WO2018104387A1 - Multilayered tablet compositions of dabigatran - Google Patents
Multilayered tablet compositions of dabigatran Download PDFInfo
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- WO2018104387A1 WO2018104387A1 PCT/EP2017/081692 EP2017081692W WO2018104387A1 WO 2018104387 A1 WO2018104387 A1 WO 2018104387A1 EP 2017081692 W EP2017081692 W EP 2017081692W WO 2018104387 A1 WO2018104387 A1 WO 2018104387A1
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- layer
- pharmaceutically acceptable
- dabigatran etexilate
- pharmaceutical composition
- mixing
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to a multilayered pharmaceutical composition for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
- Dabigatran etexilate (Formula 1 ), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrilation.
- Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and augmenting further thrombin production via the activation of factors V and VIII. It also activates platelets, generates anticoagulant activity via activation of protein C and initiates numerous cellular processes.
- the methane sulphonic acid addition salt of dabigatran etexilate which is commercially available under the trade name PRADAXA® immediate release capsule (in the strength of 75, 1 10, 150 mg), is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate.
- This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core.
- Each PRADAXA® capsule contains the following inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carrageenan, potassium chloride, talc, titanium dioxide, and gelatin.
- WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395.
- weakly basic drugs such as dabigatran and dabigatran etexilate
- weakly basic drugs are formulated with an acidic excipient.
- Patent application EP1658056 discloses a conventional tablet formulation comprising dabigatran etexilate, organic acid with a solubility in water of > 1 g / 250 ml at 20 ⁇ together with conventional excipients and fillers. But in the patent application EP1658056, there is no insulating layer between the active agent and the organic acid.
- capsules In prior art, most of formulations are in the form of capsules. But it is known that capsules cost more than tablets and have significant space and potency limitations since their powdered contents cannot be compressed to a significant degree. Since capsules are not airtight, their shelf-life is shorter than tablets.
- the pellet formulation used in the marketed product Pradaxa® is produced by a difficult production method which has a lot of production steps causing the process being longer than others.
- For pellet processing specially designed production equipment has to be used.
- the main object of the present invention is to provide a multi-layered pharmaceutical composition for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
- Multi-layered tablets are known as a novel drug delivery system. Compaction of different granules in the form of various layer in single tablets are called as multi-layered tablets. It generally consists of parallel, clear, coloured, visual distinct layers two to three or more APIs or APIs along with functional or non-functional placebo layers. Multi-layered tablet dosage forms are designed for a variety of reasons such as incompatibility problems between active agents or excipients. According to main embodiment of the invention, there is an inert layer between active agent layer (first layer) and acidic layer (second layer) to avoid incompatibility problems between them.
- the multi-layered pharmaceutical composition for oral administration comprises:
- a first layer comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient
- an inert layer comprising at least one pharmaceutically acceptable excipient
- a second layer comprising one pharmaceutically acceptable acid or hydrates or acid salts thereof and at least one pharmaceutically acceptable excipient
- dabigatran etexilate free base refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
- dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is present in the first layer in an amount of between 5.00 and 60.00 %, preferably between 15.00 and 50.00 % and more preferably it is 25.00 to 40.00 % by weight of the first layer.
- dabigatran etexilate free base is present in an amount of between 30 to 350 mg, preferably 50 to 300 mg and more preferably it is 50 to 250 mg.
- said at least one pharmaceutically acceptable excipient for each layer is selected from disintegrants, lubricants, glidants, binders, fillers, colouring agents or mixtures thereof.
- the first layer of the pharmaceutical composition comprises preferably at least two different disintegrants.
- the amount of total disintegrants in the first layer is at least 40% by weight of the first layer.
- the amount of total disintegrants in the first layer is between 40% and 60% by weight of the first layer. More preferably the amount of total disintegrants in the first layer is between 40% and 50% by weight of the first layer.
- Suitable disintegrants are selected from a group comprising pregelatinized starch, low- substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose, sodium starch glycolate, starch, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
- L-HPC low- substituted hydroxypropyl cellulose
- microcrystalline cellulose sodium starch glycolate, starch, crospovidone (cross-linked polyvinil pyrrolidone), povidone, po
- the disintegrants are selected from microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate.
