EP2408424A2 - Transformation à sec de rétigabine - Google Patents
Transformation à sec de rétigabineInfo
- Publication number
- EP2408424A2 EP2408424A2 EP10711009A EP10711009A EP2408424A2 EP 2408424 A2 EP2408424 A2 EP 2408424A2 EP 10711009 A EP10711009 A EP 10711009A EP 10711009 A EP10711009 A EP 10711009A EP 2408424 A2 EP2408424 A2 EP 2408424A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- retigabine
- tablets
- optionally
- adhesion
- weight
- 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- Withdrawn
Links
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000007912 modified release tablet Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 238000010422 painting Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- PICXIOQBANWBIZ-UHFFFAOYSA-N zinc;1-oxidopyridine-2-thione Chemical class [Zn+2].[O-]N1C=CC=CC1=S.[O-]N1C=CC=CC1=S PICXIOQBANWBIZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
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- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
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- 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
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- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- the invention relates to dry processes for the preparation of oral dosage forms, in particular tablets containing retigabine and adhesion enhancers. Furthermore, the invention relates to compacted intermediates containing retigabine and an adhesion promoter.
- retigabine The IUPAC name of retigabine [INN] is 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonyl-aminobenzene.
- the chemical structure of retigabine is shown in formula (1) below:
- Epilepsy is one of the most common neurological diseases and affects about 1% of the population. While a large proportion of epilepsy patients can be treated with anticonvulsants currently available on the market, about 30% of them are
- Substance fulfills these criteria as potassium channel opener.
- no pharmaceutical dosage forms are known in the art, the advantageous oral administration of retigabine in high doses, especially for the treatment of
- WO 02/80898 A2 proposes to formulate retigabine in the form of hard gelatine capsules containing 50, 100 and 200 mg of active ingredient.
- Hard gelatin capsules are made by
- WO 01/66081 A2 also proposes retigabine formulations which have been prepared by melt granulation, a composition consisting exclusively of retigabine and sucrose fatty acid ester being used.
- a composition consisting exclusively of retigabine and sucrose fatty acid ester being used.
- the use of larger amounts of sucrose fatty acid ester is often undesirable because of emulsifier action.
- the proposed formulations allow only a delayed release.
- An object of the invention was to provide a pleasant for the patient dosage form, which makes it possible to administer active ingredient amounts of significantly more than 200 mg advantageous.
- a granular formulation of retigabine should be provided which can be advantageously used to prepare an oral suspension.
- the granules should flow well, do not segregate during storage and allow an exact dosage of single and multidose containers.
- crystalline retigabine may exist in various polymorphic forms.
- these polymorphs are often not stable, but tend to convert to other polymorphic forms.
- the commonly used retigabine Form A can convert to Form B upon exposure to heat.
- the polymorphic forms A, B and C have a different solubility profile.
- dosage forms of retigabine are to be provided which ensure good solubility and bioavailability with at the same time good storage stability.
- the invention therefore provides a process for the preparation of oral administration forms, in particular tablets containing retigabine and adhesion enhancer, wherein the oral administration forms, in particular the tablets, are produced by means of dry compaction or by means of direct compression. Furthermore, the invention relates to tablets which are obtainable according to the embodiments of the method according to the invention described below.
- the invention further provides an intermediate obtainable by co-dry-curing of retigabine with an adhesion promoter.
- the invention relates to single-dose and multi-dose containers, preferably sachets and stick packs, which contain the intermediate according to the invention.
- the term “retigabine” comprises 2-amino-4- (4-fluorobenzylamino) -1-ethoxycarbonyl-aminobenzene according to formula (1) above.
- the term “retigabine” includes all pharmaceutically acceptable salts, hydrates and solvates thereof.
- the salts may be acid addition salts.
- suitable salts are hydrochlorides (monohydrochloride, dihydrochloride), carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates.
- Retigabine is preferably used in the form of the free base or in the form of dihydrochloride. Retigabine can be used in this invention in both amorphous and crystalline form. Retigabine can also be used in the form of a solid solution.
