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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • 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
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B30—PRESSES
  • B30B—PRESSES IN GENERAL
  • B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
  • B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
  • B30B11/08—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable

Definitions

• Telmisartan is generally manufactured and supplied in the free acid form. As disclosed in WO 00/43370, crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A. Both forms are characterized by a very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1 to 7. Telmisartan is obtainable on the market under the trade name Micardis®. Starting from the free acid form Telmisartan as introduced to the market is manufactured using an expensive spray-drying process. Due to the poor solubility of the free acid form preparation of alternative telmisartan formulation is difficult.
• telmisartan dissolution rate of HCTZ from tablets comprising coated HCTZ in a telmisartan formulation was further reduced due to the gel-forming properties of the polymer.
• Another approach was to produce separate film-coated tablets for telmisartan and HCTZ in such a size and shape that these could be filled into a capsule. By dividing the doses into two to four single small tablets for telmisartan and into one or two small tablets for HCTZ, a capsule of size 1 to 0 long could be filled. Yet, with this approach the drug dissolution rate of telmisartan was reduced compared to the single
• the bilayer tablet according to the present invention provides a largely pH- independent dissolution of the poorly water-soluble telmisartan, thereby facilitating dissolution of the drug at a physiological pH level, and also provides for immediate release of the diuretic from the fast disintegrating matrix.
• the bilayer tablet structure overcomes the stability problem caused by the incompatibility of diuretics like HCTZ with basic constituents of the telmisartan formulation.
• a surfactant or emulsifier in an amount of about 1 to 20 wt.% of the final composition , (c) 25 to 70 wt.% of a wate r-soluble diluent, and
• dissolving tablet matrix refers to a pharmaceutical tablet base formulation having immediate release (fast dissolution) characteristics that readily dissolves in a physiological aqueous medium.
• the active ingredient telmisartan is generally supplied in its free acid form, although pharmaceutically acceptable salts may also be used. It is preferred to remove agglomerates from the starting material, e.g. by sieving, in order to facilitate wetting and dissolution during further processing.
• telmisartan may be produced by any suitable method known to those skilled in the art, for instance, by freeze drying of aqueous solutions, coating of carrier particles in a fluidized bed, and solvent deposition on sugar pellets or other carriers.
• telmisartan is prepared by the conventional wet granulation methods such as fluid bed granulation.
• suitable basic agents are alkali metal hydroxides such as NaOH and KOH; furthermore NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3 , Na 2 H PO 4 , K 2 HPO 4 ; basic amino acids such as arginine; and meglumine (N-methyl-D-glucamine).
• the surfactants and emulsifiers may be ionic or non-ionic, the latter being preferred.
• Specific examples of surfactants and emulsifiers are such as poloxamers or pluronics, polyethylene glycols, polyethylene glycol monostearate, polysorbates, sodium lauryl sulfate, polyethoxylated and hydrogenated castor oil etc.
• Suitable poloxamers may have an average mol weight of about 2000 to 12000, preferably 4000 to 10000, more preferred 6000 to 10000, most preferred 8000 to 9000.
• Examples for specific poloxamers are poloxamer 182LF, poloxamer 331 and poloxamer 188.
• suitable water-soluble diluents are carbohydrates such as monosaccharides like glucose; oligosaccharides like sucrose; and sugar alcohols like erythritol, sorbitol, mannitol, dulcitol, ribitol and xylitol. Mannitol, erythritol, sorbitol and sucrose are preferred diluents.
• the other excipients and/or adjuvants are, for instance, selected from binders, carriers, lubricants, flow control agents, crystallization retarders, solubilizers and coloring agents.
• the binder may be selected from the group of dry binders and/or the group of wet granulation binders, depending on the manufacturing process chosen for the pharmaceutical composition.
• Suitable dry binders are, e.g., cellulose powder, crystalline cellulose, microcrystalline cellulose or light anhydrous silicic acid.
• Specific examples of wet granulation binders are corn starch, polyvinyl pyrrolidone (Povidone), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl- cellulose and hydroxypropylmethylcellulose.
• Suitable disintegrants are, e.g., sodium starch glycolate, Crospovidon, Croscarmellose, sodium carboxymethylcellulose and dried corn starch.
• the other excipients and adjuvants are preferably selected from diluents and carriers such as cellulose powder, crystalline cellulose or microcrystalline cellulose, cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxy-propylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, polyvinyl pyrrolidone (Povidone) etc.; lubricants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol thbehenate, etc.; flow control agents such as colloidal silica, light anhydrous silicic acid, crystalline cellulose, talc, etc.; crystallization retarders such as Povidone, etc.; coloring agents, including dyes and pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc.; and mixtures of two or more of these excipients and/or adjuvants.
