WO2011161123A2 - Comprimé pharmaceutique multicouche comprenant du telmisartan et un diurétique - Google Patents

Comprimé pharmaceutique multicouche comprenant du telmisartan et un diurétique Download PDF

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Publication number
WO2011161123A2
WO2011161123A2 PCT/EP2011/060381 EP2011060381W WO2011161123A2 WO 2011161123 A2 WO2011161123 A2 WO 2011161123A2 EP 2011060381 W EP2011060381 W EP 2011060381W WO 2011161123 A2 WO2011161123 A2 WO 2011161123A2
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WO
WIPO (PCT)
Prior art keywords
tablet
layer
filler
tablet layer
diuretic
Prior art date
Application number
PCT/EP2011/060381
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English (en)
Other versions
WO2011161123A3 (fr
Inventor
Gregor Sedmak
Franc Vrecer
Original Assignee
Krka, Tovarna Zdravil, D.D., Novo Mesto
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
Priority claimed from PCT/EP2010/058754 external-priority patent/WO2010146187A2/fr
Application filed by Krka, Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka, Tovarna Zdravil, D.D., Novo Mesto
Priority to EP11728238.4A priority Critical patent/EP2582361B1/fr
Priority to PL11728238T priority patent/PL2582361T3/pl
Publication of WO2011161123A2 publication Critical patent/WO2011161123A2/fr
Publication of WO2011161123A3 publication Critical patent/WO2011161123A3/fr
Priority to HRP20141127AT priority patent/HRP20141127T1/hr

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Classifications

    • 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
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/2013—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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Multilayer pharmaceutical tablet comprising
  • telmisartan and a diuretic
  • the invention relates to a multilayer pharmaceutical tablet comprising telmisartan and a diuretic. It further relates to a process for the preparation of a multilayer pharmaceutical tablet .
  • Telmisartan the chemical name of which is 2- (4- ⁇ [4 -methyl -6- ( l-methylbenzimidazol-2-yl) -2-propylbenzimidazol-l-yl ] -methyl ⁇ - phenyl ) -benzoic acid or 4' - [ (2-n-propyl-4-methyl-6- (1- methylbenzimidazol-2-yl) benzimidazol -1-yl) methyl] biphenyl-2- carboxylic acid, is a non-peptide angiotensin II receptor type ATi antagonist useful for the treatment of hypertension that was originally disclosed in EP 0 502 314 Al and J. Med. Chem.
  • telmisartan is commercially avail- able in particular in its free acid form, which is poorly soluble in neutral or acidic media.
  • telmisartan is typi ⁇ cally formulated together with a basic agent or in the form of a basic salt for improved solubility.
  • Diuretics such as amiloride, chlorothalidone, furosemide, hy ⁇ drochlorothiazide, indapamide or piretanide are therapeutic agents which can also be used in the treatment of hyperten ⁇ sion. It is also known to use combinations of angiotensin II receptor antagonists like telmisartan and diuretics like hy ⁇ drochlorothiazide in the treatment of hypertension in order to achieve a synergistic effect. It is generally desirable for such combination formulations that the diuretic is dissolved more rapidly than the angiotensin II receptor antagonist.
  • Hydrochlorothiazide (HCTZ) , the chemical name of which is 6- chloro-1, l-dioxo-3, 4-dihydro-2H-l , 2, 4-benzothiadiazine-7-sulfon- amide, is a diuretic which is stable in neutral and relatively weak acidic environments, but poorly stable in alkaline envi- ronments.
  • HCTZ is incompatible with basic agents that are commonly used together with the free acid form of telmisartan. This incompatibility is problematic where com ⁇ bination formulations of telmisartan and a base-labile diu ⁇ retic such as HCTZ are concerned.
  • a classical approach is to coat diu ⁇ retic particles with water soluble polymers like hydroxypro- pylcellulose, hydroxypropylmethylcellulose or polyvinylpyr- rolidone.
  • water soluble polymers like hydroxypro- pylcellulose, hydroxypropylmethylcellulose or polyvinylpyr- rolidone.
  • this measure has been found not to suffi ⁇ ciently protect the diuretic from degradation when formulated together with telmisartan as a compressed tablet.
  • the polymeric coating typically results in a reduced dissolu ⁇ tion rate of the diuretic.
  • WO 2003/059327 Al discloses a bilayer tablet comprising a first tablet layer containing telmisartan in a dissolving tablet matrix and a second tablet layer containing a diuretic in a disintegrating tablet matrix.
  • WO 2004/028505 Al, WO 2004/ 096215 Al, WO 2006/063737 Al and WO 2007/060170 A2 describe further embodiments of bilayer tablets.
  • the telmisartan containing layer is based on a composition that is generally pre ⁇ pared using spray-drying or fluid bed granulation.
  • the diuretic containing layer is based on a composition that is par- ticularly prepared by mixing or granulation of a diuretic with the constituents of a disintegrating tablet matrix.
  • WO 2007/144175 A2 discloses a pharmaceutical composition com ⁇ prising first units in the form of granules, pellets or tablet cores comprising telmisartan and second units in the form of granules, pellets, or tablet cores comprising HCTZ .
  • the first and second units can be compressed into tablets together with a suitable carrier such that the units are substantially evenly distributed throughout the tablets.
  • the first and sec ⁇ ond units are optionally coated.
  • a separating coating of the first units is contemplated.
  • poly ⁇ vinylpyrrolidone should be incorporated into the HCTZ contain- ing part of the composition in order to achieve better stabil ⁇ ity.
  • the invention also re ⁇ lates to a process for the preparation of a multilayer pharma ⁇ ceutical tablet comprising telmisartan and a diuretic.
