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WO1992005786A1 - Ibuprofen-diuretic combinations - Google Patents

Ibuprofen-diuretic combinations Download PDF

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Publication number
WO1992005786A1
WO1992005786A1 PCT/US1991/007008 US9107008W WO9205786A1 WO 1992005786 A1 WO1992005786 A1 WO 1992005786A1 US 9107008 W US9107008 W US 9107008W WO 9205786 A1 WO9205786 A1 WO 9205786A1
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WO
WIPO (PCT)
Prior art keywords
ibuprofen
diuretic
effective amount
female
salt
Prior art date
Application number
PCT/US1991/007008
Other languages
French (fr)
Inventor
Robert T. Sims
William Slivka
Original Assignee
Merck & Co., Inc.
Mcneil-Ppc, 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 Merck & Co., Inc., Mcneil-Ppc, Inc. filed Critical Merck & Co., Inc.
Priority to JP3516780A priority Critical patent/JPH06501475A/en
Publication of WO1992005786A1 publication Critical patent/WO1992005786A1/en

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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

Definitions

  • the non-steroidal anti-inflammatory drugs are the non-steroidal anti-inflammatory drugs.
  • NSAID NSAID
  • NSAID have been utilized in the treatment of pain/ inflammation and have been disclosed as useful in the treatment, management and mitigation of cold symptoms and the pain associated therewith.
  • Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID. Recently, it has been found that a faster onset of pain relief and an enhanced analgesic response can be obtained by the utilization of the single enantiomer S(+)-ibuprofen in comparison to racemic ibuprofen, (see for example U.S. Patent 4,877,620). Diuretics, such as the thiazides, are useful in the relief of water retention. In optional combination with a tension reliever such as
  • diuretics may offer relief of a variety of symptoms often appearing in the menstrual cycle such as cramps, bloating, tension, and
  • This invention relates to a pharmaceutical composition for use in the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female:
  • This invention is also directed to a method of relieving pain, cramps, bloating and tension, experienced during menstruation or premenstruation in a female in need of such relief comprising
  • This invention is also directed to a method of eliciting an onset hastened and enhanced response for the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief, comprising
  • Substantially free of (R)-ibuprofen should be taken to mean that the ration of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.
  • Salts of (S)-ibuprofen include salts with alkali metals, such as sodium or potassium, salts with alkaline earth metals, such as calcium, or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or coaalt.
  • Salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine and arginine. Specifically included within the above composition is (S)-ibuprofen- (S)-lysine.
  • (S)-ibuprofen may be prepared following the procedures disclosed in U.S. Patent 4,877,620.
  • Metal salts of ibuprofen may be obtained by contacting a hydroxide, or carbonate with ibuprofen.
  • Amino acid salts of ibuprofen may be obtained by contacting an amino acid in solution with ibuprofen.
  • (S)-ibuprofen provides a faster onset of pain-antiinflammatory relief and an enhanced degree of relief compared to racemic ibuprofen.
  • These benefits are increased in an (S)-ibuprofen/diuretic combination as the inhibition of prostaglandin synthetase and the water volume minimization may synergistically cooperate.
  • This has not heretofore been observed because the art has not proposed the combination of the (S)-ibuprofen enantiomer, absent (R)-ibuprofen, with a diuretic. The presence of the (R)-ibuprofen may blur the synergistic effect.
  • the subject using the (S)-ibuprofen/diuretic combination will no longer need to divert metabolic energy to the inversion of the (R)-enantiomer or the removal of this enantiomer.
  • the absence of inversion reduces or eliminates the formation and incorporation into fatty tissue of hybrid-ibuprofen containing triglycerides.
  • combination dosage form particularly a sustained release dosage form.
  • a sustained release dosage of ibuprofen may have required 800 to 1000 mg
  • the employment of (S)-ibuprofen reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/diuretic combination.
  • An effective amount of (S)-ibuprofen, or a pharmaceutically acceptable salt thereof, for use in a unit dose composition of this invention may range from 50 to 800 mg (S)-ibuprofen.
  • the preferred amount of (S)-ibuprofen is about 100 to 400 mg.
  • the amount of a salt such as (S)-ibuprofen-(S)-lysine is determined based on the amount of (S)-ibuprofen contained therein.
  • the diuretic employed herein may be selected from the benzothiadiazides or acetazolamide and its analogs, or ethacrynic acid, or furosemide or
  • bumetanide or a potassium-sparing diuretic such as amiloride or triamterene, or a xanthine or a
  • combination diuretic such as pamabrom.
  • Preferred diuretics include: Acetazolamide, dichlorophenamide, methazolamide, chlorothiazide, hydrochlorothiazide, benzthiazide, indapamide, trichlormethazide,
  • methylclothiazide polythiazide, ethacrynic acid, torasemide, furosemide, bumetamide, panabrom, amiloride, or triamterene.
  • a particularly preferred diuretic is hydrochlorothiazide.
  • the amount of diuretic useful in the practice of the present invention may-vary from about 2 mg to 50 mg depending on the specific diurectic.
  • compositions may be administered in the form of tablets, capsules, elixirs, syrups or a suspension.
  • active components may be admixed with a pharmaceutically acceptable carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and in a liquid
  • composition ethyl alcohol.
  • Acceptable binders such as PVP starch, gelatin, natural sugars, corn
  • sweeteners natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary
  • lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride and disintegrators such as starch, methylcellulose, agar, bentonite and guar gum and super disintegrators such as docusate sodium, sodium starch glycollate or cross-linked PVP may also be included.
  • the active components may also be formulated in sustained release formulations.
  • formulations may be employed in oral, dermal, rectal or vaginal administration. Such sustained release
  • forms also include layered formulations which provide for distinct release ratio and thus may be more
  • compositions of the present invention and as such are not to be considered as limiting the invention set

