EP1435917A1 - Formulation pharmaceutique solide d'un derive piperazine uree - Google Patents

Formulation pharmaceutique solide d'un derive piperazine uree

Info

Publication number
EP1435917A1
EP1435917A1 EP02801884A EP02801884A EP1435917A1 EP 1435917 A1 EP1435917 A1 EP 1435917A1 EP 02801884 A EP02801884 A EP 02801884A EP 02801884 A EP02801884 A EP 02801884A EP 1435917 A1 EP1435917 A1 EP 1435917A1
Authority
EP
European Patent Office
Prior art keywords
methyl
formulation according
piperazine
fluorobenzyl
ureido
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Withdrawn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
EP02801884A
Other languages
German (de)
English (en)
Inventor
Heiko Kranz
Christoph Völkel
Ralph Lipp
Johannes Tack
Herbert Wiesinger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1435917A1 publication Critical patent/EP1435917A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K9/14—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
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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

Definitions

  • the invention relates to a solid pharmaceutical formulation containing (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof.
  • WO 98/56771 describes benzylpiperazine urea compounds and especially (2f?) - 1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine and its salts. These substances are antagonists of the CCR-1 receptor and find use in the treatment of inflammatory diseases and the like. of multiple sclerosis and rheumatoid arthritis. In addition, they are used in psoriasis and atopic dermatitis. They are very poorly soluble at basic pH's.
  • (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine hydrogensulfate dissolves about 5 mg / ml, while at a pH of 6.35 or 6.8 only about 0.15 mg / ml or 0.1 mg / ml dissolve. Due to this very poor solubility in the intestinal tract can not be achieved therapeutically required uniform plasma levels, avoiding significant side effects in conventional oral formulation. In addition to increasing the solubility in the intestinal tract, it would also be desirable that the release of the active ingredient be controlled over a longer period of time, so as to substantially extend dosing intervals. At the same time, however, a large-scale production of the drug would have to be possible.
  • the present invention solves the problem of increasing the solubility and the pH-independent release while being industrially producible by a solid pharmaceutical formulation containing (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2 methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, wherein the pharmaceutical formulation additionally comprises a polymer matrix, an organic acid and one or more adjuvants for the targeted control of pH independent drug release (release modification) and for influencing the mechanical strength of the dosage form contains and the particle sizes of the powder mixtures are 90% in the range between 0.1 and 750 microns.
  • piperazine urea (2) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine is hereinafter called piperazine urea and has the following structure:
  • (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine and its salts is carried out by the method described in WO98 / 56771 in Example 2 is described.
  • Salts of these are, for example, the hydrochloride, dihydrogen phosphate, hydrogen sulfate, sulfate, mesylate, ethylsulfonate, malate, fumarate and tartrate.
  • Solid drug formulations according to the invention are single-unit systems, such as e.g. Tablets, and multiparticulate systems.
  • Multiparticulate systems can e.g. Granules, pellets or minitablets. These can be filled in hard or soft gelatin capsules, and compressed into tablets. The original formation usually breaks down into many subunits in the stomach. The minidots then gradually pass from the stomach into the intestine. The mini spots can usually pass through the pylorus with the sphincter closed.
  • a polymer matrix may be selected from the group consisting of cellulose derivatives [e.g. Methylcellulose, hydroxypropylmethylcellulose (eg hydroxypropylmethylcellulose K 4 M, hydroxypropylmethylcellulose K 15 M), hydroxypropylcellulose, hydroxyethylcellulose, sodium-carboxymethylcellulose, ethylcellulose (eg ethylcellulose 100), cellulose acetate (eg cellulose acetate CA-398-10 NF), cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate (eg Cellulose acetate butyrate 171-15 PG), cellulose butyrate, cellulose nitrate, hydroxypropylmethyl cellulose phthalate,
  • cellulose derivatives e.g. Methylcellulose, hydroxypropylmethylcellulose (eg hydroxypropylmethylcellulose K 4 M, hydroxypropylmethylcellulose K 15 M), hydroxypropylcellulose, hydroxyethylcellulose, sodium
  • Hydroxypropyl methylcellulose acetate succinate acrylic derivatives
  • acrylic derivatives e.g. Polyacrylates, cross-linked polyacrylates (e.g., polymethacrylates, polyethyl acrylates, polymethyl acid ethyl acrylates, polymethyl methyl methacrylates, polymethyl methyl methacrylates, polymethyl acrylate trimethyl ammonium ethyl methacrylate chlorides, polyethyl acrylate trimethyl ammonium ethyl methacrylate gallate,
