EP1143936A2 - FORMULATIONS DE MEDICAMENTS CONTENANT UN OPIOIDE ET UN $g(a)-AGONISTE - Google Patents

FORMULATIONS DE MEDICAMENTS CONTENANT UN OPIOIDE ET UN $g(a)-AGONISTE

Info

Publication number
EP1143936A2
EP1143936A2 EP00901108A EP00901108A EP1143936A2 EP 1143936 A2 EP1143936 A2 EP 1143936A2 EP 00901108 A EP00901108 A EP 00901108A EP 00901108 A EP00901108 A EP 00901108A EP 1143936 A2 EP1143936 A2 EP 1143936A2
Authority
EP
European Patent Office
Prior art keywords
formulation according
pharmaceutical formulation
opioid
cellulose
release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00901108A
Other languages
German (de)
English (en)
Inventor
Johannes Bartholomäus
Jürgen Betzing
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1143936A2 publication Critical patent/EP1143936A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the invention relates to pharmaceutical formulations containing an opioid, an ⁇ -agonist and / or in each case its physiologically tolerable salt, from which at least one drug active ingredient is released with a delay.
  • opioids are used to relieve medium-weight and severe acute pain.
  • a major disadvantage of using opioids is the strong side effects associated with them. So side effects often occur on the gastrointestinal tract, such. B. constipation. Respiratory depression also arises as well as with repeated administration a dependency that can lead to abuse. Another disadvantage is the rapid development of tolerance.
  • opioids and ⁇ -agonists as monopreparations using various pharmaceutical formulations is known.
  • retard systems with opioids as described in WO95 / 14460 or EP-A-0 647 448, in which butyrates, ketobemidones, codeins and the like are also used, among others.
  • EP-B-0 271 193 discloses a retard system that uses only hydromorphone.
  • Retardation systems with ⁇ -agonists are disclosed in EP-A-0 805 677 or US 5,484,607. In both cases, only clonidine is used as the ⁇ -agonist.
  • the object of the present invention was therefore to provide a pharmaceutical formulation which is suitable for the treatment of severe to very severe pain, which does not have the typical side effects of the opioids, and which in particular delays the development of an opioid tolerance for a very long time or completely prevents it .
  • this object is achieved by the provision of pharmaceutical formulations which contain an opioid, an ⁇ -agonist and / or in each case its physiologically compatible salt, from which at least one active pharmaceutical ingredient is released with a delay.
  • the opioid is preferably released with a delay from the pharmaceutical formulation according to the invention.
  • the delayed release of the opioid preferably takes place over a period of 8 hours, especially during preferably 12 hours and very particularly preferably over 24 hours.
  • Both pharmaceutical active ingredients are also preferably released with a delay from the pharmaceutical formulation according to the invention.
  • the pharmaceutical formulation according to the invention preferably contains morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphene, buprenorphine, levomethadone, fentanyl, sufentanil, etorphin, pentazocin, tilidine, tramadol, levorphanol, methadone and piridone or piridone, dihydromine or dihydromine as opioid physiologically acceptable salt of the opioids mentioned.
  • the pharmaceutical formulation according to the invention particularly preferably contains morphine, tramadol and / or a physiologically tolerable salt thereof as opioids.
  • the pharmaceutical formulation according to the invention preferably contains, as ⁇ -agonists, clonidine, guanfacin, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, teryzoline, ST-91, medetomidine, dexmedetomidine, agmatine, UK 14,304-paronidine U-47,476A, DJ-741, ICI-106270, xylazine, talipexol (BHT-920), naphazoline, tizanidine and / or a physiologically acceptable salt of the said ⁇ -agonists.
  • ⁇ -agonists clonidine, guanfacin, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, tery
  • the pharmaceutical formulation according to the invention particularly preferably contains clonidine, guanfacin and / or a physiologically tolerable salt thereof as ⁇ -agonists.
  • the pharmaceutical formulation according to the invention very particularly preferably contains morphine and / or tramadol as the opioid and clonidine and / or its physiologically tolerable salt in each case as the ⁇ -agonist.
  • Acetates, tatrates, sulfates, hydrochlorides, phosphates and additionally salicylates and acetylsalicylates for the group of opioids are preferably used as physiologically compatible salts of the active ingredients.
  • the weight ratio of the opioid to the ⁇ -agonist in the pharmaceutical formulations according to the invention is preferably 200 to 1 to 10 to 1. In a particularly preferred embodiment, the weight ratio of the opioid to the ⁇ -agonist is 100 to 1 to 10 to 1.
  • the pharmaceutical formulation according to the invention is preferably administered orally.
  • Preferred oral medicament formulations are tablets, dragees or capsules, particularly preferably tablets, very particularly preferably multilayer tablets.
  • the pharmaceutical formulation according to the invention can also be present in multiparticulate form, such as, for. B. in the form of microtables, microcapsules, ion exchangers, granules, active ingredient crystals or pellets.
  • the pharmaceutical formulation according to the invention can preferably also be in the form of a pellet tablet, which particularly preferably disintegrates quickly.
  • the respective active ingredients can be retarded preferably by means of a retarding coating, fixation to an ion exchange resin, embedding in a retarding matrix or a combination thereof.
  • Suitable sustained release coatings preferably include water-insoluble waxes or polymers such as acrylic resins Poly (meth) acrylates, or water-insoluble celluloses, preferably ethyl cellulose. These materials are known from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang “Coated Pharmaceutical Formulas,ticianliche Verlagsgesellschaft mbH Stuttgart, 1988, page 69 ff. They are hereby introduced as a reference.
