SK15542001A3 - Pharmaceutical composition in unit form containing acetylsalicylic acid and clopidogrel hydrogenosulphate - 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

A pharmaceutical composition in unit form comprising a combination of acetylsalicylic acid and clopidogrel hydrogen sulfate and its use

Technical field

The invention relates to a pharmaceutical composition in unit galenic form comprising a combination of active substances with an antiplatelet effect on platelets consisting of aspirin and clopidogrel hydrogen sulphate. The unit galenical form may be administered orally and is preferably a tablet, gelatin capsule or 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 sulphate Form 1 is a salt described in EP 281459 and clopidogrel hydrogen sulphate Form 2 is a salt described in patent application FR 98/07464.

The therapeutic interest of combining aspirin and clopidogrel is described, inter alia, in WO 97/29753.

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

However, no pharmaceutical composition that is in unit galenic form and that is suitable for the simultaneous administration of aspirin and clopidogrel hydrogen sulfate is disclosed.

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Assuming that it has been clearly established that doses of each of the anti-platelet aggregating agents on the platelets may be pre-associated and may 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 contains the two active ingredients.

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

Thus, the publication, which appeared in the International Journal of Pharmaceutics (Netherlands) 1984, 18, 287 and 298, demonstrates 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 the rate of aspirin degradation 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 these drawbacks, which are well known to those skilled in the art, would not lead to the rapid preparation of a combination of aspirin and a base salt such as clopidogrel hydrogen sulfate in the same tablet or in the same gelatin capsule or in the same sachet.

SUMMARY OF THE INVENTION

Quite unexpectedly and surprisingly, it was possible according to the invention to prepare a pharmaceutical composition in unit galenic form comprising aspirin in combination with another basic salt, namely clopidogrel hydrogen sulphate, using a variety of manufacturing methods and techniques well known to one skilled in the art.

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The tablets of the invention may thus be produced 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 having a predetermined mesh size to equalize the particle size of the components. Stirring 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.

pregranulation method, wherein the granulation consists in combining and concentrating the active substances and the selected excipients (internal phase components) to obtain, after calibration on a given screen, grain consisting of particles which are homogeneous in terms of the active substance content suitable for compression after the addition of specific excipients (external phase components). Granulation allows the rheological properties of the composition to be compressed and the physical properties of the tablets to be improved, especially in the case of large doses of active ingredients. When two active substances are combined in the same tablet, it is possible, depending on the case, to incorporate one of them into the external phase.

Three granulation processes are currently used: wet granulation, dry granulation (compaction) 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 which rotate in opposite directions, thereby obtaining according to the applied forces of the plate of a given mechanical force. These plates are calibrated. Specific excipients are added and the final mixture is tabletted.

Hot melt granulation is a granulation method that can be used when the active ingredient is decomposed in the presence of water. The active substances and excipients selected are calibrated and then

··························· blend. The mixture is brought under slow stirring to a temperature slightly above the melting point of the excipient, stirred under 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 air bed granulator is described. The active ingredients and selected excipients in addition to the fusible excipient are calibrated and then transferred to a fluidized air bed granulator. The whole is mixed by fluidization with a hot air inlet until a temperature which is slightly lower than the melting point of the granulating excipient is reached. The molten excipient is then sprayed onto the fluidized mixture. The temperature of the fluidizing air is lowered. The obtained grain is calibrated. Specific excipients are added and the final mixture is tabletted.

Gelatin capsules and individual sachets are prepared according to techniques well known in the art.

dose with the skilled person

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, stroke, restenosis endenosis or endothelial vascular endothelectomy, 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 bypasses, or during radiotherapy to reduce its effects.

conditions.

