KR20020005735A - Pharmaceutical Composition in Unit Form Containing Acetylsalicylic Acid and Clopidogrel Hydrogenosulphate - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising a combination of active ingredients having antiplatelet aggregation activity, in unit herbal form, consisting of acetylsalicylic acid and clopidogrel hydrogen sulfate.

Description

Pharmaceutical Composition in Unit Form Containing Acetylsalicylic Acid and Clopidogrel Hydrogenosulphate

The present invention relates to a pharmaceutical composition comprising a combination of active ingredients having antiplatelet aggregation activity, consisting of acetylsalicylic acid and clopidogrel hydrogen sulfate, provided in unit herbal form. The unit herbal form may be administered orally and preferably consists of a tablet, gelatin capsule or single dose sachet.

In the compositions according to the invention, acetylsalicylic acid is used in acid form, and clopidogrel hydrogen sulfate can be used in one of the polymorphic forms, known form 1 (F1) or form 2 (F2), known to date. Clopidogrel hydrogen sulfate form 1 is described in European patent 281459, and clopidogrel hydrogen sulfate form 2 is described in patent application FR 98/07464.

The therapeutic benefit of using acetylsalicylic acid and clopidogrel in particular is described in patent application WO 97/29753. However, this document does not specifically mention that the pharmaceutically acceptable salt used in the pharmaceutical composition is clopidogrel hydrogen sulfate. The document states that the composition can be used parenterally or orally, and the active ingredient is administered according to four methods of administration, i.e. both orally, both parenterally, or one orally and the other parentally. It can be said. However, pharmaceutical compositions suitable for simultaneous administration of acetylsalicylic acid and clopidogrel hydrogen sulfate, which are provided in herbal form, are not described.

Each dose of the antiplatelet aggregation component of the combination can be predetermined and need not be adjusted according to the condition of the patient to be treated, so that a single pharmaceutical form containing the two active ingredients and which can be administered orally can be obtained. Having has been found to be advantageous and useful.

Although studies have been made on various combinations of acetylsalicylic acid with other active ingredients, many disadvantages have emerged during the preparation of the herbal form, in particular during the manufacture of tablets comprising acetylsalicylic acid in combination with salts of the active ingredient.

That is, International Journal of Pharmaceutics (Netherlands) 1984, 18, 287-298 describes the incompatibility between acetylsalicylic acid and other solid phase active ingredients. The model was confirmed by experiments with acetylsalicylic acid and mepyramine maleate. The addition of mepyramine maleate to acetylsalicylic acid lowers the melting point, which in turn affects the rate of degradation of acetylsalicylic acid in the mixture. Thus, it has been observed that the lower the melting point, the more the active ingredient in the combination of this type decomposes.

Due to all of the above disadvantages known to those skilled in the art, it was not recommended to prepare a combination of base salts such as clopidogrel hydrogen sulfate and acetylsalicylic acid in the same tablet or in the same gelatin capsule or in the same sachet.

Surprisingly surprisingly, in the form of unit herbal formulations comprising acetylsalicylic acid together with other active ingredients consisting of base salts, more particularly clopidogrel hydrogen sulfate, using various preparation methods and techniques known to those skilled in the art according to the invention. It has become possible to provide the pharmaceutical compositions provided.

Thus, tablets according to the present invention can be prepared by various manufacturing methods such as, for example, the following direct method and pregranulation method.

In the direct hit method, the active ingredients are first mixed with selected excipients, and the resulting mixture is sieved (calibrated) to a screen of a predetermined mesh size to make the particle size of the ingredients uniform. Mix again to ensure that the active ingredients are mixed evenly. Certain excipients (eg flow agents) and lubricants are added and mixed. The resulting final mixture is then compressed.

