WO2004098593A1 - Amorphous clopidogrel hydrogen sulfate composition - Google Patents

Amorphous clopidogrel hydrogen sulfate composition Download PDF

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Publication number
WO2004098593A1
WO2004098593A1 PCT/IN2003/000175 IN0300175W WO2004098593A1 WO 2004098593 A1 WO2004098593 A1 WO 2004098593A1 IN 0300175 W IN0300175 W IN 0300175W WO 2004098593 A1 WO2004098593 A1 WO 2004098593A1
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Prior art keywords
hydrogen sulfate
pharmaceutical composition
clopidogrel hydrogen
calcium stearate
calcium
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PCT/IN2003/000175
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Male Srinivas Reddy
Pothireddy Venkateswar Reddy
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Hetero Drugs Limited
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Publication date
Application filed by Hetero Drugs Limited filed Critical Hetero Drugs Limited
Priority to AU2003241149A priority Critical patent/AU2003241149A1/en
Priority to PCT/IN2003/000175 priority patent/WO2004098593A1/en
Publication of WO2004098593A1 publication Critical patent/WO2004098593A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine

Definitions

  • the present invention relates to a non-hygroscopic, stable pharmaceutical composition of amorphous clopidogrel hydrogen sulfate.
  • Clopidogrel hydrogen sulfate, ( ⁇ S)- ⁇ -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester hydrogen sulfate is a platelet aggregation inhibitor.
  • Clopidogrel hydrogen sulfate is commercially available as a 75 mg tablet (as clopidogrel free base). It is sold under the name PLAVIX. The therapeutic uses of clopidogrel and its salts were disclosed in US
  • US 6,215,005, US 6,180,793, US 5,132,435, US 6,080,875 and WO 02/059128 described various methods of synthesis of clopidogrel and its salts.
  • US 6,429,210 disclosed a crystalline form of clopidogrel hydrogen sulfate designated as form II.
  • the process described in EP 281459 for the preparation of clopidogrel hydrogen sulfate leads to a crystalline form (form I).
  • crystalline clopidogrel hydrogen sulfate was used in pharmaceutical compositions.
  • Clopidogrel hydrogen sulfate in amorphous form has a higher bioavailability than the crystalline forms. Over extended storage periods an amorphous clopidogrel hydrogen sulfate can convert to a crystalline form, with consequent changes in its dissolution profile. So, there is a need for a stable, non-hygroscopic composition comprising amorphous clopidogrel hydrogen sulfate.
  • Amorphous clopidogrel hydrogen sulfate can be prepared from a crystalline form of clopidogrel hydrogen sulfate or clopidogrel hydrogen sulfate solvate.
  • amorphous clopidogrel hydrogen sulfate may be prepared by dissolving crystalline clopidogrel hydrogen sulfate or clopidogrel hydrogen sulfate isopropyl alcohol solvate in, for example, methanol, refluxing for about 2 hours and distilling off the solvent s from the solution.
  • a high dosage strength solid unit oral dosage form of amorphous clopidogrel hydrogen sulfate having satisfactory stability has not been successfully developed prior to the present invention.
  • the object of the present invention is to provide a stable, non- hygroscopic composition of amorphous clopidogrel hydrogen sulfate.
  • the present invention provides a non-hygroscopic, stable pharmaceutical formulation of amorphous clopidogrel hydrogen sulfate. More particularly the invention relates to a composition comprising a mixture of amorphous clopidogrel hydrogen sulfate; either or both of calcium stearate and magnesium stearate; and a non-hygroscopic additive. Optionally at least one additional excipient is used.
  • the additional excipients include pharmaceutical lubricants, disintegrators, glidents, adsorbants, fillers, or mixtures thereof.
