EP1957048A2 - Feste, oral applizierbare pharmazeutische darreichungsformen mit schneller wirkstofffreisetzung - Google Patents

Feste, oral applizierbare pharmazeutische darreichungsformen mit schneller wirkstofffreisetzung

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Publication number
EP1957048A2
EP1957048A2 EP06792199A EP06792199A EP1957048A2 EP 1957048 A2 EP1957048 A2 EP 1957048A2 EP 06792199 A EP06792199 A EP 06792199A EP 06792199 A EP06792199 A EP 06792199A EP 1957048 A2 EP1957048 A2 EP 1957048A2
Authority
EP
European Patent Office
Prior art keywords
active ingredient
pharmaceutical dosage
dosage form
release
form according
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.)
Withdrawn
Application number
EP06792199A
Other languages
German (de)
English (en)
French (fr)
Inventor
Klaus Benke
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 Intellectual Property GmbH
Original Assignee
Bayer Healthcare 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
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Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1957048A2 publication Critical patent/EP1957048A2/de
Withdrawn legal-status Critical Current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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to solid, orally administrable, 5-chloro-N - ( ⁇ (5-S) -2-oxo-3- [4- (3-oxo-4-methylphenyl) -phenyl] -1,3-oxazolidine -5-yl ⁇ -methyl) -2-thiophencarboxamide in pharmaceutical compositions containing amorphous form and / or thermodynamically metastable crystal modification with rapid release of active ingredient and process for their preparation, their use as medicaments, their use for 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.
  • 2-thio - - phencarboxamide (I) is a low molecular weight, orally administered inhibitor of the blood coagulation factor Xa, which can be used for the prophylaxis, secondary prophylaxis and / or treatment of various thromboembolic diseases (see WO-A 01/47919, the disclosure of which is hereby incorporated by reference
  • the active ingredient (I) when the active ingredient (I) is mentioned, all crystal modifications and the amorphous form of 5-chloro-N - ( ⁇ (5iS) -2-oxo-3- [4- (3-oxo 4-morpholinyl) -phenyl] -l, 3-oxazolidin-5-yl ⁇ -methyl) -2-thiophenecarbox
  • the physico-chemical and biological properties of the active compound (I) to be considered such as the relatively low water solubility (approximately 7 mg / L; 25 ° C) and the relatively high melting point of about 230 0 C of Active substance (S) in the crystal modification, in which the active ingredient (I) is obtained in the preparation according to the method described in WO 01/47919 (Chem. Abstr., 2001, / 3-5, 92625) under Example 44 and the following is referred to as crystal modification I.
  • WO 2005/060940 describes pharmaceutical administration forms which contain the active ingredient (I) in hydrophilized form. Preference is given to fast-release tablets which have a Q value (30 minutes) of 75% according to USP (United States Pharmacopeia) release method with apparatus 2 (paddle).
  • dosage forms containing active ingredient (I) in amorphous form and / or in the form of thermodynamically metastable crystal modifications have improved bioavailability.
  • the present invention relates to solid, orally administrable, rapid-release pharmaceutical dosage forms containing 5-chloro-N- ( ⁇ (55) -2-oxo-3- [4- (3- oxo-4-mo ⁇ holinyl) -phenyl] -l, 3-oxazolidin-5-yl ⁇ -methyl) -2-thiophenecarboxamide (I), characterized in that they contain active substance (I) in amorphous form and / or thermodynamically metastable Kristallmodif ⁇ kation and that 80% of the active ingredient (I) is released for a maximum of 2 hours according to the USP release method with apparatus 2 (paddle, 75 rpm). The further conditions of these in vitro release studies according to the USP release method are described in the experimental part (sink conditions). The amount of 80% active ingredient (I) to be released refers to the total amount of active ingredient (I) contained in the dosage form.
  • 80% of the active ingredient (I) is released in a period of a maximum of 1 hour according to USP release method with apparatus 2 (paddle, 75 rpm).
