EP2309996A2 - Ambrisentan amorphe - Google Patents

Ambrisentan amorphe

Info

Publication number
EP2309996A2
EP2309996A2 EP09777744A EP09777744A EP2309996A2 EP 2309996 A2 EP2309996 A2 EP 2309996A2 EP 09777744 A EP09777744 A EP 09777744A EP 09777744 A EP09777744 A EP 09777744A EP 2309996 A2 EP2309996 A2 EP 2309996A2
Authority
EP
European Patent Office
Prior art keywords
ambrisentan
surface stabilizer
preparation
amorphous
crystalline
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Withdrawn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
EP09777744A
Other languages
German (de)
English (en)
Inventor
Kathrin Rimkus
Frank Muskulus
Sandra Brueck
Jana Paetz
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.)
Ratiopharm GmbH
Original Assignee
Ratiopharm GmbH
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 Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of EP2309996A2 publication Critical patent/EP2309996A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to amorphous ambrisentan, preferably together with a surface stabilizer in the form of a stable intermediate.
  • the invention further relates to processes for the preparation of stable amorphous ambrisentan and pharmaceutical formulations containing stable amorphous ambrisentan.
  • Ambrisentan is an endothelin receptor antagonist and is approved for the treatment of pulmonary hypertension (pulmonary hypertension).
  • Ambrisentan as an antagonist, displaces endothelin-1, the strongest known endogenous blood vessel constrictor, selectively from its ET IA receptors, thereby abrogating the endothelin-1 effect, causing the vessels to dilate, thus increasing the endothelin-induced (pulmonary) Blood pressure is counteracted, whereby it comes to a (pulmonary) blood pressure reduction.
  • ambrisentan [INN] is (2S) -2- (4,6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3,3-di (phenyl) propanoic acid.
  • the chemical structure of ambrisentan is shown in formula (1) below:
  • ambrisentan has been described by Riechers et al., J. Med. Chem. 39 (11), 2123 (1996) and in WO 96/1 1914, and results in a white, crystalline solid.
  • Volibris ® Ambrisentan is marketed under the trade name Volibris ® as film-coated tablets. Volibris contains ambrisentan in crystalline form, with tabletting by direct compression (see EMEA Assessment Report for Volibris, 2008, Procedure No. EMEA / H / C / 000839). To the required bioavailability too ensure crystalline ambrisentan is preferably used in micronized form.
  • micronization results in an undesirably lower active ingredient
  • micronized active ingredient is more difficult to compress, occasionally there is uneven distribution of active ingredients within the pharmaceutical formulation to be compressed. Due to the strong enlargement of the
  • Object of the present invention was therefore to overcome the disadvantages mentioned above. It should provide the active ingredient in a form that has good flowability and good compression possible. Furthermore, a uniform distribution of the active ingredient should be ensured. Micronization of the active ingredient should be avoided.
  • the active ingredient should be provided in a form which ensures good solubility and at the same time good storage stability. Furthermore, a storage stability of 12 months at 40 0 C and 75% humidity is to be achieved.
  • the impurities should be after such storage ⁇ 2 wt .-%, in particular ⁇ 1 wt .-%.
  • the invention therefore relates to amorphous ambrisentan in stabilized form.
  • the invention relates to an intermediate containing amorphous ambrisentan and a surface stabilizer, preferably a polymer having a glass transition temperature (Tg) greater than 25 0 C, wherein the weight ratio of ambrisentan to surface stabilizer 1: 50 to 2: 1.
  • the intermediate represents amorphous ambrisentan in stabilized form.
  • the invention further provides various processes for the preparation of amorphous ambrisentan or of stabilized amorphous ambrisentan in the form of the intermediate according to the invention.
  • ambrisentan comprises (2S) -2- (4,6-dimethylpyrimidin-2-yl) oxy-3-methoxy-3,3-di (phenyl) propanoic acid according to formula (1) above.
  • ambrisentan includes all pharmaceutically acceptable salts and solvates thereof.
  • Solid amorphous materials are isotropic in contrast to the anisotropic crystals. They usually have no defined melting point, but gradually go over slow softening in the liquid state. Their experimental differentiation of crystalline materials can be done by X-ray diffraction, which gives them no sharp, but usually only a few diffuse interferences at small diffraction angles.
  • Crystalline ambrisentan has the following characteristic peaks in the DSC analysis: exothermic at 157 ° C, endothermic at 180 ° C, exothermic at 181 ° C.
  • the amorphous ambrisentan according to the invention usually shows a softening range of 40 to 70 0 C, preferably from 45 to 65 0 C.
  • the determination of melting point and softening range in the context of this invention by means of differential scanning calorimetry (DSC).
  • the amorphous ambrisentan according to the invention may consist of amorphous ambrisentan. Alternatively, it may still contain minor amounts of crystalline ambrisentan constituents, with the proviso that no defined melting point of crystalline ambrisentan can be recognized in the DSC.
  • Preferred is a mixture containing 60 to 99.999% by weight of amorphous ambrisentan and 0.001 to 40% by weight of crystalline ambrisentan, more preferably 90 to 99.99% by weight of amorphous ambrisentan and 0.01 to 10% crystalline ambrisentan, more preferred 95 to 99.9 wt .-% amorphous ambrisentan and 0.1 to 5% crystalline ambrisentan.
  • ambrisentan according to the invention is in a stabilized form, namely in the form of an intermediate, the amorphous
  • Ambrisentan and a surface stabilizer contains.
  • that exists Intermediate according to the invention essentially of amorphous ambrisentan and surface stabilizer.