  • the process for preparing a non-hygroscopic, stable oral pharmaceutical formulations of amorphous clopidogrel hydrogen sulfate includes the blending of ingredients including amorphous clopidogrel hydrogen sulfate, calcium stearate or magnesium stearate and a non-hygroscopic additive.
  • the process further includes the step of compressing the ingredients into a solid dosage form after the step of blending.
  • amorphous clopidogrel hydrogen sulfate is present in an amount of from about 5% to about 90% of the weight of the final composition, more preferably from about 10% to about 40% and most preferably from about 20% to 30% of the weight of the final composition.
  • a non-hygroscopic additive in combination with calcium stearate or magnesium stearate prevents the liquefaction of amorphous clopidogrel hydrogen sulfate as a result of moisture uptake and indeed prevents the finished composition from absorbing significant amounts of water over a wide range of relative humidities.
  • the combination of calcium stearate or magnesium stearate and a non-hygroscopic additive is particularly advantageous since such a combination prevents the liquefaction of amorphous clopidogrel hydrogen sulfate, prevents the conversion of amorphous clopidogrel hydrogen sulfate to a crystalline over an extended period of time and forms a non-hygroscopic and stable mixture which is highly compressible and have optimal flow properties, thereby providing the tablets with excellent physical properties.
  • the pharmaceutical composition is stable under relative humidity of from about 30% to about 75% at 40°C and more preferably from about 30% to about 60% at 25°C.
  • the non-hygroscopic additive includes, but is not limited to heavy calcium carbonate, heavy magnesium carbonate, light magnesium oxide, dibasic calcium phosphate anhydrous and calcium silicate.
  • the non-hygroscopic additive is present in an amount of from about 0.5% to about 20% of the weight of the final composition and more preferably from about 2% to 12% of the weight of the final composition.
  • calcium stearate or magnesium stearate is present in an amount of from about 0.1% to about 5% of the weight of the final composition and more preferably from about 0.2% to 2.5% of the weight of the final composition.
  • Calcium stearate and magnesium stearate can also be useful as lubricants.
  • the additional excipients may be, for example, lubricants, disintegrators, glidents, adsorbents, fillers, or mixtures thereof.
  • the filler includes, but is not limited to lactose anhydrous, microcrystalline cellulose, mannitol, or mixtures thereof.
  • the lubricant includes, but is not limited to stearic acid, a salt of stearic acid, talc, sodium stearyl fumarate, or mixtures thereof.
  • the disintegrator includes, but is not limited to sodium starch glycolate, starch, magnesium aluminium silicate, or mixtures thereof.
  • the glidents may be for example colloidal silicon dioxide, talc or mixtures thereof.
  • the pharmaceutical composition may be, for example, in the form of a tablet, a caplet, a pellet, a capsule, a granule, a pil, a powder or a sachet preferably the pharmaceutical composition is in the form of a tablet.
  • the capsule may contain a powder, a compressed powder or a granule.
  • the pharmaceutical composition of the present invention is administered orally.
  • the pharmaceutical composition may further be coated with a moisture barrier film, an enteric-coating film or a combination thereof to improve the non- hygroscopic properties of the composition. , , .
  • Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
  • Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
  • Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
  • Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
  • Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.

