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
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic 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
  • A61K9/48—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 relates to a solid pharmaceutical composition comprising telmisartan or a pharmaceutically acceptable derivative thereof and at least one calcium channel blocker. More specifically, the invention discloses a pharmaceutical composition comprising a first portion comprising telmisartan and a second portion comprising amlodipine.
• the amlodipine portion further comprises at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not exhibit disintegrating effect and/or at least one hydrophilic lubricant, wherein said second portion does not exhibit a disintegrating effect.
• Telmisartan the chemical name of which is 2- ( 4- ⁇ [ 4-methyl- 6- ( 1- methylbenzimidazol-2 -yl ) -2-propylbenzimidazol-l-yl ] -methyl ⁇ - phenyl ) -benzoic acid, is an angiotensin II receptor antagonist useful for the treatment of hypertension that was originally disclosed in EP 0 502 314 Al .
• Telmisartan is commercially available in particular in its free acid form, which is poorly soluble in neutral or acidic media. Thus, telmisartan is typically formulated together with a basic agent or in the form of a basic salt for improved solubility.
• Calcium channel blockers such as amlodipine, nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine , nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine, aranidipine and pranidipine, exert antihypertensive action by reducing the availability of calcium ions for muscular contraction and, therefore, resulting in decreased peripheral vascular resistance and reduced blood pressure.
• Amlodipine the chemical name of which is 3-ethyl 5-methyl 2- [ (2-aminoethoxy) methyl ] -4 - ( 2-chlorophenyl ) - 6-methyl- 1 , 4 - dihydropyridine-3 , 5-dicarboxylate is a long-acting calcium channel blocker (dihydropyridine class) used as an antihypertensive and in the treatment of angina that was originally disclosed in EP 0 089 167 Al .
• Amlodipine is commercially available in the form of maleate, besylate or mesylate salt. It is known that amlodipine and/or pharmaceutically acceptable salts thereof are susceptible to hydrolysis when exposed to an alkaline medium.
• compositions are provided in physically separated forms selected from the group consisting of powders, granules, pellets, beads, mini- tablets or tablets and similar.
• Another approach is to coat particles that readily disintegrates with water-soluble polymers.
• Yet another approach is to place each incompatible substance into a particular layer while layers could be additonally separated by an inert intermediate layer.
• WO 2006/048208 addresses the stability problem caused by the incompatibility of amlodipine with basic constituents of the telmisartan formulation by preparing a bilayer pharmaceutical tablet comprising a first layer of telmisartan in substantially amorphous form in a dissolving tablet matrix and a second layer of amlodipine in a disintegrating or eroding tablet matrix.
• the term 'dissolving tablet matrix' refers to a 'pharmaceutical tablet base formulation having instant release (fast dissolution) characteristics that readily dissolves in a physiological aqueous medium' and the term 'disintegrating or eroding tablet matrix' refers to a pharmaceutical tablet base formulation having instant release characteristics that readily disintegrates or erodes in a physiological aqueous medium' .
• the dissolving tablet matrix is described to have neutral or basic properties, with a basic tablet matrix being preferred. It comprises a basic agent, a water soluble diluent and optionally other excipients and adjuvants.
• disintegrants used to prepare a disintegrating or eroding tablet matrix the following group of disintegrants is listed: croscarmellose sodium (crosslinked carboxymethylcellulose sodium) , sodium starch glycolate, crospovidone (crosslinked polyvinylpyrrolidone), corn starch, pregelatini zed starch, low-substituted hydroxypropylcellulose and microcrystalline cellulose. Particularly preferred are sodium starch glycolate and crospovidone.
• WO 2007/001067 relates to a solid dosage form comprising an angiotensin II receptor antagonist such as inter alia telmisartan and a calcium channel blocker such as inter alia amlodipine wherein active ingredients are not intimately mixed in the dosage form.
• angiotensin II receptor antagonist such as inter alia telmisartan
• a calcium channel blocker such as inter alia amlodipine wherein active ingredients are not intimately mixed in the dosage form.
• the application discloses double-layer tablet comprising olmesartan medoxomile and amlodipine besylate both present in disintegrating matrix.
