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
  • A61K9/48—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
• • 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
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4816—Wall or shell material
• • 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
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

• the present invention relates to pharmaceutical compositions comprising a first component comprising dabigatran or a pharmaceutically acceptable salt thereof in the form of a tablet and a second component comprising an organic acid.
• the invention also relates to processes for the preparation of such compositions and using those compositions to reduce the risk of stroke and systemic embolism in patients with non- valvular atrial fibrillation.
• Dabigatran etexilate is known as (3-[(2- ⁇ [4-(hexyloxycarbonylamino-imino-methyl)- phenylaminoj-methyl ' - 1 -methyl- 1 H-benzimidazole-5-carbonyl)-pyridine-2 ⁇ yl- amino]-propionic acid ethyl ester) and it has the following chemical structural formula:
• Dabigatran etexilate is already known from PCT Publication No. WO 1998/37075. which discloses compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time.
• the solubility o dabigatran in water is only 1.8 mg/ml. Moreover, dabigatran has a strong pH-dependent solubility thai is greatly increased in the acidic environment. This leads to the problem that conventional oral pharmaceutical compositions have large variations in the bioavailability since the solubility of the active ingredient depends on the pH value in the patient's stomach. This is particularly problematic with patients in whom the stomach pH value is changed by physiological variability. illness, or premedications (for example, proton pump inhibitors).
• PCT Publication No. WO 2005/018615 discloses a tablet comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof; one or more pharmaceutically acceptable organic acids with solubility in water of more than I g/250ml at 20°C and a pharmaceutically acceptable excipient or tiller.
• the presence of an organic acid in close contact with the active in a tablet composition without any special steps taken to separate the two from each other, can make the active highly susceptible to hydrolysis in the presence of humidity.
• PCT Publication No. WO 2003/074056 discloses a pharmaceutical composition comprising an active ingredient and one or more pharmaceutically acceptable organic acids having a water solubility of >l g/250 ml at 20°C. wherein the active ingredient layer is applied on an organic acid core while spatially separating the organic acid and active ingredient by an insulating layer.
• PCT Publication No. WO 2011/107427 discloses an oral pharmaceutical composition
• an oral pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, and an inorganic acidic excipient.
• the composition as described comprises mixing dabigatran with the inorganic acidic excipient and optionally compressing the mixture to tablets or filling the mixture into capsules.
• PCT Publication No. WO 2013/110567 discloses an oral pharmaceutical composition comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof, and at least one water soluble cyclodextrin agent as an excipient.
• PCT Publication No. WO 2013/124340 discloses dabigatran etexilate compositions comprising a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient. wherein a) the first type of particles comprise the active agent; b) the second type of particles comprise at least one pharmaceutically acceptable organic acid; and c) optionally at least one type of particles are coated with a protective coating layer.
• the aim of the present invention is to provide an alternative solid composition, i.e.. a pharmaceutical composition, for oral administration of dabiagtran etexilate or a pharmaceutically acceptable salt thereof, particularly dabigatran etexilate mesylate (dabigatran etexilate methanesulphonate) by providing a composition characterized by two components separating dabigatran and an organic acid.
• a pharmaceutical composition for oral administration of dabiagtran etexilate or a pharmaceutically acceptable salt thereof, particularly dabigatran etexilate mesylate (dabigatran etexilate methanesulphonate)
• a pharmaceutical composition comprising: a) a first component comprising dabigatran or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients; and
• first component is in the form of a tablet and wherein the composition is in the form of a capsule.
• second component is in the form of a tablet, granules, pellets or powder.
• a pharmaceutical composition of dabigatran wherein the organic acid has a solubility in water of more than 1 g/250ml at 2( ⁇
• a pharmaceutical composition of dabigatran wherein the organic acid comprises tartaric acid, fu marie acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid or hydrates or acid salts thereof.
• composition oi ⁇ dabigatran wherein the composition comprises dabigatran etexilate mesylate.
• a composition of dabigatran comprising from about 50 mg to about 200 mg of dabigatran etexilate mesylate.
• the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
• the pharmaceutically acceptable excipients may include one or more fillers, binders, disintegrants. surfactants, lubricants, glidants, anti-tacking agents, plaslicizers, and the like.
• composition wherein the first component is substantially free of an organic acid.
• pharmaceutical composition wherein the second component is substantially free of dabigatran.
• composition comprising:
• the second component further comprises a pH independent coating.
• the pH independent coating comprises acrylic or methacrylic polymers, copolymers, esters or derivatives thereof, or combinations thereof.
