WO2005070464A2 - A tablet formulation of clopidogrel bisulphate - Google Patents

A tablet formulation of clopidogrel bisulphate Download PDF

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Publication number
WO2005070464A2
WO2005070464A2 PCT/TR2005/000005 TR2005000005W WO2005070464A2 WO 2005070464 A2 WO2005070464 A2 WO 2005070464A2 TR 2005000005 W TR2005000005 W TR 2005000005W WO 2005070464 A2 WO2005070464 A2 WO 2005070464A2
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WO
WIPO (PCT)
Prior art keywords
formulation
lubricant
magnesium stearate
thieno
composition according
Prior art date
Application number
PCT/TR2005/000005
Other languages
French (fr)
Other versions
WO2005070464A3 (en
Inventor
Hatice Öncel
Ayse Gül ERKAHRAMAN
Original Assignee
Biofarma Ilac Sanayi Ve Ticaret A.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biofarma Ilac Sanayi Ve Ticaret A.S. filed Critical Biofarma Ilac Sanayi Ve Ticaret A.S.
Publication of WO2005070464A2 publication Critical patent/WO2005070464A2/en
Publication of WO2005070464A3 publication Critical patent/WO2005070464A3/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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to stable pharmaceutical composition of clopidogrel bisulphate.
  • Thieno pyridine derivative clopidogrel in the structure of ( ⁇ S)- ⁇ -(2- Chorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester is an inhibitor of platelet agregation and acts as anthitrombotic by irreversibly modifying the platelet ADP receptor.
  • Clopidogrel inhibits adenosine diphosphate (ADP) binding to its receptor and subsequently inhibits ADP mediated activation of the glycoprotein GPIIb/IIIa complex.
  • ADP adenosine diphosphate
  • EP0099802 relates to antithrombotic activities of thieno[3,2-c] pyridine derivatives.
  • Compositions containing thieno [3,2-c] pyridine derivatives have exhibited unacceptably rapid decomposition as a result of the inclusion of certain excipients such as magnesium stearate, povidone or gelatine. In order to solve this degradation and stability problems many studies have been done.
  • EP1310245 teaches that there is an interaction between platelet aggregation inhibitor clopidogrel and magnesium stearate and magnesium stearate cause degradation of clopidogrel.
  • This patent purports to overcome this problem by using zinc stearate, stearic acid, sodium stearyl fumarate as lubricant instead of magnesium sterate.
  • US5520928 relates to use of stearic acid
  • WO0001364 relates to use of PEG and talc instead of magnesium stearate.
  • US4591592 relates to use of a chelating agent such as stearic acid, benzoic acid, tartaric acid or fumaric acid and an antioxidant together with magnesium stearate.
  • This study provides a new and stable formulation of thieno [3,2-c] pyridine derivative by using a lubricant other than magnesium stearate.
  • This study comprises a new, stable pharmaceutical formulation of a thieno [3,2- c] pyridine derivative clopidogrel bisulphate wherein hydrogenated vegetable oil is used as lubricant.
  • direct compression method is used as tablet manufacturing process, known from the prior art.
  • Diluent, disintegrant and lubricant is added to the formulation together with the active ingredient.
  • Lactose, starch and derivatives, cellulose, mannitol and sorbitol are widely used excipients in direct compressions and magnesium stearate is the most used lubricant.
  • hydrogenated vegetable oil is used as lubricant instead of magnesium stearate in order to prevent discoloration and odour. Hydrogenated vegetable oil is used at concentrations of 1-6% in the pharmaceutical formulations.
  • This study also comprises the use of sodium carboxymethyl starch which excipient was told to be causing degradation in thieno [3,2-c] pyridine derivatives in WO0001364.
  • sodium carboxymethyl starch together with hydrogenated vegeatable oil provides suitable tablet formulation and solves problems occuring in tablet compression. It is observed that sodium carboxymethyl starch has no effect on degradation.
  • Sodium carboxymethyl starchis used at concentrations of 2-8% in this pharmaceutical formulation.
  • lactose monohydrate, microcrystalline cellulose and pregelatinized starch are also used as excipients beside hyrogenated vegetable oil and sodium carboxymethyl starch. Lactose monohydrate is used at concentrations of 65-85%) in the pharmaceutical formulations.
  • suitable concentration of lactose monohydrate is found to be between 20-40%.
  • Microcrystalline cellulose is used at concentrations of 20-90% in the pharmaceutical formulations as diluent.
  • suitable concentration of microcrystalline cellulose is found to be between 20-30%.
  • Pregelatinized starch is used at concentrations of 5-75% in pharmaceutical formulations as binder, disintegrant and diluent. In this formulation suitable concentration of pregelatinized starch is found to be between 5- 30% and it is used as disintegrator.

