WO2024217830A1 - Procédé de préparation de capsules dures remplies de pastilles de dabigatran - Google Patents

Procédé de préparation de capsules dures remplies de pastilles de dabigatran Download PDF

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Publication number
WO2024217830A1
WO2024217830A1 PCT/EP2024/058017 EP2024058017W WO2024217830A1 WO 2024217830 A1 WO2024217830 A1 WO 2024217830A1 EP 2024058017 W EP2024058017 W EP 2024058017W WO 2024217830 A1 WO2024217830 A1 WO 2024217830A1
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range
process according
core
tartaric acid
pellet
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English (en)
Inventor
Lukasz WOZNIAK
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Adamed Pharma SA
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Adamed Pharma SA
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    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/1682—Processes

Definitions

  • the invention relates to a process for the preparation of pharmaceutical capsule oral dosage form of the active substance dabigatran etexilate and the pharmacologically acceptable salts thereof, in particular dabigatran etexilate methane sulfonate.
  • the reference drug product containing dabigatran, Pradaxa is marketed in the form of pellets in hard HPMC capsules. These pellets are prepared by the powder layering method described in W003/074056, W02009/118321, W02009/118322, and WO2010/007016.
  • Dabigatran is known to degrade easily in the presence of water, the same is true for its salts, especially etexilate methanesulfonate.
  • W02012001156 provides the information that LOD of the dabigatran-containing pellets should be below 1% at any stage of pellets manufacturing, i.e. from starting cores through all subsequent coatings, including the active coating with dabigatran active substance and drying is performed at every step of the dabigatran pellets manufacturing process.
  • EP1485094B1 discloses that finished layered dabigatran pellets are dried and also drying is performed after each layer deposition.
  • Water is a strong degrading factor responsible for the formation of Dabigatran etexilate impurity; Ethyl 3- ⁇ [(2- ⁇ [(4- ⁇ N'-hexyloxy-carbonyl-carbamoyl ⁇ phenyl) amino] methyl ⁇ -l- methyl-lH-benzimidazol-5- yl) carbonyl]pyridin-2-yl-amino ⁇ propanoate. It is described as an Impurity - G.
  • impurity G By elimination of the moisture from the composition and tight closure of the product, the better stability can be achieved of the dabigatran etexilate, manifesting lower impurity level (impurity G and overall impurity level) in specified timepoints of the storage.
  • the present invention relates to the following aspects:
  • the present invention relates to a process for the preparation of solid oral pharmaceutical composition comprising dabigatran etexilate methanesulfonate, comprising the following steps:
  • a core is coated with a solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in water,
  • step (b) the coated core of step (a) is coated with an isolating layer
  • step (c) the insulated core of step (b) is coated with a layer comprising dabigatran etexilate methane sulfonate, thus providing pellets, wherein a powder coating is not used at any step of the process, and
  • step (e) the capsule obtained in step (d) is dried until the moisture content in the capsule body measured as Loss on drying according to European Pharmacopoeia edition 11.0 monography 2.2.32 is in a range 1.0 - 3.5 wt.%.
  • step a) The process according to (1), wherein the core in step a) is spherical or non-spherical.
  • step a) The process according to (1) or (2), wherein the core in step a) is comprised of sugar, microcrystalline cellulose, starch or tartaric acid.
  • step a) is a non-spherical tartaric acid core in a form of an irregular crystal
  • step a) The process according to (1) to (7), wherein the solution comprising tartaric acid and a binder and optionally further pharmaceutical excipients in step a) is a homogenous solution, without any undissolved particles.
  • step a) The process according to any of (1) to (9), wherein the cores in step a) are coated with the use of fluid bed coating method.
  • step a) The process according to any of (1) to (10), wherein the binder in step a) is acacia or Hypromellose, preferably spray-dried acacia or Hypromellose 2910.
  • step b) The process according to (13), wherein the amount of HPMC in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet.
  • step b) The process according to any of (12) to (14), wherein the amount of talk in the insulation coat of step b) is in a range of 1.0- 2.0 wt.%, most preferably 1.4 wt.% calculated on the total mass of the pellet, and 2,5 -3,5 wt.%, preferably 3,0 wt.% calculated on the total mass of the isolated core obtained in step b).
