WO2005123720A1 - Fines particules d'un antagoniste de l'angiotensine ii a base de candesartan cilexetil et leur procede de production - Google Patents

Fines particules d'un antagoniste de l'angiotensine ii a base de candesartan cilexetil et leur procede de production Download PDF

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Publication number
WO2005123720A1
WO2005123720A1 PCT/IB2005/001713 IB2005001713W WO2005123720A1 WO 2005123720 A1 WO2005123720 A1 WO 2005123720A1 IB 2005001713 W IB2005001713 W IB 2005001713W WO 2005123720 A1 WO2005123720 A1 WO 2005123720A1
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WIPO (PCT)
Prior art keywords
candesartan cilexetil
microns
less
particle size
angiotensin
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Ceased
Application number
PCT/IB2005/001713
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English (en)
Inventor
Yatendra Kumar
Shantanu De
Swargam Sathyanarayana
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of WO2005123720A1 publication Critical patent/WO2005123720A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to fine particles of an angiotensin II antagonist having improved pharmacokinetic profile and process for production thereof.
  • Background of Invention ( ⁇ )- 1 -[[(Cyclohexyloxy)carbonyl]oxy] ethyl 2-ethoxy- 1 -[[2 ⁇ -( lH-tetrazole-5-yl) [1,1'- biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate (candesartan cilexetil) of Formula I is an ester prodrug of 2-ethoxy-l-[[2 , -(lH-tetrazole-5-yl)[l,l'-biphenyl-4-yl]methyl]-lH-0 benzimidazole-7-carboxylic acid (candesartan), known as a potent Angiotensin II receptor antagonist. It is useful in the treatment of cardiovascular complaints such as hypertension and heart failure.
  • Type C crystals of candesartan cilexetil The particle size of the pure “Type C” crystals of candesartan cilexetil obtained by following US '444 patent is variable, wherein 90% of the particles are having particle size less than (do. 9 ) about 70 microns to about 40 microns. Summary of Invention The present inventors have found that by formulating candesartan cilexetil, having do.9 about 70 microns to about 40 microns, in a solid dosage form, the pharmacokinetic profile of the dosage form is not predictable and desired therapeutic effect is not achieved.
  • the invention provides candesartan cilexetil having a particle size wherein do. 9 is about 25 microns or less. In another aspect, the invention provides candesartan cilexetil having a particle size wherein d 0 . 9 is about 25 microns or less and d 0 . 5 is about 15 microns or less.
  • the present invention provides candesartan cilexetil having a particle size wherein do. 9 is about 25 microns or less, d 0 . 5 is about 15 microns or less and drj is about 7 microns or less.
  • the present invention provides a process for preparation of candesartan cilexetil having a particle size wherein d 0 .
  • 9 is about 25 microns or less
  • the process comprises: a) dissolving candesartan cilexetil in a suitable organic solvent; b) cooling the solution obtained in step a) under stirring to crystallize candesartan cilexetil from the solution; and c) isolating candesartan cilexetil having a particle size wherein is do 9 about 25 microns or less.
  • the starting material used can be in any polymorphic form or present in an amorphous form.
  • the starting material can be completely dissolved in an organic solvent which is characterized by the fact that at ambient or higher temperatures, the solvent has greater solubility for candesartan cilexetil whereas at lower temperatures candesartan cilexetil has significantly reduced solubility in it.
  • organic solvent which is characterized by the fact that at ambient or higher temperatures, the solvent has greater solubility for candesartan cilexetil whereas at lower temperatures candesartan cilexetil has significantly reduced solubility in it.
  • solvents are lower alkanols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl isobutyl ketone; acetonitrile, tetrahydrofuran or mixtures thereof.
  • the stirring rate may play a significant role in achieving the desired particle size and is dependent upon the size of the vessel, quantity of reactants and the type of stirrer used in the process.