Granulation in progranulation involves mixing and enriching the active ingredients with selected excipients (internal phase components), then sizing to a given screen and adding specific excipients (external phase components) to make them suitable for compression. It consists of obtaining granules consisting of evenly distributed particles. The granulation method can improve the rheological properties of the mixture to be compressed and the physical properties of the tablets, in particular the properties of the tablets containing the active ingredient in high doses. When two active ingredients are mixed in the same tablet, one can optionally incorporate one of the active ingredients in the external phase.

Three granulation methods currently used are wet granulation, dry granulation (compression) and "hot melt" granulation.

Dry granulation (compression) consists of mixing the active ingredients with the selected excipients, adjusting the size and then reliably mixing again. The mixture is pressurized between two mobile rollers that rotate in opposite directions to obtain a plaque with a given mechanical strength depending on the pressure applied. Size the plaques. Add specific excipients and tablet the final mixture.

A "hot melt" granulation method is a granulation method that can be used when the active ingredient is degraded in the presence of water. The active ingredient and selected excipients are sized and then mixed. The mixture is slowly stirred to a temperature slightly above the melting point of the excipient, mixed with rapid stirring and then cooled to room temperature. The resulting granules are sized. Add specific excipients and tablet the final mixture. An example of a "hot melt" process using a fluidized air bed granulator is described below. Selected excipients and active ingredients, except for soluble excipients, are sized and then transferred to a fluidized air bed granulator. The whole is mixed by flowing with introduction of hot air until the temperature of the mixture reaches a temperature slightly below the melting point of the granulation excipient. The molten excipient is then sprayed onto the flowable mixture. Lower the flow air temperature. The resulting granules are sized. Add specific excipients and tablet the final mixture.

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

The pharmaceutical composition according to the present invention is a thromboembolic disease associated with atherosclerosis and diabetes, or rethrombosis after thrombolysis, such as unstable angina, stroke, angioplasty, endometrial resection or restenosis after insertion of an intravascular metallic prosthesis, Cardiovascular diseases such as infarction, ischemic dementia, peripheral arterial disease, hemodialysis, thromboembolic diseases associated with atrial fibrillation and diseases caused by platelet aggregation, including cerebrovascular disease, stable or unstable angina, or vascular prostheses or It is used in the treatment of diseases caused by platelet aggregation during the use of coronary artery bypass or during radiation therapy to reduce its side effects.

The pharmaceutical composition according to the present invention is used for the manufacture of a medicament for the treatment of the above-mentioned diseases, and enables the treatment of the diseases.

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

In humans, 1 to 500 mg / day of clopidogrel hydrogen sulfate and 1 to 500 mg / day of acetylsalicylic acid are administered, wherein the dose can be expressed in free form of clopidogrel. Preferably, 97.875 mg of clopidogrel hydrogen sulfate and 75-325 mg of acetylsalicylic acid are administered.

Particular preference is given to compositions comprising 97.875 mg of clopidogrel hydrogen sulfate and 75 mg of acetylsalicylic acid. Also preferred are compositions comprising 97.875 mg of clopidogrel hydrogen sulfate and 375 mg of acetylsalicylic acid.

<Example 1>

Tablets comprising 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example Granulation by Compression

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75 Pregelatinized Corn Starch 30 Anhydrous colloidal silica 2 Anhydrous β-lactose 324.625 Microcrystalline cellulose (90 μm) 30 Hydroxypropyl cellulose with low degree of substitution 30 Hydrogenated castor oil 10.5 Total amount 600

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

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

c) The mixture b) was sized and then mixed again.

d) The mixture was compressed and then scaled to a 1000 mm size mesh.

e) 75 g of acetylsalicylic acid, 250 g of anhydrous lactose, 30 g of microcrystalline cellulose and 30 g of hydroxypropyl cellulose having low substitution degree were mixed with the sized granules.

f) 10.5 g of hydrogenated castor oil was added followed by final mixing.

g) The final mixture was compressed into a theoretical unit weight of 600 mg.

Anhydrous β-lactose can be replaced by the same amount of mannitol.

