EP1572162A1 - Verfahren zur herstellung von überzogenen arzneiformen und nahrungsergänzungsmitteln mit konzentrationsgradienten im überzug - Google Patents
Verfahren zur herstellung von überzogenen arzneiformen und nahrungsergänzungsmitteln mit konzentrationsgradienten im überzugInfo
- Publication number
- EP1572162A1 EP1572162A1 EP03772233A EP03772233A EP1572162A1 EP 1572162 A1 EP1572162 A1 EP 1572162A1 EP 03772233 A EP03772233 A EP 03772233A EP 03772233 A EP03772233 A EP 03772233A EP 1572162 A1 EP1572162 A1 EP 1572162A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- active ingredient
- meth
- substance
- coating agent
- spray
- 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- Withdrawn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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- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BYNVYIUJKRRNNC-UHFFFAOYSA-N docosanoic acid;propane-1,2,3-triol Chemical class OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(O)=O BYNVYIUJKRRNNC-UHFFFAOYSA-N 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000001034 iron oxide pigment Substances 0.000 description 1
- 230000001788 irregular Effects 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000009481 moist granulation Methods 0.000 description 1
- 239000006082 mold release agent Substances 0.000 description 1
- 239000012170 montan wax Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 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
- 150000007530 organic bases Chemical class 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000019809 paraffin wax Nutrition 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
- A23L33/24—Cellulose or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
- A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
- A23L33/25—Synthetic polymers, e.g. vinylic or acrylic polymers
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
- A23L5/40—Colouring or decolouring of foods
- A23L5/42—Addition of dyes or pigments, e.g. in combination with optical brighteners
-
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Definitions
- the invention relates to a process for the production of coated pharmaceutical forms and food supplements with concentration gradients in the coating
- Abletshauser CB in "Film coating of pellets with insoluble polymers obtained in situ crosslinking in fluidized bed” in Journal of Controlled Release 27 (1993), pp. 149-156, describes a process in which a film-forming polymer, sodium alginate, in aqueous solution and a crosslinking agent, for example a CaCl 2 solution or a (meth) acrylate copolymer with tertiary amino group residues (EUDRAGIT E®), are simultaneously sprayed onto pellets containing active ingredient from two separate spray nozzles.
- a crosslinking agent for example a CaCl 2 solution or a (meth) acrylate copolymer with tertiary amino group residues (EUDRAGIT E®)
- WO 00/05307 describes a process for the preparation of a coating and binder for oral or dermal pharmaceutical forms consisting of (a) 35-98% by weight of a copolymer consisting of free-radically polymerized C1 to C4 esters of acrylic or methacrylic acid and further (meth) acrylate monomers which have functional tertiary ammonium groups and (b) 1-50% by weight of a plasticizer and 1-15% by weight of an emulsifier with an HLB value of at least 14, components (a), (b) and (c) with or without addition of water and optionally with the addition of an active pharmaceutical ingredient and other customary additives, and the coating and binder are produced by melting, pouring, spreading or spraying, the copolymer (a) being introduced in powder form with an average particle size of 1-40 ⁇ m.
- Pigments can be incorporated as additives. As a rule, aluminum or iron oxide pigments are dispersed. Usual amounts for pigments are between 20 and 60% by weight, based on the polymer mixture. Because of the high pigment binding capacity, however, quantities of up to 100% by weight can also be processed.
- pigments are added in a concentrated form as the final layer. It is applied as a powder or from an aqueous suspension with a solids content of 5 to 30% by spraying. The amount required is lower than for incorporation into the polymer layer and is 0.1 - 2% based on the weight of the dosage form.
- EP-A 0 848 960 describes an adhesive and binder for dermal or transdermal therapy systems consisting of (a1) 55-99.9% by weight of a (meth) acrylate copolymer of structural and functional monomers, the functional monomers being tertiary or quaternary amino groups have (a2) 0.1-45% by weight of an acid group-containing acrylate or (meth) acrylate polymer or copolymer and (b) 25-80% by weight, based on the sum of (a1) and (a2) , a plasticizer.
