WO2002013823A1 - Micronized torsemide - Google Patents

Micronized torsemide Download PDF

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Publication number
WO2002013823A1
WO2002013823A1 PCT/US2001/025415 US0125415W WO0213823A1 WO 2002013823 A1 WO2002013823 A1 WO 2002013823A1 US 0125415 W US0125415 W US 0125415W WO 0213823 A1 WO0213823 A1 WO 0213823A1
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WO
WIPO (PCT)
Prior art keywords
torsemide
micronized
present
microns
mean particle
Prior art date
Application number
PCT/US2001/025415
Other languages
French (fr)
Inventor
Marco Kordova
Anchel Schwartz
Ben-Zion Dolitzky
Judith Aronhime
David Leonov
Shlomo Zavurov
Szabolcs Salyi
Erzsebet Meszaros-Sos
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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 Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to KR10-2003-7002074A priority Critical patent/KR20030051618A/en
Priority to JP2002518966A priority patent/JP2004511439A/en
Priority to AU2001286468A priority patent/AU2001286468A1/en
Priority to IL15445701A priority patent/IL154457A0/en
Priority to EP01965915A priority patent/EP1318809A1/en
Priority to CA002419081A priority patent/CA2419081A1/en
Publication of WO2002013823A1 publication Critical patent/WO2002013823A1/en
Priority to IS6712A priority patent/IS6712A/en
Priority to NO20030700A priority patent/NO20030700D0/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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

  • This invention relates to micronized torsemide and to the preparation thereof.
  • Torsemide is essentially insoluble in water.
  • PSD Particle Size Distribution
  • 10 torsemide crystals may be used to determine the available surface area for the drag dissolution. Often, it is observed that the available surface area for drag dissolution correlates
  • the PSD of torsemide, and i 5 in particular, the mean particle diameter are important parameters to characterize and predict the bioavailability of the drag. It is desirable to have torsemide with a particle size in which the mean particle size enhances the reproducibility of; (a) the rate of dissolution and (b) the reproducibility of the dissolution. It is desirable to have torsemide in which the mean particle size imparts an improved and stable dissolution profile. >0
  • An object of the present invention is to provide torsemide formulations containing torsemide having relatively small particles, and corresponding relatively large surface area.
  • It is also an object of the present invention is to provide torsemide with a particle size p
  • the present invention provides torsemide and formulations containing torsemide
  • the present invention also provides torsemide and formulations containing torsemide
  • the present invention also provides processes for preparing micronized torsemide.
  • the present invention also provides processes for preparing micronized torsemide, where in the torsemide to be micronized is pure torsemide.
  • the present invention also provides processes for preparing micronized torsemide, where in the torsemide to be micronized is dry torsemide.
  • the present invention also provides pharmaceutical compositions comprising micronized torsemide.
  • the present invention provides torsemide formulations containing torsemide having relatively small particles, and corresponding relatively large surface area.
  • the present invention also provides torsemide and formulations containing torsemide having a mean particle diameter of less than 200 micrometer, preferably the mean particle
  • the mean particle diameter is less than 100 microns, more preferably the mean particle diameter is less than 20
  • microns most preferably the mean particle size is about 10 microns.
  • the present invention also provides torsemide having a mean particle diameter of
  • torsemide has a mean length of about 4.2 microns, more preferably a mean length of 4.0 microns.
  • micronized is used herein as referring to particles having a mean
  • Micronized particles of torsemide may be obtained by methods disclosed in U.S. Patent No. 5,834,472, the contents of which are
  • the present invention also provides processes for preparing micronized torsemide.
  • torsemide which is prepared by methods known in the art, is separated by sieves to produce torsemide wherein 50% has a mean particle diameter of below about 250 microns and about 80% has is below about 500 microns.
  • the sieved torsemide is then micronized by methods known in the art, e.g., in a micronizer, to yield
  • microns preferably 99% of the torsemide has a mean particle size of less than about 45 microns, more preferably, 93% of the torsemide has a mean particle size of less than about 7.5 microns, more preferably the torsemide isolated has a mean particle diameter of less than 10 micron.
  • Micronized particles of torsemide can be obtained by the use of conventional micronizing techniques after, sieving to pro vide- torsemide wherein about 50% has a particle
  • micronized than 250 microns and about 80% has-a particle sized below about 500 microns, is micronized
  • ultrasonic means fluid energy attrition mills, or using a jet mill, or other suitable means as
  • the present invention also provides processes for preparing micronized torsemide
  • micronized torsemide is made from dry torsemide.
  • the present micronized torsemide may be 0 prepared as pharmaceutical compositions that are particularly useful for the treatment of hypertension and edema associated with congestive heart failure, renal disease, or hepatic
  • compositions comprise micronized torsemide with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
  • compositions are prepared as medicaments to be administered orally, " or intravenously.
  • suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions. While one of ordinary skill in the art will understand that dosages will vary according to the indication, age of the patient, etc., generally micronized torsemide of the present invention will be administered at a daily dosage of about 2 to about 200 mg per day, and preferably '.0 about 5 to about 100 mg per day.
  • Example 1 Pure dry torsemide was micronized in a micronizer. The result was micronized torsemide of a particle size of less than 5 micrometer.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Cosmetics (AREA)