Abstract

This invention comprises a new formulation which solves the stability problems of a thieno pyridine derivative, anthitrombotic clopidogrel bisulphate compositions. The object of the present invention is to use a new lubricant other than magnesium stearate which cause degradation in thieno[3,2-c] pyridine derivatives. Another object of the invention is to form a new formulation and to increase stability.

Description

DESCRIPTION
A TABLET FORMULATION OF CLOPIDOGREL BISULPHATE
The present invention relates to stable pharmaceutical composition of clopidogrel bisulphate.
Thieno pyridine derivative clopidogrel (Formul-I), in the structure of (αS)-α-(2- Chorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester is an inhibitor of platelet agregation and acts as anthitrombotic by irreversibly modifying the platelet ADP receptor. Clopidogrel inhibits adenosine diphosphate (ADP) binding to its receptor and subsequently inhibits ADP mediated activation of the glycoprotein GPIIb/IIIa complex.
EP0099802 relates to antithrombotic activities of thieno[3,2-c] pyridine derivatives. Compositions containing thieno [3,2-c] pyridine derivatives have exhibited unacceptably rapid decomposition as a result of the inclusion of certain excipients such as magnesium stearate, povidone or gelatine. In order to solve this degradation and stability problems many studies have been done.
EP1310245 teaches that there is an interaction between platelet aggregation inhibitor clopidogrel and magnesium stearate and magnesium stearate cause degradation of clopidogrel. This patent purports to overcome this problem by using zinc stearate, stearic acid, sodium stearyl fumarate as lubricant instead of magnesium sterate. US5520928 relates to use of stearic acid, WO0001364 relates to use of PEG and talc instead of magnesium stearate. US4591592 relates to use of a chelating agent such as stearic acid, benzoic acid, tartaric acid or fumaric acid and an antioxidant together with magnesium stearate. This study provides a new and stable formulation of thieno [3,2-c] pyridine derivative by using a lubricant other than magnesium stearate.
Figure imgf000003_0001
Formul-I
This study comprises a new, stable pharmaceutical formulation of a thieno [3,2- c] pyridine derivative clopidogrel bisulphate wherein hydrogenated vegetable oil is used as lubricant.
In this invention direct compression method is used as tablet manufacturing process, known from the prior art. Diluent, disintegrant and lubricant is added to the formulation together with the active ingredient. Lactose, starch and derivatives, cellulose, mannitol and sorbitol are widely used excipients in direct compressions and magnesium stearate is the most used lubricant. In this study, hydrogenated vegetable oil is used as lubricant instead of magnesium stearate in order to prevent discoloration and odour. Hydrogenated vegetable oil is used at concentrations of 1-6% in the pharmaceutical formulations.
This study also comprises the use of sodium carboxymethyl starch which excipient was told to be causing degradation in thieno [3,2-c] pyridine derivatives in WO0001364. However,in this invention it is find out that using sodium carboxymethyl starch together with hydrogenated vegeatable oil provides suitable tablet formulation and solves problems occuring in tablet compression. It is observed that sodium carboxymethyl starch has no effect on degradation. Sodium carboxymethyl starchis used at concentrations of 2-8% in this pharmaceutical formulation. In this study lactose monohydrate, microcrystalline cellulose and pregelatinized starch are also used as excipients beside hyrogenated vegetable oil and sodium carboxymethyl starch. Lactose monohydrate is used at concentrations of 65-85%) in the pharmaceutical formulations. In this formulation suitable concentration of lactose monohydrate is found to be between 20-40%. Microcrystalline cellulose is used at concentrations of 20-90% in the pharmaceutical formulations as diluent. In this formulation suitable concentration of microcrystalline cellulose is found to be between 20-30%. Pregelatinized starch is used at concentrations of 5-75% in pharmaceutical formulations as binder, disintegrant and diluent. In this formulation suitable concentration of pregelatinized starch is found to be between 5- 30% and it is used as disintegrator.
Example 1:
Figure imgf000004_0001
Example 2:
Figure imgf000004_0002
Preparation of the formulation: Active ingredient and excipients are weighed seperately and siewed. All of them are mixed except hydrogenated vegetable oil. Hydrogenated vegetable oil is added, mixed again and tablets compressed. Tablets are coated with a coating material which includes polyvinyl alcohol, polyethylene glycol and some coloring agents. This formulation can be used in dosage forms such as tablet, film tablet and capsule.