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

This invention relates to a pharmaceutical composition for use in the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female: (i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and (ii) a diuretically effective amount of a diuretic; and (iii) optionally a tension relieving effective amount of pyrilamine maleate.

Description

TITLE OF TEE INVENTION
IBUPROFEN-DIURETIC COMBINATIONS
BACKGROUND OF THE INVENTION
The non-steroidal anti-inflammatory drugs
(NSAID) have been utilized in the treatment of pain/ inflammation and have been disclosed as useful in the treatment, management and mitigation of cold symptoms and the pain associated therewith.
Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a well known and commonly employed NSAID. Recently, it has been found that a faster onset of pain relief and an enhanced analgesic response can be obtained by the utilization of the single enantiomer S(+)-ibuprofen in comparison to racemic ibuprofen, (see for example U.S. Patent 4,877,620). Diuretics, such as the thiazides, are useful in the relief of water retention. In optional combination with a tension reliever such as
pyrilamine maleate, diuretics may offer relief of a variety of symptoms often appearing in the menstrual cycle such as cramps, bloating, tension, and
irritability.
Combinations of ibuprofen with a diuretic such as pamabrom have been disclosed in U.S. Patent 4,888.343. However, despite the fact that the menstrual pain sufferer is in need of quick and enhanced relief, there has been no consideration given to the employment of (S)-ibuprofen, or a salt thereof, in combination with a diuretic and
optionally with a tension reliever for the treatment of menstrual symptoms.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a pharmaceutical composition for use in the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen; and
(ii) a diuretically effective amount of a diuretic; and
(iii) optionally a tension relieving effective amount of pyrilamine maleate.
This invention is also directed to a method of relieving pain, cramps, bloating and tension, experienced during menstruation or premenstruation in a female in need of such relief comprising
administering to such female:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen:
(ii) a diuretically effective amount of a diuretic; and
(iii) optionally a tension relieving effective amount of pyrilamine maleate.
This invention is also directed to a method of eliciting an onset hastened and enhanced response for the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief, comprising
administering to such female:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen;
(ii) a diuretically effective amount of a diuretic; and
(iii) optionally a tension relieving effective amount of pyrilamine maleate.
Substantially free of (R)-ibuprofen should be taken to mean that the ration of (S)-ibuprofen to (R)-ibuprofen is at least 90:10.
Salts of (S)-ibuprofen include salts with alkali metals, such as sodium or potassium, salts with alkaline earth metals, such as calcium, or salts with other metals such as magnesium, aluminum, iron, zinc, copper, nickel or coaalt. Salts of (S)-ibuprofen further include the amino acid salts, particularly the basic amino acids such as lysine and arginine. Specifically included within the above composition is (S)-ibuprofen- (S)-lysine.
(S)-ibuprofen may be prepared following the procedures disclosed in U.S. Patent 4,877,620. Metal salts of ibuprofen may be obtained by contacting a hydroxide, or carbonate with ibuprofen. Amino acid salts of ibuprofen may be obtained by contacting an amino acid in solution with ibuprofen.
The utilization of (S)-ibuprofen in an analgesic-antiinflammatory/diuretic combination offers significant advantages over the combination of racemic ibuprofen with a diuretic which has already been shown to have advantages over acetaminophen combinations (see for example U.S. Patent 4,888,343).
(S)-ibuprofen provides a faster onset of pain-antiinflammatory relief and an enhanced degree of relief compared to racemic ibuprofen. These benefits are increased in an (S)-ibuprofen/diuretic combination as the inhibition of prostaglandin synthetase and the water volume minimization may synergistically cooperate. This has not heretofore been observed because the art has not proposed the combination of the (S)-ibuprofen enantiomer, absent (R)-ibuprofen, with a diuretic. The presence of the (R)-ibuprofen may blur the synergistic effect.