• WO 2008/146178 discloses a pharmaceutical composition
• a pharmaceutical composition comprising a telmisartan blend layer having a disintegrating matrix and amlodipine tablets having a disintegrating matrix which amlodipine tablets are inlayed in an inert excipients layer representing a disintegrating matrix as well.
• complex fixed dose formulations of telmisartan and amlodipine are necessary to address the incompatibility of the active agents and to stabilize the compositions.
• These complex formulations require the use of substantial amounts of expensive specialty excipients.
• preparation of these formulations involves complex and costly processing steps such as wet granulation.
• the pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts described herein below.
• the pharmaceutical composition comprises telmisartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof present in different portions of the pharmaceutical composition and at least one non- hygroscopic filler and/or at least one non-hygroscopic binder that do not exhibit disintegrating effect and/or at least one hydrophilic lubricant wherein the amlodipine portion does not exhibit a disintegrating effect.
• telmisartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof present in different portions of the pharmaceutical composition are separated by means of layers, coating and/or units.
• the pharmaceutical composition according to the present invention may be formulated in the form of a tablet comprising at least two layers or in the form of telmisartan tablets coated with amlodipine or pharmaceutically acceptable salts, or in the form of a capsule comprising at least one unit comprising telmisartan or pharmaceutically acceptable salts thereof and at least one unit comprising amlodipine or pharmaceutically acceptable salts thereof.
• the invention also relates to a process for the preparation of said pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and amlodipine or pharmaceutically acceptable salts thereof in a fixed dosage form.
• the invention relates to a solid pharmaceutical composition
• a solid pharmaceutical composition comprising
• amlodipine or a pharmaceutically acceptable salt thereof
• the non-hygroscopic excipient is selected from non- hygroscopic fillers and/or non-hygroscopic binders.
• the at least one non-hygroscopic excipient does preferably not exhibit any disintegrating effect, i.e. the second portion of the composition readily dissolves in a physiological aqueous medium, but does not disintegrates or erodes in such medium.
• the second portion comprises less than 2 wt.-%, particularly less than 1 wt.-%, more preferably less than 0.5 wt.-%, most preferably less than 0.1 wt.-% of a disintegrant as defined herein below, based on the weight of the second portion .
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof present in one portion and amlodipine or pharmaceutically acceptable salts thereof and at least one non-hygroscopic filler and/or at least one non- hygroscopic binder that do not exhibit disintegrating effect and/or at least one hydrophilic lubricant present in another portion of the pharmaceutical composition wherein said amlodipine portion does not exhibit disintegrating effect.
• portion means that both active ingredients are not in intimate contact and that they are separated from each other, for example by means of layers, coating and/or units.
• portion refers to a physical part of the solid pharmaceutical composition, wherein the components of said part are not intimately mixed with the components of another portion or part of the composition.
• the interaction between the components of one portion and the components of another portion is reduced, for example by physically separating the first portion composition from the second portion composition, e.g. by the provision of the first portion composition and the second portion composition in different tablet layers or units and/or by provision of a separating layer.
• the composition exhibits a dissolution profile that is comparable to the one typically found for tablets containing telmisartan in a dissolving portion and amlodipine in a disintegrating portion.
• the stability of amlodipine can be increased and the amount of degradation products of amlodipine formed via hydrolysis upon storage of the composition is reduced.
• the solid pharmaceutical composition according to the invention comprises (a) at least one first portion comprising telmisartan or a pharmaceutical acceptable salt thereof;
• amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient are included in the composition.
• non-hygroscopic refers to a material that has a low ability to take up and retain water. More specifically, the term “non-hygroscopic” refers to a material that has an equilibrium moisture content of about 6% (w/w) or less as determined by dynamic vapor sorption (DVS) at a relative humidity of 60% and a temperature of 25°C. In particular, the equilibrium moisture content is determined on the basis of the sorption isotherm curve measured by DVS at a relative humidity of 60% and a temperature of 25°C.
• the second portion of the composition further comprises at least one hydrophilic lubricant .
• non-hygroscopic excipient is preferably selected from the group consisting of non-hygroscopic fillers, non-hygroscopic binders and mixtures thereof.
