MXPA01011071A

MXPA01011071A - Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel hydrogenosulphate.

Info

Publication number: MXPA01011071A
Application number: MXPA01011071A
Authority: MX
Inventors: Bernard Abramovici
Original assignee: Sanofi Synthelabo
Priority date: 1999-04-30
Filing date: 2000-04-25
Publication date: 2002-07-22
Also published as: AU4303600A; HK1041823A1; JP2002543137A; IL145648A0; EA200100959A1; PL351923A1; NO20015295D0; FR2792836A1; FR2792836B3; SK15542001A3; BR0010194A; EE200100559A; NZ514248A; CZ20013887A3; EP1178809A1; CA2371231A1; AR023789A1; UY26131A1; CN1359294A; TR200103039T2

Abstract

The invention concerns a pharmaceutical composition containing in galenical unit form a combination of active principles with platelet antiaggregating activity consisting of acetylsalicylic acid and clopidogrel hydrogenosulphonate.

Description

PHARMACEUTICAL COMPOSITION IN A UNIT FORM CONTAINING ACETILSALICYLIC ACID AND CLOPIDOGREL HYDROGENOSULPHATE The present invention relates to a pharmaceutical composition provided in a unitary galenic form, containing a combination of active ingredients with antiplatelet activity of platelets, which consists of aspirin and clopidogrel hydrogen sulfate. The unit dosage form can be administered orally and preferably consists of a tablet, a gelatin capsule or a single dose sachet. In the compositions according to the invention, aspirin is used in its acid form and clopidogrel hydrogen sulfate can be used in any of its polymorphic forms known to date and which are named Form 1 (F1) or Form 2 ( F2). Form 1 of clopidogrel hydrogen sulfate is the salt described in EP 281459 and the Hydrogensulfate form of clopidogrel is that described in Patent Application FR 98/07464. The therapeutic interest of the combination of aspirin and clopidogrel is described, inter alia, in Patent Application WO 97/29753. The pharmaceutical compositions are mentioned herein without specifying however that the pharmaceutically acceptable salt used is clopidogrel hydrogen sulfate. This document indicates in any way that the composition can be used parenterally or orally and that it is possible administering the active principles according to four methods of administration, that is, orally or parenterally or one orally and the other parenterally or in a contrary manner. However, a pharmaceutical composition that is provided in a unit dosage form and that is suitable for concomitant administration of aspirin and clopidogrel hydrogen sulfate is not described. Since it has been clearly determined that the doses of each of the platelet antiplatelet constituents of the combination can be pre-assembled and do not require adjustment according to the patients to be treated, it has been found useful and advantageous to have only one form of medicine that can be administered orally and that contains these two active ingredients. Several combination studies have been carried out with aspirin and other active ingredients, but many disadvantages have been demonstrated during the production of galenic forms, in particular, tablets containing aspirin combined with salts of an active ingredient. Therefore, the publication that appeared in the International Journal of Pharmaceutics (The Netherlands) 1984, 18, 287-298, demonstrates the incompatibility between aspirin and other active, solid ingredients. The experimental confirmation of these models was demonstrated by the use of aspirin and mepyramine maleate. The addition of mepyramine maleate to aspirin decreases its melting point, with a resultant effect on the rate of decomposition of aspirin in this mixture. It has thus been observed that a decrease in the melting point leads to the degradation of the active ingredients in this type of combination. All these disadvantages, which are well known to the person skilled in the art, have not promoted the preparation of a combination of aspirin and a base salt such as clopidogrel hydrogen sulfate in the same tablet or the same or in the same gelatin capsule. sachet Unexpectedly or surprisingly completely, it was possible, according to the invention, to prepare a pharmaceutical composition provided in a unitary galenic form, containing aspirin in combination with another active principle, which consists of a base salt, more specifically hydrogen sulfate of clopidogrel, through the use of various methods of preparation and various techniques that are well known to those skilled in the art. Therefore, the tablets according to the invention can be produced by various processing methods, such as, for example: the direct tablet-forming method, in