- Crystalline retigabine can be present in three different polymorphic forms according to WO 98/31663 (polymorphic forms A, B and C).
- polymorphic form A is preferably used in the case of crystalline retigabine.
- the adhesion enhancer is generally a material capable of stabilizing retigabine in compacted or compressed form.
- adhesion enhancer usually results in one
- Adhesion enhancers by increasing the plasticity of the Tablettiermischung so that solid tablets are formed during compression.
- the adhesion promoter is a polymer.
- the term "adhesion enhancer” also includes substances that behave polymer-like. Examples of these are fats and waxes, but not sucrose fatty acid esters.
- the adhesion promoter comprises solid, non-polymeric compounds which preferably have polar side groups. Examples of these are sugar alcohols or disaccharides.
- the adhesion enhancer used in the context of this invention is preferably a polymer which has a glass transition temperature (Tg) greater than 15 ° C., more preferably from 40 ° C. to 150 ° C., in particular from 50 ° C. to 100 ° C.
- Tg glass transition temperature
- 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, a. Below the Tg, a polymer is usually glassy and hard, above the Tg it turns into a rubbery to viscous state.
- the determination of the glass transition temperature is carried out in the context of this invention by means of differential scanning calorimetry (DSC). For this purpose, z. B. a device from Mettler Toledo DSC 1 can be used. It is carried out at a heating rate of 1-20 0 C / min, preferably 5-15 ° C / min or with a cooling rate of 5-25, preferably 10-20 ° C / min.
- the polymer useful as an adhesion promoter preferably has a weight average or number average molecular weight of 1,000 to 500,000 g / mol, more preferably from 2,000 to 90,000 g / mol.
- the resulting solution preferably exhibits a viscosity of from 0.1 to 8 mPas, more preferably from 0.3 to 7 mPas, especially from 0 , 5 to 4 mPa's, measured at 25 0 C, and preferably according to Ph. Eur., 6th edition, chapter 2.2.10, determined.
- hydrophilic polymers for the preparation of the intermediate. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, alkoxy, acrylate, methacrylate, sulfonate, carboxylate and quaternary ammonium groups.
- the intermediate according to the invention may comprise, for example, the following polymers as adhesion enhancers: polysaccharides, such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC, in particular sodium and calcium salts), ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose (HPC); microcrystalline cellulose, silicon-modified microcrystalline cellulose (such as Prosolv ®), guar gum, alginic acid and / or alginates; synthetic polymers such as polyvinylpyrrolidone (povidone), polyvinyl acetate (PVAC), polyvinyl alcohol (PVA), polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ® VA64, BASF), polyalkylene glycols such as polypropylene glycol or, preferably,
- Polyvinylpyrrolidone preferably having a weight-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 weight-average molecular weight of 40,000 to 70,000 g / mol and / or are particularly preferably used as adhesion promoters
- Polyethylene glycol in particular having a weight-average molecular weight of 2,000 to 10,000 g / mol
- HPMC in particular having a weight-average molecular weight of 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of 10 to 35% and a proportion of hydroxy groups of 1 up to 35%.
- microcrystalline cellulose in particular those having a specific surface area of 0.7-1.4 m 2 / g.
- the determination of the specific surface was carried out by gas adsorption method according to Brunauer, Emmet and Plate.
- pregelatinized starch in particular in formulations having an active ingredient content of more than 70% by weight.
- the adhesion promoter also comprises solid, non-polymeric compounds which preferably have polar side groups.
- these are sugar alcohols or disaccharides.
- suitable sugar alcohols and / or disaccharides are lactose, mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof.
- sugar alcohols here also includes monosaccharides.
- lactose and mannitol are used as adhesion enhancers.
- retigabine and adhesion enhancers are used in an amount wherein the weight ratio of retigabine to adhesion enhancer is from 20: 1 to 1:10, more preferably from 10: 1 to 1: 5, even more preferably from 5: 1 to 1: 2 , in particular 4: 1 to 2: 1.
