WO1994009778A1 - Combinations of angiotensin-ii receptor antagonists and diuretics - Google Patents

Combinations of angiotensin-ii receptor antagonists and diuretics Download PDF

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Publication number
WO1994009778A1
WO1994009778A1 PCT/US1993/010163 US9310163W WO9409778A1 WO 1994009778 A1 WO1994009778 A1 WO 1994009778A1 US 9310163 W US9310163 W US 9310163W WO 9409778 A1 WO9409778 A1 WO 9409778A1
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Prior art keywords
diuretic
antagonist
hydrochlorothiazide
formulation
dose
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PCT/US1993/010163
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French (fr)
Inventor
Edward B. Nelson
Charles S. Sweet
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Merck & Co., Inc.
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Priority to AU54491/94A priority Critical patent/AU5449194A/en
Publication of WO1994009778A1 publication Critical patent/WO1994009778A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin

Definitions

  • A-II antagonists Both diuretics and A-II antagonists have an effect on the renin-angiotensin-aldosterone system.
  • A-II antagonists lower blood pressure by blocking the angiotensin II receptors important in regulating blood pressure.
  • Diuretics regulate the sodium-balance, and
  • This invention is concerned with pharmaceutical formulations for the treatment of essential hypertension and disorders associated therewith such as heart failure, cardiac or vascular hypertrophy, renal failure, proteinuria, ischemia or restenosis, which have as active ingredients an A-II antagonist and a diuretic wherein the diuretic is at a dose level below the recognized clinically effective dose.
  • the A-II antagonist is found to have greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose as monotherapy.
  • the diuretic is being administered at dose levels that would be ineffective as an antihypertensive if used alone and similarly ineffective in causing adverse reactions.
  • novel pharmaceutical formulations of this invention comprise: a pharmaceutical carrier; an A-II antagonist at the dose level normally employed in monotherapy, which is usually about 0.1 to about 1000 mg preferably about 1-100 mg, depending on the A-II antagonist; and a diuretic at a dose level which is the highest non-pharmacological dose.
  • the formulation is designed for oral administration and is presented as tablets, capsules, gel caps, caplets, sublingual dosage form or as a sustained release formulation. It may also be designed as an elixir for oral administration, a suppository for rectal administration, or a patch for transdermal administration, or a biodegradable stint for local intraarterial administration.
  • excipients which can be incorporated in tablets, capsules and the like are: a binder such as gum tragacanth, acacia, com starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as com starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry.
  • a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • novel formulations of this invention are useful in the treatment of essential hypertension, and heart failure, cardiac or vascular hypertrophy, renal failure, proteinuria, ischemia or restenosis.
  • Typical of the A-II antagonists useful in the novel formulation and method of treatment of this invention are the following compounds I through XI:
  • the preferred A-II antagonist for use in the novel formulation and method of treatment of this invention is compound IV.
  • the diuretics useful in the novel formulation and method of treatment of this invention are: hydrochlorothiazide (HCTZ), furosemide, altizide, trichlormethazide, triflumethazide, bemetizide, cyclothiazide, methylchlothiazide, azosemide, chlorothiazide, butizide, bendroflumethazide, cyclopenthiazide, benzclortriazide, polythiazide, hydroflumethazide, benzthiazide, ethiazide, penflutazide, chlorthalidone, butazolimide, spironolactone, amiloride or triamterene.
  • Preferred diuretics for incorporation in the novel formulation of this invention are hydrochlorothiazide, trichlormethazide, furosemide, chlorthalidone, and altizide, especially hydrochlorothiazide.
  • the novel method of treatment of this invention comprises the administration of a unit dose of the novel pharmaceutical formulation, one to three times a day depending on the patient and the severity of the indication being treated. Usually once or twice a day is adequate.
  • Compound I 100 50 25 hydrochlorothiazide 6.25 6.25 6.25
  • Compound II 100 50 25 hydrochlorothiazide 6.25 6.25 6.25

Abstract

Pharmaceutical formulations comprising as active ingredients an angiotensin-II receptor (A-II) antagonist at a dose level normally found effective as an antihypertensive and a diuretic at a dose level below its minimum effective dose, demonstrate greater efficacy than would be expected in returning the blood pressure of hypertensive patients to normotensive values.