  • the active ingredient (I) can be present in the dosage forms according to the invention partially or completely in amorphous form and / or thermodynamically metastable Kristallmodif ⁇ kation.
  • the administration forms according to the invention preferably comprise active ingredient (I) in amorphous form and / or in the form of metastable crystal modifications in an amount based on: the total amount of active ingredient (I) present of at least 50%, particularly preferably more than 50%, in particular, at least 90%.
  • the active ingredient (I) in the dosage forms of the invention may be partially or completely contained in amorphous form.
  • the dosage forms according to the invention preferably contain active ingredient (I) in amorphous form in an amount, based on the total amount of active ingredient (I), of at least 50%, particularly preferably more than 50%, in particular at least 90%.
  • the partial or complete presence of the active ingredient (I) in amorphous form and / or in the form of one or more thermodynamically metastable crystal modifications in addition to a rapid release rate also increases the drug solubility.
  • the dosage forms of the invention contain active ingredient (I) in amorphous form and / or in the form of metastable crystal modifications preferably in an amount based on the contained Total amount of active ingredient (I), of at least 50%, more preferably more than 50%, especially at least 90%.
  • the term “supersaturation” in this context means that the inventive formulations compared to crystalline, micronized drug (I) in the Rristallmodtechnik I under the in vitro defined in the experimental part Release conditions under non-sink conditions at a dose of 20 mg of active ingredient (I) after one hour at least a factor of 1.5 higher release drug.
  • the dosage forms of the invention contain active ingredient (I) in a total amount of 20 mg and set a compared to 20 mg micronized crystalline active ingredient (I) in the crystal modification I at least the
  • the micronized active ingredient (I) under these conditions after one hour release of 40% (8 mg), so the formulations of the invention release values of at least 60% (12 mg).
  • the micronized active ingredient (I) has an average particle size X 50 -WeIt (50% proportion) of 1 to 8 microns and an X 90 - (90% proportion) of less than 20 microns.
  • the partial or complete presence of the active compound (I) in amorphous form in addition to a rapid release rate, also increases the drug solubility.
  • the dosage forms of the invention contain active ingredient (I) in amorphous form preferably in an amount, based on the total amount of active ingredient (I) contained, of at least .50. %, more preferably more than 50%, especially at least 90%.
  • the dosage forms of the invention contain active ingredient (I) in a total amount of 20 mg and set a compared to 20 mg micronized crystalline active ingredient (I) in the crystal modification I at least a factor of 1.5 higher amount of active ingredient (I) in a period of one hour according to the USP release method with apparatus 2 (paddle) free. If, for example, the micronised active substance (I) has a release of 40% (8 mg) after one hour under these conditions, the formulations according to the invention show release values of at least 60% (12 mg).
  • the micronized active ingredient (I) has a mean Particle size X 50 value (50% proportion) of 1 to 8 microns and an X 90 -WeIt (90% proportion) of less than 20 microns on.
  • the Lieremethode in which an active ingredient and optionally used adjuvant (s) such as polyvinylpyrrolidone are dissolved and then further processed, less well suited, since this only a limited solubility in pharmaceutically suitable organic solvents - such as acetone or ethanol and therefore must use disproportionately large amounts of solvent must be.
  • an active ingredient and optionally used adjuvant (s) such as polyvinylpyrrolidone are dissolved and then further processed, less well suited, since this only a limited solubility in pharmaceutically suitable organic solvents - such as acetone or ethanol and therefore must use disproportionately large amounts of solvent must be.
  • An exception is pure acetic acid as a suitable solvent for the crystalline active ingredient (I) - a suitable method of preparation is described in the experimental part.
  • the active ingredient (I) is preferably present in a concentration of 0.1 to 30%, particularly preferably 0.1 to 20%, in particular 5 to 15%, based on the total weight of the dissolved components, in the mixture present after the dissolving process.
