EP1458681A1 - Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions - Google Patents

Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions

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)
French (fr)
Other versions
EP1458681A4 (en
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/en
Publication of EP1458681A4 publication Critical patent/EP1458681A4/en
Ceased legal-status Critical Current

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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.

Abstract

The compounds of the invention, hydrophilic (S)-amlodipine salts or their hydrates and pharmaceutical compositions, are useful for the treatment of hypertension and angina. The molecular formula of the salt hydrates is C20H25N2O5C1 • n1X • n2H2O, in which, X=organic acids, such as benzene sulfonic acid, aspartic acid, acetic acid, tartaric acid; inorganic acids, such as sulfuric acid and hydrobromic acid; monatomic acid n1=1, biatomic acid, n1=0.5; n2=0, 1, 2. Hydrophilic (S)-amlodipine salts or their hydrates, with a very high bioavailability, can be made into pharmaceutical compositions.

Description

HYDROPHILIC (SVAMLODIPINE SALTS OR THETR HYDRATES AND PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION
The invention is about hydrophilic (S)-amlodipine salts or their hydrates and pharmaceutical compositions. The molecular formula of the salt hydrates is C20H25N2O5CI • ni X • n2H20, in which, X=organic acids, such as benzene sulfonic acid, aspartic acid, acetic acid, tartaric acid; inorganic acids, such as sulfuric acid and hydrobromic acid; monatomic acid 1, 2.
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.
BACKGROUND OF THE INVENTION
(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. The use of both dimethyl sulphoxide (DMSO) and chiral reagent tartaric acid are essential to this method.
ZHANG Xitian's invention indicates that hexadeuterium dimethyl sulphoxide (DMSO-d6), 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.
On March 17, 1999, (S)-amlodipine besylate tablets came into the market in China, but the product that only gave the molecular formula of (S)-amlodiρine besylate, C20H25N2O5C • C6H603S, has not disclosed the information about (S)-amlodipine salt capable of generating hydrate yet.
The 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.
SUMMARY OF THE INVENTION
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.
In general, 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
Table 1.
The crystal water content and the dissociation temperature were measured by the PERKIN-ELMER 7 Series Thermal Analysis System and
H-NMR spectrometer. The dissociation temperature of the crystal water of (S)-amlodipine salt hydrates were within 110 °C .
Table 1 The crystal water number and dissociation temperature of (S)-amlodipine salts
(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 (such as diuretic, ACE inhibitor and ATI receptor antagonist, epinephrine inhibitor and calcium channel blocker), can be made into compound preparations. Hydrophilic (S)-amlodipine salts and their hydrate, together with other antihyperlipidemic drugs (Hmg-CoA reductase inhibitors, such as Simvastatin, Pravastatin, Lovastatin, Fluvastatin, atorvastantin) can be made into compound preparations.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Example 1 Preparation of (S)-amlodipine besylate hydrate.
5g (S)-amlodipine was put in 120 ml water. Then 1.4 g benzene sulfonic acid was added to it and stirred, which was heated to 60 °C under protection of nitrogen. With stirring stopped after dissolution, the solution was cooled to room temperature and then crystallized overnight. The solid was collected by filtration, washing with 20 ml water, to give (S)-amlodipine besylate, which was dried at room temperature to constant weight, to give 6.6 g (90%> of theoretical yield). Found: C 51.68%o, H 5.72%, N 4.71 %; Calc. for C2oH25N2θ5Cl • C6H603S • 2H20: C .51.74%, H 5.80%, N 4.64%.
Example 2 Preparation of (S)-amlodipine besylate tablets
The ingredients are as follows:
1. (S)-amlodipine besylate dihydrate 3.678g
2. Microcrystalline cellulose (M80) 15g
3. Microcrystalline cellulose (A300) 20g
4. Lactose 53.822g
5. Starch 7g
6. Magnesium stearate 0.5g
1000 tablets The above materials mixed uniformly were pressed to give a 100 mg tablet containing 2.5 mg (S)-amlodipine.
Example 3 Preparation of (S)-amlodipine besylate capsule
The ingredients are as follows:
l.(S)-amlodipine besylate 3.678g dihydrate
2. Starch 30g
1000 capsules
The above materials mixed uniformly were put into 1000 capsules containing 2.5mg (S)-amlodipine each.
INDUSTRIAL APPLICABILITY
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.