  • the invention relates to a multilayer pharma ⁇ ceutical tablet comprising
  • telmisartan 1 to 50 wt.-% telmisartan or a pharmaceutically acceptable salt thereof by weight of the first tablet layer
  • the invention also relates to a multilayer pharmaceutical tab ⁇ let comprising
  • telmisartan 1 to 50 wt.-% telmisartan or a pharmaceutically acceptable salt thereof by weight of the first tablet layer
  • the invention also relates to a process for the preparation of a multilayer pharmaceutical tablet comprising at least one layer comprising telmisartan and at least one layer comprising a diuretic, the process comprising
  • the invention also relates to a process for the preparation of a multilayer pharmaceutical tablet comprising at least one layer comprising telmisartan and at least one layer comprising a diuretic, the process comprising
  • the invention relates to a multilayer phar ⁇ maceutical tablet comprising (a) at least one first tablet layer comprising
  • telmisartan 1 to 50 wt.-% telmisartan or a pharmaceutically acceptable salt thereof by weight of the first tablet layer
  • multilayer pharmaceutical tablet refers to a pharmaceutical tablet which is made up of at least two distinct layers, such as at least two layers, at least three layers, at least four layers, at least five layers, etc., with the individual layers being arranged one on top of another.
  • the multilayer tablet generally has a sandwich-like appearance because the edges of each layer are exposed. Typi ⁇ cally, adjacent layers of the tablet will be of different com- position.
  • first tablet layer and second tablet layer refer to tab ⁇ let layers having a particular composition. However, these terms do not necessarily reflect the order in which the layers are arranged in the tablet.
  • the multilayer pharmaceu ⁇ tical tablet of the invention exhibits a dissolution profile that is comparable to the one typically found for tablets con ⁇ taining telmisartan in a dissolving tablet matrix and a diu- retic in a disintegrating tablet matrix.
  • the first tablet layer comprises telmisartan or a pharmaceuti ⁇ cally acceptable salt thereof. Telmisartan is typically em ⁇ ployed in its free acid form although pharmaceutically accept- able salts can also be used.
  • the first tablet layer preferably comprises 3 to 50 wt.-%, particularly 5 to 35 wt.-%, more preferably 10 to 20 wt.-% of telmisartan or a pharmaceutically acceptable salt thereof.
  • the first tablet layer comprises telmisartan and a basic agent.
  • basic agent refers to a substance which is characterized in that a 3 wt.-% aqueous solution thereof has a pH value of at least 8.0.
  • Suitable basic agents include ammonia, NaOH, KOH, Ca(OH) 2 , Na 2 C0 3 , K 2 C0 3 , NaHC0 3 , KHCO3 , Na 3 P0 4 , K3PO4, Na 2 HP0 4 , K 2 HP0 4 , cho ⁇ line, tert-butylamine, ethanolamine, meglumine, piperazine, diethylamine, L-arginine and mixtures thereof.
  • Alkali metal hydroxides such as NaOH and KOH, amino sugars such as meglu ⁇ mine and mixtures thereof are preferred basic agents. It is particularly preferred that the basic agent comprises a mix ⁇ ture of an alkali metal hydroxide such as NaOH or KOH and an amino sugar such as meglumine in a weight ratio of 1:1 to 1:10, more particularly 1:2 to 1:5, more preferably 1:3 to 1:4, most preferably about 1:3.5.
  • the first tablet layer pref ⁇ erably comprises 0.25 to 20 wt.-%, particularly 1 to 15 wt.-%, more preferably 2 to 10 wt.-% of basic agent.
  • the telmisartan can be amorphous or crystalline.
  • amorphous includes amorphous and partly crystallized forms.
  • Amorphous telmisartan can be obtained by methods generally known in the art such as freeze drying of aqueous solutions, coating of carrier particles by a solution of telmisartan in a fluidized bed, and solvent deposition on sugar pellets or other carriers.
  • the first tablet layer com ⁇ prises a pharmaceutically acceptable salt of telmisartan.
  • Suitable pharmaceutically acceptable salts include alkaline salts such as the sodium salt of telmisartan.
  • the pharmaceuti- cally acceptable salt of telmisartan can be amorphous or crys ⁇ talline .
  • the first tablet layer can comprise pharmaceuti- cally acceptable excipients.
  • pharmaceutical accept ⁇ able excipient refers to additives useful for converting pharmacologically active compounds into pharmaceu ⁇ tical dosage forms which are suitable for administration to patients.
  • Excipients suitable for use in the first tablet layer include fillers, binders, surfactants, crystallization retarders, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included.
  • the first tablet layer typically comprises at least one filler.
  • Water-soluble fillers are generally preferred.
  • Suit ⁇ able fillers for use in the first tablet layer include mono ⁇ saccharides, oligosaccharides and sugar alcohols such as glu ⁇ cose, fructose, saccharose, lactose (anhydrous and monohy- drate) , raffinose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible sugar, calcium hydrogen phosphate, calcium carbonate, calcium lactate and mixtures thereof.
  • Preferred fillers are monosaccharides and oligosaccharides such as glucose, fructose, saccharose and lactose, sugar alcohols such as mannitol, erythritol, sorbi- tol, maltitol, xylitol and lactitol and mixtures thereof. Lac ⁇ tose, sorbitol and mixtures thereof are particularly pre ⁇ ferred. It is particularly preferred that the filler comprises a monosaccharide or oligosaccharide such as lactose and a sugar alcohol such as sorbitol in a weight ratio of 1:1 to 1:10, particularly 1:2 to 1:5, most preferably about 1:2.5.
  • the first tablet layer preferably comprises 30 to 95 wt.-%, particularly 60 to 90 wt.-%, more preferably 70 to 80 wt.-% of filler .