Abstract

The present invention provides a non-hygroscopic, stable pharmaceutical formulation of amorphous clopidogrel hydrogen sulfate. More particularly the invention relates to a composition comprising a mixture of amorphous clopidogrel hydrogen sulfate, calcium stearate or magnesium stearate and a non-hygroscopic additive.

Description

AMORPHOUS CLOPIDOGREL HYDROGEN SULFATE COMPOSITION
FIELD OF THE INVENTION
The present invention relates to a non-hygroscopic, stable pharmaceutical composition of amorphous clopidogrel hydrogen sulfate.
BACKGROUND OF THE INVENTION
Clopidogrel hydrogen sulfate, (αS)- α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester hydrogen sulfate is a platelet aggregation inhibitor.
Clopidogrel hydrogen sulfate is commercially available as a 75 mg tablet (as clopidogrel free base). It is sold under the name PLAVIX. The therapeutic uses of clopidogrel and its salts were disclosed in US
4,529,596 and US 4,847,265.
US 5,989,578 reported pharmaceutical compositions containing pharmaceutically acceptable salts of clopidogrel and aspirin.
US 6,215,005, US 6,180,793, US 5,132,435, US 6,080,875 and WO 02/059128 described various methods of synthesis of clopidogrel and its salts. US 6,429,210 disclosed a crystalline form of clopidogrel hydrogen sulfate designated as form II. The process described in EP 281459 for the preparation of clopidogrel hydrogen sulfate leads to a crystalline form (form I). In the prior art crystalline clopidogrel hydrogen sulfate was used in pharmaceutical compositions.
Clopidogrel hydrogen sulfate in amorphous form has a higher bioavailability than the crystalline forms. Over extended storage periods an amorphous clopidogrel hydrogen sulfate can convert to a crystalline form, with consequent changes in its dissolution profile. So, there is a need for a stable, non-hygroscopic composition comprising amorphous clopidogrel hydrogen sulfate.
Amorphous clopidogrel hydrogen sulfate can be prepared from a crystalline form of clopidogrel hydrogen sulfate or clopidogrel hydrogen sulfate solvate. Thus amorphous clopidogrel hydrogen sulfate may be prepared by dissolving crystalline clopidogrel hydrogen sulfate or clopidogrel hydrogen sulfate isopropyl alcohol solvate in, for example, methanol, refluxing for about 2 hours and distilling off the solvent s from the solution.
A high dosage strength solid unit oral dosage form of amorphous clopidogrel hydrogen sulfate having satisfactory stability has not been successfully developed prior to the present invention.
The object of the present invention is to provide a stable, non- hygroscopic composition of amorphous clopidogrel hydrogen sulfate.
DESCRIPTION OF THE INVENTION
The present invention provides a non-hygroscopic, stable pharmaceutical formulation of amorphous clopidogrel hydrogen sulfate. More particularly the invention relates to a composition comprising a mixture of amorphous clopidogrel hydrogen sulfate; either or both of calcium stearate and magnesium stearate; and a non-hygroscopic additive. Optionally at least one additional excipient is used. The additional excipients include pharmaceutical lubricants, disintegrators, glidents, adsorbants, fillers, or mixtures thereof. Preferably, the process for preparing a non-hygroscopic, stable oral pharmaceutical formulations of amorphous clopidogrel hydrogen sulfate includes the blending of ingredients including amorphous clopidogrel hydrogen sulfate, calcium stearate or magnesium stearate and a non-hygroscopic additive.
Preferably, the process further includes the step of compressing the ingredients into a solid dosage form after the step of blending. Preferably, amorphous clopidogrel hydrogen sulfate is present in an amount of from about 5% to about 90% of the weight of the final composition, more preferably from about 10% to about 40% and most preferably from about 20% to 30% of the weight of the final composition.
Surprisingly, it has been found that a non-hygroscopic additive in combination with calcium stearate or magnesium stearate prevents the liquefaction of amorphous clopidogrel hydrogen sulfate as a result of moisture uptake and indeed prevents the finished composition from absorbing significant amounts of water over a wide range of relative humidities. The combination of calcium stearate or magnesium stearate and a non-hygroscopic additive is particularly advantageous since such a combination prevents the liquefaction of amorphous clopidogrel hydrogen sulfate, prevents the conversion of amorphous clopidogrel hydrogen sulfate to a crystalline over an extended period of time and forms a non-hygroscopic and stable mixture which is highly compressible and have optimal flow properties, thereby providing the tablets with excellent physical properties.
Preferably, the pharmaceutical composition is stable under relative humidity of from about 30% to about 75% at 40°C and more preferably from about 30% to about 60% at 25°C. Preferably, the non-hygroscopic additive includes, but is not limited to heavy calcium carbonate, heavy magnesium carbonate, light magnesium oxide, dibasic calcium phosphate anhydrous and calcium silicate.