Abstract

The present invention relates to torsemide having relatively small particles, and corresponding relatively large surface area. In one embodiment, the invention relates to torsemide and formulations containing torsemide having a mean particle diameter of less than 200 micrometers.

Description

MICRONIZED TORSEMIDE
CROSS-REFERENCE TO RELATED APPLICATION
The present application claims benefit of U.S provisional application Ser. No. 60/225,365, filed August 14, 2000, which is incorporated by reference.
FIELD OF THE INVENTION
This invention relates to micronized torsemide and to the preparation thereof.
BACKGROUND OF THE INVENTION l-Isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea, which has the chemical structure
Figure imgf000002_0001
is approved, under the trademark DEMADEX®, by the U.S. Food and Drug Administration for the treatment of hypertension and edema associated with congestive heart failure, renal
disease, or hepatic disease. The USAN approved generic name for this compound is .
torsemide, although this compound is also referred to as "torasemide" in the art. Torsemide
is a loop diuretic that has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
U.S. Patent No. Re. 30,633, the contents of which are incorporated by reference, 5 describes a synthesis of torsemide. The references, Acta Cryst. 1978, pp. 2659-2662; Acta
Cryst, 1978, pp. 1304-1310;and Pharmaceutical Dosage Forms: Tablets, Vol. 2, 2nd Ed.,
Lieberman et al. Ed., Marcel Dekker, Inc, New York, (1990) p.107-200; and U.S. Patent
Nos. 4,822,807, and Re. 34,672 are all incorporated herein by reference.
Torsemide is essentially insoluble in water. The Particle Size Distribution (PSD) of
10 torsemide crystals may be used to determine the available surface area for the drag dissolution. Often, it is observed that the available surface area for drag dissolution correlates
to both (a) the rate of dissolution and solubility where a greater surface area enhances the solubility of a drag; and (b) enhances the rate of dissolution of a drug. Further, the velocity of dissolution of a drug often effects the drag's bioavailability. Thus, the PSD of torsemide, and i 5 in particular, the mean particle diameter, are important parameters to characterize and predict the bioavailability of the drag. It is desirable to have torsemide with a particle size in which the mean particle size enhances the reproducibility of; (a) the rate of dissolution and (b) the reproducibility of the dissolution. It is desirable to have torsemide in which the mean particle size imparts an improved and stable dissolution profile. >0
SUMMARY OF THE INVENTION An object of the present invention is to provide torsemide formulations containing torsemide having relatively small particles, and corresponding relatively large surface area.
It is also an object of the present invention is to provide torsemide with a particle sizep
25 in which the mean particle size enhances the reproducibility of; (a) the rate of dissolution and
(b) the reproducibility of the dissolution.
It is also an object of the present invention to provide torsemide in which the mean particle size imparts an improved and stable dissolution profile.
The present invention provides torsemide and formulations containing torsemide
having a mean particle diameter of less than 200 micrometer.
The present invention also provides torsemide and formulations containing torsemide
having a mean particle diameter of less than 20 micrometers.
The present invention also provides processes for preparing micronized torsemide. The present invention also provides processes for preparing micronized torsemide, where in the torsemide to be micronized is pure torsemide.
The present invention also provides processes for preparing micronized torsemide, where in the torsemide to be micronized is dry torsemide.
The present invention also provides pharmaceutical compositions comprising micronized torsemide.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides torsemide formulations containing torsemide having relatively small particles, and corresponding relatively large surface area.
