WO2019004979A2 - Solid oral pharmaceutical compositions of dabigatran etexilate - Google Patents

Solid oral pharmaceutical compositions of dabigatran etexilate Download PDF

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Publication number
WO2019004979A2
WO2019004979A2 PCT/TR2018/050220 TR2018050220W WO2019004979A2 WO 2019004979 A2 WO2019004979 A2 WO 2019004979A2 TR 2018050220 W TR2018050220 W TR 2018050220W WO 2019004979 A2 WO2019004979 A2 WO 2019004979A2
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Prior art keywords
acid
capsule
granules
pellets
formulation
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PCT/TR2018/050220
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French (fr)
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WO2019004979A3 (en
Inventor
Ezel URAZ
Ali TÜRKYILMAZ
Arzu Palantöken
Yildiz GÜLKOK
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to EP18811674.3A priority Critical patent/EP3621599A2/en
Publication of WO2019004979A2 publication Critical patent/WO2019004979A2/en
Publication of WO2019004979A3 publication Critical patent/WO2019004979A3/en

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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
    • A61K9/14—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
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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 present invention relates to solid oral pharmaceutical compositions, comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid in a dosage unit form comprising of a first capsule and a second capsule, the second capsule which is located within the first capsule.
  • Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. Dabigatran was first disclosed in WO98/37075, which claimed compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time, under the name 1 -methyl-2-[N-[4-(N-n- hexyloxycarbonylamidino) phenyl] aminomethyl] benzimidazol-5-ylcarboxylic acid-N-(2- pyridyl)-N-(2 ethoxycarbonylethyl)amides.
  • Dabigatran etexilate a novel direct thrombin inhibitor, is a prodrug of dabigatran and is a non-peptide thrombin inhibitor.
  • the structural formula is:
  • Dabigatran is currently available as dabigatran etexilate mesylate, under the trade name Pradaxa from Boehringer Ingelheim is used for the reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
  • the solubility of dabigatran etexilate in water is 1 .8 mg/mL and dependent on the pH value.
  • EP1658056B1 suggests a tablet formulation containing dabigatran etexilate and an organic acid with a solubility in water of > 1 g / 250 ml at 20 ⁇ O.
  • EP2740471 B1 discloses a pharmaceutical composition contains the following main components: a core material comprising an inorganic acid layer, an active substance layer and an insulating layer between inorganic acid layer and active substance layer.
  • EP2588090A2 discloses a process for the preparation of an oral dosage comprising a spherical core coated with tartaric acid, a isolating layer on the coated tartaric acid layer and a layer comprising dabigatran etexilate on the isolating layer.
  • WO2015145462A1 discloses a pharmaceutical composition comprising a first component in the form of tablet comprising dabigatran and a second component in the form of capsule comprising organic acid.
  • the main object of the present invention is to provide solid oral pharmaceutical compositions, comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid in a unit dosage form with good stability and effective dissolution profile.
  • Another object of the present invention is to obtain a stable dabigatran etexilate formulation with high bioavailability.
  • Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition.
  • said pharmaceutical composition comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid, wherein the composition is in a dosage unit form comprising a first capsule and a second capsule which is located within the first capsule.
  • the term "unit dosage form” refers to nested capsule technology which is comprising a first capsule and a second capsule, the second capsule being located within the body of the first capsule.
  • the first capsule comprises a first formulation which may be a direct thrombin inhibitor, an organic acid or an inorganic acid.
  • the second capsule comprises a second formulation which may be a direct thrombin inhibitor, an organic acid or an inorganic acid.
  • the term “dabigatran etexilate free base” refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
  • the first capsule is comprising a first formulation held between the first and second capsule, and a second formulation held in the second capsule.
  • compatible formulations refers to the first and the second formulation which are comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
  • the first formulation and the second formulation are in the form of mini tablets or granules or pellets or powder or beads or capsules.
  • the first formulation is comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
  • the second formulation is comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
  • the direct thrombin inhibitor is dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof.
  • Suitable organic acid is comprising at least one carboxylic group.
  • It may include but not limited to citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.
  • Suitable inorganic acid may include but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, hydroiodic acid, sulfurous acid, hyposulfurous acid, pyrosulfuric acid, dithionous acid, thiosulfurous acid, peroxydisulfuric acid, or mixtures thereof.
