WO2016131896A1 - Combinaisons pharmaceutiques de dronédarone et de rivaroxaban - Google Patents

Combinaisons pharmaceutiques de dronédarone et de rivaroxaban Download PDF

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Publication number
WO2016131896A1
WO2016131896A1 PCT/EP2016/053407 EP2016053407W WO2016131896A1 WO 2016131896 A1 WO2016131896 A1 WO 2016131896A1 EP 2016053407 W EP2016053407 W EP 2016053407W WO 2016131896 A1 WO2016131896 A1 WO 2016131896A1
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Prior art keywords
pharmaceutical combination
pellets
tablets
dronedarone
combination according
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PCT/EP2016/053407
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English (en)
Inventor
Ali TÜRKYILMAZ
Gülay Yelken
Sevgi Gökcek
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret A.S.
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Application filed by Sanovel Ilac Sanayi Ve Ticaret A.S. filed Critical Sanovel Ilac Sanayi Ve Ticaret A.S.
Publication of WO2016131896A1 publication Critical patent/WO2016131896A1/fr

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to a pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with rivaroxaban and at least one pharmaceutically acceptable excipient.
  • Dronedarone is a noniodinated benzofuran derivative with antiarrhythmic properties. It is an amiodarone analog that differs structurally from amiodarone in that the iodine moiety was removed and a methane sulfonyl group was added. These modifications reduce thyroid and other adverse effects and makes dronedarone less lipophilic, with a shorter half-life.
  • the chemical name of dronedarone is N-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1 - benzofuran-5-yl]methanesulfonamide and it has the structure shown in the following formula I.
  • Dronedarone hydrochloride (shown in formula II) is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF. Following oral administration in fed conditions, it is well absorbed from intestines to blood. It was approved by the FDA on 2009 and marketed under the brandname MULTAQTM. Recommended dose is one tablet of 400 mg twice a day with morning and evening meals. In prior art, dronedarone and pharmaceutically acceptable salts thereof are described in EP 0 471 609 B1 . US 7 323 493 B1 discloses tablet formulations of dronedarone HCI.
  • Rivaroxaban is an anticoagulant to treat deep vein thrombosis (DVT) and pulmonary embolism (PE). It is also used to help prevent strokes or serious blood clots in people who have atrial fibrillation. Anticoagulant drugs target various procoagulant factors in the coagulation pathway. Rivaroxaban is the first orally active direct factor Xa inhibitor. Direct factor Xa inhibitors play a central role in the cascade of blood coagulation by inhibiting factor Xa directly.
  • Rivaroxaban molecule is a substituted oxazolidinaone disclosed in WO0147919. It has the chemical structure shown in Formula III. Its chemical name is 5-chloro-N-[[(5S)-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-1 ,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide.
  • Rivaroxaban Rivaroxaban tablet formulation is commercially available under the trade name Xarelto® in the strengths of 10, 15 and 20mg. After oral administration, it achieves maximal absorption from the stomach, with a bioavailability of 80 to 100%.
  • antiarrhythmic drugs are commonly used in combination with anticoagulants.
  • prior art there is no formulation which combines dronedarone and rivaroxaban in one dosage form. Instead of one per se use, combining more than one molecule in one dosage form increases the patients' quality of life and patients' compliance. Therefore, a combination of dorenedarone and rivaroxaban in a suitable pharmaceutical dosage formulation is needed in the art.
  • there are many challenges while combining two or more molecules in a dosage form such as dissolution, compatibility and stability problems. Each drug molecule has different chemical properties and dissolution properties. They may follow different absorption and distribution pathways after administration.
  • dronedarone as an antiarithmic and rivaroxaban as an anticoagulant are combined in one dosage form and an effective and safe treatment of cardiovascular diseases is achieved.
  • the present invention relates to a pharmaceutical combination comprising dronedarone or a pharmaceutically acceptable salt thereof in combination with rivaroxaban and at least one pharmaceutically acceptable excipients.
  • dronedarone or a pharmaceutically acceptable salt used in this present invention is dronedarone hydrochloride.
  • dronedarone hydrochloride (HCI) is present in an amount of between 5 to 98 %, preferably between 20 to 98 % and more preferably it is 40 to 98 % by weight of total formulation.