• composition wherein the first component is prepared by a process comprising:
• composition wherein the second component is prepared by a process comprising:
• the pharmaceutical composition may include one or more of the following features.
• the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients.
• the pharmaceutically acceptable excipients may include one or more fillers, binders, disintegrants, surfactants, lubricants, glidants, anti-tacking agents, plasticizers. and the like.
• composition of dabigatran wherein the composition releases at least about 50% dabigatran within 10 minutes and at least about 90% dabigatran within 30 minutes after subjecting the composition to dissolution testing at pi I 2.0 according to the USP basket method at lOOrpm.
• composition of dabigatran wherein the composition retains at least 90% of the potency of dabigatran in the pharmaceutical composition after storing the composition at 40°C and 75% relative humidity for at least three months.
• the present invention relates to an oral pharmaceutical composition of dabigatran etexilate or a pharmaceutically acceptable salt thereof as an active ingredient.
• the oral pharmaceutical composition of the present invention is characterized by two components separating dabigatran and an organic acid.
• dabigatran compositions can now be prepared by easy processing by incorporation of two components in a capsule with the added advantage of chemical, physical and organoleptic stablility and no dabigatran degradation due to hydrolysis.
• the compositions of the invention also provide faster in-vitro dabigatran release.
• the compositions of the present invention are stable, easy to prepare, and provide an in-vitro release of dabigatran similar to that of the currently marketed product "PRADAXA", dabigatran etexilate mesylate capsules.
• dabigatran includes dabigatran etexilate or any pharmaceutically acceptable salts or derivatives thereof, including polymorphs, hydrates, solvates or amorphous forms, preferably dabigatran etexilate mesylate.
• component used throughout the specification refers to an active ingredient or an organic acid containing powder, particles, agglomerates, granules, pellets, microspheres, minitablets, microcapsules, tablets, cores, coats on tablets or any solid physical form known to the person skilled in the art.
• the first component is substantially free of an organic acid.
• the first component comprises less than 5% organic acid, preferably less than 2% organic acid, more preferably less than 1% organic acid, and even more preferably 0% organic acid.
• a pharmaceutical composition wherein the second component is substantially free of dabigatran.
• the second component comprises less than 5% dabigatran, preferably less than 2% dabigatran, more preferably less than 1% dabigatran, and even more preferably 0% dabigatran.
• the pharmaceutical compositions of the present invention comprise about 25 mg to about 500 mg of dabigatran. preferably about 50 mg to about 300 mg.
• dabigatran is present in an amount from about 5% by weight to about 75% by weight of the composition, more preferably from about 10% to about 60%). more prelerably from about 15% to about 50% and even more prelerably from about 20% to about 50% by weight of the composition.
• dabigatran is present in an amount from about 20% to about 80%) by weight of the first component, more preferably from about 30% U.v about 75%, even more preferably from about 40% to about 70%) by weight of the first component.
• Particularly suitable organic acids include, but are not limited to tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid and the like or combinations thereof including the hydrates and acid salts thereof.
• the organic acid is present in an amount from about l%> by weight to about 95% by weight of the composition, more preferably from about 10% to about 80%, more preferably from about 20% to about 70%> and even more preferably from about 20% to about 50% by weight of the composition.
• the organic acid is present in the composition in an amount from about 30% to about 90% by weight of the second component, more preferably from about 40% to about 85%, even more preferably from about 50% to about 85% by weight of the second component.
• the current invention describes a pharmaceutical composition wherein dabigatran and the organic acid are not in direct contact with each other.
• Yet another embodiment describes a pharmaceutical composition wherein the two components comprising dabigatran in the form of a tablet and the organic acid separately, further comprise a coating layer to avoid the instance of direct contact between dabigatran and the organic acid.
• This coating layer may be applied on any or both of the components.
• the coating layer may be in an aqueous/non-aqueous solution or dispersion form or in powder form.
• coat as used herein is defined to mean a coating substantially surroundings a core which provides desirable properties to the dosage form.
• the coat may serve several purposes, like protecting the dosage form from environmental conditions, such as light or moisture, providing esthetic or taste-masking properties to the dosage form, making the dosage form, easier to swallow or to handle during the production process, or modifying the release . properties of the dosage form, such that pharmaceutically active ingredient is released at a different rate from the coated core than from the uncoated core.
• One or more than one coat, with the same or different functions or properties, may be applied to a core.
• the term "coat” includes, but is not limited to. modified release coat, immediate release coat and non-functional soluble coat, pH dependent and independent release coat.
• the pharmaceutically acceptable excipients may include one or more tillers, binders. disintegrants, surfactants, lubricants, glidants, anti-tacking agents, plasticizers. and the like.