  • the sustained release coatings can also be non-retarding, preferably water-soluble polymers in amounts of up to 30% by weight, such as polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethyl cellulose or hydroxypropyl cellulose, and / or hydrophilic pore formers , such as sucrose, sodium chloride or mannitol and / or the known plasticizers.
  • Colestyramine is preferably used as the anionic ion exchange resin
  • polystyrene sulfonates are preferably used as the cationic ion exchange resins.
  • the active ingredients can also be present in a retarding matrix, preferably evenly distributed therein.
  • hydrophilic materials which are known to the person skilled in the art can be used as matrix materials.
  • Polymers particularly preferably cellulose ethers, cellulose esters and / or acrylic resins, are preferably used as the hydrophilic matrix materials.
  • Particularly preferred matrix materials are ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and / or their derivatives, such as their salts, amides or esters.
  • Matrix materials made of hydrophobic materials such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof, are likewise preferred.
  • Mono- or diglycerides of C12-C30 fatty acids and / or C12-C30 fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.
  • sustained-release pharmaceutical formulations can also contain both active ingredients in a delayed form.
  • the pharmaceutical formulation according to the invention can also contain at least one of the active ingredients in addition to its retarded form in the non-retarded form. By combining it with the immediately released active ingredient, a high initial dose can be achieved for quick pain relief. The slow release from the retarded form then prevents the analgesic effect from subsiding. It is particularly preferred to set the release of the active ingredients in such a way that the sustained-release pharmaceutical formulation has to be administered at most twice, preferably only once a day. Because of the effect of the analgesics, the person skilled in the art knows in which mixing ratios they are to be used so that the desired release of the active compounds is achieved.
  • the pharmaceutical formulations according to the invention can have further coatings. Coatings that dissolve depending on the pH can also be present as coatings. In this way it can be achieved that the subunits pass through the gastrointestinal tract unresolved and are only released in the intestinal tract. Coatings can also be used to improve the taste.
  • the pharmaceutical formulations according to the invention can be prepared by the various methods known to the person skilled in the art, for example Tablets are produced by the customary processes, such as, for example, by extrusion, build-up processes, wet granulation, fluidized bed processes, dry mixtures or pressing processes. If the pharmaceutical formulation according to the invention, e.g. the tablet has coatings, these can be made using conventional methods, e.g. Drying, spraying on solutions, dispersions or suspensions, by melt processes or by powder application processes.
  • the amount of active ingredient to be administered depends on the active ingredients to be used and on the route of administration.
  • clonidine is particularly preferably in an amount between 1 ⁇ g and 500 ⁇ g, particularly preferably between 10 ⁇ g and 50 ⁇ g, in each case based on the base, and guanfacin preferably in an amount between 5 ⁇ g and 900 ⁇ g between 100 ⁇ g and 500 ⁇ g, based in each case on the base.
  • morphine is preferably used in an amount between 0.1 mg and 20 mg, particularly preferably in an amount between 0.5 mg and 5 mg, in each case based on the base, and tramadol preferably in an amount between 1 mg and 50 mg, particularly preferably in an amount between 1 mg and 20 mg, based in each case on the base.
  • the pharmaceutical formulations according to the invention are preferably administered orally, parenterally or transdermally, particularly preferably orally.
  • Transdermal slow release formulations can e.g. B. in the form of plasters with one or more drug matrices or one or more drug depots and a control membrane.
  • the pharmaceutical formulations according to the invention can contain, in addition to an opioid, an ⁇ -agonist and / or in each case its physiologically compatible salt, further active pharmaceutical ingredients and / or auxiliaries.
  • the pharmaceutical auxiliaries are preferably binders, fillers, lubricants, carrier materials, disintegrants, solvents, diluents, dyes, retarding auxiliaries and / or mixtures thereof.
  • the choice of excipients and the megnen to be used depend on whether the slow-release medicinal forms according to the invention are used orally, parenterally or transdermally.
  • fillers is understood to mean, inter alia, starch, microcrystalline cellulose, dextrose, mannitol or mixtures thereof.
  • Hydroxypropyl methyl celluloses polyvinyl pyrrolidines, hydroxypropyl celluloses, starch paste or mixtures thereof can preferably be used as binders.
  • Low-substituted hydroxypropyl celluloses crosspovidones, Crosscarmellose, starches, pectins, alginates, surfactants or mixtures thereof are used.
  • Magnesium tearat, stearic acid, calcium stearate, fatty alcohols or mixtures thereof are examples of the group of the lubricants that are used.
  • Another object of the present invention is. also the use of the pharmaceutical formulations according to the invention for combating moderate to very severe pain.
  • the pharmaceutical formulations according to the invention show a marked increase in the analgesic effect. This means that with the same analgesic effect, the amount of opioid used can be significantly reduced. In addition, the dependency potential caused by opioids and the constipating effect compared to the sole use of an opioid are significantly reduced.