<Example 2>

Tablets comprising 75 mg clopidogrel base and 200 mg acetylsalicylic acid

Example Granulation by Compression

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 200 Pregelatinized Corn Starch 30 Anhydrous colloidal silica 2 Anhydrous β-lactose 199.625 Microcrystalline cellulose (90 μm) 30 Hydroxypropyl cellulose with low degree of substitution 30 Hydrogenated castor oil 10.5 Total amount 600

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

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

c) The mixture b) was sized and then mixed again.

d) The mixture was compressed and then scaled to a 1000 mm size mesh.

e) 200 g of acetylsalicylic acid, 125 g of anhydrous lactose, 30 g of microcrystalline cellulose and 30 g of hydroxypropyl cellulose having low substitution degree were mixed with the sized granules.

f) 10.5 g of hydrogenated castor oil was added followed by final mixing.

g) The final mixture was compressed into a theoretical unit weight of 600 mg.

Anhydrous β-lactose can be replaced by the same amount of mannitol.

<Example 3>

Tablets comprising 75 mg clopidogrel base and 325 mg of acetylsalicylic acid

Example Granulation by Compression

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 325 Pregelatinized Corn Starch 30 Anhydrous colloidal silica 2 Anhydrous β-lactose 74.625 Microcrystalline cellulose (90 μm) 30 Hydroxypropyl cellulose with low degree of substitution 30 Hydrogenated castor oil 10.5 Total amount 600

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

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

c) The mixture b) was sized and then mixed again.

d) The mixture was compressed and then scaled to a 1000 mm size mesh.

e) 325 g of acetylsalicylic acid, 30 g of microcrystalline cellulose and 30 g of hydroxypropyl cellulose having low degree of substitution were mixed with the sized granules.

f) 10.5 g of hydrogenated castor oil was added followed by final mixing.

g) The final mixture was compressed into a theoretical unit weight of 600 mg.

Anhydrous β-lactose can be replaced by the same amount of mannitol.

<Example 4>

Tablets comprising 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example: Direct Method

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75 Corn starch 30 Anhydrous colloidal silica 2 Mannitol 300 DC 324.625 Microcrystalline cellulose (90 μm) 60 Hydrogenated castor oil 10.5 Total amount 600

a) 97.875 g of clopidogrel hydrogen sulfate was 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 were added to a) and mixed.

c) The mixture b) was sized and then mixed again.

d) 10.5 g of hydrogenated castor oil was added to c) followed by final mixing.

e) The final mixture was compressed into a theoretical unit weight of 600 mg.

Mannitol can be replaced by the same amount of anhydrous β-lactose.

Example 5

Tablets comprising 75 mg clopidogrel base and 325 mg of acetylsalicylic acid

Example: Direct Method

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 325 Corn starch 30 Anhydrous colloidal silica 2 Mannitol 300 DC 124.625 Microcrystalline cellulose (90 μm) 60 Hydrogenated castor oil 10.5 Total amount 600

a) 97.875 g of clopidogrel hydrogen sulfate was 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 were added to a) and mixed.

c) The mixture b) was sized and then mixed again.

d) 10.5 g of hydrogenated castor oil was added to c) followed by final mixing.

e) The final mixture was compressed into a theoretical unit weight of 650 mg.

Mannitol can be replaced by the same amount of anhydrous β-lactose.

<Example 6>

Gelatin capsules comprising 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example: Simple Mixing

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75 Pregelatinized Corn Starch 50 Anhydrous colloidal silica 2.5 Mannitol 300 DC 265.875 Hydrogenated castor oil 8.75 Total amount 500

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

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

c) The mixture b) was sized and then mixed again.

d) 8.75 g of hydrogenated castor oil was added to c) followed by final mixing.

e) The final mixture was dispensed into gelatin capsules so that the theoretical unit weight was 500 mg.

Mannitol can be replaced by the same amount of anhydrous β-lactose.