  • the insulating coat further comprises dimethicone, preferably in the form of an 35% aqueous emulsion, preferably dimethicone is present in the insulation coat of step b) in a range of 0.01- 0.03 wt.%, most preferably 0.02 wt.% calculated on the total mass of the pellet.
  • step c) The process according to any of (1) to (17), wherein the layer in step c) comprises dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • step c) The process according to any of (1) to (22), wherein the layer comprising dabigatran etexilate in step c) further comprises talk, preferably the amount of talk is in a range of 5.0 - 7.0 wt.%, most preferably 6.05 wt.% calculated on the total mass of the pellet.
  • wt.% preferably 1.0 - 3.0 wt.%, more preferably 1.0 - 2.5 wt.%; particularly preferably 1.17, 1.65, 1.69, 2.03, 2.09 2.19, 2.2, 2.31 and 2.4 wt.%
  • step (e) is performed in a drum dryer with the use of dry air or in a tray dryer, preferably a drum dryer.
  • drying in step (e) is performed in a temperature from a range of 20-80°C, preferably 25-80°C, 30-80°C, 35-75°C and most preferably 40- 80°C; 40-70°C and most preferably 42-65°C.
  • step (e) The process according to any of the claims 1 to 28, wherein drying in step (e) is performed during 1 - 12h, preferably 5 - 12h or also preferably 1-2 h, such as at least Ih.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6) and (26).
  • the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the spherical or non-spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm, measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methane sulfonate, wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (5), (7) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20-80°C for at least Ih and Loss on drying is in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (5), (7) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (9) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises coating of the spherical or non-spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of cores is in the size of not more than 0.4 mm, measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0 - 45.0 wt.%, preferably 42.83 wt.%. calculated on the total mass of the pellet obtained in step c).
  • the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) and (10) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (9) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of cores is in the size of not more than 0.4 mm, measured by Ph. Eur.
  • the obtained coated core is further coated with an isolating layer
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0 - 45.0 wt.%, preferably 42.83 wt.%. calculated on the total mass of the pellet obtained in step c).
  • the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (7), (8) and (10) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (9), (11) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the coating of the spherical or non- spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the core is in the size of not more than 0.4 mm, monograph by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0 - 45.0 wt.%, preferably 42.83 wt.% calculated on the total mass of the pellet and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to method 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) and (10), (12) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (9), (11) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the core is in the size of not more than 0.4 mm, monograph by Ph. Eur.
  • the obtained coated core is further coated with an isolating layer
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0 - 45.0 wt.%, preferably 42.83 wt.% calculated on the total mass of the pellet and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to method 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (7), (8) and (10), (12) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (11), (13) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the spherical or non-spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm, measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 -
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) to (10), (12) and (14) to (25) and (27) to (30) .
  • the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (11), (13) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm, measured by Ph. Eur.
  • the obtained coated core is further coated with an isolating layer comprising HPMC, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 -
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (7), (8) to (10), (12) and (14) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (11), (13), (14) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the spherical or non- spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3 - 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12 - 18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) to (10), (12) and (15) to (25) and (27) to (30)..
  • the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (11), (13), (14) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph. Eur.
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3 - 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12 - 18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate, wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (7), (8) to (10), (12) and (15) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (11), (13), (14), (18) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the spherical or non- spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm, measured by Ph.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet, where
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) to (10), (12) and (15) to (17) and (19) to (25) and (27) to (30).
  • the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (11), (13), (14), (18) and (26).
  • the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein fraction Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm, measured by Ph. Eur.
  • PSD fraction Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20000 -60000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet, wherein powder coating
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above 7), (8) to (10), (12) and (15) to (17) and (19) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (11), (13), (14), (18), (19) and (26).
  • a the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the spherical or non-spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3 - 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20 000
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • the layer in step c) is coated as a HPC-talk suspension in isopropanol and wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1 .0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) to (10), (12) and (15) to (17) and (20) to (25) and (27) to (30).
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (11), (13), (14), (18) and (26)..
  • the process for the preparation of pharmaceutical composition comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3 - 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s (2 wt.% in water at 20°C), and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methane sulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • the layer in step c) is coated as a HPC-talk suspension in isopropanol and wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above 7), (8) to (10), (12) and (15) to (17) and (20) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (3), (6), (11), (13), (14), (18), (19), (20) and (26).