The present invention also provides torsemide and formulations containing torsemide having a mean particle diameter of less than 200 micrometer, preferably the mean particle
diameter is less than 100 microns, more preferably the mean particle diameter is less than 20
microns, most preferably the mean particle size is about 10 microns.
The present invention also provides torsemide having a mean particle diameter of
between about 200 microns and about 10 microns. In another embodiment of the present 5 invention, torsemide has a mean length of about 4.2 microns, more preferably a mean length of 4.0 microns. The term "micronized" is used herein as referring to particles having a mean
particle diameter of less than about 200 microns. Micronized particles of torsemide, may be obtained by methods disclosed in U.S. Patent No. 5,834,472, the contents of which are
incorporated herein by reference.
0 The present invention also provides processes for preparing micronized torsemide.
By the methods of the present invention, torsemide, which is prepared by methods known in the art, is separated by sieves to produce torsemide wherein 50% has a mean particle diameter of below about 250 microns and about 80% has is below about 500 microns. The sieved torsemide is then micronized by methods known in the art, e.g., in a micronizer, to yield
5 torsemide wherein 100% of the torsemide has a mean particle size of less than about 45
] microns, preferably 99% of the torsemide has a mean particle size of less than about 45 microns, more preferably, 93% of the torsemide has a mean particle size of less than about 7.5 microns, more preferably the torsemide isolated has a mean particle diameter of less than 10 micron.
0 Micronized particles of torsemide can be obtained by the use of conventional micronizing techniques after, sieving to pro vide- torsemide wherein about 50% has a particle
size less than 250 microns and about 80% has a particle sized below about 500 microns. By the methods of the present invention, the torsemide where about 50% has a particle size less
than 250 microns and about 80% has-a particle sized below about 500 microns, is micronized
',5 to the desired particle size range by methods known in the art, for example, using a ball mill,
ultrasonic means, fluid energy attrition mills, or using a jet mill, or other suitable means as
disclosed in Pharmaceutical Dosage Forms: Tablets, Vol. 2, 2nd Ed., Lieberman et al. Ed., 5 Marcel Dekker, Inc, New York, ( 1990) p.107-200, the contents of which are incorporated
herein by reference.
The present invention also provides processes for preparing micronized torsemide,
wherein the micronized torsemide is made from dry torsemide.
In accordance with the present invention, the present micronized torsemide may be 0 prepared as pharmaceutical compositions that are particularly useful for the treatment of hypertension and edema associated with congestive heart failure, renal disease, or hepatic
disease. Such compositions comprise micronized torsemide with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
Preferably, these compositions are prepared as medicaments to be administered orally, " or intravenously. Suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups and suspensions. While one of ordinary skill in the art will understand that dosages will vary according to the indication, age of the patient, etc., generally micronized torsemide of the present invention will be administered at a daily dosage of about 2 to about 200 mg per day, and preferably '.0 about 5 to about 100 mg per day.
EXAMPLES The present invention will now be further explained in the following example. However, the present invention should not be constraed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired
'.5 results.
Example 1 Pure dry torsemide was micronized in a micronizer. The result was micronized torsemide of a particle size of less than 5 micrometer.
It should be understood that some modification, alteration and substitution is
anticipated and expected from those skilled in the art without departing from the teachings of
the invention. Accordingly, it is appropriate that the following claims be construed broadly and in a manner consistent with the scope and spirit of the invention.