- a transdermal therapy system can be produced by a pharmaceutical Active ingredient is incorporated by coating or by spraying or brushing with solutions, dispersions, suspensions or melts an adhesive and binder and then drying or cooling
- the components may be incompatible with one another or incompatible with the active ingredient contained in the pharmaceutical form.
- film-forming coating agent and the further substance are initially separated from one another as liquid, sprayable individual portions in the form of a solution or dispersion and
- the quantities of the individual portions are varied during the spraying process such that the coating agent and the further substance are present in a concentration gradient from the inside to the outside, based on the dried film coating.
- the invention relates to a method for producing pharmaceutical forms or parts of pharmaceutical forms or nutritional supplements or parts thereof
- film-forming coating agent and the further substance are initially separated from one another as liquid, sprayable individual portions in the form of a solution or dispersion and
- the amounts of the individual portions during the spraying process are varied so that the coating agent and the other substance based on the dried film coating from the inside to the outside in a concentration gradient.
- film-forming coating compositions are understood to mean all pharmaceutically customary polymeric coating compositions, such as, for. B. cellulose derivatives or (meth) acrylate copolymers.
- the film-forming coating agent can apart from the other substance with which the gradient mixture is generated, other pharmaceutical excipients, such as. B. plasticizers and / or a pharmaceutical ingredient.
- the film-forming coating agent can be in the form of an organic solution or preferably in the form of a dispersion.
- the film-forming coating agent is preferably a (meth) acrylate copolymer.
- the (meth) acrylate copolymer consists of 40 to 100, preferably 45 to 99, in particular 85 to 95% by weight of free-radically polymerized C to C alkyl esters of acrylic or methacrylic acid and can be 0 to 60, preferably 1 contain up to 55, in particular 5 to 15 wt .-% (meth) acrylate monomers with an anionic group in the alkyl radical.
- the proportions mentioned add up to 100% by weight.
- small amounts in the range from 0 to 10, z. B. 1 to 5 wt .-% of other vinyl copolymerizable monomers, such as. B. hydroxyethyl methacrylate or hydroxyethyl acrylate may be included.
- C to C alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
- a (meth) acrylate monomer with an anionic group in the alkyl group can e.g. As acrylic acid, but preferably methacrylic acid.
- Anionic (meth) acrylate copolymers of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate are also suitable.
- EUDRAGIT® L is a copolymer of 50% by weight methyl methacrylate and 50% by weight methacrylic acid.
- EUDRAGIT® L 30D is a dispersion containing 30% by weight EUDRAGIT® L.
- EUDRAGIT® L100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid.
- EUDRAGIT® L 30-55 is a dispersion containing 30% by weight EUDRAGIT® L 100-55.
- Anionic (meth) acrylate copolymers of 20 to 40% by weight methacrylic acid and 80 to 60% by weight methyl methacrylate are also suitable.
- (Meth) acrylate copolymers consisting of 10 to 30% by weight, methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid (type EUDRAGIT® FS) are particularly suitable.
- EUDRAGIT® FS is a copolymer of 25% by weight, methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid.
- EUDRAGIT® FS 30 D is a dispersion containing 30% by weight EUDRAGIT® FS.
- EUDRAGIT® NE is a copolymer of 30% by weight ethyl acrylate and 70% by weight methyl methacrylate.
- copolymers are obtained in a manner known per se by radical substance, solution, bead or emulsion polymerization. Before processing, they have to be brought into the particle size range according to the invention by suitable grinding, drying or spraying processes. This can be done by simply breaking extruded and cooled granulate strands or by hot cutting.
- powders can be particularly advantageous when mixed with other powders or liquids.
- Suitable devices for the production of the powder are known to the person skilled in the art, e.g. B. air jet mills, pin mills, fan mills. If necessary, appropriate screening steps can be included.