• the combined weight of the amlodipine or pharmaceutically acceptable salt thereof and the non-hygroscopic excipient or the combined weight of the amlodipine or pharmaceutically acceptable salt thereof, the non- hygroscopic excipient and the hydrophilic lubricant, if present, is at least 50 wt.-%, preferably at least 85 wt.-%, more preferably at least 93 wt.-%, like at least 95 wt.-% or at least 97 wt.-%, such as at least 98 wt.-%, and most preferably at least 99 wt.-% by weight of the second portion.
• the second portion of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient. In another embodiment, the second portion of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof, at least one non-hygroscopic excipient and at least one hydrophilic lubricant.
• the second portion of the composition according to the invention comprises less than 2 wt.-%, particularly less than 1 wt.-%, more preferably less than 0.5 wt.-%, most preferably less than 0.1 wt.-% of a disintegrant, based on the weight of the second portion.
• the second portion is substantially free of disintegrant.
• disintegrant refers to any material that has wicking and/or swelling properties when it comes in contact with water.
• disintegrant refers to the group of compounds consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatini zed starch, low-substituted hydroxypropylcellulose and microcrystalline cellulose.
• disintegrant refers 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.
• disintegrant refers to the group of compounds consisting of povidone, crospovidone, starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, 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 bilayer tablets according to the prior art tend to be slightly hygroscopic and are therefore preferably packaged using a moisture-proof packaging material such as aluminium foil blister packs or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
• a moisture-proof packaging material such as aluminium foil blister packs or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
• disintegrants are hygroscopic or even very hygroscopic in nature. Typically, disintegrants may contain 5% w/w of water or more.
• amlodipine is susceptible to hydrolysis, it has been found beneficial to prepare a pharmaceutical formulation that substantially comprises or essentially consists of materials that contain as little water as possible.
• the composition of the invention is in the form of a multilayer tablet, wherein the at least one first portion is an at least one first tablet layer and the at least one second portion is an at least one second tablet layer.
• multilayer 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. Typically, adjacent layers of the tablet will be of different composition.
• first tablet layer and second tablet layer refer to tablet layers having a particular composition. However, these terms do not necessarily reflect the order in which the layers are arranged in the tablet .
• composition according to the invention is in the form of a coated tablet, wherein the at least one first portion is a tablet and the at least one second portion is at least one coating on said tablet.
• the multilayer tablet or coated tablet according to the invention can further comprise at least one separating coating.
• the separating coating is arranged between at least one first tablet layer and at least one second tablet layer.
• the separating coating is an isolating or intermediate coating arranged between the tablet representing the first portion and the coating representing the at least one second portion.
• the separating layer can comprise a pharmaceutically acceptable excipient such as a polymeric excipient and is particularly selected from the group consisting of Povidone and cellulose derivatives like hydroxypropyl methylcellulose.
• the composition according to the invention is in the form of a capsule comprising the at least one first portion in form of a first unit and the at least one second portion in form of a second unit.
• unit refers to tablets, microtablets , pellets, powder forms, granules and granulates.
• the first and the second unit are independently selected from the group consisting of tablets, microtablets, pellets, powder forms, granules and granulates .
• the multilayer tablet, coated tablet as well as capsule embodiments described above may be characterized by the same features as disclosed in connection with the general embodiment of the composition of the invention, i.e. the composition comprising at least one first portion comprising telmisartan or a pharmaceutically salt thereof and at least one second portion comprising amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient.
• the present invention relates to a pharmaceutical composition in the form of a tablet comprising a) at least one layer comprising
• telmisartan or a pharmaceutically acceptable salt thereof, b) optionally at least one separating layer comprising any pharmaceutically acceptable excipient and
• the present invention relates to a pharmaceutical composition in the form of a tablet comprising a) at least one layer comprising
• telmisartan 1 to 50 wt.-% telmisartan or a pharmaceutically acceptable salt thereof by weight of said layer
• cl 1 to 50 wt.-% of amlodipine or a pharmaceutically acceptable salt thereof by weight of said layer and c2) 1 to 99 wt.-% of at least one non-hygroscopic filler and/or 1 to 99 wt.-% of at least one non-hygroscopic binder that do not exhibit disintegrating effect and/or 1 to 99 wt.-% of at least one non-hydrophobic lubricant by weight of said layer,
• the present invention relates to a pharmaceutical composition in the form of a coated tablet comprising
• telmisartan portion comprising
• amlodipine portion does not exhibit disintegrating effect.
