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WO2016087322A1 - Formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif - Google Patents

Formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif Download PDF

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Publication number
WO2016087322A1
WO2016087322A1 PCT/EP2015/077864 EP2015077864W WO2016087322A1 WO 2016087322 A1 WO2016087322 A1 WO 2016087322A1 EP 2015077864 W EP2015077864 W EP 2015077864W WO 2016087322 A1 WO2016087322 A1 WO 2016087322A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical dosage
active ingredient
dosage form
solid dispersion
prophylaxis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2015/077864
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German (de)
English (en)
Inventor
Anke Stroyer
Michael Formell
Anka Uffrecht
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of WO2016087322A1 publication Critical patent/WO2016087322A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/14—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
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—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 solid, orally administrable, (2- ⁇ [(l l S) -l- (3-chlorophenyl) -2-fluoroethyl] amino ⁇ -7-methoxy-l, 3-benzoxazol-5-yl) [ (2 S l, 5 l S) -5- (2-hydroxyethyl) -2-methyl-morpholin-4-yl] methanone (I) in amorphous form containing pharmaceutical dosage forms with rapid active ingredient release and to processes for their preparation, their application as a medicament, their use for the prophylaxis, secondary prophylaxis and / or treatment of diseases and their use for the manufacture of a medicament for the prophylaxis, secondary prophylaxis and / or treatment of diseases.
  • the active ingredient (I) is a low molecular weight, orally applicable inhibitor of the blood coagulation factor IIa, which can be used for the prophylaxis, secondary prophylaxis and / or treatment of various thromboembolic disorders.
  • the active ingredient (I) so is the amorphous form of (2- ⁇ [(l l S) -1- (3-chlorophenyl) -2-fluoroethyl] amino ⁇ -7-methoxy l, 3-benzoxazol-5-yl) [(2 l S ', 5 l S') - 5- (2-hydroxyethyl) -2-methyl-morpholin-4-yl] methanone (I) and the respective hydrates and or solvates with.
  • the active ingredient (I) is in amorphous form. It shows a low water solubility (about 230 mg / L, 25 ° C). In organic solvents, a higher solubility is observed (for example in ethanol> 100 ⁇ g / 100 ml, in acetone> 3000 mg / ml).
  • the active ingredient (I) is hygroscopic.
  • Object of the present invention are solid, orally administrable pharmaceutical representation reichungsformen with rapid active ingredient release, comprising (2- ⁇ [(l l S) -l- (3-chlorophenyl) -2-fluoroethyl] amino ⁇ -7-methoxy-l, 3-benzoxazol-5-yl) [(2 S l, 5 l S) -5- (2-hydroxyethyl) -2-methyl-morpholin-4-yl] methanone (I), characterized in that
  • the amount of 80% active ingredient (I) to be released refers to the total amount of active ingredient (I) contained in the dosage form.
  • the rapid release rate of the active ingredient (I) is achieved by the presence of the active ingredient (I) in amorphous form.
  • the dosage forms of the invention contain active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total mass of the formulation, preferably in a concentration of 5 to 50% based on the total weight of the formulation, more preferably in a concentration of 5 to 30% based on the total weight of the formulation.
  • Solid dispersion a state of the active ingredient in the pharmaceutical dosage form referred to as "solid dispersion”.
  • Solid dispersions such as solid solutions, glassy solutions, glassy suspensions, amorphous precipitates in a crystalline support, eutectics or monotektives, active substance complexes and combinations thereof referred to the term "solid dispersion”.
  • the amorphous state of the active ingredient in the pharmaceutical preparation must be stabilized.
  • the same pharmaceutical manufacturing methods are used as for the amorphization of originally crystalline active ingredients.
  • the dissolution method, the melt method or a combination of both methods are used [Chiou, W.L .; Riegelman, S., "Pharmaceutical Applications of Solid Dispersion System", Journal of Pharmaceutical Sciences
  • Active substances can also have amorphous and crystalline regions at the same time.
  • the uniformly amorphous state would have to be stabilized by means of the described methods and for the quality assurance reasons listed.
  • the active ingredient (I) in amorphous form it is meant that the active ingredient (I) is> 95% in amorphous form.
  • a pharmaceutical dosage form of the present invention consists of a solid dispersion containing the active ingredient (I) as well as a pharmaceutically acceptable matrix and optionally a carrier material.
  • matrix or “matrix former” as used in the present invention refers to both polymeric and non-polymeric adjuvants and combinations of these to suitably dissolve or disperse drug (I).
  • the matrix consists of a pharmaceutically acceptable polymer such as polyvinylpyrrolidone,
  • Vinyl pyrrolidone / vinyl acetate copolymer crospovidone
  • polyalkylene glycols e.g.
  • Polyethylene glycol polyethylene oxide
  • poloxamer polyethylene oxide
  • hydroxyalkylcelluloses e.g.
  • Hydroxypropylcellulose hydroxyalkylmethylcelluloses (e.g., hydroxypropylmethylcellulose),
  • Carboxymethylcellulose sodium carboxymethylcellulose, ethylcellulose, cellulose succinates (e.g., cellulose acetate succinates and hydroxypropyl methylcellulose acetate succinate), cellulose phthalates
  • polymethacrylates e.g., cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate
  • polymethacrylates e.g., cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate
  • Eudragit ® types polyhydroxyalkyl, polyhydroxyalkyl, polyacrylates,
  • At least one of the substances used as matrix formers in the solid dispersion is selected from the group consisting of polyvinylpyrrolidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol and polyethylene oxide.
  • polyvinylpyrrolidone serves as a matrix former.
  • the active ingredient (I) and polyvinylpyrrolidone are present as matrix formers in a mass ratio of 1: 0.5 to 1:20, particularly preferably 1: 2 to 1: 5.
  • the present invention further provides a pharmaceutical dosage form consisting of a solid dispersion in which the matrix contains a sugar and / or sugar alcohol and / or cyclodextrin, such as sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, Erythritol, threitol, adonitol, arabitol, xylitol, dulcitol, inositol, trehalose, isomalt, inulin, maltodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl ether
  • auxiliaries are, for example, alcohols, organic acids, organic bases, salts, amino acids, peptides, phospholipids, lipids (eg mono-, di- and triglycerides), fatty acids, fatty alcohols, waxes, Fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides, sucrose esters, urea and combinations thereof.
  • the solid dispersion consisting of at least the active ingredient (I) and a matrix may contain some additional pharmaceutically acceptable ingredients, e.g. Support materials, surface-active substances, fillers, disintegrants, adsorbents, recrystallization inhibitors, plasticizers, defoamers, antioxidants, anti-adhesives, fluxes, pH modifiers, lubricants and / or lubricants.
  • additional pharmaceutically acceptable ingredients e.g. Support materials, surface-active substances, fillers, disintegrants, adsorbents, recrystallization inhibitors, plasticizers, defoamers, antioxidants, anti-adhesives, fluxes, pH modifiers, lubricants and / or lubricants.
  • a carrier material in the sense of the present invention is an excipient which is mixed with a mixture consisting of at least the matrix and the active ingredient (I) during the preparation of the solid dispersion, e.g. by melt extrusion, melt coating, spray condensation, solidification, solvent evaporation processes / solvent method (e.g., coating, painting, granulation), thus becoming an integral part of the solid dispersion.
  • the solid dispersion as carrier material contains, for example, croscarmellose sodium, sodium starch glycolate, crospovidone, low-substituted hydroxypropylcellulose (L-HPC), starch, microcrystalline cellulose or a combination of the same. These ingredients can also be used as disintegrants.
  • the carrier material or the combination of carrier materials may be present in a concentration of 5 to 90% based on the total mass of the pharmaceutical composition, preferably from 10 to 60% based on the total mass of the pharmaceutical composition.
  • the solid dispersion contains polyvinylpyrrolidone as matrix and croscarmellose sodium as carrier material. In a particularly preferred embodiment of the present invention, the solid dispersion contains polyvinylpyrrolidone as matrix, croscarmellose sodium and microcrystalline cellulose as carrier material.
  • the solid dispersion according to the present invention is prepared by means of production processes of solid dispersions known in the art, such as melt / sinter technology, melt extrusion, melt coating, spray condensation, solidification, solvent evaporation / dissolution methods (eg freeze drying, spray drying, vacuum drying, coating of powders, granules or pellets and fluidized bed granulation ), Coprecipitation, processes made with supercritical fluids and electrostatic centrifugation.
  • the dissolution method is the preferred production process for producing the solid dispersion in the sense of the present invention.
  • the active ingredient (I) is stabilized via the Lendermethode in its amorphous state.
  • suitable solvent may be any substance in which the active ingredient (I) dissolves.
  • Preferred solvents are alcohols, e.g. Methanol, ethanol, n-propanol, isopropanol and butanol, ketones such as e.g. Acetone, methyl ethyl ketone and methyl isobutyl ketone, esters such as e.g.
  • Ethyl acetate and propyl acetate, and various other solvents such as acetonitrile, methylene chloride, chloroform, hexane, toluene, tetrahydrofuran, cyclic ethers and 1,1,1-trichloroethane.
  • Low volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used.
  • Mixtures of these solvents, e.g. 20% ethanol and 80% acetone can be used in the same way as mixtures with water, provided that the active ingredient (I) shows sufficient solubility in the mixture and, if appropriate, the matrix former displays sufficient solubility in the mixture in order to carry out the process.
  • the solvent for preparing a solid dispersion is a mixture of two or more solvents selected from the group consisting of methanol, ethanol, n-propanol, isopropanol and acetone.
  • a mixture of ethanol and acetone is used as the solvent for the solvent method for the preparation of a solid dispersion.
  • the solid dispersion is homogeneous, that is to say the active substance distribution in the matrix and in any one present Carrier material is homogeneous.
  • homogeneous is understood to mean the uniform distribution of the active ingredient (I), the matrix and the optionally present support material in the solid dispersion.
  • the active ingredient (I) is present in the solid dispersion prepared by the dissolution method, preferably in a concentration of 2 to 30% based on the total mass of the dissolved components, more preferably in a concentration of 2 to 20% based on the total mass of the dissolved components, in particular in a concentration of 5 to 15% based on the total mass of the dissolved components.