The subject using the (S)-ibuprofen/diuretic combination will no longer need to divert metabolic energy to the inversion of the (R)-enantiomer or the removal of this enantiomer. The absence of inversion reduces or eliminates the formation and incorporation into fatty tissue of hybrid-ibuprofen containing triglycerides.
Although fluid retention is recognized or a possible side effect of ibuprofen usage the prior art has not heretofore considered the employment of an (S)-ibuprofen/diuretic combination. The absence of the (R)-ibuprofen in these combinations is
particularly advantageous as a lesser metabolic burden is placed on the urogenital system for the excretion of the (R)-enantiomer or its metabolites. The renal burden and renal toxicities sometimes associated with ibuprofen therapy are reduced or absent in a substantially (R)-ibuprofen free
composition.
The absence of (R)-ibuprofen provides for significant size and weight advantages in a
combination dosage form, particularly a sustained release dosage form. Where a sustained release dosage of ibuprofen may have required 800 to 1000 mg, the employment of (S)-ibuprofen reduces the weight to 400 to 500 mg, and provides for a more practical size tablet for an ibuprofen/diuretic combination.
An effective amount of (S)-ibuprofen, or a pharmaceutically acceptable salt thereof, for use in a unit dose composition of this invention may range from 50 to 800 mg (S)-ibuprofen. The preferred amount of (S)-ibuprofen is about 100 to 400 mg. The amount of a salt such as (S)-ibuprofen-(S)-lysine is determined based on the amount of (S)-ibuprofen contained therein.
The diuretic employed herein may be selected from the benzothiadiazides or acetazolamide and its analogs, or ethacrynic acid, or furosemide or
bumetanide or a potassium-sparing diuretic such as amiloride or triamterene, or a xanthine or a
combination diuretic such as pamabrom. Preferred diuretics include: Acetazolamide, dichlorophenamide, methazolamide, chlorothiazide, hydrochlorothiazide, benzthiazide, indapamide, trichlormethazide,
methylclothiazide, polythiazide, ethacrynic acid, torasemide, furosemide, bumetamide, panabrom, amiloride, or triamterene. A particularly preferred diuretic is hydrochlorothiazide.
The amount of diuretic useful in the practice of the present invention may-vary from about 2 mg to 50 mg depending on the specific diurectic.
The present compositions may be administered in the form of tablets, capsules, elixirs, syrups or a suspension. For oral administration the active components may be admixed with a pharmaceutically acceptable carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and in a liquid
composition, ethyl alcohol. Acceptable binders such as PVP starch, gelatin, natural sugars, corn
sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes, may also be admixed with the active components. Where necessary
lubricants such as boric acid, sodium benzoate, sodium acetate, sodium chloride and disintegrators such as starch, methylcellulose, agar, bentonite and guar gum and super disintegrators such as docusate sodium, sodium starch glycollate or cross-linked PVP may also be included. The active components may also be formulated in sustained release formulations. These
formulations may be employed in oral, dermal, rectal or vaginal administration. Such sustained release
forms also include layered formulations which provide for distinct release ratio and thus may be more
beneficial in allowing for short and long term relief.
The following examples illustrate the
compositions of the present invention and as such are not to be considered as limiting the invention set
forth in the claims appended hereto.
EXAMPLE 1
(S)-ibuprofen. Diuretic Tablet
(S)-ibuprofen-(S)-lysine 342 mg
Hydrochlorothiazide 15 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium stearate 4 mg
EXAMPLE 2
(S)-ibuprofen-(S)-Lysine, Pyrilamine Maleate, Diuretic Table
(S)-ibuprofen-(S)-lysine 342 mg
Hydrochlorothiazide 15 mg
Pyrilamine Maleate 8 mg
PVP 15 mg
Avicel PH101 40 mg
Magnesium stearate 4 mg EXAMPLE 3
(S)-ibuprofen-(S)-lysine, Diuretic Sustained Release
(S)-ibuprofen 400 mg
Hydrochlorothiazide 30 mg
PVP 30 mg
Avicel PH101 80 mg
Magnesium stearate 8 mg
Methocel E10MCR 66 mg
Methocel K100MLV 200 mg