  • the term "essentially” here indicates that, if appropriate, even small amounts of solvent etc. may be present.
  • the surface stabilizer is generally a material which inhibits the recrystallization of amorphous to crystalline ambrisentane.
  • the surface stabilizer is a polymer.
  • the surface stabilizer also includes substances that behave polymer-like. Examples are fats and waxes.
  • the surface stabilizer comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides.
  • the term surface stabilizer comprises surfactants, in particular surfactants, which are in solid form at room temperature.
  • the polymer which can be used for the preparation of the intermediate preferably has a glass transition temperature (Tg) of greater than 25 ° C., more preferably from 40 ° C. to 150 ° C., in particular from 50 ° C. to 100 ° C.
  • Tg glass transition temperature
  • a polymer with appropriately selected T g is prevented by immobilization the recrystallization of the amorphous ambrisentane particularly advantageous.
  • the "glass transition temperature” is the temperature at which amorphous or partially crystalline polymers change from the solid state to the liquid state. In this case, a significant change in physical characteristics, z. As the hardness and elasticity. Below the Tg, a polymer is usually glassy and hard, above the Tg it turns into a rubbery to viscous state.
  • DSC differential scanning calorimetry
  • a device of Mettler Toledo DSC 1 can be used. It is at a heating rate of 1-20 ° C / min, preferably 5-15 ° C / min, or at a cooling rate of 5-25 ° C / min, preferably 10-20 ° C / min, worked.
  • the polymer usable for the preparation of the intermediate preferably has a number-average molecular weight of from 1,000 to 500,000 g / mol, more preferably from 2,000 to 50,000 g / mol.
  • the resulting solution preferably exhibits a viscosity of 1 to 20 mPaxs, more preferably either 1 to 5 mPaxs, and still more preferably from 2 to 4 mPa.s or (in particular in the case of HPMC) 12 to 18 mPa.s, measured at 25 0 C, and in accordance with Ph. Eur., 6th edition, chapter 2.2.10 determined.
  • Hydrophilic polymers are preferably used to prepare the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, sulfonate, carboxylate and quaternary ammonium groups.
  • the intermediate according to the invention may comprise, for example, the following polymers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); Polyvinylpyrrolidone, polyvinyl alcohol, polymers of acrylic acid and their salts, vinylpyrrolidone-vinyl acetate copolymers (for example Kollidon VA64, BASF), gelatin polyalkylene glycols, such as polypropylene glycol or preferably polyethylene glycol; Gelatin and mixtures thereof.
  • polysaccharides such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts
  • HPMC hydroxypropylmethylcellulose
  • CMC carboxymethylcellulose
  • HPCMC carboxymethylcellulose
  • HPMC carboxymethylcellulose
  • sugar alcohols such as mannitol, sorbitol, xylitol may preferably be used.
  • Cetyl palmitate, carnauba wax are preferably used as waxes.
  • Glycerol fatty acid esters for example glycerol palmitate, behenate, laurate, stearate, PEG-glycerol fatty acid ester are preferably used as fats.
  • Polyvinylpyrrolidone preferably having a number average molecular weight of 10,000 to 60,000 g / mol, in particular 12,000 to 40,000 g / mol, copolymer of vinylpyrrolidone and vinyl acetate, in particular having a number average molecular weight of 45,000 to 75,000 g / mol and / or polymers, are preferably used as the surface stabilizer the acrylic acid and its salts, in particular having a number average molecular weight of 50,000 to 250,000 g / mol used.
  • HPMC in particular having a number average molecular weight of from 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of from 10 to 35% and a proportion of hydroxyl groups of from 1 to 35%, is preferably used.
  • HPC in particular having a number-average molecular weight of 50,000 to 100,000 g / mol.
  • polyethylene glycol having a number-average molecular weight of from 2,000 to 40,000 g / mol, in particular from 3,500 to 25,000 g / mol.
  • a polyethylene-polypropylene block copolymer is used, wherein the polyethylene content is preferably 70 to 90 wt .-%.
  • the polyethylene-polypropylene block copolymer preferably has a number-average molecular weight of from 1,000 to 30,000 g / mol, more preferably from 3,000 to 15,000 g / mol. The determination of the number average molecular weight is usually carried out by means of gel permeation chromatography.
  • the surface stabilizer used is a copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of 45,000 to 75,000 g / mol.
  • the copolymer can be characterized by the following structural formula (2):
  • polymers of acrylic acid or its salts are used as surface stabilizer.
  • This is preferably a polymer composed of structures according to the general formulas (4) and (3).
  • R 1 is a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a methyl radical, in particular a methyl radical;
  • R 2 is a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a C 1 to C 4 alkyl radical, in particular a methyl radical or an ethyl radical;
  • R 3 is a hydrogen atom or an alkyl radical, preferably a hydrogen atom or a
  • R 4 is an organic radical, preferably a carboxylic acid group or a derivative thereof, more preferably a group of the formula -COOH, -COOR 5
  • R 5 is an alkyl radical or a substituted alkyl radical, preferably methyl, ethyl, propyl or butyl as alkyl radical or -CH 2 -CH 2 -N (CH 3 J 2 or -CH 2 -CH 2 -N (CH 3 J 3 + halogen ⁇ in particular Cl) as substituted alkyl radical.
  • the acrylic polymer usually contains structures of the formulas (4) and (3) in molar ratios of 1:40 to 40: 1.
  • the ratio of structures of the formula (4) to structures of the formula (3) is 2: 1 to 1 1, in particular 1: 1.