- a suitable mill for large industrial quantities is, for example, a counter jet mill (Multi No. 4200), which is operated at approx. 6 bar overpressure.
- anionic (meth) acrylate copolymers composed of 20 to 34% by weight of methacrylic acid and / or acrylic acid, 20 to 69% by weight of methyl acrylate and 0 to 40% by weight of ethyl acrylate and optionally 0 to 10% by weight of others vinyl copolymerizable monomer, with the proviso that the glass transition temperature of the copolymer according to ISO 11357-2, point 3.3.3, is at most 60 ° C. (Type EUDRAGIT® with medium content of methacrylic acid).
- the copolymer is composed in particular of radical-polymerized units of
- 0 to 40 preferably 5 to 35, particularly preferably 15 to 35% by weight of ethyl acrylate, with the proviso that the glass transition temperature of the copolymer (without plasticizer additive) according to ISO 11357-2, item 3.3.3, at most 60, preferably 40 to 60, particularly preferably 45 to 55 ° C.
- the (meth) acylate copolymer preferably consists essentially or exclusively of the monomers methacrylic acid, methyl acrylate and ethyl acrylate in the proportions given above.
- the proportions mentioned add up to 100% by weight.
- By weight of other vinyl copolymerizable monomers such as, for.
- methyl methacrylate, butyl methacrylate, butyl acrylate or hydroxyethyl methacrylate may be included.
- the (meth) acrylate copolymer consists of 30 to 80% by weight of radically polymerized C to C 4 alkyl esters of acrylic or methacrylic acid and 70 to 20% by weight of (meth) acrylate monomers with a tertiary amino group in the Alkyl group together.
- Suitable monomers with functional tertiary amino groups are listed in US Pat. No. 4,705,695, column 3, line 64 to column 4, line 13. Particular mention should be made of dimethylaminoethyl acrylate, 2-dimethylaminopropyl acrylate, dimethylaminopropyl methacrylate, dimethylaminobenzyl acrylate, dimethylaminobenzyl methacrylate, (3-dimethylamino-2,2-dimethyl) propyl acrylate, dimethylamino-2,2-dimethyl) propyl methacrylate, (3-diethylamino) propyl acrylate and diethylamino-2,2-dimethyl) propyl methacrylate. Dimethylaminoethyl methacrylate is particularly preferred.
- the content of the monomers with tertiary ammonium groups in the copolymer can advantageously be between 20 and 70% by weight, preferably between 40 and 60% by weight.
- the proportion of the C to C 4 alkyl esters of acrylic or methacrylic acid is 70-30% by weight. Mention should be made of methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.
- a suitable (meth) acrylate copolymer with tertiary amino groups can e.g. B. from 20-30% by weight methyl methacrylate, 20-30% by weight butyl methacrylate and 60-40% by weight dimethylaminoethyl methacrylate.
- a specifically suitable commercial (meth) acrylate copolymer with tertiary amino groups is e.g. B. from 25 wt .-% methyl methacrylate, 25 wt .-% butyl methacrylate and 50 wt .-% dimethylaminoethyl methacrylate (EUDRAGIT® E100).
- the (meth) acrylate copolymer can be obtained in a manner known per se by free-radical substance, solution, bead or emulsion polymerization. Before processing, it can be brought into suitable particle size ranges by suitable grinding, drying or spraying processes.
- Suitable devices for the production of the powder are known to the person skilled in the art, e.g. B. air jet mills, pin mills, fan mills. If necessary, appropriate screening steps can be included.
- a suitable mill for large industrial quantities is, for example, a counter jet mill (Multi No. 4200), which is operated at approx. 6 bar overpressure.
- the average particle size of the powder can be determined as follows:
- Another well-suited measuring method is laser diffraction to determine the grain size distribution.
