WO2003043989A1 - Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques - Google Patents

Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques Download PDF

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Publication number
WO2003043989A1
WO2003043989A1 PCT/CN2002/000730 CN0200730W WO03043989A1 WO 2003043989 A1 WO2003043989 A1 WO 2003043989A1 CN 0200730 W CN0200730 W CN 0200730W WO 03043989 A1 WO03043989 A1 WO 03043989A1
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WO
WIPO (PCT)
Prior art keywords
amlodipine
acid
hydrate
hydrophilic
salt
Prior art date
Application number
PCT/CN2002/000730
Other languages
English (en)
Inventor
Xitian Zhang
Original Assignee
Xitian Zhang
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 Xitian Zhang filed Critical Xitian Zhang
Priority to EP02769861A priority Critical patent/EP1458681A4/fr
Priority to AU2002336032A priority patent/AU2002336032A1/en
Publication of WO2003043989A1 publication Critical patent/WO2003043989A1/fr

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Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention is about hydrophilic (S)-amlodipine salts or their hydrates and pharmaceutical compositions.
  • Hydrophilic (S)-amlodipine salts or their hydrates have higher hydrophilicity, therefore their bioavailability is higher than other (S)-amlodipine salts.
  • Hydrophilic (S)-amlodipine salts or their hydrates can be made into pharmaceutical compositions, such as tablet, capsule, transdermal drug delivery system, spray, injection, suppository, oral liquid and others. They can be made into compound preparations together with other antihypertensive or antihyperlipidemic drugs.
  • (S)-amlodipine and its salts are long-acting calcium channel blockers, and are thus useful for the treatment of hypertension and angina.
  • Pflizer invented a feasible method for the separation of the enantiomers of amlodipine (W095 / 25722), in very good optical purity and yield.
  • DMSO dimethyl sulphoxide
  • chiral reagent tartaric acid are essential to this method.
  • ZHANG Xitian's invention indicates that hexadeuterium dimethyl sulphoxide (DMSO-d 6 ), in optical purity of up to 100%e.e. and very good yield, is a chiral auxiliary reagent better than DMSO.
  • Sepracor a company in the United States, applied for the patent about optically pure of (-) amlodipine (WO 93/10779). But the patent does not give a description of both the preparation and composition about hydrophilic (S)-amlodipine salts or their hydrates.
  • hydrophilic (S)-amlodipinesalts and their hydrates are more easily soluble in water, so it has a higher bioavailability and a better effect of medicine, so they are better than other (S)-amlodipine salt.
  • Amlodipine comprises S-enantiomer and R-enantiomer equivalently, in which (S)-amlodipine is an active ingredient for the treatment of hypertension and angina. Whether amlodipine can be absorbed by the body or not is the key to achieving the effect of medicine, similarly, whether (S)-amlodipine can be absorbed by the body or not is also the key to achieving the effect of medicine.
  • (S)-amlodipine salt is more easily soluble in water than (S)-amlodipine, so it is more easily absorbed by the body.
  • (S)-amlodipine salt has a different hydrophilicity. Hydrophilic (S)- amlodipine salt or its hydrate is more easily soluble in water than other (S)-amlodipine salts, so it is more easily absorbed by the body.
  • the bioavailability of calcium channel blockers is 8 - 10% because they have a lower solubility in water, which leads to a lower bioavailability.
  • Amlodipine besylate belongs to salts, so it is more easily soluble in water, which leads to a higher bioavailability.
  • the bioavailability of amlodipine besylate is about 68 - 80%, not 100% yet.
  • (S)-amlodipine besylate is much more easily soluble in water, so it is much more easily be absorbed by the body, achieving better potency. Hydrophilic (S)-amlodipine salts and their hydrates are showed in
  • the crystal water content and the dissociation temperature were measured by the PERKIN-ELMER 7 Series Thermal Analysis System and
  • (S)-amlodipine salt hydrate can be generated in the synthetic process in the presence of aqueous medium, or by placing (S)-amlodipine salt in the air, or in the process of administration.
  • the solvent for the preparation of (S)-amlodipine salt hydrate was water. Under protection of nitrogen, (S)-amlodipine was added to the acid water solution at 60 ° C equivalent to (S)-amlodipine and stirred until dissolution. With stirring stopped, it was then cooled to crystallize. The solid was collected by filtration and then dried at room temperature to give the hydrate. Every (S)-amlodipine salt hydrate has a different solubility, so an appropriate regulation of the water solution concentration of inorganic or organic acid is needed. The water solution of (S)-amlodipine salt can also be concentrated appropriately before crystallized. (S)-amlodipine salt dried in vacuo at an appropriate temperature can produce the hydrate or solution of hydrate when encountering moist air or water.
  • (S)-amlodipine salts and their hydrates can be made into tablet, capsule, transdermal drug delivery system, spray, injection, suppository, oral liquid and others, in which the tablet and capsule are the most common.
  • Hydrophilic (S)-amlodipine salts and their hydrate, together with other antihypertensive drugs can be made into compound preparations.
  • Hydrophilic (S)-amlodipine salts and their hydrate, together with other antihyperlipidemic drugs can be made into compound preparations.
  • Hydrophilic (S)-amlodipine salts and their hydrate, together with other antihyperlipidemic drugs can be made into compound preparations.
  • Hmg-CoA reductase inhibitors such as Simvastatin, Pravastatin, Lovastatin, Fluvastatin, atorvastantin
  • the invention is industrially feasible without any technical barrier. Because (S)-amlodipine salt capable of generating hydrate and its hydrate have a higher bioavailability than that of incapable of generating hydrate, it has a better effect of medicine.