  • Suitable binders for use in the first tablet layer include povidone (polyvinylpyrrolidone) , copovidone (vinylpyrrolidone- vinylacetate copolymer) , cellulose powder, crystalline cellu ⁇ lose, microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellu- lose, hydroxyethylcellulose, hydroxypropylcellulose and hy- droxypropylmethylcellulose, starch, pregelatinized starch, po- lymethacrylates and mixtures thereof. Povidone is particularly preferred.
  • the first tablet layer preferably comprises 1 to 30 wt.-%, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt . - % of binder.
  • Suitable surfactants for use in the first tablet layer include anionic, cationic, ampholytic and non-ionic surfactants such as sodium lauryl sulfate, cetrimide, N-dodecyl-N, N-dimethyl- betaine, polysorbates (such as Tweens®) , poloxamers and mix ⁇ tures thereof. Non-ionic surfactants such as polysorbates and poloxamers are preferred.
  • the first tablet layer preferably comprises 0 to 30 wt.-% like 1 to 30 wt.-%, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt.-% of surfactant.
  • Suitable crystallization retarders for use in the first tablet layer include povidone, copovidone, crospovidone, carboxy- methylcellulose sodium, hydroxypropylcellulose and hydroxypro- pylmethylcellulose .
  • the first tablet layer preferably com- prises 0 to 10 wt.-% like 0.1 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 2 wt.-% of crystallization retarder .
  • Suitable lubricants for use in the first tablet layer include stearic acid and stearic acid salts such as magnesium stearate, magnesium palmitate and magnesium oleate, hydrogen- ated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof. Stearic acid, magnesium stearate and hydrogenated vegetable oil are particularly preferred.
  • the first tablet layer preferably com ⁇ prises 0.1 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 2 wt.-% of lubricant.
  • Suitable glidants for use in the first tablet layer include colloidal silicon dioxide and magnesium trisilicate.
  • the first tablet layer preferably comprises 0 to 10 wt.-% like 0.1 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 2 wt.-% of glidant.
  • Suitable coloring agents for use in the first tablet layer in ⁇ clude dyes and pigments such as iron oxide and titanium oxide.
  • the first tablet layer preferably comprises 0 to 1 wt.-% like 0.001 to 1 wt.-%, particularly 0.01 to 0.5 wt.-%, more pref ⁇ erably 0.05 to 0.2 wt.-% of coloring agent.
  • the first tablet layer comprises
  • the first tablet layer comprises
  • filler 30 to 95 wt.-%, particularly 60 to 90 wt.-%, more pref ⁇ erably 70 to 80 wt.-% of filler, wherein said filler is preferably selected from monosaccharides and oligosaccha ⁇ rides such as glucose, fructose, saccharose and lactose, sugar alcohols such as mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol and mixtures thereof, and is more preferably selected from lactose, sorbitol and mixtures thereof;
  • binder 1 to 30 wt.-%, particularly 2 to 10 wt.-%, more prefera ⁇ bly 3 to 7 wt.-% of binder, wherein said binder is pref- erably selected from povidone, copovidone cellulose pow ⁇ der, crystalline cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose deriva ⁇ tives such as hydroxymethylcellulose, hydroxyethylcellu- lose, hydroxypropylcellulose and hydroxypropylmethylcel- lulose, starch, pregelatinized starch, polymethacrylates and mixtures thereof, and is more preferably selected from povidone;
  • lubri- cant is preferably selected from stearic acid and stearic acid salts such as magnesium stearate, magnesium palmi- tate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof, and is more preferably selected from magnesium stearate, sodium stearyl fumarate and mixtures thereof; and
  • the second tablet layer comprises a diuretic and at least one filler.
  • Preferred diuretics include amiloride, chlorothali- done, furosemide, hydrochlorothiazide, indapamide or piretanide.
  • Hydrochlorothiazide (HCTZ) is particularly pre ⁇ ferred .
  • the diuretic has preferably an average particle size of less than 80 ym, particularly less than 50 ym, more preferably less than 30 ym.
  • average particle size refers to the volume mean diameter of particles.
  • the volume mean diameter can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit.
  • the second tablet layer comprises at least one filler, wherein the combined weight of the diuretic and the at least one filler is at least 87 wt.-% by weight of the second tablet layer. It is particularly preferred that the combined weight of the diuretic and the filler is at least 90 wt . ⁇ 6 , more preferably at least 93 wt.-%, further more preferably at least 95 wt.-%, like at least 96 wt.-% or at least 97 wt.-% such as at least 98 wt.-%, and most preferably at least 99 wt.-% by weight of the second tablet layer.
  • Water-soluble fillers are generally preferred. Suitable fill- ers for use in the second tablet layer include monosaccha ⁇ rides, oligosaccharides and sugar alcohols such as glucose, fructose, saccharose, lactose (anhydrous and monohydrate) , raffinose, trehalose, dextrates, mannitol, erythritol, sorbi ⁇ tol, maltitol, xylitol and lactitol, compressible sugar, cal- cium hydrogen phosphate, calcium carbonate, sodium carbonate in anhydrous or hydrated form, sodium hydrogen carbonate, cal ⁇ cium lactate and mixtures thereof.
  • monosaccha ⁇ rides oligosaccharides and sugar alcohols such as glucose, fructose, saccharose, lactose (anhydrous and monohydrate) , raffinose, trehalose, dextrates, mannitol, erythritol
  • Preferred fillers are mono ⁇ saccharides and oligosaccharides such as glucose, fructose, saccharose and lactose, sugar alcohols such as mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol and mix ⁇ tures thereof.
  • sugar alcohols like mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol and mix ⁇ tures thereof are used as a filler in the second tablet layer.
  • Mannitol is a particularly preferred filler of the second tab- let layer.
  • the second tablet layer preferably comprises 50 to 99 wt.-%, particularly 80 to 98 wt.-%, more preferably 90 to 96 wt.-% of filler.
  • the second tablet layer can generally comprise additional pharmaceutically acceptable excipients.