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

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

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

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

Particularly preferred are compositions comprising 97.857 mg of clopidogrel hydrogen sulfate and 75 mg of aspirin.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

Example: compaction granulation method

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding 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 μιη) 30

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Low-grade hydroxypropylcellulose substitutions 30 Hydrogenated castor oil 10.5 Pretty 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) Compress the mixture and then calibrate to a mesh size 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 are mixed with the calibrated grain

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

g) The final blend 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 mg of clopidogrel base and 200 mg of aspirin

Example: compaction granulation method

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Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding 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 pm) 30 Low-grade hydroxypropylcellulose substitutions 30 Hydrogenated castor oil 10.5 Pretty 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) Compress the mixture and then calibrate to a mesh size of 1000 mm

(e) 200 g aspirin, 125 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 dose weight of 600 mg ⁺ Anhydrous beta-lactose may be replaced by an equivalent amount of mannitol.

Example 3

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

Example: compaction granulation method

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 325 Pregelatinised maize starch 30 Anhydrous colloidal silica 2 Anhydrous beta-lactose 74.625 Microcrystalline cellulose (90 pm) 30 Low-grade hydroxypropylcellulose substitutions 30 Hydrogenated castor oil 10.5 Pretty 600

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

(b) Add 30 g of pregelatinised maize starch and 74,6 g of anhydrous lactose to (a) and mix.

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

(d) the mixture is compacted and then calibrated to a mesh size of 1000 mm

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

(f) 10.5 g of 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 4

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

Example: direct tableting method

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 75 Maize starch 30 Anhydrous colloidal silica 2 Mannitol 300 DC 324.625 Microcrystalline cellulose (90 μπι) 60 Hydrogenated castor oil 10, 5 Pretty 600

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

(b) 75 g of aspirin, 30 g of corn starch, 324,6 g of mannitol 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 blend 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 mg of clopidogrel base and 325 mg of aspirin

Example: direct tableting method

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 325 Maize starch 30 Anhydrous colloidal silica 2 Mannitol 300 DC 124,625 Microcrystalline cellulose (90 gm) 60 Hydrogenated castor oil 10.5 Pretty 600

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999 · 99 · 9 · 9 · 9

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

(b) 325 g of aspirin, 30 g of corn starch, 124.6 g of mannitol 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 650 mg ⁺ Mannitol may be replaced by an equivalent amount of anhydrous beta-lactose.

Example 6

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

Example: method using simple mixing

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 75 Pregelatinised maize starch 50 Anhydrous colloidal silica 2.5 Mannitol 300 DC 265.875 Hydrogenated castor oil 8, 75 Pretty 500

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(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, 265.9 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 7

Gelatin capsule containing 75 mg of clopidogrel base and 325 mg of aspirin

Example: method using simple mixing

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding 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 Pretty 500

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

(b) 325 g of aspirin, 50 g of pregelatinised maize starch, 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 the 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 mg of clopidogrel base and 75 mg of aspirin

Example: method using simple mixing

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 75 Anhydrous colloidal silica 2.5 Mannitol 300 DC 824.625 Pretty 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.

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(c) 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

Bag containing 75 mg of clopidrogel base and 325 mg of aspirin

Example: method using simple mixing

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 325 Anhydrous colloidal silica 2.5 Mannitol 300 DC 574.625 Pretty 1000

(a) 97,875 g of clopidogrel hydrogen sulphate are mixed with 2,5 g of anhydrous 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 dispensed into sachets at a theoretical unit dose weight of 1 g ^+. A powdered flavoring may be added to the mixture.

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Example 10

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

Example: hot-melt granulation method

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 75 Makrogol 6000 97.5 Maize starch 32.5 Anhydrous colloidal silica 2 Mannitol 300 DC 273.625 Microcrystalline cellulose (50 pm) 65 Hydrogenated castor oil 6, 5 Pretty 650

(a) 97,875 g clopidogrel hydrogen sulphate, 97,5 mg 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 thermostat incubator with gentle stirring to 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 shall be added to the calibrated grain and mixed.

(e) 6.5 g of hydrogen are added to the d) castor oil before final mixing; (e) the final mixture is tableted at a theoretical unit dose of 650 mg by weight.