- Commercial devices allow measurement in air (Malvern S3.01 particle sizer) or preferably in liquid media (LOT, Galai CIS 1). Prerequisite for the measurement in Liquids that the polymer does not dissolve in them or change the particles in another way during the measurement.
- a suitable medium is e.g. B. a highly diluted (about 0.02%) aqueous polysorbate 80 solution.
- At least 70, preferably 90% of the particles based on the mass (mass distribution) can preferably be in the size range of 1-40 ⁇ m.
- (meth) acrylate copolymers with an average particle diameter in the range between 1 and 40, preferably between 5 and 35, in particular between 10 and 20 ⁇ m. (Type EUDRAGIT® EPO).
- Corresponding (meth) acrylate copolymers are e.g. B. from EP-A 181 515 or from DE-PS 1 617 751 known. They are polymers that are soluble or swellable regardless of the pH value and are suitable for drug coatings. Bulk polymerization in the presence of a free radical initiator dissolved in the monomer mixture is a possible preparation process.
- the polymer can also be prepared by means of solution or precipitation polymerization. The polymer can be obtained in this way in the form of a fine powder, which in the case of substance polymerization by grinding, in solution and precipitation polymerization, for. B. can be reached by spray drying.
- the (meth) acrylate copolymer consists of 85 to 98% by weight of free-radically polymerized C1 to C4 alkyl esters of acrylic or methacrylic acid and 15 to 2 wt .-% (meth) acrylate monomers together with a quaternary ammonium group in the alkyl group.
- Preferred C1 to C4 alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.
- 2-Trimethylammoniumethyl methacrylate chloride is particularly preferred as the (meth) acrylate monomer with quaternary ammonium groups.
- a corresponding copolymer, for. B. from 50 - 70 wt .-% methyl methacrylate, 20 - 40 wt .-% ethyl acrylate and 7 - 2 wt .-% 2-trimethylammonium ethyl methacrylate chloride.
- a specifically suitable copolymer contains 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RS).
- Another suitable (meth) acrylate copolymer can e.g. B. from 85 to less than 93 wt .-% C1- to C4-alkyl esters of acrylic or methacrylic acid and more than 7 to 15 wt .-% (meth) acrylate monomers with a quaternary ammonium group in the alkyl radical.
- Such (meth) acrylate monomers are commercially available and have long been used for retarding coatings.
- a specifically suitable copolymer contains e.g. B. 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RL).
- the other substance e.g. B. 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RL).
- EUDRAGIT® RL 2-trimethylammonium ethyl methacrylate chloride
- the further substance in the sense of the invention is a substance which is in some way incompatible with the film-forming coating agent, the active ingredient contained in the dosage form and / or with the environment of the dosage form.
- the other substance can e.g. B. an acid, a base, a plasticizer, a release agent, a pigment, a stabilizer, an antioxidant, another film-forming coating agent or a pharmaceutical agent or a mixture thereof.
- the other substance is in the form of a solution or dispersion.
- An acid-sensitive active ingredient is incompatible with (meth) acrylate copolymer containing anionic groups, but is said to have a polymer coating of this type.
- the anionic groups cause a relatively low pH in the dispersion, for. B. from 2.5 to 3.0. This already causes the active ingredient to become chemically unstable. This effect can be prevented by neutralizing the acidic groups. However, a neutralization necessary to raise the pH abolishes the required gastric juice resistance of the dosage form.
- the principle according to the invention stabilizes the active ingredient and at the same time achieves the desired gastric juice resistance with only one coating layer. This is a significant simplification.
- a substrate which contains an acid-sensitive active ingredient can be coated with a gradient composed of a coating agent which is (meth) acrylate copolymer and contains anionic groups which are completely or partially neutralized.
- a further substance used is a (meth) acrylate copolymer which contains anionic groups and which is not neutralized or is neutralized to a lesser extent than the former, the concentration of the further substance increasing from the inside to the outside.
- a substrate which contains an acid-sensitive active ingredient can also be coated with a gradient composed of a coating agent, the (meth) acrylate copolymer containing anionic groups and a base.