Claims

WHAT IS CLAIMED IS:
Micronized torsemide.
PCT/US2001/025415 2000-08-14 2001-08-14 Micronized torsemide WO2002013823A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
KR10-2003-7002074A KR20030051618A (en) 2000-08-14 2001-08-14 Micronized torsemide
JP2002518966A JP2004511439A (en) 2000-08-14 2001-08-14 Finely divided torsemide
AU2001286468A AU2001286468A1 (en) 2000-08-14 2001-08-14 Micronized torsemide
IL15445701A IL154457A0 (en) 2000-08-14 2001-08-14 Mircronized torsemide
EP01965915A EP1318809A1 (en) 2000-08-14 2001-08-14 Micronized torsemide
CA002419081A CA2419081A1 (en) 2000-08-14 2001-08-14 Micronized torsemide
IS6712A IS6712A (en) 2000-08-14 2003-02-11 Angular torsemide
NO20030700A NO20030700D0 (en) 2000-08-14 2003-02-13 Micronized torsemide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22536500P 2000-08-14 2000-08-14
US60/225,365 2000-08-14

Publications (1)

Publication Number Publication Date
WO2002013823A1 true WO2002013823A1 (en) 2002-02-21

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PCT/US2001/025415 WO2002013823A1 (en) 2000-08-14 2001-08-14 Micronized torsemide

Country Status (11)

Country Link
US (1) US20020120147A1 (en)
EP (1) EP1318809A1 (en)
JP (1) JP2004511439A (en)
KR (1) KR20030051618A (en)
AU (1) AU2001286468A1 (en)
CA (1) CA2419081A1 (en)
IL (1) IL154457A0 (en)
IS (1) IS6712A (en)
NO (1) NO20030700D0 (en)
PL (1) PL366219A1 (en)
WO (1) WO2002013823A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005056561A1 (en) * 2003-12-11 2005-06-23 Kyowa Hakko Kogyo Co., Ltd. Microcrystal and medicinal preparation containing the same

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006090350A1 (en) * 2005-02-28 2006-08-31 Ranbaxy Laboratories Limited A method for sieving pharmaceutical substances
JP5564943B2 (en) * 2007-05-21 2014-08-06 東レ株式会社 Crystalline finely divided particles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202129A (en) * 1989-08-04 1993-04-13 Tanabe Seiyaku Co., Ltd. Process for micronizing slightly-soluble drug
US5663198A (en) * 1993-07-15 1997-09-02 Hoechst Aktiengesellschaft Drug formulations comprising coated, very sparingly water-soluble drugs for inhalational pharmaceutical forms, and process for their preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202129A (en) * 1989-08-04 1993-04-13 Tanabe Seiyaku Co., Ltd. Process for micronizing slightly-soluble drug
US5663198A (en) * 1993-07-15 1997-09-02 Hoechst Aktiengesellschaft Drug formulations comprising coated, very sparingly water-soluble drugs for inhalational pharmaceutical forms, and process for their preparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005056561A1 (en) * 2003-12-11 2005-06-23 Kyowa Hakko Kogyo Co., Ltd. Microcrystal and medicinal preparation containing the same

Also Published As

Publication number Publication date
AU2001286468A1 (en) 2002-02-25
NO20030700L (en) 2003-02-13
CA2419081A1 (en) 2002-02-21
US20020120147A1 (en) 2002-08-29
NO20030700D0 (en) 2003-02-13
KR20030051618A (en) 2003-06-25
EP1318809A1 (en) 2003-06-18
IS6712A (en) 2003-02-11
IL154457A0 (en) 2003-09-17
JP2004511439A (en) 2004-04-15
PL366219A1 (en) 2005-01-24

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