  • Additional excipients suitable for use in the second tablet layer may include bind ⁇ ers, surfactants, lubricants, glidants and coloring agents.
  • Suitable binders for use in the second tablet layer include povidone (polyvinylpyrrolidone) , copovidone (vinylpyrrolidone- vinylacetate copolymer) , polyvinyl alcohol, graft copolymer of polyethyleneglycol and polyvinyl alcohol obtainable as Kolli- coat IR, polyethylene glycol having a molecular weight in the range of 200 to 10, 000, preferably in the range 1, 000 to 8,000, cellulose powder, crystalline cellulose, microcrystal- line cellulose, siliconized microcrystalline cellulose, cellu ⁇ lose derivatives such as hydroxymethylcellulose, hydroxyethyl- cellulose, hydroxypropylcellulose and hydroxypropylmethylcel- lulose, starch, pregelatinized starch, polymethacrylates and mixtures thereof.
  • povidone polyvinylpyrrolidone
  • copovidone vinylpyrrolidone- vinylacetate copolymer
  • polyvinyl alcohol graft cop
  • the second tablet layer can comprise 0.1 to 20 wt.-% like 0.5 to 20 wt.-% or 1 to 20 wt . - %, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt.-% of binder.
  • water soluble binders such as povidone (polyvinylpyrrolidone) , copovidone (vinylpyrrolidone- vinylacetate copolymer) , polyvinyl alcohol, graft copolymer of polyethyleneglycol and polyvinyl alcohol obtainable as Kolli- coat IR, polyethyleneglycol with molecular weight in the range of 200 to 10,000, preferably in the range 1,000 to 8,000, hy- droxypropylmethylcellulose having a viscosity (2 wt/vol% solu- tion in water at 25°C) of less than 50 mPas, preferably of less than 15 mPas can be used.
  • povidone polyvinylpyrrolidone
  • copovidone vinylpyrrolidone- vinylacetate copolymer
  • polyvinyl alcohol graft copolymer of polyethyleneglycol and polyvinyl alcohol obtainable as Kolli- coat IR
  • hydroxypropyl ⁇ cellulose such as hydroxypropylcellulose having a viscosity of about 100 to 800 mPas when measured in a 10 wt.-% solution in ethanol and determined at 25°C using a Brookfield LVF vis- cosimeter with spindle, is used as binder in the second tablet layer. It is particularly preferred that the second tablet layer comprises 0.1 to 1 wt.-% of hydroxypropylcellulose.
  • Suitable surfactants for use in the second tablet layer in- elude anionic, cationic, ampholytic and non-ionic surfactants such as sodium lauryl sulfate, cetrimide, N-dodecyl-N, N- dimethylbetaine, polysorbates (such as Tweens®) , poloxamers and mixtures thereof.
  • Non-ionic surfactants such as polysor ⁇ bates and poloxamers are preferred.
  • the second tablet layer can comprise 1 to 30 wt.-%, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt.-% of surfactant.
  • Suitable lubricants for use in the second tablet layer include stearic acid or stearic acid salts, such as magnesium stearate, magnesium palmitate and magnesium oleate, hydrogen- ated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof. Stearic acid, magnesium stearate and hydrogenated vegetable oil are particularly preferred.
  • the second tablet layer can comprise 0.1 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 2 wt.-% of lubricant, such as sodium stearyl fumarate.
  • Suitable glidants for use in the second tablet layer include colloidal silicon dioxide and magnesium trisilicate.
  • the second tablet layer can comprise 0.1 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 2 wt.-% of glidant.
  • Suitable coloring agents for use in the second tablet layer include dyes and pigments such as iron oxide and titanium ox ⁇ ide.
  • the second tablet layer can comprise 0.001 to 1 wt.-%, particularly 0.01 to 0.5 wt.-%, more preferably 0.1 to 0.4 or 0.05 to 0.2 wt.-% of coloring agent.
  • the second tablet layer comprises
  • (cc) 0 to 30 wt.-%, particularly 2 to 10 wt.-%, more prefera ⁇ bly 3 to 7 wt.-% of surfactant;
  • the second tablet layer comprises
  • binder preferably selected from povidone, copovidone, polyvinyl alcohol, graft copolymer of polyethyleneglycol and polyvinyl alcohol obtainable as Kollicoat IR, polyethylene glycol having a molecular weight in the range of 200 to 10, 000, preferably in the range 1,000 to 8,000, cellulose powder, crystalline cel ⁇ lulose, microcrystalline cellulose, siliconized micro- crystalline cellulose, cellulose derivatives such as hy- droxymethylcellulose, hydroxyethylcellulose, hydroxypro- pylcellulose and hydroxypropylmethylcellulose, polyme- thacrylates and mixtures thereof, and more preferably hy- droxypropylcellulose ;
  • lubricant preferably selected from stearic acid, stearic acid salts, hydrogenated vege ⁇ table oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof;
  • glidant preferably selected from colloidal silicon dioxide and magnesium trisilicate ; and (ff) 0 to 1 wt.-%, particularly 0.01 to 0.8 wt.-%, more pref ⁇ erably 0.1 to 0.7 wt.-% of coloring agent.
  • the second tablet layer does not comprise sub ⁇ stantial amounts of disintegrant . It is further preferred that the second tablet layer comprises less than 2 %, particularly less than 1 %, more preferably less than 0.5 %, most prefera- bly less than 0.1 % by weight of the second tablet layer of a disintegrant. According to a particularly preferred embodi ⁇ ment, the second tablet layer is substantially free of disin ⁇ tegrant .
  • disintegrant refers to any material that has wicking and/or swelling properties when it comes in contact with water.
  • disintegrant re ⁇ fers to the group of compounds consisting of crospovidone, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, carboxymethylcellulose sodium and calcium, cross- linked carboxymethylcellulose sodium, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium and calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan and alginic acid.