- the adhesion promoter is used in particulate form and a volume-average particle size (D50) of the adhesion enhancer is less than 500 ⁇ m, preferably 5 to 200 ⁇ m.
- retigabine is used in micronized form.
- micronized retigabine in the context of this invention refers to particulate retigabine, which generally has an average particle diameter of from 0.1 to 200 ⁇ m, preferably from 0.5 to 100 ⁇ m, more preferably from 1 to 50 ⁇ m, particularly preferably 1 , 5 to 25 microns and especially from 2 to 10 microns.
- mean particle diameter in the context of this invention always refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry.
- the evaluation according to the Fraunhofer model is carried out, preferably, in which the non-dissolved substance to be measured at 20 0 C
- 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.
- average particle size and “average particle diameter” are used interchangeably throughout this application.
- the process according to the invention can generally be carried out in two embodiments, namely as a dry granulation process and as a direct compression process. Both embodiments are carried out in the absence of solvent.
- One aspect of the present invention therefore relates to a dry granulation process comprising the steps
- step (a) retigabine and adhesion enhancers, and optionally further pharmaceutical excipients (described below), are mixed.
- the mixing can be done in conventional mixers.
- the mixing can be done in compulsory mixers or tumble mixers, e.g. by means of Turbula T 1OB (Bachofen AG, Switzerland).
- Turbula T 1OB Turbula T 1OB (Bachofen AG, Switzerland).
- the retigabine is first mixed with only a portion of the hips (e.g., 50 to 95%) prior to compaction (b) and that the remaining TEU of the hips be added after the granulation step (c).
- the admixing of the hides should preferably take place before the first compaction step, between several compaction steps or after the last granulation step.
- the mixing conditions in step (a) and / or the compacting conditions in step (b) are usually selected so that at least 30% of the surface area of the resulting retigabine particles is covered with adhesion promoter, more preferably at least 50% of the surface, most preferably at least 70 % of the surface, in particular at least 90% of the surface.
- step (b) of the process according to the invention the mixture from step (a) is compacted into a rag.
- This is dry compaction, i. the compaction is preferably carried out in the absence of solvents, in particular in the absence of organic solvents.
- the compaction is preferably carried out in a roll granulator.
- the rolling force is usually 5 to 70 kN / cm, preferably 10 to 60 kN / cm, more preferably 15 to 50 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 (c) of the process the slug is granulated.
- the granulation can be carried out by methods known in the art.
- the granulation is carried out with the device Comill ® U5 (Quadro Engineering, USA).
- the granulation conditions are selected so that the resulting particles (granules) have a volume average particle size ((D 50 ) value) of 50 to 800 microns, more preferably 100 to 750 microns, even more preferably 150 to 500 microns , in particular from 200 to 450 microns.
- D 50 volume average particle size
- the granulation conditions can be selected so that not more than 55% of the particles have a size of less than 200 microns or the average particle diameter (D50) is between 100 and 450 microns.
- the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.2 to 0.85 g / ml, more preferably 0.3 to 0.8 g / ml, especially 0.4 to 0.7 g / ml , exhibit.
- the Hausner factor is usually in the range of 1, 02 to 1, 3, more preferably from 1, 04 to 1, 20 and in particular from 1, 04 to 1, 15. In this case, "Hausner factor" is the ratio of tamped density understood to bulk density.
- 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 method is adapted such that a multiple compaction takes place, wherein the granulate resulting from step (c) is recycled one or more times for compaction (b).
- the granules from step (c) are preferably recycled 1 to 5 times, in particular 2 to 3 times.
- the granules resulting from step (c) can be processed into pharmaceutical dosage forms.
- the granules are filled, for example, in sachets or capsules.
- the invention therefore also capsules and Sachets containing a granulated pharmaceutical composition obtainable by the dry granulation process of the present invention.
- step (d) compression into tablets takes place.
- the compression can be done with tableting machines known in the art.