- Suitable lubricants are selected from a group comprising magnesium stearate, sodium stearyl fumarate, 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, glyseryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.
- the lubricant is magnesium stearate.
- the lubricant is present an amount of between 0.1 % and 10.00%, preferably 0.1 % and 5.00% and more preferably 0.1 % and 3.00% by weight of each layer.
- Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
- the glidant is colloidal silicon dioxide.
- the glidant is present an amount of between 0.1 % and 10.00%, 0.5% and 5.00% and more preferably 0.9% and 3.00% by weight of each layer.
- Suitable fillers are selected from a group comprising lactose, mannitol, spray-dried mannitol, 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, polyols, dextrose, maltitol or mixtures thereof.
- the filler is lactose in the first layer and microcrystalline cellulose in the inert layer and the second layer.
- Suitable binders are selected from the group comprising pregelatinized starch, povidone, copovidone, copolyvidone, polyvinylpyrrolidone, carnauba wax, hydroxypropyl methyl cellulose, pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, cellulose
- the binders are selected from pregelatinized starch, povidone or mixtures thereof.
- said one pharmaceutically acceptable acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid or hydrates or salts thereof.
- the pharmaceutically acceptable acid is selected from citric acid and tartaric acid.
- the pharmaceutically acceptable acid is present in the second layer in an amount of between 10% and 90, preferably between 15% and 70%, more preferably between 20% and 40% by weight of the second layer.
- the weight ratio of dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate to pharmaceutically acceptable acid is between 0.5 and 2.0, preferably between 1 .0 and 2.0, more preferably between 1 .0 and 1 .6.
- the inert layer comprises a colouring agent such as yellow iron oxide.
- colouring agent is present in an amount of between 0.1 % and 2.0, preferably between 0.5 and 2.0, more preferably between 0.5 and 1 .0 by weight of the inert layer.
- Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, dabigatran esylate, tartrate, oxalate, camphor sulfonate.
- suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
- Example 1 Multi-layered tablet
- Second Layer amount (w/w)
- Second Layer amount (w/w)
- Second Layer amount (w/w)
- Second Layer amount (w/w)
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Abstract
The present invention relates to a multilayered pharmaceutical composition for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
Description
MULTI LAYERED TABLET COMPOSITIONS OF DABIGATRAN
Technical Field
The present invention relates to a multilayered pharmaceutical composition for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient. Background of the Invention
Dabigatran etexilate (Formula 1 ), which is already known from WO 98/37075, is a direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrilation. Thrombin is a multifunctional enzyme which converts fibrinogen to fibrin, cross-linking fibrin monomers via activation of factor XIII and augmenting further thrombin production via the activation of factors V and VIII. It also activates platelets, generates anticoagulant activity via activation of protein C and initiates numerous cellular processes.
Formula 1 : Dabigatran etexilate
The methane sulphonic acid addition salt of dabigatran etexilate, which is commercially available under the trade name PRADAXA® immediate release capsule (in the strength of 75, 1 10, 150 mg), is disclosed in EP1870100, wherein also disclosed, pellet formulation of dabigatran etexilate methanesulphonate. This composition is formulated with a core material consisting of organic acid and an active layer which encloses the core. Each PRADAXA® capsule contains the following inactive ingredients: acacia,
dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carrageenan, potassium chloride, talc, titanium dioxide, and gelatin.
Apart from the methanesulfonate salt of dabigatran etexilate, other acid addition salts of the compound are provided in prior art. For example, WO2012/077136 is directed to the oxalate salt of dabigatran etexilate and besides, its hydrochloride salt is identified in EP1877395.
It is known that the solubility of weakly basic drugs, such as dabigatran and dabigatran etexilate, is pH-dependent and may be increased by the provision of an acidic environment. Therefore, weakly basic drugs are formulated with an acidic excipient.
Patent application EP1658056 discloses a conventional tablet formulation comprising dabigatran etexilate, organic acid with a solubility in water of > 1 g / 250 ml at 20^ together with conventional excipients and fillers. But in the patent application EP1658056, there is no insulating layer between the active agent and the organic acid.
In prior art, most of formulations are in the form of capsules. But it is known that capsules cost more than tablets and have significant space and potency limitations since their powdered contents cannot be compressed to a significant degree. Since capsules are not airtight, their shelf-life is shorter than tablets.