  • the said composition comprises at least one pharmaceutically acceptable excipient selected from fillers, disintegrants, diluents, dispersing agents, binders, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings, melting components, coloring agents or mixtures thereof.
  • Suitable fillers may include but not limited to lactose, sugar, starches, modified starches, mannitol, calcium sulfate, xylitol or mixtures thereof.
  • Suitable disintegrants may include but not limited to cross-linked polyvinil pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacrylate potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • cross-linked polyvinil pyrrolidone crospovidone
  • povidone povidone
  • carboxymethyl cellulose croscarmellose sodium
  • low-substituted hydroxypropyl cellulose pregelatinized starch
  • Suitable diluents may include but not limited to microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • Suitable dispersing agents may include but not limited to calcium silicate, magnesium aluminum silicate or mixtures thereof.
  • Suitable binders may include but not limited to polyvinylpyrrolidone, carnauba wax, pullulan, glyceryl behenate, polycarbophil, polyvinyl acetate and its copolymers, cellulose acetate phthalate, hydroxypropyl starch, sugars, tragacanth gum, cetostearyl alcohol, acacia mucilage, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, carrageenan, guar gum, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, xant
  • Suitable lubricants may include but not limited to magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmito stearate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • Suitable glidants may include but not limited to colloidal silicon dioxide, talc, aluminium silicate, silica or mixtures thereof.
  • Suitable plasticizers may include but not limited to polyethylene glycols of different molecular weights, propylene glycol or mixtures thereof.
  • Suitable preservatives may comprise but not limited to methyl paraben and propyl paraben and their salts (such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene and butylated hydroxyanisole or mixtures thereof.
  • Suitable sweeteners may include but not limited to aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose and sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
  • Suitable flavorings may include but not limited to menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries etc. or mixtures thereof.
  • Suitable melting components are selected from gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butil pthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethly phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
  • Suitable coloring agents may include but not limited to ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine), iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
  • FD&C Food, Drug & Cosmetic
  • D&C Drug & Cosmetic
  • compositions of the present invention may be prepared by a process comprising the following steps: a. Preparing the first formulation in the form of mini tablets or granules or pellets or powder or beads or capsules;
  • Fig. 1 shows Table-1 containing Examples 1 -6.
  • Fig. 2 shows Table-2 containing Examples 1 -6.
  • granulating represents a process to provide granular product consisting of particles each having almost same size and shape, from a starting material in the form of powder, melt or aqueous solution.
  • granules refers to agglomerates of particles.
  • compositions of the present invention may be prepared using wet-granulating processes in which a powder is added with a binder and a solvent then granulated, dry- granulating processes such as slugging or compaction and direct compression, or melt- granulating processes in which a powder is mixed with a heat-melting binder and then heat-granulated.
  • granulating processes may be combined with various granulating processes such as agitating granulation method used with machines such as planetary mixers and screw mixers, high shear granulation method used with machines such as Henschel mixers and super mixers, extrusion granulation method used with machines such as cylindrical, rotary granulator, screw-extruding granulator and pellet-mill granulator, or other processes like, tumbling-granulation method, fluidized-bed granulation method, compression granulation method, crushing granulation method, and spray dry granulation method.
  • the foregoing granulation processes may be used alone and no limitation in usage.
  • the particles Once, the particles have been granulated, they may then be milled to achieve the desired particle size. Examples of suitable processes for milling the granules include hammer milling, ball milling, fluid-energy milling, roller milling, cutting milling, or other milling processes known in the art.
  • pellets refers to small particles with approximately uniform shapes and sizes produced by an extrusion process.
  • a "small particle” refers to a particle of which diameter, length, height, and width is at most 10 mm (e.g., at most 2, 3, 4, 5, 6, 7, 8, or 9 mm).
  • spherical pellet refers to beads, beadlets, spherical particles, spheroids, or the like that are of round or about round in shape and are generally made by an extrusion and spheronization process.
  • mini tablet refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm.
  • the mini tablets have round shape and smooth surface to ease coating process.
  • Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
  • step (a) Granulating the blend of step (a);
  • step (b) Drying or cooling the granules obtained in step (b);
  • step (c) optionally adding at least one pharmaceutically acceptable excipient to the granules obtained in step (c) and mixing;
  • Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
  • step (a) Blending organic acid or inorganic acid and optionally at least one pharmaceutically acceptable excipient; b. Granulating the blend of step (a) to form organic acid granules or inorganic acid granules or extruding or spheronizing the blend of step (a) to form organic acid pellets or inorganic acid pellets;
  • step (c) Filling the organic acid granules or pellets or inorganic acid granules or pellets obtained in step (c) into the first capsule or the second capsule.
  • Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
  • Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
  • the organic acid pellets or the organic acid granules are coated with isolation solution.
  • the inorganic acid pellets or the inorganic acid granules are coated with isolation solution.
  • isolation solution is formed of a polymeric or a non-polymeric pharmaceutically acceptable agent or any combination thereof.
  • Example 1 is formed of a polymeric or a non-polymeric pharmaceutically acceptable agent or any combination thereof.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
  • Organic acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
  • HPMC and sucrose are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC HPMC is added to purified water and mixed in homogenisator.
  • Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
  • Organic acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
  • Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed.
  • the powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes.
  • the powder mixture is compressed into mini tablets.
  • Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate in the form of mini tablets are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
  • Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
  • Organic acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
  • HPMC and sucrose are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC HPMC is added to purified water and mixed in homogenisator.
  • Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
  • Organic acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
  • Dabigatran etexilate granules are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the first capsule.
  • Production method 2 :
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed.
  • the powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.
  • Dabigatran etexilate in the form of mini tablets are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed. Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
  • Tartaric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
  • HPMC and sucrose are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC HPMC is added to purified water and mixed in homogenisator.
  • Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
  • isolation solution which is selected from Formula 1 to 3.
  • Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed.
  • the powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.
  • Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate in the form of mini tablets are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
  • Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
  • Tartaric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
  • HPMC and sucrose are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC HPMC is added to purified water and mixed in homogenisator.
  • Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
  • Tartaric acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
  • isolation solution which is selected from Formula 1 to 3.
  • Tartaric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
  • Dabigatran etexilate granules are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed.
  • the powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.
  • Dabigatran etexilate in the form of mini tablets are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
  • Dabigatran etexilate granules are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the first capsule.
  • Example 5
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
  • Citric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC HPMC is added to purified water and mixed in homogenisator.
  • Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
  • Citric acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
  • isolation solution which is selected from Formula 1 to 3.
  • Citric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
  • Coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed.
  • the powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes.
  • the powder mixture is compressed into mini tablets.
  • Coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the second capsule.
  • the second capsule is inserted into the first capsule and dabigatran etexilate in the of mini tablets are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed. Coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
  • Example 6 Example 6:
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
  • Citric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
  • HPMC and sucrose are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC and triethyl citrate are added to purified water and mixed.
  • Talc is added to the obtained mixture and mixed.
  • HPMC HPMC is added to purified water and mixed in homogenisator.
  • Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
  • Citric acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
  • isolation solution which is selected from Formula 1 to 3.
  • Citric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
  • Dabigatran etexilate granules are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed.
  • the powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes.
  • the powder mixture is compressed into mini tablets.
  • Dabigatran etexilate in the form of mini tablets are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the first capsule.
  • Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
  • Dabigatran etexilate granules are filled into the second capsule.
  • the second capsule is inserted into the first capsule and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the first capsule.

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Abstract

The present invention relates to solid oral pharmaceutical compositions, comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof.

Description

SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN ETEXILATE
Field of the invention
The present invention relates to solid oral pharmaceutical compositions, comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid in a dosage unit form comprising of a first capsule and a second capsule, the second capsule which is located within the first capsule.
Background of the invention
Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. Dabigatran was first disclosed in WO98/37075, which claimed compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time, under the name 1 -methyl-2-[N-[4-(N-n- hexyloxycarbonylamidino) phenyl] aminomethyl] benzimidazol-5-ylcarboxylic acid-N-(2- pyridyl)-N-(2 ethoxycarbonylethyl)amides.