• the first tablet layer containing telmisartan according to the present invention provides solubilization of the poorly water-soluble telmisartan of up to a concentration of more than 4.4 ⁇ mg/10OmL, thereby facilitating dissolution of the drug at a physiological pH level, and also provides for immediate release from the fast disintegrating matrix.
• compositions according to the invention comprises 15 to 25 wt.% of telmisartan dispersed in a dissolving matrix comprising
• the most preferred non-ionic surfactants are selected from poloxamers
• the most preferred water-soluble diluents are selected from mannitol, erythritol, sorbitol and sucrose, and
• the second tablet layer composition contains a diuretic in a fast disintegrating tablet matrix.
• the disintegrating tablet matrix comprises a filler, a binder, a disintegrant and, optionally, other excipients and adjuvants.
• the diuretic is usually employed as a fine-crystalline powder, optionally i n fine-milled, peg-milled or micronized form.
• the binder is selected from the group of dry binders and/or the group of wet granulation binders, depending on the manufacturing process chosen for the second tablet layer.
• Suitable dry binders are, e.g., cellulose powder and microcrystalline cellulose.
• Specific examples of wet granulation binders are corn starch, polyvinyl pyrrolidone (Povidon), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl-cellulose and hydroxypropylmethylcellulose.
• the other excipients and adjuvants are preferably selected from diluents and carriers such as cellulose powder, microcrystalline cellulose, cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, polyvinyl pyrrolidone (Povidone) etc.; lubricants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc.; flow control agents such as colloidal silica, talc, etc.; crystallization retarders such as Povidone, etc.; solubilizers such as Pluronic, Povidone, etc.; coloring agents, including dyes and pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc.; pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic
• the second tablet layer composition generally comprises 1.5 to 35 wt.%, preferably 2 to 25 wt.%, of active ingredient; 25 to 85 wt.%, preferably 35 to 75 wt.%, of filler; 1 to 40 wt.%, preferably 10 to 30 wt.%, of binder; 0.5 to 10 wt.%, preferably 1 to 5 wt.%, of wet granulation binder; and 1 to 10 wt.%, preferably 2 to 8 wt.%, of disintegrant.
• the other excipients and adjuvants are generally employed in the same amount as in the first tablet layer composition.
• the tablets so obtained can be further processed using conventional techniques, for instance can be coated using suitable coatings known in the art which do not negatively affect the dissolution properties of the final formulation.
• the tablets can be provided with a film coat for moisture protection by film forming polymers such as polyvinyl alcohol, hydroxypropyl cellulose, ethylcellulose, polyvinylacetal diethylaminoacetate and polymeric methacrylates together with plasticizers such as polyethylene glycols onto the core tablets. Even though the polymer is water soluble, its rate of solution is slow enough to afford the core tablets moisture protection. Other polymers, which offer similar water solubility and a similar degree of moisture protection may also be used.
• agents such as beeswax, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, zein, can be dissolved in a suitable solvent together with plasticizers such as polyethylene glycol and applied to the tablets, provided that the coating has no substantial effect on the disintegration/dissolution of the dosage form and that the coated dosage form is physiochemically stable.
• the bilayer tablet according to the present i nvention generally contains 1 0 to 1 60 mg, preferably 40 to 80 mg, of telmisartan and 5 to 50 mg, preferably 6.25 to 25 mg, of diuretic.
• Presently preferred forms are bilayer tablets comprising 40/6.25mg, 40/1 2.5 mg, 80/12.5 mg and 80/25 mg of telmisartan and HCTZ, respectively.
• the total composition of the telmisartan layer according to the invention may vary within the following ranges, with the proviso that the proportional composition given above with respect to the basic pharmaceutical compositions is met:
• telmisartan 10 to 1 60 mg of telmisartan; 10 to 1 60 mg of meglumine or arginine, or 2 to 33 mg of NaOH, or
• telmisartan 20 to 80 mg of telmisartan; 10 to 90 mg of meglumine, or 4 to 1 6 mg of NaOH, or 6 to 23 mg of KOH; 2 to 40 mg of non-ionic surfactants or emulsifiers selected from poloxamers, polyethylene glycols, polyethoxylated and hydrogenated castor oil, poloxamers being especially preferred;
• telmisartan 20 to 80 mg of meglumine
• water soluble diluents selected from mannitol, erythritol, sorbitol and sucrose; and 0.1 to 20 mg of further excipients and/or adjuvants selected from crystalline cellulose, light anhydrous silicic acid and magnesium stearate.
• HCTZ is incompatible with basic agents being a component of the telmisartan tablet formulations according to the invention.
• This problem can be overcome by means of a bilayer pharmaceutical tablet comprising a first telmisartan containing tablet layer prepared from a pharmaceutical composition mentioned hereinbefore under the first aspect of the invention, and a second tablet layer containing a diuretic in a disintegrating tablet matrix.
