US20080234353A1 - Formulations of Ramipril - Google Patents

Formulations of Ramipril Download PDF

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Publication number
US20080234353A1
US20080234353A1 US10/593,627 US59362705A US2008234353A1 US 20080234353 A1 US20080234353 A1 US 20080234353A1 US 59362705 A US59362705 A US 59362705A US 2008234353 A1 US2008234353 A1 US 2008234353A1
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Prior art keywords
amount
ramipril
tablet formulation
compactrol
hydrogen carbonate
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US10/593,627
Inventor
Reynir Eyjolfsson
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Actavis Group hf
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Actavis Group hf
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Priority claimed from IS7196A external-priority patent/IS2197B/en
Application filed by Actavis Group hf filed Critical Actavis Group hf
Priority claimed from IS7772A external-priority patent/IS2204B/en
Assigned to ACTAVIS GROUP HF. reassignment ACTAVIS GROUP HF. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EYJOLFSSON, REYNIR
Priority to US11/777,849 priority Critical patent/US7589064B2/en
Publication of US20080234353A1 publication Critical patent/US20080234353A1/en
Abandoned legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/407Heterocyclic 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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54Heterocyclic 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
    • A61K31/549Heterocyclic 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 having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to stable pharmaceutical formulations of ramipril, optionally in combination with a diuretic.
  • Ramipril, (2S,3aS,6aS)-1[(S)—N—[(S)-1-carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid, 1-ethyl ester is an angiotensin converting enzyme (ACE) inhibitor.
  • ACE angiotensin converting enzyme
  • Ramipril can undergo cyclization via internal nucleophilic attack to form substituted diketopiperazines and also degrade via hydrolysis and oxidation.
  • EP 1 501 546 A1 describes stable pharmaceutical formulation for combinations of a statin and an ACE inhibitor.
  • the problem underlying the invention is that if an ACE inhibitor is in the presence of a stabilised statin, the ACE inhibitor decomposes to such extent that even after short storage period the content of decomposition products exceeds the permissible limit of degradation.
  • EP 1 501 546 A1 provides a formulation wherein the statin and the ACE inhibitor are separated by physiologically acceptable inert material. Calcium sulfate is mentioned as a possible inorganic filler in the formulation but it is neither claimed nor mentioned in any example. In fact all the examples are concerned with three-layer tablet, wherein the statin layer and ACE inhibitor layer are separated by a layer of microcrystalline cellulose. Combinations of the ACE inhibitor with a diuretic are not mentioned.
  • US 2003/0215526 claims formulations of ACE inhibitor a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an ACE inhibitor which is susceptible to degradation or its salt; a greater than stoichiometric amount of an alkali or alkaline earth metal carbonate, relative to the amount of ACE inhibitor or its salt, and a pharmaceutically acceptable carrier.
  • the excipient calcium sulphate is not mentioned.
  • EP 0 280 999 B1 describes a composition comprising ACE inhibitor (i.e. ramipril), an alkali or alkaline earth metal carbonate and saccharide wherein the ACE inhibitor is stabilized against degradation (cyclization, discoloration and hydrolysis) by means of the other mentioned ingredients.
  • ACE inhibitor i.e. ramipril
  • alkali or alkaline earth metal carbonate i.e. alumipril
  • saccharide i.e. ramipril
  • saccharide i.e. ramipril