Dabigatran etexilate, a novel direct thrombin inhibitor, is a prodrug of dabigatran and is a non-peptide thrombin inhibitor. The structural formula is:
Figure imgf000003_0001
Formula 1 : Dabigatran etexilate
Dabigatran is currently available as dabigatran etexilate mesylate, under the trade name Pradaxa from Boehringer Ingelheim is used for the reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. The solubility of dabigatran etexilate in water is 1 .8 mg/mL and dependent on the pH value. To increase the solubility of dabigatran etexilate, EP1658056B1 suggests a tablet formulation containing dabigatran etexilate and an organic acid with a solubility in water of > 1 g / 250 ml at 20 <O.
Dabigatran etexilate is also less stable in acidic environment. To avoid stability problem, many solutions were offered in the prior art. EP2740471 B1 discloses a pharmaceutical composition contains the following main components: a core material comprising an inorganic acid layer, an active substance layer and an insulating layer between inorganic acid layer and active substance layer. EP2588090A2 discloses a process for the preparation of an oral dosage comprising a spherical core coated with tartaric acid, a isolating layer on the coated tartaric acid layer and a layer comprising dabigatran etexilate on the isolating layer. WO2015145462A1 discloses a pharmaceutical composition comprising a first component in the form of tablet comprising dabigatran and a second component in the form of capsule comprising organic acid.
There is still a need to prepare alternate compositions of dabigatran etexilate that are stable, cost-effective, easy to prepare, provide the desired in vitro release, improved dissolution profile and bioavailability. We have found an easy way to separate the organic acid or the inorganic acid formulation from the dabigatran etexilate formulation by using nested capsule technology. It also provides good stability and improvement in dissolution profile.
Detailed description of the Invention
The main object of the present invention is to provide solid oral pharmaceutical compositions, comprising dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid in a unit dosage form with good stability and effective dissolution profile.
Another object of the present invention is to obtain a stable dabigatran etexilate formulation with high bioavailability. Another object of the present invention is to provide an easy and cost-effective process for the preparation of the said pharmaceutical composition. In one embodiment, said pharmaceutical composition comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid, wherein the composition is in a dosage unit form comprising a first capsule and a second capsule which is located within the first capsule.
As used herein, the term "unit dosage form" refers to nested capsule technology which is comprising a first capsule and a second capsule, the second capsule being located within the body of the first capsule. The first capsule comprises a first formulation which may be a direct thrombin inhibitor, an organic acid or an inorganic acid. The second capsule comprises a second formulation which may be a direct thrombin inhibitor, an organic acid or an inorganic acid. As used herein, the term "dabigatran etexilate free base" refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
According to this embodiment of the present invention, the first capsule is comprising a first formulation held between the first and second capsule, and a second formulation held in the second capsule.
According to these embodiments of the present invention provides combination of incompatible formulations in a single dosage unit. To prepare nested capsules is easier and eliminates the preparation of isolation layer which was most frequently used in the prior art.
As used herein, the term "incompatible formulations" refers to the first and the second formulation which are comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
According to these embodiments of the present invention, the first formulation and the second formulation are in the form of mini tablets or granules or pellets or powder or beads or capsules. In one embodiment of the present invention, the first formulation is comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
In one embodiment of the present invention, the second formulation is comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
According to an embodiment of the present invention, the direct thrombin inhibitor is dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof. Suitable organic acid is comprising at least one carboxylic group. It may include but not limited to citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.
Suitable inorganic acid may include but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, hydroiodic acid, sulfurous acid, hyposulfurous acid, pyrosulfuric acid, dithionous acid, thiosulfurous acid, peroxydisulfuric acid, or mixtures thereof.
In one embodiment, the said composition comprises at least one pharmaceutically acceptable excipient selected from fillers, disintegrants, diluents, dispersing agents, binders, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings, melting components, coloring agents or mixtures thereof.
Suitable fillers may include but not limited to lactose, sugar, starches, modified starches, mannitol, calcium sulfate, xylitol or mixtures thereof.
Suitable disintegrants may include but not limited to cross-linked polyvinil pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacrylate potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
Suitable diluents may include but not limited to microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
Suitable dispersing agents may include but not limited to calcium silicate, magnesium aluminum silicate or mixtures thereof.
Suitable binders may include but not limited to polyvinylpyrrolidone, carnauba wax, pullulan, glyceryl behenate, polycarbophil, polyvinyl acetate and its copolymers, cellulose acetate phthalate, hydroxypropyl starch, sugars, tragacanth gum, cetostearyl alcohol, acacia mucilage, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, carrageenan, guar gum, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. Suitable lubricants may include but not limited to magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmito stearate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof. Suitable glidants may include but not limited to colloidal silicon dioxide, talc, aluminium silicate, silica or mixtures thereof.
