EP1210127A1 - Produits radiopharmaceutiques et leur procede de preparation - Google Patents

Produits radiopharmaceutiques et leur procede de preparation

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Publication number
EP1210127A1
EP1210127A1 EP00951784A EP00951784A EP1210127A1 EP 1210127 A1 EP1210127 A1 EP 1210127A1 EP 00951784 A EP00951784 A EP 00951784A EP 00951784 A EP00951784 A EP 00951784A EP 1210127 A1 EP1210127 A1 EP 1210127A1
Authority
EP
European Patent Office
Prior art keywords
polysaccharide
groups
sequestering
starch
product according
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Withdrawn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
EP00951784A
Other languages
German (de)
English (en)
Inventor
Emmanuel Bellande
Pierre Jallet
Benoít DENIZOT
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 EP1210127A1 publication Critical patent/EP1210127A1/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Withdrawn legal-status Critical Current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
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to radiopharmaceutical products which can be used for diagnosis or therapy and to their preparation procedure .
  • radiopharmaceutical products formed for example from a suspension of particles labelled by a radioactive isotope utilisable in particular for pulmonary scintigraphy, for example in order to establish a diagnosis when a pulmonary embolism is suspected.
  • the products are used under the form of particles which are preferably spherical in shape and of a size ranging from 10 to lOO ⁇ m.
  • the pulmonary capillaries have a diameter of about 7 ⁇ m, the particles remain blocked in the capillaries after their intravenous injection, which makes it possible to visualise anomalies of pulmonary blood perfusion.
  • these products must fulfil a certain number of pharmaceutical restrictions.
  • they must have a suitable degradation rate in vivo, that is sufficiently slow to allow imagery to be carried out, for example by a gamma-ray camera, a minimum of about one hour, but also sufficiently rapid so as not to provoke permanent obstruction of the pulmonary capillaries, which could give rise to small thromboses.
  • these products must not be toxic for the organism, they must be able to be sterilised for example by autoclaving or by irradiation, they must be able to be labelled easily with a radioactive metal and be able to be packaged under the form of a stable labelling kit.
  • the inventors demonstrated other defects of these microparticles in the comparative examples 1 and 2 below.
  • the particles comprise chelating groups linked by covalent bonds to which the radioactive nucleus is linked under the form of chelate type complexes which are principally composed of at least four, and preferably at least five to eight cyclic nuclei with 5 to 6 groups, enclosing the metal, and two metal-coordinating atoms.
  • the polysaccharide is a polysaccharide reticulated chemically, for example by means of epichlorhydrin or epibromhydrin.
  • the labelling procedure comprises heating to 100°C in the presence of the radioactive element, a washing and a drying after labelling, which is not at all compatible with the idea of the above- mentioned labelling kit and the restrictions of sterility of usage.
  • the labelling method described allows the particles to be labelled in a relatively stable manner, it does not make it possible to prepare a labelling kit which is pharmaceutically acceptable, in particular because it contains epichlorhydrin, and easily usable in a nuclear medicine service.
  • microspheres described in these two brevet applications are thus not adapted to the pharmaceutical restrictions and they cannot be exploited. Moreover they have never been used for pulmonary scintigraphy. This type of product has been abandoned since.
  • radioactive particles intended for the study of pulmonary perfusion.
  • the particles described in this document are macro-aggregates of radio- iodinated serum albumin ( 131 I-MAA) or microspheres of denatured human serum albumin labelled with technetium
  • the microspheres of 99m Tc-HAM are preferable, because of their uniformity of particle size ranging essentially between 40 and 50 urn. Moreover this document describes the general characteristics required for such radiopharmaceutical particles.
  • the precise aim of the invention is to overcome the inconveniences mentioned above for prior art products, by providing a radiopharmaceutical product being able to be easily labelled, for example with 99m Tc, presenting a very good pulmonary captation which has been demonstrated by inventors for rats, non-toxic, easily biodegradable, easily sterilisable and able to be packaged as a kit ready for labelling, stable and fulfilling the pharmaceutical restrictions for this type of product.
  • the utilisable alkyl groups for R' can be linear or branched, and preferably they have 1 to 5 carbon atoms .