  • lactose and mannitol mannitol
  • Modified starch is mentioned as disintegrant in the specification.
  • EP 0 317 878 B1 claims a stable, compressed pharmaceutical formulation containing a compound of a defined formula (i.e. ramipril) wherein, for stabilization before compression, a compound of the formula is a) coated with a polymeric, physiologically tolerated protective coating, or b) mixed with a physiologically tolerated buffer which ensures that a pH in the weakly acidic to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture, where sodium bicarbonate is excepted as buffer, or c) mixed with a physiologically tolerated buffer which ensures that a pH in the weakly acid to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture, and is coated with a polymeric, physiologically tolerated protective coating, where, in the case of stabilization according to b) with alkali metal or alkaline earth metal carbonate, the formulation is free of sugar.
  • a compound of a defined formula i.e. ramipril
  • WO 93/17685 claims combinations of ACE inhibitors and diuretics such as hydrochlorothiazide.
  • Sodium hydrogen carbonate, pregelatinised starch and magnesium stearate are mentioned as excipients. Calcium sulphate is not mentioned.
  • compositions of ramipril and piretanide is described in EP 215 357 B1. Calcium sulfate is not mentioned in this patent.
  • WO 03/028707 claims a formulation containing ramipril and lactose monohydrate. Calcium sulfate is mentioned in the specification as a possible diluent. Calcium sulfate is not included in any example.
  • Calcium sulphate dihydrate is known as an inert diluent in compressed tablets. However, it was surprising that the stability of the tablets proved to be very satisfying.
  • the invention provides a pharmaceutical formulation comprising ramipril,
  • the pharmaceutical formulation of the present invention comprises typically:
  • disintegrant e.g. starch
  • binder and/or lubricant e.g. sodium stearyl fumarate
  • the formulation optionally also includes a diuretic, such as hydrochlorothiazide or piretanide.
  • a diuretic such as hydrochlorothiazide or piretanide.
  • the preferred amount of ramipril is 0.5-1.5% w/w
  • the amount of Compactrol is 85-90% w/w
  • the amount of sodium hydrogen carbonate is 0.5-1.5% w/w
  • the amount of starch pregelatinised is 7-13% w/w
  • the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • the preferred amount of ramipril is 1.4-2.5% w/w
  • the amount of Compactrol is 78-95% w/w
  • the amount of sodium hydrogen carbonate is 1.4-2.5% w/w
  • the amount of starch pregelatinised is 7-13% w/w
  • the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • ramipril is 1.4-2.5% w/w
  • hydrochlorothiazide is 8.5-10.5% w/w
  • the amount of Compactrol is 65-75% w/w
  • the amount of sodium hydrogen carbonate is 1.0-2.5% w/w
  • the amount of starch pregelatinised is 12-18% w/w
  • the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • the preferred amount of ramipril is 1.5-2.5% w/w
  • the amount of piretanide is 1.8-3.0% w/w
  • the amount of Compactrol is 65-85% w/w
  • the amount of sodium hydrogen carbonate is 3.0-5.0% w/w
  • the amount of starch pregelatinised is 10-20% w/w
  • the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • ramipril is susceptible to certain types of degradation, there are several impurities formed during the manufacturing process and storing of the tablet. It is of high importance to minimize this degradation. The strength of different exipients was adjusted until a useful formulation was found.
  • Ramipril diketopiperazine is one of the compounds formed via degradation.
  • the present formulation proved to be especially stable with regard to formation of the diketopiperazine.
  • the example demonstates a very good stability with regard to ramipril diketopiperazine formation.