• Suitable fillers may include one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin. magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol, erythritol and the like.
• the filler may be present in an amount of 5 to 80% by weight of the composition.
• Suitable binders may include one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomer, dextrin, ethyl cellulose, methylcellulose, shellac, zein. gelatin, polymethacrylates (eg.
• euclragli polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins, silicic acid, hydrophilic polymers and the like.
• the binder may be present in an amount of 2 to 60% by weight of the composition, more preferably in an amount of 2 to 40% by weight of the composition.
• hydrophilic polymer comprises polymers with polar groups.
• polar groups are hydroxy, amino, carboxy, carbonyl, ethers, esters, and sulfonates. Hydroxy groups are particularly preferred.
• suitable hydrophilic polymers are cellulose derivatives, in particular hydrophilic derivatives of the cellulose (e.g. IIPMC. HPC, carboxymelhylcellulose. preferably as sodium or calcium salt, hydroxyethylcellulose, hydroxypropylcelluiose).
• polyvinylpyrrolidone preferably with a molecular weight of from 10,000 to 60,000 g/mol
• copolymers of PVP preferably co-polymers comprising vinylpyrrolidone and vinylacetate units (e.g.
• povidone. VA64, BASF preferably with a molecular weight between 40.000 and 70,000 g/mol, poly(oxyethylene) alkyl ether, polyethylene glycol, co-block polymers of ethylene oxide, and propylene oxide (poloxamer, pluronic), derivatives of polymethacrylates, polyvinyl alcohol, polyvinyl alcohol, derivatives, polyethylene glycol, and polyethylene glycol derivatives.
• Suitable disintegrants may include one or more of croscarmellose sodium, sodium starch glycolate, low substituted hydroxylpropyl cellulose(L. hydroxylpropyl cellulose), pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and the like.
• the disintegrants may be present in an amount of 0.5 to 20% by weight of the composition.
• Suitable surfactants may include one or more of anionic, cationic. non-ionic or amphoteric surfactants or those known to the person skilled in the art.
• Non-limiting examples of surfactants include. polyoxyethylene-polyoxypropylene co-polymers and block co-polymers, commercially available as PluronicTM or PoloxamerTM.
• ethoxylated cholesterins commercially available as SolulanTM vitamin derivatives, e.g. vitamin E derivatives such as tocopherol polyethylene glycol succinate (TPGS). sodium dodecylsul ate or sodium lauryl sulfate; a bile acid or salt thereof, for example cholic acid, glycol ic acid or a sail.
• TPGS tocopherol polyethylene glycol succinate
• Suitable lubricants and glidants may include one or more of talc, metallic stearales such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide. finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate. polyethylene glycols, sodium stearyl fumarate. ; and the like. It would be appreciated that a person skilled in the art is cognizant of the fact that lubricant, glidanl or anti-lacking agent may be used interchangeably.
• the lubricant, glidant or anti-tacking agent may be present in an amount ranging from 0.1 % to 15 % vv/w of the composition.
• Suitable plasticizers may include one or more of triacetin, diethyl phthalate. tri butyl sebacate, polyethylene glycol and the like.
• Suitable coating materials suitable for present application include but are not limited to cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy propyl methylcellulose, polyvinylpyrrolidone, polyvin ylpyrrolidone/vinyl acetate copolymer, ethyl cellulose, EU DRAG IT" RLPO, EU DRAG IT* RSPO, OPADRY" " and the like.
• Preferred coating materials for second component comprise
• compositions as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet granulation, dry granulation or melt granulation.
• the current invention encompasses process of preparing compositions of dabigatran, comprising a first component comprising dabigatran and one or more pharmaceutically acceptable excipients in the form of a tablet and a second component comprising an organic acid and one or more pharmaceutically acceptable excipients.
• the pharmaceutical composition of the present invention comprises a first component contained in a tablet characterized by the presence of dabigatran, and a second component characterized by the presence of an organic acid, wherein the composition is prepared by a process comprising:
• Another embodiment describes a pharmaceutical composition wherein the first component comprising dabigatran is in the form of a tablet and the second component comprising an organic acid is in the form of a tablet, granules, beads, pellets, powder, particles, agglomerates, microspheres, minitablets, microcapsules.