  • athe process for the preparation of pharmaceutical composition comprises: coating of the spherical or non-spherical sugar, microcrystalline cellulose, starch or tartaric acid core, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3 - 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s, and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • the layer in step c) is coated as a HPC-talk suspension in isopropanol.
  • HPC in the layer in step c) has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C, and wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the weight ratio of HPC to the active substance in the layer of step c) is in a range of 2: 10 to 1: 10, preferably 1: 10.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (2), (7), (8) to (10), (12) and (15) to (17) and (21) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4), (6), (11), (13), (14), (18) and (26).
  • the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal, wherein Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph. Eur.
  • PSD Particle Size Distribution
  • the obtained coated core is further coated with an isolating layer comprising HPMC in a range of 1.3 - 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the pellet, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s, and the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • the layer in step c) is coated as a HPC-talk suspension in isopropanol.
  • HPC in the layer in step c) has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C, and wherein powder coating is not used at any step of the process and the obtained pellet is packed into a hard capsule and dried until the moisture content in the capsule body measured as Loss on drying according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 is in a range 1.0 - 3.5 wt.%.
  • the weight ratio of HPC to the active substance in the layer of step c) is in a range of 2: 10 to 1: 10, preferably 1: 10.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above 7), (8) to (10), (12) and (15) to (17) and (19) to (25) and (27) to (30).
  • the process is performed in from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the process for the preparation of a pharmaceutical composition of dabigatran etexilate methanesulfonate for oral administration has the features according to the above (1), (4) (6), (9), (11), (13), (18), (21) and (26).
  • the process for the preparation of pharmaceutical composition is provided, which comprises: coating of the non-spherical tartaric acid in form of an irregular crystal fraction Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4 - 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm measured by Ph. Eur.
  • the obtained coated core is further coated with an isolating layer comprising HPMC, said HPMC has molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12-18 mPa-s (2 wt.% in water at 20°C), preferably 15 mPa-s.
  • the obtained insulated core is further coated with a layer comprising dabigatran etexilate methanesulfonate in an amount in a range of 35 - 45%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • the amount of HPC in the dabigatran layer of step c) is in a range of 3.7 - 4.3 wt.%, preferably 4.0 - 4.2, most preferably 4.17 wt.% calculated on the total mass of the pellet.
  • Powder coating is not used at any step of the process and wherein the tartaric acid amount in the pellet is in a range of 40.0 - 45.0 wt.%, preferably 42.83 wt.%.
  • the process for preparation of pharmaceutical composition according to this aspect may be further characterized according to any one of the above (7), (8), (10), (12) and (14) to (17) and (19) to (20) and (22) to (25) and (27) to (30). Such that in a preferred variant of this aspect the process is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the capsule is a HPMC capsule.
  • the active substance dabigatran etexilate methanesulfonate is present in polymorphic form I. No change of polymorphic form I of dabigatran etexilate methanesulfonate is observed during any steps of the process according to the invention as well as during stability studies in accelerated conditions.
  • the dabigatran etexilate methanesulfonate has a d(90) particle size of less than 150 pm, more preferably less than 80 pm and most preferably less than 40 pm.
  • the d90 or d50 particle size mentioned herein refers to the size of at least 90 or 50 wt.% by volume of the particles. It is measured by using light scattering methods and in particular using a Malvern Mastersizer and standard measurement methods recommended by the manufacturer of the instrument and well known in the art.
  • the starting tartaric acid crystals contain water in a range of 0.4 wt.% or less, more preferably in a range of 0.3%, in a most preferred embodiment in a range of 0.2%, calculated on the mass of the crystals.
  • the final dabigatran pellets contain water in a range of 0.6 wt.% or less, more preferably in a range of 0.5 wt.%, in a most preferred embodiment in a range of 0.4 wt.%, calculated on the total mass of the final pellet.
  • the process step a) utilizes 42.83 wt.% of tartaric acid in form of non- spherical crystals, 2.18% of acacia suspended in purified water;
  • process step b) utilizes 0.02 wt.% of dimethicone, 1.45 wt.% of HPMC, 1.45 wt.% of talc suspended in 90 v/v% ethanol and
  • process step c) utilizes 41.85 wt.% of Dabigatran etexilate methanesulfonate, 4.17 wt.% of HPC, 6.05 wt.% of talc suspended in iPrOH, wherein all wt.% are calculated on the total mass of the final pellet, and wherein the amount of solvents is determined as quantum satis (abbreviation q.s.