Abstract

The present invention relates to stable tablet formulations of ramipril, optionally in combination with a diuretic.

Description

    FIELD OF THE INVENTION
  • The present invention relates to stable pharmaceutical formulations of ramipril, optionally in combination with a diuretic.
  • TECHNICAL BACKGROUND AND PRIOR ART
  • Ramipril, (2S,3aS,6aS)-1[(S)—N—[(S)-1-carboxy-3-phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid, 1-ethyl ester is an angiotensin converting enzyme (ACE) inhibitor. Ramipril is used for the treatment of hypertension, heart failure, stroke, myocardial infarction, diabetes and cardiovascular disease.
  • Ramipril and the acid form, ramiprilat, is described in EP 0 097 022 B1.
  • The preparation of stable pharmaceutical formulations of ramipril is complicated since it is susceptible to certain types of degradation. Ramipril can undergo cyclization via internal nucleophilic attack to form substituted diketopiperazines and also degrade via hydrolysis and oxidation.
  • EP 1 501 546 A1 describes stable pharmaceutical formulation for combinations of a statin and an ACE inhibitor. The problem underlying the invention is that if an ACE inhibitor is in the presence of a stabilised statin, the ACE inhibitor decomposes to such extent that even after short storage period the content of decomposition products exceeds the permissible limit of degradation. EP 1 501 546 A1 provides a formulation wherein the statin and the ACE inhibitor are separated by physiologically acceptable inert material. Calcium sulfate is mentioned as a possible inorganic filler in the formulation but it is neither claimed nor mentioned in any example. In fact all the examples are concerned with three-layer tablet, wherein the statin layer and ACE inhibitor layer are separated by a layer of microcrystalline cellulose. Combinations of the ACE inhibitor with a diuretic are not mentioned.
  • US 2003/0215526 claims formulations of ACE inhibitor a pharmaceutical composition comprising a therapeutically effective amount of an ACE inhibitor which is susceptible to degradation or its salt; a greater than stoichiometric amount of an alkali or alkaline earth metal carbonate, relative to the amount of ACE inhibitor or its salt, and a pharmaceutically acceptable carrier. The excipient calcium sulphate is not mentioned.
  • EP 0 280 999 B1 describes a composition comprising ACE inhibitor (i.e. ramipril), an alkali or alkaline earth metal carbonate and saccharide wherein the ACE inhibitor is stabilized against degradation (cyclization, discoloration and hydrolysis) by means of the other mentioned ingredients. In the specifications the relevant saccharides are lactose and mannitol. Modified starch is mentioned as disintegrant in the specification.
  • EP 0 317 878 B1 claims a stable, compressed pharmaceutical formulation containing a compound of a defined formula (i.e. ramipril) wherein, for stabilization before compression, a compound of the formula is a) coated with a polymeric, physiologically tolerated protective coating, or b) mixed with a physiologically tolerated buffer which ensures that a pH in the weakly acidic to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture, where sodium bicarbonate is excepted as buffer, or c) mixed with a physiologically tolerated buffer which ensures that a pH in the weakly acid to weakly alkaline range is set up in a pharmaceutical formulation in the presence of moisture, and is coated with a polymeric, physiologically tolerated protective coating, where, in the case of stabilization according to b) with alkali metal or alkaline earth metal carbonate, the formulation is free of sugar.
  • WO 93/17685 claims combinations of ACE inhibitors and diuretics such as hydrochlorothiazide. Sodium hydrogen carbonate, pregelatinised starch and magnesium stearate are mentioned as excipients. Calcium sulphate is not mentioned.
  • Compositions of ramipril and piretanide is described in EP 215 357 B1. Calcium sulfate is not mentioned in this patent.
  • WO 03/028707 claims a formulation containing ramipril and lactose monohydrate. Calcium sulfate is mentioned in the specification as a possible diluent. Calcium sulfate is not included in any example.
  • SUMMARY OF THE INVENTION
  • In an attempt to prepare a stable tablet formulation of ramipril, it was discovered that useful formulations can be produced by the use of calcium sulphate dihydrate (e.g. Compactrol) as filler material.
  • Properties of calcium sulphate are described in A. H. Kibbe, Handbook of pharmaceutical excipients, 73-76, American Pharmaceutical Association, Washington, and Pharmaceutical Press, London, 2000.