  • the polysaccharide can be soluble, or in the form of microparticles.
  • the polysaccharide can be chosen, for example, from among natural starch, cellulose or reticulated amyl pectin.
  • the natural starch can, for example, be maize starch.
  • the polysaccharide can be in the form of microparticles, for example in the form of microspheres .
  • modified cellulose according to the present invention offers very good pulmonary captation and an elimination speed slower than with starch.
  • the modified cellulose of the present invention can therefore also be used for radiotherapy, for example with labelling with rhenium, copper, or with one of the above-mentioned metals, since it corresponds to the radiotherapy necessity of using microparticles with a longer half-life.
  • the sequestering groups can be chosen for example from the groups with formulae:
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently hydrogen atoms , saturated or unsaturated hydrocarbonic groups , carboxylic groups or aromatic groups,
  • n is an aromatic nucleus possibly containing one or several hetero-atoms, and n is a whole number between 1 and 5.
  • the microparticles for example in the shape of microspheres, can be of a dimension from 0.01 to 100 ⁇ m, preferably from 10 to 50 ⁇ m for diagnosis by pulmonary scintigraphy and from 0.1 to 5 ⁇ m for therapy.
  • the levels of sequestering groups can be from 0.1 to 50% compared to the saccharide patterns of the polysaccharide, preferably from 2 to 15%.
  • the radioactive metal in the radiopharmaceutical product, particularly when it is used for diagnosis, can be 99 Tc or gallium-67.
  • the radioactive metal in the radiopharmaceutical product, in particular when it is used for therapy, can be rhenium-
  • said radiopharmaceutical product can be in the form of a suspension of microspheres in a physiologically acceptable liquid or in lyophilised form.
  • the present invention also provides a preparation procedure for the radiopharmaceutical product of the invention comprising the following stages:
  • a radioactive metal chosen from among technetium, rhenium, copper, yttrium, erbium and samarium.
  • the oxidation controlled by means of a periodate can be that described, for example, in CL. Mehltretter, "Methods in Carbohydrate Chemistry", vol. IV, 1964, applied in particular to the oxidation of starch, dextrane or cellulose. It is used in the examples given below.
  • the compound containing a primary amine function can correspond to the formula NH 2 - (CH 2 ) n -SH with n being a whole number between 1 and 5, and can include a supplementary reducing stage of this compound with sodium borohydride between stages (b) and (c) .
  • the compound bonded to the polysaccharide can correspond, for example, to one of the following formulae:
  • the level of sequestering groups fixed on the polysaccharide can be regulated by controlling the level of oxidation of the polysaccharide in stage (a) mentioned above.
  • This oxidation level of polysaccharide can, for example, be between 10 to 50%.
  • the level of the sequestering group can, for example, be between 2 and 15%.
  • the inventors have therefore used a two-stage transformation method.
  • This method can be presented as consisting of carrying out a controlled oxidation of the polysaccharide by the periodate in the first stage.
  • Each unit of oxidised glucose thus generates two aldehyde groups in neighbouring positions following the chemical reaction diagram given below:
  • the level of oxidation of the polysaccharide can be variable and easily adjusted. In fact, the yield of this oxidation reaction is close to 100% and the level of oxidaton can be calculated from the quantities of periodate added. In general, oxidation levels lower than 50% are used so as to modify the structure of the macromolecule only slightly. The real oxidation level, ranging from 1 to 100%, can easily be determined by a colorometric method.
  • the oxidised polysaccharide is made to react with a molecule containing an amine or hydrazin grouping with the general formula RNH 2 or RNHNH 2 to form a chelating grouping able to sequester technetium.
  • a Schiff base type ligand or thiosemicarbazone is obtained.
  • This second stage can be summarised as follows: 0
  • stage (c) can for example consist of putting into contact the microspheres of polysaccharide comprising the sequestering groups for example with a solution of pertechnetate 99m Tc0 4 " in the presence of a reducing agent, for example stannous chloride.
  • microparticles for example microspheres, for example maize starch or starch with a base of reticulated amyl pectin can thus be oxidised, then coupled to a molecule containing an amine or hydrazin function, for example S-methyl dithiocarbazate.
  • a molecule containing an amine or hydrazin function for example S-methyl dithiocarbazate.
  • the present invention thus provides in particular microparticles prepared for example from a base of starch particles, which therefore do not present the inconveniences of the albumin mentioned above.