  • Dimethylaminoethylmethacrylatmethacrylatcopolymere Carbopol ® 971 P, Carbopol ® 974 P, Carbopol ® 71 G)] vinyl polymers (eg, polyvinyl pyrrolidones, polyvinyl acetates, Polyvinylacetatphthalate), polyethylene glycols, polyanhydrides, polyester polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polysaccharides (eg, xanthans, xanthan Gum), Zuckerester (for example sucrose stearate, Saccharosepaimitat, sucrose laurate, sucrose behenate, saccharose oleate, Saccharoseerucat and Saccharoseester with mixed fatty acids), diethylene glycol monoethyl ether (for example Transcutol ® P), diethylene glycol monopalmitostearat (eg Hydrines ®), ethylene
  • Particularly suitable is a physical mixture consisting of water-insoluble polyvinyl acetate and water-soluble polyvinylpyrrolidone as polymer matrix.
  • This mixture which in addition contains sodium lauryl sulfate and silicon dioxide, for example, is sold under the trade name Kollidon SR ® sold (Kollidon SR, Technical Information, ME 397e, BASF, July 2000: 80% polyvinyl acetate, 19% polyvinyl pyrrolidone, 0.8% sodium lauryl sulfate and 0, 2% silica)
  • the organic acid can be selected from the group consisting of fumaric acid, citric acid, trisodium citrate, Na hydrogen citrate, ascorbic acid, maleic acid, maleic anhydride, tartaric acid, adipic acid, Na hydrogen phosphate, succinic acid, glutaric acid, glutaric anhydride, potassium sorbate and sorbic acid. Preference is given to fumaric acid.
  • water-soluble or water-insoluble adjuncts such as. Lactose, calcium diphosphates, mannitol, sorbitol, sucrose, fructose, glucose, starch or a starch derivative. It is also possible to use mixtures of one or more auxiliaries. Lactose is preferred. Particularly advantageous is coarse-grained lactose.
  • cellulose or cellulose derivatives can be used as an additional aid for the targeted control of the pH-independent drug release (release modification) and for influencing the mechanical strength of the pharmaceutical form.
  • cellulose or cellulose derivatives can be used.
  • Particularly advantageous is microcrystalline cellulose. This swells in an aqueous environment and leads to an improved pH-independent release of Piperzinhamstoffs and its salts.
  • the single-unit drug forms such as tablets, in addition, lubricants to reduce the inter-particle friction and to reduce the sliding friction between Gut- and Matrizenwandung can be added.
  • lubricant substances are used, which have layers due to their lamellar structure, which can be easily shifted against each other.
  • Pharmaceutically usable organic substances are, for example, the divalent metal soaps, the higher fatty alcohols and the polyethylene glycols with higher Molecular weights. Particularly advantageous are the magnesium and calcium salts of higher fatty acids.
  • a flow control agent can be added to improve the flow properties of the material to be tabletted. This causes the material to be tableted to regularly fill the die of the machine with sufficient packing density.
  • the addition of a flow control agent may be necessary especially in direct tableting.
  • Substances with a purely flow regulating action are mainly the fumed silicas, i. the micronized silica gels and the pyrolytic silicas.
  • Starches and talc are substances that can be used as Freteregulianssstoff- as well as Zerfalltos- or as a lubricant.
  • the material to be tabletted have granule-like properties such as good flowability, high bulk density and defined particle size distribution.
  • the grain size of the Guts to be tabletted depends on the size of the tablets to be produced and generally varies between 0.1 and 750 ⁇ m. Within the material to be tabletted, a particle size distribution which is as uniform as possible is important in order to prevent segregation (for example when shaking the tablet machine) and thus accumulation of larger particles in the upper part of the product, since otherwise larger variations in the dosage may occur.
  • a defined particle size and particle size distribution is achieved by classification (e.g., wet or dry screening) or by granulation of the starting materials.
  • the particle size can be measured by the method described in Example 5.
  • the particle sizes should be 90% in the range between 0.1 - 750 microns. Preferred is a range of 20-400 microns.
  • the piperazine urea or its salts may be homogeneously distributed in the matrix or surrounded by the matrix. In the latter case, the drug forms a nucleus surrounded by the matrix shell.
  • the solid drug formulation according to this invention may be coated with a lake for optical and flavor purposes.
  • a lake for optical and flavor purposes usually consists of a binder (for example hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol), lubricants (for example talc) and color pigment (for example iron oxide pigment, titanium dioxide).
  • a preferred solid pharmaceutical agent formulation contains (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, lactose, Kollidon SR ® , Silica and magnesium stearate, with 90% of the particles ranging from 0.1-750 microns.
