EP1322296A1 - Kolloidale suspension submikronischer teilchen der vektorisation aktiver hydrophiler prinzipien (insulin) und deren herstellung - Google Patents

Kolloidale suspension submikronischer teilchen der vektorisation aktiver hydrophiler prinzipien (insulin) und deren herstellung

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Publication number
EP1322296A1
EP1322296A1 EP01974417A EP01974417A EP1322296A1 EP 1322296 A1 EP1322296 A1 EP 1322296A1 EP 01974417 A EP01974417 A EP 01974417A EP 01974417 A EP01974417 A EP 01974417A EP 1322296 A1 EP1322296 A1 EP 1322296A1
Authority
EP
European Patent Office
Prior art keywords
particles
suspension
insulin
pag
hydrophilic
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Withdrawn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
EP01974417A
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English (en)
French (fr)
Inventor
Nathan Bryson
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.)
Flamel Technologies SA
Original Assignee
Flamel Technologies SA
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Filing date
Publication date
Application filed by Flamel Technologies SA filed Critical Flamel Technologies SA
Publication of EP1322296A1 publication Critical patent/EP1322296A1/de
Withdrawn legal-status Critical Current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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the field of the present invention is that of Vectorization Particles (PV), useful for the administration of active principles (PA).
  • PV Vectorization Particles
  • PA active principles
  • the latter are preferably drugs or nutrients for administration to an animal or human body by the oral or nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal, intracerebral, parenteral, etc. routes.
  • the APs more particularly concerned with the invention are hydrophilic, for example, proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, or polynucleotides.
  • the present invention relates, more specifically, to colloidal suspensions of Vectorization Particles, advantageously of the submicron type, based on blocks of hydrophobic polyamino acids and hydrophilic polymers of the polyalkylene glycol (PAG) type, preferably polyethylene glycol (PEG).
  • PAG polyalkylene glycol
  • PEG polyethylene glycol
  • the present invention is aimed both at naked particles (insulin) as such, as well as hydrophilic AP vector systems, constituted by particles loaded with the PA (s).
  • the present invention also relates to pulverulent solids comprising these PV.
  • the invention also relates to methods for preparing said colloidal suspensions of particles loaded with hydrophilic PA (insulin).
  • the purpose of encapsulating PA in PV is in particular to modify their duration of action and / or to route it to the place of treatment and / or to increase the bioavailability of said PA.
  • Many encapsulation techniques have already been proposed. On the one hand, such techniques aim to allow the transport of PA to its site of therapeutic action, while protecting it against attacks by the organism (hydrolysis, enzymatic digestion, etc.) and, on the other hand, to control the release of the PA on its site of action, in order to maintain the quantity available for the organism at the desired level.
  • the AP concerned by these avatars of transport and stay in the organism are, for example, proteins but can be, also, quite different products, organic molecules of synthetic or natural origin.
  • the first specification sought for PV would be that the polymer constituting PV is biocompatible, eliminable (by excretion) and / or biodegradable and, even better, that it is metabolized into non-toxic products for the organism.
  • biodegradation in the body should be of a sufficiently short duration.
  • 2 PV would have the advantage of being able to form, without the aid of organic solvent and / or surfactant, a stable aqueous suspension.
  • the PVs it would also be desirable for the PVs to be of sufficiently small size to be able to undergo, in suspension in a liquid, sterilizing filtration by a filter whose pore diameter is less than or equal to 0.2 ⁇ m.
  • PV and PV-PA systems can be obtained by a non-denaturing process for PA.
  • PV-PA systems can be excellent injectable drugs.
  • This improved ability to administration by injection - intravenous or intramuscular eg - "injectability" is characterized by: (i) a reduced injected volume (for a given therapeutic dose), (ii) low viscosity.
  • PV must have a high PA loading rate. 7
  • the specific cost of PV in an injectable preparation must be reduced and here again, PV must have a high PA loading rate.
  • the small size and a high loading rate are major specifications sought for PV. 8 It is also advantageous for the polymer constituting the PVs not to induce an immune response.
  • PVs which are adapted to this family of PAs in terms of ease of association and release and in terms of character. non denaturing.
  • US-A-5,286,495 relates to a process of encapsulation by vaporization of proteins in aqueous phase, using materials having opposite charges, namely: alginate
  • patent application WO 88/01213 proposes a system based on a mixture of synthetic polypeptides, the solubility of which depends on the pH.