<Example 7>

Gelatin capsules comprising 75 mg clopidogrel base and 325 mg of acetylsalicylic acid

Example: Simple Mixing

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 325 Pregelatinized Corn Starch 50 Anhydrous colloidal silica 2.5 Mannitol 300 DC 15.875 Hydrogenated castor oil 8.75 Total amount 500

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

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

c) The mixture b) was sized and then mixed again.

d) 8.75 g of hydrogenated castor oil was added to c) followed by final mixing.

e) The final mixture was dispensed into gelatin capsules so that the theoretical unit weight was 500 mg.

Mannitol can be replaced by the same amount of anhydrous β-lactose.

<Example 8>

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

Example: Simple Mixing

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75 Anhydrous colloidal silica 2.5 Mannitol 300 DC 824.625 Total amount 1000

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

b) 75 g of acetylsalicylic acid and 824.6 g of mannitol were added to a) and mixed.

c) The mixture b) was sized and then mixed again.

d) The mixture was partitioned into sausage to bring the theoretical weight to 1 g.

Flavor powder can be added to the mixture.

Example 9

Sase comprising 75 mg clopidogrel base and 325 mg of acetylsalicylic acid

Example: Simple Mixing

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 325 Anhydrous colloidal silica 2.5 Mannitol 574.625 Total amount 1000

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

b) 325 g of acetylsalicylic acid and 574.6 g of mannitol were added to a) and mixed.

c) The mixture b) was sized and then mixed again.

d) The mixture was partitioned into sausage to bring the theoretical weight to 1 g.

Flavor powder can be added to the mixture.

<Example 10>

Tablets comprising 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example: "Hot Melt" Granulation

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75 Macrogol 6000 97.5 Corn starch 32.5 Anhydrous colloidal silica 2 Mannitol 273.625 Microcrystalline cellulose (50 μm) 65 Hydrogenated castor oil 6.5 Total amount 650

a) 97.875 g of clopidogrel hydrogen sulfate, 97.5 g of macrogol 6000, 32.5 g of corn starch and 273.6 g of mannitol were mixed and scaled.

b) The mixing temperature was brought to 65 ° C. with slow stirring in a constant temperature incubator.

c) The mixture was granulated with rapid stirring, cooled to room temperature and then sized.

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

e) 6.5 g hydrogenated castor oil was added to d) followed by final mixing.

f) The final mixture was compressed into a theoretical unit weight of 650 mg.

<Example 11>

Tablets comprising 75 mg clopidogrel base and 325 mg of acetylsalicylic acid

Example: "Hot Melt" Granulation

Unit dosage form

ingredient Amount (mg) Clopidogrel hydrogen sulfate (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 325 Macrogol 6000 97.5 Corn starch 32.5 Anhydrous colloidal silica 2 Mannitol 23.625 Microcrystalline cellulose (50 μm) 65 Hydrogenated castor oil 6.5 Total amount 650

a) 97.875 g of clopidogrel hydrogen sulfate, 97.5 g of macrogol 6000, 32.5 g of corn starch and 23.6 g of mannitol were sized and mixed.

b) The mixing temperature was brought to 65 ° C. with slow stirring in a constant temperature incubator.

c) The mixture was granulated with rapid stirring, cooled to room temperature and then sized.

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

e) 6.5 g hydrogenated castor oil was added to d) followed by final mixing.

f) The final mixture was compressed into a theoretical unit weight of 650 mg.

<Example 12>

Tablets comprising 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example: Direct Method

Unit dosage form

ingredient Amount (mg) Clopidogrel Form 2 (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75.00 Emdex ^R 136.605 Hydrogenated castor oil 5.520 Total amount 315

Example 13

ingredient Amount (mg) Clopidogrel Form 2 (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 75.00 Cellactose 80 121.875 Hydrogenated castor oil 5.25 Total amount 300

Method of Examples 12 and 13

The active ingredients and diluents were mixed for 10 minutes using a mini-rhoen machine.

Lubricant (hydrogenated castor oil) was added and mixed for 5 minutes using a mini-lon machine.