  • the solid dispersion containing the active ingredient (I) in amorphous form obtained by the dissolution method can be further processed in different ways:
  • the solid dispersion containing the active ingredient (I) in amorphous form can be further processed into tablet formulations.
  • tabletting excipients such as fillers and dry binders (for example cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose, dextrose, maltose, sucrose, glucose, fructose or maltodextrins), disintegrants / disintegrants (e.g., carboxymethylcellulose, croscarmellose (cross-linked carboxymethylcellulose), crospovidone (cross-linked polyvinylpyrrolidone), L-HPC (low substituted hydroxypropylcellulose), sodium carboxymethylstarch, potato starch sodium glycolate, partially hydrolyzed starch, wheat starch, corn starch, rice starch or potato starch ), Lubricating, lubricating and flow regulating agents such as fumaric acid,
  • tabletting excipients such as fillers and dry
  • Suitable materials for a sunscreen and / or lake are for example polymers such as polyvinyl alcohol, hydroxypropyl cellulose and / or hydroxypropylmethyl cellulose, optionally in combination with suitable plasticizers such as polyethylene glycol or polypropylene glycol and pigments such as titanium dioxide or iron oxides such as iron oxide yellow or iron oxide red.
  • suitable plasticizers such as polyethylene glycol or polypropylene glycol and pigments such as titanium dioxide or iron oxides such as iron oxide yellow or iron oxide red.
  • the lacquer may further contain talc and / or lecithin.
  • the paint may, for example, have the following composition: polyvinyl alcohol, talc, polyethylene glycol, lecithin, iron oxide yellow, iron oxide red and titanium dioxide.
  • lacquer may for example have the following composition:
  • the tablets are preferably rapidly disintegrating tablets with a disintegration time of a maximum of 30 minutes.
  • Another object of the present invention is a process for the preparation of the tablet formulation according to the invention, wherein by means of the Lcaptivatethethode a active ingredient (I) in amorphous form containing solid dispersion is prepared, which then optionally ground, mixed with other pharmaceutical excipients known in the art and in capsules or are filled as Sachet or mixed with the usual Tablettierinstoffen and then preferably pressed by direct tableting into tablets, which can be coated with a final paint.
  • the solid dispersion may optionally be ground, otherwise comminuted, sieved or screened before further processing.
  • Another object of the present invention is the use of (2- ⁇ [(lS) -1- (3-chlorophenyl) -2-fluoroethyl] amino ⁇ -7-methoxy-1, 3-benzoxazol-5-yl) [(2S , 5S) -5- (2-hydroxyefhyl) -2- Methyl-morpholin-4-yl] methanone (I) for the preparation of a solid, orally administered pharmaceutical dosage form according to the invention with rapid release of active ingredient.
  • compositions containing a solid, orally administrable, active ingredient (I) in amorphous form-containing pharmaceutical dosage form with rapid release of active ingredient according to the invention are pharmaceutical compositions containing a solid, orally administrable, active ingredient (I) in amorphous form-containing pharmaceutical dosage form with rapid release of active ingredient according to the invention.
  • Another object of the present invention is the use of a solid, orally applicable, active ingredient (I) in amorphous form containing pharmaceutical dosage form with rapid release of active ingredient for the manufacture of a medicament for the prophylaxis, secondary prophylaxis and / or treatment of diseases, in particular of arterial and / or venous thromboembolic disorders.
  • Another object of the present invention is the use of the solid, orally administered pharmaceutical dosage form according to the invention with rapid release of active ingredient containing amorphous active ingredient (I) for the prophylaxis, secondary prophylaxis and / or treatment of diseases, in particular of arterial and / or venous thromboembolic diseases such as myocardial infarction, angina Pectoris (including unstable angina), reocclusion and restenosis following angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
  • diseases in particular of arterial and / or venous thromboembolic diseases such as myocardial infarction, angina Pectoris (including unstable angina), reocclusion and restenosis following angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombo
  • the compounds according to the invention are very particularly suitable for the treatment and / or prophylaxis of acute coronary syndrome (ACS), venous thromboembolism, venous thrombosis, in particular in deep leg veins and renal veins, pulmonary embolisms, stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context surgical intervention in patients who have cancer.
  • ACS acute coronary syndrome
  • venous thromboembolism venous thrombosis
  • venous thrombosis in particular in deep leg veins and renal veins
  • pulmonary embolisms pulmonary embolisms
  • stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context surgical intervention in patients who have cancer.
  • Another object of the present invention is a method for the prophylaxis, secondary prophylaxis and / or treatment of diseases, in particular of arterial and / or venous thromboembolic diseases such as myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke , transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thrombosis.