  • the erfmdungswash preferred method for amorphization of the active ingredient (I) and for generating thermodynamically metastable crystal modifications or for stabilizing the amorphous state of the active ingredient (I) in the pharmaceutical preparations is the melting process in which an active ingredient together with or in one or more suitable excipients is melted.
  • ureas citric acid, stearic acid, sugars, sugar alcohols such as mannitol or xylitol and hydrophilic polymers such as polyethylene glycols (PEG), polyethylene oxides, polyoxyethylene-polyoxypropylene block copolymers and vinylpyrrolidone-vinyl acetate copolymers, hydroxypropylcellulose (HPC ), saturated polyglycolized glycerides (Gelucire, Gattefosse) or mixtures of these excipients.
  • PEG polyethylene glycols
  • HPC hydroxypropylcellulose
  • Gelucire Gattefosse
  • Preferred auxiliaries are polyethylene glycols, mixtures of polyethylene glycols and mixtures of one or more polyethylene glycols with one or more other suitable excipients, particularly preferably polyethylene glycols and mixtures of polyethylene glycols, in particular polyethylene glycols.
  • the active ingredient (I) is added to the molten adjuvant mixture and the temperature is increased until a clear melt is present or the active ingredient (I) and the excipient (s) are first mixed and then melted.
  • the melt After melting, the mixture is cooled and then comminuted, so that preferably a powder or granulate is present, which can also be referred to as a "solid solution.” Alternatively, the melt can be filled after comminution, for example, into capsules or as Sachet, optionally after admixing suitable pharmaceutical.
  • this melting process ensures that the active ingredient degradation during the melting process does not exceed pharmaceutically acceptable limits, which is a difficult one with a melting point of about 230 ° C. of the active ingredient (I) in the crystal modification I. Task, since in this high temperature range usually significant decomposition rates of the active ingredient and / or the excipients are to be expected.
  • the active ingredient (I) is present in the mixture present after the melting process preferably in a concentration of 0.1 to 30%, more preferably of 0.1 to 20%, in particular of 5 to 15%, based on the total mass of the melt.
  • melt extrusion process is particularly preferred for the preparation of active ingredient (I) in pharmaceutical forms containing amorphous form or metastable crystal modifications [Breitenbach, J., "Melt extrusion: From process to drug delivery technology”, European Journal of Pharmaceutics and Biopharmaceutics 54 (US Pat. Werbach, J., "Solid solutions by melt extrusion - an integrated manufacturing concept", Pharmacy in our time 29 (2000), 46-49].
  • the melt extrusion process for preparing the active ingredient (I) in amorphous form or in the form of metastable crystal modifications is preferably in the presence of a polymer such as polyvinylpyrrolidone (PVP), polyethylene glycol, polymethacrylate, polymethyl methacrylate, polyethylene oxide, polyoxyethylene-polyoxypropylene block copolymers, vinyl -pyrrolidone-vinyl acetate copolymers or a cellulose ether such as hydroxypropyl cellulose (HPC) or performed mixtures of various polymers.
  • PVP polyvinylpyrrolidone
  • HPC hydroxypropyl cellulose
  • HPC Hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • HPC hydroxypropyl cellulose
  • PVP polyvinylpyrrolidone
  • the polymer content in the melt extrudate according to the invention is preferably at least 40% of the total mass of the melt extrudate.
  • the active ingredient (I) is present in the melt extrudate according to the invention preferably in a concentration of 0.1 to 20%, in particular of 5 to 15%, based on the total mass of the melt extrudate.
  • these pharmaceutically suitable substances are added according to the invention in a concentration of 0.2 to 40%, based on the total mass of the melt extrudate.
  • urea polymers such as polyethylene glycol, polymethacrylates, polymethyl methacrylates, polyethylene oxide, polyoxyethylene-polyoxypropylene block copolymers, vinylpyrrolidone-vinyl acetate copolymers, saturated polyglycolized glycerides (Gelucire, Gattefosse) or sugar alcohols such as erythritol, maltitol, mannitol, sorbitol and xylitol.