<Example 14>

Tablets comprising 75 mg clopidogrel base and 75 mg acetylsalicylic acid

Example: Direct Method

Unit dosage form

ingredient Amount (mg) Clopidogrel Form 2 (corresponds to base 75 mg) 97.875 Acetylsalicylic acid 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 amount 240

Way:

The active ingredients were mixed for 10 minutes using diluent and mini-lon machine.

Anhydrous colloidal silica was added to the mixture and then sieved through a screen of mesh size 0.315 mm.

Mix for 5 minutes using a mini-lon machine.

Lubricant (hydrogenated castor oil) was added and mixed for 5 minutes using a mini-lon machine.

Claims (14)

A pharmaceutical composition provided in the form of an orally administrable unit herbal medicine comprising a combination of clopidogrel hydrogen sulfate and acetylsalicylic acid active ingredients. The pharmaceutical composition of claim 1 comprising a combination of active ingredients in combination with a pharmaceutical excipient. Pharmaceutical composition comprising a combination of active ingredients according to claim 1 or 2, characterized in that clopidogrel hydrogen sulfate is used in polymorph form 1. A pharmaceutical composition comprising a combination of active ingredients according to claim 1 or 2, characterized in that clopidogrel hydrogen sulfate is used in polymorph form 2. The pharmaceutical composition according to claim 1 or 4 in the form of a tablet. The pharmaceutical composition according to claim 1 or 4, which is in the form of a gelatin capsule. The pharmaceutical composition of claim 1 or 4 in the form of a single dose sachet. The pharmaceutical composition according to any one of claims 1 to 7, wherein the clopidogrel hydrogen sulfate and acetylsalicylic acid are present at a clopidogrel hydrogen sulfate / acetylsalicylic acid molar ratio of 2.5 to 11.5. The pharmaceutical composition according to any one of claims 1 to 8, wherein the clopidogrel hydrogen sulfate and acetylsalicylic acid are present at a clopidogrel hydrogen sulfate / acetylsalicylic acid molar ratio of 5 to 9. The pharmaceutical composition according to any one of claims 1 to 9, wherein clopidogrel hydrogen sulfate and acetylsalicylic acid are present at a ratio of 97.875 mg clopidogrel hydrogen sulfate and 75 mg of acetylsalicylic acid. The pharmaceutical composition according to any one of claims 1 to 10, wherein clopidogrel hydrogen sulfate and acetylsalicylic acid are present in a ratio of 97.875 mg clopidogrel hydrogen sulfate and 375 mg acetylsalicylic acid. The thromboembolic disease according to any one of claims 1 to 11, which is associated with atherosclerosis and diabetes, such as unstable angina, stroke, angioplasty, endometrial resection or restenosis after insertion of an intravascular metallic prosthesis, Or cardiovascular diseases such as rethrombosis after thrombolysis, infarction, ischemic dementia, peripheral arterial disease, hemodialysis, thromboembolic diseases associated with atrial fibrillation and platelet aggregation, including cerebrovascular disease, stable or unstable angina A pharmaceutical composition for the treatment of a disease, or a disease caused by platelet aggregation during radiotherapy to reduce side effects, or by using vascular prostheses or coronary artery bypass. Use of a composition according to any one of claims 1 to 12 for the manufacture of a medicament for the treatment of diseases caused by platelet aggregation. Thromboembolic disorders associated with atherosclerosis and diabetes, such as unstable angina, stroke, angioplasty, endometrial resection or restenosis after insertion of an intravascular metal prosthesis, or rethrombosis after thrombolysis, infarction, ischemic dementia, peripheral arteries Diseases, hemodialysis, cardiovascular diseases such as thromboembolic diseases associated with atrial fibrillation and cerebrovascular diseases, diseases caused by platelet aggregation, including stable or unstable angina, or using vascular prostheses or coronary artery bypass Or the use of a composition according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of diseases caused by platelet aggregation during radiotherapy to reduce their side effects.