75 g of clopidogrel base and 75 mg aspirin

Example: direct tableting method

Composition of the unit

Folders Quantity in mg Clopidogrel form 2 (equivalent to 75 mg of base) 97,875 Aspirin 75,00 Emdex ^R 136,605 Hydrogenated castor oil 5,520 Total 315 Example 13 Folders Quantity in mg Clopidogrel form 2 (equivalent to 75 mg base) 97,875 Aspirin 75,00 Cellalactosa 80 121,875 Hydrogenated castor oil 5.25 Total 300

99 9 * · · ♦ • •• 9 9 9 * 9 999 • 99 999 99

9900 99 99 «9

9 9 9 9 9

9999 99 999 99 99

Procedure for Examples 12 and 13

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

A lubricant (hydrogenated castor oil) is added and then mixed by mini-rhon for 5 minutes.

Example 14

Tablets containing 75 g of clopidogrel base and 75 mg aspirin

Example: direct tableting method

Composition of the unit

Folders Amount in mg Clopidogrel form 2 (equivalent to 75 mg of base) 97,875 Aspirin 75,00 Emdex ^R 10.00 Avicel PH 112 21,125 Pearlitol SD 200 24,00 Anhydrous colloidal silica 2.00 Hydrogenated castor oil 4.20 Total 420

·· · 4 · 4 · 4 · 4 · 4 ·

44 44 4

Method :

The active ingredients are mixed with diluents for 10 minutes using a mini-rhon.

Colloidal silicon dioxide was added to the above mixture and then screened through a 0.315 mm screen.

Mixing with a mini-rhon is performed for 5 minutes.

A lubricant (hydrogenated castor oil) is added and mixing is continued with a mini-rhon apparatus for 5 minutes.

Claims (10)

PATENTOVÉ Claims A pharmaceutical composition in unit galenic form, which can be administered orally, comprising a combination of the active ingredients clopidogrel hydrogen sulphate and aspirin. A pharmaceutical composition comprising a combination of active ingredients according to claim 1 in combination with a pharmaceutical excipient. Pharmaceutical composition comprising a combination of active substances according to claims or 2, characterized in that clopidogrel hydrogen sulphate is used in polymorph form 1. A pharmaceutical composition comprising an active ingredient combination according to claim 1 or 2, characterized in that clopidogrel hydrogen sulphate is used in polymorph form 2. 5. Pharmaceutical means according to of claims 1 and 4 ve form tablet. 6. Pharmaceutical gelatin capsules. means according to of claims 1 and 4 ve form 7. Pharmaceutical composition in the form of unit dose sachets. according to claims 1 and 4 ve 8. Pharmaceutical means according to of claims 1 to 7, you- characterized in that clopidogrel hydrogensulfate and aspirin are present in a mixture of clapidogrel hydrogensulfate with aspirin in a molar ratio between 2.5 and 11.5. Pharmaceutical composition according to claims 1 to 8, 9 9 99 99 4 99 9 4 9 9 949 499,999 94 9 • 9949 99,999 4 9 9 9 999994 9944 99 999 * 4 94 999, characterized in that clopidogrel hydrogen sulphate and aspirin are present in a mixture of clapidogrel hydrogen sulphate with aspirin in a molar ratio between 5 and 9. Pharmaceutical composition according to claims 1 to 9, characterized in that clopidogrel hydrogen sulphate and aspirin are present in a ratio of 97.875 mg clopidogrel hydrogen sulphate and 75 mg aspirin. Pharmaceutical composition according to claims 1 to 10, characterized in that clopidogrel hydrogen sulphate and aspirin are present in a ratio of 97.875 mg clopidogrel hydrogen sulphate and 375 mg aspirin. Pharmaceutical composition according to claims 1 to 11 for the treatment of diseases caused by platelet aggregation including stable or unstable angina, cardiovascular and cerebrovascular disorders such as thromboembolic disorders associated with atherosclerosis and gins, stroke, darteroctomia or introduction with diabetes such as unstable anrestenosis after angioplasty, enkovic endovascular prosthesis, or thromboembolic disorders associated with retrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral artery disease, hemodialysis, atrial fibrillation, or during use of vascular prostheses or coronary artery bypass therapies, or during or side effects. Use of a composition according to claims 1 to 12 for the preparation of a medicament for the treatment of a disease caused by platelet aggregation. Use of a composition according to claims 1 to 13 for the preparation of a medicament for treating a disease caused by platelet aggregation including stable or unstable angina, cardiovascular and cerebrovascular disorders such as thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, stroke, restenosis after an25 • gioplasty, endarteroctomia or the introduction of metallic endovascular prosthesis, or thromboembolic disorders associated with retrombosis after thrombolysis, heart attack, dementia of ischemic origin, peripheral artery disease, hemodialysis, with atrial fibrillation or during the use of vascular prostheses or coronary arterial bypass surgery or during radiotherapy to reduce its side effects.