  • a particular advantage of the slow-release pharmaceutical formulations according to the invention is that the development of a tolerance to the opioid is very much delayed or completely avoided.
  • the following examples serve to explain the invention, but do not restrict the general idea of the invention.
  • the granulation was carried out in a Lödiger high-speed mixer FM 5 and the tablets were produced with a fat eccentric press.
  • PVP polyvinylpyrrolidones
  • morphine HCl in the context of the present invention means morphine HCl trihydrate.
  • tramadol HCl means tramadol HCl trihydrate.
  • RPM revolutions per minute
  • the two-layer tablet produced consisted of a retarded layer containing the active ingredient morphine HCl and an unretarded layer containing the active ingredient clonidine.
  • Morphine HCl, part of the lactose, hydroxyethyl cellulose and cetostearyl alcohol were processed in a suitable mixer for the retarded granules. The mixture was heated to 80 ° C and granulated. After cooling, the granules were sieved and mixed with magnesium stearate and talc.
  • the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dried granulate. The two granules were pressed into two-layer tablets.
  • the two-layer tablets produced consisted of a retarded layer containing the active ingredient morphine HCl and an unretarded layer containing the active ingredient clonidine.
  • Morphine HCl part of the lactose, hydroxethyl cellulose and cetostearyl were used for the retarded granules.
  • alcohol processed in a suitable mixer. The mixture was heated to 80 ° C and granulated. After cooling, the granules were sieved and mixed with magnesium stearate and talc.
  • the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dried granulate. The two granules were pressed into two-layer tablets.
  • the two-layer tablets produced consisted of a delayed-release layer with the active ingredient Tramadol HCl and a further delayed-release layer which contained the active ingredient clonidine HCL.
  • Tramadol HCl was mixed with microcrystalline cellulose, methyl hydroxypropyl cellulose, part of the highly disperse silicon dioxide and magnesium stearate and pressed into tablets. After that, the tab Lithuanian sifted, mixed with the remaining magnesium stearate and highly disperse silicon dioxide.
  • Lactose and hydroxyethyl cellulose were placed in a suitable mixer and mixed.
  • the mixture was moistened with a solution of clonidine HCl in water. After drying, the mixture was mixed with cetostearyl alcohol, heated to 80 ° C. and then granulated. The cooled granules were sieved and mixed with talc and magnesium stearate and the two granules were compressed into two-layer tablets.
  • the two-layer tablets produced consisted of a delayed-release layer with the active ingredient Tramadol HCl and a further delayed-release layer which contained the active ingredient clonidine HCL.
  • HCl was mixed with microcrystalline cellulose, methylhydroxypropyl cellulose, part of the highly disperse silicon dioxide and magnesium stearate and pressed into tablets. After that, the tablets were broken screened, mixed with the remaining magnesium stearate and the highly disperse silicon dioxide.
  • Lactose and hydroxyethyl cellulose were placed in a suitable mixer and mixed. The mixture was moistened with an aqueous solution of clonidine HCl. After drying, it was mixed with cetostearyl cellulose, heated to 80 ° C. and then granulated. The cooled granules were sieved and mixed with talc and magnesium stearate and the two granules pressed into two-layer tablets.
  • the active ingredient clonidine was applied to slow-release morphine pellets as an ⁇ -agonist using a suitable coating system.
  • the pellets produced were filled into capsules or pressed into tablets.
  • the components of the delayed pellets contained:
  • Neutral starter cores were placed in a paint shop and moistened with an ethanolic polyethylene glycol 4000 solution. A mixture of morphine sulfate and lactose was applied several times to the wet cores and the cores were dried. This process was repeated until the morphine sulfate / lactose mixture was completely applied.
  • the total amount per capsule was 31.98 mg.
  • Microcrystalline cellulose and low-substituted hydroxypropyl cellulose were moistened with an aqueous solution of hydroxypropyl methyl cellulose and clonidine HCl.
  • the mixture was extruded through a 0.5 mm perforated disk with a Pharmatex 35 T extruder, rounded in a Spheromat and dried in the fluidized bed.
  • the coated tramadol and clonidine pellets were filled into capsules and compressed into tablets.
  • the matrix tablet contained the following composition
  • Morphine HCl, lactose, hydroxyethyl cellulose and cetostearyl alcohol were mixed.
  • the mixture was moistened with aqueous clonidine HCl.
  • the resulting mixture was dried, then heated to 80 ° C. and granulated. After cooling, the granules were sieved, mixed with magnesium stearate and tableted.
  • the total amount of starting materials was 200 g.
  • the components were sieved (0.63 mm), then mixed in a small cube mixer for 10 minutes and compressed on a Korsch EK 0 eccentric tablet press to tablets of 10 mm diameter with a radius of curvature of 8.5 mm and an average weight of 300 mg .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Pain & Pain Management (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des formulations de médicaments contenant un opioïde et un alpha -agoniste et/ou leur sel physiologiquement tolérable respectif, à partir desquelles au moins un principe actif de médicament est libéré de manière contrôlée.
EP00901108A 1999-01-18 2000-01-17 FORMULATIONS DE MEDICAMENTS CONTENANT UN OPIOIDE ET UN $g(a)-AGONISTE Withdrawn EP1143936A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19901684 1999-01-18
DE19901684 1999-01-18
PCT/EP2000/000318 WO2000041681A2 (fr) 1999-01-18 2000-01-17 FORMULATIONS DE MEDICAMENTS CONTENANT UN OPIOIDE ET UN α-AGONISTE