Description

• ■4
TITLE OF THE INVENTION
COMBINATIONS OF ANGIOTENSIN-II RECEPTOR
ANTAGONISTS AND DIURETICS
- BACKGROUND OF THE INVENTION
Both diuretics and A-II antagonists have an effect on the renin-angiotensin-aldosterone system. A-II antagonists lower blood pressure by blocking the angiotensin II receptors important in regulating blood pressure. Diuretics regulate the sodium-balance, and
10 thereby also extracellular fluid volume. The resultant decrease, both in sodium and fluid volume, following therapy with diuretics activates the renin-angiotensin-aldosterone system. This compensatory response will, to some degree, counteract the blood-pressure lowering effect of the diuretic. When a diuretic and an A-II antagonist are combined the
15 different pharmacological actions ofthese two drugs will, influence the effect of the other. There is accordingly a logical rationale for combining these two pharmacological agents.
It is possible to establish the highest non-pharmacological active dose of diuretic, i.e. a dose that is so low that it has essentially no
20 effect on blood pressure, and no apparent adverse effects. The clinically non-effective dose of diuretic, however, will still activate the renin-angiotensin-aldosterone system and although it has no effect on blood pressure, it will, nonetheless, have a potentiating effect on an A-II antagonist action in lowering blood pressure.
25 In a recently completed study of the effects of different doses of HCTZ on blood pressure and various metabolic parameters, doses ranging from 3 mg to 25 mg were investigated. 25 mg HCTZ produced significant effects on blood pressure and the metabolic parameters. 12.5 mg of HCTZ was at the threshold of an effective
3 ° antihypertensive response, and this dose also altered metabolic parameters. In contrast, HCTZ at 3 and 6 mg were not different from placebo in terms of blood pressure and metabolic end-points.
Based on this study it can be concluded that the 6 mg or 6.25 mg dose is close to the highest non-pharmacological dose of HCTZ. SUMMARY OF THE INVENTION
This invention is concerned with pharmaceutical formulations for the treatment of essential hypertension and disorders associated therewith such as heart failure, cardiac or vascular hypertrophy, renal failure, proteinuria, ischemia or restenosis, which have as active ingredients an A-II antagonist and a diuretic wherein the diuretic is at a dose level below the recognized clinically effective dose. With these formulations the A-II antagonist is found to have greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose as monotherapy. At the same time the diuretic is being administered at dose levels that would be ineffective as an antihypertensive if used alone and similarly ineffective in causing adverse reactions.
DETAILED DESCRIPTION OF THE INVENTION
The novel pharmaceutical formulations of this invention comprise: a pharmaceutical carrier; an A-II antagonist at the dose level normally employed in monotherapy, which is usually about 0.1 to about 1000 mg preferably about 1-100 mg, depending on the A-II antagonist; and a diuretic at a dose level which is the highest non-pharmacological dose.
The formulation is designed for oral administration and is presented as tablets, capsules, gel caps, caplets, sublingual dosage form or as a sustained release formulation. It may also be designed as an elixir for oral administration, a suppository for rectal administration, or a patch for transdermal administration, or a biodegradable stint for local intraarterial administration.
Illustrative of the excipients which can be incorporated in tablets, capsules and the like are: a binder such as gum tragacanth, acacia, com starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as com starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The novel formulations of this invention are useful in the treatment of essential hypertension, and heart failure, cardiac or vascular hypertrophy, renal failure, proteinuria, ischemia or restenosis.
Typical of the A-II antagonists useful in the novel formulation and method of treatment of this invention are the following compounds I through XI:
Figure imgf000006_0001
10
Figure imgf000006_0002
II in
25
30
Figure imgf000007_0001
Ar Ar
Figure imgf000007_0002
XI The preferred A-II antagonist for use in the novel formulation and method of treatment of this invention is compound IV.
The diuretics useful in the novel formulation and method of treatment of this invention are: hydrochlorothiazide (HCTZ), furosemide, altizide, trichlormethazide, triflumethazide, bemetizide, cyclothiazide, methylchlothiazide, azosemide, chlorothiazide, butizide, bendroflumethazide, cyclopenthiazide, benzclortriazide, polythiazide, hydroflumethazide, benzthiazide, ethiazide, penflutazide, chlorthalidone, butazolimide, spironolactone, amiloride or triamterene. Preferred diuretics for incorporation in the novel formulation of this invention are hydrochlorothiazide, trichlormethazide, furosemide, chlorthalidone, and altizide, especially hydrochlorothiazide.
In the specification and claims hereof, the naming of an A- II antagonist or diuretic such as losartan or hydrochlorothiazide respectfully is meant to include salts thereof.
The novel method of treatment of this invention comprises the administration of a unit dose of the novel pharmaceutical formulation, one to three times a day depending on the patient and the severity of the indication being treated. Usually once or twice a day is adequate.
EXAMPLE 1
Component Amount (mg
-Δ_ -B- -C losartan (IV) 100 50 25 hydrochlorothiazide 6.25 6.25 6.25 sodium bicarbonate 10 5 2.5 lactose 154 164.1 198.1 starch NF 22 22 22.77 pregelatinized starch NF 2.2 2.2 5.06 magnesium stearate 1.1 1.0 0.90 The excipients shown in Example 1 are exemplary of the excipients used in each of the other examples that follow.
EXAMPLE 2
Component Amount (mg)
1 2 3
Compound I 100 50 25 hydrochlorothiazide 6.25 6.25 6.25
EXAMPLE 3
Component Amount (mg)
1 2 3
Compound II 100 50 25 hydrochlorothiazide 6.25 6.25 6.25
EXAMPLE 4
Component Amount (mg)
1 2 3
Compound HI 100 50 25 hydrochlorothiazide 6.25 6.25 6.25
EXAMPLE 5
Component Amount (mg)
1 2 3
Compound V 100 50 25 hydrochlorothiazide 6.25 6.25 6.25 EXAMPLE 6
Component Amount (mg)
1 3
Compound VI 100 50 25 hydrochlorothiazide 6.25 6.25 6.25