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

Abstract

La présente invention se rapporte à des composés qui sont des sels hydrophiles de (S)-amlodipine, ainsi qu'à leurs hydrates et à des compositions pharmaceutiques les contenant. Ces composés s'avèrent utiles pour le traitement de l'hypertension et de l'angine de poitrine. La formule moléculaire des hydrates de ces sels est C20H25N2O5C1 • n1X • n2H2O, où X représente des acides organiques, tels que l'acide benzène sulfonique, l'acide aspartique, l'acide acétique, l'acide tartarique ; des sels inorganiques tels que l'acide sulfurique et l'acide hydrobromique ; un acide monoatomique n1 = 1, un acide biotique, n1 =0,5 et n2 = 0, 1 ou 2. Ces sels de (S)-amlodipine ainsi que leurs hydrates, qui possèdent une biodisponibilité très élevée, peuvent servir à la fabrication de compositions pharmaceutiques.
PCT/CN2002/000730 2001-11-22 2002-10-18 Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques WO2003043989A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP02769861A EP1458681A4 (fr) 2001-11-22 2002-10-18 Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques
AU2002336032A AU2002336032A1 (en) 2001-11-22 2002-10-18 Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN01140027.7 2001-11-22
CNB011400277A CN1152013C (zh) 2001-11-22 2001-11-22 一类左旋氨氯地平盐的水合物及其制剂

Publications (1)

Publication Number Publication Date
WO2003043989A1 true WO2003043989A1 (fr) 2003-05-30

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PCT/CN2002/000730 WO2003043989A1 (fr) 2001-11-22 2002-10-18 Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques

Country Status (5)

Country Link
EP (1) EP1458681A4 (fr)
KR (1) KR20050037498A (fr)
CN (1) CN1152013C (fr)
AU (1) AU2002336032A1 (fr)
WO (1) WO2003043989A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005070462A2 (fr) * 2004-01-12 2005-08-04 Sepracor, Inc. Compositions comprenant de la (s)-amlodipine et un bloqueur du recepteur de l'angiotensine, et leurs methodes d'utilisation
WO2005097191A2 (fr) * 2004-04-04 2005-10-20 Sepracor Inc. Combinaisons comprenant de la (s)-amlodipine et un inhibiteur de la hmg-coa reductase ou un inhibiteur de l'absorption de cholesterol ou les deux a la fois et methodes permettant de reduire l'hypertension
WO2005099699A1 (fr) * 2004-04-07 2005-10-27 Sepracor Inc. Combinaison de (s)-amlodipine et d'un betabloquant, et procedes pour la reduction de l'hypertension
US7279492B2 (en) 2002-09-11 2007-10-09 Hanlim Pharmaceutical Co., Ltd. S-(−)-amlodipine nicotinate and process for the preparation thereof
WO2008010659A1 (fr) * 2006-07-21 2008-01-24 Hanmi Pharm. Co., Ltd. Camsylate de (s)-(-)-amlodipine ou hydrate associé et composition pharmaceutique contenant ce composé
WO2008054096A1 (fr) * 2006-10-31 2008-05-08 Cj Cheiljedang Corporation Sel d'acide adipique s-(-)-amlodipine cristallin anhydre et procédé d'élaboration
WO2008060093A1 (fr) * 2006-11-14 2008-05-22 Cj Cheiljedang Corporation Anhydride de sel d'acide s-(-)-amlodipine maléique cristallin, et son procédé de préparation
WO2008065424A1 (fr) * 2006-12-01 2008-06-05 Selamine Ltd Sel d'amlodipine ramipril
WO2008069469A1 (fr) * 2006-12-04 2008-06-12 Cj Corporation Anhydride de s-(-)-amlodipine camsylate cristalin et son procédé de préparation
KR100840069B1 (ko) * 2007-01-23 2008-06-20 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 오로테이트 무수물 및 이의제조방법