  • the capsule is a HPMC capsule.
  • the process step a) utilizes 42.83 wt.% of tartaric acid in form of non-spherical crystals, 2.
  • process step b) utilizes 0.02 wt.% of dimethicone, 1.45 wt.% of HPMC, 1.45 wt.% of talc suspended in of 90 v/v% ethanol and process step c) utilizes 41.85 wt.% of Dabigatran etexilate methanesulfonate, 4.17 wt.% of HPC, 6.05 wt.% of talc suspended in iPrOH, wherein all wt.% are calculated on the total mass of the final pellet, and wherein the amount of solvents is determined as quantum satis (abbreviation q.s.
  • Q.S. is a Latin term meaning the amount which is enough to perform the operations of process step a), b) and c), respectively. All the solvent evaporate during the process operations and the process is performed in temperature from a range of 40 - 70°C for at least 6h preferably 20 - 80°C for at least Ih , Loss on drying is in a range of 1.0 - 3.5 wt.%, preferably 1.0 - 2.5 wt.%, the capsule is a HPMC capsule. In each of the above preferred aspect and variant of such aspect, including the presence of HPMC capsule and the process step e) is performed in a drum drier with the use of dry air.
  • the process enables the production of the pharmaceutical composition using simple, non-expensive and widely available starting ingredients, conventional tools and well-known technologies, while significantly simplifying the manufacturing process, and reducing its costs, comparing to manufacturing standards known in the art.
  • the pharmaceutical composition can be prepared by coating methods, such as film coating with water-based solutions or water / organic solvent suspensions.
  • the coating agent comprises binder.
  • dabigatran etexilate methane sulfonate composition in form of pellets fdled into hard capsuled and subsequently dried, bioequivalent to the referent dabigatran etexilate methanesulfonate composition Pradaxa can be obtained when non-spherical tartaric acid in form of an irregular crystal is coated with a solution comprising tartaric acid, a binder and optionally further pharmaceutical excipients in water, the obtained coated core is further coated with an isolating layer, and the insulated core of the step is coated with a layer comprising dabigatran etexilate methanesulfonate, and such obtained pellet is fdled into hard capsule and subsequently dried.
  • the process starts from non-spherical irregular tartaric acid crystals which have the diameter in a range of 0.3 - 0.7 mm ⁇ 5 wt.%. It is preferrable that Particle Size Distribution (PSD) of the core in step a) is in a range of 0.4- 0.6 mm ⁇ 5 wt.% and ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm.
  • PSD Particle Size Distribution
  • 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5 - 0.63 mm
  • ⁇ 20 wt.% of the cores is in the size of not more than 0.4 mm
  • 25 - 60 wt.% of the tartaric acid crystals is in a range of 0.5 - 0.63 mm, measured by Ph. Eur. Sieve analysis method.
  • Such non-spherical tartaric acid crystals are coated with a water solution comprising tartaric acid a binder and optionally further pharmaceutical excipients.
  • acacia or Hypromellose preferably spray- dried acacia or Hypromellose 2910, even more preferably spray-dried acacia is used as the binder and the coating solution is homogenous solution, without any undissolved particles.
  • the solution can be subsequently fdtered via fdtration mesh of the size of 0.5 - 0.8 mm.
  • the said solution is mixed by a low- shear equipment, preferably by a propeller. So more sophisticated equipment is not needed in the operation of coating (process step a)) and as a result the composition can be produced economically.
  • the total amount of tartaric acid in the resulting pellet can be in a range of 40.0-45.0 wt.%, however most preferably is equal to 42.83 wt.% calculated on the total mass of the pellet.
  • the crystals in step a) are coated with the use of any known coating method, however fluid bed coating method is preferred. Powder coating is not necessary to achieve tartaric acid cores, suitable for application of insulating coat and active coat during process steps b) and c), respectively. Coating in process step a) is performed with the use of water solution. Thus, difficult for validation and technically demanding powdering and the use of organic solvents is avoided, and this process step a) is more economic and environmentally friendly comparing to the prior art.
  • the tartaric acid cores obtained in process step a) are further coated in step b) with an ethanolic HPMC- talk suspension.