  • a tablet with this formulation shows a 60% release of the piperazine urea after 6 hours.
  • Another preferred pharmaceutical formulation contains (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, microcrystalline cellulose, lactose, Kollidon SR ®, silicon dioxide and magnesium stearate, whereby 90% of the particles in the range 0.1 to 750 microns are.
  • Particularly preferred is the use of the hydrogen sulfate as a salt is particularly preferred.
  • a tablet with this formulation shows an 80-90% release of the piperazine urea after 4 hours.
  • Another preferred solid drug formulation contains (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, lactose, Kollidon SR ®, silicon dioxide and magnesium stearate, whereby 90% of the particles in the range 0.1 to 750 microns are, and the tablet is subsequently coated with a color coat consisting of hydroxypropylmethylcellulose, talc, titanium dioxide and iron oxide pigment.
  • a tablet with this formulation shows a 60% release of the piperazine urea after 6 hours.
  • the pharmaceutical formulation according to the invention considerably increases the solubility and the release of the piperazine urea and its salts. While in a conventional formulation consisting of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) -piperazine or a salt thereof, lactose, Corn starch, polyvinylpyrrolidone, croscarmellose sodium and magnesium stearate, only about 10% is released after 8-10 hours at pH 6.8, the release increases by the inventive formulation to about 60-90%.
  • the advantage of the pharmaceutical formulation according to the invention is also evident in clinical studies.
  • the formulation of the invention has all the properties that are necessary for large-scale production, such as good flow properties, high bulk density, good Dosing accuracy, high plastic deformability and thus easy compressibility and high mechanical strength of the tablets produced.
  • the invention further provides a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof is mixed with the polymer matrix, the organic acid, the lubricant and the auxiliary and tableted (direct tabletting).
  • the direct production of tablets is basically carried out by mixing the powder constituents, metering via the filling device of the tablet machine and subsequent compression of the powder mixture.
  • direct tableting the particle size and particle size distribution of the piperazine urea used and its salts, polymer matrix, organic acid and auxiliaries have a considerable influence on the large-scale production of the tablets.
  • the entire powder mixture or individual components of the powder mixture may be classified together (e.g., sieved).
  • the powder ingredients are weighed as described in the examples and mixed for a sufficient period of time in a free fall (e.g., Turbulam mixer, V mixer) or compulsory mixer (e.g., ploughshare mixer, planetary mixer).
  • the addition of the flow control agent and lubricant takes place shortly before the loading of the tableting machine.
  • the FST complex must be finely sieved onto the pre-mixed tabletting material and mixed in as described above, whereby the mixing time must not be too short (inhomogeneous distribution) or too long (dead mixing of the material).
  • the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a Salt thereof, the polymer matrix, the organic acid and the adjuvants prior to mixing and tableting are subjected to an operation called granulating. After granulation and addition of the lubricant, tabletting is carried out as described above.
  • the granulation can be carried out by stepwise enlargement or agglomeration of primary particles of the powder mixture to the desired secondary size (building granulation) or by dividing a dandy powder mass to the desired Granulatkomown (degradation end granulation).
  • building granulation building granulation
  • degradation end granulation plate granulation and fluidized-bed granulation are among the constituent granulations.
  • the degrading granulation can For example, by compaction of the starting materials and subsequent mechanical fragmentation and screening of the compressed done. Degrading or nascent granulation may be moist (eg, adhesive or crust granules) or dry (eg, briquette or melt solidification granules).
  • a further subject of the invention is a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by extrusion and subsequent spheronization.
  • (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by extrusion and subsequent spheronization.
  • the invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the organic acid and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by means of extrusion and subsequent spheronization. The pellets containing the active ingredient are then coated with the polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac).
  • the polymer matrix preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac
  • the active substance-containing pellets can be coated with a subcoat (preferably cellulose derivatives and vinyl polymers) before application of the polymer matrix.
  • Function of the subcoat is the prevention of incompatibilities between (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof and the Polymer matrix or a premature diffusion of (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof in the Polymer matrix during pellet storage.
  • the invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof and the auxiliaries (preferably cellulose, cellulose derivatives and lactose) are processed into pellets by means of extrusion and subsequent spheronization. The pellets containing the active ingredient are then coated with the organic acid and the polymer matrix (preferably cellulose derivatives, acrylic derivatives, vinyl polymers and shellac).
  • the auxiliaries preferably cellulose, cellulose derivatives and lactose
  • the active substance-containing pellets can be coated with a subcoat (preferably cellulose derivatives and vinyl polymers) before application of the polymer matrix.
  • a subcoat preferably cellulose derivatives and vinyl polymers
  • the invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the adjuvants are processed into pellets by direct pelletization.
  • the starting materials are mixed and processed into pellets by means of a binder solution (wet granulation) or melted additives (eg fats).
  • the invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the adjuvants are processed into pellets by spray-drying or spray-drying.
  • the invention further provides a process for the preparation of a solid multiparticulate pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof, the polymer matrix, the organic acid and the auxiliaries are processed into pellets by means of rotor granulation.
  • the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein the polymer matrix, the organic acid and the auxiliaries by applying in layers on (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl ) Carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof are processed into pellets (layering).
  • the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a Salt thereof, the polymer matrix, the organic acid and the aids are processed by applying in layers to a drug-free core (so-called non-pareils) to pellets.
  • a drug-free core so-called non-pareils
  • the invention relates to a method for filling the pellets produced in pharmaceutically used capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules) or the compression of the pellets produced into tablets.
  • the filling of the pellets into capsules or processing of the pellets into tablets may optionally be carried out with the addition of further auxiliaries (preferably cellulose, cellulose derivatives, lactose, lubricants and flow regulators).
  • the invention further provides a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a salt thereof are mixed with the polymer matrix, the organic acid, the lubricant and the adjuvants, and then processed by direct tableting into minitablets (more preferably tablet diameter 1-5 mm).
  • the invention relates to a process for the preparation of a solid pharmaceutical formulation according to the invention wherein (2R) -1 - ((4-chloro-2- (ureido) phenoxy) methyl) carbonyl-2-methyl-4- (4-fluorobenzyl) piperazine or a Salt thereof, the polymer matrix, the organic acid and the adjuvants prior to mixing and tableting are subjected to an operation called granulating. After granulation and addition of the lubricant, the starting materials are processed into mini-tablets (preferably tablet diameter 1-5 mm).
  • the invention relates to a method for filling the minitablets produced in pharmaceutically used capsules (preferably gelatin capsules, starch capsules or cellulose derivative capsules).
  • the filling of the minitablets into capsules may, if appropriate, be carried out with the addition of further auxiliaries (preferably cellulose, cellulose derivatives, lactose).
  • the invention also provides the use of the solid pharmaceutical formulation of the invention for the manufacture of a medicament for the treatment of inflammatory diseases.
  • the inflammatory disease can be, for example, multiple sclerosis, rheumatoid arthritis, psoriasis or atopic dermatitis.
  • the treatment of a patient suffering from an inflammatory disease is by administering one tablet a day. Description of the pictures
  • Fig. 1 describes the solubility of piperazine urea bisulfate as a function of pH.
  • Fig. 2 shows the effect of the addition of SDS (sodium dodecyl sulfate) on the release of piperazineurea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% Piperazinhamstoff- hydrogen sulfate and 25% Kollidon SR ®, based on the total weight of the tablet).
  • SDS sodium dodecyl sulfate
  • Fig. 3 shows the effect of fumaric acid (%, relative to the total weight of the tablet) on the release of piperazineurea-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% Piperazinhamstoff-hydrogen sulfate and 25% Kollidon SR ®, based on the total weight of the tablet ).