  • dronedarone hydrochloride present in an amount of between 50 to 1000 mg, preferably 200 to 800 mg and more preferably it is 400 to 800 mg.
  • rivaroxaban is present in an amount of between 0.01 to 50 %, preferably between 0.01 to 30 % and more preferably it is 0.01 to 10 % by weight of total formulation.
  • rivaroxaban is present in an amount of between 3 to 50 mg, preferably 5 to 40 mg and more preferably it is 10 to 20 mg.
  • dronedarone HCI is used as an antiarrithmic in combination with rivaroxaban as an anticoagulant, for use in the treatment of cardiac arrhythmia and blood clotting and to prevent serious or life-threatening side effects in patients.
  • a pharmaceutical dosage form comprising dronedarone HCI in combination with rivaroxaban has been developed providing a stable pharmaceutical combination with safe and effective dissolution profiles for each drug molecule.
  • the ratios used in this present invention ensure the required effective doses for the treatment and provide stability for both dronedarone HCI and rivaroxaban.
  • pharmaceutical combination formulated in one dosage form provides desired dissolution profile for both dronedarone HCI and rivaroxaban.
  • the pharmaceutical combination is in the form of solid, liquid or semisolid dosage form.
  • these pharmaceutical combinations are administrated oral, parenteral, intranasal, sublingual, transdermal, transmucosal, ophthalmic, intravenous, pulmonary, intramuscular or rectal administration, and preferably for oral administration.
  • the pharmaceutical combination is in the form of tablets comprising compressed tablets, coated or uncoated tablets, capsules, multilayer tablets, buccal tablets, sublingual tablets, tablet in tablets, in-lay tablets, effervescent combinations, effervescent tablets, immediate release tablets, modified release tablets, ODT (orally disintegrating tablet), film-coated tablets, orally disintegrating tablets, gastric disintegrating tablets, pills, hard or soft gelatin capsules, powders, mini tablets, pellets, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions or suspensions, sterile ocular solutions, aerosols, sprays, drops, ampoules, suppositories, ocular systems, parenteral systems, creams, gels, ointments, dragees, sachets; films, orally administrable films, solutions, solids; elixirs, tinctures, suspensions, syrups, colloidal dispersions, dispersions, emulsion
  • said pharmaceutical combination is formulated in the form of tablet or capsule or multilayer tablet.
  • said pharmaceutical combination is formulated in the form of tablet or capsule or multilayer tablet comprising dronedarone HCI pellets and rivaroxaban pellets.
  • Dronedarone is a drug molecule which is well absorbed in intestine and rivaroxaban is a drug molecule which is well absorbed in stomach.
  • said pharmaceutical combination dronedarone HCI pellets comprises an enteric coating.
  • enteric coating used in this present invention ensures absorption of dronedarone HCI not in stomach but in intestine.
  • the present invention provides a pharmaceutical combination comprises an enteric coating which covers dronedarone HCI layer and which separates rivaroxaban and dronedarone HCI layers.
  • Enteric coating ensures the stability of dronedarone HCI in stomach and by the virtue of the enteric coating, interaction between the rivaroxaban and dronedarone HCI molecules is also prevented at the same time. Another important reason is that the formulations of the drug molecules with different release properties can be provided in the same dosage form with the enteric coating.
  • rivaroxaban and dronedarone HCI molecules are formulated in a way not to interact, and at the same time it is provided that these molecules remain stable in their own form.
  • desired release profiles are achieved for each drug molecules for a safe and effective treatment of cardiovascular diseases.
  • dronedarone HCI pellets comprises an enteric coating is selected from the group comprises cellulose acetate phthalate, methacrylic acid copolymers (Eudragit L types (methacrylic acid, ethyl acrylate copolymers), Eudragit RL and RS types (copolymer of ethyl acrylate, methyl methacrylate and ammonia methacrylate), Eudragit-S types (Methacrylic acid, methyl methacrylate copolymer)), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid co-polymer type C.
  • methacrylic acid copolymers Eudragit L types (methacrylic acid, ethyl acrylate copolymers), Eudragit RL and RS types (copolymer of ethyl acrylate, methyl methacrylate and ammonia methacryl
  • said pharmaceutical combination is in the form of tablet or capsule or multilayer tablet comprising rivaroxaban pellets and dronedarone HCI pellets which are separated pellets or bilayer or multilayer pellets.
