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EP1458681A1 - Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques - Google Patents

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

Info

Publication number
EP1458681A1
EP1458681A1 EP02769861A EP02769861A EP1458681A1 EP 1458681 A1 EP1458681 A1 EP 1458681A1 EP 02769861 A EP02769861 A EP 02769861A EP 02769861 A EP02769861 A EP 02769861A EP 1458681 A1 EP1458681 A1 EP 1458681A1
Authority
EP
European Patent Office
Prior art keywords
amlodipine
acid
hydrate
hydrophilic
salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP02769861A
Other languages
German (de)
English (en)
Other versions
EP1458681A4 (fr
Inventor
Xitian Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP1458681A1 publication Critical patent/EP1458681A1/fr
Publication of EP1458681A4 publication Critical patent/EP1458681A4/fr
Ceased legal-status Critical Current

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (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.
EP02769861A 2001-11-22 2002-10-18 Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques Ceased EP1458681A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN01140027 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
PCT/CN2002/000730 WO2003043989A1 (fr) 2001-11-22 2002-10-18 Sels hydrophiles de (s)-amlodipine ou leurs hydrates et compositions pharmaceutiques

Publications (2)

Publication Number Publication Date
EP1458681A1 true EP1458681A1 (fr) 2004-09-22
EP1458681A4 EP1458681A4 (fr) 2005-04-27

Family

ID=4675599

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02769861A Ceased EP1458681A4 (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)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1537083A4 (fr) 2002-09-11 2006-11-22 Hanlim Pharmaceutical Co Ltd Nicotinate de s-(-)-amlodipine, et son procede de preparation
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
KR100913791B1 (ko) * 2006-07-21 2009-08-26 한미약품 주식회사 (ｓ)-(-)-암로디핀 캠실레이트 또는 이의 수화물 및 이를함유하는 약학적 조성물
KR100830003B1 (ko) 2006-10-31 2008-05-15 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 아디핀산 염 무수물 및 이의 제조방법
KR100843400B1 (ko) * 2006-11-14 2008-07-04 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 말레익산 염 무수물 및 이의제조방법
GB0624087D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril combination salt
KR100843401B1 (ko) * 2006-12-04 2008-07-04 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 캠실레이트 무수물 및 이의제조방법
KR100840069B1 (ko) * 2007-01-23 2008-06-20 씨제이제일제당 (주) 결정성 ｓ-(-)-암로디핀 오로테이트 무수물 및 이의제조방법
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

Family Cites Families (9)

* 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
WO1993010779A1 (fr) * 1991-11-26 1993-06-10 Sepracor, Inc. Procedes et compositions destines a traiter l'hypertension, l'angine de poitrine et d'autres troubles a l'aide de (-)amlodipine optiquement pure
US6057344A (en) * 1991-11-26 2000-05-02 Sepracor, Inc. Methods for treating hypertension, and angina using optically pure (-) amlodipine
GB9317773D0 (en) * 1993-08-26 1993-10-13 Pfizer Ltd Therapeutic compound
GB9405833D0 (en) * 1994-03-24 1994-05-11 Pfizer Ltd Separation of the enantiomers of amlodipine
HN2000000050A (es) * 1999-05-27 2001-02-02 Pfizer Prod Inc Sal mutua de amlodipino y atorvastatina
CN1100038C (zh) * 2000-02-21 2003-01-29 张喜田 氨氯地平对映体的拆分
AR037565A1 (es) * 2001-11-21 2004-11-17 Synthon Bv Formas de sales de amlodipina y procedimientos para prepararlas.
GB2415696B (en) * 2003-04-25 2007-06-20 Cipla Ltd Process for preparing amlodipine mesylate monohydrate

Also Published As

Publication number Publication date
CN1355162A (zh) 2002-06-26
WO2003043989A1 (fr) 2003-05-30
CN1152013C (zh) 2004-06-02
KR20050037498A (ko) 2005-04-22
AU2002336032A1 (en) 2003-06-10
EP1458681A4 (fr) 2005-04-27

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