  • the starch is described as an excipient in the pharmacopoeia. It is therefore easily available and at low cost.
  • microparticles of the present invention also have the advantage of being able to be sterilised easily, for example by irradiation, and to be processed under the form of a kit ready for labelling.
  • the present inventors have demonstrated according to the present invention that the speed of pulmonary clearance can be modified according to the level of oxidation of the microparticles used in the present invention, which is not possible, for example, with human albumin microspheres.
  • Another advantage of the present invention lies in the simplicity of operation of the procedure: the reaction conditions being very gentle: reactions at ambient temperature, in an aqueous medium, quasi- quantitative yields.
  • the sequestering reactions for example with technetium, are quantitative; they take place at room temperature and without final purification which makes it possible to adapt to the requirements of sterility and simplicity of preparation necessary for the utilisation of technetised kits in the hospital environment.
  • the present invention also provides a diagnosis kit which can be used, for example, for pulmonary scintigraphy.
  • R' in which R is a hydrocarbonic or aromatic group comprising at least one atom of sulphur, and in which R' is a hydrogen atom or an alkyl grouping such as methyl.
  • the polysaccharide can, for example, be in the form of microparticles, for example in the shape of microspheres, the microparticles being able to be in lyophilised form or in suspension in a pharmaceutically acceptable liquid.
  • the kit of the present invention can furthermore comprise a second flask containing stannous chloride preferably uin lyophilised form, or also when the polysaccharide is in lyophilised form, for example in the form of microparticles, in the first flask, said first flask can besides contain lyophilised stannous chloride.
  • the kits of the present invention are stable for at least twelve months as demonstrated in the examples given below.
  • the radiopharmaceutical product of the present invention therefore presents all the qualities required for a use such as radiopharmaceutical usage, for example for scintigraphy of pulmonary perfusion or for radiotherapy.
  • a suspension of 10 g of maize starch from the pharmacopoeia is prepared, previously sieved between 10 and 40 ⁇ m, containing about 10% water, that is 0.055 mole of glucose in 100 ml of water.
  • the suspension is then stirred for 18 hours at room temperature.
  • the solution is filtered and the oxidised starch is rinsed by 5 times 20 ml of water and then 2 times 50 ml of acetone.
  • the assay of the powder by elementary analysis gives a sulphur content of 5.4%, which corresponds to a coupling level of S-methyl dithiocarbazate (DTCZ) of 7% (7 units dithiocarbazate for 100 theoretical aldehyde functions that is 14 dithiocarbazate units for 100 glucose units) .
  • the coupling yield is therefore 70%.
  • the assay of the powder by elementary analysis gives a sulphur content of 5%, which corresponds to a coupling level of the N- methyl S-methyl dithiocarbazate of 6.5% (6.5 units dithiocarbazate for 100 theoretical aldehyde functions, that is 13 dithiocarbazate units for 100 units glucose).
  • the coupling yield is thus 65%.
  • the assay of the powder by elementary analysis gives a sulphur content of 3%, which corresponds to a coupling level of the 4,4-dimethyl 3-thiosemicarbazone of 7.5% (7.5 units thiosemicarbazide for 100 theoretical aldehyde functions, that is 15 thiosemicarbazone units for 100 units glucose).
  • the coupling yield is thus 75%.
  • the assay of the powder by elementary analysis gives a sulphur content of 3%, which corresponds to a coupling level of the 4-allyl 3-thiosemicarbazone of 7.5% (7.5 units thiosemicarbazide for 100 theoretical aldehyde functions, that is 15 thiosemicarbazone units for 100 units glucose).
  • the coupling yield is thus 75%.
  • Starch modification One proceeds as for example 1 to obtain 10 g of starch oxidised at 30%.
  • a suspension is prepared of 10 g of starch oxidised at 30% in 60 ml of a mixture of water/ethanol (2/1 by volume).
  • 0.1 eq 0.1x0.055x2
  • 0.1 eq 0.1x0.055x2
  • the suspension is stirred for 18 hours at room temperature.
  • the solution is then filtered and the modified starch washed by 3 times 20 ml ethanol and then vacuum dried.
  • the assay of the powder by elementary analysis gives a sulphur content of 2.9%, which corresponds to a coupling level of the 3-thiosemicarbazone of 7.3% (7.3 units thiosemicarbazide for 100 theoretical aldehyde functions, that is 14.6 thiosemicarbazone units for 100 units glucose).
  • the coupling yield is thus 73%.