Claims

CLAIMS:
1) New and stable pharmaceutical composition of clopidogrel bisulphate where magnesium stearate is not used as lubricant
2) A composition according to claim 1 wherein hydrogenated vegetable oil is used as lubricant
3) A composition according to claim 2 which comprises 1 to 6wt% hydrogenated vegetable oil 4) A composition according to claim 1,2 and 3 wherein sodium carboxymethyl starch is used
5) A composition according to claim 4 which comprises 1 to 3 wt% sodium carboxymethyl starch
6) A composition according to claim 1 ,2 and 4 wherein the dosage form is tablet, film coated tablet or capsule.
PCT/TR2005/000005 2004-01-21 2005-01-17 A tablet formulation of clopidogrel bisulphate WO2005070464A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2004/00111 2004-01-21
TR200400111 2004-01-21

Publications (2)

Publication Number Publication Date
WO2005070464A2 true WO2005070464A2 (en) 2005-08-04
WO2005070464A3 WO2005070464A3 (en) 2005-11-03

Family

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Country Status (2)

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TR (1) TR200505165T1 (en)
WO (1) WO2005070464A2 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049868A1 (en) * 2005-10-24 2007-05-03 Sk Chemicals Co., Ltd. Stabilized pharmaceutical oral preparation containing clopidogrel bisulfate
WO2007091279A1 (en) * 2006-02-10 2007-08-16 Actavis Group Hf. Formulations of clopidogrel bisulphate
WO2007128476A1 (en) * 2006-05-04 2007-11-15 Sandoz Ag Pharmaceutical compositions containing clopidogrel hydrochloride
CN100400035C (en) * 2006-10-18 2008-07-09 深圳信立泰药业股份有限公司 Clopidogrel sulfate solid preparation, and its preparing method
EP1970054A2 (en) 2007-03-14 2008-09-17 Ranbaxy Laboratories Limited Clopidogrel tablets
WO2008059298A3 (en) * 2006-11-14 2008-10-23 Egis Gyogyszergyar Nyilvanosan Pharmaceutical composition containing clopidogrel hydrogenesulphate of polymorph 1 form
EP2095815A1 (en) 2008-02-26 2009-09-02 Laboratorios Lesvi, S.L. Pharmaceutical formulations containing 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
JP2014015442A (en) * 2012-07-11 2014-01-30 Ohara Yakuhin Kogyo Kk Manufacturing method of tablet containing clopidogrel sulfate
WO2015189650A1 (en) 2014-06-13 2015-12-17 Skillpharm Kft. Clopidogrel for use in the treatment of benign prostatic hyperplasia