- the compression is preferably carried out in the absence of solvents.
- Suitable tableting machines are eccentric presses or concentric presses.
- a fats 102i (Fette GmbH, Germany) can be used.
- step (d) of the process pharmaceutical excipients may optionally be added to the granules of step (c).
- the amounts of excipients added in step (d) usually depend on the type of tablet to be prepared and on the amount of excipients already added in steps (a) or (b).
- step (e) of the process according to the invention the tablets from step (d) are film-coated.
- the usual in the prior art method for filming tablets can be used.
- macromolecular materials are used for the coating, for example modified celluloses, polymethacrylates, polyvinyl pyrrolidone, polyvinyl acetate phthalate, zein and / or shellac or natural gums, e.g. Carrageenan.
- HPMC in particular HPMC having a weight-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 2 to 100 .mu.m, in particular 5 to 50 microns.
- Another aspect of the present invention is a compacted intermediate containing retigabine.
- a further subject of the invention is therefore an intermediate obtainable by co-dry-drying of retigabine with an adhesion promoter.
- the intermediate according to the invention can be prepared by the steps (a) and (b) of the method according to the invention explained above.
- the compaction conditions for the preparation of the intermediate according to the invention are usually selected such that the intermediate according to the invention is in the form of a compactate (slug), the density of the intermediate being 0.8 to 1.3 g / cm 3 , preferably 0.9 to 1.20 g / cm 3 , in particular 1, 01 to 1, 15 g / cm 3 .
- the term "density” herein preferably refers to the "true density” (i.e., not the bulk density or tamped density).
- the true density can be determined with a gas pycnometer.
- the gas pycnometer is preferably a helium pycnometer, in particular the device AccuPyc 1340 helium pycnometer manufactured by Micromeritics, Germany is used.
- the type and amount of the adhesion promoter be chosen so that the resulting intermediate has a glass transition temperature (Tg) of more than 20 0 C, preferably> 30 0 C.
- the type and amount of the adhesion promoter be chosen so that the resulting intermediate is storage stable.
- “Storage-stable” means that in the intermediate according to the invention after 3 years of storage at 25 ° C. and 50% relative atmospheric humidity, the proportion of crystalline retigabine-based on the total amount of retigabine-is at most 60% by weight, preferably at most 30% by weight. %, more preferably at most 15 wt .-%, in particular at most 5 wt .-%, is.
- the intermediates according to the invention can be comminuted, for example granulated (as described above under step (c) of the process according to the invention).
- the intermediates according to the invention are usually in particulate form and have an average particle diameter (D 50 ) of from 1 to 750 ⁇ m, preferably from 1 to 350 ⁇ m, depending on the preparation process.
- the intermediate of the invention is usually used for the preparation of a pharmaceutical formulation.
- the intermediate of the invention is usually used for the preparation of a pharmaceutical formulation.
- single and multidose containers preferably sachets and embroidery Packs, filled.
- the invention therefore also single and multidose containers, preferably sachets and stick packs containing the granules of the invention.
- the intermediate according to the invention is preferably compressed into tablets as described above in step (d) of the method according to the invention.
- step (a) in the case of direct compression in step (a), a common grinding of retigabine and adhesion enhancer takes place.
- additional pharmaceutical excipients may be added.
- the milling conditions are usually selected to cover at least 30% of the surface area of the resulting retigabine particles with adhesion enhancer, more preferably at least 50% of the surface, more preferably at least 70% of the surface, especially at least 90% of the surface.
- Milling is generally carried out in conventional grinding equipment, for example in a ball mill, air jet mill, pin mill, classifier mill, cross beater mill, disc mill, mortar mill, rotor mill.
- the meal is usually 0.5 minutes to 1 hour, preferably 2 minutes to 50 minutes, more preferably 5 minutes to 30 minutes.
- step (d) a mixture is used, wherein the particle size of the active ingredient and excipients is coordinated.
- D50 average particle size
- further pharmaceutical auxiliaries can be used.