Claims

What is claimed is:
1. The invention is (S)-amlodipine (C20H25N2O5CI) salt capable of generating hydrate and its hydrate and pharmaceutical compositions.
2. hydrophilic (S)-amlodipine, salt or its hydrate ,such as (S)-amlodipine besylate, aspartic acid (S)-amlodipine, acetic acid (S)-amlodipine, (R, R) tartaric acid (S)-amlodipine (bihydrate), sulfuric acid (S)-amlodipine and hydrobromic acid (S)-amlodipine.
3. (S)-amlodipine salt hydrate can be generated in the synthetic process in the presence of aqueous medium, or by placing anhydro(S)-amlodipine in the air, or in the process of administration.
4 .(S)-amlodipine salt hydrate comprises C20H25N2O5CI • ni X • n2H20, in which, X=organic acids, such as benzene sulfonic acid, aspartic acid, acetic acid, tartaric acid; inorganic acids, such as sulfuric acid and hydrobromic acid; monatomic acid n^l, biatomic acid, n^O.5; n2=0, 1, 2.
5. hydrophilic (S)-amlodipine, salt or its hydrate can be prepared in the forms of tablet, capsule, transdermal drug delivery system, spray, injection, suppository, oral liquid and others, which are useful for the treatment of hypertension and angina.
6. Hydrophilic (S)-amlodipine salts and their hydrate, together with other antihypertensive drugs (such as diuretic, ACE inhibitor and ATI receptor antagonist, epinephrine inhibitor and calcium channel blocker), can be made into compound preparations.
7. Hydrophilic (S)-amlodipine salts and their hydrate, together with antihyperlipidemic drugs can be made into compound preparations;
EP02769861A 2001-11-22 2002-10-18 Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions Ceased EP1458681A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN01140027 2001-11-22
CNB011400277A CN1152013C (en) 2001-11-22 2001-11-22 Levo-amlodipine salt able to generate hydrate and its hydrate and preparation
PCT/CN2002/000730 WO2003043989A1 (en) 2001-11-22 2002-10-18 Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions

Publications (2)

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

Family

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Family Applications (1)

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EP02769861A Ceased EP1458681A4 (en) 2001-11-22 2002-10-18 Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions

Country Status (5)

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

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Publication number Priority date Publication date Assignee Title
EP1537083A4 (en) 2002-09-11 2006-11-22 Hanlim Pharmaceutical Co Ltd S-(-)-amlodipine nicotinate and process for the preparation thereof
WO2005070462A2 (en) * 2004-01-12 2005-08-04 Sepracor, Inc. Compositions comprising (s)-amlodipine and an angiotensin receptor blocker and methods of their use
WO2005097191A2 (en) * 2004-04-04 2005-10-20 Sepracor Inc. COMBINATIONS COMPRISING (S)- AMLODIPINE AND A HMG-CoA REDUCTASE INHIBITOR OR CHOLESTEROL ABSORPOTION INHIBITOR OR BOTH, AND METHODS FOR REDUCING HYPERTENSION
WO2005099699A1 (en) * 2004-04-07 2005-10-27 Sepracor Inc. Combination of (s)-amlodipine and a beta-blocker, and methods for reducing hypertension
KR100913791B1 (en) * 2006-07-21 2009-08-26 한미약품 주식회사 S---amlodipine camsylate or hydrate thereof and pharmaceutical composition containing same
KR100830003B1 (en) * 2006-10-31 2008-05-15 씨제이제일제당 (주) Crystalline S---amlodipine adipic acid salt anhydrous and preparation method thereof
KR100843400B1 (en) * 2006-11-14 2008-07-04 씨제이제일제당 (주) Crystalline S---amlodipine maleic acid salt anhydrous and preparation method thereof
GB0624087D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril combination salt
KR100843401B1 (en) * 2006-12-04 2008-07-04 씨제이제일제당 (주) Crystalline S---amlodipine camsylate anhydrous and preparation method thereof
KR100840069B1 (en) * 2007-01-23 2008-06-20 씨제이제일제당 (주) Crystalline s-(-)-amlodipine orotate anhydrous and preparation method thereof
CN105111137B (en) * 2015-08-21 2016-04-27 薛传校 Levamlodipine besylate crystal, its preparation method and application
CN111689894B (en) * 2019-03-13 2023-05-02 鲁南制药集团股份有限公司 Levamlodipine besylate crystal form
CN112110850B (en) * 2019-06-20 2023-05-02 鲁南制药集团股份有限公司 Novel crystal form of levamlodipine besylate
CN110882249B (en) * 2019-11-08 2021-04-30 北京吾为尔创科技有限公司 Composition containing levamlodipine besylate hydrate and preparation method thereof
CN112704667A (en) * 2021-02-24 2021-04-27 施慧达药业集团(吉林)有限公司 Composition containing levamlodipine besylate hydrate and preparation method thereof

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Also Published As

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WO2003043989A1 (en) 2003-05-30
KR20050037498A (en) 2005-04-22
EP1458681A4 (en) 2005-04-27
CN1152013C (en) 2004-06-02
CN1355162A (en) 2002-06-26
AU2002336032A1 (en) 2003-06-10

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