- the base or the aqueous solution of the base is used as a further substance, the concentration of the base decreasing from the inside to the outside.
- Typical bases are aqueous solutions of inorganic bases such as e.g. B. ammonia, alkali or alkaline earth metal hydroxides, such as NaOH or KOH, or organic bases such as. B. Triethanolamine.
- the anionic groups are neutralized in the immediate vicinity of the acid-sensitive active ingredient, so that the active ingredient is not adversely affected.
- the anionic (meth) acrylate copolymer is increasingly in the non-neutralized state and can, for. B. develop an enteric effect without a harmful interaction with the active substance takes place.
- the acid sensitive active ingredient can e.g. B. a protein, a peptide or a proton pump blocker, e.g. B. Omeprazole, Esomeprazole, Lanzoprazole, Rabeprazole, Pantoprazole.
- An alkali-sensitive active ingredient is incompatible with (meth) acrylate copolymer containing cationic groups, but is said to have a polymer coating of this type.
- the cationic groups cause a relatively high pH in the dispersion, for. B. from 8.0 to 9.0. This already causes the active ingredient to become chemically unstable. This effect can be prevented by neutralizing the basic groups. However, a neutralization necessary to lower the pH changes the desired pH-dependent release characteristic of the pharmaceutical form.
- the principle according to the invention stabilizes the active substance and at the same time achieves the desired pH-dependent release characteristic with only one coating layer. This is a significant simplification.
- a substrate which contains an alkali-sensitive active ingredient can be coated with a gradient of a coating agent, the (meth) acrylate copolymer containing cationic groups, which are completely or partially neutralized.
- a (meth) acrylate copolymer containing cationic groups is used which is not neutralized or is neutralized less than or less than the former, the concentration of the further substance increasing from the inside out.
- a substrate which contains an alkali-sensitive active ingredient can also be coated with a gradient consisting of a coating agent which comprises a (meth) acrylate copolymer containing cationic groups and an acid.
- the acid or the aqueous solution of the acid is used as a further substance, the concentration of the acid decreasing from the inside to the outside.
- Typical acids are aqueous solutions of inorganic acids such as HCL, H 2 SO 4 , phosphoric acids, organic acids such as. B. acetic acid, lactic acid, citric acid, malic acid, succinic acid etc.
- the cationic groups in the immediate vicinity of the alkali-sensitive active substance are neutralized so that the active substance is not adversely affected.
- the cationic (meth) acrylate copolymer is increasingly in the non-neutralized state and can, for. B. contribute to a rapid release of the active ingredient in the stomach without causing a harmful interaction with the active ingredient.
- the alkali sensitive active ingredient can e.g. B may be an analgesic, an antihistamine, a protein, or a peptide.
- the alkali sensitive active ingredient can e.g. B. acetylsalicylic acid, ranitidine or famotidine or their salt or a stereoisomer thereof.
- An active ingredient that is sensitive to a pigment should be provided with a polymer coating colored with this pigment.
- a substrate which contains a pigment-sensitive active ingredient is coated with a gradient composed of a (meth) acrylate copolymer which contains no or only uncritical amounts of a pigment for the active ingredient.
- a pigment is used in an amount harmful to the active ingredient, which may optionally also be in a mixture with a (meth) acrylate copolymer, the concentration of the pigment increasing from the inside to the outside without any harmful interaction with the Active ingredient takes place.
- the cationic groups in the immediate vicinity of the alkali-sensitive active substance are neutralized so that the active substance is not adversely affected.
- the cationic (meth) acrylate copolymer is increasingly in the non-neutralized state and can, for. B. contribute to a rapid release of the active ingredient in the stomach.
- the pigment-sensitive active ingredient can e.g. B. acetylsalicylic acid or ascorbic acid.
- the substrates for pharmaceutical applications can e.g. B. active ingredient crystals, active ingredient cores, cores without active ingredient, granules, tablets, pellets or capsules. These can be of regular or irregular shape.