  • sugar alcohols are used.
  • the product obtained, for example, by the dissolution method, the melt or the melt extrusion method, active substance (I) in amorphous form or metastable crystal modification (s) containing product can be processed in different ways: It can, for example, be comminuted and administered as a powder or granules, optionally after filling as sachet or in capsules.
  • customary pharmaceutical auxiliaries can be added, for example fillers, flow regulators, adsorbents, wetting agents, flavors and dyes.
  • the product containing the active ingredient (I) in amorphous form or metastable crystal modifications can be further processed into tablet formulations.
  • it can be cut, ground and mixed with conventional 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 (for example, 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
  • 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.
  • 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 Lcaptivatemethode, preferably by means of the melting process, most preferably by means of melt extrusion, an active ingredient (I) in amorphous form or metastable crystal modification containing solid solution or Extrudate is prepared, which (s) then ground, mixed with other pharmaceutical excipients known in the art and filled into capsules or Sachet or mixed with other known in the art Tablettieragisstoffn (see above) and then preferably compressed by direct tableting into tablets, the final can be coated with a varnish.
  • active ingredient (I) is present in amorphous form.
  • multiparticulate dosage forms are understood as meaning those formulations which consist of a plurality of small particles, such as, for example, spherical granules (pellets) or minitablets The diameter of these particles is generally 0.5 to 3.0 mm
  • the cut and rounded extrudates or small-format tablets may optionally be varnished and filled into capsules or prepared as Sachet.
  • active ingredient (I) is present in amorphous form.
  • Another object of the present invention are pharmaceutical dosage forms, preferably capsules, sachets or tablets containing the multiparticulate dosage forms described above.
  • Another object of the present invention is a process for the preparation of multiparticulate pharmaceutical dosage forms according to the invention, wherein preferably by melt extrusion an active ingredient (I) in amorphous form and / or thermodynamically metastable crystal modification containing extrudate is obtained.
  • a pellet-shaped multiparticulate dosage form is prepared directly by cutting this extrudate strand and optionally subsequent rounding. The pellets thus obtained can then be coated with a varnish and filled into capsules or sachets.
  • active ingredient (I) is present in amorphous form.
  • the present invention further relates to medicaments containing a solid, orally administrable, rapidly releasable pharmaceutical preparation containing active ingredient (I) in amorphous form and / or thermodynamically metastable crystal modification (s).
  • active ingredient (I) is present in amorphous form.
  • 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 and / or thermodynamically metastable 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), reocclusions and restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive disease, pulmonary embolism or deep venous thrombosis.
  • active ingredient (I) is present in amorphous form.
  • Another object of the present invention is the use of the solid, orally administrable, the amorphous and / or thermodynamically metastable active ingredient (I) containing pharmaceutical dosage form with rapid release drug, 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 such as myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenosis following angioplasty or aortocoronary bypass, stroke, transient ischemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms, or deep venous thrombosis.
  • active ingredient (I) is present in amorphous form.
  • Another object of the present invention is the use of 5-chloro-N - ( ⁇ (5iS) -2-oxo-3- [4- (3-oxo-4-mo ⁇ holinyl) -phenyl] -l, 3-oxazolidin-5 -yl ⁇ -methyl) -2-thiophenecarboxamide (I) for the preparation of a solid, orally administrable pharmaceutical dosage form according to the invention with rapid release of active ingredient.
  • Another object of the present invention is a method for the prophylaxis, secondary prophylaxis and / or treatment of arterial and / or venous thromboembolic diseases by administering a solid, orally administrable, active ingredient (I) in amorphous form and / or thermodynamically metastable crystal modification containing pharmaceutical dosage form with faster drug release.