which the active ingredients and the selected excipients are mixed. The obtained mixture is sieved (calibrated) on a screen of predefined mesh size, to homogenize the particle sizes of the constituents. The mixing is carried out again to ensure a good homogeneity of the active principles. The specific excipients (example - a flow agent) and a lubricant are added and they mix The final mixture obtained is then formed into tablets. the pregranulation method, in which the granulation consists in the combination and densification of the active principles and the selected excipients (internal phase constituents) to obtain, after calibration on a given screen, a grain consisting of particles that are homogeneous in the content of the active principle, which is suitable for compression, after adding the specific excipients (constituents of external phase). The granulation makes it possible to improve the Theological properties of the mixture to be compressed and the physical properties of the tablets, in particular in the case of two high active ingredients. When two active ingredients are combined in the same tablet, it is possible, depending on the case, to incorporate one of them in the external phase. Currently, three granulation methods are used: wet granulation, dry granulation (compaction) and "hot melt" granulation. Dry granulation (compaction) consists in making sure that the active ingredients and the selected excipients are mixed, calibrated and then mixed again. The mixture is forced between two movable rollers, which rotate in opposite directions, to obtain, according to the forces exerted, plates of given mechanical strength. These plates are calibrated. The specific excipients are added and the final mixture is tabletted. "Hot-melt" granulation is a granulation method that can be used when an active ingredient degrades in presence of water The active ingredients and selected excipients are calibrated and then mixed. The mixture is conducted, under slow stirring, to a temperature which is slightly higher than the melting point of the excipient, mixed under rapid stirring and then cooled to room temperature. The grain obtained is calibrated. The 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 below. The active ingredients and selected excipients, except the fusible excipient, are calibrated and then transferred to a fluidized air bed granulator. Everything is mixed by fluidization with introduction of hot air until a mixing temperature is reached which is slightly lower than the melting point of the granulation excipient. The molten excipient is then sprayed onto the fluidized mixture. The fluidization air temperature is lowered. The grain obtained is calibrated. The specific excipients are added and the final mixture is tabletted. The gelatin capsules and the single dose sachets are prepared according to techniques well known to a person skilled in the art. The pharmaceutical compositions according to the invention are used to treat a pathology induced by platelet aggregation, including stable or unstable angina, disorders of the cardiovascular or cerebrovascular system such as thromboembolic disorders associated with atherosclerosis and with diabetes, such as unstable angina, apoplexy, restenosis after angioplasty, endarterectomy or installation of metal endovascular prostheses, or thromboembolic disorders associated with rethrombosis after thrombolysis, with infarction, with dementia of ischemic origin, with peripheral arterial diseases, with hemodialysis, with atrial fibrillation or during the use of vascular prostheses or coronary arterial deviations or during radiotherapy to reduce the side effects of it. The pharmaceutical compositions according to the invention are used to prepare a medical product proposed to treat the aforementioned pathologies and allow the treatment of these pathologies. In the pharmaceutical compositions according to the invention, clopidogrel hydrogen sulfate and aspirin are present in a molar ratio of clopidogrel hydrogen sulfate / aspirin of between 2.5 and 11.5, preferably between 5 and 9. In humans, 1 to 500 mg per day of hydrogen sulfate are administered. of clopidogrel and from 1 to 500 mg per day of aspirin, expressing the doses in equivalent amount of clopidogrel in the free form. Preferably, 97,875 mg of clopidogrel hydrogensulfate and 75 to 325 mg of aspirin are administered. Particularly preferred are compositions containing 97,875 mg of clopidogrel hydrogen sulfate and 75 mg of aspirin. Also preferred are compositions containing 97,875 mg of clopidogrel hydrogen sulfate and 375 mg of aspirin.

