WO2010057449A2 - A solid pharmaceutical composition with atorvastatin and telmisartan as the active substances - Google Patents

A solid pharmaceutical composition with atorvastatin and telmisartan as the active substances Download PDF

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Publication number
WO2010057449A2
WO2010057449A2 PCT/CZ2009/000138 CZ2009000138W WO2010057449A2 WO 2010057449 A2 WO2010057449 A2 WO 2010057449A2 CZ 2009000138 W CZ2009000138 W CZ 2009000138W WO 2010057449 A2 WO2010057449 A2 WO 2010057449A2
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WO
WIPO (PCT)
Prior art keywords
telmisartan
atorvastatin
pharmaceutical composition
composition according
mixture
Prior art date
Application number
PCT/CZ2009/000138
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English (en)
French (fr)
Other versions
WO2010057449A3 (en
Inventor
Alena Prokopova
Eva Gryczova
Original Assignee
Zentiva, K.S.
Linek Jan
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 Zentiva, K.S., Linek Jan filed Critical Zentiva, K.S.
Publication of WO2010057449A2 publication Critical patent/WO2010057449A2/en
Publication of WO2010057449A3 publication Critical patent/WO2010057449A3/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
    • A61K31/40—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
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the invention solves the problem of a pharmaceutical composition containing at the same time two substances, namely atorvastatin, an efficient inhibitor of HMG Co A reductase, and telmisartan, a blocker of ATII receptors. Both these substances exhibit a number of positive effects for treatment and prevention of cardiovascular problems.
  • atorvastatin is primarily used for treatment of hypercholesterolemia while telmisartan is effective against hypertension. It is obvious that a combination of treatment of these two best-known risk factors will significantly improve the development prognosis of various cardiovascular diseases. Pharmaceutical compositions containing both these substances in one dose will improve compliance compared to administration of each dose separately.
  • EP1514543 further describes combinations of atorvastatin with various ATII blockers. The effect of this combination is again focused on treatment and prevention of cardiovascular diseases and reduction of the two risk factors.
  • WO 2004/62557 deals with the use of atorvastatin in combination with telmisartan for treatment of cardiovascular, cardiopulmonary and cardiorenal disorders. According to the application this composition is especially useful for metabolic disorders related to disorders of sugar management of the body. But this application does not mention any composition that would contain both the substances together.
  • Several patent applications are known that deal with the problem of combining telmisartan with another substance. Namely it is the case of hydrochlorothiazide (WO03059327A1 and WO07060170A2) or amlodipine (WO06048208A1). In all the cases the substances are contained in a layered tablet.
  • WO04096215A1 describes a composition of telmisartan with hydrochlorothiazide together in one layer.
  • Atorvastatin is known to be quite an unstable substance and its composition must always be designed from this point of view.
  • a composition of two different active substances must be not only stable, but it also must manifest a corresponding rate of releasing of both the substances. For this reason it is not possible to simply apply the knowledge of behaviour of one composition to another one.
  • the invention provides a solid pharmaceutical composition of telmisartan and atorvastatin in the form of their alkali or alkaline earth salts, containing a basically reacting substance, together either: a) with a mono- or oligosaccharide, soluble in water, or with an alcoholic sugar; or b) with an insoluble polysaccharide
  • Solid particles of the saccharide may appear separately or in granules. In any case, virtually all particles of saccharides are smaller than 0.355 mm.
  • sorbitol is selected as the soluble saccharide. In this case selecting 50 to 80% of the total number of particles smaller than 160 ⁇ m has proved to the beneficial.