  • the assay of the powder by elementary analysis gives a sulphur content of 3.4%, which corresponds to a coupling level of the 2-mercaptoethylamine of 8.5% (8.5 units 2-mercaptoethylamine for 100 theoretical aldehyde functions, that is 17 2-mercaptoethylamine units for 100 units glucose).
  • the coupling yield is thus 85%.
  • the assay of the powder by elementary analysis gives a sulphur content of 2.8%, which corresponds to a coupling level of the 2-amino 4-mercaptotriazole of 7% (7 units mercaptotriazole for 100 theoretical aldehyde functions, that is 14 mercaptotriazole units for 100 units glucose) .
  • the coupling yield is thus 75%.
  • Comparative example 1 One uses 10 g of sieved pharmacopoeia maize which has not undergone chemical transformation and one caries out the same procedure as in example 1 to label it with 99m Tc.
  • the RCP is 19%.
  • Example 14 One proceeds as in example 1.
  • the RCP is 99.1%.
  • Example 14 One proceeds as in example 1.
  • the RCP is 99.1%.
  • Sprague Dawley rats weighing about 200 g are anaesthetised with sodium thiopental, and are injected intravenously with different solutions of microspheres labelled with 99 Tc according to examples 1 to 9 and 13.
  • Each animal receives 0.2 ml of solution in the penis vein, that is 0.2 mc per animal.
  • the animals are then placed under a gamma-ray camera and successive static images are shot over a period of 3 hours. One thus obtains successive images after acquiring 15,000 shots per image. Then, manually, one defines the zones of interest in order to estimate the activity present in the different organs 15 minutes after the injection. The results are given in tables I below.
  • modified microspheres show very good pulmonary captation.
  • microspheres of reticulated amyl pectin not modified chemically are labelled by 99m Tc but do not present any pulmonary captation, doubtless due to the weak link between 99 Tc and the microspheres.
  • these microspheres transformed chemically by the procedure of the invention demonstrate good pulmonary captation.
  • Starch microspheres prepared as in example 1 (starch oxidised at 30%, coupled with DTCZ at 7%) are used to produce sterile labelling kits and are ready for labelling with 99m Tc . Sterilisation of the microspheres
  • microspheres 10 g are introduced into a flask crimped and then irradiated by a source of cobalt-60.
  • the microspheres receive a total dose of gamma radiation of 25kGy over 20 hours.
  • 200 mg of sterilised microspheres are introduced in a sterile way into a reactor containing 20 ml of NaCl 9/1000.
  • the solution is de-aerated by nitrogen bubbling and then one adds 400 ⁇ l of a sterile solution of SnCl 2 , 2H 2 0 at 0.5 mg/ml in HCI 0.1N.
  • Each flask thus contains :
  • Sprague Dawley rats weighing about 200 g are anaesthetised with sodium thiopental, and are then injected intravenously with different solutions of microspheres labelled with 99m Tc as in example 14. Each animal receives 0.2 ml of solution in the penis vein, that is 0.2 mc per animal. The animals are then killed 15 minutes after the injection. Next, the different organs are retrieved, the measurement of radioactivity present in each organ is counted and thus the percentage of activity present in each organ is determined. The results are given in table IV below:
  • HSA human serum albumin
  • Sprague Dawley rats weighing about 200 g are anaesthetised and then injected with 0.2 ml (0.1 mc) of cellulose microsphere solution labelled with Re 186 as in example 18.
  • the animals are then placed under a gamma-ray camera and images are registered over 48 hours.
  • the activity present in the zones of interest is then calculated as in example 14.
  • liver cancers after injection, not intravenously but directly into the hepatic artery (metabolic radiotherapy) .
  • Another possible application is to inject this type of particle subcutaneously in breast cancer.
  • the particles migrating through the lymphatic system may make it possible to treat the sentinel nodes invaded by cancerous cells .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des produits radiopharmaceutiques et leur procédé de préparation. Ces produits peuvent être utilisés en scintigraphie pulmonaire ou en thérapie. Ils sont constitués d'un polysaccharide et de groupes séquestrants de formules R-NH-, R-N= et la formule (I). R est un groupe hydrocarbone ou aromatique comprenant au moins un atome de soufre. R' représente un atome d'hydrogène ou un groupement alkyle tel que méthyle. Les groupes séquestrants forment un complexe de type chélate avec un métal radioactif, par exemple le technetium.
EP00951784A 1999-09-01 2000-08-23 Produits radiopharmaceutiques et leur procede de preparation Withdrawn EP1210127A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9910970A FR2797769B1 (fr) 1999-09-01 1999-09-01 Produits radiopharmaceutiques et leur procede de preparation
FR9910970 1999-09-01
PCT/IB2000/001161 WO2001015746A1 (fr) 1999-09-01 2000-08-23 Produits radiopharmaceutiques et leur procede de preparation