The pellet formulation used in the marketed product Pradaxa® is produced by a difficult production method which has a lot of production steps causing the process being longer than others. For pellet processing specially designed production equipment has to be used.
Thus, there is still a need in the art to develop stable and bioavailable pharmaceutical formulations comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate with a long shelf-life and a pH independent release by a simplified and cost effective process. By this need, the formulation has been developed to overcome the solubility and stability problems of dabigatran etexilate in a safe manner disclosed above.
Detailed description of the Invention
The main object of the present invention is to provide a multi-layered pharmaceutical composition for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
Multi-layered tablets are known as a novel drug delivery system. Compaction of different granules in the form of various layer in single tablets are called as multi-layered tablets. It generally consists of parallel, clear, coloured, visual distinct layers two to three or more APIs or APIs along with functional or non-functional placebo layers. Multi-layered tablet dosage forms are designed for a variety of reasons such as incompatibility problems between active agents or excipients. According to main embodiment of the invention, there is an inert layer between active agent layer (first layer) and acidic layer (second layer) to avoid incompatibility problems between them.
According to this embodiment, the multi-layered pharmaceutical composition for oral administration comprises:
a) A first layer comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient
b) an inert layer comprising at least one pharmaceutically acceptable excipient c) a second layer comprising one pharmaceutically acceptable acid or hydrates or acid salts thereof and at least one pharmaceutically acceptable excipient
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 one embodiment, dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is present in the first layer in an amount of between 5.00 and 60.00 %, preferably between 15.00 and 50.00 % and more preferably it is 25.00 to 40.00 % by weight of the first layer.
According to another embodiment, dabigatran etexilate free base is present in an amount of between 30 to 350 mg, preferably 50 to 300 mg and more preferably it is 50 to 250 mg. According to one embodiment of this present invention, wherein said at least one pharmaceutically acceptable excipient for each layer is selected from disintegrants, lubricants, glidants, binders, fillers, colouring agents or mixtures thereof.
According to another embodiment of this present invention, wherein at least one pharmaceutically acceptable excipient in the first layer is disintegrant. During the development study of the present invention, it has been observed that, dissolution and stability problems of the active agent are overcome by using particularly at least two different disintegrants in the first layer in a specific amount. According to one embodiment, the first layer of the pharmaceutical composition comprises preferably at least two different disintegrants.
According to another embodiment, the amount of total disintegrants in the first layer is at least 40% by weight of the first layer. Preferably the amount of total disintegrants in the first layer is between 40% and 60% by weight of the first layer. More preferably the amount of total disintegrants in the first layer is between 40% and 50% by weight of the first layer.
Suitable disintegrants are selected from a group comprising pregelatinized starch, low- substituted hydroxypropyl cellulose (L-HPC), microcrystalline cellulose, sodium starch glycolate, starch, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
In a preferred embodiment, the disintegrants are selected from microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC) and sodium starch glycolate.
Suitable lubricants are selected from a group comprising magnesium stearate, sodium stearyl fumarate, 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, glyseryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.
In a preferred embodiment, the lubricant is magnesium stearate.
According to these embodiments, the lubricant is present an amount of between 0.1 % and 10.00%, preferably 0.1 % and 5.00% and more preferably 0.1 % and 3.00% by weight of each layer.
Suitable glidants are selected from a group comprising colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
In a preferred embodiment, the glidant is colloidal silicon dioxide.
According to this embodiment, the glidant is present an amount of between 0.1 % and 10.00%, 0.5% and 5.00% and more preferably 0.9% and 3.00% by weight of each layer. Suitable fillers are selected from a group comprising lactose, mannitol, spray-dried mannitol, 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, polyols, dextrose, maltitol or mixtures thereof.
In a preferred embodiment, the filler is lactose in the first layer and microcrystalline cellulose in the inert layer and the second layer. Suitable binders are selected from the group comprising pregelatinized starch, povidone, copovidone, copolyvidone, polyvinylpyrrolidone, carnauba wax, hydroxypropyl methyl cellulose, pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen,
kollagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polaxomer, polyethylene glycol, sugars, glycose syrups, natural gums, tragacanth gum, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose or mixtures thereof.
In a preferred embodiment, the binders are selected from pregelatinized starch, povidone or mixtures thereof. According to one embodiment, wherein said one pharmaceutically acceptable acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid or hydrates or salts thereof.