  • stirring rates of approximately 250 rpm can produce particles with do. 9 of about 25 microns or less.
  • Stirring rates of approximately 150 rpm can produce particles with do. 9 of about 50 microns or less, and stirring rates of approximately 100 rpm can produce particles having do. 9 of about 75 microns or less.
  • the particle size distribution was do. 9 of about 13 microns and do. 5 of about 4 to 5 microns.
  • the shear generated by anchor-type agitators appears to result in generally lower particle size distributions.
  • the product is isolated from the reaction mass and dried suitably to get candesartan cilexetil having particle size, wherein do. 9 is about 25 microns or less, for example 15 microns or less, for example 13 microns or less.
  • "C-type" crystals are used as starting material, it may be dissolved in a suitable second organic solvent characterized by the fact that crystalline candesartan cilexetil is soluble in it.
  • Examples of the second organic solvent are chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and ethylene dichloride; polar aprotic solvents such as tetrahydrofuran, 1,4-dioxane, N,N-dimethylacetamide, N,N- dimethylformamide and dimethylsulphoxide; aromatic hydrocarbons such as toluene, benzene or xylene; esters such as ethyl acetate, isopropyl acetate, ethyl formate, methyl formate, n- propyl acetate and butyl acetate or mixtures thereof.
  • the resultant solution obtained can be concentrated to dryness.
  • the residue so obtained is then dissolved in suitable organic solvents and crystallized by the process mentioned above.
  • the residue so obtained is treated with a third organic solvent characterized by the fact that candesartan cilexetil is insoluble, sparingly soluble or less soluble in it.
  • the powdered product obtained is isolated by means of filtration and optionally dried.
  • the powder of candesartan cilexetil thus obtained is dissolved in suitable organic solvent and crystallized by the process mentioned above.
  • the present invention a process for preparation of candesartan cilexetil having a particle size wherein do. 9 is about 25 microns or less, and wherein the process comprises micronization of candesartan cilexetil.
  • the micronization can be carried out using any conventionally known process of milling, grinding such as jet milling, media milling, pulverization and the like.
  • the present invention provides a pharmaceutical composition for antagonizing angiotensin II comprising candesartan cilexetil having a particle size wherein do. 9 is about 25 microns or less.
  • the present invention provides a method of antagonizing angiotensin II in mammal which comprises administering to the said mammal a therapeutically effective amount of candesartan cilexetil having a particle size wherein do. 9 is about 25 microns or less.
  • Example 1 Preparation of Candesartan Cilexetil Crystalline candesartan cilexetil (300 g, Type C crystals) was dissolved in dichloromethane (300 ml) at 25 to 30°C. The clear solution thus obtained was filtered through a bed of celite. The solvent was recovered under vacuum to get a residue. To this residue was added cyclohexane (2100 ml).
  • the resultant mixture was stirred for 2 hours and then filtered.
  • the wet cake was washed with cyclohexane (300 ml) and then dried.
  • the dried product was dissolved completely in methanol (2700 ml) at 25 to 30°C and stirred for 10 to 15 minutes.
  • the clear solution thus obtained was filtered through a bed of celite.
  • the clear filtrate was cooled to 13 to 17°C and stirred at this temperature for a period of 6 to 8 hours.
  • the reaction mass was filtered, washed with chilled methanol and dried to get title compound in the form of "Type C" crystals, in a yield of 253 g, assayed at 99.2% purity, and with Chromatographic purity by HPLC: 99.516%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de fines particules d'un antagoniste de l'angiotensine II à base de candésartan cilexétil, possédant un profil pharmacocinétique amélioré, ainsi que leur procédé de production.
PCT/IB2005/001713 2004-06-18 2005-06-17 Fines particules d'un antagoniste de l'angiotensine ii a base de candesartan cilexetil et leur procede de production Ceased WO2005123720A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1153DE2004 2004-06-18
IN1153/DEL/2004 2004-06-18