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical formulation comprising a pharmaceutical carrier; about 0.1-1000 mg of an A-II antagonist; and an effective non-pharmacological dose of a diuretic.
2. The pharmaceutical formulation of Claim 1, wherein the A-II antagonist is selected from
Figure imgf000011_0001
Figure imgf000011_0002
II ID
Figure imgf000012_0001
Ar Ar
Figure imgf000012_0002
XI and the diuretic is selected from hydrochlorothiazide (HCTZ), furosemide, altizide, trichlormethazide, triflumethazide, bemetizide, cyclothiazide, methylchlothiazide, azosemide, chlorothiazide, butizide, bendroflumethazide, cyclopenthiazide, benzclortriazide, polythiazide, hydroflumethazide, benzthiazide, ethiazide, penflutazide, chlorthalidone, butazolimide, spironolactone, amiloride or triamterene.
3. The formulation of Claim 2, wherein the A-II antagonist is losartan.
4. The formulation of Claim 3, wherein the the diuretic is hydrochlorothiazide.
5. The formulation of Claim 4 comprising 2.5, 5.0, 10, 12.5, 25, 50 or 100 mg of losartan and 6.25 mg of hydrochlorothiazide.
6. A method of treating hypertension and heart failure, which comprises the administration to a patient in need of such treatment of a pharmaceutical formulation comprising a pharmaceutical carrier; about 0.1-1000 mg of an A-II antagonist; and an effective non- pharmacological dose of a diuretic.
7. The method of Claim 6, wherein the A-II antagonist is selected from
Figure imgf000014_0001
10
Figure imgf000014_0002
π m
25
30
Figure imgf000015_0001
Ar Ar
Figure imgf000015_0002
XI and the diuretic is selected from hydrochlorothiazide (HCTZ), furosemide, altizide, trichlormethazide, triflumethazide, bemetizide, cyclothiazide, methylchlothiazide, azosemide, chlorothiazide, butizide, bendroflumethazide, cyclopenthiazide, benzclortriazide, polythiazide, hydroflumethazide, benzthiazide, ethiazide, penflutazide, chlorthialidone, butazolimide, spironolactone, amiloride or triamterene.
8. The method of Claim 7 wherein the A-II antagonist is losartan.
9. The formulation of Claim 8 wherein the the diuretic is hydrochlorothiazide.
10. The method of Claim 9 comprising 2.5, 5.0, 10, 12.5, 25, 50 or 100 mg of losartan and 6.25 mg of hydrochlorothiazide.
PCT/US1993/010163 1992-10-26 1993-10-22 Combinations of angiotensin-ii receptor antagonists and diuretics WO1994009778A1 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5459148A (en) * 1992-12-17 1995-10-17 Sankyo Company, Limited Biphenyl derivatives and their use for the treatment of hypertension and cardiac disease
WO1996040255A2 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Method to treat cardiofibrosis with a combination therapy of an angiotensin ii antagonist and an epoxy-steroidal aldosterone antagonist
WO1996040258A2 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
WO1996040257A1 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Epoxy-steroidal aldosterone antagonist and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