  • Fig. 4 shows the effect of the addition of different concentrations of fumaric acid (%, relative to the total weight of the tablet) on the release of Piperazinhamstoff-hydrogen sulfate in phosphate buffer solution pH 6.8 (33% Piperazinharnstoff- hydrogen sulfate and 25% Kollidon SR ®, based on the total weight of the tablet).
  • Figure 5 shows the effect of pH on the release of the piperazine urea hydrogen sulfate (33% piperazine urea hydrogen sulfate, 25% Kollidon SR and 16% fumaric acid, based on the total weight of the tablet).
  • Fig. 6 shows the effect of pH on the release of Piperazinhamstoff- hydrogen sulfate (33% piperazineurea-hydrogen sulfate, Kollidon SR ® 12.5% and 16% fumaric acid, relative to the total weight of the tablet).
  • Fig. 7 shows the effect of pH on the release of Piperazinharnstoff- hydrogen sulfate (33% piperazineurea-hydrogen sulfate, 25% Kollidon SR ®, 16% fumaric acid and 10% microcrystalline cellulose, based on the total weight of the tablet).
  • Fig. 8 shows the particle size distribution determined by laser diffractometry of a typical Pulverpreßmasse for direct tableting.
  • Figure 9 shows the effect of adding different polymer matrices (Examples 3-9) to the release of piperazine urea bisulfate in phosphate buffer solution pH 6.8.
  • Figure 10 shows the effect of adding different organic acids (Examples 10-13) to the release of piperazine urea bisulfate in phosphate buffer solution pH 6.8.
  • FIG. 11 shows, in semilogarithmic representation, the effect of the drug formulation on in vivo plasma levels in humans after administration of 100 mg piperazineurea hydrogensulfate in the form of a conventional oral formulation and after administration of the formulations mentioned in Example 1 (matrix tablet C) and 2 (matrix tablet E) formulations.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate, Kollidon SR ® and microcrystalline cellulose are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all Components mixed for another 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate and Precirol ® ATO 5 are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate and Compritol ® 888 ATO are individually sieved and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients for mixed for another 5 min in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, Piperazinhamstoff-hydrogen sulfate and Carbopol 71 G ® are individually sieved and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, Piperazinhamstoff-hydrogen sulfate and Xantural ® 75 are individually sieved and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazine urea hydrogensulfate and ethylcellulose 100 are individually screened and mixed in order in the turbula for 10 minutes.
  • Fumaric acid, sieved is added and all ingredients mixed for a further 5 min in the Turbula.
  • Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula.
  • Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazine urea bisulfate and cellulose acetate butyrate 171-15 PG are sieved individually and mixed in order in the turbula for 10 minutes.
  • Fumaric acid, sieved, is added and all ingredients for further Mixed for 5 min in the Turbula.
  • Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula.
  • Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-bisulfate and hydroxypropylmethylcellulose K 15 M are sieved individually and mixed in the order mentioned in the turbula for 10 min.
  • Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula.
  • Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula.
  • Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes.
  • Glutaric acid, sieved becomes Add and mix all ingredients for another 5 min in the Turbula.
  • Colloidal silica, sieved is added and all ingredients are mixed for a further 5 minutes in the Turbula.
  • Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, Piperazinhamstoff-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes.
  • Tartaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula.
  • Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula.
  • Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, Piperazinhamstoff-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes.
  • Adipic acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula.
  • colloidal anhydrous Silica, sieved, is added and all ingredients mixed for an additional 5 minutes in the Turbula.
  • Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Ascorbic acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound is then carried out by means of an eccentric or rotary tablet press.
  • Example 14 Production of a matrix tablet by means of direct tabletting with subsequent film coating
  • composition per basic unit Composition per basic unit:
  • iron oxide pigment yellow 0.02 mg iron oxide pigment yellow, E 172 (EOP yellow) Lactose, Piperazinhamstoff-Hydrogensuifat and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound by means of an eccentric or rotary tablet press (tablet cores).