According to this embodiment, preferably the pharmaceutically acceptable acid is selected from citric acid and tartaric acid.
According to another embodiment, the pharmaceutically acceptable acid is present in the second layer in an amount of between 10% and 90, preferably between 15% and 70%, more preferably between 20% and 40% by weight of the second layer.
According to one embodiment, wherein the weight ratio of dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate to pharmaceutically acceptable acid is between 0.5 and 2.0, preferably between 1 .0 and 2.0, more preferably between 1 .0 and 1 .6.
In one embodiment, the inert layer comprises a colouring agent such as yellow iron oxide.
According to this embodiment, colouring agent is present in an amount of between 0.1 % and 2.0, preferably between 0.5 and 2.0, more preferably between 0.5 and 1 .0 by weight of the inert layer.
Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, dabigatran esylate, tartrate, oxalate, camphor sulfonate.
Preferably suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
Example 1 : Multi-layered tablet
First Layer (%) amount (w/w)
Dabigatran etexilate free base or
pharmaceutically acceptable salts of
dabigatran etexilate 5.00-60.00
Sodium starch glycolate 0.25-8.00
Microcrystalline celluose 10.00-70.00
Colloidal silicon dioxide 0.1 -5.00
Starch, pregelatinize 5.00-30.00
Lactose 5.00-50.00
Magnesium stearate 0.1 -5.00
Total (First layer) 100
Inert Layer (%) amount (w/w)
Povidone 1 .00-10.00
Microcrystalline cellulose 70.00-95.00
Yellow iron oxide 0.1 -2.00
Colloidal silicon dioxide 0.05-5.00
Magnesium stearate 0.1 -5.00
Total (Inert Layer) 100
Second Layer (%) amount (w/w)
Tartaric acid 10.00-90.00
L-HPC 1 .00-20.00
Microcrystalline cellulose 30.00-70.00
Colloidal silicon dioxide 0.05-5.00
Magnesium stearate 0.1 -5.00
Total (Second Layer) 100
Example 2: Multi-layered tablet
First Layer (%) amount (w/w)
Dabigatran etexilate free base or
pharmaceutically acceptable salts of
dabigatran etexilate 25.00-40.00
Sodium starch glycolate 1 .00-2.00
Microcrystalline celluose 25.00-35.00
Colloidal silicon dioxide 0.5-2.00
Starch, pregelatinize 10.00-20.00
Lactose 15.00-25.00
Magnesium stearate 0.5-2.00
Total (First layer) 100
Inert Layer (%) amount (w/w)
Povidone 5.00-10.00
Microcrystalline cellulose 90.00-95.00
Yellow iron oxide 0.5-1 .00
Colloidal silicon dioxide 0.1 -1 .00
Magnesium stearate 0.1 -1 .00
Total (Inert Layer) 100
Second Layer (%) amount (w/w)
Tartaric acid 20.00-40.00
L-HPC 1 .00-5.00
Microcrystalline cellulose 50.00-70.00
Colloidal silicon dioxide 0.5-5.00
Magnesium stearate 0.5-2.00
Total (Second Layer) 100
The pharmaceutical compositions mentioned above are prepared by following these steps:
First layer
· Weighing, sieving and mixing sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized starch, lactose.
• Granulating the powder mixture with dabigatran etexilate which is dispersed in water
• Drying in a vacuum oven at 50-55°C.
· Adding sieved magnesium stearate to the mixture and mixing.
Inert layer
• Weighing povidone, microcrystalline cellulose, colloidal silicon dioxide and yellow iron oxide and mixing them in a mixer.
· Adding magnesium stearate to the mixture and mixing.
Second layer
• Weighing and mixing tartaric acid, L-HPC, microcrystalline cellulose and colloidal silicon dioxide and mixing them in a mixer.
· Adding magnesium stearate to the mixture and mixing.
Pressing these three mixtures for each layer into trilayer tablets.
Coating these tablets.