EXAMPLE 1 Tablet containing 75 mg of clopidogrel base and 75 mg of aspirin Example: method for granulation by compaction. Unitary formula a) 97.875 g of clopidogrel hydrogensulphate are mixed with 2 g of anhydrous colloidal silica b) 30 g of pregelatinized maize starch and 74.6 g of anhydrous lactose are added to a) and mixed c) the mixture b) is calibrated and then mix again d) the mixture is compacted and then calibrated to a mesh size of 1000 mm e) 75 g of aspirin, 250 g of anhydrous lactose, 30 g of microcrystalline cellulose and 30 g of hydroxypropylcellulose with a low degree of substitution are mixed with the calibrated grain f) 10.5 g of hydrogenated castor oil are added before the final mixture g) the final mixture is tabletted to the theoretical unit mass of 600 mg • The anhydrous ß-lactose can be replace with an equivalent amount of mannitol. EXAMPLE 2 Tablet containing 75 mg of clopidogrel base and 200 mg of aspirin Example: method for granulation by compaction. Unitary formula l? í¡á. ÁíáJ k¡tM, .i ,. ...- «- t ----» --- ----.- ^ --- a ---. »«? -. . < ---- ^. ^ - is ------.- »- - ^ > - "-.----,; " "..---_ to----. --K - -ia) 97,875 g of clopidogrel hydrogensulfate are mixed with 2 g of anhydrous colloidal silica b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a) and mixed c) the mixture b) is calibrated and then mixed again d) the mixture is compacted and then calibrated to a mesh size of 1000 mm e) 200 g of aspirin, 125 g of anhydrous lactose, 30 g of microcrystalline cellulose and 30 g of hydroxypropylcellulose with a low degree of substitution are mixed with the calibrated grain f) 10.5 g of hydrogenated castor oil are added before the final mixture g) the final mixture is tabletted to the theoretical unit mass of 600 mg • The ß Anhydrous lactose can be replaced with an equivalent amount of mannitol.

