Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—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
• • 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

Definitions

• the present invention relates to pharmaceutical compositions for an oral administration comprising a first component comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and a second component comprising an organic acid.
• 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 etexilate and dabigatran etexilate salt
• 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°C 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.
• Dabigatran etexilate is also less stable in acidic environment. To avoid this stability problem, many solutions were offered in the prior art. Separating layer between the acidic core and the active substance layer is the most preferred way. In this invention, the separating layer is used and in comparison to prior art, the composition of this invention is more stable since the active agent is not in the outer layer of the composition.
• W003/074056 discloses a composition contains the following components: a core material comprising an organic acid, an insulating layer which separates the acid core from the layer containing the active substance and an active agent layer.
• Patent application WO2012001 156 relates to a process for the preparation of a solid oral dosage form comprising dabigatran etexilate.
• the pellets comprise a neutral core comprised of sucrose, microcrystalline cellulose or starch, or a commercially available tartaric acid pellet; the tartaric acid layer, the isolating layer, the active pharmaceutical ingredient layer and, optionally, an overcoat.
• Patent application WO2013124340 discloses dabigatran etexilate compositions comprising a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, wherein the first type of particles comprises the active agent; the second type of particles comprise at least one pharmaceutically acceptable organic acid; and optionally at least one type of particles are coated with a protective layer.
• the invention provides a quick dissolution particularly at earlier time points as compared to formulation having one type of particles/pellets.
• the main object of the present invention is to provide pH-independent pharmaceutical compositions for oral administration comprising dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient.
• a further object of the present invention is to provide stable pharmaceutical compositions which are not prone to phase transformation and degradation.
• a further object of the present invention is to provide pharmaceutical compositions which have desired chemical and polymorphic stability.
• Another object of the present invention is to provide pharmaceutical compositions which are easy to prepare.
• the pharmaceutical composition for oral administration comprising:
• a first component comprising dabigatran etexilate or pharmaceutically acceptable salts of dabigatran etexilate and at least one pharmaceutically acceptable excipient
• a second component comprising an organic acid and at least one pharmaceutically acceptable excipient
• the term“dabigatran etexilate free base” refers to dabigatran etexilate which is free from other forms of the active moiety, especially acid addition salts.
• mini tablet refers to small tablets with a diameter equal to or less than 6 mm that are typically filled into a capsule or further compressed into larger tablets.
• Mini tablets have many advantages. Due to increased surface in relation to volume, the drug can be released more efficiently incase of mini-tablets. Some benefits of mini-tablets include excellent size uniformity, regular shape and a smooth surface. In mini tablets, smooth surface offers an excellent substrate for coating with polymeric systems. It can be concluded that pharmaceutical mini-tablets offer several advantages when compared to single unit dosage forms and are also good substitutes for granules and pellets. They have well defined size, shape, surface, low degree of porosity and high mechanical strength. The mini tablets have round shape and smooth surface to ease coating process. Due to significant smaller dimensions of the mini tablets, when compared to normal tablets, they pass through the stomach at a more even rate. As a result, the concentration of the drug in the blood can be easily reproduced. It has been found that, dissolution and stability problems are overcome by using mini tablet form.
• mini-tablets have a diameter more than 3 mm. Preferably this value is between 3 mm and 5 mm, more preferably between 3 mm and 4 mm, more preferably 3 mm and 3.5 mm.
• mini-tablet thickness ranges are important for stability of the composition. Furthermore, when the mini-tablets have a diameter mentioned here, process for the preparation of mini-tablets and process for the filling mini-tablets into the capsule get easy.
• mini-tablets comprise one coating layer for ensuring the stability of the composition.