- auxiliaries used are disintegrants, release agents, emulsifiers, pseudo-emulsifiers, fillers, additives to improve the powder flowability, lubricants, wetting agents, gelling agents and / or lubricants.
- other auxiliaries can be used.
- disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water.
- Suitable disintegrants are e.g. organic disintegrants such as carrageenan, croscarmellose and crospovidone.
- alkaline disintegrants are meant disintegrating agents which when dissolved in water produce a pH of more than 7.0.
- inorganic alkaline disintegrants may be 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.
- the formulation according to the invention optionally contains fillers.
- Fillers are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small quantities of active ingredient (for example less than 70% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.
- Examples of preferred fillers are talc, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin, dextrose, hydrogenated vegetable oil, kaolin, sodium chloride, and / or potassium chloride.
- Fillers are usually used in the present case in a small amount, since a high active ingredient content is desired.
- the Fillers in an amount of 0 to 20 wt .-%, more preferably from 0 to 10 wt .-%, based on the total weight of the formulation can be used.
- An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ®.
- Additives for improving 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 in tableting on the one hand between the in the die bore moving up and down punches and the die wall and on the other hand between the tablet web and die wall exists.
- Suitable lubricants are e.g. Stearic acid, adipic acid, sodium stearyl fumarate and / or magnesium stearate.
- Lubricants are usually used in an amount of from 0.1 to 5% by weight, preferably from 0.5 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.
- the ratio of active ingredient to auxiliaries is preferably selected such that the formulations resulting from the process according to the invention (ie, for example, the tablets according to the invention) contain from 35 to 90% by weight, more preferably from 55 to 85% by weight, in particular from 60 to 80% by weight. % Retigabine and
- the amount of adhesion enhancer which was used in the process according to the invention or for the preparation of the intermediate according to the invention calculated as an adjuvant. That is, the amount of active ingredient refers to the amount of retigabine contained in the formulation.
- the formulations according to the invention ie the tablets according to the invention or the granules according to the invention, which consist of Step (c) of the method according to the invention results and can be filled in, for example, stick packs or sachets) both as an immediate release dosage form (immediate release or "IR”) and as a dosage form with modified release (modi fi ed release or "MR" for short). ) to serve.
- immediate release dosage form immediate release or "IR”
- MR modified release
- the pharmaceutical formulation of the invention contains 1 to 30 wt .-%, more preferably 3 to 15 wt .-%, in particular 5 to 12 wt .-% disintegrant, based on the total weight of the formulation.
- an MR formulation especially in the form of a peroral tablet, a relatively small amount of disintegrant is used.
- this preferred embodiment therefore, contains the inventive pharmaceutical formulation
- croscarmellose or crospovidone is preferred as disintegrants.
- crospovidone is preferred as disintegrants.
- alkaline disintegrants are preferred.
- the conventional retardation techniques can be used for the MR formulation.
- the abovementioned pharmaceutical excipients can be used in the two preferred embodiments (dry granulation and direct compression).
- the tableting conditions in both embodiments of the method according to the invention are furthermore preferably chosen such 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 method according to the invention is preferably carried out such that the tablet according to the invention contains retigabine in an amount of more than 200 mg to 1000 mg, more preferably from 250 mg to 900 mg, in particular 300 mg to 600 mg.
- the invention thus relates to tablets containing 300 mg, 400 mg, 450 mg, 600 mg or 900 mg of retigabine.
- the resulting tablets preferably have a hardness of from 50 to 300 N, particularly preferably from 80 to 250 N, in particular from 100 to 220 N. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8.
- the resulting tablets preferably have a friability of less than 3%, particularly preferably less than 2%, in particular less than 1%. The friability is calculated according to Ph.Eur. 6.0, section 2.9.7.
- the tablets according to the invention usually have a uniformity of content of 95 to 105%, preferably 98 to 102%, in particular 99 to 101% of the average content. (That is, all tablets have an active ingredient content between 95 and 105%, preferably between 98 and 102%, in particular between 99 and 101% of the average active ingredient content.)