  • Calcium sulphate dihydrate is known as an inert diluent in compressed tablets. However, it was surprising that the stability of the tablets proved to be very satisfying.
  • DETAILED DESCRIPTION
  • The invention provides a pharmaceutical formulation comprising ramipril,
  • Figure US20080234353A1-20080925-C00001
  • Compactrol as filling agent, and sodium hydrogen carbonate as stabilization agent.
  • The pharmaceutical formulation of the present invention comprises typically:
  • a) 0.1-5.0% w/w of ramipril;
  • b) 50-95% w/w of Compactrol;
  • c) 0.1-5.0% w/w of sodium hydrogen carbonate;
    and optionally disintegrant (e.g. starch), binder and/or lubricant (e.g. sodium stearyl fumarate).
  • The formulation optionally also includes a diuretic, such as hydrochlorothiazide or piretanide.
  • For the tablet formulation containing 1.25 mg ramipril, the preferred amount of ramipril is 0.5-1.5% w/w, the amount of Compactrol is 85-90% w/w, the amount of sodium hydrogen carbonate is 0.5-1.5% w/w, the amount of starch pregelatinised is 7-13% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • For the tablet formulation containing 2.5 mg, 5 mg and 10 mg ramipril, the preferred amount of ramipril is 1.4-2.5% w/w, the amount of Compactrol is 78-95% w/w, the amount of sodium hydrogen carbonate is 1.4-2.5% w/w, the amount of starch pregelatinised is 7-13% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • For the tablet formulation containing 2.5 mg ramipril/2.5 mg hydrochlorothiazide and 5 mg ramipril/25 mg hydrochlorothiazide, preferred amount of ramipril is 1.4-2.5% w/w, the amount of hydrochlorothiazide is 8.5-10.5% w/w, the amount of Compactrol is 65-75% w/w, the amount of sodium hydrogen carbonate is 1.0-2.5% w/w, the amount of starch pregelatinised is 12-18% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • For the tablet formulation containing 5 mg ramipril and 6 mg piretanide, the preferred amount of ramipril is 1.5-2.5% w/w, the amount of piretanide is 1.8-3.0% w/w, the amount of Compactrol is 65-85% w/w, the amount of sodium hydrogen carbonate is 3.0-5.0% w/w, the amount of starch pregelatinised is 10-20% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
  • Since ramipril is susceptible to certain types of degradation, there are several impurities formed during the manufacturing process and storing of the tablet. It is of high importance to minimize this degradation. The strength of different exipients was adjusted until a useful formulation was found.
  • There are certain criterias that these compounds are not allowed to exceed. The present formulation has proved to be stable.
  • Ramipril diketopiperazine is one of the compounds formed via degradation. The present formulation proved to be especially stable with regard to formation of the diketopiperazine.
  • EXAMPLES
  • The following example is merely illustrative of the present invention and it should not be considered as limiting the scope of the invention.
  • Example 1 Formulation for 1.25 mg Ramipril Tablets
  • Ramipril  0.96%
    Compactrol 87.08% w/w
    Sodium hydrogen carbonate  0.96% w/w
    Starch pregelatinised 10.00% w/w
    Sodium stearyl fumarate  1.00% w/w
  • Example 2 Formulation for 2.5 mg, 5 mg and 10 mg Ramipril Tablets
  • Ramipril 1.9% w/w
    Compactrol 85.2% w/w 
    Sodium hydrogen carbonate 1.9% w/w
    Starch pregelatinised 10.0% w/w 
    Sodium stearyl fumarate 1.0% w/w
  • Example 3 Formulation for 2.5/12.5 mg and 5/25 mg Ramipril Hydrochlorothiazide (HCT) Tablets
  • Ramipril 1.9% w/w
    Hydrochlorothiazide 9.6% w/w
    Compactrol 70.5% w/w 
    Sodium hydrogen carbonate 1.9% w/w
    Starch pregelatinised 15.0% w/w 
    Sodium stearyl fumarate 1.0% w/w
  • Example 4 Formulation for 5/6 mg Ramipril Piretanide Tablets
  • Ramipril 1.9% w/w
    Piretanide 2.3% w/w
    Compactrol  76% w/w
    Sodium hydrogen carbonate 3.7% w/w
    Starch pregelatinised  15% w/w
    Sodium stearyl fumarate   1% w/w
  • Example 5
  • Stability of 5 mg and 10 mg tablets prepared in Example 2 and of marketed preparation were tested at 40° C. and 75% relative humidity (RH) for six months. Conversion of ramipril into ramipril diketopiperazine was assayed and measured as relativeomount of initial amount of ramipril.
  • Assay Ramipril diketopiperazine
     5 mg
    Tablets from Ex. 2 4.0% 0.478-1.06% 
    Marketed prepn**. 4.0% 2.77%
    10 mg
    Tablets from Ex. 2 4.0% 0.471-0.806%
    Marketed prepn**. 4.0% 2.27%
    **Ramitab ™ ramipril 5 and 10 mg tablets
  • The example demonstates a very good stability with regard to ramipril diketopiperazine formation.