  • disin- tegrant refers to the group of compounds consisting of povi ⁇ done, crospovidone, starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cel ⁇ lulose, carboxymethylcellulose sodium and calcium, cross- linked carboxymethylcellulose sodium, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium and calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan and alginic acid.
  • the second tablet layer consists of a diuretic and at least one filler.
  • the second tablet layer comprises at least one binder.
  • the second tablet layer comprises granules and an extragranular phase.
  • the granules comprise a diuretic, and in particular hy ⁇ drochlorothiazide, at least one filler, at least one binder and optionally further excipients like a coloring agent.
  • the extragranular phase of the sec ⁇ ond tablet layer comprises at least one filler, at least one lubricant and optionally addi ⁇ tional excipients such as at least one coloring agent and at least one glidant. More preferably, the extragranular phase comprises at least one filler, at least one lubricant, at least one coloring agent and at least one glidant.
  • the at least one filler of the extragranular phase can be the same as or different from the filler of the granules.
  • the filler of the extragranular phase is the same as the filler of the granules.
  • preferred embodiments with regard to specific components and their amounts are described above.
  • the filler used in the granules and in the extra ⁇ granular phase is a sugar alcohol and more particularly manni- tol. It is further preferred that the combined weight of the diuretic, the at least one filler of the granules and the at least one filler of the extragranular phase is at least 94 wt.-%, more preferably at least 95 wt.-% and most preferably at least 96 wt.-% such as about 97 wt.-% of the second tablet layer.
  • the combined weight of the diuretic and the at least one sugar alcohol, such as mannitol, of the granules and the extragranular phase is at least 94 wt.-%, more preferably at least 95 wt.-% and most preferably at least 96 wt.-% such as about 97 wt.-% of the second tablet layer.
  • the combined weight of the filler, and in particular the sugar alcohol such as mannitol, of the granules and the filler, and in particular the sugar alcohol such as mannitol, of the extragranular phase is at least 85 wt.-%, preferably at least 87 wt.-%, more pref ⁇ erably at least 88 wt.-% like at least 89 wt.-% or at least 92 wt.-% of the second tablet layer.
  • the weight ratio of the filler, and in particular the sugar alcohol such as mannitol, of the granules to the filler, and in particular the sugar alcohol such as mannitol, of the ex- tragranular phase is preferably ranging from 1:1 to 1:10, more preferably from 1:3 to 1:6, and most preferably from 1:4 to 1:5.
  • the weight ratio of the diuretic, and in particular the hydrochlorothiazide, of the granules to the filler, and in particular the sugar alcohol such as mannitol, of the granules is preferably ranging from 1:1 to 1:10, more preferably from 1:1.5 to 1:6, and most preferably from 1:2 to 1:4.5.
  • the weight ratio of the binder, and in particular hydroxypropylcellulose, of the granules to the filler, and in particular the sugar alcohol such as mannitol, of the granules is preferably ranging from 1:8 to 1:100, more preferably from 1:20 to 1:50, and most preferably from 1:30 to 1:40.
  • the weight ratio of the binder, and in particular hydroxypropylcellulose, of the granules to the filler, and in particular the sugar alcohol such as mannitol, of the granules and the extragranular phase i.e. the weight ratio of the amount of binder to the total amount of filler, is ranging from 1:50 to 1:400, more preferably from 1:130 to 1:280, and most preferably from 1:150 to 1:250.
  • the second tablet layer preferably comprises (A) granules comprising, based on the total weight of the sec ⁇ ond tablet layer,
  • binder preferably selected from povidone, copovidone, polyvinyl alcohol, graft copolymer of polyethyleneglycol and polyvinyl alcohol obtainable as Kollicoat IR, polyethylene glycol having a molecular weight in the range of 200 to 10, 000, preferably in the range 1,000 to 8,000, cellulose powder, crystalline cel ⁇ lulose, microcrystalline cellulose, siliconized micro- crystalline cellulose, cellulose derivatives such as hy- droxymethylcellulose, hydroxyethylcellulose, hydroxypro- pylcellulose and hydroxypropylmethylcellulose, polyme- thacrylates and mixtures thereof, and more preferably hy- droxypropylcellulose ; and
  • filler preferably selected from a sugar alcohol like mannitol
  • filler preferably selected from a sugar alcohol like mannitol
  • lubricant preferably selected from stearic acid, stearic acid salts, hydrogenated vege ⁇ table oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof;
  • glidant preferably selected from colloidal silicon dioxide and magnesium trisilicate ;
  • (dd) 0 to 1 wt.-%, particularly 0.01 to 0.8 wt.-%, more pref ⁇ erably 0.1 to 0.7 wt.-% of coloring agent, preferably se ⁇ lected from iron oxide and titanium dioxide.
  • the second tablet layer comprises
  • (B) an extragranular phase comprising, based on the total weight of the second tablet layer, (aa) 30 to 90 wt.-%, particularly 50 to 85 wt.-%, more pref ⁇ erably 65 to 80 wt.-% of filler, preferably a sugar alco ⁇ hol like mannitol;
  • (cc) 0 to 10 wt.-%, particularly 0.01 to 5 wt.-%, more pref ⁇ erably 0.05 to 0.5 wt.-% of glidant, preferably colloidal silicon dioxide; and
  • (dd) 0 to 1 wt.-%, particularly 0.01 to 0.8 wt.-%, more pref ⁇ erably 0.1 to 0.7 wt.-% of coloring agent, preferably iron oxide.
  • the multilayer pharmaceutical tablet according to the invention comprises more than two layers
  • various embodiments are possible with respect to the composition and order of ar ⁇ rangement of layers.
  • the multilayer phar ⁇ maceutical tablet is a three-layer tablet
  • the tablet com ⁇ prises an additional layer in addition to a first tablet layer and a second tablet layer as defined above.