  • microcrystalline cellulose was selected as the insoluble saccharide the size of which is, in a preferable embodiment, limited by max. 30% by weight of all particles larger than 75 ⁇ m and at least 50% of the total number of all particles larger than 32 ⁇ m.
  • the particles of microcrystalline cellulose are agglomerated in granules, then advantageously about 75% by weight of all the granules are smaller than 0.5 mm and the size of about 40% by weight of all the granules is in the range of 0.1 to 0.25 mm.
  • the pharmaceutical composition consists of two mixtures, usually produced separately while one of them is a telmisartan mixture and the other one is an atorvastatin mixture.
  • the weight of both the mixtures varies between 50 and 600 mg/tablet in the case of the telmisartan layer and between 140 and 1000 mg/tablet in the case of the atorvastatin layer.
  • these mixtures can only be homogenized and compressed in tablets.
  • a more preferable, but more laborious solution consists in forming a two-layer tablet where each layer will contain one of the mixtures.
  • the invention also provides preferable technical parameters of the product. They include sizes of particles of the active substances, sizes of granules where the active substances may be incorporated, as well as of other pharmaceutical additives.
  • composition stability and the required releasing of both the active substances can be best solved by means of tablets composed of two layers one of which contains an atorvastatin mixture and the other contains a telmisartan mixture. If for technical reasons the problem must be solved by means of a tablet that contains both the active substances in one layer, using an alkali salt of telmisartan in the form of particles obtained by spray drying appears to be convenient.
  • Spray drying is preferably carried out in the following manner: Telmisartan is dissolved in water, preferably in a water/ethanol mixture, in the presence of basic substances, such as NaOH, KOH, meglumine, and the like, conveniently only NaOH, and a binder, e.g. povidone, which does not only serve as a binder, but also a stabilizer of the solution. This solution is spray dried.
  • basic substances such as NaOH, KOH, meglumine, and the like, conveniently only NaOH, and a binder, e.g. povidone, which does not only serve as a binder, but also a stabilizer of the solution.
  • a binder e.g. povidone
  • the spray mixture After drying the spray mixture is mixed with a soluble filler selected from saccharides or sugar alcohols, with an atorvastatin salt, which can be in a granulate form, and other auxiliary substances.
  • a soluble filler selected from saccharides or sugar alcohols
  • an atorvastatin salt which can be in a granulate form
  • other auxiliary substances auxiliary substances.
  • the selection of auxiliary substances is in principle equal to the substances for the atorvastatin layer described below.
  • atorvastatin which would not be in the form of granules additives for direct tabletting of atorvastatin are selected. If atorvastatin has the granulate form, the intergranular additives mentioned below are used.
  • the rate of releasing is controlled by the size of particles of the telmisartan spray dried mixture and the auxiliary substance.
  • the first layer contains telmisartan, which is slowly dissolved from the matrix, and the other layer contains atorvastatin; unlike the first one this layer is quickly disintegrated and so atorvastatin is released quickly. With different disintegration rates or washing of individual layers different dissolution profiles can be achieved, which are important for optimum absorption of both the active substances.
  • a filler that is soluble in water on the basis of carbohydrates is used, such as glucose, sucrose, anhydrous lactose or lactose monohydrate and alcoholic sugars such as sorbitol, mannitol, xylitol, or insoluble saccharides such as microcrystalline cellulose and the like.
  • a filler that is soluble in water on the basis of carbohydrates such as glucose, sucrose, anhydrous lactose or lactose monohydrate and alcoholic sugars such as sorbitol, mannitol, xylitol, or insoluble saccharides such as microcrystalline cellulose and the like.
  • sorbitol or microcrystalline cellulose were preferred.
  • an organic or inorganic base may be used as the basic constituent, such as sodium or potassium hydroxide, meglumine, arginine, and the like. Conveniently, a combination of sodium hydroxide and meglumine in a suitable proportion was used.