• the present invention relates to a pharmaceutical composition in the form of a coated tablet comprising
• telmisartan portion comprising
• telmisartan 1 to 50 wt.-% of telmisartan or a pharmaceutically acceptable salts thereof by weight of said portion compressed into tablet wherein said tablet is coated with
• an amlodipine portion comprising cl) 1 to 90 wt.-% of amlodipine or a pharmaceutically acceptable salt thereof by weight of said portion and
• amlodipine layer does not exhibit a disintegrating effect
• the present invention relates to a pharmaceutical composition in the form of a capsule comprising a) at least one unit comprising telmisartan or pharmaceutically acceptable salts thereof and
• the present invention relates to a pharmaceutical composition in the form of a capsule comprising b) at least one unit comprising 1 to 50 wt.-% of telmisartan or pharmaceutically acceptable salts thereof by weight of said unit and
• amlodipine unit does not exhibit disintegrating effect.
• unit refers to tablets, microtablets , pellets, or powder form that does not include tablet comprising layers and coated tablets as defined above.
• unit refers to tablets, microtablets , pellets, or powder form that does not include tablet comprising layers and coated tablets as defined above.
• the following description of preferred embodiments of the composition according to the invention is intended to apply to the general embodiment of the composition described above which is characterized by the presence of at least one first portion and at least one second portion as well as to the multilayer tablet, coated tablet and capsule embodiments described above.
• the first portion of the composition according to the invention comprises telmisartan or a pharmaceutically acceptable salt thereof.
• Telmisartan is typically employed in its free acid form although pharmaceutically acceptable salts can also be used.
• the portion comprising telmisartan preferably comprises 1 to 50 wt.-%, particularly 5 to 35 wt.-%, more preferably 10 to 20 wt.-% of telmisartan or a pharmaceutically acceptable salt thereof by weight of said first portion.
• the first portion of the pharmaceutical composition according to the present invention 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 , KHC0 3 , Na 3 P0 4 , K 3 P0 4 , Na 2 HP0 4 , K 2 HP0 4 , choline, tert-butylamine , ethanolamine , meglumine, piperazine, diethylamine , L-arginine and mixtures thereof.
• Alkali metal hydroxides such as NaOH and KOH, amino sugars such as meglumine and mixtures thereof are preferred basic agents. It is particularly preferred that the basic agent comprises a mixture 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 portion comprising telmisartan preferably 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 in a fluidized bed, and solvent deposition on sugar pellets or other carriers.
• the pharmaceutical composition according to the present invention comprises a pharmaceutically acceptable salt of telmisartan.
• Suitable pharmaceutically acceptable salts include alkaline salts such as the sodium salt of telmisartan.
• the pharmaceutically acceptable salt of telmisartan can be amorphous or crystalline.
• Telmisartan or its pharmaceutically acceptable salts can be prepared by any method known from the state of the art as for example disclosed in EP 0 502 314 Al, EP 1 173 407 Bl, J. Med. Chem.
• telmisartan or its pharmaceutically acceptable salts can be in any known stable polymorphic forms known from the state of the art as for example disclosed in EP 1144386, EP 1442023, WO 2006/050509, US 2006/111417, IN 2005MU00164, US 2006/0276525 or WO 2009/006860.
• the first portion, such as the first tablet layer, of the pharmaceutical composition according to the present invention can comprise pharmaceutically acceptable excipients .
• pharmaceutically acceptable excipient refers to additives useful for converting pharmacologically active compounds into pharmaceutical dosage forms which are suitable for administration to patients.
• Excipients suitable for use in the first portion can include fillers, binders, surfactants, crystallization retarders, lubricants, glidants and coloring agents. Other pharmaceutically acceptable excipients can also be included .