Claims (11)

1. A tablet formulation comprising:
a) 0.5-5.0% w/w of ramipril;
b) 50-95% w/w of calcium sulphate dihydrate; and
c) 0.1-5.0% W/w of sodium hydrogen carbonate,
optionally in combination with a disintegrant, binder and lubricant and other excipients.
2. The tablet formulation of claim 1, wherein the calcium sulphate dihydrate is Compactrol.
3. The tablet formulation of claim 1 or claim 2, additionally in combination with a diuretic.
4. The tablet formulation of claim 3, wherein the diuretic is hydrochlorothiazide.
5. The tablet formulation of claim 3, wherein the diuretic is piretanide.
6. The tablet formulation of any of claims 1 to 5, wherein the disintegrant and binder is pregelatinised starch.
7. The tablet formulation of any of claims 1 to 6, wherein the lubricant is sodium stearyl fumarate.
8. The tablet formulation of claim 1 or claim 2 containing 1.25 mg ramipril, wherein the amount of ramipril is 0.5-1.5% w/w, the amount of Compactrol is 85-90% w/w, the amount of sodium hydrogen carbonate is 0.5-1.5% w/w, the amount of starch pregelatinised is 7-13% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
9. The tablet formulation of claim 1 or claim 2 containing 2.5 mg, 5 mg or 10 mg ramipril, wherein the amount of ramipril is 1.4-2.5% w/w, the amount of Compactrol is 78-95% w/w, the amount of sodium hydrogen carbonate is 1.4-2.5% w/w, the amount of starch pregelatinised is 7-13% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
10. The tablet formulation of any of claims 1 to 4, containing 2.5 mg ramipril/2.5 mg hydrochlorothiazide or 5 mg ramipril/25 mg hydrochlorothiazide, wherein the amount of ramipril is 1.4-2.5% w/w, the amount of hydrochlorothiazide is 8.5-10.5% w/w, the amount of Compactrol is 65-75% w/w, the amount of sodium hydrogen carbonate is 1.0-2.5% w/w, the amount of starch pregelatinised is 12-18% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
11. The tablet formulation of any of claims 1 to 3 and 5, containing 5 mg ramipril and 6 mg piretanide, the preferred amount of ramipril is 1.5-2.5% w/w, the amount of piretanide is 1.8-3.0% w/w, the amount of Compactrol is 65-85% w/w, the amount of sodium hydrogen carbonate is 3.0-5.0% w/w, the amount of starch pregelatinised is 10-20% w/w and the amount of sodium stearyl fumarate is 0.5-1.5% w/w.
US10/593,627 2004-03-24 2005-03-23 Formulations of Ramipril Abandoned US20080234353A1 (en)

Priority Applications (1)

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Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IS7196A IS2197B (en) 2004-03-24 2004-03-24 Ramipril Pharmaceutical Compositions
IS7196 2004-03-24
IS7772A IS2204B (en) 2005-03-23 2005-03-23 Pharmaceutical formulations of ramipril and pyranetide
PCT/IS2005/000008 WO2005067887A2 (en) 2004-03-24 2005-03-23 Formulations of ramipril
IS7772 2005-03-23

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US20070254030A1 (en) * 2004-03-24 2007-11-01 Reynir Eyjolfsson Formulations of Ramipril
US20070259941A1 (en) * 2005-10-28 2007-11-08 Selamine Limited Ramipril formulation
US20100062062A1 (en) * 2008-09-11 2010-03-11 Aethos Pharmaceuticals, Inc. Stabilized Coating for Pharmaceutical Formulations
WO2011034513A1 (en) 2009-08-17 2011-03-24 Mahmut Bilgic The granules with improved solubility and stability

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GB0518129D0 (en) * 2005-09-06 2005-10-12 Arrow Int Ltd Ramipril formulation
EP1937220A2 (en) * 2005-10-21 2008-07-02 Selamine Ltd. Ramipril formulation with increased stability
US20070098782A1 (en) * 2005-10-28 2007-05-03 Selamine Limited Ramipril Formulation
GB0624087D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril combination salt
GB0624084D0 (en) * 2006-12-01 2007-01-10 Selamine Ltd Ramipril amino acid salts
WO2010029571A2 (en) * 2008-07-30 2010-03-18 Panacea Biotec Limited Modified release ramipril compositions and uses thereof
RU2479310C2 (en) * 2011-02-09 2013-04-20 Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") Pharmaceutical composition for treating arterial hypertension and congestive cardiac failure and method for preparing it
EA030466B1 (en) 2012-02-17 2018-08-31 Эгиш Дьёдьсердьяр Зрт. Pharmaceutical formulation having improved stability
RU2618471C2 (en) * 2012-12-03 2017-05-03 Закрытое Акционерное Общество "Вертекс" Oral pharmaceutical composition of diuretics and ace inhibitor in micronized form, drug and its application
HUP1300496A2 (en) 2013-08-16 2015-03-02 Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag Stable pharmaceutical composition

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