  • diseases in particular of arterial and / or venous thromboembolic diseases such as myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke , transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thrombosis.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of acute coronary syndrome (ACS), venous thromboembolism, venous thrombosis, especially in deep leg veins and renal veins, pulmonary embolism, stroke and / or thrombosis prophylaxis in the context of surgical procedures, especially in Surgical intervention framework in patients suffering from cancer by administering a solid, orally administrable, active ingredient (I) amorphous form pharmaceutical formulation of the invention with rapid release of active ingredient.
  • ACS acute coronary syndrome
  • I active ingredient
  • the present invention further provides the solid, orally administrable pharmaceutical dosage forms with rapid release of active substance, containing amorphous active substance (I) for use in a method for the prophylaxis, secondary prophylaxis and / or treatment of diseases, in particular of arterial and / or venous thromboembolic diseases, such as Myocardial infarction, angina pectoris (including unstable angina), reocclusion and restenosis following angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
  • diseases in particular of arterial and / or venous thromboembolic diseases, such as Myocardial infarction, angina pectoris (including unstable angina), reocclusion and restenosis following angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous
  • the present invention further provides the solid, orally administrable pharmaceutical dosage forms of the invention with rapid release of active ingredient, containing amorphous active ingredient (I) for use in a method for the treatment and / or prophylaxis of acute coronary syndrome (ACS), venous thromboembolism, venous thrombosis, in particular deep veins of the leg and renal veins, pulmonary embolism, stroke and / or thrombosis prophylaxis in the context of surgical interventions, in particular in the context of surgical interventions in patients who have cancer.
  • ACS acute coronary syndrome
  • the present invention is a process for preparing a solid, orally administrable pharmaceutical dosage form containing active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total weight of the formulation, characterized in that Loosening method, a drug containing the active ingredient (I) in amorphous form containing solid dispersion is prepared.
  • the present invention is a process for preparing a solid, orally applicable pharmaceutical dosage form containing active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total weight of the formulation, characterized in that
  • the present invention is a process for preparing a solid, orally administrable pharmaceutical dosage form comprising active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total mass of the formulation, characterized in that (a) First, using the Lendermethode a solid active ingredient (I) containing in amorphous form is prepared, which then optionally ground
  • the present invention is a solid, orally administered pharmaceutical dosage forms with rapid release drug containing active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total weight of the formulation, characterized in that it is prepared in that a solid dispersion containing the active substance (I) in amorphous form is produced by means of the solvent method.
  • the present invention is a solid, orally administered pharmaceutical dosage forms with rapid release drug containing active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total weight of the formulation, characterized in that it is prepared by doing
  • the present invention is a solid, orally administered pharmaceutical dosage forms with rapid release drug containing active ingredient (I) in amorphous form in an amount of active ingredient (I) of> 2% based on the total weight of the formulation, characterized in that it is prepared by doing
  • the dosage form is tested with apparatus 2 (paddle).
  • the speed of rotation of the stirrer is 50-100 rpm (revolutions per minute) in 900 ml of phosphate buffer pH 6.8.
  • the release criterion is fulfilled when all 6 test specimens have released at least 80% active substance (I) into the release medium after a test period of 2 hours.
  • This method is used for fast-release tablets in which the tablet dose is ⁇ 100 mg to ensure sinking conditions in the release medium.
  • sink conditions is meant the 3-fold volume of release media needed to make a saturated solution with the amount of drug contained in the tablet.
  • the resulting tablet can then be coated with a varnish:
  • Lacquer 10 mg Preparation: Active substance (I) and polyvinylpyrrolidone are dissolved in the organic solvent mixture consisting of acetone and ethanol (80:20). The solution thus prepared is called Granulierwhikeit sprayed as part of a fluidized bed granulation on the template of microcrystalline cellulose and croscarmellose sodium. After drying and sieving (0.8 mm mesh size) of the resulting granules, croscarmellose sodium and magnesium stearate are added successively and mixed in each case. The thus obtained ready-to-press mixture is compressed into tablets of 12 mm diameter (12x6wr5 + 2) and a breaking strength of 25 to 80 N. The subsequent coating of the tablets is carried out with titanium dioxide and iron oxide, which are suspended in an aqueous solution of hydroxypropylmethylcellulose and talc.
  • Example Formulation 2 An acetone-ethanol mixture (80:20) containing active ingredient (I) in amorphous form and polyvinylpyrrolidone in the ratio 1: 3 resulting in granules (solid dispersion) of the following composition:
  • Croscarmellose Sodium 125 mg The resulting granules are then processed into a tablet of the following composition:
  • the resulting tablet can then be coated with a varnish:
  • Croscarmellose Sodium 30 mg The resulting granules are then processed into a tablet of the following composition:
  • the resulting tablet can then be coated with a varnish:

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif, qui contiennent du (2-{[(1S)-1-(3-chlorophényl)-2-fluoroéthyl]amino}-7-méthoxy-1,3-benzoxazol-5-yl)[(2S,5S)-5-(2-hydroxyéthyl)-2-méthyle-morpholin-4-yl]méthanone (I) sous forme amorphe. L'invention concerne également des procédés de production desdites formes, leur utilisation en tant que médicaments, leur utilisation pour la prophylaxie, la prophylaxie secondaire et/ou le traitement de maladies, et leur utilisation dans la fabrication d'un médicament destiné à la prophylaxie, à la prophylaxie secondaire et/ou au traitement de maladies.
PCT/EP2015/077864 2014-12-01 2015-11-27 Formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif Ceased WO2016087322A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14195631 2014-12-01
EP14195631.8 2014-12-01

Publications (1)

Publication Number Publication Date
WO2016087322A1 true WO2016087322A1 (fr) 2016-06-09

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PCT/EP2015/077864 Ceased WO2016087322A1 (fr) 2014-12-01 2015-11-27 Formes galéniques pharmaceutiques solides administrables par voie orale, à libération rapide de principe actif

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140982A1 (fr) * 2006-06-08 2007-12-13 Bayer Healthcare Ag Benzoxazole substitué
WO2014195231A1 (fr) * 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Benzoxazoles substitués

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007140982A1 (fr) * 2006-06-08 2007-12-13 Bayer Healthcare Ag Benzoxazole substitué
WO2014195231A1 (fr) * 2013-06-03 2014-12-11 Bayer Pharma Aktiengesellschaft Benzoxazoles substitués

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"[711] DISSOLUTION", STAGE 6 HARMONIZATION, 1 December 2011 (2011-12-01), pages 1 - 8, XP055155057, Retrieved from the Internet <URL:http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/2011-02-25711DISSOLUTION.pdf> [retrieved on 20141125] *
"EUROPEAN PHARMACOPOEIA , DISSOLUTION TEST FOR SOLID DOSAGE FORMS", 1 January 2004, EUROPEAN PHARMACOPOEIA, DIRECTORATE FOR THE QUALITY OF MEDICINES, COUNCIL OF EUROPE (EDQM), STRASBOURG, PAGE(S) 194 - 197, XP002635527 *

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