- the "Content Unfi ormity" is according to Ph. Eur.6.0, Section 2.9. 6, determined.
- the release profile of the tablets according to the invention usually has a released content of at least 30%, preferably at least 60%, in particular at least 90%, in the case of an IR formulation according to the USP method after 10 minutes.
- the release profile of the tablets according to the invention usually has a released content of 10, preferably 20, in particular 30% after 60 minutes in the case of an MR formulation according to the USP method.
- the above information on hardness, friability, content uniformity and release profile preferably relate here to the unformed tablet for an IR formulation.
- the release profile refers to the total formulation.
- the tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably film-coated). It may also be Disperstabletten. "Disperstablette” is here understood to mean a tablet for the production of an aqueous suspension for oral use.
- step (e) In the case of tablets which are swallowed whole, it is preferred, as explained above under step (e), that they be coated with a film layer.
- the above-mentioned ratios of active ingredient to excipient relate to the unpainted tablet.
- auxiliaries are usually used:
- flavoring agent is usually 0.1 to 10% by weight, preferably 2 to 4% by weight, based on the total weight of the formulation.
- flavorings is to be understood as defined in Council Directive 88/388 / EEC of 22 June 1988.
- other flavors such as spearmint, lemon or the like can be used.
- the intermediate is added to a sweetener, the sweetening agent preferably being used in an amount of from 0.1 to 4, more preferably from 1 to 3,% by weight, based on the total weight of the formulation.
- a sweetener preferably being used in an amount of from 0.1 to 4, more preferably from 1 to 3,% by weight, based on the total weight of the formulation.
- sachharin sodium e.g. in a concentration of 1 -3 wt.
- Aspartame in a concentration of 2 to 4 wt .-% are used.
- other common sweeteners can be used.
- the sachet formulation can also contain an effervescent body consisting of a mixture of citric acid and sodium bicarbonate, for example in the ratio 1: 2, and preferably 5 to 15% by weight, e.g. about 10 wt .-%, of the total amount.
- an effervescent body consisting of a mixture of citric acid and sodium bicarbonate, for example in the ratio 1: 2, and preferably 5 to 15% by weight, e.g. about 10 wt .-%, of the total amount.
- the subject of the invention is not only the method according to the invention, but also the tablets produced by this method. It has also been found that the tablets produced by this process preferably have a bimodal pore size distribution.
- the invention thus relates to tablets containing retigabine or a pharmaceutically acceptable salt thereof and adhesion enhancers and optionally pharmaceutically acceptable auxiliaries, wherein the tablets have a bimodal pore size distribution.
- This tablet according to the invention is produced when the granules from method step (c) are compressed.
- This compact consists of solid and pores.
- the pore structure can be further characterized by determining the pore size distribution.
- the pore size distribution was determined by mercury porosimetry. Mercury porosimetry measurements were carried out with the "Poresizer” porosimeter from Micromeritics, Norcross, USA. The pore sizes were calculated assuming a surface tension of mercury of 485 raN / m. From the cumulative pore volume, the pore size distribution was calculated as the sum distribution or proportion of the pore fractions in percent. The average pore diameter (4V / A) was calculated from the total specific Mercury intrusion volume (VgCS 1n ,) and the total pore area (Ages, * ,,.) Determined according to the following equation.
- bimodal pore size distribution is meant that the pore size distribution has two maxima. The two maxima are not necessarily separated by a minimum, but a head-and-shoulders formation is also considered bimodal in the sense of the invention.
- the formulations according to the invention are preferably used for the treatment of epilepsy and neuropathic pain.
- the invention thus relates to the use of dry-compacted retigabine for the treatment of epilepsy and neuropathic pain.
- retigabine is preferably used as retigabine dihydrochloride, the amount given being based on the amount of free base retigabine. That is, the statement 300 mg retigabine corresponds to about 372 mg retigabine dihydrochloride.