  • R 4 is -COO-CH 2 -CH 2 -N (CH 3 J 3 + Cr, the ratio of structures of the formula (4) to structures of the formula (3) is preferably 20: 1 to 40: 1.
  • polyacrylates according to the above formulas (4) and (3) where R 1 and R 3 are alkyl, in particular methyl, R 2 is methyl or butyl, preferably methyl, and R 4 is -COO-CH 2 -CH 2 -N (CH is J 2 3 in this case, preferably, the ratio of structures of the formula (2) to structures of the formula (3).
  • R 1 and R 3 are alkyl, in particular methyl
  • R 2 is methyl or butyl, preferably methyl
  • R 4 is -COO-CH 2 -CH 2 -N (CH is J 2 3 in this case, preferably, the ratio of structures of the formula (2) to structures of the formula (3).
  • a suitable polymer has in particular a number average molecular weight of from 50,000 to 250,000 g / mol, more preferably from 120,000 up to 180,000 g / mol, on.
  • the intermediate of the invention comprises amorphous ambrisentan and surface stabilizer, wherein the weight ratio of ambrisentan to surface stabilizer is from 1:50 to 2: 1, more preferably 1:20 to 1: 1, even more preferably 1:15 to 1: 2, especially 1: 12 to 1: 5.
  • the intermediate according to the invention is a "single-phase" intermediate. By this is meant that
  • the type and amount of the surface stabilizer be chosen so that the resulting intermediate has a glass transition temperature (Tg) of more than 20 0 C, preferably> 40 0 C.
  • Tg glass transition temperature
  • the Tg of the intermediate should not be above 90 0 C.
  • the type and amount of the polymer be chosen so that the resulting intermediate is storage stable.
  • storage-stable is meant that in the intermediate according to the invention after 3 years of storage at 25 0 C and 50% relative humidity, the proportion of crystalline ambrisentan - based on the total amount of ambrisentan - a maximum of 60% by weight, preferably at most 30 wt. %, more preferably at most 15 wt .-%, in particular at most 5 wt .-% is.
  • the intermediates according to the invention can be obtained by various preparation processes. Depending on the preparation method, the intermediates are obtained in different particle sizes.
  • the intermediates according to the invention are usually in particulate form and have an average particle diameter (D 50 ) of 50 to 750 ⁇ m.
  • average particle diameter in the context of this invention refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry.
  • a Mastersizer 2000 from Malvern Instruments was used for the determination (wet measurement with ultrasound 60 sec, 2000 rpm, preferably shading 4 to 13%, preferably dispersion in liquid paraffin, the evaluation being carried out according to the Fraunhofer model).
  • the average particle diameter also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value.
  • the invention further provides a process for the preparation of the amorphous ambrisentan or the intermediate according to the invention.
  • a process for the preparation of the amorphous ambrisentan or the intermediate according to the invention will be explained.
  • the invention relates to a freeze-drying process, ie a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps
  • step (a) ambrisentan, preferably ambrisentan and the surface stabilizer described above, are dissolved in a solvent or solvent mixture, preferably completely dissolved.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • acetone butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • a mixture of water and DMSO is used.
  • Suitable surface stabilizers in this embodiment are in particular modified celluloses such as HPMC and sugar alcohols such as mannitol and sorbitol. It is also particularly preferred to use polyvinylpyrrolidone, especially with the molecular weights given above.
  • the solution from step (al) is cooled to about 10 to 50 C C below the freezing point (ie brought to freezing). Subsequently, the solvent is removed by sublimation. This is preferably done when the conductivity of the solution is less than 2%.
  • the sublimation temperature is preferably determined by the intersection of product temperature and Rx - 10 0 C. Sublimation is preferably at a pressure of less than 0.1 mbar.
  • the lyophilized amorphous ambrisentan preferably the lyophilized intermediate, is warmed to room temperature.
  • the process conditions in this first embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D50) of from 5 to 250 ⁇ m, more preferably from 20 to 150 ⁇ m, in particular from 50 to 100 ⁇ m.
  • D50 volume average particle diameter
  • the invention relates to a "pellet layering process", ie a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps (a2) dissolving the crystalline ambrisentan and the surface stabilizer in a solvent or solvent mixture, and (b2) spraying the solution of step (a2) onto a carrier core.
  • a "pellet layering process” ie a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps (a2) dissolving the crystalline ambrisentan and the surface stabilizer in a solvent or solvent mixture, and (b2) spraying the solution of step (a2) onto a carrier core.
  • step (a2) ambrisentan, preferably ambrisentan and the surface stabilizer described above, are dissolved in a solvent or solvent mixture, preferably completely dissolved.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • acetone butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • a mixture of water and DMSO is used.
  • Suitable surface stabilizers in this second embodiment are in particular modified celluloses such as HPMC, sugar alcohols such as mannitol and sorbitol and polyethylene glycol, in particular polyethylene glycol having a molecular weight of from 2,000 to 10,000 g / mol.
  • step (b2) the solution from step (a2) is sprayed onto a carrier core.
  • Suitable carrier cores are particles consisting of pharmaceutically acceptable adjuvants, in particular so-called “neutral pellets”. Pellets are preferably used, which are available under the trade name Cellets ® and contain microcrystalline cellulose.