  • they dissolve the mixture of polypeptides, then with a change in pH, they cause the precipitation of proteinoid particles. When the precipitation takes place in the presence of an AP, this is encapsulated in the particle.
  • AP proteinoid particles
  • These implants are hollow tubes or capsules of microscopic size (160 ⁇ m and length equal to 2000 ⁇ m), made up of copolymers of copoly (amino acids) -eg poly (glutamic acid-leucine) or poly (benzylglutamate-leucine) - obtained by copolymerization of monomers of N-carboxyanhydrides of amino acids (NCA).
  • the inclusion of a PA is carried out by a technique of evaporation of solvent from a mixture of polymer and PA.
  • the US patent 4,450,150 belongs to the same family as the US patent 4,351,337 studied above and has essentially the same subject.
  • the constituent PAAs are poly (glutamic acid-ethyl glutamate).
  • PCT / FR patent application WO 97/02810 discloses a composition for the controlled release of active principles, comprising a plurality of lamellar particles of a biodegradable polymer, at least partly crystalline (lactic acid polymer) and of a PA absorbed on said particles. In this case, the release of the active ingredient takes place by desorption.
  • the publication "CHEMISTRY LETTERS 1995, 707, AKIYOSHI ET AL” concerns the stabilization of insulin by supramolecular complexation with hydrophobized polysaccharides by grafting of cholesterol.
  • PCT application WO 96/29991 relates to polyamino acid particles useful for vectorization of PA including in particular hydrophilic PA such as insulin. These particles have a size between 10 and 500 nm.
  • the particles according to WO 96/29991 are formed spontaneously by bringing PAA into contact with an aqueous solution.
  • PAAs include neutral and hydrophobic AAO amino acid monomers and ionizable and hydrophilic AAI monomers. These particles can be loaded with insulin, at most up to 6.5% by dry weight of insulin relative to the mass of PAA. Ta is measured according to a procedure Ma described below.
  • the AANO can be: Leu, Val, Phe, Bz-O-Glu, Bz-O-Asp, the latter being preferred.
  • the hydrophobic active ingredients PA trapped in these PEG / polyAANO micelles are eg: adriamycin, indomethacin, daunomycin, methotrexate, mitomycin.
  • adriamycin indomethacin
  • daunomycin daunomycin
  • methotrexate mitomycin
  • one of the essential objectives is to be able to supply new PVs which spontaneously form, and without the aid of surfactants or organic solvents, stable aqueous suspensions of PV and suitable for the vectorization of hydrophilic PAs (including proteins such as insulin). It is a question of obtaining suspensions of particles loaded with hydrophilic active principle, preferably in proteins such as insulin.
  • Another essential objective of the present invention is to provide new PVs in a stable colloidal aqueous suspension (especially on hydrolysis) or in powder form and based on pol (amino acids) (PAA), these new PVs having to satisfy the better to specifications 1 to 9 of the above mentioned specifications.
  • PAA amino acids
  • Another essential objective of the invention is to improve the particles disclosed in application EP 0 583 955.
  • Another essential objective of the invention is to provide a new suspension of PV whose characteristics are perfectly mastered, in particular in terms of the rate PA loading and in terms of controlling PA release kinetics.
  • Another essential objective of the invention is to provide injectable hydrophilic drug suspensions.
  • the specifications required for such suspensions are a low injection volume and a low viscosity. It is important that the mass of colloidal particles per injection dose is as low as possible and this without limiting the amount of the active ingredient PA transported by these particles, so as not to harm therapeutic efficacy.
  • Another essential objective of the invention is to provide an aqueous colloidal suspension or a pulverulent solid comprising vectoring particles of active principles satisfying the specifications referred to above and which constitutes an appropriate dosage form suitable for administration, for example oral , to humans or animals.
  • Another essential objective of the invention is to provide a colloidal suspension comprising vectoring particles of active principles which can be filtered on 0.2 ⁇ m filters for sterilization purposes.
  • Another essential objective of the invention is to provide a process for the preparation of particles (dry or in suspension in a liquid) of PAA useful, in particular, as vectors for hydrophilic active principles (in particular proteins such as insulin), said process should be, simpler to implement, non-denaturing for the active ingredients and should also always allow fine control of the average particle size of the particles obtained.