Example 3: Multi-layered tablet
First Layer (%) amount (w/w)
Dabigatran etexilate free base or
pharmaceutically acceptable salts of
dabigatran etexilate 5.00-60.00
Sodium starch glycolate 0.25-8.00
Microcrystalline celluose 10.00-70.00
Colloidal silicon dioxide 0.1 -5.00
Starch, pregelatinize 5.00-30.00
Lactose 5.00-50.00
Magnesium stearate 0.1 -5.00
Total (First layer) 100
Inert Layer (%) amount (w/w)
Starch, pregelatinize 1 .00-10.00
Microcrystalline cellulose 70.00-95.00
Yellow iron oxide 0.1 -2.00
Colloidal silicon dioxide 0.05-5.00
Magnesium stearate 0.1 -5.00
Total (Inert Layer) 100
Second Layer (%) amount (w/w)
Citric acid 10.00-90.00
Starch, pregelatinize 1 .00-20.00
Microcrystalline cellulose 30.00-70.00
Colloidal silicon dioxide 0.05-5.00
Magnesium stearate 0.1 -5.00
Total (Second Layer) 100
Example 4: Multi-layered tablet
First Layer (%) amount (w/w)
Dabigatran etexilate free base or
pharmaceutically acceptable salts of
dabigatran etexilate 25.00-40.00
Sodium starch glycolate 1 .00-2.00
Microcrystalline celluose 25.00-35.00
Colloidal silicon dioxide 0.5-2.00
Starch, pregelatinize 10.00-20.00
Lactose 15.00-25.00
Magnesium stearate 0.5-2.00
Total (First layer) 100
Inert Layer (%) amount (w/w)
Povidone 5.00-10.00
Microcrystalline cellulose 90.00-95.00
Yellow iron oxide 0.5-1 .00
Colloidal silicon dioxide 0.1 -1 .00
Magnesium stearate 0.1 -1 .00
Total (Inert Layer) 100
Second Layer (%) amount (w/w)
Citric acid 20.00-40.00
Starch, pregelatinize 1 .00-5.00
Microcrystalline cellulose 50.00-70.00
Colloidal silicon dioxide 0.5-5.00
Magnesium stearate 0.5-2.00
Total (Second Layer) 100
The pharmaceutical compositions mentioned above are prepared by following these steps:
First layer
• Weighing, sieving and mixing sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized starch, lactose and dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate.
• Granulating the powder mixture with water.
· Drying in a vacuum oven at 50-55°C.
• Adding magnesium stearate to the mixture and mixing.
Inert layer
• Sieving pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide and yellow iron oxide and mixing them in a mixer.
• Adding magnesium stearate to the mixture and mixing.
Second layer
• Sieving and mixing citric acid, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide and mixing them in a mixer.
• Adding magnesium stearate to the mixture and mixing 1 -2 more minutes
Pressing these three mixtures for each layer into trilayer tablets.
Coating these tablets.
Claims
1 . A pharmaceutical composition for oral administration comprising: a) A first layer comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient
b) an inert layer comprising at least one pharmaceutically acceptable excipient c) a second layer comprising one pharmaceutically acceptable acid or hydrates or acid salts thereof and at least one pharmaceutically acceptable excipient
2. The oral pharmaceutical composition according to claim 1 , wherein the amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is 5.00% to 60.00% by weight of the first layer.
3. The pharmaceutical composition according to claim 2, wherein the amount of dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate is between 30 to 350 mg.
4. The pharmaceutical composition according to claim 1 , wherein said at least one pharmaceutically acceptable excipient for each layer is selected from disintegrants, lubricants, glidants, binders, fillers, colour agents or mixtures thereof.
5. The pharmaceutical composition according to claim 4, wherein the first layer of the pharmaceutical composition comprising preferably at least two different disintegrants.
6. The pharmaceutical composition according to claim 4, wherein the second layer of the pharmaceutical composition comprising at least one disintegrant.
7. The pharmaceutical comporision according to claim 5, wherein the amount of total disintegrants in the first layer is at least 40% by weight of the first layer.
8. The pharmaceutical composition according to claim 6, wherein the disintegrants are selected from a group comprising starch, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinil pyrrolidone), povidone, poloxomer, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar
gum, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof, preferably the disintegrants are sodium starch glycolate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch or mixtures thereof.
9. The pharmaceutical composition according to claim 1 , wherein said one pharmaceutically acceptable acid is selected from tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid or hydrates or salts thereof.