  • said dronedarone HCI pellets comprises mannitol or pregelatinized starch or polyvinyl alcohol (PVA) carbomer or croscarmellose sodium or polyvinylpyrrolidone (PVP K30) or sugar pellet or microcrystalline cellulose (MCC) pellet or hydroxypropyl cellulose or coloring agent or mixtures thereof as pharmaceutically acceptable excipients.
  • PVA polyvinyl alcohol
  • PVP K30 croscarmellose sodium or polyvinylpyrrolidone
  • MCC microcrystalline cellulose
  • said rivaroxaban pellets comprises polyvinyl alcohol (PVA) or isopropyl alcohol (IPA) or sodium alginate or methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or PVA or propylene glycol or mannitol or sugar pellet or polyvinylpyrrolidone (PVP) or mixtures thereof as pharmaceutically acceptable excipients.
  • PVA polyvinyl alcohol
  • IPA isopropyl alcohol
  • PVA sodium alginate or methacrylic acid-ethyl acrylate copolymer
  • PVA propylene glycol or mannitol or sugar pellet or polyvinylpyrrolidone (PVP) or mixtures thereof as pharmaceutically acceptable excipients.
  • one or more pharmaceutically acceptable excipient is selected from the group comprising buffering agents, stabilizers, binders, diluents, dispersing agents, lubricants, glidants, disintegrants, plasticizers, preservatives, sweeteners, flavoring agents, coloring agents or mixtures thereof.
  • Suitable buffering agents may comprise but not limited to alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof, and preferably citric acid, fumaric acid, ascorbic acid, sodium dihydrogen phosphate or mixtures thereof.
  • Suitable stabilizers may comprise but not limited to citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, lysine, meglamine, tocopherol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbic acid, gallic acid esters or the mixtures thereof, and preferably, citric acid, fumaric acid, arginine or mixtures thereof.
  • Suitable binders may include but not limited to polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagens, proteins like gelatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponit, bentonit, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • Suitable diluents may comprise but not limited to mannitol, lactose, microcrystalline cellulose, 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 or mixtures thereof.
  • Suitable dispersing agents may comprise but not limited to calcium silicate, magnesium aluminum silicate or mixtures thereof.
  • Suitable lubricants may comprise 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, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • Suitable glidants may comprise but not limited to talc, aluminium silicate, colloidal silica, starch or mixtures thereof.
  • Suitable disintegrants may comprise 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, low substituted hydroxypropyl cellulose, polyacryline 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 prege
  • Suitable plasticizers may comprise but not limited to polyethylene glycols of different molecular weights, propylene glycol, glycerine, triethyl citrate (TEC), triacetin, diethyl phthalate (DEP), dibutyl phthalate (DBP), tributhyl citrate (TBC), castor oil, dibutyl sebacate (DBS), diacetylated monogglycerides or mixtures thereof.
  • TEC triethyl citrate
  • DEP diethyl phthalate
  • DBP dibutyl phthalate
  • THC tributhyl citrate
  • DBS dibutyl sebacate
  • Suitable preservatives may comprise but not limited to methyl paraben, propyl paraben and their salts (such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene, boric acid, sorbic acid, benzyl alcohol, benzalconium chloride, parahydroxybenzoic acids or butylated hydroxyanisole or mixtures thereof.
  • Suitable sweeteners may comprise but not limited to aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.
  • Suitable flavoring agents may comprise but not limited to menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof.
  • Suitable coloring agents may comprise 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.
  • Example 1 ingredients amount (%)
  • PVA polyvinyl alcohol
  • IPA isopropyl alcohol
  • Dronedarone HCI pellets Dronedarone HCI, mannitol and pregelatinized starch are mixed together then by spraying polyvinyl pyrrolidone solution a wet mass is formed. Pellets produced from this wet mass by extrusion/spheronization pelletizing technique. A solution/dispersion is prepared by adding cellulose acetate phthalate as enteric coating and the dronedarone HCI are coated by spraying this mixture.
  • Rivaroxaban pellets Alcoholic Methacrylic acid-Ethyl acrylate copolymer (Eudragit EPO) or Polyvinyl alcohol (PVA) solution is sprayed onto rivaroxaban. PVA or IPA (isopropyl alcohol) and propylene glycol solution is sprayed onto this mixture and pellets produced by fluidized bed pelletizing technique. The pellets are coated with sodium alginate in fluidized bed so rivaroxaban pellets are manufactured.