• the first portion comprising telmisartan typically comprises at least one filler.
• Water-soluble fillers are generally preferred. Suitable fillers for use in the portion comprising telmisartan can include monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, saccharose, lactose (anhydrous and monohydrate ) , 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, sorbitol, maltitol, xylitol and lactitol and mixtures thereof. Lactose, sorbitol and mixtures thereof are particularly preferred. 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 portion comprising telmisartan 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 portion comprising telmisartan can include povidone (polyvinylpyrrolidone), copovidone ( vinylpyrrolidone-vinylacetate copolymer), cellulose powder, crystalline cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, maltose, starch, pregelatinized starch, polymethacrylates and mixtures thereof. Povidone is particularly preferred.
• the portion comprising telmisartan 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 portion of the pharmaceutical composition according to the present invention can include 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 polysorbates and poloxamers are preferred.
• the first portion preferably comprises 1 to 30 wt.-%, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt.-% of surfactant by weight of said portion.
• the pharmaceutical composition preferably comprises 1 to 30 wt.-%, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt.-% of surfactant by weight of said composition.
• Suitable crystallization retarders for use in the first portion of the pharmaceutical composition according to the present invention can include povidone, copovidone, crospovidone, carboxymethylcellulose sodium, hydroxypropylcellulose and hydroxypropylmethylcellulose.
• the first portion preferably comprises 0.1 to 20 wt.-%, particularly 0.25 to 10 wt.-%, more preferably 0.25 to 4 wt.-% of crystallization retarder by weight of said portion.
• the pharmaceutical composition preferably comprises 0.1 to 20 wt.-%, particularly 0.25 to 10 wt.-%, more preferably 0.25 to 4 wt.-% of crystallization retarder by weight of said composition.
• Suitable lubricants for use in the first portion comprising telmisartan can include stearic acid and stearic acid salts such as magnesium stearate, magnesium palmitate and magnesium oleate, hydrogenated 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 portion comprising telmisartan preferably comprises 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 portion of the pharmaceutical composition according to the present invention include colloidal silicon dioxide and magnesium trisilicate.
• the first portion comprising telmisartan preferably comprises 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 portion of the pharmaceutical composition according to the present invention include dyes and pigments such as iron oxide and titanium oxide.
• the first portion comprising telmisartan preferably comprises 0.001 to 1 wt.-%, particularly 0.01 to 0.5 wt.-%, more preferably 0.05 to 0.2 wt.-% of coloring agent.
• the first portion of the composition such as the first tablet layer, the first tablet or the first unit, comprises (aa) 3 to 50 wt.-%, particularly 5 to 35 wt.-%, more preferably
• telmisartan 10 to 20 wt.-% of telmisartan or a pharmaceutically acceptable salt thereof;
• binder 3 to 7 wt.-% of binder
• the first portion of the composition such as the first tablet layer, the first tablet or the first unit, comprises
• filler 30 to 95 wt.-%, particularly 60 to 90 wt.-%, more preferably 70 to 80 wt.-% of filler, wherein said filler is preferably selected from monosaccharides and oligosaccharides 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;
• monosaccharides and oligosaccharides 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 preferably 3 to 7 wt.-% of binder, wherein said binder is preferably selected from povidone, copovidone cellulose powder, crystalline cellulose, microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose , starch, pregelatinized starch, polymethacrylates and mixtures thereof, and is more preferably selected from povidone;
• lubricant is preferably selected from stearic acid and stearic acid salts such as magnesium stearate, magnesium palmitate 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
• (ff) 0 to 1 wt.-%, particularly 0.01 to 0.5 wt.-%, more preferably 0.05 to 0.2 wt.-% of coloring agent.
• the second portion of the composition according to the invention comprises a calcium channel blocker and at least one non- hygroscopic excipient.
• the second portion comprises amlodipine or a pharmaceutically acceptable salt thereof and at least one non-hygroscopic excipient.
• Amlodipine can be in the form of pharmaceutically acceptable salts such as for example the maleate, besylate or mesylate salt or in the form of free base.
• amlodipine is in the form of besylate or maleate salt.