WO1996040256A1 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Method to treat cardiofibrosis with a combination of an angiotensin ii antagonist and spironolactone
FR2735365A1 (en) * 1995-06-14 1996-12-20 Sanofi Sa USE OF AN ANGIOTENSIN II ANTAGONIST AND A BENZOFURANE DERIVATIVE FOR THE PREPARATION OF A MEDICAMENT USEFUL IN THE TREATMENT OF CARDIOVASCULAR CONDITIONS
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
US5721263A (en) * 1993-06-07 1998-02-24 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
US6294197B1 (en) 1996-06-27 2001-09-25 Novartis Ag Solid oral dosage forms of valsartan
EP1275391A1 (en) 1995-06-07 2003-01-15 Sanofi-Synthelabo Pharmaceutical compositions containing irbesartan and a diuretic
EP1306088B1 (en) * 1993-06-07 2007-09-05 Takeda Pharmaceutical Company Limited Combination of a benzimidazole having angiotensin-II antagonistic activity with a diuretic
US8226977B2 (en) 2004-06-04 2012-07-24 Teva Pharmaceutical Industries Ltd. Pharmaceutical composition containing irbesartan
WO2013050339A1 (en) 2011-10-03 2013-04-11 Ems S/A Pharmaceutical compositions of antihypertensives
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
US5646171A (en) * 1991-02-21 1997-07-08 Sankyo Company, Limited Angiotensin II antagonist 1-biphenylmethylimidazole compounds and their therapeutic use
US5459148A (en) * 1992-12-17 1995-10-17 Sankyo Company, Limited Biphenyl derivatives and their use for the treatment of hypertension and cardiac disease
US6420405B2 (en) 1993-06-07 2002-07-16 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
EP1306088B1 (en) * 1993-06-07 2007-09-05 Takeda Pharmaceutical Company Limited Combination of a benzimidazole having angiotensin-II antagonistic activity with a diuretic
EP1844774A3 (en) * 1993-06-07 2008-08-20 Takeda Pharmaceutical Company Limited A pharmaceutical composition for angiotensin II-mediated diseases
US5721263A (en) * 1993-06-07 1998-02-24 Takeda Chemical Industries, Ltd. Pharmaceutical composition for angiotensin II-mediated diseases
EP2277520A3 (en) * 1993-06-07 2011-08-24 Takeda Pharmaceutical Company Limited A pharmaceutical composition for angiotensin ii-mediated diseases
WO1996040256A1 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Method to treat cardiofibrosis with a combination of an angiotensin ii antagonist and spironolactone
WO1996040255A3 (en) * 1995-06-07 1997-01-23 Searle & Co Method to treat cardiofibrosis with a combination therapy of an angiotensin ii antagonist and an epoxy-steroidal aldosterone antagonist
WO1996040258A3 (en) * 1995-06-07 1997-01-23 Searle & Co Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
EP1275391B1 (en) * 1995-06-07 2011-03-30 Sanofi-Aventis Pharmaceutical compositions containing irbesartan and a diuretic
EP1275391A1 (en) 1995-06-07 2003-01-15 Sanofi-Synthelabo Pharmaceutical compositions containing irbesartan and a diuretic
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