Example 11

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

Example: hot-melt granulation method

Unit composition

ingredients Amount in mg Clopidogrel hydrogen sulphate (corresponding to 75 mg of base) 97.875 aspirin 325 Makrogol 6000 97.5 Maize starch 32.5 Anhydrous colloidal silica 2 Mannitol 300 DC 23,625 Microcrystalline cellulose (50 pm) 65 Hydrogenated castor oil 6.5 Pretty 650

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

(b) bring the temperature of the mixture in a thermostat incubator with gentle stirring at 65 ° C. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

c) the mixture is 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 at a theoretical unit dose weight of 650 mg

Example 12

Tablets containing 75 mg clopidogrel base and 75 mg aspirin

Example: direct tableting method

Unit composition

ingredients Amount in mg Clopidogrel Form 2 (corresponding to 75 mg base) 97.875 aspirin 75,00 Emdex ^R 136.605 Hydrogenated castor oil 5,520 Pretty 315

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Example 13

ingredients Amount in mg Clopidogrel Form 2 (corresponding to 75 mg base) 97.875 aspirin 75,00 Cellactosa 80 121.875 Hydrogenated castor oil 5.25 Pretty 300

Procedure for Examples 12 and 13

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

A lubricant (hydrogenated castor oil) is added, and then the mixing is performed with a mini-rhinometer for 5 minutes.

Example 14

Tablets containing 75 mg clopidogrel base and 75 mg aspirin

Example: direct tableting method

Unit composition

ingredients Amount in mg Clopidogrel Form 2 (corresponding to 75 mg base) 97.875 aspirin 75,00 Emdex ^R 10,0

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Avicel PH 112 21,125 Pearlitol SD 200 24,00 Anhydrous colloidal silica 2.00 Hydrogenated castor oil 4.20 Pretty 420

Approach:

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

Colloidal silicon dioxide is added to the mixture, and then screening is carried out with a sieve having a mesh size of 0.315 mm.

Stirring is carried out with a mini-horn for 5 minutes.

A lubricant (hydrogenated castor oil) is added and stirring is continued with a mini-rhinometer for 5 minutes.

Claims (14)

PATENT 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 an active ingredient combination according to claims 1 or 2, characterized in that clopidogrel hydrogen sulphate is used in polymorph form 1. Pharmaceutical composition comprising an active ingredient combination according to claims 1 or 2, characterized in that clopidogrel hydrogen sulphate is used in polymorph form 2. Pharmaceutical composition according to claims 1 and 4 in the form of tablets. Pharmaceutical composition according to claims 1 and 4 in the form of gelatin capsules. The pharmaceutical composition according to claims 1 and 4 in the form of unit dose sachets. Pharmaceutical composition according to claims 1 to 7, characterized in that clopidogrel hydrogen sulphate and aspirin are present in a mixture of clopidogrel hydrogen sulphate with aspirin in a molar ratio between 2.5 and 11.5. ·· ···· · · · · _ο - ······ 21 · ······· · · · · · · ················ Pharmaceutical composition according to claims 1 to 8, characterized in that clopidogrel hydrogen sulphate and aspirin are present in a mixture of clopidogrel 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 and unstable angina, cardiovascular and cerebrovascular disorders such as thromboembolic disorders associated with atherosclerosis and diabetes, such as unstable angina, stroke, restenosis after angioplasty, endothelial insertion, angioplasty endovascular prosthesis or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral artery disease, hemodialysis, atrial fibrillation or during the use of vascular prostheses or coronary artery bypass therapies, or during. Use of a composition according to any one of the preceding claims for the preparation of a medicament for the treatment of a disease caused by platelet aggregation. Use of a composition according to any one of the preceding claims for the preparation of a medicament for the treatment of a disease caused by platelet aggregation including stable or unstable angina, cardiovascular and cerebrovascular disorders such as thromboembolic disorders associated with atherosclerosis and dia22. • Beta, such as unstable angina, stroke, restenosis after angioplasty, endarteroctomy or the introduction of 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 bypasses or during radiotherapy to reduce its side effects.