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066130A1 (en) * 1999-04-30 2000-11-09 Sanofi-Synthelabo Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel hydrogenosulphate
WO2001012194A1 (en) * 1999-08-11 2001-02-22 Sanofi-Synthelabo Combinations with antithrombotic activity consisting of clopidogrel hydrogenosulphate and a gpiib/iiia receptor antagonist
EP1310245A1 (en) * 2001-11-09 2003-05-14 SHERMAN, Bernard Charles Clopidogrel bisulfate tablet formulation
WO2004026879A1 (en) * 2002-09-19 2004-04-01 Cipla Limited Clopidogrel
WO2004074215A1 (en) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Process for preparation of clopidogrel, its salts and pharmaceutical compositions
WO2005048992A1 (en) * 2003-11-03 2005-06-02 Sandoz Ag Process for preparing clopidogrel compositions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3397385B2 (en) * 1993-09-20 2003-04-14 第一製薬株式会社 Disintegration delay prevention tablets

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066130A1 (en) * 1999-04-30 2000-11-09 Sanofi-Synthelabo Pharmaceutical composition in unit form containing acetylsalcylic acid and clopidogrel hydrogenosulphate
WO2001012194A1 (en) * 1999-08-11 2001-02-22 Sanofi-Synthelabo Combinations with antithrombotic activity consisting of clopidogrel hydrogenosulphate and a gpiib/iiia receptor antagonist
EP1310245A1 (en) * 2001-11-09 2003-05-14 SHERMAN, Bernard Charles Clopidogrel bisulfate tablet formulation
WO2004026879A1 (en) * 2002-09-19 2004-04-01 Cipla Limited Clopidogrel
WO2004074215A1 (en) * 2003-02-03 2004-09-02 Sunil Sadanand Nadkarni Process for preparation of clopidogrel, its salts and pharmaceutical compositions
WO2005048992A1 (en) * 2003-11-03 2005-06-02 Sandoz Ag Process for preparing clopidogrel compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; MATSUMOTO, TAKAHIRO ET AL: "Pharmaceutical tablets prevented from delayed disintegration" XP002343276 retrieved from STN Database accession no. 123:17941 & JP 07 089875 A2 (DAIICHI SEIYAKU CO, JAPAN) 4 April 1995 (1995-04-04) *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049868A1 (en) * 2005-10-24 2007-05-03 Sk Chemicals Co., Ltd. Stabilized pharmaceutical oral preparation containing clopidogrel bisulfate
WO2007091279A1 (en) * 2006-02-10 2007-08-16 Actavis Group Hf. Formulations of clopidogrel bisulphate
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
WO2007128476A1 (en) * 2006-05-04 2007-11-15 Sandoz Ag Pharmaceutical compositions containing clopidogrel hydrochloride
CN100400035C (en) * 2006-10-18 2008-07-09 深圳信立泰药业股份有限公司 Clopidogrel sulfate solid preparation, and its preparing method
WO2008059298A3 (en) * 2006-11-14 2008-10-23 Egis Gyogyszergyar Nyilvanosan Pharmaceutical composition containing clopidogrel hydrogenesulphate of polymorph 1 form
EA015440B1 (en) * 2006-11-14 2011-08-30 Эгиш Дьёдьсердьяр Ньильваношан Мюкёдё Ресвеньтаршашаг Solid dosage form containing clopidogrel hydrogenesulphate of polymorph form 1
EP1970054A2 (en) 2007-03-14 2008-09-17 Ranbaxy Laboratories Limited Clopidogrel tablets
EP2095815A1 (en) 2008-02-26 2009-09-02 Laboratorios Lesvi, S.L. Pharmaceutical formulations containing clopidogrel
EP2107061A1 (en) 2008-04-02 2009-10-07 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of optically enriched clopidogrel
JP2014015442A (en) * 2012-07-11 2014-01-30 Ohara Yakuhin Kogyo Kk Manufacturing method of tablet containing clopidogrel sulfate
WO2015189650A1 (en) 2014-06-13 2015-12-17 Skillpharm Kft. Clopidogrel for use in the treatment of benign prostatic hyperplasia

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WO2005070464A3 (en) 2005-11-03

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