  • Etagit EPO Alcoholic Methacrylic acid-Ethyl acrylate copolymer
  • PVA Polyvinyl alcohol
  • IPA isopropyl alcohol
  • propylene glycol solution is sprayed onto this mixture and pellets produced by fluidized bed pelletizing technique.
  • the pellets are coated with sodium alginate in fluidized bed so rivaroxaban pellets are manufactured.
  • the rivaroxaban and dronedarone HCI pellets first mixed with silicon dioxide and then with magnesium stearate. Finally, the pellets are pressed as tablets or filled into the capsules.
  • Dronedarone HCI pellets Dronedarone HCI, mannitol and pregelatinized starch are mixed together then by spraying carbomer solution a wet mass is formed. Pellets produced from this wet mass by extrusion/spheronization pelletizing technique. A solution/dispersion is prepared by adding copolymer of ethyl acrylate, methyl methacrylate and ammonia methacrylate as enteric coating and the dronedarone HCI pellets are coated by spraying this mixture in fluidized bed.
  • Rivaroxaban pellets Rivaroxaban and lactose monohydrate are mixed together. Alcoholic Methacrylic acid-Ethyl acrylate copolymer (Eudragit EPO) or Polyvinyl alcohol (PVA) solution is sprayed onto this mixture and pellets produced by fluidized bed pelletizing technique.
  • Alcoholic Methacrylic acid-Ethyl acrylate copolymer Eudragit EPO
  • Polyvinyl alcohol (PVA) solution is sprayed onto this mixture and pellets produced by fluidized bed pelletizing technique.
  • the rivaroxaban and dronedarone HCI pellets first mixed with silicon dioxide and then with magnesium stearate. Finally, the pellets are pressed as tablets or filled into the capsules.
  • PVP polyvinylpyrrolidone
  • Dronedarone HCI pellets Dronedarone HCI, mannitol and croscarmellose sodium are mixed together then by spraying carbomer solution a wet mass is formed. Pellets produced from this wet mass by extrusion/spheronization pelletizing technique. A solution/dispersion is prepared by adding methacrylic acid, methyl methacrylate copolymer as enteric coating and the dronedarone HCI pellets which were coated with the enteric coating by spraying this mixture.
  • Rivaroxaban pellets Alcoholic solution/dispersion is prepared by adding rivaroxaban and PVP. Sugar pellets are coated with this solution/dispersion. The sugar pellets which were coated with the active ingredient are coated with methacrylic acid-ethyl acrylate copolymer (Eudragit EPO or Polyvinyl alcohol (PVA)) so rivaroxaban pellets are manufactured.
  • Dronedarone HCI pellets and rivaroxaban pellets are mixed. The pellets are first mixed with silicon dioxide and then with magnesium stearate. Finally, the pellets are pressed as tablets or filled into the capsules.
  • Example 4
  • a solution/dispersion is prepared by adding dronedarone HCI and PVP K30. Sugar pellets are coated with this solution/dispersion. The sugar pellets which were coated with the dronedarone HCI are coated with polyvinyl acetate phthalate so dronedarone HCI pellets are manufactured. Rivaroxaban and lactose monohydrate are mixed with alcoholic methacrylic acid-ethyl acrylate copolymer (Eudragit EPO) or polyvinyl alcohol (PVA) solution. This mixture is sprayed onto dronedarone HCI pellets so multilayer pellets are manufactured.
  • Ecodragit EPO alcoholic methacrylic acid-ethyl acrylate copolymer
  • PVA polyvinyl alcohol
  • Example 5 The multilayer pellets first mixed with silicon dioxide and then with magnesium stearate. The pellets are pressed as tablets or filled into the capsules.
  • Example 5 The multilayer pellets first mixed with silicon dioxide and then with magnesium stearate. The pellets are pressed as tablets or filled into the capsules.
  • Dronedarone HCI pellets A solution/dispersion is prepared by adding Dronedarone HCI and PVP K30. Sugar pellets are coated with this solution/dispersion. The sugar pellets which were coated with the active ingredient are coated with methacrylic acid copolymer type C so Dronedarone HCI pellets are manufactured.
  • Rivaroxaban pellets Rivaroxaban and lactose monohydrate are mixed together. Alcoholic Methacrylic acid-Ethyl acrylate copolymer (Eudragit EPO) or Polyvinyl alcohol (PVA) solution is sprayed onto this mixture and pellets produced by fluidized bed pelletizing technique.
  • Alcoholic Methacrylic acid-Ethyl acrylate copolymer Eudragit EPO
  • Polyvinyl alcohol (PVA) solution is sprayed onto this mixture and pellets produced by fluidized bed pelletizing technique.
  • Rivaroxaban and dronedarone HCI pellets first mixed with silicon dioxide and then with magnesium stearate. Finally, the pellets are pressed by multilayer rotary tablet press machine or dry coating-intertwined tablets which have dronedarone HCI pellets on the core are produced with special tablet press machine.