  • Another essential objective of the invention is the use of the above particles in aqueous suspension or in solid form for the preparation of medicaments (eg vaccines), in particular for administration in particular oral, nasal, vaginal, ocular, subcutaneous, intravenous , intramuscular, intradermal, intraperitoneal, intracerebral or parenteral,
  • medicaments eg vaccines
  • the hydrophilic active principles of these drugs can be, in particular, proteins, glycoproteins, peptides, polysaccharides, lipopolysaccharides, oligonucleotides and- polynucleotides.
  • Another objective of the present invention is to provide a medicament, of the system of sustained release system of active principles, which is easy and economical to produce and which is, moreover, biocompatible and capable of ensuring a very high level of bioavailability of the AP. .
  • the present invention which relates, first of all, to a colloidal suspension of submicronic particles capable of being used, in particular for the vectorization of active principle (s) (PA), these particles being individualized supramolecular arrangements: • based on an amphiphilic copolymer comprising: ⁇ at least one block of linear polyamino acid (PAA), hydrophobic (s) with ⁇ -peptide sequences, hydrophobic amino acids AAO constituting this PAA block being identical or different from each other; and at least one block of hydrophilic polymer (s) of the polyalkylene glycol (PAG) type, preferably polyethylene glycol (PEG);
  • PAA polyamino acid
  • PAG polyalkylene glycol
  • PEG polyethylene glycol
  • One of the inventive foundations of these new PV vectoring particles, in stable colloidal aqueous suspension or in the form of a pulverulent solid, is due to the original selection of a hydrophilic polymer / poly-amino acid hydrophobic block copolymer making it possible to obtain particles of submicron size, which form a stable aqueous colloidal suspension in the absence of surfactants or solvents and which are suitable for hydrophilic APs.
  • the particles based on hydrophilic polymer block polymer polyalkylene glycol / hydrophobic polyamino acid known to trap hydrophobic active principles can associate and release in vivo hydrophilic PA, in particular proteins such as insulin.
  • PVs associate with proteins or other hydrophilic PAs in an aqueous medium, by a spontaneous and non-denaturing mechanism for the protein
  • PVs release hydrophilic PAs in a physiological medium and, more precisely, in vivo; the release kinetics are a function of the nature of the PAG / Poly AAO copolymer precursor of PV.
  • the particular structure of the copolymer it is possible to control the phenomena of association and of release of the AP on the kinetic and quantitative plan.
  • the PAG corresponds to Polyethylene Glycol (PEG) or to Polypropylene Glycol (PPG), PEG being particularly preferred.
  • PEG Polyethylene Glycol
  • PPG Polypropylene Glycol
  • the PAG - preferably the PEG - has a molar mass by weight of between 500 and 50,000 D, preferably between 1,000 and 10,000 D, and more preferably still between 1,000 and 5,000 D.
  • the suspension according to the invention is characterized by a loading rate Ta of the particles of vectorization with insulin, expressed in% of mass of insulin associated with respect to the mass and measured according to a procedure Ma, Ta being such that: 7 ⁇ Ta preferably, 8 ⁇ Ta ⁇ 50 and, more preferably still, 10 ⁇ Ta ⁇ 30.
  • Procedure Ma (a) Preparation of an aqueous insulin solution: Lyophilized human recombinant insulin (Sigma No. 10259) is poured into 0.1 N HCl solution for 5 min at 25 ° C. This solution is then poured into a phosphate buffer solution which is finally neutralized by adding 0.1 N NaOH. The solution is then left to stand for 30 min at room temperature, then filtered through a membrane.
  • AAOs are hydrophobic neutral amino acids AANO, the PAG / AANO ratio is> 1, - and the absolute length of the PEG block is> 2 monomers, preferably> 10 monomers, and more preferably> 20 monomers.
  • the PAA block (s) based on AANO comprise at least 5, preferably at least 10, and more preferably still at least between 10 and 50.
  • the particles are "diblocks" of PEG / AANO.
  • hydrophilic neutral amino acids are in practice chosen from the group comprising: • natural neutral amino acids: Leu, Ile, Val, Ala, Pro, Phe, their mixtures, • neutral, rare or synthetic amino acids: norleucine , norvaline, • derivatives of polar amino acids: methyl glutamate, ethyl glutamate, benzyl aspartate, N-acetyllysine.
  • the PAA blocks constituting the particles have degrees of polymerization
  • DP between 30 and 600, preferably between 50 and 200 and, more preferably still, between 60 and 150.
  • the present invention relates not only to suspensions of bare particles, as defined above, but also to particles comprising at least one active principle PA.
  • the suspension according to the invention is aqueous and stable.