  • iron oxide pigment yellow and titanium dioxide are suspended with stirring (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropylmethylcellulose is dissolved with stirring (eg Ultra-Turrax mixer or colloid mill) in water (binder solution). Dye suspension and binder solution are combined with stirring (eg Ultra-Turrax mixer or colloid mill) (film paint). The produced film paint is sprayed onto the tablet cores with the introduction of heat in a drum coater, the water used evaporating.
  • stirring eg Ultra-Turrax mixer or colloid mill
  • Example 15 Production of a matrix tablet by means of direct tabletting with subsequent film coating
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting of Pulverpreßmasse done by means of an eccentric or rotary tablet press (tablet cores).
  • iron oxide pigment yellow and titanium dioxide are suspended with stirring (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropylmethylcellulose is dissolved with stirring (eg Ultra-Turrax mixer or colloid mill) in water (binder solution). Dye suspension and binder solution are combined with stirring (eg Ultra-Turrax mixer or colloid mill) (film paint). The produced film paint is sprayed onto the tablet cores with the introduction of heat in a drum coater, the water used evaporating.
  • stirring eg Ultra-Turrax mixer or colloid mill
  • Lactose, Piperazinhamstoff-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting of the powder molding compound to minitablets by means of an eccentric or rotary tablet press. The minitablets produced are filled into hard gelatine capsules.
  • composition per basic unit 10 mg piperazinurea hydrogen sulfate 8.25 mg lactose
  • Lactose, piperazineurea-hydrogen sulfate and Kollidon SR ® are sieved individually and mixed in the order indicated in the Turbula for 10 minutes. Fumaric acid, sieved, is added and all ingredients mixed for a further 5 min in the Turbula. Colloidal silica, sieved, is added and all ingredients are mixed for a further 5 minutes in the Turbula. Magnesium stearate, sieved, is sprinkled and all ingredients mixed for a further 30 seconds in the Turbula. Tabletting the powder molding compound to minitablets is then carried out by means of an eccentric or rotary tablet press (tablet cores).
  • iron oxide pigment yellow and titanium dioxide are suspended with stirring (eg Ultra-Turrax mixer or colloid mill) in water (dye suspension). Hydroxypropylmethylcellulose is dissolved with stirring (eg Ultra-Turrax mixer or colloid mill) in water (binder solution). Dye suspension and binder solution are combined with stirring (eg Ultra-Turrax mixer or colloid mill) (film paint). The produced film paint is sprayed onto the tablet cores with the introduction of heat in a drum coater, the water used evaporating. The minitablets produced are filled into hard gelatine capsules.
  • composition per basic unit Composition per basic unit:
  • Lactose, piperazineurea-hydrogen sulfate, Kollidon SR ® and fumaric acid are introduced into a fluid bed granulator and granulated by spraying water. On the dried granules magnesium stearate is scattered and mixed for 30 seconds in the Turbula. The tabletting of the granules is then carried out by means of an eccentric or rotary tablet press.
  • Lactose, Piperazinhamstoff-hydrogen sulfate, Kollidon SR ® and fumaric acid are introduced into a fluid bed granulator and granulated by spraying water. On the dried granules magnesium stearate is scattered and mixed for 30 seconds in the Turbula. The pellets are then tableted into minitablets by means of an eccentric or rotary tablet press. The minitablets produced are filled into hard gelatine capsules.
  • composition per capsule Composition per capsule:
  • Piperazine urea bisulfate, microcrystalline cellulose and fumaric acid are pelletized using a Nica pelleting system.
  • piperazine urea hydrogensulfate, microcrystalline cellulose and fumaric acid are first dry blended.
  • the powder mixture is then extruded with the addition of water.
  • the processing of the extrudate into pellets is done using a spheronizer.
  • An aqueous suspension consisting of Eudragit ® NE 30 D and talc is sprayed under heat supply by means of a fluid bed granulator with a Wurster insert onto the pellets.
  • the film-coated pellets are filled into hard gelatine capsules with the addition of silicon dioxide.
  • Example 21 Measurement of Release of Piperazine Urea Hvdroxide Sulfate Measurement of the release of active ingredient is carried out according to a one-compartment method (paddle stirrer apparatus) as described in USP XXIV.
  • the release of the piperazineurea bisulfate was achieved at pH 1 (0.1 N hydrochloric acid) and in phosphate buffer. pH 4.5 and 6.8 (composition see USP XXIV).
  • an addition of surfactant (SDS) or hydroxypropyl- ⁇ -cyclodextrin to the release medium occurs.
  • Example 1 to 9 The particle size of Piperazinhamstoff-hydrogen sulfate, lactose, Kollidon SR ®, fumaric acid, microcrystalline cellulose or referred to in Example 1 to 9 the powder mixtures was measured by laser diffractometry (Muller, RH, Schuhmann, R., particle size measurement in the laboratory practice,ticianliche Verlagsgesellschaft mbH, Stuttgart, 1996). The volume distribution of the particle sizes was used as measurement parameter.