Abstract

La présente invention concerne une combinaison pharmaceutique comprenant du dronédarone ou un sel pharmaceutiquement acceptable de celui-ci en combinaison avec du rivaroxaban et au moins un excipient pharmaceutiquement acceptable.
PCT/EP2016/053407 2015-02-19 2016-02-18 Combinaisons pharmaceutiques de dronédarone et de rivaroxaban WO2016131896A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2015/01970A TR201501970A2 (en) 2015-02-19 2015-02-19 Pharmaceutical combinations of dronedarone.
TR2015/01970 2015-02-19

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WO2016131896A1 true WO2016131896A1 (fr) 2016-08-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3263096A1 (fr) * 2016-06-28 2018-01-03 Sanovel Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique en capsule de rivaroxaban

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609B1 (fr) 1990-08-06 1996-11-27 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
US7323493B1 (en) 1997-06-23 2008-01-29 Sanofi-Aventis Solid pharmaceutical composition containing benzofuran derivatives
WO2010146179A2 (fr) * 2009-06-18 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique solide comprenant du rivaroxaban
WO2012023024A2 (fr) * 2010-08-17 2012-02-23 Lupin Limited Formulations de dronédarone à libération contrôlée
US20130143861A1 (en) * 2009-11-23 2013-06-06 Armetheon, Inc. Methods for treating atrial fibrillation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0471609B1 (fr) 1990-08-06 1996-11-27 Sanofi Dérivés de Benzofuranne, Benzothiophène, Indole ou Indolizine, leur procédé de préparation ainsi que les compositions les contenant
US7323493B1 (en) 1997-06-23 2008-01-29 Sanofi-Aventis Solid pharmaceutical composition containing benzofuran derivatives
WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
WO2010146179A2 (fr) * 2009-06-18 2010-12-23 Krka, Tovarna Zdravil, D.D., Novo Mesto Composition pharmaceutique solide comprenant du rivaroxaban
US20130143861A1 (en) * 2009-11-23 2013-06-06 Armetheon, Inc. Methods for treating atrial fibrillation
WO2012023024A2 (fr) * 2010-08-17 2012-02-23 Lupin Limited Formulations de dronédarone à libération contrôlée

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A. G VISHWAKARMA ET AL: "Bi-Layer Tablet -A New Ways in Oral Drug Delivery System", INTERNATIONAL JOURNAL OF PHARMTECH RESEARCH CODEN (USA), vol. 6, no. 5, October 2014 (2014-10-01), pages 1416 - 1428, XP055206478 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3263096A1 (fr) * 2016-06-28 2018-01-03 Sanovel Ilac Sanayi ve Ticaret A.S. Composition pharmaceutique en capsule de rivaroxaban
WO2018001914A1 (fr) * 2016-06-28 2018-01-04 Sanovel Ilac Sanayi Ve Ticaret A.S. Composition de la capsule pharmaceutique de rivaroxaban

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