  • Substances from the group of polyvinyl pyrrolidones can be used as the binders, such as various types of povidones, povidone 25, povidone 30, or povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, e.g. povidone VA 64, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and pregelatinized starch. Out of this group of substances the use of povidone and hydroxypropyl cellulose is preferred.
  • Substances such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate or talc can be used as lubricants. Out of this group of substances mainly magnesium stearate is preferred.
  • the other layer which contains a calcium salt of atorvastatin, gets quickly disintegrated, which means that it quickly releases the active substance.
  • fillers from the group of substances such as pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, sorbitol, xylitol, anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen or dihydrogen calcium phosphate, and the like can be used. Out of this group a mixture of lactose monohydrate and microcrystalline cellulose is preferred for the second layer.
  • excipients that can be used as the basic constituent include an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, etc.
  • an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, etc.
  • meglumine or magnesium oxide can be used.
  • Substances from the group of polyvinyl pyrrolidones are used as the binders, such as various types of povidones, povidone 25, povidone 30, or povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, e.g. povidone VA 64, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and pregelatinized starch. Out of this group of substances the use of hydroxypropyl cellulose is preferred.
  • disintegrants from the group of substances such as maize starch, pregelatinized starch, low substituted hydroxypropyl methylcellulose, microcrystalline cellulose, and further substances from the group of super disintegrants such as sodium salt of crosscarmellose, sodium salt of carboxymethyl starch of type A, B or C, or crosspovidone are used.
  • a mixture of low substituted hydroxypropyl cellulose and sodium salt of crosscarmellose is preferred.
  • colloidal silicon dioxide Colloidal silicon dioxide is conveniently used
  • a substance such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate, talc, cutin, can be used as the lubricant Out of this group of substances mainly magnesium stearate is preferred
  • Purified water or a mixture of water and ethanol, or possibly methanol in various proportions is used as the solvents
  • Preferred solvents are pu ⁇ fied water and ethanol These solvents are lemoved from the tablet mass in the course of the production process by drying For coating of tablets film-forming substances, lubricants, pigments, softeners are used
  • Two-layered tablets in accordance with the invention may contain 10 - 80 mg of telmisartan and 10 - 80 mg of atorvastatin in the calcium salt form Preferably 20, 40 and 80 mg of telmisartan and 10, 20, 40 and 80 mg of atorvastatin in the calcium salt form
  • the telmisartan layer can be prepared by the following procedures:
  • telmisartan in the tablet mass is in the amorphous form
  • Spray drying - Telmisartan is dissolved in water, conveniently in a water/ethanol mixture, in the presence of basic substances such as NaOH, KOH, meglumine, and the like, preferably only NaOH, and a binder, e g povidone, which serves not only as a binder, but also as stabilizer of the solution
  • a binder e g povidone
  • This solution is spray dried After drying the spray mixture is mixed with a soluble filler, such as sorbitol, or an insoluble filler, microcrystalline cellulose with a suitable particle size, and other excipients such as meglumine or magnesium stearate
  • Fluid gianulation - Telmisartan is dissolved in water, conveniently in a water/ethanol mixture in the presence of basic substances such as NaOH, KOH, meglumine, and the like, preferably only NaOH, and a binder, e g povidone, which serves not only as a binder, but also as stabilizer of the solution.
  • a soluble filler such as sorbitol or monosaccharides, or an insoluble filler, e.g. microcrystalline cellulose, is fluid granulated with this solution.