  • This coating insulates the acidic environment of tartaric acid from the active coating. Such layer is necessary as the tartaric acid degrades dabigatran etexilate methanesulfonate when in contact.
  • the insulation can be provided by any non-functional polymer suitable to be used as a coating, HPMC with molecular weight of approximately 20 000 - 60 000 g/mol, and viscosity in a range of 12 - 18 mPa’s, preferably 15 mPa-s (2 wt.% in water at 20°C) is particularly preferrable.
  • Best insulation performance is achieved when the amount of HPMC in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, preferably 1.45 wt.% calculated on the total mass of the final pellet.
  • Other excipients can be used in insulating layer as to improve the performance of coating and characteristic of this coat.
  • Best performance is achieved when the amount of talk in the insulation coat of step b) is in a range of 1.3- 1.5 wt.%, most preferably 1.45 wt.% calculated on the total mass of the final pellet.
  • the insulating coat can further comprise dimethicone, preferably used in the form of an 35% aqueous emulsion, preferably in a range of 0.01- 0.03 wt.%, most preferably 0.02 wt.% calculated on the total mass of the pellet.
  • dimethicone preferably used in the form of an 35% aqueous emulsion, preferably in a range of 0.01- 0.03 wt.%, most preferably 0.02 wt.% calculated on the total mass of the pellet.
  • a suspending agent any liquid suitable for coating can be used, however, a suspension of 90 v/v% ethanol is particularly preferred.
  • the active layer in step c) comprises dabigatran etexilate methanesulfonate in an amount in a range of 35- 45wt.%, most preferably 41.85 wt.%, calculated on the total mass of the pellet.
  • a suspending agent in process step c) any liquid suitable for coating can be used, however, a HPC-talk suspension in isopropanol is particularly preferred. Best performance is achieved when the HPC in the layer in step c), has molecular weight of approximately 80 000 Da, and its 10% aqueous solution has viscosity of 300 - 600 mPa-s in 25 °C.
  • the amount of HPC in the layer of step c) can be in a range of 3.7 - 4.3 wt.%, preferably 4.0-4.2 wt.%, most preferably 4.17 wt.% calculated on the total mass of the pellet.
  • the weight ratio of HPC to the active substance is in a range of 2 : 10 to 1: 10, preferably 1: 10.
  • the layer comprising dabigatran etexilate in step c) can further comprises talk, preferably the amount of talk is in a range of 5.0 - 7.0 wt.%, most preferably 6.05 wt.% calculated on the total mass of the final pellet.
  • step (d) The pellet obtained in steps (a) to (c) is then in step (d) packed into a hard capsule, preferably a HPMC capsule.
  • a hard capsule preferably a HPMC capsule.
  • Such capsule is a standard one suitable for pharmaceutical manufacturing and medical use. Such capsule is not pre-dried before entry into the process according to the invention.
  • step (e) in which the capsule from step (d) filled with the pellet containing dabigatran etexilate methanesulfonate obtained in step (c) is dried until the moisture content in the capsule body measured as Loss on drying according to European Pharmacopoeia edition 11.0 monography 2.2.32 is in a range 1.0 - 3.5 wt.%.
  • the capsule drying process in step (e) is performed in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the capsule is a HPMC capsule.
  • the present invention relates to the pharmaceutical composition in the form of pellets obtainable by the manufacturing process comprising subsequently performed process step a), b) and c).
  • the final pellet composition comprises 41.85 wt.% of Dabigatran etexilate methanesulfonate, 42.83 wt.% of tartaric acid, 2.18 wt.% of acacia, spray-dried 1.45 wt.% of Hypromellose 15cP, 7.50 wt.% of talc, 0.02 wt.% of dimethicone (as 35% aqueous emulsion) and 4.17 wt.% of hydroxypropylcellulose (molecular weight approx.
  • composition obtainable by the manufacturing process comprising subsequently performed process step a), b) and c) is packed into a hard HPMC capsule, and thus providing capsules with different strengths of the active substance, 150mg, 110 mg and 75 mg.
  • the qualitative composition of these respective strengths is as follows:
  • the capsules contain 75mg, HOmg, or 150mg of Dabigatran active substance, which corresponds to 86.48mg, 126.83mg, and 172.95mg, respectively, of Dabigatran etexilate methanesulfonate.
  • the capsules fdled with the compositions listed in the Table above are then dried in temperature from a range of 20 - 80°C for at least Ih and Loss on drying is achieved in a range of 1.0 - 3.5 wt.%.