- the size of granules, pellets or crystals is between 0.01 and 2.5 mm, that of tablets between 2.5 and 30.0 mm.
- Capsule consist e.g. B. from gelatin, starch or cellulose derivatives.
- the substrates can contain a biologically active substance (active ingredient) up to 95% and further pharmaceutical auxiliaries up to 99.9% by weight.
- Usual manufacturing processes are direct pressing, pressing of dry, moist or sinter granules, extrusion and subsequent rounding, moist or dry granulation or direct pelleting (e.g. on plates) or by binding powders (powder layering) to active substance-free balls (nonpareilles) or active substance-containing ones particles.
- binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegrators, lubricants, disintegrants, (meth) acrylates, starch and their derivatives, sugar solubilizers or others.
- Those with two or more two-substance nozzles or one or more three-substance nozzles can be used as the spray device.
- one of the nozzle openings for compressed air is used to atomize the simultaneously sprayed liquid.
- the further or the two further spray nozzles serve to eject the respective film-forming coating agent.
- To execute the The process therefore requires either at least two two-component nozzles, one spraying the first film-forming coating agent and the liquid with the other substance, or a three-component nozzle spraying both at the same time.
- the flow rates of the sprayed liquids can be adjusted independently of one another by setting parameters such as. B. influence the pump performance or the spray pressure and / or the air flow rates.
- the settings of the spray devices can be made manually during the spraying process.
- spray gun Pilot SIL XII two-substance nozzle; manufacturer: Walther, Wuppertal, Germany
- model “Concentric Dual-Feed Nozzle” three-substance nozzle, manufacturer: ShinEtsu, Japan
- model 946-S15 three-substance nozzle, Manufacturer: Düsen Schlick GmbH, D-96253 Untersiemau, Germany
- the spray application is carried out by means of one or more spray devices which, individually or together, have at least two separate nozzles for liquids and overlap their spray jets.
- the film-forming coating agent and sprayable form of the further substance are sprayed in such a way that the individual portions mix during the spraying process, the mixture hits the substrate and then after Evaporation of the liquid forms a continuous film coating, whereby the dosage form or the component of a dosage form is obtained,
- the amounts of the individual portions are varied during the spraying process in such a way that the coating agent and the further substance, based on the dried film coating, are present from the inside out in a concentration gradient. Since it is not absolutely necessary for the gradient to extend over the entire layer thickness of the coating.
- the simultaneous spraying is preferably carried out at a respective spray pressure in the range from 0.6 to 2.0, preferably from 0.8 to 1.5, bar.
- the spray application can e.g. B. in a drum coater, a coating pan, a fluidized bed device or a spray classifier.
- the spray application can be carried out by means of hand-operated spray devices. However, better and more reproducible results are usually achieved by means of permanently installed spray devices, so that these are preferred.
- the gradient can e.g. B. be linear and extend over the entire layer thickness.
- the concentration of the film-forming coating agent rises constantly, the concentration of the further substance decreases constantly or vice versa.
- the gradient can be linear, but only over part of the layer thickness z. B. extend 10 to 90% of the layer thickness, the gradient being in the inner region of the layer, in the central region of the layer or in the outer region of the layer. This is achieved by spraying the additional substance only temporarily in increasing or decreasing amounts, while the film-forming coating agent is sprayed during the entire spraying process.
- the further substance is a further film-forming coating agent, this can at times be sprayed alone at the beginning, at the end of the spraying process or in the middle of the spraying process.
- the gradient can e.g. B. not be linear.
- the concentration of the film-forming coating agent increases, for. B. exponentially or with another function, the concentration of the further substance decreases exponentially or with another function or vice versa.
- the gradient can e.g. B. be carried out in stages.