10. The pharmaceutical composition according to claim 9, wherein the amount of pharmaceutically acceptable acid in the second layer is between 10% and 90, preferably between 15% and 70%, more preferably between 20% and 40% by weight of the second layer.
1 1 . The pharmaceutical composition according to claim 1 or 9, wherein the weight ratio of dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate to pharmaceutically acceptable acid is between 0.5 and 2.0, preferably between 1 .0 and 2.0, more preferably between 1 .0 and 1 .6.
12. The pharmaceutical composition according to any of the preceding claims, comprising:
a. 5.00 to 60.00 % dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate
b. 0.25 to 8.00 % sodium starch glycolate
c. 10.00 to 70.00 % microcrystalline celluose
d. 0.1 to 5.00 % colloidal silicon dioxide
e. 5.00 to 30.00 % starch, pregelatinize
f. 5.00 to 50.00 % lactose
g. 0.1 to 5.00 % magnesium stearate
in the first layer by weight of the first layer
h. 1 .00 to 10.00 % povidone
i. 70.00 to 95.00 % microcrystalline cellulose
j. 0.1 to 2.00 % yellow iron oxide
k. 0.05 to 5.00 % colloidal silicon dioxide
I. 0.1 to 5.00 % magnesium stearate
in the inert layer by weight of the inert layer
m. 10.00 to 90.00 % tartaric acid
n. 1 .00 to 20.00 % low-substituted hydroxypropyl cellulose
0. 30.00 to 70.00 % microcrystalline cellulose
p. 0.05 to 5.00 % colloidal silicon dioxide
r 0.1 to 5.00 % magnesium stearate
in the second layer by weight of the second layer
13) The pharmaceutical composition according to any of the preceding claims, comprising:
a. 5.00 to 60.00 % dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate
b. 0.25 to 8.00 % sodium starch glycolate
c. 10.00 to 70.00 % microcrystalline celluose
d. 0.1 to 5.00 % colloidal silicon dioxide
e. 5.00 to 30.00 % starch, pregelatinize
f. 5.00 to 50.00 % lactose
g. 0.1 to 5.00 % magnesium stearate
in the first layer by weight of the first layer h. 1 .00 to 10.00 % starch, pregelatinize
1. 70.00 to 95.00 % microcrystalline cellulose
j. 0.1 to 2.00 % yellow iron oxide
k. 0.05 to 5.00 % colloidal silicon dioxide
I. 0.1 to 5.00 % magnesium stearate
in the inert layer by weight of the inert layer m. 10.00 to 90.00 % citric acid
n. 1 .00 to 20.00 % starch, pregelatinize
o. 30.00 to 70.00 % microcrystalline cellulose
p. 0.05 to 5.00 % colloidal silicon dioxide
r. 0.1 to 5.00 % magnesium stearate
in the second layer by weight of the second layer 14) The process for preparation of the pharmaceutical composition according to claim 12, wherein the process comprising the following steps:
a. first layer
i. weighing, sieving and mixing sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized starch, lactose.
ii. granulating the powder mixture with dabigatran etexilate which is dispersed in water
iii. drying in a vacuum oven at 50-55°C.
iv. adding sieved magnesium stearate to the mixture and mixing. b. inert layer
i. weighing povidone, microcrystalline cellulose, colloidal silicon dioxide and yellow iron oxide and mixing them in a mixer.
ii. adding magnesium stearate to the mixture and mixing. c. second layer
i. weighing and mixing tartaric acid, L-HPC, microcrystalline cellulose and colloidal silicon dioxide and mixing them in a mixer.
ii. adding magnesium stearate to the mixture and mixing.
d. pressing these three mixtures for each layer into trilayer tablets,
e. coating these tablets.
15) The process for preparation of the pharmaceutical composition according to claim 13, wherein the process comprising the following steps: a. first layer
i. weighing, sieving and mixing sodium starch glycolate, microcrystalline cellulose, colloidal silicon dioxide, pregelatinized starch, lactose and dabigatran etexilate free base or pharmaceutically acceptable salt of dabigatran etexilate ii. granulating the powder mixture with water
iii. drying in a vacuum oven at 50-55°C.
iv. adding magnesium stearate to the mixture and mixing. b. inert layer
i. sieving pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide and yellow iron oxide and mixing them in a mixer.