EXAMPLE 3 Tablet containing 75 mg of clopidogrel base and 325 mg of aspirin Example: method for granulation by compaction. Unitary formula Constituents Amount in mg a) 97.875 g of clopidogrel hydrogensulfate are mixed with 2 g of anhydrous colloidal silica b) 30 g of pregelatinized corn starch and 74.6 g of anhydrous lactose are added to a) and mixed c) the mixture b) is calibrated and then mix again d) the mixture is compacted and then gauged to a mesh size of 1000 mm e) 325 g of aspirin, 30 g of microcrystalline cellulose and 30 g of hydroxypropylcellulose with a low degree of substitution are mixed with the grain calibrated f) 10.5 g of hydrogenated castor oil are added before the final mixture g) the final mixture is tabletted to the theoretical unit mass of 600 mg I? IiLíÁ Aiá iiá, M &áX -ja -.-. -r-J.J --.-- A-. anta--. --- SJMft I.U < The t-? . .. faith--, -. , .A- ^ i «-njjfc i • Anhydrous ß-lactose can be replaced with an equivalent amount of mannitol. EXAMPLE 4 Tablet containing 75 mg of ciopidogrel base and 75 mg of aspirin Example: method by direct tablet formation. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate 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 with ) the mixture b) is calibrated and then mixed again d) 10.5 g of hydrogenated castor oil are added before the final mixture e) the final mixture is formed into tablets in the mass of theoretical unit of 600 mg • Mannitol can be replaced with an equivalent amount of anhydrous ß-lactose. EXAMPLE 5 Tablet containing 75 mg of clopidogrel base and 325 mg of aspirin Example: method by direct tablet formation. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate 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 with ) the mixture b) is calibrated and then mixed again d) 10.5 g of hydrogenated castor oil are added before the final mixture e) the final mixture is formed into tablets in the theoretical unit mass of 650 mg • Mannitol can be replaced with an equivalent amount of anhydrous β-lactose. EXAMPLE 6 Gelatin capsule containing 75 mg of clopidogrel base and 75 mg of aspirin Example: method by simple mixing. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate are mixed with 2.5 g of anhydrous colloidal silica b) 75 g of aspirin, 50 g of pregelatinized corn starch and 265.9 g of mannitol are added to a) and mixed c) mixture b) it is calibrated and then mixed again l-.i - Al - fc ----- Mttit-aBE-t ----.- rii »an-i-4- 4-4 * - -.» - d) 8.75 g of hydrogenated castor oil are added to c) before final mixing e) the final mixture is divided into gelatin capsules in the theoretical unit mass of 500 mg • Mannitol can be replaced with an equivalent amount of anhydrous ß-lactose . EXAMPLE 7 Gelatin capsule containing 75 mg of clopidogrel base and 325 mg of aspirin Example: method by simple mixing. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate are mixed with 2.5 g of anhydrous colloidal silica b) 325 g of aspirin, 50 g of pregelatinized maize starch and 15.9 g of mannitol are added to a) and mixed ? -t ---? - ia, i¡ -J-Al-i-i -ri-. c) mixture b) is calibrated and then mixed again d) 8.75 g of hydrogenated castor oil are added to c) before final mixing e) the final mixture is divided into gelatin capsules in the theoretical unit mass of 500 mg • Mannitol can be replaced with an equivalent amount of anhydrous ß-lactose. EXAMPLE 8 Sachet containing 75 mg of clopidogrel base and 75 mg of aspirin Example: method by simple mixing. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate 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 mixed again ) the mixture is divided into sachets in the unit mass & *, * * - • * d * M > theoretical 1 g • A powdery flavor can be added to the mixture. EXAMPLE 9 Sachet containing 75 mg of clopidogrel base and 325 mg of aspirin Example: method by simple mixing. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate 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) the mixture b) is calibrated and then mixed again ) the mixture is divided into sachets in the theoretical unit mass of 1 g • A powdery flavor can be added to the mixture EXAMPLE 10 Tablet containing 75 mg of clopidogrel base and 75 mg of aspirin Example: method for "hot melt" granulation. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate, 97.5 g of macrogol 6000, 32.5 g of corn starch and 273.6 g of mannitol are mixed after calibration b) the temperature of the mixture is conducted up to 65 ° C in a thermostable incubator, under slow stirring c) the mixture is granulated under rapid stirring, cooled to room temperature and then calibrated d) 75 g of aspirin, 2 g of anhydrous colloidal 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 ad) before the final mixture á-j-a-áji-,. M ..., «-.---, 5-i .-- c.-lf) the final mixture is tabletted to the theoretical unit mass of 650 mg EXAMPLE 1 1 Tablet containing 75 mg of base of clopidogrei and 325 mg of aspirin Example: method for "hot melt" granulation. Unitary formula a) 97.875 g of clopidogrel hydrogensulfate, 97.5 g of macrogol 6000, 32.5 g of corn starch and 273.6 g of mannitol are mixed after calibration b) the temperature of the mixture is conducted up to 65 ° C in a thermostable incubator, under slow stirring c) the mixture is granulated under rapid stirring, cooled to room temperature and then calibrated d) 325 g of aspirin, 2 g of anhydrous colloidal 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 ad) before the final mixture f) the final mixture is tabletted to the theoretical unit mass of 650 mg EXAMPLE 12 Tablet containing 75 mg of clopidogrel base and 75 mg of aspirin Example: method by direct shaping of the tablet Unitary formula EXAMPLE 1 3 Procedure for EXAMPLES 12 and 13 The mixture of the active principles and the diluents is carried out with a Mini-Rhon machine for 10 minutes. Lubricant (hydrogenated castor oil) is added and then the mixture is carried out with a Mini-Rhon machine for 5 minutes. EXAMPLE 14 Tablets containing 75 mg of clopidogrel base and 75 mg of aspirin Example: method by direct shaping of tablet Unitary formula l- - i -? - fcé-Í - Áí -? - afati -.-- fcjit-, ¿lii¿aA - a-a ni * - * -. .? t?? tí? HiSt í. * i > ¡??? ** M * m? * »? - r? I» .-. * M.-jcr *. - ^. m ^ a-aiíi, Procedure: The active ingredients are mixed with the diluents for 10 minutes with a Mini-Rhon machine. The anhydrous colloidal silica is added to the previous mixture and then the screening is carried out through a screen of 0.315 mm mesh size. The mixing is carried out with a Mini-Rhon machine for 5 minutes. Lubricant is added (hydrogenated castor oil and the mixing is carried out with a Mini-Rhon machine for 5 minutes.