Suitable plasticizers may include but not limited to polyethylene glycols of different molecular weights, propylene glycol or mixtures thereof.
Suitable preservatives may comprise but not limited to methyl paraben and propyl paraben and their salts (such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene and butylated hydroxyanisole or mixtures thereof.
Suitable sweeteners may include but not limited to aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose and sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
Suitable flavorings may include but not limited to menthol, peppermint, cinnamon, chocolate, vanillin and fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries etc. or mixtures thereof. Suitable melting components are selected from gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene-polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylated monoglyceride, butil pthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethly phthalate, ethyl phthalylethly glycolate, glycerin, propylene glycol, triacetin, triacetin citrate, tripropionin or mixtures thereof.
Suitable coloring agents may include but not limited to ferric oxide, titanium dioxide, Food, Drug & Cosmetic (FD&C) dyes (such as; FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lakes), poncau, indigo Drug & Cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine), iron oxides (such as; iron oxide red, yellow, black), quinoline yellow, flaming red, carmine, carmoisine, sunset yellow or mixtures thereof.
According to an embodiment of the present invention, pharmaceutical compositions of the present invention may be prepared by a process comprising the following steps: a. Preparing the first formulation in the form of mini tablets or granules or pellets or powder or beads or capsules;
b. Preparing the second formulation in the form of mini tablets or granules or pellets or powder or beads or capsules;
c. Filling the second formulation into the second capsule and;
d. Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.
Fig. 1 shows Table-1 containing Examples 1 -6.
Fig. 2 shows Table-2 containing Examples 1 -6.
According to Table 1 and Table 2, all of the examples numbered from 1 to 6 are comprising a dabigatran etexilate and a organic acid or a inorganic acid. These tables show all alternative pharmaceutical formulations.
The term "granulating" or "granulation" represents a process to provide granular product consisting of particles each having almost same size and shape, from a starting material in the form of powder, melt or aqueous solution. The term "granules" as used herein refers to agglomerates of particles.
The compositions of the present invention may be prepared using wet-granulating processes in which a powder is added with a binder and a solvent then granulated, dry- granulating processes such as slugging or compaction and direct compression, or melt- granulating processes in which a powder is mixed with a heat-melting binder and then heat-granulated. These granulating processes may be combined with various granulating processes such as agitating granulation method used with machines such as planetary mixers and screw mixers, high shear granulation method used with machines such as Henschel mixers and super mixers, extrusion granulation method used with machines such as cylindrical, rotary granulator, screw-extruding granulator and pellet-mill granulator, or other processes like, tumbling-granulation method, fluidized-bed granulation method, compression granulation method, crushing granulation method, and spray dry granulation method. The foregoing granulation processes may be used alone and no limitation in usage. Once, the particles have been granulated, they may then be milled to achieve the desired particle size. Examples of suitable processes for milling the granules include hammer milling, ball milling, fluid-energy milling, roller milling, cutting milling, or other milling processes known in the art.
The term "pellets" refers to small particles with approximately uniform shapes and sizes produced by an extrusion process. A "small particle" refers to a particle of which diameter, length, height, and width is at most 10 mm (e.g., at most 2, 3, 4, 5, 6, 7, 8, or 9 mm).
The term "spherical pellet" refers to beads, beadlets, spherical particles, spheroids, or the like that are of round or about round in shape and are generally made by an extrusion and spheronization process.
The term "mini tablet", as used herein, refers to small tablets with a diameter equal to or less than 4 mm that are typically filled into a capsule or further compressed into larger tablets. Thickness of this mini tablets equal to or less than 3 mm. The mini tablets have round shape and smooth surface to ease coating process.
Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
a. Blending dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one pharmaceutically acceptable excipient;
b. Granulating the blend of step (a);
c. Drying or cooling the granules obtained in step (b);
d. Optionally adding at least one pharmaceutically acceptable excipient to the granules obtained in step (c) and mixing;
e. Filling the mixture into the first capsule or the second capsule. Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
a. Blending organic acid or inorganic acid and optionally at least one pharmaceutically acceptable excipient; b. Granulating the blend of step (a) to form organic acid granules or inorganic acid granules or extruding or spheronizing the blend of step (a) to form organic acid pellets or inorganic acid pellets;
c. Optionally coating the organic acid granules or pellets or inorganic acid granules or pellets with a isolation solution;
d. Filling the organic acid granules or pellets or inorganic acid granules or pellets obtained in step (c) into the first capsule or the second capsule.
Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
a. Sieving and mixing dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one pharmaceutically acceptable excipient;
b. Passing the powder mixture through the compactor or slugging;
c. Sieving the powder which passed through the compactor or grinding the slugs and sieving;
d. Optionally adding at least one pharmaceutically acceptable excipient to the mixture and mixing for 1 -2 more minutes.
e. Compressing the powder mixture into mini tablets.
f. Filling the mini tablets into the first capsule or the second capsule.
Another embodiment of the present invention provides a method of preparing of the pharmaceutical composition, wherein the process for the first or second formulation comprising the following steps:
a. Sieving and mixing organic acid or inorganic acid and optionally at least one pharmaceutically acceptable excipient;
b. Passing the powder mixture through the compactor or slugging
c. Sieving the powder which passed through the compactor or grinding the slugs and sieving
d. Optionally adding at least one pharmaceutically acceptable excipient to the mixture and mixing for 1 -2 more minutes.
e. Compressing the powder mixture into mini tablets.
f. Filling the mini tablets into the first capsule or the second capsule. In one embodiment, the organic acid pellets or the organic acid granules are coated with isolation solution.
In one embodiment, the inorganic acid pellets or the inorganic acid granules are coated with isolation solution.
In one embodiment, isolation solution is formed of a polymeric or a non-polymeric pharmaceutically acceptable agent or any combination thereof. Example 1 :
Figure imgf000012_0001
Production method 1 :
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed. Preparation of Organic Acid Pellets:
Organic acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets) :
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 3:
HPMC is added to purified water and mixed in homogenisator. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
Organic acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
Preparation of Powder Mixture Containing Organic Acid
Organic acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes. Preparation of Nested Capsules
Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule. Production method 2:
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets. Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate in the form of mini tablets are filled into the first capsule. Production method 3:
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
Example 2:
First Capsule Content % by weight
Coated (Isolated) Organic Acid Pellets /
Organic Acid Pellets / Powder Mixture 10.0 - 50.0
Containing Organic Acid
Second Capsule Content
Dabigatran etexilate in the form of the free
base or in the form of pharmaceutically
30.0 - 80.0
acceptable salts, polymorphs, solvates,
hydrates or esters thereof
Microcrystalline cellulose 10.0 - 50.0
Hydroxypropyl methyl cellulose 10.0 - 30.0
Colloidal Silicon dioxide 0.5 - 3.0
Croscarmellose sodium 1 .0 - 15.0
Magnesium stearate 0.1 - 5.0
TOTAL 100.0 Production method 1 :
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
Preparation of Organic Acid Pellets:
Organic acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets) :
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 3:
HPMC is added to purified water and mixed in homogenisator. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator. Organic acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
Preparation of Powder Mixture Containing Organic Acid
Organic acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
Preparation of Nested Capsules
Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the first capsule. Production method 2:
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.
Dabigatran etexilate in the form of mini tablets are filled into the second capsule. The second capsule is inserted into the first capsule and coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the first capsule.
Production method 3:
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed. Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated organic acid pellets or organic acid pellets or powder mixture containing organic acid are filled into the first capsule.
Example 3:
First Capsule Content % by weight
Dabigatran etexilate in the form of the free
base or in the form of pharmaceutically
30.0 - 80.0
acceptable salts, polymorphs, solvates,
hydrates or esters thereof
Microcrystalline cellulose 10.0 - 50.0
Hydroxypropyl methyl cellulose 10.0 - 30.0
Colloidal Silicon dioxide 0.5 - 3.0
Croscarmellose sodium 1 .0 - 15.0
Magnesium stearate 0.1 - 5.0
Second Capsule Content Coated (Isolated) Tartaric Acid Pellets /
Tartaric Acid Pellets / Powder Mixture 10.0 - 50.0
Containing Tartaric Acid
TOTAL 100.0
Production method 1 :
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
Preparation of Tartaric Acid Pellets:
Tartaric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
Preparation of Isolated Tartaric Acid Pellets (Coated Tartaric Acid Pellets) :
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 3:
HPMC is added to purified water and mixed in homogenisator. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
Tartaric acid pellets are coated with isolation solution which is selected from Formula 1 to 3.