- Retigabine was premixed together with lactose in the tumbler mixer (Turbula) for 10 min. Subsequently, all other constituents were supplemented except for magnesium stearate and mixed for a further 30 minutes. After addition of magnesium stearate was remixed again for 2 min. The final mixture was on a rotary press with punches, which have the following properties: 10 mm round blconvex, pressed. The tablets had a hardness of about 1 10 N. Subsequently, the tablets could optionally be coated with a coating.
- Example Ia was repeated using 10 mg of magnesium stearate.
- Example 2a Dry Granulation of Retigabine and Compression to Tablets (IR)
- Retigabine has been pre-mixed together with povidone VA64, sodium bicarbonate and 50 wt .-% of Prosolv ®, magnesium stearate and silicon dioxide and then compacted (rolling force 30 kN / cm, slit width 2 mm), The resulting intermediate was purified by a sieve mill (1, 0 mm) granulated and compressed with the remaining Prosolv ® , magnesium stearate and silica to tablets.
- the resulting tablets could be film-coated (as described under Example Ia).
- Example 2a was repeated using 8 mg of magnesium stearate.
- Magnesium stearate 4 mg Retigabine was mixed with hydroxypropylmethylcellulose and Prosolv ® (Turbula Tlob, 30 minutes).
- Gurggelnstearät and talc were added to the mixture and all mixed together for another 3 minutes.
- the finished mixture is pressed into tablets.
- an eccentric press Korsch EKO is used with a pressing force of 10 kN.
- Example 3a was repeated using 8 mg of magnesium stearate.
- Example 4a Direct compression of retigabine (IR)
- the active ingredient was mixed with the starch for 20 minutes in the tumbler (Turbula WOBO) and then the magnesium stearate was added.
- the finished mixture was mixed again for 3 minutes and then pressed on an eccentric press (Korsch, EKO).
- Example 4a was repeated, 10 mg of magnesium stearate was used.
- Example 5 Sachet containing dry granulated intermediate
- Retigabine was mixed with sodium bicarbonate, microcrystalline cellulose, polyvinylpyrrolidone, citric acid and peppermint flavor and then compacted (40 kN, 2 mm). The compact was sieved through a sieve of grain size 0.8 mm with concomitant comminution (Comill ® U5). The resulting granules were filled into sachets.
- the ingredients except the lubricant were dry mixed (Turbula W 10B) and sieved (710 ⁇ n). The magnesium stearate was added and the final mixture was compressed to an effervescent tablet.
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Abstract
L'invention porte sur un procédé à sec de préparation de formes posologiques orales, en particulier de comprimés, contenant de la rétigabine et un renforçateur d'adhérence. L'invention porte en outre sur des intermédiaires compactés contenant de la rétigabine et un renforçateur d'adhérence. Enfin, l'invention porte sur des récipients monodoses et multidoses, de préférence des sachets et des bâtons, contenant l'intermédiaire selon l'invention.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102009013613A DE102009013613A1 (de) | 2009-03-17 | 2009-03-17 | Trockenverarbeitung von Retigabin |
PCT/EP2010/001690 WO2010105822A2 (fr) | 2009-03-17 | 2010-03-17 | Transformation à sec de rétigabine |
Publications (1)
Publication Number | Publication Date |
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EP2408424A2 true EP2408424A2 (fr) | 2012-01-25 |
Family
ID=42136030