  • step (b2) takes place in a fluidized-bed dryer, for example in a Glatt GPCG 3 (Glatt GmbH, Germany).
  • the process conditions in this second embodiment are preferably selected such that the resulting intermediate particles have a volume-average particle diameter (D 50 ) of 50 to 750 ⁇ m, more preferably of 100 to 500 ⁇ m.
  • the invention relates to a process for the preparation of the amorphous ambrisentan according to the invention, in particular of the intermediate according to the invention, comprising the steps
  • step (a3) dissolving the crystalline ambrisentane and the surface stabilizer in a solvent or solvent mixture, and (b3) spray-drying the solution of step (a3).
  • step (a3) ambrisentan, preferably ambrisentan and the surface stabilizer described above, are dissolved in a solvent or solvent mixture, preferably completely dissolved.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • acetone butanol, ethyl acetate, heptane, pentanol, or mixtures thereof.
  • a DMSO / water mixture is used.
  • Suitable surface stabilizers in this embodiment are in particular modified celluloses such as HPMC, polyvinylpyrrolidone and copolymers thereof and sugar alcohols such as mannitol and sorbitol. Also particularly preferred are acrylic polymers, in particular the above-described under the formulas (3) and (4) acrylic polymers.
  • the solution from step (a3) is spray-dried.
  • the spray-drying is usually carried out in a spray tower.
  • a Büchi B-191 is suitable (Büchi Labortechnik GmbH, Germany).
  • an inlet temperature of 100 0 C to 150 0 C is selected.
  • the amount of air is for example 500 to 700 liters / hour and the aspirator preferably runs at 80 to 100%.
  • the process conditions are preferably chosen in this third embodiment so that the resulting intermediate particles have a volume-average particle diameter (D 50) of 5 to 250 microns, preferably greater of 20 to 150 / an, in particular from 50 to 100 microns.
  • D 50 volume-average particle diameter
  • the invention relates to a melt extrusion process, i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (a4) crystalline ambrisentan is preferably mixed with the surface stabilizer in a mixer.
  • a surface stabilizer in polymeric form is used.
  • Suitable polymeric surface stabilizers in this fourth embodiment are in particular polyvinylpyrrolidone and copolymers thereof (in particular a copolymer according to the above formula (2)), and also polyvinyl alcohols, methacrylates and HPMC.
  • polyethylene glycol especially with the molecular weights given above, is preferably used.
  • step (b4) the mixture is extruded.
  • conventional melt extruders can be used.
  • a Leistritz Micro 18 is used.
  • the cooled melt is comminuted by a rasping screen (e.g., Comill U5) and concomitantly subjected to a uniform grain size.
  • a rasping screen e.g., Comill U5
  • the extrusion temperature depends on the type of polymeric surface stabilizer. Usually, it is between 40 and 250 0 C, preferably between 80 and 160 0 C.
  • the cooled melt is preferably comminuted by a rasp screen and thus subjected to a uniform grain size.
  • the process conditions in this fourth embodiment are preferably selected such that the resulting intermediate particles have a volume average particle diameter (D 50 ) to 1000 ⁇ m, more preferably a D 90 of 500 to 1000 ⁇ m.
  • the invention relates to a so-called "hot melt process", i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (a5) crystalline ambrisentan is dissolved in a melt of the surface stabilizer, preferably completely dissolved.
  • waxes and fats are preferably used as the surface stabilizer.
  • An example of a preferably used surface stabilizer is poloxamer ®.
  • step (b5) an application is carried out, preferably a spraying of the melt from step (b2) onto a carrier core.
  • Suitable carrier cores are Teflchen consisting of pharmaceutically acceptable excipients, in particular so-called “neutral pellets”.
  • Pellets are preferably used, which are available under the trade name Cellets ® and containing a mixture of lactose and microcrystalline cellulose.
  • the process conditions in this fifth embodiment are preferably selected so that the resulting intermediate particles have a volume-average particle diameter (D 50 ) of from 50 to 750 /, more preferably from 100 to 500 ⁇ m.
  • the invention relates to a milling process, i. a process for the preparation of the intermediate according to the invention, comprising the steps
  • step (a6) mixing crystalline ambrisentan and surface stabilizer, and (b6) grinding the mixture of step (a6), wherein the milling conditions are selected to transition from crystalline to amorphous ambrisentane.
  • Crystalline ambrisentan and surface stabilizer are mixed in step (a6).
  • the mixture is ground in step (b6).
  • the mixing can be done before or during the milling, i. Steps (a6) and (b6) can be done simultaneously.
  • the milling conditions are chosen so that a transition from crystalline to amorphous ambrisentan occurs.
  • Milling is generally carried out in conventional grinding devices, preferably in a ball mill, for example in a Retsch PM 100.
  • the meal is usually 10 minutes to 10 hours, preferably 30 minutes to 8 hours, more preferably 2 hours to 6 hours.
  • Suitable surface stabilizers in this sixth embodiment are in particular modified celluloses such as HPMC, sugar alcohols such as mannitol and sorbitol and polyethylene glycol, in particular polyethylene glycol having a molecular weight of 2,000 to 10,000 g / mol. Also, polyvinylpyrrolidone is preferably used.
  • amorphous ambrisentan of this invention and the intermediate of the invention are commonly used to prepare a pharmaceutical formulation.
  • the invention therefore relates to a pharmaceutical formulation comprising amorphous ambrisentan according to the invention or intermediate according to the invention as well as pharmaceutical excipients.