Publications (1)

Publication Number Publication Date
EP1210127A1 true EP1210127A1 (fr) 2002-06-05

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ID=9549465

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EP00951784A Withdrawn EP1210127A1 (fr) 1999-09-01 2000-08-23 Produits radiopharmaceutiques et leur procede de preparation

Country Status (23)

Country Link
EP (1) EP1210127A1 (fr)
JP (1) JP2003508455A (fr)
KR (1) KR20020040799A (fr)
CN (1) CN1371292A (fr)
AU (1) AU6463100A (fr)
BG (1) BG106438A (fr)
BR (1) BR0013729A (fr)
CA (1) CA2383517A1 (fr)
CZ (1) CZ2002782A3 (fr)
EA (1) EA200200307A1 (fr)
EE (1) EE200200105A (fr)
FR (1) FR2797769B1 (fr)
HK (1) HK1044893A1 (fr)
HU (1) HUP0202714A2 (fr)
IL (1) IL148076A0 (fr)
MX (1) MXPA02001923A (fr)
NO (1) NO20021001L (fr)
NZ (1) NZ517377A (fr)
PL (1) PL353803A1 (fr)
SK (1) SK2772002A3 (fr)
WO (1) WO2001015746A1 (fr)
YU (1) YU14202A (fr)
ZA (1) ZA200201057B (fr)

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US7842377B2 (en) 2003-08-08 2010-11-30 Boston Scientific Scimed, Inc. Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient
US8012454B2 (en) 2002-08-30 2011-09-06 Boston Scientific Scimed, Inc. Embolization
US7883490B2 (en) 2002-10-23 2011-02-08 Boston Scientific Scimed, Inc. Mixing and delivery of therapeutic compositions
US7976823B2 (en) 2003-08-29 2011-07-12 Boston Scientific Scimed, Inc. Ferromagnetic particles and methods
US7901770B2 (en) 2003-11-04 2011-03-08 Boston Scientific Scimed, Inc. Embolic compositions
US7736671B2 (en) 2004-03-02 2010-06-15 Boston Scientific Scimed, Inc. Embolization
US8173176B2 (en) 2004-03-30 2012-05-08 Boston Scientific Scimed, Inc. Embolization
US7311861B2 (en) 2004-06-01 2007-12-25 Boston Scientific Scimed, Inc. Embolization
US9000040B2 (en) 2004-09-28 2015-04-07 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
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US9463426B2 (en) 2005-06-24 2016-10-11 Boston Scientific Scimed, Inc. Methods and systems for coating particles
US7947368B2 (en) 2005-12-21 2011-05-24 Boston Scientific Scimed, Inc. Block copolymer particles
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PL240772B1 (pl) 2018-06-11 2022-06-06 Nanothea Spolka Akcyjna Sposób wytwarzania nanocząstek polimerowych chelatujących izotopy promieniotwórcze do zastosowania w diagnostyce i terapii

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Also Published As

Publication number Publication date
BR0013729A (pt) 2002-05-07
EE200200105A (et) 2003-04-15
CZ2002782A3 (cs) 2002-08-14
KR20020040799A (ko) 2002-05-30
NZ517377A (en) 2003-08-29
WO2001015746A1 (fr) 2001-03-08
ZA200201057B (en) 2003-07-30
MXPA02001923A (es) 2003-07-21
HUP0202714A2 (en) 2002-12-28
IL148076A0 (en) 2002-09-12
CN1371292A (zh) 2002-09-25
PL353803A1 (en) 2003-12-01
CA2383517A1 (fr) 2001-03-08
JP2003508455A (ja) 2003-03-04
FR2797769B1 (fr) 2003-07-25
HK1044893A1 (zh) 2002-11-08
EA200200307A1 (ru) 2002-08-29
FR2797769A1 (fr) 2001-03-02
AU6463100A (en) 2001-03-26
NO20021001L (no) 2002-04-11
YU14202A (sh) 2004-09-03
SK2772002A3 (en) 2002-09-10
NO20021001D0 (no) 2002-02-28
BG106438A (bg) 2002-09-30

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