  • These particles, loaded or not with PA, are advantageously in the form dispersed in a liquid (suspension), preferably aqueous, but can also be in the form of a pulverulent solid, obtained from the PV suspension as defined above.
  • the invention relates, in addition to a colloidal (preferably aqueous) suspension of PV, a pulverulent solid comprising PV and obtained from the suspension according to the invention.
  • Another essential object of the invention relates to the preparation of the selected particles (as described above), both in the form of a colloidal suspension and in the form of a pulverulent solid.
  • the preparation process under consideration essentially consists in synthesizing precursor PAG / polyAAO copolymers and in transforming them into structured particles.
  • an amphiphilic copolymer comprising: at least one block of linear polyamino acid (s) (PAA), hydrophobic (s) with ⁇ -peptide sequences, the hydrophobic amino acids AAO constituting this PAA block being identical or different from each other; and at least one block of hydrophilic polymer (s) of the polyalkylene glycol (PAG) type, preferably polyethylene glycol (PEG);
  • PAA linear polyamino acid
  • PAG polyalkylene glycol
  • PEG polyethylene glycol
  • At least one hydrophilic active ingredient PA is associated with the particles
  • step 1 The functions of the PAG and PAA segments of step 1 can be amine or carboxylic acid functions. It is possible to envisage carrying out the polymerization leading to the PAG and / or PAA block before, during or after the formation of the PAG-PAA bond. All these variants are within the reach of those skilled in the art.
  • step 1 1.1) a copolymerization of monomers formed by anhydrides of N-CarboxyAminoacids (NCA) of 1 hydrophobic AAO amino acids is carried out in the presence of:
  • NCA N-CarboxyAminoacids
  • N-aromatic polar solvent preferably chosen from the group comprising:
  • MethylPyrrolidone NMP
  • DiMethylFormamide DMF
  • DiMethylsuifOxide DMSO
  • aprotic solvent preferably 1,4-dioxane
  • protic solvents preferably 1,4-dioxane
  • At least one PAG polymer block of poly-alkylene glycol (preferably PEG or PPG) is used or prepared by polymerization of alkylene glycol monomers (preferably ethylene or propylene glycol); this PAG block being functionalized (advantageously at at least one of its ends) by at least one reactive nucleophilic group, preferably chosen from the group comprising amines (in particular primary or secondary amines), alcohols or thiols; 1.3) the functionalized PAG from step 2 is added to the polymerization medium of the poly-AAO block, before, during or after the polymerization.
  • Step 1.1 of the process is inspired by the known techniques for the polymerization of N-carboxy- ( ⁇ -amino acids (NCA) anhydrides, described, for example, in the article "Biopolymers, 15, 1869
  • the poly (AOO) (pAAI) copolymer obtained is precipitated - preferably in water - and this precipitate is collected.
  • This variant corresponds to a discontinuous mode of preparation of particles, in which the poly (AAO) (pAAI) copolymer is isolated in the form of a precipitate forming a stable intermediate product. This precipitate can be, for example, filtered, washed and dried.
  • the functionalized PAG block (s) is (are) introduced before and / or at the start of the polymerization, which preferably takes place at a temperature between 20 and 120 ° C. at pressure normal atmospheric.
  • the PAGs of step 1.2 are available commercial products (e.g. PEG), or else are obtained in a manner known per se by polymerization of ethylene oxide
  • step 3 To carry out the association (step 3) of one or more APs with the particles, it is possible to implement several methods in accordance with the invention. Non-limiting examples of these methods are listed below.
  • the association of PA with the particles is carried out by bringing a liquid phase (aqueous or not) containing the PA into contact with the colloidal suspension of particles.
  • the association of the PA with the particles is carried out by bringing a PA in the solid state into contact with the colloidal suspension of particles.
  • the solid AP can be, for example, in the form of lyophilisate, precipitate, powder or the like.
  • the pulverulent solid (PAA) is brought into contact, as described above as a product and by its production characteristics, with a liquid phase (aqueous or not) containing the PA.
  • the pulverulent solid is brought into contact, as described above as a product and by its production characteristics, with the PA in solid form.
  • the PA used can be in pure or preformulated form.
  • the impurities (salts) and the solvent are eliminated, by any appropriate physical separation treatment, for example by diafiltration (dialysis) (step 4), filtration, pH modification, chromatography, etc. leads to an aqueous suspension of structured particles which can be concentrated, for example by distillation or any other suitable physical means: ultrafiltration, centrifugation.