  • the conditions of the process in step (e) shall be adjusted in the manner that allow evaporation of the moisture from the product and especially the capsule shell to the desired LOD, according to the second law of thermodynamics.
  • the relative humidity of the air used in step (e) of the inventive process shall be kept low allowing mass transfer to the environmental compartment, such as relative humidity not exceeds 30%RH, preferably not exceeds 20%RH, preferably not exceeds 15%RH, and most preferably not exceeds 10%RH.
  • relative humidity not exceeds 30%RH preferably not exceeds 20%RH, preferably not exceeds 15%RH, and most preferably not exceeds 10%RH.
  • the temperature have to be increased in order to achieve appropriate air dryness according to Mollier chart plot.
  • the fdled capsules are subjected to drying phase for a period of 1 - 12 hours, preferably 1 - 8 hours, and most preferably 1 - 6 hours at a temperature of about 20-80°C, preferably 25-80°C, 30-80°C, 35-75°C and most preferably 40-80°C; 40-70°C and 42-65°C in a relative humidity of not exceeding 30%RH, preferably not exceeding 20% RH, preferably not exceeds 15% RH, and most preferably not exceeds 10% RH.
  • the filled capsules could be also exposed to a relative humidity of not more than 30% RH, preferably not more than 20% RH, not exceeds 15%RH, and most preferably not exceeds 10%RH, for a period of during 1 - 12h, preferably 1 - 8h, and most preferably 1 - 6 h. hours, at a temperature of about 20-80°C, preferably 25-80°C, 30-80°C, 35-75°C and most preferably 40-80°C; 40-70°C and 42-65°C.
  • the moisture contained in the capsule ensures its flexibility, therefore encapsulation using a material with standard moisture content, ensures trouble-free process, such as separation of the capsule halves (body and cap) in the capsule machine hopper, breaking of capsules in the opening or blocking station.
  • This also enables the performance of the encapsulation process in standard environmental conditions, this not requiring adjustment and monitoring of production zone to more restricted temperature/moisture conditions.
  • the pellet of dabigatran etexilate methanesulfonate can be prepared from non-expensive and commercially available substrates, starting from crude tartaric acid crystals and utilizing standard capsule bodies.
  • the process according to the first aspect of the invention is economically less demanding than powder layering of tartaric acid crystals, since several repeated steps of powder-layering are omitted. It is also economically beneficial comparing to the use of pre-dried capsules and ensuring required environmental conditions for its handling.
  • dabigatran etexilate methanesulfonate pellets are stable in intermediate and accelerated aging conditions for 6M or during 2 or 3 years shelf life as well as bioequivalent to the referent drug product, which makes them ready to be applied in medicinal uses.
  • the coated pellets obtained according to the second aspect of the invention are of narrow size distribution and reveal a smooth surface. Satellites of tartaric acid crystals don’t protrude into the isolating layer and subsequently the layer comprising the active pharmaceutical ingredient, thus degradation of dabigatran etexilate methanesulfonate, is not observed.
  • Sieve analysis method for measurement of Crystal diameters are measured according to the sieve analysis method using screens of aperture 0.7; 0.63; 0.5; 0.4 mm and receiver. They are placed on the automatic vibratory sieve shaker. 100 g sample of measured material is then placed on the top of the screens set.
  • the apparatus setup is: interval: 10 s, amplitude 1,5 mm, analysis time: 5 minutes. The outcome is presented as a percentage of the fractions.
  • Tartaric acid crystals Ph Eur: Tartaric Acid, colourless monoclinic crystals of Acidum tartaricum; [R- (R*,R*)] -2,3 -Dihydroxybutanedioic acid CAS Registry Number [87-69-4],
  • These crystals are of prism shape with the diameter of the circle circumscribed on the smallest dimension is withing 0,4 - 0,6 mm range.
  • Active coat' a coat comprising a pharmaceutically active substance of Dabigatran etexilate methane sulfonate
  • Particle Size Distribution (PSD) - range of particles size as measured by Sieve analysis method as described above.
  • Loss on drying (LOD) - is understood and measures according to monograph 2.2.32 of the European Pharmacopoeia edition 11.0 (07/2019:20232). Shortly, is the loss of mass after drying under specified conditions, calculated as a percentage (m/m, i.e. wt.%).