  • the dried and sieved granulate is mixed with a portion of the soluble or insoluble filler with a suitable particle size and with other excipients such as meglumine or magnesium stearate.
  • the particle size of the soluble filler can be in the range of 0 - 355 microns, preferably 100 microns.
  • the particle size of the insoluble filler can be in the range of 0 - 250 microns, preferably 50 microns.
  • An example of using a soluble saccharide as the filler can include sorbitol with the particle size of at most 7% of all particles greater than 315 ⁇ m; 20 to 50% greater than 160 ⁇ m; and at least 80% greater than 40 ⁇ m.
  • Another method of characterization is by means of percentiles, e.g. D50 greater than 125 ⁇ m.
  • an insoluble saccharide as the filler microcrystalline cellulose can by conveniently used with at most 1% by weight of particles greater than 250 ⁇ m; at most 30% greater than 75 ⁇ m and at least 50% greater than 32 ⁇ m.
  • the size of used particles can be characterized by means of percentiles, namely DlO smaller than 30 ⁇ m; D50 in the range of 40-60 ⁇ m and D90 larger than 80 ⁇ m.
  • meglumine as the basic constituent of the telmisartan solution may cause hardening of the granulate after drying, so that it is difficult to process afterwards. This hardening is manifested even after additional mixing with tabletting additives, e.g. magnesium stearate. It has been surprisingly found out that if meglumine is only added in the extragranulation stage, this effect does not appear and the granulate or tablet mass are much easier to process. Description of preparation of the atorvastatin layer:
  • Atorvastatin calcium salt is in the tablets in the amorphous form, or a crystalline modification can be used
  • a/ Granulation by mastication - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose and possibly a poition of crosscarmellose, or magnesium oxide or calcium carbonate
  • This mixture is granulated with an aqueous or spirituous-aqueous solution of meglumine, or with only water oi a water/ethanol mixture
  • the resulting granulate is dned in a fluid way or on metal sheets
  • the dried granulate is sieved to a suitable size of granules, which are subsequently mixed with additional extragranular excipients such as magnesium stearate and colloidal silicon dioxide, or a portion of crosscarmellose
  • b/ Dry granulation - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose and possibly a portion of crosscarmellose, or magnesium oxide or meglumine
  • the resulting mixture is compacted in a suitable compactor or compressed in a tabletting press using large dies
  • the resulting compactates are sieved to a suitable size of granules, which are subsequently mixed with additional extragranular excipients such as magnesium stearate and colloidal silicon dioxide, oi a portion of crosscarmellose
  • c/ Direct mixing - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and possibly a portion of crosscarmellose, or magnesium oxide or meglumine Extragranular excipients such as magnesium stearate and colloidal silicon dioxide, or a portion of crosscarmellose are admixed to the iesulting mixture
  • compositions are compressed to two-layer tablets, which are coated with a coat of a film-forming substance containing softeners, pigments and other fillers
  • the coated tablets are conveniently adjusted into Al/Al blister packs, optionally under an inert atmosphere.
  • the speed of releasing of individual constituents was monitored in a dissolution device with the use of the paddle method in a phosphate buffer with pH 7.5.
  • composition A7 Under these conditions e.g. in the case of composition A7 the following percentages of active constituents were released:
  • T he speed of releasing of individual constituents was monitored in a dissolution device with the use of the paddle method in a phosphate buffer with pH 7.5. Under these conditions e.g. in the case of composition A9 the following percentages of active constituents were released:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
PCT/CZ2009/000138 2008-11-24 2009-11-16 A solid pharmaceutical composition with atorvastatin and telmisartan as the active substances WO2010057449A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2008-740 2008-11-24
CZ20080740A CZ301299B6 (cs) 2008-11-24 2008-11-24 Pevná farmaceutická kompozice s úcinnými látkami atorvastatinem a telmisartanem