• a process lor preparing the first component wherein the component is in the form of a tablet, wherein the process comprises the steps: a) mixing dabigatran with one or more pharmaceutically acceptable excipients, b) granulating the mixture obtained in a granulator or by top spray granulation, c) drying the granules followed by blending, lubrication and compression to obtain the first component; and
• step 'a' granulating the blend of step 'a' with a binder solution to form organic acid granules
• the smoothness (or roughness) of the coating layer can enhance solvent evaporation from the surface and decreases the amount of surface residual solvent, in doing so reducing the amount of solvent which may cause organic acid leaching and possible interaction and subsequent degradation ofdabigatran due to hydrolysis or other means.
• the coating layer may provide a weight gain from about 5% to about 30%, more preferably, from about 10% to about 30% by weight of the organic acid beads.
• the required quantities of two components prepared by any of the above mentioned techniques may be compressed into a tablet, filled into pouches, encapsulated into a capsule of any desirable size, for example, a size 000, 00. Oel, 0, 1.2, 3, 4, or 5 to provide a final dosage form.
• a capsule shell is a hydroxypropyl methylcellulose (HPMC) shell.
• HP C capsules include small amounts of water, colorants (e.g., Ti0 2 and iron oxides), and optionally gelling agents and gelling promoters. They have relatively low moisture content, making them suitable for moisture-sensitive materials. Such capsules resist breakage even at low moisture levels.
• the capsules of cellulose ether film suffer from the problem that the gelling aid which is blended for assisting in film formation will precipitate out on the film surface during long-term storage.
• Patent no. US 6.649.180 suggests means to overcome this problem by limiting the total content of alkoxyl and hydroxyalkoxyl groups in the cellulose ether to 37.6% by weight. More particularly, the total content corresponds to the total content of methoxyl groups (abbreviated as "MO groups " ) and hydroxypropoxyl groups (abbreviated as "HPO groups " ) in the case of HPMC is considered.
• MO groups methoxyl groups
• HPO groups hydroxypropoxyl groups
• compositions of the present invention were found to be physically and organoleptically stable during the entire stability conditions i.e., the capsule shells showed no signs of white precipitates.
• HPMC capsule shells used for the present invention preferably comprise methoxyl groups and hydroxypropoxyl groups combined of 23 to 39% by weight of the hydroxypropyl methyl cellulose; more prelerably 30 to 39%, even more preferably .37 to 39% and still more preferably 37.7 to 39%.
• compositions of the present invention provide a faster dabigatran release than available marketed composition, wherein it releases at least about 50%) dabigatran within 10 minutes, more preferably at least about 60% dabigatran within 10 minutes; releases at least about 90% dabigatran within 30 minutes, more preferably at least about 95% dabigatran within 30 minutes after subjecting said composition to dissolution testing in 0.0 IN HCI (900ml) at pH 2.0 according to the USP basket method at lOOrpm.
• the pharmaceutical compositions of the present invention are found to be stable and may retain at least 90% of the potency of dabigatran in the composition after storing the composition at 40° C and 75% relative humidity for at least three months.
• the pharmaceutical composition provides for a relative AUCn 24h, C IT 1X and C m ,,, in the range of 80% to 125%), as compared to Pradaxa* ' , the currently marketed composition in the USA..
• Another embodiment discloses a method for prophylaxis or treatment of venous and arterial thrombotic disease condition comprising orally administering to the subject a therapeutically effective , amount of the composition of the present invention, wherein said condition is selected from a group consisting of deep leg vein thrombosis, reocclusion after a bypass operation or angioplasty, occlusion in peripheral arterial disease, pulmonary embolism, disseminated intravascular coagulation, coronary thrombosis, stroke, and the occlusion of a shunt or stent, systemic embolism in patients with non-valvular atrial fibrillation.
• Dabigatran etexilate mesylate, microcrystalline cellulose, L- Hydroxypropyl cellulose and sodium starch glycolate were mixed and granulated using a solution of hydroxypiOpyl cellulose LP in acetone in a granulator. The granules were dried, sized and blended with microcrystalline cellulose. L- hydroxypropyl cellulose, sodium starch glycolate. The blend was lubricated using talc, colloidal silicon dioxide, hydrogenated castor oil and magnesium stearate. The lubricated granules were compressed using suitable size punches.
• Citric acid anhydrous was top sprayed using eudragit. talc and PEG solution in IPA. acetone and water in a bombard. The wet granular mass was dried at a specified inlet temperature till specific moisture content was achieved. The dried granules were sized and lubricated with talc.
• the required quantities of the first and the second component obtained were filled in capsules.
• the dissolution performance for the composition was measured using a IJSP-l rotating basket apparatus. Release times were measured by placing the capsule in a small wire basket placed on the end of a rod spinning at 100 rpm. Aliquots were withdrawn from pH 2.0 HCI buffer up to I hr.

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Cited By (8)

Citations (7)

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