  • active ingredient (I) is present in amorphous form.
  • the in vitro release studies are performed according to USP release method with apparatus 2 (paddle) at a temperature of 37 0 C.
  • the speed of rotation of the stirrer is 75 rpm (revolutions per minute) in 900 ml of an acetate buffer solution of pH 4.5, which is prepared from 29.9 g sodium acetate trihydrate and 16.6 ml glacial acetic acid in 10 L water.
  • the investigations are carried out under sink or non-sink conditions.
  • Sink conditions The drug release rate is determined under sink conditions.
  • a surfactant preferably sodium lauryl sulfate
  • the solubility of the medium for the active ingredient (I) is optionally adjusted by the addition of surfactant, preferably sodium lauryl sulfate, so that it is higher by a factor of 3 to 10 than the saturation solubility of the drug dose to be tested.
  • Non-sink conditions The tests for checking the supersaturation (increase in solubility) are carried out without addition of a surfactant and with a dose of 20 mg of active substance (I) to be released.
  • the tablet formulation was tablet B described in WO 2005/060940 in the experimental section under point 5.1 with regard to composition and preparation, which was then subsequently lacquered with the following composition of the lacquer (in mg / tablet):
  • Polyethylene glycol is melted in a heatable reaction vessel (with stirrer and temperature probe). After reaching a temperature of about 210 0 C, the micronized active ingredient (I) is added and further heated. After reaching a temperature of 220-230 0 C, the clear Melt drained in sheets and these cooled using ⁇ on dry ice. After rasping the comminution takes place in an impact mill, so that a powdery product is formed.
  • example formulation 1 has a significantly increased solubility (supersaturation) in comparison with the micronized active ingredient (I) (Comparison 1.1). After 1 hour, a higher solubility by a factor of 2 can be detected.
  • Hydroxypropyl cellulose (type HPC-M, Nisso) 3900 g Xylitol 900 g 5250 g
  • Micronized drug (I), hydroxypropylcellulose and xylitol are mixed and processed in a twin-screw extruder (Leistritz Micro 18 PH) with a 2 mm diameter exit nozzle.
  • the mixture is extruded at a rate of about 1 kg / h and the following temperatures of the heating zones: 20 ° C. (zone 1), 100 ° C. (zone 2), 174 ° C. (zone 3) and 194 ° C. (zones A - 8 and nozzle exit).
  • the extrudate strand obtained is cut into approximately 1 mm pieces and then ground in an impact mill.
  • Example Formulation 2 In vitro release (non-sink conditions) of Example Formulation 2 (drug dose 20 mg, sieve fraction ⁇ 315 ⁇ m):
  • example formulation 2 has a significantly increased solubility (supersaturation) in comparison with the micronized active compound (I) (Comparison 1.1). After 1 hour, a higher solubility by a factor of 2.1 can be detected.
  • Micronized drug (I), polyvinylpyrrolidone and xylitol are mixed and processed in a twin-screw extruder (Leistritz Micro 18 PH) with a 2 mm diameter exit nozzle.
  • the mixture is extruded at a rate of about 1 kg / h and the following temperatures of the heating zones: 20 ° C. (zone 1), 100 ° C. (zone 2), 180 ° C. (zone 3) and 200 ° C. (zones 4 -8 and nozzle exit).
  • the extrudate strand obtained is cut into approximately 1 mm pieces and then ground in an impact mill.
  • example formulation 3 has a significantly increased solubility (supersaturation) compared to the micronized active ingredient (I) (Comparison 1.1). After 1 hour, the solubility is 2.4 times higher.
  • Tablets comprising active substance (I) in metastable crystal modification in the form of a PEG melt
  • composition for tablets containing 10 mg of active ingredient (I) (mg / tablet): Active ingredient (I) -PEG 6000 melt (see Example 1) 100 mg *
  • a drug (I) -PEG melt is prepared as described in Example 1. After sieving (0.63 mm), the other auxiliaries (see above table) are mixed in and this mixture is compressed on a tablet press into tablets in oblong format 17 ⁇ 7 mm with a flexural strength of about 40 N.