  • auxiliaries used are disintegrants, release agents, pseudo-emulsifiers, fillers, additives to improve the powder flowability, lubricants, wetting agents, gelling agents and / or lubricants.
  • the ratio of active ingredient to auxiliaries is preferably chosen so that the resulting formulations
  • the amount of active ingredient refers to the amount of amorphous
  • the pharmaceutical formulation preferably contains one or more of the abovementioned excipients.
  • disintegrants in general substances are referred to accelerate the disintegration of a dosage form, in particular a tablet, after introduction into water.
  • Suitable disintegrants are e.g. organic disintegrants like
  • Carrageenan, croscarmellose, sodium carboxymethyl starch and crospovidone Carrageenan, croscarmellose, sodium carboxymethyl starch and crospovidone.
  • alkaline disintegrating agents are meant disintegrating agents which when dissolved in water produce a pH of more than 7.0.
  • inorganic alkaline disintegrants are used, especially salts of alkali and alkaline earth metals.
  • Preferred are sodium, potassium, magnesium and calcium.
  • As anions carbonate, bicarbonate, phosphate, hydrogen phosphate and dihydrogen phosphate are preferred. Examples are sodium hydrogencarbonate, sodium hydrogenphosphate, calcium hydrogencarbonate and the like.
  • Sodium bicarbonate is particularly preferably used as disintegrant, in particular in the abovementioned amounts.
  • the pharmaceutical formulation additionally contains
  • (Iii) release agent preferably in an amount of 0.1 to 5 wt .-%, more preferably 0.5 to 3 wt .-%, based on the total weight of the formulation.
  • release agents are usually understood substances which reduce the agglomeration in the core bed.
  • examples are talc, silica gel, polyethylene glycol (preferably with 2000 to 10,000 g / mol weight average molecular weight) and / or glycerol monostearate.
  • Examples of preferred release agents are talc and polyethylene glycol 4000, agar and / or carrageenan.
  • the pharmaceutical formulation additionally contains a
  • emulsifier and / or pseudo-emulsifier preferably in an amount of 0, 1 to 5 wt .-%, more preferably 0.5 to 3 wt .-%, based on the total weight of the formulation.
  • Pseudo-emulsifiers are usually (preferably polymeric) substances which, when added to a solution, increase the viscosity of this solution.
  • the addition of 5% by weight of pseudo-emulsifier to distilled water at 20 ° C. preferably leads to an increase in the viscosity of at least 1%, preferably at least 2%, in particular at least 5%.
  • plant gums are preferably used.
  • Plant gums are polysaccharides of natural origin which cause the above viscosity increase.
  • pseudo-emulsifiers examples include agar, alginic acid, alginate, chicle, dammar, marshmallow extracts, gellan (E 418), guar gum (E 412), gum arabic (E 414), maple gum gum, spruce juice gum, locust bean gum E 410 ), Karaya (E 416), Konjac flour (E 425), obtained from the konjac root, Tarakernmehl (E 417), tragacanth (E 413), xanthan (E 415), preferably produced by bacterial fermentation, and / or lecithin.
  • Possible emulsifiers are anionic emulsifiers, e.g. Soaps, preferably alkali salts of higher fatty acids salts of bile acids (alkali salts); cationic emulsifiers, e.g. Benzalkonium chloride, cetylpyridinium chloride, cetrimide; nonionic emulsifiers, e.g. Sobitan derivatives, especially sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyethylene glycol derivatives / polyoxyethylene derivative, especially polyoxyethylene (20) sorbitan monostearate, polyoxyethylene stearate or
  • Partial fatty acid esters of polyhydric alcohols e.g. Glycerol monostearate, fatty acid esters of sucrose, fatty acid esters of polyglycol or casein. Also, mixtures of these substances are possible.
  • the formulation according to the invention may also comprise further abovementioned pharmaceutical auxiliaries. These are explained in more detail below.
  • the formulation according to the invention preferably contains fillers.
  • Fillers are generally to be understood as meaning substances which serve for the formation of the tablet body in the case of tablets with small amounts of active ingredient (eg less than 70% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermassse. So fillers are usually used to obtain a suitable tablet size.
  • Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, talc, calcium phosphate, hydrogen phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and / or potassium chloride. Also Prosolv® ® (Rettenmaier & Söhne, Germany) can be used.
  • Fillers are usually used in an amount of from 1 to 80% by weight, more preferably from 15 to 70% by weight, particularly preferably from 30 to 60% by weight, based on the total weight of the formulation.
  • silica such as known under the trade name Aerosil ®. Preference is given to using silica having a specific surface area of from 50 to 400 m 2 / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition, Sept. 2, 1966.
  • Additives to improve the powder flowability are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation.
  • Lubricants can be used.
  • Lubricants are generally used to reduce sliding friction.
  • the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall.
  • Suitable lubricants are e.g. Stearic acid, adipic acid, sodium stearyl fumarate and / or magnesium stearate.
  • Lubricants are usually used in an amount of 0.1 to 3% by weight, based on the total weight of the formulation.
  • the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
  • a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
  • PEG 4000 if used as a surface stabilizer, is not additionally used as a release agent (although PEG 4000 also shows a release effect).
  • microcrystalline cellulose - if used as a surface stabilizer - not additionally used as a disintegrant (although microcrystalline cellulose also shows a certain explosive effect).