Publications (1)

Publication Number Publication Date
EP1143936A2 true EP1143936A2 (fr) 2001-10-17

Family

ID=7894563

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00901108A Withdrawn EP1143936A2 (fr) 1999-01-18 2000-01-17 FORMULATIONS DE MEDICAMENTS CONTENANT UN OPIOIDE ET UN $g(a)-AGONISTE

Country Status (15)

Country Link
US (1) US20020044966A1 (fr)
EP (1) EP1143936A2 (fr)
JP (1) JP2002534458A (fr)
AR (1) AR022252A1 (fr)
AU (1) AU772886B2 (fr)
BR (1) BR0000578A (fr)
CA (1) CA2359273A1 (fr)
CO (1) CO5160243A1 (fr)
HU (2) HUP0105043A3 (fr)
NO (2) NO20000225D0 (fr)
NZ (1) NZ513501A (fr)
PE (1) PE20001396A1 (fr)
SK (1) SK10012001A3 (fr)
UY (1) UY25936A1 (fr)
WO (1) WO2000041681A2 (fr)

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WO2000041681A2 (fr) 2000-07-20
HUP0105043A2 (en) 2002-06-29
JP2002534458A (ja) 2002-10-15
AU772886B2 (en) 2004-05-13
BR0000578A (pt) 2001-08-14
PE20001396A1 (es) 2000-12-23
UY25936A1 (es) 2001-07-31
AU2109000A (en) 2000-08-01
CA2359273A1 (fr) 2000-07-20
HU0000139D0 (en) 2000-03-28
NO20013302L (no) 2001-07-03
NZ513501A (en) 2003-11-28
HUP0105043A3 (en) 2005-06-28
AR022252A1 (es) 2002-09-04
CO5160243A1 (es) 2002-05-30
US20020044966A1 (en) 2002-04-18
WO2000041681A3 (fr) 2000-12-07
NO20000225D0 (no) 2000-01-17
SK10012001A3 (sk) 2002-01-07

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