  • Drum dryer an equipment allowing to dry bulk product by contact with low relative humidity air, while moving and/or vibrating bed (continuously or in intervals).
  • the low relative humidity may be achieved by, but not limited to, heating, dehumidifying, freezing.
  • drum dryers Rotating Tray, Vibrating Conveyor, Pan Dryer, Pan Coater, Fluid bed dryer, Paddle, rotary (tumble), agitation dryer, micro wave dryer, etc.
  • the low relative humidity may be achieved by, but not limited to, heating, dehumidifying, freezing, examples of try dryers: shelf dryer, container dryer.
  • Dry air - is air that has a low relative humidity, i.e. a relative humidity of 30% or less.
  • Relative humidity is a the ratio of the partial vapor pressure and the vapor pressure at a given temperature.
  • Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg are manufactured with standard technologies of sieving, three steps fluid bed granulation (coating) and drying and encapsulation. Table 2. Types of manufacturing equipment for production of Dabigatran etexilate, capsules hard, 75mg, llOmg, 150mg The manufacturing process of Dabigatran etexilate, capsules hard, 75mg, l lOmg, 150mg is described below with three process main stages appearing in the following order:
  • Process stage a) - Cores non-spherical tartaric acid crystals or Sugar spheres (Nonparail seeds) or MCC spheres are coated with tartaric acid water solution with acacia.
  • Process stage b) - Insulated tartaric acid pellets tartaric acid cores obtained in process step a) are coated with an insulating coat.
  • Process stage c) - Dabigatran Pellets/ active coating insulated tartaric acid cores are coated with an active coat.
  • Encapsulation capsules with finished pellets.
  • Drying capsules filled with pellets are dried to the pre-set LOD value.
  • Packaging capsules packed into blisters.
  • Tartaric acid core crystals a.1.
  • PSD Particle Size Distribution
  • Preparation of Coating suspension 2 Mix together Ethanol, water purified and dimethicone to the attained solution dose specified amount of Hypromellose. After its complete dissolution add specified amount of Talc. Mix until solution is free of lumps.
  • Fluid bed coating of the Tartaric acid cores Load specific amount of Tartaric acid cores obtained in step a) to the fluid bed granulator. Spray coating suspension 2 using pump onto the surface of the cores achieving Insulated tartaric acid pellets.
  • Drying of the Insulated tartaric acid cores after coating process is finished, elevate the temperature of the bed and dry the pellets to eliminate exceeding solvents from it.
  • Process stage c) Dabigatran Pellets/ active coating c.l.
  • Preparation of Coating suspension 3 Add specified amount of isopropyl alcohol to the mixer. Dose defined amount of Hydroxypropylcellulose and mix until component is dissolved. Afterward add Dabigatran etexilate methanesulfonate and Talc to the liquid and mix until solution is free of lumps.
  • Fluid bed coating of the Insulated Tartaric acid cores - Load Insulated tartaric acid cores to the fluid bed granulator. Spray coating suspension 3, using pump, onto the surface of the cores, achieving ready Dabigatran pellets. c.3.
  • Table 8 Description of capsule shells. Table 9. Compositions of the experimental formula of finished Dabigatran etexilate methanesulfonate pellets. Determination of water content in the non-spherical tartaric acid cores vs commercial spherical tartaric acid cores:
  • Dabigatran is sensitive to acid hydrolysis in an aqueous medium, therefore to maintain the stability, maximally dry tartaric acid cores should be used as a starting material.
  • standard tartaric acid crystals according to the invention is advantageous because such material has much lower water content compared to spherical tartaric acid pellets, i.e. no more than 0.2 wt.% vs up to 0.5 wt.%
  • Particle Size Distribution (PSD) of the irregular tartaric acid crystal entering in step a) is acceptable in a range of 0.3 - 0.7 mm
  • Particle Size Distribution (PSD) of the insulated pellets resulting from step b) is acceptable in a range of 0.63 - 0.80 mm.
  • the use of larger tartaric acid crystals, i.e. in a range 0.5 - 0.7 mm and subsequent coating with smaller amount of tartaric acid-binder Solution results in insulated pellets of similar mass and size.
  • composition according to Table 13 has been used to prepare pellets batches according to process step a) with varying content of fraction with size ⁇ 0.4mm, presented in Table 14.