  • the additional layer can be a further first tablet layer or a further second tablet layer as defined above.
  • a three-layer tablet can have one first tablet layer arranged between two second tablet layers or one second tablet layer arranged be- tween two first tablet layers.
  • the additional layer can be a layer differing in composition from both the first tablet layer as well as the second tablet layer.
  • the additional layer can be a telmisartan containing layer of different composition than the first tablet layer or a diuretic containing layer of different composition that the second tablet layer. It can also be a layer containing neither telmisartan nor diuretic.
  • the multilayer pharmaceutical tablet is a bilayer tablet having a first tablet layer com ⁇ prising telmisartan and a second tablet layer comprising a diuretic as defined above.
  • the multilayer pharmaceutical tablet is a three-layer tablet having a first tablet layer comprising telmisartan arranged between two second tablet layers comprising a diuretic.
  • the invention relates to a multilayer pharmaceutical tablet comprising
  • telmisartan 1 to 50 wt.-% telmisartan or a pharmaceutically acceptable salt thereof by weight of the first tablet layer
  • the second tablet layer com ⁇ prises less than 2 wt.-%, in particular less than 1 wt.-%, more preferably less than 0.5 wt.-%, most preferably less than 0.1 wt.-% by weight of the second tablet layer of one or more disintegrants selected from the group consisting of crospovi- done, pregelatinized starch, sodium starch glycolate, hy- droxypropyl starch, carboxymethylcellulose sodium and calcium, cross-linked carboxymethylcellulose sodium, polacrilin potas ⁇ sium, low-substituted hydroxypropylcellulose, sodium and cal- cium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan and alginic acid.
  • disintegrants selected from the group consisting of crospovi- done, pregelatinized starch, sodium starch glycolate, hy- droxypropyl starch, carboxymethylcellulose sodium and
  • the second tablet layer comprises less than 2 wt.-%, in particular less than 1 wt.-%, more preferably less than 0.5 wt.-%, most preferably less than 0.1 wt.-% by weight of the second tablet layer of one or more disintegrants se ⁇ lected from the group consisting of povidone, crospovidone, starch, pregelatinized starch, sodium starch glycolate, hy- droxypropyl starch, microcrystalline cellulose, carboxymethyl- cellulose sodium and calcium, cross-linked carboxymethylcellu- lose sodium, polacrilin potassium, low-substituted hydroxypro- pylcellulose, sodium and calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan and alginic acid.
  • the second tablet layer comprises less than 1 wt.-%, more preferably less than 0.5 wt.-%, most preferably less than 0.1 wt.-% of disintegrant by weight of the second tablet layer.
  • the second tablet layer is substantially or en- tirely free of disintegrant.
  • the multilayer pharmaceutical tablet of the invention comprising only low amounts of or being substantially free of disintegrant can be formulated very effec- tively.
  • the multilayer pharmaceutical tablet thus formulated exhibits a dissolution profile that is compa ⁇ rable to the one typically found for tablets containing tel- misartan in a dissolving tablet matrix and a diuretic in a disintegrating tablet matrix.
  • the multilayer pharmaceutical tablet according to the inven ⁇ tion can be prepared in principle by any method used for manu ⁇ facturing tablet formulations.
  • Preparation of the tablet gen ⁇ erally comprises preparing a first tablet layer composition comprising telmisartan and a second tablet layer composition comprising a diuretic and compressing the tablet layer compo ⁇ sitions to produce a multilayer tablet.
  • the first tablet layer composition comprising telmisartan can be prepared by various methods. Suitable methods include spray-drying and fluid-bed granulation.
  • One method for preparing the first tablet layer composition comprises preparing a spray-solution by dissolving telmisartan together with at least one basic agent in an appropriate sol ⁇ vent (e.g. water or organic solvent).
  • an appropriate sol ⁇ vent e.g. water or organic solvent.
  • additional excipients such as a crystallization retarder and/or a surfactant can be included in the spray-solution.
  • the spray solu ⁇ tion is subsequently spray-dried to give a spray-dried granu- late.
  • the spray-dried granulate is mixed with further excipi ⁇ ents to give a tablet layer composition ready for tableting.
  • Another method for preparing the first tablet layer composi ⁇ tion comprises preparing a granulation liquid by dissolving telmisartan together with at least one basic agent in an appropriate solvent (e.g. water or organic solvent).
  • an appropriate solvent e.g. water or organic solvent.
  • additional excipients such as a crystallization retarder and/or a surfactant can be included in the spray-solution.
  • At least one excipient selected from fillers, binders and mix- tures thereof is placed into a fluid-bed granulating machine and sprayed with the granulation liquid.
  • the granulate is dried and optionally mixed with further excipients to give a tablet layer composition ready for tableting.
  • the second tablet layer composition comprising a diuretic can also be prepared by various methods such as direct compres ⁇ sion, compression of a granulate obtained by state of the art processes like wet, dry or thermoplastic granulation or melt extrusion.
  • the second tablet layer composition can in a first embodiment of the present invention be prepared using a wet granulation technique.
  • a suitable wet granulation technique comprises preparing a granulation liquid by dissolving at least a part of a filler and/or binder in an appropriate solvent (e.g. water, organic solvent or a mixture thereof) and adding like spraying the granulation liquid onto a premix comprising diuretic and optionally additional excipients.
  • the obtained wet granulate is dried, optionally sieved and option ⁇ ally mixed with further excipients to give a tablet layer com ⁇ position ready for tableting.
  • the invention also relates to a process for the prepara ⁇ tion of a multilayer pharmaceutical tablet comprising at least one layer comprising telmisartan and at least one layer comprising a diuretic, the process comprising providing a first tablet layer composition comprising tel misartan; providing a second tablet layer composition comprising a diuretic by
  • the granulating in step (b) (i) is a wet granula ⁇ tion step.