ii. adding magnesium stearate to the mixture and mixing, second layer
i. sieving and mixing citric acid, pregelatinized starch, microcrystalline cellulose and colloidal silicon dioxide and mixing them in a mixer.
ii. adding magnesium stearate to the mixture and mixing 1 -2 more minutes pressing these three mixtures for each layer into trilayer tablets,
coating these tablets.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2016/17984 | 2016-12-07 | ||
| TR2016/17984A TR201617984A2 (en) | 2016-12-07 | 2016-12-07 | PHARMACEUTICAL COMPOSITIONS OF DABIGATRAN |
| TR2016/19828A TR201619828A2 (en) | 2016-12-07 | 2016-12-28 | MULTI LAYERED TABLET COMPOSITIONS OF DABIGATRAN |
| TR2016/19828 | 2016-12-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018104387A1 true WO2018104387A1 (en) | 2018-06-14 |
Family
ID=60582520
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2017/081692 Ceased WO2018104387A1 (en) | 2016-12-07 | 2017-12-06 | Multilayered tablet compositions of dabigatran |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP3332771A1 (en) |
| WO (1) | WO2018104387A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020147542A (en) * | 2019-03-14 | 2020-09-17 | 日本ケミファ株式会社 | Multilayer tablets containing dabigatran etexilate or a pharmaceutically acceptable salt thereof |
| JP2020180099A (en) * | 2019-04-26 | 2020-11-05 | 沢井製薬株式会社 | Dabigatran etexylate methanesulfonate formulation |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR201722630A2 (en) * | 2017-12-28 | 2019-07-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi |
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| WO1998037075A1 (en) | 1997-02-18 | 1998-08-27 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| EP1658056A1 (en) | 2003-08-16 | 2006-05-24 | 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 |
| EP1870100A1 (en) | 2002-03-07 | 2007-12-26 | Boehringer Ingelheim Pharma GmbH & Co. KG | Pharmaceutical composition for oral application comprising ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-2-pyridylamino)propionate mesylate |
| EP1877395A2 (en) | 2005-04-27 | 2008-01-16 | Boehringer Ingelheim International GmbH | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]propionic acid ethyl ester |
| WO2012077136A2 (en) | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN104042588A (en) * | 2014-06-17 | 2014-09-17 | 浙江京新药业股份有限公司 | Multi-layer tablets containing dabigatran etexilate mesylate |
| CN105919962A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Dabigatran tablet, and preparation method and application thereof |
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2017
- 2017-12-06 WO PCT/EP2017/081692 patent/WO2018104387A1/en not_active Ceased
- 2017-12-06 EP EP17205656.6A patent/EP3332771A1/en not_active Withdrawn
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037075A1 (en) | 1997-02-18 | 1998-08-27 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| EP1870100A1 (en) | 2002-03-07 | 2007-12-26 | Boehringer Ingelheim Pharma GmbH & Co. KG | Pharmaceutical composition for oral application comprising ethyl 3-(2-(4-(hexyloxycarbonylamidino)phenylaminomethyl)-1-methyl-1H-benzimidazole-5-carbonyl)-2-pyridylamino)propionate mesylate |
| EP1658056A1 (en) | 2003-08-16 | 2006-05-24 | 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 |
| EP1877395A2 (en) | 2005-04-27 | 2008-01-16 | Boehringer Ingelheim International GmbH | Physiologically acceptable salts of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]propionic acid ethyl ester |
| WO2012077136A2 (en) | 2010-12-06 | 2012-06-14 | Msn Laboratories Limited | Process for the preparation of benzimidazole derivatives and its salts |
| CN104042588A (en) * | 2014-06-17 | 2014-09-17 | 浙江京新药业股份有限公司 | Multi-layer tablets containing dabigatran etexilate mesylate |
| CN105919962A (en) * | 2015-12-18 | 2016-09-07 | 重庆两江药物研发中心有限公司 | Dabigatran tablet, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020147542A (en) * | 2019-03-14 | 2020-09-17 | 日本ケミファ株式会社 | Multilayer tablets containing dabigatran etexilate or a pharmaceutically acceptable salt thereof |
| JP2020180099A (en) * | 2019-04-26 | 2020-11-05 | 沢井製薬株式会社 | Dabigatran etexylate methanesulfonate formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3332771A1 (en) | 2018-06-13 |
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