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WO2010057449A2 true WO2010057449A2 (en) 2010-05-27
WO2010057449A3 WO2010057449A3 (en) 2011-03-17

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013526516A (ja) * 2010-05-14 2013-06-24 ハンミ・サイエンス・カンパニー・リミテッド ＨＭＧ−ＣｏＡ還元酵素阻害剤及びイルベサルタンを含む二層錠の薬学的剤型
WO2014068507A1 (en) * 2012-11-02 2014-05-08 Abbott Healthcare Pvt. Ltd. Solid oral pharmaceutical compositions of telmisartan, essentially free of surfactants
CN106176658A (zh) * 2016-06-29 2016-12-07 扬子江药业集团四川海蓉药业有限公司 一种阿托伐他汀钙片及其制备方法
WO2019130049A1 (en) 2017-12-29 2019-07-04 Grünenthal GmbH Pharmaceutical combination comprising extended-release tramadol hydrochloride and immediate-release etoricoxib, and its use for the treatment of pain

Citations (7)

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WO1995026188A1 (en) 1994-03-29 1995-10-05 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin ii receptor blocking imidazoles
WO2003059327A1 (en) 2002-01-16 2003-07-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof
WO2004062557A2 (de) 2003-01-16 2004-07-29 Boehringer Ingelheim International Gmbh Pharmazeutische kombination aus telmisartan und atorvastatinph zur prophylaxe oder therapie von kardiovaskulären, kardiopulmonalen, pulmonalen oder renalen krankheiten
WO2004096215A1 (de) 2003-04-30 2004-11-11 Boehringer Ingelheim International Gmbh Pharmazeutische formulierung des telmisartan natriumsalzes
EP1514543A1 (en) 1997-08-29 2005-03-16 Pfizer Inc. Combination therapy comprising atorvastatin and an antihypertensive agent
WO2006048208A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim International Gmbh Bilayer tablet comprising telmisartan and amlodipine
WO2007060170A2 (en) 2005-11-24 2007-05-31 Boehringer Ingelheim International Gmbh Bilayer tablet comprising telmisartan and diuretic

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GT199800126A (es) * 1997-08-29 2000-01-29 Terapia de combinacion.
SE526257C2 (sv) * 2003-12-22 2005-08-09 Operax Ab Metod för att kontrollera vidarebefordringskvaliteten i ett datanät
US20060078615A1 (en) * 2004-10-12 2006-04-13 Boehringer Ingelheim International Gmbh Bilayer tablet of telmisartan and simvastatin
CN101312714A (zh) * 2005-11-22 2008-11-26 特瓦制药工业有限公司 替米沙坦的药用组合物
US8642083B2 (en) * 2006-10-30 2014-02-04 Hanall Biopharma Co., Ltd. Controlled release complex composition comprising angiotensin-II-receptor blockers and HMG-CoA reductase inhibitors
WO2008068217A2 (en) * 2006-12-04 2008-06-12 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a coated hmg-coa reductase inhibitor and an inhibitor of the renin-angiotensin system
CZ300047B6 (cs) * 2007-03-02 2009-01-21 Zentiva, A. S. Farmaceutická kompozice s obsahem úcinné látky atorvastatinu

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995026188A1 (en) 1994-03-29 1995-10-05 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin ii receptor blocking imidazoles
EP1514543A1 (en) 1997-08-29 2005-03-16 Pfizer Inc. Combination therapy comprising atorvastatin and an antihypertensive agent
WO2003059327A1 (en) 2002-01-16 2003-07-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bilayer pharmaceutical tablet comprising telmisartan and a diuretic and preparation thereof
WO2004062557A2 (de) 2003-01-16 2004-07-29 Boehringer Ingelheim International Gmbh Pharmazeutische kombination aus telmisartan und atorvastatinph zur prophylaxe oder therapie von kardiovaskulären, kardiopulmonalen, pulmonalen oder renalen krankheiten
WO2004096215A1 (de) 2003-04-30 2004-11-11 Boehringer Ingelheim International Gmbh Pharmazeutische formulierung des telmisartan natriumsalzes
WO2006048208A1 (en) 2004-11-05 2006-05-11 Boehringer Ingelheim International Gmbh Bilayer tablet comprising telmisartan and amlodipine
WO2007060170A2 (en) 2005-11-24 2007-05-31 Boehringer Ingelheim International Gmbh Bilayer tablet comprising telmisartan and diuretic

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013526516A (ja) * 2010-05-14 2013-06-24 ハンミ・サイエンス・カンパニー・リミテッド ＨＭＧ−ＣｏＡ還元酵素阻害剤及びイルベサルタンを含む二層錠の薬学的剤型
WO2014068507A1 (en) * 2012-11-02 2014-05-08 Abbott Healthcare Pvt. Ltd. Solid oral pharmaceutical compositions of telmisartan, essentially free of surfactants
CN106176658A (zh) * 2016-06-29 2016-12-07 扬子江药业集团四川海蓉药业有限公司 一种阿托伐他汀钙片及其制备方法
WO2019130049A1 (en) 2017-12-29 2019-07-04 Grünenthal GmbH Pharmaceutical combination comprising extended-release tramadol hydrochloride and immediate-release etoricoxib, and its use for the treatment of pain

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CZ301299B6 (cs) 2010-01-06
WO2010057449A3 (en) 2011-03-17

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