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105111137B (zh) * 2015-08-21 2016-04-27 薛传校 苯磺酸左旋氨氯地平晶体、其制备方法和应用
CN111689894B (zh) * 2019-03-13 2023-05-02 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平晶型
CN112110850B (zh) * 2019-06-20 2023-05-02 鲁南制药集团股份有限公司 一种苯磺酸左旋氨氯地平新晶型
CN113041244B (zh) * 2019-11-08 2022-06-21 施慧达药业集团(吉林)有限公司 含苯磺酸左氨氯地平水合物的组合物及其制备方法
CN112704667A (zh) * 2021-02-24 2021-04-27 施慧达药业集团(吉林)有限公司 含苯磺酸左氨氯地平水合物的组合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2233974A (en) * 1989-07-22 1991-01-23 Pfizer Ltd Dihydropyridine antiinflammatory agent
CN1144523A (zh) * 1994-03-24 1997-03-05 辉瑞研究与发展公司 由阿罗地平的非对映的酒石酸盐分离其对映体
CN1267669A (zh) * 2000-02-21 2000-09-27 张喜田 氨氯地平对映体的拆分
US6262092B1 (en) * 1999-05-27 2001-07-17 Pfizer Inc. Mutual salt of amlodipine and atorvastatin
US6291490B1 (en) * 1991-11-26 2001-09-18 Sepracor Inc. Methods and compositions for treating conditions caused by excessive calcium influx in cells using optically pure (-) amlodipine

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JPH07501547A (ja) * 1991-11-26 1995-02-16 セプラコア，インコーポレーテッド 光学的に純粋な（−）アムロジピンを用いる，高血圧，狭心症および他の疾患を治療するための方法および組成物
GB9317773D0 (en) * 1993-08-26 1993-10-13 Pfizer Ltd Therapeutic compound
US6828339B2 (en) * 2001-11-21 2004-12-07 Synthon Bv Amlodipine salt forms and processes for preparing them
GB2415696B (en) * 2003-04-25 2007-06-20 Cipla Ltd Process for preparing amlodipine mesylate monohydrate

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
GB2233974A (en) * 1989-07-22 1991-01-23 Pfizer Ltd Dihydropyridine antiinflammatory agent
US6291490B1 (en) * 1991-11-26 2001-09-18 Sepracor Inc. Methods and compositions for treating conditions caused by excessive calcium influx in cells using optically pure (-) amlodipine
CN1144523A (zh) * 1994-03-24 1997-03-05 辉瑞研究与发展公司 由阿罗地平的非对映的酒石酸盐分离其对映体
US6262092B1 (en) * 1999-05-27 2001-07-17 Pfizer Inc. Mutual salt of amlodipine and atorvastatin
CN1267669A (zh) * 2000-02-21 2000-09-27 张喜田 氨氯地平对映体的拆分

Non-Patent Citations (1)