• the non-hygroscopic excipient of the second portion is preferably selected from the group consisting of non-hygroscopic fillers, non-hygroscopic binders and mixtures thereof.
• the second portion comprising amlodipine preferably comprises at least one non-hygroscopic filler that does not exhibit a disintegrating effect.
• the filler of the second portion is selected from the group of fillers defined above in connection with the first portion of the composition or mixtures thereof.
• the filler of the second portion is preferably selected from the group consisting of monsaccharides , oligosaccharides, sugar alcohols and mixtures thereof.
• Preferred non-hygroscopic fillers that do not exhibit a disintegrating effect are mannitol and lactose monohydrate .
• the filler of the second portion is preferably selected from the group consisting of mannitol, lactose monohydrate and mixtures thereof.
• the second portion comprising amlodipine can further comprises at least one binder and in particular at least one non- hygroscopic binder that does not exhibit disintegrating effect selected from the group of binders defined above in connection with the first portion of the composition.
• Preferred non- hygroscopic binders that do not exhibit disintegrating effect are hydroxypropylcellulose and maltose.
• the binder of the second portion is preferably selected from the group consisting of hydroxypropylcellulose, maltose and mixtures thereof.
• the second portion comprising amlodipine preferably further comprises at least one non-hydrophobic lubricant selected from the group of lubricants defined above in connection with the first portion of the composition.
• Preferred non-hydrophobic lubricants are sodium stearyl fumarate and macrogols.
• the second portion of the composition preferably comprises at least one hydrophilic lubricant selected from the group consisting of stearic acid, magnesium stearate, magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, macrogols and mixtures thereof. More preferably, the second portion of the composition preferably comprises at least one hydrophilic lubricant selected from the group consisting of sodium stearyl fumarate, macrogols and mixtures thereof.
• the second portion of the composition according to the invention can generally comprise additional pharmaceutically acceptable excipients.
• additional excipients suitable for use in the second portion may include glidants, coloring agents and coating agents .
• Suitable glidants for use in the second portion of the pharmaceutical composition according to the present invention include colloidal silicon dioxide and magnesium trisilicate.
• Suitable coloring agents for use in the second portion of the pharmaceutical composition according to the present invention include dyes and pigments such as iron oxide and titanium oxide.
• the second portion of the composition such as the second tablet layer, comprises
• (cc) 0 to 30 wt.-%, particularly 2 to 10 wt.-%, more preferably 3 to 7 wt.-% of binder; (dd) 0 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 2 wt.-% of lubricant;
• (ff) 0 to 1 wt.-%, particularly 0.01 to 0.5 wt.-%, more preferably 0.05 to 0.2 wt.-% of coloring agent.
• the second portion such as the second tablet layer, comprises
• filler 50 to 99 wt.-%, particularly 80 to 98 wt.-%, more preferably 88 to 94 wt.-% of filler, preferably selected from a sugar alcohol, like isomalt, xilitol or mannitol, lactose monohydrate and mixtures thereof;
• binder preferably selected from hydroxypropylcellulose, maltose and mixtures thereof, and more preferably hydroxypropylcellulose;
• (dd) 0 to 10 wt.-%, particularly 0.25 to 5 wt.-%, more preferably 0.5 to 3 wt.-% of lubricant, preferably selected from sodium stearyl fumarate, macrogols and mixtures thereof .
• suitable coating agents for use in the second portion of the pharmaceutical composition of the present invention include carmellose calcium, shellac, copovidone, hydroxyethylcellulose, methylhydroxy- ethylcellulose, polymethacrylate , hydroxypropylcellulose, chitosan, hypromellose, polyvinyl alcohol, methylcellulose, polyethylene oxide, povidone, cetyl alcohol or mixtures thereof.
• the second portion comprising amlodipine preferably comprises 0.01 to 20 wt.-%, more preferably 0.1 to 10 wt.-% of coating agent based on the total mass of coated pharmaceutical composition including tablet core and coating together.
• the second portion is a tablet layer which comprises granules and an extragranular phase.
• the granules comprise amlodipine, at least one non-hygroscopic filler, at least one non-hygroscopic binder and optionally further excipients like a coloring agent.