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Abstract

L'invention concerne une formulation pharmaceutique solide qui contient de la (2R)-1-((4-chloro-2-(uréido)phénoxy)méthyl)carbonyl-2-méthyl-4-(4-fluorobenzyl)pipérazine ou un sel de celle-ci.
EP02801884A 2001-10-18 2002-10-07 Formulation pharmaceutique solide d'un derive piperazine uree Withdrawn EP1435917A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10152351A DE10152351B4 (de) 2001-10-18 2001-10-18 Feste Arzneimittelformulierung für ein Piperazinharnstoffderivat
DE10152351 2001-10-18
PCT/EP2002/011229 WO2003035037A1 (fr) 2001-10-18 2002-10-07 Formulation pharmaceutique solide d'un derive piperazine uree

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NO (1) NO20042022L (fr)
NZ (1) NZ532287A (fr)
PE (1) PE20030472A1 (fr)
PL (1) PL367987A1 (fr)
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NZ529973A (en) 2001-06-27 2006-01-27 Smithkline Beecham Corp Fluoropyrrolidines as dipeptidyl peptidase inhibitors
EP1749519A1 (fr) * 2005-08-05 2007-02-07 Schering Aktiengesellschaft Forme galénique à libération prolongée pH-indépendant pour les substances actives avec une solubilité pH-dépendante
PL2010158T3 (pl) * 2006-04-26 2016-09-30 Formulacje o kontrolowanym uwalnianiu zawierające niepowlekaną odrębną jednostkę(-i) i macierz o przedłużonym uwalnianiu
DE102008047910A1 (de) 2008-09-19 2010-03-25 Molkerei Meggle Wasserburg Gmbh & Co. Kg Tablettierhilfsstoff auf Laktose- und Cellulosebasis
KR101654582B1 (ko) 2016-05-12 2016-09-06 그린로드(주) 원뿔형 부유 고분자 필터, 및 그의 제조장치 및 제조방법, 및 그를 포함하는 수처리 필터
RU2729223C1 (ru) * 2020-05-13 2020-08-05 Мераб Георгиевич Чикобава Дозированная форма для амплификации нуклеиновых кислот

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WO1999040061A2 (fr) * 1998-02-05 1999-08-12 Pfizer Products Inc. Nouveaux derives d'acide dihydroxyhexanoique

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US6207665B1 (en) * 1997-06-12 2001-03-27 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
DE60039377D1 (de) * 1999-02-09 2008-08-21 Pfizer Prod Inc Zusammensetzungen basischer Arzneistoffe mit verbesserter Bioverfügbarkeit

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WO1999040061A2 (fr) * 1998-02-05 1999-08-12 Pfizer Products Inc. Nouveaux derives d'acide dihydroxyhexanoique

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KR20040047920A (ko) 2004-06-05
PE20030472A1 (es) 2003-06-16
DE10152351A1 (de) 2003-05-08
CO5580740A2 (es) 2005-11-30
AU2002333896B2 (en) 2007-07-26
UY27500A1 (es) 2003-06-30
AU2002333896A2 (en) 2003-05-06
BR0213340A (pt) 2004-10-05
WO2003035037A1 (fr) 2003-05-01
CN1571660A (zh) 2005-01-26
HRP20040435A2 (en) 2005-06-30
RU2311172C2 (ru) 2007-11-27
ECSP045108A (es) 2004-06-28
PL367987A1 (en) 2005-03-21
CA2463951A1 (fr) 2003-05-01
NO20042022L (no) 2004-05-14
ZA200403781B (en) 2004-11-29
JP2005506365A (ja) 2005-03-03
AR037111A1 (es) 2004-10-20
NZ532287A (en) 2007-04-27
RS32204A (en) 2006-10-27
IL161166A0 (en) 2004-08-31
MXPA04003522A (es) 2004-07-23
RU2004115328A (ru) 2005-06-10

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