  • the at least one binder is dissolved in a granulation liquid like water and the obtained solution is used to granulate the diuretic, the at least one filler and the optional other excipients such as a coloring agent.
  • the obtained granules are optionally dried and/or sieved prior to the blending in step (b) (ii) .
  • the optional other pharmaceuti ⁇ cally acceptable excipients used in step (b) (ii) preferably include at least one glidant, at least one lubricant and at least one coloring agent.
  • Preferred embodiments of the first tablet layer composition comprising telmisartan with regard to specific components and their amounts as well as to methods for its preparation are as described above.
  • the first and second tablet layer compositions and op ⁇ tionally further tablet layer compositions are compressed in a multilayer tableting mode as described in more detail below.
  • the invention also relates to a multilayer pharmaceutical tab ⁇ let prepared by the process according to the invention.
  • the second tablet layer com ⁇ position is prepared using a dry granulation method as described below.
  • the invention also relates to a process for the prepara ⁇ tion of a multilayer pharmaceutical tablet comprising at least one layer comprising telmisartan and at least one layer comprising a diuretic, the process comprising
  • Preferred embodiments of the first tablet layer composition comprising telmisartan with regard to specific components and their amounts as well as to methods for its preparation are as described above.
  • Preferred embodiments of the second tablet layer composition with regard to specific components and their amounts are as described above. It has surprisingly been found that a process for the prepara ⁇ tion of a multilayer tablet, wherein a dry granulation method is used for preparing the second tablet layer composition comprising a diuretic, provides a number of advantages. Such process is particularly suitable for application on an indus- trial scale. In particular, the process is simple and highly cost effective.
  • the tablet layer composition ready for tablet- ing which is obtained according to the process exhibits excel ⁇ lent physical characteristics particularly with regard to flowability and provides for very fast dissolution of the diu- retic in the final tablet.
  • the second tablet layer composition is prepared by mixing the diuretic and at least one filler in a suitable mixer in order to prepare a pre-mixture.
  • the pre-mixture is then compacted on a dry granulation machine and the compact milled into granules of appropriate particle size. It is pre ⁇ ferred that the compact is milled into granules having an av ⁇ erage particle size of less than 80 ym, particularly less than 50 ym, more preferably less than 30 ym.
  • the first and second tablet layer compositions and op ⁇ tionally further tablet layer compositions are compressed in a multilayer tableting mode as described in more detail below.
  • the invention also relates to a multilayer pharmaceutical tab ⁇ let prepared by the process according to the invention.
  • the second tablet layer com- position is prepared using a thermoplastic granulation, wherein a mixture of diuretic and least one exipient is granu ⁇ lated with a binder having a melting or softening point below 170°C, preferably below 150°C and most preferably below 130°C.
  • Suitable binders having low melting or softening point can be selected from polymers such as, but not limited to, polyethyl ⁇ ene glycol having a molecular weight in the range 1,000 to 10, 000, poloxamer, povidone with a K value of less than 50, copovidone, Soluplus ® or mixtures thereof.
  • thermoplastic granu ⁇ lates can be used in preparation of thermoplastic granu ⁇ lates.
  • Agglomeration can be achieved by adding melted binder or by in situ melting or softening of a binder having low melting or softening point.
  • In situ melting can be achieved by heating the components to the temperature of at least 5 de- grees (°C) above the melting or softening temperature of a binder or by heat release due to mixing the powders or ele ⁇ vated pressure.
  • the obtained granulate can optionally be mixed with further excipients and compressed into multilayer tablet.
  • the second tablet layer com ⁇ position is prepared using a direct compression method where a powder premix of diuretic and at leas one further exicient se ⁇ lected from filler, binder, lubricant, glidant and mixtures thereof is directly compressed onto the first layer containing telmisartan.
  • the first and second tab ⁇ let layer compositions can be compressed in a manner generally known in the art, such as using a rotary tablet press in an appropriate multilayer tableting mode.
  • the first tablet layer compo ⁇ sition comprising telmisartan can be introduced into the tableting machine first, followed by introducing the second tab- let layer composition comprising diuretic and compressing the two layers in a bilayer tableting mode.
  • part of the second tablet layer composition comprising diuretic can be introduced into the tableting machine first, followed by introducing the first tablet layer composition comprising telmisartan and then the remaining second tablet layer composition comprising diuretic and compressing all three layers in a three layer tableting mode .
  • the invention will be further illustrated by way of the fol ⁇ lowing examples.
  • Example 1 Bilayer tablet - Dry granulation
  • Bilayer tablet composition comprising 80 mg telmisartan and 12.5 mg HCTZ:
  • Hydrochlorothiazide (HCTZ) was mixed with mannitol and com- pacted in a dry granulation apparatus.
  • the obtained compact was milled into granules having an average particle size (vol ⁇ ume mean diameter) of less than 30 ym.
  • the particle size was determined by laser light scattering using a Malvern Master- sizer Apparatus MS 2000 equipped with a Hydro S dispersion unit. Vegetable oil was used as the dilution medium.
  • a tablet layer composition containing only HCTZ and mannitol was obtained .
  • Bilayer tablets containing telmisartan and HCTZ were prepared by first introducing the telmisartan containing tablet layer composition into the tableting machine, followed by the HCTZ containing tablet layer composition. These two layers were then compressed on a rotary tablet press in a bilayer tablet ⁇ ing mode.
  • the dissolution profile of the finished bilayer tablet was de ⁇ termined in simulated gastric fluid (pH 2.0, USP apparatus II, 50 rpm) .
  • the dissolution profiles thus obtained are shown in Figure 1 (dissolution profile of telmisartan) and Figure 2 (dissolution profile of HCTZ) .