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Title
See also references of EP1458681A4 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7579475B2 (en) 2002-09-11 2009-08-25 Hanlim Pharmaceutical Co., Ltd. S-(-)-amlodipine nicotinate and process for the preparation thereof
US7279492B2 (en) 2002-09-11 2007-10-09 Hanlim Pharmaceutical Co., Ltd. S-(−)-amlodipine nicotinate and process for the preparation thereof
WO2005070463A2 (fr) * 2004-01-12 2005-08-04 Sepracor, Inc. Compositions comprenant du malate de (s)-amlodipine et un bloqueur du recepteur de l'angiotensine, et leurs methodes d'utilisation
WO2005070462A3 (fr) * 2004-01-12 2006-03-16 Sepracor Inc Compositions comprenant de la (s)-amlodipine et un bloqueur du recepteur de l'angiotensine, et leurs methodes d'utilisation
WO2005070463A3 (fr) * 2004-01-12 2006-03-16 Sepracor Inc Compositions comprenant du malate de (s)-amlodipine et un bloqueur du recepteur de l'angiotensine, et leurs methodes d'utilisation
WO2005070462A2 (fr) * 2004-01-12 2005-08-04 Sepracor, Inc. Compositions comprenant de la (s)-amlodipine et un bloqueur du recepteur de l'angiotensine, et leurs methodes d'utilisation
WO2005097191A2 (fr) * 2004-04-04 2005-10-20 Sepracor Inc. Combinaisons comprenant de la (s)-amlodipine et un inhibiteur de la hmg-coa reductase ou un inhibiteur de l'absorption de cholesterol ou les deux a la fois et methodes permettant de reduire l'hypertension
WO2005097191A3 (fr) * 2004-04-04 2005-12-08 Sepracor Inc Combinaisons comprenant de la (s)-amlodipine et un inhibiteur de la hmg-coa reductase ou un inhibiteur de l'absorption de cholesterol ou les deux a la fois et methodes permettant de reduire l'hypertension
WO2005099699A1 (fr) * 2004-04-07 2005-10-27 Sepracor Inc. Combinaison de (s)-amlodipine et d'un betabloquant, et procedes pour la reduction de l'hypertension
WO2008010659A1 (fr) * 2006-07-21 2008-01-24 Hanmi Pharm. Co., Ltd. Camsylate de (s)-(-)-amlodipine ou hydrate associé et composition pharmaceutique contenant ce composé
US20090326234A1 (en) * 2006-07-21 2009-12-31 Hanmi Pharm Co., Ltd. (S)-(-)-Amlodipine Camsylate or Hydrate Thereof And Pharmaceutical Composition Comprising Same
KR100830003B1 (ko) * 2006-10-31 2008-05-15 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 아디핀산 염 무수물 및 이의 제조방법
WO2008054096A1 (fr) * 2006-10-31 2008-05-08 Cj Cheiljedang Corporation Sel d'acide adipique s-(-)-amlodipine cristallin anhydre et procédé d'élaboration
JP2010508264A (ja) * 2006-10-31 2010-03-18 シージェイ チェイルジェダン コーポレイション 結晶性ｓ−（−）−アムロジピンアジピン酸塩無水物およびその製造方法
US8362263B2 (en) 2006-10-31 2013-01-29 Cj Cheiljedang Corporation Crystalline S-(−)-amlodipine adipic acid salt anhydrous and preparation method thereof
WO2008060093A1 (fr) * 2006-11-14 2008-05-22 Cj Cheiljedang Corporation Anhydride de sel d'acide s-(-)-amlodipine maléique cristallin, et son procédé de préparation
WO2008065424A1 (fr) * 2006-12-01 2008-06-05 Selamine Ltd Sel d'amlodipine ramipril
WO2008069469A1 (fr) * 2006-12-04 2008-06-12 Cj Corporation Anhydride de s-(-)-amlodipine camsylate cristalin et son procédé de préparation
KR100840069B1 (ko) * 2007-01-23 2008-06-20 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 오로테이트 무수물 및 이의제조방법
WO2008091085A1 (fr) * 2007-01-23 2008-07-31 Cj Cheiljedang Corporation Orotate de s-(-)-amlodipine cristalline anhydre et sa méthode de préparation

Also Published As

Publication number Publication date
EP1458681A1 (fr) 2004-09-22
CN1152013C (zh) 2004-06-02
CN1355162A (zh) 2002-06-26
EP1458681A4 (fr) 2005-04-27
AU2002336032A1 (en) 2003-06-10
KR20050037498A (ko) 2005-04-22

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