  • the pharmaceutical formulation of the invention is preferably compressed into tablets.
  • the prior art proposes direct compression of ambrisentan formulation (see EMEA Assessment Report for Volibris, 2008, Procedure No. EMEA / H / C / 000839).
  • the properties of the resulting tablets can be improved if the pharmaceutical formulation according to the invention is subjected to dry granulation prior to compression to the tablet.
  • the subject of the present invention is therefore a method comprising the steps
  • ambrisentan and auxiliaries are preferably mixed.
  • the mixing can be done in conventional mixers.
  • the amorphous ambrisentan is first mixed with only a part of the excipients (e.g., 50 to 95%) before compaction (II), and that the remaining part of the excipients is added after the granulation step (Ui).
  • the admixing of the excipients should preferably take place before the first compacting step, between several compacting steps or after the last granulating step.
  • step (II) of the process according to the invention the mixture from step (I) is compacted into a rag. It is preferred that this is dry compaction, i. the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.
  • step (II) are preferably selected such that the slug has a density of 1.03 to 1.3 g / cm 3 , in particular from 1.05 to 1.2 g / cm 3 .
  • the true density can be determined with a gas pycnometer. Preferably, it is in the Gas pycnometer to a helium pycnometer, in particular, the device AccuPyc 1340 Helium Pycnometer of the manufacturer Micromeritics, Germany is used.
  • the compaction is preferably carried out in a roll granulator.
  • the rolling force is 2 to 50 kN / cm, more preferably 4 to 30 kN / cm, especially 10 to 25 kN / cm.
  • the gap width of the rolling granulator is, for example, 0.8 to 5 mm, preferably 1 to 4 mm, more preferably 1.5 to 3 mm, in particular 1.8 to 2.8 mm.
  • the compacting device used preferably has a cooling device. In particular, it is cooled in such a way that the temperature of the compactate 50 0 C, in particular 40 0 C does not exceed.
  • step (Ui) of the process the slug is granulated.
  • the granulation can be carried out by methods known in the art.
  • the granulation conditions are selected such that the resulting particles (granules) have a volume average particle size (d ( 50 ) value) of 50 to 600 microns, more preferably 100 to 500 microns, even more preferably 150 to 400 microns , in particular from 200 to 350 microns.
  • d ( 50 ) value volume average particle size
  • the granulation is carried out in a sieve mill.
  • the mesh size of the sieve insert is usually 0, 1 to 5 mm, preferably 0.5 to 3 mm, more preferably 0.75 to 2 mm, in particular 0.8 to 1, 8 mm.
  • the process is adapted such that a multiple compaction takes place, wherein the granulate resulting from step (III) is recycled once or several times for compaction (II).
  • the granules from step (III) are preferably recycled 1 to 5 times, in particular 2 to 3 times.
  • the resulting from step (III) granules can be processed into pharmaceutical dosage forms.
  • the granules are filled, for example, in sachets or capsules.
  • the granules resulting from step (III) are compressed into tablets (IV).
  • step (IV) of the process the granules obtained in step (III) are compressed into tablets, ie they are compressed into tablets.
  • the compression can be done with tableting machines known in the art.
  • pharmaceutical excipients may optionally be added to the granules from step (III).
  • step (IV) usually depend on the type of tablet to be prepared and on the amount of excipients already added in steps (I) or (II).
  • the tabletting conditions are preferably chosen so that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg.
  • the resulting tablets preferably have a hardness of 35 or 50 to 200 N, more preferably from 60 or 80 to 150 N. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8.
  • the resulting tablets preferably have a friability of less than 10%, particularly preferably less than 5%, in particular less than 3%.
  • the friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.
  • the tablets according to the invention usually have a “content uniformity” of 85 to 115%, preferably from 90 to 110%, in particular from 95 to 105%, of the average content.
  • the "Content Uniformity” is according to Ph. Eur.6.0, Section 2.9.6. certainly.
  • the release profile of the tablets according to the invention usually has a released content of at least 30%, preferably at least 50%, in particular at least 70%, according to the USP method after 10 minutes.
  • the above information on hardness, friability, content uniformity and release profile in this case relate preferably to the uninfiltrated tablet.
  • the tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably film-coated). It can also be chewable tablets or disperse tablets.
  • Disperse tablets is here understood to mean a tablet for the production of an aqueous suspension for oral use.
  • macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac.
  • HPMC in particular HPMC having a number average molecular weight of from 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH 3 groups of from 1.2 to 2.0.
  • the layer thickness of the coating is preferably 10 to 100 ⁇ m.
  • a "Hüttlin spheric coater Unilab-05 / -5-TJ" was used: supply air temperature 250 ° C, microclimate 100 ° C, spray pressure 0.4 bar.
  • Example 13 Melt (in the DSC crucible)
  • Kollidon ® 25 heating to 160 0 C, cooling rate 50 ° C / min
  • Kollidon ® VA 64 heating to 145 0 C, cooling rate 30 ° C / min
  • Example 14 calcium hydrogen phosphate, sodium carboxymethyl starch and sodium bicarbonate were mixed and sieved together for 20 minutes. Furthermore, magnesium stearate was added and mixed for 3 minutes. Then talc, sodium stearyl fumarate and Aerosil® were added and mixed again for 3 minutes. From the mixture tablets of 149 mg were pressed (containing 5 mg ambrisentan).