Claims

CLAIMS 1. The pharmaceutical composition provided in a unit dosage form, characterized in that it can be administered orally and which contains a combination of active principles of clopidogrel hydrogen sulfate and aspirin.
2. The pharmaceutical combination containing a combination of active ingredients according to claim 1, characterized in that it is in combination with a pharmaceutical excipient.
3. The pharmaceutical combination containing a combination of active ingredients according to claim 1 or 2, characterized in that the clopidogrel hydrogensulfate is used in a 1 polymorphic.
4. The pharmaceutical combination containing a combination of active ingredients according to claim 1 or 2, characterized in that clopidogrel hydrogen sulfate is used in a 2 polymorphic.
5. The pharmaceutical combination according to any of claims 1 and 4, characterized in that it is in the form of a tablet.
6. The pharmaceutical combination according to any of claims 1 and 4, characterized in that it is in the form of a gelatin capsule.
7. The pharmaceutical combination according to any of claims 1 and 4, characterized in that it is in the form of a single dose sachet.
8. The pharmaceutical combination according to any of claims 1 to 7, characterized in that clopidogrel hydrogen sulfate and aspirin are present in a molar ratio of clopidogrel hydrogen sulfate / aspirin of between 2.5 and 1 .5.
9. The pharmaceutical combination according to any of claims 1 to 8, characterized in that clopidogrel hydrogen sulfate and aspirin are present in a molar ratio of clopidogrel hydrogen sulfate / aspirin between 5 and 9.
10. The pharmaceutical combination according to any of the claims 1 to 9, characterized in that clopidogrel hydrogen sulfate and aspirin are present in a proportion of 97,875 mg of clopidogrel hydrogen sulfate and 75 mg of aspirin. The pharmaceutical combination according to any of claims 1 to 10, characterized in that clopidogrel hydrogen sulfate and aspirin are present in a proportion of 97,875 mg of clopidogrel hydrogen sulfate and 375 mg of aspirin. 12. The pharmaceutical combination according to any of claims 1 to 1, characterized in that it treats a pathology induced by aggregation of platelets, including stable or unstable angina, disorders of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis and with diabetes, such as unstable angina, apoplexy, restenosis after angioplasty, endarterectomy or installation of metal stents, or thromboembolic disorders associated with rethrombosis after thrombolysis, with infarction, with dementia of ischemic origin, with peripheral arterial diseases, with hemodialysis, with atrial fibrillation or during the use of vascular prostheses or coronary arterial deviations or during radiotherapy to reduce the collateral effects thereof. 13. The use of a composition according to any of the preceding claims, characterized in that it prepares a medical product proposed for the treatment of a pathology induced by platelet aggregation. 14. The use of a composition according to any of the preceding claims, characterized in that it prepares a medical product proposed for the treatment of a pathology induced by platelet aggregation, including stable or unstable angina, disorders of the cardiovascular and cerebrovascular system such as associated thromboembolic disorders with atherosclerosis and with diabetes, such as unstable angina, stroke, restenosis after angioplasty, endarterectomy or installation of metal stents, or thromboembolic disorders associated with rethrombosis after thrombolysis, with infarction, with dementia of ischemic origin, with peripheral arterial diseases, with hemodialysis, with atrial fibrillation or during the use of vascular prostheses or coronary arterial deviations or during radiotherapy to reduce the collateral effects thereof. Í.Á íá.Á. .-. & - í-- *: - é ^ i - fe-fefe