Preferably, the non-hygroscopic additive is present in an amount of from about 0.5% to about 20% of the weight of the final composition and more preferably from about 2% to 12% of the weight of the final composition.
Preferably, calcium stearate or magnesium stearate is present in an amount of from about 0.1% to about 5% of the weight of the final composition and more preferably from about 0.2% to 2.5% of the weight of the final composition. Calcium stearate and magnesium stearate can also be useful as lubricants.
The additional excipients may be, for example, lubricants, disintegrators, glidents, adsorbents, fillers, or mixtures thereof.
The filler includes, but is not limited to lactose anhydrous, microcrystalline cellulose, mannitol, or mixtures thereof. The lubricant includes, but is not limited to stearic acid, a salt of stearic acid, talc, sodium stearyl fumarate, or mixtures thereof.
Preferably, the disintegrator includes, but is not limited to sodium starch glycolate, starch, magnesium aluminium silicate, or mixtures thereof.
The glidents may be for example colloidal silicon dioxide, talc or mixtures thereof.
Other ingredients such as diluents, stabilizers and antiadherants, conventionally used for pharmaceutical formulations may be included in the present formulation. The pharmaceutical composition may be, for example, in the form of a tablet, a caplet, a pellet, a capsule, a granule, a pil, a powder or a sachet preferably the pharmaceutical composition is in the form of a tablet. The capsule may contain a powder, a compressed powder or a granule. The pharmaceutical composition of the present invention is administered orally.
The pharmaceutical composition may further be coated with a moisture barrier film, an enteric-coating film or a combination thereof to improve the non- hygroscopic properties of the composition. , , .
The invention is further illustrated by the following non-limiting examples.
Example 1
Figure imgf000005_0001
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Lactose Anhydrous (2.49 Kg), Hydrogenated Caster Oil (100 g), Heavy Calcium Carbonate (150 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes. The final blend was then compressed into 410 mg tablets using 'D' tooling Cadmach compression machine.
Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
Example 2
Figure imgf000006_0001
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Lactose Anhydrous (2.29 Kg), Hydrogenated Caster Oil (100 g), Light Magnesium Oxide (150 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes. The final blend was then compressed into 390 mg tablets using 'D' tooling Cadmach compression machine.
Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
Example 3
Figure imgf000006_0002
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Lactose Anhydrous (1.94 Kg), Hydrogenated Caster Oil (100 g), Light Magnesium Carbonate (400 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes. The final blend was then compressed into 380 mg tablets using 'D' tooling Cadmach compression machine. Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
Example 4
Figure imgf000007_0001
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Mannitol (2.29 Kg), Hydrogenated Caster Oil (100 g), Calcium Silicate
(150 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes.
The final blend was then compressed into 390 mg tablets using 'D' tooling
Cadmach compression machine.
Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
Example 5
Figure imgf000007_0002
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Mannitol (2.04 Kg), Hydrogenated Caster Oil (100 g), Heavy Calcium carbonate (200 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes. The final blend was then compressed into 370 mg tablets using 'D' tooling Cadmach compression machine.
Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
Example 6
Figure imgf000008_0001
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Mannitol (Pearlitol SD-200) (1.94 Kg), Hydrogenated Caster Oil (100 g), Light Magnesium Carbonate (400 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes. The final blend was then compressed into 380 mg Otablets using 'D' tooling Cadmach compression machine. Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.
Example 7
Figure imgf000008_0002
Figure imgf000009_0001
10,000 tablets of the above formulation were prepared as follows. A blend was prepared of Clopidogrel Hydrogen Sulfate (978.8 g), Microcrystalline Cellulose (350 g), Lactose Anhydrous (2.49 Kg), Hydrogenated Caster Oil (100 g), Calcium silicate (150 g) and Calcium Stearate (30 g) in a blender and mix for 5 to 10 minutes. The final blend was then compressed into 410 mg tablets using 'D' tooling Cadmach compression machine.
Coating solution is prepared by using 102.5 gm of opadry organic with 1.25 L of isopropyl alcohol and 1.25 L of methylene chloride.