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'ambrisentan amorphe, de préférence associé à un stabilisant de surface, sous la forme d'un composé intermédiaire stable. L'invention concerne également des procédés de production d'ambrisentan amorphe stable et des formulations pharmaceutiques contenant l'ambrisentan amorphe stable.
EP09777744A 2008-08-11 2009-08-07 Ambrisentan amorphe Withdrawn EP2309996A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008037325 2008-08-11
PCT/EP2009/005750 WO2010017918A2 (fr) 2008-08-11 2009-08-07 Ambrisentan amorphe

Publications (1)

Publication Number Publication Date
EP2309996A2 true EP2309996A2 (fr) 2011-04-20

Family

ID=41228785

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09777744A Withdrawn EP2309996A2 (fr) 2008-08-11 2009-08-07 Ambrisentan amorphe

Country Status (4)

Country Link
US (1) US20120022087A1 (fr)
EP (1) EP2309996A2 (fr)
CA (1) CA2732931A1 (fr)
WO (1) WO2010017918A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2712865B1 (fr) 2009-07-10 2016-03-16 Cadila Healthcare Limited Procédé amélioré pour la préparation d'ambrisentan
CN102781429A (zh) * 2010-03-05 2012-11-14 巴斯夫欧洲公司 经熔体涂覆的药物剂型
EP2476670A1 (fr) 2011-01-07 2012-07-18 Zentiva, K.S. Seuls solides stabiles de l'ambrisentane
CN102219748B (zh) * 2011-05-04 2014-05-07 天津市医药集团技术发展有限公司 无定型安贝生坦及其制备方法
CN102887861B (zh) * 2011-07-18 2015-04-15 天津市医药集团技术发展有限公司 一种安贝生坦新晶型及其制备方法
CN106822007B (zh) 2015-09-11 2021-12-31 西姆莱斯股份公司 口服制剂
CN111511365A (zh) * 2017-11-10 2020-08-07 分散技术有限责任公司 改进的药物制剂
TR202020618A2 (tr) * 2020-12-16 2022-06-21 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Mi̇kroni̇ze ambri̇sentan i̇çeren bi̇r fi̇lm kapli tablet