- the concentration of the film-forming coating agent increases gradually, that
- the variation of the sprayed quantities of the individual portions can, for. B. can be achieved by spraying a single portion in a constant amount, while the other single portion are sprayed over time in increasing amounts or in decreasing amounts. Likewise, e.g., a single portion can also be sprayed in increasing amounts, while a decreasing amount is sprayed from the other single portion. It is obvious to the person skilled in the art that the gradient types mentioned are only given by way of example and can be combined or modified in a variety of ways.
- Drum coaters, coating pans, fluidized bed devices or spray classifiers, containing as the spray device one or more, in particular permanently installed, three-substance nozzles are particularly preferred for carrying out the method.
- Coated pharmaceutical forms or parts of pharmaceutical forms or food supplements or parts thereof can be produced or obtained by means of the method according to the invention.
- the sprayed individual portions are mixed with one another in fractions of a second during the spray application and, due to the practically simultaneous evaporation of the water, form a polymer matrix on the surface of the substrates.
- the molecular matrix structure obtained is therefore likely to be different from a matrix structure which is formed when both film-forming coating agents are already contained in a polymer dispersion before spraying. Despite this difference, the quality of the coating, e.g. B. gloss or uniformity, no impairments compared to conventional methods found.
- the film-forming coating agent is preferably in the form of sprayable dispersions.
- the dispersions can e.g. B one Solids content of 10 to 60, preferably 20 to 40 wt .-% (meth) acrylate copolymer included.
- the (meth) acrylate copolymers are finely distributed in water in the form of particles with particle sizes in the range of, for. B. 5 nm - 30 microns before.
- the dispersions are stable on their own. When water is removed by drying after spraying, the particles combine and give continuous (meth) acrylate copolymer coatings on the respective substrate.
- Plasticizers generally have a molecular weight between 100 and 20,000 and contain one or more hydrophilic groups in the molecule, e.g. B. hydroxyl, ester or amino groups. Citrates, phthalates, sebacates, castor oil are suitable. Examples of suitable plasticizers are alkyl citrate, propylene glycol, glycerol ester, alkyl phthalate, alkyl sebacate, sucrose ester, sorbitan ester, diethyl sebacate, dibutyl sebacate and polyethylene glycols 4,000 to 20,000.
- Preferred plasticizers are tributyl citrate, triethyl citrate, acetyl triethyl citrate, dibutyl sebacate and diethyl sebacate. Usual amounts are between 1 and 20, preferably 2 to 10 wt .-%, based on the (meth) acrylate copolymer.
- emulsifiers are contained in the coating agents, they should be toxicologically safe. In principle, nonionic emulsifiers are preferred for pharmaceuticals. Suitable emulsifier classes are ethoxylated fatty acid esters or ethers, ethoxylated sorbitan ethers, ethoxylated alkylphenols, glycerol or sugar esters or wax derivatives
- Suitable emulsifiers are, for example, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene 25-cetyl stearate, polyoxyethylene (25) oxypropylene monostearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16-tert.-octylphenol, polyoxyethylene-20-methylene glycol, ethoxylated ethoxylate (1000) methylene glycol, ethoxylated ethoxylated ethoxylated ether , Polyoxyethylene sorbitol wool wax derivatives, polyoxyethylene (25) propylene glycol stearate, polyoxyethylene sorbitol ester polyoxyethylene 25 cetyl stearate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 16 tert.octylphenol and polyoxyethylene 20 cetyl ether.
- polyoxyethylene glycerol monolaurate polyoxyethylene
- Drying agents have the following properties: they have large specific surfaces, are chemically inert, are easy to pour and have fine particles. Because of these properties, they can advantageously be homogeneously distributed in melts and reduce the stickiness of polymers which contain highly polar comonomers as functional groups.
- drying agents are:
- Barium sulfate, carbon black and cellulose Barium sulfate, carbon black and cellulose.
- release agents are: Esters of fatty acids or fatty acid amides, aliphatic, long-chain carboxylic acids, fatty alcohols and their esters, montan or paraffin waxes and metal soaps, particularly mentionable are glycerol monostearate, stearyl alcohol, glycerol behenic acid esters, cetyl alcohol, palmitic acid, cannula wax, beeswax etc.