  • Fraction 0.63 - 0.80 shall be within 65 - 85%.
  • Coated pellets obtained in step a) are obtained in preferable size range of 0,63 - 0,80 mm when ⁇ 20%, preferably ⁇ 15 wt.% of the tartaric acid crystals entering the step a) is in the size of not more than 0.4 mm, measured by Ph. Eur. sieve analysis method.
  • Blisters Pack Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg into Foil: Polyamide- Aluminium-PVC (laminate), Lidding foil: Aluminium. Pack the obtained blisters into carton boxes.
  • Batch 2 Dry Dabigatran etexilate, capsules hard, 75mg, HOmg, 150mg in the dryer in the conditions below, then pack into Foil: Polyamide -Aluminium-P VC (laminate), Lidding foil: Aluminium. Pack the obtained blisters into carton boxes.
  • Capsules used for manufacturing of Dabigatran etexilate are HPMC capsules, due to the fact, that it contain much less water in the composition. Furthermore, drying process (loosing water content) doesn’t change elastic properties of capsules. For the capsules of all sizes tests were conducted. They were dried in 40 - 50 °C and Loss on drying (LOD) and resistance to crushing was evaluated. Specification for capsules indicate LOD of capsule shell at 4.0 - 6.0%. It was checked when capsules reach LOD equilibrium and if for any of the samples mechanical properties would deteriorate. For that issue, test was conducted, where capsules with pellets inside were checked for the resistance to crushing. Number of fractured capsules were measured for every 10 examined samples. Deformation was preferred outcome.

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Abstract

L'invention concerne un procédé de préparation d'une composition pharmaceutique orale de la substance active dabigatran étexilate et de sels pharmacologiquement acceptables de celle-ci, en particulier de dabigatran étexilate méthanesulfonate sous la forme de capsules dures, et ladite composition pharmaceutique pouvant être obtenue par ledit procédé.
PCT/EP2024/058017 2023-03-30 2024-03-26 Procédé de préparation de capsules dures remplies de pastilles de dabigatran Ceased WO2024217830A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074056A1 (fr) 2002-03-07 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme de presentation a administrer par voie orale pour l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique et ses sels
WO2009118322A1 (fr) 2008-03-28 2009-10-01 Boehringer Ingelheim International Gmbh Procédé pour préparer des formulations de dabigatran administrées par voie orale
WO2009118321A1 (fr) 2008-03-28 2009-10-01 Boehringer Ingelheim International Gmbh Procédé de production de granules d'acide
WO2010007016A1 (fr) 2008-07-14 2010-01-21 Boehringer Ingelheim International Gmbh Procédé de fabrication de composés médicinaux contenant du dabigatran
WO2012001156A2 (fr) 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Formes pharmaceutiques posologiques orales comprenant de l'étéxilate de dabigatran et ses sels pharmaceutiquement acceptables
CN114191394A (zh) * 2020-09-02 2022-03-18 北京四环制药有限公司 一种达比加群酯药物组合物及其制备方法和其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074056A1 (fr) 2002-03-07 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Forme de presentation a administrer par voie orale pour l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionique et ses sels
EP1485094B1 (fr) 2002-03-07 2012-07-04 Boehringer Ingelheim International GmbH Forme posologique pour administration par voie orale de l'ethylester d'acide 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino] propionique ou ses sels
WO2009118322A1 (fr) 2008-03-28 2009-10-01 Boehringer Ingelheim International Gmbh Procédé pour préparer des formulations de dabigatran administrées par voie orale
WO2009118321A1 (fr) 2008-03-28 2009-10-01 Boehringer Ingelheim International Gmbh Procédé de production de granules d'acide
WO2010007016A1 (fr) 2008-07-14 2010-01-21 Boehringer Ingelheim International Gmbh Procédé de fabrication de composés médicinaux contenant du dabigatran
WO2012001156A2 (fr) 2010-07-01 2012-01-05 Krka, Tovarna Zdravil, D.D., Novo Mesto Formes pharmaceutiques posologiques orales comprenant de l'étéxilate de dabigatran et ses sels pharmaceutiquement acceptables
CN114191394A (zh) * 2020-09-02 2022-03-18 北京四环制药有限公司 一种达比加群酯药物组合物及其制备方法和其应用

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no. 872728-81-9

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