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10711009A Withdrawn EP2408424A2 (fr) | 2009-03-17 | 2010-03-17 | Transformation à sec de rétigabine |
Country Status (6)
Country | Link |
---|---|
US (1) | US20120122973A1 (fr) |
EP (1) | EP2408424A2 (fr) |
CA (1) | CA2760040A1 (fr) |
DE (2) | DE102009013613A1 (fr) |
EA (1) | EA201171140A1 (fr) |
WO (1) | WO2010105822A2 (fr) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2525788A2 (fr) * | 2010-01-20 | 2012-11-28 | Glaxo Group Limited | Nouvelle composition du retigabine |
EA201390464A1 (ru) | 2010-09-28 | 2013-08-30 | Рациофарм Гмбх | Способ сухой обработки атазанавира |
US9320725B2 (en) | 2012-05-18 | 2016-04-26 | Gruenenthal Gmbh | Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and a gabapentinoid |
US9345689B2 (en) | 2012-05-18 | 2016-05-24 | Gruenenthal Gmbh | Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N, N-dimethyl-4-phenyl-4,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and an anticonvulsant |
US20130310385A1 (en) | 2012-05-18 | 2013-11-21 | Gruenenthal Gmbh | Pharmaceutical Composition Comprising (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine and Antidepressants |
CN114760990A (zh) * | 2019-12-02 | 2022-07-15 | 泽农医药公司 | 钾通道开放剂埃佐加滨的儿科即释制剂 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4200259A1 (de) | 1992-01-08 | 1993-07-15 | Asta Medica Ag | Neue 1,2,4-triaminobenzol-derivate und verfahren zu deren herstellung |
DE19701694A1 (de) | 1997-01-20 | 1998-07-23 | Asta Medica Ag | Neue Modifikationen des 2-Amino-4-(4-fluorbenzylamino)-l-ethoxycarbonyl-aminobenzen sowie Verfahren zu ihrer Herstellung |
US6117900A (en) | 1999-09-27 | 2000-09-12 | Asta Medica Aktiengesellschaft | Use of retigabine for the treatment of neuropathic pain |
SK13252002A3 (sk) | 2000-03-08 | 2003-07-01 | Awd. Pharma Gmbh & Co. Kg | Farmaceutické prípravky |
AR033095A1 (es) | 2001-04-04 | 2003-12-03 | Wyeth Corp | Metodos para el tratamiento de motilidad gastrica hiperactiva |
DE20321314U1 (de) * | 2002-05-31 | 2006-10-12 | Desitin Arzneimittel Gmbh | Pharmazeutische Zusammensetzung mit verzögerter Wirkstofffreisetzung |
KR101405545B1 (ko) * | 2005-11-28 | 2014-07-03 | 마리누스 파마슈티컬스 | ganaxolone 제형, 이의 제조방법 및 용도 |
WO2010009433A1 (fr) * | 2008-07-18 | 2010-01-21 | Valeant Pharmaceuticals International | Formulation à libération modifiée et procédés d'utilisation |
DE102009013612A1 (de) * | 2009-03-17 | 2010-09-23 | Ratiopharm Gmbh | Retigabin-Tabletten, bevorzugt mit modifizierter Freisetzung |
DE102009013611A1 (de) * | 2009-03-17 | 2010-09-23 | Ratiopharm Gmbh | Festes Retigabin in nicht-kristalliner Form |
-
2009
- 2009-03-17 DE DE102009013613A patent/DE102009013613A1/de not_active Withdrawn
-
2010
- 2010-03-17 EA EA201171140A patent/EA201171140A1/ru unknown
- 2010-03-17 EP EP10711009A patent/EP2408424A2/fr not_active Withdrawn
- 2010-03-17 WO PCT/EP2010/001690 patent/WO2010105822A2/fr active Application Filing
- 2010-03-17 DE DE202010017303U patent/DE202010017303U1/de not_active Expired - Lifetime
- 2010-03-17 US US13/257,056 patent/US20120122973A1/en not_active Abandoned
- 2010-03-17 CA CA2760040A patent/CA2760040A1/fr not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO2010105822A2 * |
Also Published As
Publication number | Publication date |
---|---|
US20120122973A1 (en) | 2012-05-17 |
EA201171140A1 (ru) | 2012-04-30 |
WO2010105822A2 (fr) | 2010-09-23 |
DE102009013613A1 (de) | 2010-09-23 |
WO2010105822A3 (fr) | 2011-04-21 |
CA2760040A1 (fr) | 2010-09-23 |
DE202010017303U1 (de) | 2011-12-13 |
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