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition for use in the relief of pain, cramps, bloating and tension in a female and adapted for unit dosage oval
administration said composition comprising:
(i) an analgesically and anti-inflammatory effective amount of (S)-ibuprofen or a
pharmaceutically acceptable salt thereof,
substantially free of (R)-ibuprofen; and
(ii) a therapeutically effective amount of a diuretic; and
(iii) optionally a therapeutically effective amount of pyrilamine maleate.
2. A composition of Claim 1 wherein the (S)-ibuprofen is present as the salt (S)-ibuprofen- (S)-lysine.
3. A composition of Claim 1 comprising at least 50 mg of (S)-ibuprofen.
4. A composition of Claim 1 wherein the diuretic is selected from the group consisting of:
Acetazolamide, dichlorophenamide, methazolamide, chlorothiazide, hydrochlorothiazide,
benzthiazide, indapamide, trichlormethazide, methylclothiazide, polythiazide, ethacrynic acid, torasemide, furosemide. bumetamide, panabrom, amiloride, or triamterene.
5. A composition of Claim 4 wherein the diuretic is hydrochlorothiazide.
6. A method of relieving pain, cramps, bloating and tension, experienced during menstruation or premenstruation in a female in need of such relief comprising administering to such female:
(i) an analgesically and anti-inflammatory
effective amount of (S)-ibuprofen, or a salt thereof, substantially free of
(R)-ibuprofen; and
(ii) a diuretically effective amount of a
diuretic; and
(iii)optionally a tension relieving effective
amount of pyrilamine maleate.
7. A method of eliciting an onset hastened and enhanced response for the relief of pain, cramps, bloating and tension experienced during menstruation or premenstruation in a female in need of such relief, comprising administering to such female:
(i) an analgesically and anti-inflammatory
effective amount of (S)-ibuprofen, or a salt thereof, substantially free of
(R)-ibuprofen; and
(ii) a diuretically effective amount of a
diuretic: and
(iii)optionally a tension relieving effective
amount of pyrilamine maleate .
8. A method of reducing the side effects associated with the administration of an ibuprofen/ diuretic combination which comprises the
administration of (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen, and a diurttic.
9. A method of reducing the size and weight of an ibuprofen/diuretic combination dosage form, which comprises combining (S)-ibuprofen, or a salt thereof, substantially free of (R)-ibuprofen, and a diuretic.
PCT/US1991/007008 1990-09-28 1991-09-25 Ibuprofen-diuretic combinations WO1992005786A1 (en)

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US589,242 1990-09-28

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WO (1) WO1992005786A1 (en)

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US5462950A (en) * 1993-12-21 1995-10-31 Eli Lilly And Company Methods of treating menstrual symptoms and compositions therefore
EP2847175A4 (en) * 2012-05-08 2016-04-20 Cellix Bio Private Ltd Compositions and methods for suppression of carbonic anhydrase activity

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GB9613470D0 (en) * 1996-06-27 1996-08-28 Ciba Geigy Ag Small solid oral dosage form

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Title
CHEMICAL ABSTRACTS, Vol. 106, No. 23, issued 1987, June 8 (Columbus, Ohio, USA) B. GRYSTAL et al.; "On the mechanism of gastric ulcerations induced by ibuprofen in rats", see page 36 column 1, Abstract No. 188647a, Indian Journal Pharmacol 1985, 17(1) 51-4 (Eng.). No. 188647a. *
CHEMICAL ABSTRACTS, Vol. 110, No. 3, issued 1989, January 16 (Columbus, Ohio, U.S.A.) BRISTAO MYERS CO., "Pharmaceutical compositions comtaining an inflammation inhibitor and diuretic for treatments of menstruction disorder and premenstrual syndrome", see page 342, column 1, the Abstract No. 291138, Japan Kokai Tokkyo *
See also references of EP0550689A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5462950A (en) * 1993-12-21 1995-10-31 Eli Lilly And Company Methods of treating menstrual symptoms and compositions therefore
US5760061A (en) * 1993-12-21 1998-06-02 Eli Lilly And Company Methods of treating menstrual symptoms and compositions therefore
US5770612A (en) * 1993-12-21 1998-06-23 Eli Lilly And Company Methods of treating menstrual symptoms and compositions there for
EP2847175A4 (en) * 2012-05-08 2016-04-20 Cellix Bio Private Ltd Compositions and methods for suppression of carbonic anhydrase activity

Also Published As

Publication number Publication date
CA2092565A1 (en) 1992-03-29
JPH06501475A (en) 1994-02-17
EP0550689A4 (en) 1994-02-16
AU8710691A (en) 1992-04-28
EP0550689A1 (en) 1993-07-14

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