Preparation of Powder Mixture Containing Tartaric Acid
Tartaric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes. Preparation of Nested Capsules
Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
Production method 2:
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.
Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate in the form of mini tablets are filled into the first capsule.
Production method 3:
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
Example 4:
First Capsule Content % by weight
Coated (Isolated) Tartaric Acid Pellets/
Tartaric Acid Pellets / Powder Mixture 10.0 - 50.0
Containing Tartaric Acid
Second Capsule Content
Dabigatran etexilate in the form of the free
30.0 - 80.0
base or in the form of pharmaceutically acceptable salts, polymorphs, solvates,
hydrates or esters thereof
Microcrystalline cellulose 10.0 - 50.0
Hydroxypropyl methyl cellulose 10.0 - 30.0
Colloidal Silicon dioxide 0.5 - 3.0
Croscarmellose sodium 1 .0 - 15.0
Magnesium stearate 0.1 - 5.0
TOTAL 100.0
Production method 1 :
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
Preparation of Tartaric Acid Pellets:
Tartaric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets.
Preparation of Isolated Tartaric Acid Pellets (Coated Tartaric Acid Pellets) :
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 3:
HPMC is added to purified water and mixed in homogenisator. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
Tartaric acid pellets are coated with isolation solution which is selected from Formula 1 to 3. Preparation of Powder Mixture Containing Tartaric Acid
Tartaric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
Preparation of Nested Capsules
Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the first capsule.
Production method 2:
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets.
Dabigatran etexilate in the form of mini tablets are filled into the second capsule. The second capsule is inserted into the first capsule and coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the first capsule.
Production method 3:
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid are filled into the first capsule. Example 5:
Figure imgf000021_0001
Production method 1 :
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed. Preparation of Citric Acid Pellets:
Citric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets. Preparation of Isolated Citric Acid Pellets (Coated Citric Acid Pellets) :
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed. Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 3:
HPMC is added to purified water and mixed in homogenisator. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
Citric acid pellets are coated with isolation solution which is selected from Formula 1 to 3. Preparation of Powder Mixture Containing Citric Acid
Citric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
Preparation of Nested Capsules
Coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule.
Production method 2:
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets. Coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate in the of mini tablets are filled into the first capsule.
Production method 3:
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed. Coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the second capsule. The second capsule is inserted into the first capsule and dabigatran etexilate granules are filled into the first capsule. Example 6:
Figure imgf000023_0001
Production method 1 :
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water. The granules are dried at 50 °C and sieved. Magnesium stearate is added to the dried granules and mixed.
Preparation of Citric Acid Pellets:
Citric acid and microcrystalline cellulose are blended and this blend is added solution of hydroxypropyl cellulose in isopropyl alcohol to get a wet mass. This wet mass is extruded, spheronized, dried and screened to give pellets. Preparation of Isolated Citric Acid Pellets (Coated Citric Acid Pellets) :
Preparation isolation solution:
Formula 1 :
HPMC and sucrose are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 2:
HPMC and triethyl citrate are added to purified water and mixed. Talc is added to the obtained mixture and mixed.
Formula 3:
HPMC is added to purified water and mixed in homogenisator. Talc and PEG 6000 are added to the obtained mixture and mixed in homogenisator.
Citric acid pellets are coated with isolation solution which is selected from Formula 1 to 3. Preparation of Powder Mixture Containing Citric Acid
Citric acid, lactose spray dried, colloidal silicone dioxide and pregellatinize starch are sieved and blended. Magnesium stearate is added and mixed 1 -2 more minutes.
Preparation of Nested Capsules
Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the first capsule.
Production method 2:
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water and dried in an oven at 50 °C. Magnesium stearate is added and mixed 1 -2 more minutes. The powder mixture is compressed into mini tablets. Dabigatran etexilate in the form of mini tablets are filled into the second capsule. The second capsule is inserted into the first capsule and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the first capsule. Production method 3:
Preparation of Dabigatran Etexilate Granules
Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are mixed. Some of the magnesium stearate is added to the blend and mixed. The mixture is compressed by roller compaction. The compressed mixture (granules) is sieved. Remaining magnesium is added to the sieved granules and mixed.
Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid are filled into the first capsule.
According to another embodiment of the invention in the above given examples of 1 to 6, instead of coated organic acid pellets or organic acid pellets or powder mixture containing organic acid, we can put coated inorganic acid pellets or inorganic acid pellets or powder mixture containing inorganic acid.

Claims

A pharmaceutical composition comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one organic acid or at least one inorganic acid, wherein the composition is in a dosage unit form comprising a first capsule and a second capsule which is located within the first capsule.
The pharmaceutical composition according to claim 1 , wherein the first capsule is comprising a first formulation held between the first and second capsule, and a second formulation held in the second capsule.
The pharmaceutical composition according to claim 2, wherein the first formulation and the second formulation are in the form of mini tablets or granules or pellets or powder or beads or capsules.
The pharmaceutical composition according to claim 2 or 3, wherein the first formulation is comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
The pharmaceutical composition according to claim 2 or 3, wherein the second formulation is comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or an organic acid or an inorganic acid.
The pharmaceutical composition according to any of the preceding claims, wherein the direct thrombin inhibitor is dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof.
The pharmaceutical composition according to any of the preceding claims, wherein the organic acid is comprising at least one carboxylic group.
The pharmaceutical composition according to claim 7, wherein the organic acid is selected from a group comprising citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or mixtures thereof.
9. The pharmaceutical composition according to any of the preceding claims, wherein the inorganic acid is selected from a group comprising hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, boric acid, hydrofluoric acid, hydrobromic acid, perchloric acid, hydroiodic acid, sulfurous acid, hyposulfurous acid, pyrosulfuric acid, dithionous acid, thiosulfurous acid, peroxydisulfuric acid, or mixtures thereof.
10. The pharmaceutical composition according to any of the preceding claims, wherein the composition is further comprising at least one pharmaceutically acceptable excipient which is selected from fillers, disintegrants, diluents, dispersing agents, binders, lubricants, glidants, plasticizers, preservatives, sweeteners, flavorings, melting components, coloring agents or mixtures thereof.
1 1 . A process for preparation of the pharmaceutical composition according to any preceding claims , wherein the process comprising the following steps:
a. Preparing the first formulation in the form of mini tablets or granules or pellets or powder or beads or capsules;
b. Preparing the second formulation in the form of mini tablets or granules or pellets or powder or beads or capsules;
c. Filling the second formulation into the second capsule and;
d. Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.
12. The process for preparation of the pharmaceutical composition according to claim 1 1 , wherein the process for the first or second formulation comprising the following steps:
a. Blending dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one pharmaceutically acceptable excipient;
b. Granulating the blend of step (a);
c. Drying or cooling the granules obtained in step (b);
d. Optionally adding at least one pharmaceutically acceptable excipient to the granules obtained in step (c) and mixing;
e. Filling the mixture into the first capsule or the second capsule.
13. The process for preparation of the pharmaceutical composition according to claim 1 1 , wherein the process for the first or second formulation comprising the following steps:
a. Blending organic acid or inorganic acid and optionally at least one pharmaceutically acceptable excipient;
b. Granulating the blend of step (a) to form organic acid granules or inorganic acid granules or extruding or spheronizing the blend of step (a) to form organic acid pellets or inorganic acid pellets;
c. Optionally coating the organic acid granules or pellets or inorganic acid granules or pellets with a isolation solution;
d. Filling the organic acid granules or pellets or inorganic acid granules or pellets obtained in step (c) into the first capsule or the second capsule.
PCT/TR2018/050220 2017-05-10 2018-05-10 Solid oral pharmaceutical compositions of dabigatran etexilate WO2019004979A2 (en)

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EP1658056B1 (en) 2003-08-16 2008-05-07 Boehringer Ingelheim International Gmbh Tablet containing 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]- methyl}-1-methyl-1h-benzimidazolo-5-carbonyl)-pyridino-2-yl- amino]-ethyl propionate or the salts thereof
EP2588090A2 (en) 2010-07-01 2013-05-08 Krka Tovarna Zdravil, D.D., Novo Mesto Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
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