• the second tablet layer composition generally comprises 1.5 to 35 wt.%, preferably 2 to 25 wt.%, of active ingredient; 25 to 85 wt.%, preferably 35 to 75 wt.%, of filler; 10 to 40 wt.%, preferably 10 to 30 wt.%, of dry binder; 0.5 to 10 wt.%, preferably 1 to 5 wt.%, of wet granulation binder; and 1 to 10 wt.%, preferably 2 to 8 wt.%, of disintegrant.
• the other excipients and adjuvants are generally employed in the same amount as in the first tablet layer composition.
• the filler is may be selected from D- mannitol, erytthritol, anhydrous lactose, spray-dried lactose and lactose monohydrate.
• Tablets of the present invention tend to be very low hygroscopic and may be packaged using PVC-blisters, PVC/PVDC-blisters or a moisture-proof packaging material such as aluminium foil blister packs, polypropylene tubes, glass bottles and HDPE bottles.
• a further object of the invention is directed to methods for producing the bilayer tablets hereinbefore.
• the tablet layers comprising telmisartan according to the invention may be prepared by any suitable method known to those skilled in the art, for instance, by freeze drying of aqueous solutions, coating of carrier particles in a fluidized bed, and by solvent deposition on sugar pellets or other carriers.
• the pharmaceutical compositions are prepared using a granulation process, e.g. the fluid-bed granulation process (A), or, in the alternative, the spray-drying process (B) described specifically hereinafter.
• A fluid-bed granulation process
• B spray-drying process
• telmisartan Since during subsequent processing telmisartan is normally dissolved and transformed into a substantially amorphous form, its initial crystal morphology and particle size are of little importance for the physical and biopharmaceutical properties of the pharmaceutical composition obtained.
• a fluid-bed granulation process (A) can be used for preparation of the pharmaceutical compositions according to the invention, characterized by the following steps: (i) preparing a granulation liquid as an aqueous solution by dissolving 3 to 50 wt.% of telmisartan together with the following components in water or in a mixture solution of ethanol and water:
• telmisartan 1 :1 to 10:1
• a non-ionic surfactant or emulsifier in an amount of about 1 to 20 wt.%
• step (ii) an inlet air temperature of about 60 to 120 °C may be used.
• step (iii) an inlet temperature of about 80 to 100 °C may be used.
• the spraying rate greatly depends on the type of granulator used as well as the batch size and can be adjusted by the skilled person by routine. Only for instance, a spraying rate of 400 to 1000 imL/min may be suitable for a 200 kg granulate batch. Lower or higher spray rates may also used.
• a spraying rate of 400 to 1000 imL/min may be suitable for a 200 kg granulate batch. Lower or higher spray rates may also used.
• an inlet temperature of about 60 to 120 °C, and a duration of drying of about 1 to 30 minutes may be used.
• a screen with a mesh size of 0.5 to 3 mm may be suitable.
• the optional milling step (vi) can be carried out conventionally by the skilled person.
• a spray-drying process (B) can be used for preparation of the pharmaceutical compositions according to the invention, characterized by the following steps:
• step (v) optionally, adding further excipients and/or adjuvants in any of steps (i) to (iv), wherein all percentage amounts given are related to the final composition to be prepared.
• a conventional milling step may be applied, preferably before optional addition of a lubricant according to step (iv). Furthermore, a powdery composition may be converted into a granular composition applying conventional granulation techniques.
• Process data drying step Inlet air temperature: 80 - 100 °C
• the granules are screened, for i nstance using an oscillator or comil screen machine, with a mesh size of 1.5 mm.
• a suitable rotary tablet press i.e. bi-layer and/or triple-layer tablet press
• the final mixtures of telmisartan layer and HCTZ layer for tablet compression are compressed into bilayer tablets.
• the target weight is about 240 mg for T40+H12.5 FDC.
• the tablet hardness can be adjusted by variation of the main compression force.

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• 2006
  • 2006-11-15 US US11/560,059 patent/US8637078B2/en active Active
  • 2006-11-22 JP JP2008541736A patent/JP2009517366A/ja active Pending
  • 2006-11-22 WO PCT/EP2006/068737 patent/WO2007060170A2/en not_active Ceased
  • 2006-11-22 CA CA2625404A patent/CA2625404C/en not_active Expired - Fee Related
  • 2006-11-22 EP EP06819653A patent/EP1959934A2/en not_active Withdrawn
  • 2006-11-23 TW TW095143437A patent/TW200806288A/zh unknown
  • 2006-11-24 AR ARP060105184A patent/AR057932A1/es not_active Application Discontinuation
• 2013
  • 2013-02-08 JP JP2013023562A patent/JP5833037B2/ja active Active

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