• the extragranular phase of the second tablet layer according to this embodiment comprises at least one non-hygroscopic filler, at least one hydrophilic lubricant and optionally additional excipients such as 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.
• the filler used in the granules and in the extragranular phase is a sugar alcohol, like mannitol, and/or lactose monohydrate.
• non-hygroscopic filler and non-hygroscopic binder or the combined weight of the amlodipine or pharmaceutically acceptable salt thereof, the non-hygroscopic excipient, i.e. non-hygroscopic filler and non-hygroscopic binder, and the hydrophilic lubricant of the second portion, such as the second tablet layer, is at least 50 wt.-%, preferably at least 85 wt.-%, more preferably at least 93 wt.-%, like at least 95 wt.-% or at least 97 wt.-%, such as at least 98 wt.-%, and most preferably at least 99 wt.-% by weight of the second portion.
• the second portion of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof and the at least one non-hygroscopic excipient.
• the second portion of the composition essentially consists of amlodipine or a pharmaceutically acceptable salt thereof, the at least one non-hygroscopic excipient and the at least one hydrophilic lubricant.
• the present invention is directed to a process for preparing the pharmaceutical composition according to the invention.
• the mode of preparation can be direct compression, dry granulation or wet granulation or any other known method or combination thereof.
• the process for the preparation of a solid pharmaceutical composition according to the invention typically comprises
• composition according to the invention is in form of a multilayer pharmaceutical tablet
• such tablet can be prepared in principle by any method used for manufacturing tablet formulations.
• Preparation of the tablet generally comprises preparing a first tablet layer composition comprising telmisartan and a second tablet layer composition comprising amlodipine and compressing the tablet layer compositions 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 solvent (e.g. water or organic solvent) .
• excipients such as a crystallization retarder and/or a surfactant can be included in the spray-solution.
• the spray solution is subsequently spray- dried to give a spray-dried granulate.
• the spray-dried granulate is mixed with further excipients to give a tablet layer composition ready for tableting.
• Another method for preparing the first tablet layer composition 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 mixtures 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 amlodipine or a pharmaceutically acceptable salt thereof can also be prepared by various methods such as direct compression, 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 granulating the amlodipine or salt thereof optionally additional excipients.
• the obtained wet granulate is optionally dried and/or sieved and blended with at least one filler and optionally other pharmaceutical excipients such as at least one lubricant to provide a second tablet layer composition.
• the second tablet layer composition is prepared using a direct compression method where a powder premix of amlodipine or a salt thereof and at least one further excipient selected from filler, binder, lubricant, glidant and mixtures thereof is directly compressed onto the first layer containing telmisartan.
• 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.
• second tablet layer composition with regard to specific components and their amounts are as described above.
• coated tablets can be prepared by first preparing a tablet containing telmisartan or pharmaceutically acceptable salts thereof. This tablet can subsequently be coated by wet and/or dry coating procedure.
• Wet coating technique consists of dissolving suitable coating agent in a solvent together with optional other ingredients and sprayed onto tablet cores.
• Dry coating consists of spraying suitable coating agent to the tablet and/or pellet bed with simultaneous spraying of a suitable plasticizing agent. This can be achieved either with fluidized bed, perforated coating pan or other suitable equipment .
• Telmisartan, sodium hydroxide and povidone were dissolved m water q.s. in order to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in a fluid-bed granulating machine and sprayed with the granulation liquid. When granulation was completed the granulate was dried and mixed with sorbitol and magnesium stearate or sodium stearyl fumarate to form final composition ready for tabletting.
• Amlodipine in the form of besylate or maleate was mixed with either xylitol, lactose monohydrate, mannitol or isomalt.
• Lubricant magnesium stearate or sodium stearyl fumarate
• Bilayer tablets containing telmisartan and amlodipine were prepared by first introducing the telmisartan containing mixture ready for tabletting into the tabletting machine, followed by the amlodipine containing mixture ready for tabletting. These two layers were then compressed on a rotary tablet press in a bilayer tabletting mode.