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2133068A1 (fr) * 2008-06-13 2009-12-16 Ratiopharm GmbH Procédé de sélection d'un consommable secondaire adapté à la fabrication de dispersions fixes pour formules pharmaceutiques

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CL2004001884A1 (es) * 2003-08-04 2005-06-03 Pfizer Prod Inc Procedimiento de secado por pulverizacion para la formacion de dispersiones solidas amorfas de un farmaco y polimeros.
EP2091539A1 (fr) * 2006-12-12 2009-08-26 Gilead Colorado, Inc. Utilisation de l'ambrisentan associé avec un inhibiteur de rénine dans les troubles de l'hypertension
WO2008097648A1 (fr) * 2007-02-07 2008-08-14 Lightfleet Corporation Identifiant augmentant de manière monotone généré par matrice
NZ580972A (en) * 2007-06-04 2012-02-24 Egalet Ltd Controlled release pharmaceutical compositions for prolonged effect
EP2712865B1 (fr) * 2009-07-10 2016-03-16 Cadila Healthcare Limited Procédé amélioré pour la préparation d'ambrisentan

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2133068A1 (fr) * 2008-06-13 2009-12-16 Ratiopharm GmbH Procédé de sélection d'un consommable secondaire adapté à la fabrication de dispersions fixes pour formules pharmaceutiques

Also Published As

Publication number Publication date
US20120022087A1 (en) 2012-01-26
WO2010017918A3 (fr) 2010-05-14
CA2732931A1 (fr) 2010-02-18
WO2010017918A2 (fr) 2010-02-18

Similar Documents

Publication Publication Date Title
WO2010054833A1 (fr) Produits intermédiaires et formes galéniques orales contenant de la lénalidomide
DE69434640T2 (de) Heterodisperse Hydrogelsysteme zur verzögerten Freisetzung unlöslicher Arzneistoffe
WO2010017918A2 (fr) Ambrisentan amorphe
EP2408431A1 (fr) Rétigabine solide sous forme non cristalline
EP1957048A2 (fr) Formulations de presentation pharmaceutiques, solides et administrees par voie orale presentant une liberation d'agents actifs rapide
WO2010112203A1 (fr) Comprimés contenant de la dapoxétine et procédé de traitement à sec pour leur préparation
EP2309995A1 (fr) Formulation pharmaceutique pour la réduction de la pression artérielle pulmonaire
WO2012010669A2 (fr) Médicament d'administration orale contenant un mélange de silodosine et d'un copolymère basique
WO2011076412A1 (fr) Forme d'administration orale contenant de l'entecavir
DE60306120T2 (de) Pharmazeutische formulierung, die n-((1-n-butyl-4-piperidinyl)menthyl)-3,4-dihydro-2h-(1,3)oxazino(3,2-a)indol-10-carboxamid oder ein entsprechendes salz hiervon enthält, sowie deren herstellungsprozess, welcher trockengranulierung beinhaltet
WO2010066385A1 (fr) Moxifloxacine compactée
DE102008057284A1 (de) Tabletten enthaltend Lenalidomid und Adhäsionsverstärker
DE202010017303U1 (de) Trockenverarbeitung von Retigabin
DE10153934A1 (de) Verfahren zur Kristallisation von Profenen
EP2462145A1 (fr) Prasugrel sous forme non cristalline et composition pharmaceutique de celui-ci
WO2011138037A2 (fr) Tapentadol solide sous forme non cristalline
WO2010149183A1 (fr) Aprépitant sous forme de solution solide
DE10152351A1 (de) Feste Arzneimittelformulierung für ein Piperazinharnstoffderivat
DE102008057285A1 (de) 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidindion in Form einer festen Lösung
WO2013030119A1 (fr) Forme galénique comprenant des particules de principe actif stabilisées
WO2010004022A1 (fr) Comprimés d'aliskirène fabriqués par compression directe
WO2010025848A1 (fr) Composition pharmaceutique contenant des particules qui se composent de ziprasidone et d'un délitant
DE102008057335A1 (de) Amorphes Lenalidomid
WO2022101247A1 (fr) Formes posologiques à libération prolongée d'un sel de tapentadol avec de l'acide l-(+)-tartrique
DE202020005470U1 (de) Darreichungsformen mit verlängerter Freisetzung eines Salzes von Tapentadol mit L-(+)-Weinsäure

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110124

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

AX Request for extension of the european patent

Extension state: AL BA RS

RIN1 Information on inventor provided before grant (corrected)

Inventor name: PAETZ, JANA

Inventor name: BRUECK, SANDRA

Inventor name: MUSKULUS, FRANK

Inventor name: RIMKUS, KATHRIN

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: RATIOPHARM GMBH

17Q First examination report despatched

Effective date: 20150911

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20160322