  • the dissolution profiles are comparable to that of commercially available Micardis Plus tablets .
  • Example 2 Bilayer tablet - Fluid bed granulation
  • the telmisartan layer was the same as from Example 7.
  • Hydrochlorothiazide and mannitol were granulated with hy ⁇ droxypropyl cellulose or povidone dissolved in water.
  • the ob ⁇ tained granulate was dried in a fluid bed dryer.
  • the obtained granulate was then mixed with additional mannitol (if applica ⁇ ble) , Aerosil 200 and magnesium stearate to form final compo ⁇ sition ready for tableting.
  • Bilayer tablets containing telmisartan and HCTZ were prepared by first introducing the telmisartan containing mixture ready for tableting into the tableting machine, followed by intro ⁇ ducing the HCTZ containing mixture ready for tableting. These two layers were then compressed on a rotary tablet press in a bilayer tableting mode.
  • Example 3 Bilayer tablet - Direct compression
  • the telmisartan layer was the same as from Example 7.
  • Hydrochlorothiazide was mixed with either xylitol, lactose monohydrate or mannitol as well as together with Aeroperl 300 and sodium stearyl fumarate to form a final composition ready for tableting by direct compression.
  • Bilayer tablets containing telmisartan and HCTZ were prepared by firstly introducing the telmisartan containing mixture ready for tableting into the tableting machine, followed by introducing the HCTZ containing mixture ready for tableting. These two layers were then compressed on a rotary tablet press in a bilayer tableting mode.
  • Telmisartan, sodium hydroxide and povidone were dissolved in water to obtain a granulation liquid. Lactose monohydrate and meglumine were placed in a fluid-bed granulating machine and sprayed with granulation liquid. When granulation was completed the granulate was dried and mixed with sorbitol, magne ⁇ sium stearate and sodium stearyl fumarate to form final compo ⁇ sition ready for tableting. HCTZ, mannitol and iron oxide were granulated with a solution of the hydroxypropyl cellulose in water. The obtained granules were dried. The granules were subsequently mixed with the ad ⁇ ditional mannitol, iron oxide, silicon dioxide and sodium stearyl fumarate to form a final composition ready for tablet- ing .
  • Bilayer tablets containing telmisartan and HCTZ were prepared by firstly introducing the telmisartan containing mixture ready for tableting into the tabletting machine, which was followed by the HCTZ containing mixture ready for tableting. The two layers were then compressed on a rotary tablet press in a bilayer tableting mode. Telmisartan layer A was combined with HCTZ layer A, telmisartan layer B was combined with HCTZ layer B and telmisartan layer C was combined with HCTZ layer C.

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Abstract

Cette invention concerne un comprimé pharmaceutique multicouche comprenant (a) au moins une première couche de comprimé comprenant de 1 à 50 % en poids de telmisartan ou d'un sel pharmaceutiquement acceptable de celui-ci, en poids de la première couche de comprimé et (b) au moins une seconde couche de comprimé comprenant de 1 à 50 % en poids d'un diurétique et de 50 à 99 % en poids d'au moins une charge, en poids de la seconde couche de comprimé, le poids combiné du diurétique et de ladite au moins charge représentant au moins 87 % en poids de la seconde couche de comprimé. Cette invention concerne également un procédé de préparation dudit comprimé pharmaceutique multicouche.
PCT/EP2011/060381 2010-06-21 2011-06-21 Comprimé pharmaceutique multicouche comprenant du telmisartan et un diurétique WO2011161123A2 (fr)

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EP11728238.4A EP2582361B1 (fr) 2010-06-21 2011-06-21 Comprimé pharmaceutique multicouche comprenant du telmisartan et un diurétique
PL11728238T PL2582361T3 (pl) 2010-06-21 2011-06-21 Wielowarstwowa tabletka farmaceutyczna zawierająca telmisartan i diuretyk
HRP20141127AT HRP20141127T1 (hr) 2010-06-21 2014-11-19 Višeslojna farmaceutska tableta koja sadrži telmisartan i diuretik

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PCT/EP2010/058754 WO2010146187A2 (fr) 2009-06-19 2010-06-21 Procédé pour la préparation de telmisartan
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EP2612658A1 (fr) * 2012-01-05 2013-07-10 Laboratorios Lesvi, S.L. Compositions pharmaceutiques d'acide 4'-[(1,4'diméthyl-2'-propyl[2,6'-BI-1H-benzimidazol]-1'-YL)méthyl]-[1,1'-biphényl]-2-carboxylique et IS 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxyde

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WO2004028505A1 (fr) 2002-09-24 2004-04-08 Boehringer Ingelheim International Gmbh Formulations pharmaceutiques sous forme solide contenant du telmisartan
WO2004096215A1 (fr) 2003-04-30 2004-11-11 Boehringer Ingelheim International Gmbh Formulation pharmaceutique du sel de sodium telmisartan
WO2006063737A1 (fr) 2004-12-17 2006-06-22 Boehringer Ingelheim International Gmbh Therapie combinatoire impliquant le telmisartan et l'hydrochlorothiazide
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EP2612658A1 (fr) * 2012-01-05 2013-07-10 Laboratorios Lesvi, S.L. Compositions pharmaceutiques d'acide 4'-[(1,4'diméthyl-2'-propyl[2,6'-BI-1H-benzimidazol]-1'-YL)méthyl]-[1,1'-biphényl]-2-carboxylique et IS 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxyde
WO2013102651A1 (fr) * 2012-01-05 2013-07-11 Laboratorios Lesvi, S.L. Compositions pharmaceutiques 4'-[(1,4'diméthyl-2'-propyl-[2,6'-bi-1h-benzimidazol]-1'-yl)méthyl]-[1,1'-biphényl]-2-acide carboxylique et 6-chloro-3,4-dihydro-2h-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxyde

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