  • Example Formulation 4 In-vitro release (non-sink conditions) of Example Formulation 4 (drug dose 20 mg, 2 tablets / vessel):
  • example formulation 4 has a significantly increased solubility (supersaturation) in comparison with the micronized active ingredient (I) (Comparison 1.1). After 1 hour, a higher solubility by a factor of 2.1 can be detected.
  • composition for tablets containing 10 mg of active ingredient (I) (mg / tablet): Active ingredient (I> HPC extrudate (see Example 2) 1 17 mg *
  • An active compound (I) -HPC melt extrudate is prepared as described in Example 2 After sieving (0.4 mm), the other auxiliaries (see table above) are admixed and this mixture is spread on a tablet press into tablets in oblong format 17 ⁇ 7 mm with a bend. festigeit of about 40 N pressed.
  • example formulation 5 has a significantly increased solubility (supersaturation) compared to the micronized active ingredient (I) (Comparison 1.1). After 1 hour, a solubility which is higher by a factor of 2.5 is noticeable.
  • Active ingredient (I) micronized (MOD 1) 4.0 g polyvinylpyrrolidone 25 28.0 g
  • Glacial acetic acid pure acetic acid 140.0 g
  • active ingredient (I) is dissolved in glacial acetic acid at a temperature of about 90 - 100 0 C and the solvent is then distilled off under vacuum. The remaining mass is roughly crushed and transferred to a vacuum oven. In the vacuum drying is carried out for about 48 hours at a temperature of 100-120 0 C. The granules are ground in a mortar and sieved ( ⁇ 1 mm).
  • example formulation 6 has a significantly increased solubility (supersaturation) in comparison with the micronized active ingredient (I) (Comparison 1.1). After 1 hour, a higher solubility by a factor of 2 can be detected.
  • thermodynamically stable crystal modification I in the form of the micronized crystalline active substance in the thermodynamically stable crystal modification I (suspended in 0.5% aqueous methylhydroxyethylcellulose (trade name: Tylose MH 300))
  • Example formulation 1 containing active ingredient (I) in thermodynamically metastable crystal modification and example formulations 2 and 3 containing active ingredient (I) in amorphous form have a significantly improved bioavailability compared to the application of the crystalline micronized active ingredient in the thermodynamically stable crystal modification I (factor 3.2 for example formulation 1) Factor 3.5 for example formulation 2 and factor 3.7 for example formulation 3).
  • Example formulation 1 containing active ingredient (I) in thermodynamically metastable crystal modification has a significantly improved bioavailability compared to the application of the crystalline micronized active substance in the thermodynamically stable crystal modification I (factor 3.6).
  • Example formulation 4 containing active ingredient (I) in thermodynamically metastable crystal modification has in comparison to the comparative formulation 1.2 (tablet containing crystalline micronized drug (I) in the thermodynamically stable crystal modification I) improved bioavailability (factor about 1.5).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
EP06792199A 2005-10-04 2006-09-21 Feste, oral applizierbare pharmazeutische darreichungsformen mit schneller wirkstofffreisetzung Withdrawn EP1957048A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005047561A DE102005047561A1 (de) 2005-10-04 2005-10-04 Feste, oral applizierbare pharmazeutische Darreichungsformen mit schneller Wirkstofffreisetzung
PCT/EP2006/009178 WO2007039122A2 (de) 2005-10-04 2006-09-21 Feste, oral applizierbare pharmazeutische darreichungsformen mit schneller wirkstofffreisetzung

Publications (1)

Publication Number Publication Date
EP1957048A2 true EP1957048A2 (de) 2008-08-20

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AU2006299192A1 (en) 2007-04-12
UY29835A1 (es) 2007-05-31
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