Claims

We claim:
I . The pharmaceutical composition comprising amorphous clopidogrel hydrogen sulfate; either or both of calcium stearate and magnesium stearate; a non-hygroscopic additive; and at least one excipient. 2. The pharmaceutical composition of claim 1 , wherein said non- hygroscopic additive is selected from the group consisting of heavy calcium carbonate, heavy magnesium carbonate, light magnesium oxide, dibasic calcium phosphate anhydrous, calcium silicate, and a mixture thereof. 3. The pharmaceutical composition of claim 1, wherein said non- hygroscopic additive is heavy calcium carbonate. 4. The pharmaceutical composition of claim 1 , wherein said amorphous clopidogrel hydrogen sulfate is present in an amount of from about 5% to about 90% of the weight of the final composition. 5. The pharmaceutical composition of claim 1, wherein said amorphous clopidogrel hydrogen sulfate is present in an amount of from about 10% to about 40% of the weight of the final composition.
6. The pharmaceutical composition of claim 4 or 5, wherein said amorphous clopidogrel hydrogen sulfate is present in an amount of from about 20% to about 30% of the weight of the final composition.
7. The pharmaceutical composition of claim 1, wherein said non- hygroscopic additive is present in an amount of from about 0.5% to about 20% of the weight of the final composition.
8. The pharmaceutical composition of claim 7, wherein said non- hygroscopic additive is present in an amount of from about 2% to about
12% of the weight of the final composition.
9. The pharmaceutical composition of claim 1 , wherein said calcium stearate or magnesium stearate is present in an amount of from about 0.1% to about 5% of the weight of the final composition. 10. The pharmaceutical composition of claim 9, wherein said calcium stearate or magnesium stearate is present in an amount of from about 0.2% to about 2.5% of the weight of the final composition.
I I . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated in an oral dosage form.
12. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate, about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 249.0 mg of lactose anhydrous, about 15.0 mg of heavy calcium carbonate and about 3.0 mg of calcium stearate.
13. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate, about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 229.0 mg of lactose anhydrous, about
15.0 mg of light magnesium oxide and about 3.0 mg of calcium stearate.
14. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate, about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 194.0 mg of lactose anhydrous, about
40.0 mg of light magnesium carbonate and about 3.0 mg of calcium stearate.
15. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate, about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 229.0 mg of mannitol, about 15.0 mg of calcium silicate and about 3.0 mg of calcium stearate.
16. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate,. about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 204.0 mg of mannitol, about 20.0 mg of heavy calcium carbonate and about 3.0 mg of calcium stearate.
17. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate, about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 194.0 mg of mannitol, about 40.0 mg of light magnesium carbonate and about 3.0 mg of calcium stearate.
18. The pharmaceutical composition of claim 11 , wherein said oral dosage form is a tablet containing about 97.88 mg of clopidogrel hydrogen sulfate, about 35.0 mg of microcrystalline cellulose, about 10.0 mg of hydrogenated caster oil, about 249.0 mg of lactose anhydrous, about 15.0 mg of calcium silicate and about 3.0 mg of calcium stearate.
PCT/IN2003/000175 2003-05-05 2003-05-05 Amorphous clopidogrel hydrogen sulfate composition WO2004098593A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006074066A1 (en) * 2004-12-30 2006-07-13 Nektar Therapeutics Non-crystalline formulation comprising clopidogrel
WO2007113857A2 (en) * 2006-04-05 2007-10-11 Cadila Healthcare Limited Modified release clopidogrel formulation
EP1970054A2 (en) 2007-03-14 2008-09-17 Ranbaxy Laboratories Limited Clopidogrel tablets
WO2008122994A2 (en) * 2007-04-09 2008-10-16 Usv Limited Stable pharmaceutical compositions of clopidogrel bisulfate and process of preparation thereof
WO2008129468A2 (en) * 2007-04-20 2008-10-30 Wockhardt Research Centre Pharmaceutical compositions of clopidogrel
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
DE202006020892U1 (en) 2006-04-13 2010-10-21 Riemser Arzneimittel Ag Partial glycerides as lubricants for pharmaceutical compositions containing thieno [3,2-c] pyridine derivatives
US9144550B2 (en) 2010-02-05 2015-09-29 Shanghai Anbison Laboratory Co., Ltd. Preparation method of the solid formulation of Clopidogrel bisulfate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132435A (en) * 1990-07-04 1992-07-21 Sanofi 2-thienylglycidic derivative, process for its preparation and its use as synthesis intermediate
US5576328A (en) * 1994-01-31 1996-11-19 Elf Sanofi Method for the secondary prevention of ischemic events
WO1999018110A1 (en) * 1997-10-06 1999-04-15 Sanofi-Synthelabo Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132435A (en) * 1990-07-04 1992-07-21 Sanofi 2-thienylglycidic derivative, process for its preparation and its use as synthesis intermediate
US5576328A (en) * 1994-01-31 1996-11-19 Elf Sanofi Method for the secondary prevention of ischemic events
WO1999018110A1 (en) * 1997-10-06 1999-04-15 Sanofi-Synthelabo Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006074066A1 (en) * 2004-12-30 2006-07-13 Nektar Therapeutics Non-crystalline formulation comprising clopidogrel
WO2007113857A2 (en) * 2006-04-05 2007-10-11 Cadila Healthcare Limited Modified release clopidogrel formulation
WO2007113857A3 (en) * 2006-04-05 2008-02-28 Cadila Healthcare Ltd Modified release clopidogrel formulation
DE202006020892U1 (en) 2006-04-13 2010-10-21 Riemser Arzneimittel Ag Partial glycerides as lubricants for pharmaceutical compositions containing thieno [3,2-c] pyridine derivatives
EP1970054A2 (en) 2007-03-14 2008-09-17 Ranbaxy Laboratories Limited Clopidogrel tablets
WO2008122994A2 (en) * 2007-04-09 2008-10-16 Usv Limited Stable pharmaceutical compositions of clopidogrel bisulfate and process of preparation thereof
WO2008122994A3 (en) * 2007-04-09 2009-06-11 Usv Ltd Stable pharmaceutical compositions of clopidogrel bisulfate and process of preparation thereof
WO2008129468A2 (en) * 2007-04-20 2008-10-30 Wockhardt Research Centre Pharmaceutical compositions of clopidogrel
WO2008129468A3 (en) * 2007-04-20 2009-08-20 Wockhardt Research Center Pharmaceutical compositions of clopidogrel
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
US9144550B2 (en) 2010-02-05 2015-09-29 Shanghai Anbison Laboratory Co., Ltd. Preparation method of the solid formulation of Clopidogrel bisulfate

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