• Homogen coating which is very important for ensuring stability of the composition, is provided by choosing these specific mini-tablet thickness ranges. A further advantage of these ranges is simplified coating process. During the development study of the invention, it has been found that when the mini-tablets have a diameter mentioned above, homogen coating process is easier than usual for this invention.
• the second component is in the form of pellets or minitablets or granules or beads or capsules.
• the second component is in the form of pellets.
• the second component is free of dabigatran etexilate.
• dabigatran etexilate free base or a pharmaceutically acceptable salt of dabigatran etexilate 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.
• the composition comprises dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate in an amount of between 20.00% and 80.00% by weight of the first component, preferably between 30.00% and 70.00%, more preferably between 40.00% and 60.00%.
• the organic acid is selected from a group comprising tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid or aspartic acid or hydrates or salts thereof.
• the organic acid is citric acid.
• Choice of the organic acid is important for the desired dissolution profile of the composition since the dissolution of dabigatran should be pH independent. It has been found that, using citric acid ensures effective dissolution profile, especially when the second component which is free of dabigatran, is in the form of pellets.
• the amount of the organic acid is between 70.00% and 99.00% by weight of the second component., preferably between 85.00% and 99.00%.
• said at least one pharmaceutically acceptable excipient is selected from disintegrants, fillers, binders, lubricants, glidants, coating agents, solvents, anticaking agents.
• Suitable fillers are selected from a group comprising microcrystalline cellulose, 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 present in an amount of between 10.0 % and 80.0% by weight of the first component.
• the filler is selected from microcrystalline cellulose, lactose or mixtures thereof.
• microcrystalline cellulose and lactose as the fillers also helps improving the stability of the composition. Furthermore, when the weight ratio of microcrystalline cellulose to lactose is between 0.20 and 5.00, the improvement in the stability of the composition is more distinct.
• 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
• the binder is croscarmellose sodium.
• the amount of binder is between 1 .00% and 20.00%, preferably between 2.00% and 10.00% by weight of the first component.
• Suitable glidants are selected from colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
• the glidant is colloidal silicon dioxide.
• Suitable disintegrants are selected from a group comprising hydroxypropyl methylcellulose, starch, sodium starch glycolate, microcrystalline cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), povidone, poloxamer, cross-linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodecyl sulphate, sodium glycine carbonate, or mixtures thereof
• the disintegrant is hydroxypropyl methylcellulose.
• the amount of disintegrants is between 1 .00% and 15.00% by weight of the first component, preferably between 3.00% and 7.00%.
• Suitable anticaking agents are selected from a group comprising talc, magnesium silicate, magnesium trisilicate, magnesium oxide, hydroxypropyl cellulose, hydroxyethyl cellulose, hydrophobic colloidal silica, guar gum, colloidal silicon dioxide, calcium silicate, calcium phosphate or mixtures thereof.
• the anticaking agent is talc.
• the amount of anticaking agent is between 0.01% and 10.00% by weight of the second component., preferably between 0.10% and 5.00%, more preferably between 0.10% and 2.00%
• Suitable lubricants are selected from a group comprising magnesium stearate, sodium stearyl fumarate, 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 palmitostearate, sodium lauryl sulphate or mixtures thereof.
• the lubricant is magnesium stearate.
• the amount of the lubricant is between 0.10% and 5.00% by weight of the first component, preferably between 0.50% and 2.00%.
• Suitable salts of dabigatran etexilate are selected from a group comprising mesylate, maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate or camphor sulfonate.
• suitable salts of dabigatran etexilate are selected from maleate, malonate, citrate, tosylate, esylate, tartrate, oxalate, camphor sulfonate.
• the active agent is in the form of free base.
• Example 1 Capsule comprising dabigatran mini tablets and acid pellets
• compositions mentioned above are prepared by following these steps:

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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Citations (10)

• 2017
  • 2017-12-27 TR TR2017/22323A patent/TR201722323A2/tr unknown
• 2018
  • 2018-12-26 EP EP18877293.3A patent/EP3731822A1/de not_active Withdrawn
  • 2018-12-26 WO PCT/TR2018/050901 patent/WO2019132839A1/en unknown

Patent Citations (11)

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