• Amlodipine layer A [mg] B [mg] C [mg] D [mg] E [mg] F [mg]
• Amlodipine in the form of besylate or maleate and either mannitol or lactose monohydrate were granulated with a water solution of either hydroxypropyl cellulose or maltose. The obtained granules were dried. The granulate was subsequently mixed with either mannitol or lactose monohydrate.
• Lubricant magnesium stearate or sodium stearyl fumarate
• Bilayer tablets containing telmisartan and amlodipine were prepared by first introducing the telmisartan containing mixture ready for tabletting into the tabletting machine, followed by the amlodipine containing mixture ready for tabletting. These two layers were then compressed on a rotary tablet press in a bilayer tabletting mode.
• Example 3 Multilayer tablet
• Telmisartan layer was prepared by the same way as in Example Amlodipine layer was prepared by the same way as in Example (Example 3a) or Example 2 (Example 3b) .
• Separation layer was prepared by either mixing mannitol or xylitol or isomalt or maltitol with sodium stearyl fumarate in a tumbling mixer in order to obtain a final composition ready for tabletting .
• Multilayer tablets containing telmisartan and amlodipine were prepared by first introducing the telmisartan containing mixture ready for tabletting into the tabletting machine. Then, the separation layer was introduced, followed by the amlodipine containing mixture ready for tabletting. These three layers were then compressed on a rotary tablet press in a three layer tabletting mode.
• Example 4 Coated tablet
• Telmisartan, sodium hydroxide and povidone were dissolved m water in order to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in the fluid-bed granulating machine and sprayed with granulation liquid. When granulation was completed the granulate was dried and mixed with sorbitol and lubricant (magnesium stearate and sodium stearyl fumarate) to form the final composition ready for tabletting. Tablets were prepared by compression.
• hypromellose was dissolved in water.
• Amlodipine in the form of besylate or maleate was suspended in the obtained hypromellose solution.
• the telmisartan containing tablets were then coated with the obtained amlodipine suspension.
• Example 5 Coated tablet with separating coating
• Telmisartan, sodium hydroxide and povidone were dissolved m water in order to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in the fluid-bed granulating machine and sprayed with granulation liquid. When granulation was completed the granulate was dried and mixed with sorbitol and lubricant (magnesium stearate and sodium stearyl fumarate) to form the final composition ready for tabletting. Tablets were prepared by compression.
• Hypromellose or povidone was dissolved in water and telmisartan containing tablets were coated with separating coating.
• Hypromellose was dissolved in water.
• amlodipine in the form of besylate or maleate was suspended.
• the previously prepared coated tablets were then coated with the obtained amlodipine suspension.
• Example 6 Capsule comprising two or more units
• Telmisartan, sodium hydroxide and povidone were dissolved m water in order to prepare a granulation liquid. Lactose monohydrate and meglumine were placed in a fluid-bed granulating machine and sprayed with granulation liquid. After granulation had been completed the obtained granulate was dried and mixed with sorbitol and lubricant (magnesium stearate and sodium stearyl fumarate) to form a unit comprising telmisartan.
• sorbitol and lubricant magnesium stearate and sodium stearyl fumarate
• a pharmaceutical composition comprising at least one telmisartan unit was prepared by tabletting the unit into one layer tablet.
• a composition was prepared in the form of microtablets .
• a composition was preparedin a powder or pellet form.
• amlodipine unit an amlodipine portion as disclosed in Example 1 or in Example 2 was used.
• a pharmaceutical composition comprising at least one amlodipine unit was prepared by tabletting the amlodipine unit into a one layer tablet.
• a composition was prepared in a form of microtablets .
• a composition was prepared in a powder or pellet form.
• any one of the above telmisartan unit (as for example tablets, microtablets, pellets or powder form) was used together with any one of the above amlodipine unit (as for example tablets, microtablets, pellets or powder form) to be filled in any kind of hard capsules (gelatin, hypromellose or polysaccharide) .
• Example 7 Two separate units in a combo blister pack
• any one of the above telmisartan unit from Example 6 (as for example tablets, microtablets , pellets or powder form) was used together with or any one of above amlodipine unit (as for example tablets, microtablets, pellets or powder form) from Example 6 to prepare combo blister pack containing at least one telmisartan unit and at least one amlodipine unit.

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