Publications (1)

Publication Number Publication Date
WO2005123720A1 true WO2005123720A1 (fr) 2005-12-29

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PCT/IB2005/001713 Ceased WO2005123720A1 (fr) 2004-06-18 2005-06-17 Fines particules d'un antagoniste de l'angiotensine ii a base de candesartan cilexetil et leur procede de production

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WO (1) WO2005123720A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008012372A1 (fr) * 2006-07-28 2008-01-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de la forme i du candésartan cilexétil
JP2008505935A (ja) * 2005-05-10 2008-02-28 テバ ファーマシューティカル インダストリーズ リミティド 超微粉砕された安定性カンデサルタンシレキセチル及びその調製方法
EP1952806A1 (fr) 2007-02-01 2008-08-06 Helm AG Procédé de préparation des produits d'absorption de candesartan
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
CN102198129A (zh) * 2011-03-22 2011-09-28 浙江华海药业股份有限公司 含有坎地沙坦酯和氢氯噻嗪的口服片剂
CN102670603A (zh) * 2012-04-29 2012-09-19 浙江华海药业股份有限公司 含有坎地沙坦酯和苯磺酸氨氯地平的口服片剂及其制备方法
US8399501B2 (en) 2010-03-04 2013-03-19 Theravance, Inc. Crystalline alkoxyimidazol-1-ylmethyl biphenyl carboxylic acid and methods for preparing thereof
WO2013041944A1 (fr) 2011-09-19 2013-03-28 Ranbaxy Laboratories Limited Procédé pour la préparation de candésartan cilexétil micronisé
JP2013119527A (ja) * 2011-12-07 2013-06-17 Tokuyama Corp 溶解性および安定性の向上した難溶性医薬品原体及びその製造方法
CN103396407A (zh) * 2013-08-07 2013-11-20 迪沙药业集团有限公司 一种坎地沙坦酯晶体的制备方法
CN104758252A (zh) * 2014-01-03 2015-07-08 广东东阳光药业有限公司 坎地沙坦酯组合物
JP2016106139A (ja) * 2016-03-07 2016-06-16 株式会社トクヤマ 溶解性および安定性の向上した難溶性医薬品原体及びその製造方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196444A (en) * 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
EP0668272A2 (fr) * 1994-01-28 1995-08-23 Takeda Chemical Industries, Ltd. Un procédé de production de composés de tétrazole
US6551532B1 (en) * 1999-05-07 2003-04-22 Astrazeneca Ab Method and device for forming particles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5196444A (en) * 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
EP0668272A2 (fr) * 1994-01-28 1995-08-23 Takeda Chemical Industries, Ltd. Un procédé de production de composés de tétrazole
US6551532B1 (en) * 1999-05-07 2003-04-22 Astrazeneca Ab Method and device for forming particles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHAUMEIL J C: "MICRONIZATION: A METHOD OF IMPROVING THE BIOAVAILABILITY OF POORLY SOLUBLE DRUGS", METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY, PROUS, BARCELONA, ES, vol. 20, no. 3, April 1998 (1998-04-01), pages 211 - 215, XP009048140, ISSN: 0379-0355 *
HIROKAZU MATSUNAGA ET AL: "Solid-state characterization of candesartan cilexetil (TCV-116): crystal structure and molecular mobility", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, vol. 47, no. 2, February 1999 (1999-02-01), pages 182 - 186, XP002957606, ISSN: 0009-2363 *
LIST P H ET AL: "Arzneiformenlehre", ARZNEIFORMENLEHRE: EIN LEHRBUCH FUER PHARMAZEUTEN, WISSENSCHAFTLICHE VERLAGSGESELLSCHAFT, STUTTGART, DE, 1985, pages 529 - 530, XP002111539 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7692023B2 (en) 2004-02-11 2010-04-06 Teva Pharmaceutical Industries Ltd. Candesartan cilexetil polymorphs
JP2008505935A (ja) * 2005-05-10 2008-02-28 テバ ファーマシューティカル インダストリーズ リミティド 超微粉砕された安定性カンデサルタンシレキセチル及びその調製方法
WO2008012372A1 (fr) * 2006-07-28 2008-01-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de la forme i du candésartan cilexétil
WO2008012371A1 (fr) * 2006-07-28 2008-01-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de formes amorphes et cristallines de candésartan cilexétil par chromatographie sur colonne
EP1952806A1 (fr) 2007-02-01 2008-08-06 Helm AG Procédé de préparation des produits d'absorption de candesartan
US8399501B2 (en) 2010-03-04 2013-03-19 Theravance, Inc. Crystalline alkoxyimidazol-1-ylmethyl biphenyl carboxylic acid and methods for preparing thereof
CN102198129A (zh) * 2011-03-22 2011-09-28 浙江华海药业股份有限公司 含有坎地沙坦酯和氢氯噻嗪的口服片剂
CN102198129B (zh) * 2011-03-22 2016-03-30 浙江华海药业股份有限公司 含有坎地沙坦酯和氢氯噻嗪的口服片剂
WO2013041944A1 (fr) 2011-09-19 2013-03-28 Ranbaxy Laboratories Limited Procédé pour la préparation de candésartan cilexétil micronisé
JP2013119527A (ja) * 2011-12-07 2013-06-17 Tokuyama Corp 溶解性および安定性の向上した難溶性医薬品原体及びその製造方法
CN102670603A (zh) * 2012-04-29 2012-09-19 浙江华海药业股份有限公司 含有坎地沙坦酯和苯磺酸氨氯地平的口服片剂及其制备方法
CN103396407A (zh) * 2013-08-07 2013-11-20 迪沙药业集团有限公司 一种坎地沙坦酯晶体的制备方法
CN104758252A (zh) * 2014-01-03 2015-07-08 广东东阳光药业有限公司 坎地沙坦酯组合物
CN104758252B (zh) * 2014-01-03 2019-11-12 广东东阳光药业有限公司 坎地沙坦酯组合物
JP2016106139A (ja) * 2016-03-07 2016-06-16 株式会社トクヤマ 溶解性および安定性の向上した難溶性医薬品原体及びその製造方法

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