- auxiliaries B to name stabilizers, dyes, antioxidants, wetting agents, pigments, glossing agents etc. They primarily serve as processing aids and are intended to ensure a safe and reproducible manufacturing process and good long-term storage stability.
- Other pharmaceutically customary auxiliaries can e.g. B. in amounts of 0.001% by weight to 200% by weight, preferably 0.1 to 100, particularly preferably 5 to 50% by weight, based on the copolymer.
- Sodium hydroxide solution (NaOH) is added to the EUDRAGIT ® dispersion diluted with water and stirred until dissolved.
- the pH is about 5.5.
- the solids are dispersed in water using a homogenizer.
- Spray liquid 3 polymer dispersion
- Titanium dioxide 5.3 g
- HPMC hydroxypropyl cellulose
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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DE10260919A DE10260919A1 (de) | 2002-12-20 | 2002-12-20 | Verfahren zur Herstellung von überzogenen Arzneiformen und Nahrungsergänzungsmitteln mit Konzentrationsgradienten im Überzug |
DE10260919 | 2002-12-20 | ||
PCT/EP2003/011540 WO2004058225A1 (de) | 2002-12-20 | 2003-10-18 | Verfahren zur herstellung von überzogenen arzneiformen und nahrungsergänzungsmitteln mit konzentrationsgradienten im überzug |
Publications (1)
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EP1572162A1 true EP1572162A1 (de) | 2005-09-14 |
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EP03772233A Withdrawn EP1572162A1 (de) | 2002-12-20 | 2003-10-18 | Verfahren zur herstellung von überzogenen arzneiformen und nahrungsergänzungsmitteln mit konzentrationsgradienten im überzug |
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US (1) | US20050271778A1 (de) |
EP (1) | EP1572162A1 (de) |
JP (1) | JP2006515852A (de) |
KR (1) | KR20050088189A (de) |
AU (1) | AU2003280390A1 (de) |
BR (1) | BR0317481A (de) |
CA (1) | CA2509913A1 (de) |
DE (1) | DE10260919A1 (de) |
MX (1) | MXPA05006285A (de) |
PL (1) | PL375917A1 (de) |
WO (1) | WO2004058225A1 (de) |
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-
2003
- 2003-10-18 CA CA002509913A patent/CA2509913A1/en not_active Abandoned
- 2003-10-18 JP JP2004562534A patent/JP2006515852A/ja active Pending
- 2003-10-18 KR KR1020057011258A patent/KR20050088189A/ko not_active Application Discontinuation
- 2003-10-18 MX MXPA05006285A patent/MXPA05006285A/es unknown
- 2003-10-18 BR BR0317481-6A patent/BR0317481A/pt not_active IP Right Cessation
- 2003-10-18 PL PL03375917A patent/PL375917A1/xx unknown
- 2003-10-18 AU AU2003280390A patent/AU2003280390A1/en not_active Abandoned
- 2003-10-18 WO PCT/EP2003/011540 patent/WO2004058225A1/de active Application Filing
- 2003-10-18 EP EP03772233A patent/EP1572162A1/de not_active Withdrawn
- 2003-10-18 US US10/539,614 patent/US20050271778A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
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See references of WO2004058225A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2509913A1 (en) | 2004-07-15 |
BR0317481A (pt) | 2005-11-16 |
US20050271778A1 (en) | 2005-12-08 |
AU2003280390A1 (en) | 2004-07-22 |
KR20050088189A (ko) | 2005-09-02 |
JP2006515852A (ja) | 2006-06-08 |
PL375917A1 (en) | 2005-12-12 |
MXPA05006285A (es) | 2005-08-19 |
WO2004058225A1 (de) | 2004-07-15 |
DE10260919A1 (de) | 2004-07-01 |
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