  • step 6 To concentrate (step 6) or to separate (step 7) the particles from their liquid suspension medium, the aqueous phase is possibly eliminated, for example by distillation by drying (eg in an oven), by lyophilization or any other suitable physical means: ultrafiltration, centrifugation. Is recovered, at the end of this step 7, a powdery solid, white in color.
  • steps 1, 2, 3, 4 and possibly 5 of the above method corresponding to a preparation of a colloidal suspension of submicronic particles and with a high loading rate with hydrophilic PAs.
  • the amphiphilic PAG-poly (AAO) copolymers of step 1 are placed in an aqueous medium in which at least part of the PAG is soluble and at least part of the AANO is insoluble.
  • PAG / polyAANO copolymers exist in the form of nanoparticles in this aqueous medium.
  • An alternative for preparing the PV suspension according to the invention consists in bringing the pulverulent solid, as described above, into contact as a product and by its process for obtaining, with an aqueous, non-solvent medium, the AANOs.
  • the suspension can be filtered through sterilization filters, which makes it possible to obtain sterile injectable medicated liquids easily and at low cost.
  • the present invention also relates to new intermediate products of the process described above, characterized in that they consist of PAG-polyAAO copolymers which are precursors of particles.
  • the invention relates to a suspension and / or a pulverulent solid, as defined above and / or as obtained by the process presented above, this suspension and this solid comprising at least one active principle hydrophilic, preferably chosen from:
  • proteins and / or peptides among which the most preferably retained are: hemoglobins, cytochromes, albumin, interferons, antigens, antibodies, erythropoietin, insulin, growth hormones, factors VIII and IX, interleukins or their mixtures, stimulating factors of hematopoiesis;
  • nucleic acids and, preferably, RNA and / or DNA oligonucleotides; • non-peptido-protein molecules belonging to various classes of anticancer chemotherapy and, in particular, anthracyclines and taxoids, -
  • the invention relates to a pharmaceutical, nutritional, phytosanitary or cosmetic specialty, characterized in that it comprises a suspension and / or pulverulent solid loaded with hydrophilic PA and as defined above.
  • the invention also relates to the use of these PVs (in suspension or in solid form) loaded with PA, for the manufacture of medicaments of the PA release type systems. It can be, for example, those which can be administered, preferably by the oral, nasal, vaginal, ocular, subcutaneous, intravenous, intramuscular, intradermal, intraperitoneal, intracerebral or parenteral route. Possible cosmetic applications are, for example, the compositions comprising a PA associated with the PVs according to the invention and applicable transdermally.
  • Fig 1 - Evolution of glycemia G [..— o ..—] (average in% basal) and 1 insulinemia average I (in mUl / 1): [- • -] after injection of a formulation of PV loaded with insulin at the rate of 0.5 IU / kg, as a function of time T (in hours).
  • a solution of human insulin titrated at 1.4 mg / l is prepared corresponding to 40 IU / ml.
  • 10 mg of the PV prepared in Example 1 are dispersed.
  • the insulin associated with the PV and the free insulin are separated by centrifugation (60,000 g, 1 hour) and ultrafiltration (filtration threshold 300,000 D).
  • the free insulin recovered in the filtrate is measured by HPLC or by ELISA and the amount of associated insulin is deduced therefrom by difference.
  • the amount of insulin associated with PV is greater than 0.77 mg, which represents more than 55% of the total insulin used.
  • the association rate expresses the percentage of associated insulin relative to the insulin used in a preparation titrated to 1.4 mg / ml of insulin and 10 mg / ml of PV. This value is transformed into a loading rate which expresses a formulation with 100% protein fixation, in mg of insulin per 100 mg of PV.
  • the protocol of this example is as follows: The preparation of Example 4 was injected into dogs, made diabetic by total pancreatectomy, and on an empty stomach from the previous evening. The administration at 11 am by thoracic subcutaneous route of the preparation was made at the dosage of 0.5 IU / kg of insulin per kg of live weight of the animal. The volume administered is between 0.18 and 0.24 ml. At time -4, -2, 0, 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 hours, 1 ml of blood are taken by jugular puncture under vacuum on a sodium heparinate tube. 30 ⁇ l of whole blood is used extemporaneously for blood sugar measurement.
  • the tube is then centrifuged, decanted and the plasma stored at -20 ° C for insulin determination.
  • the results presented in FIG. 1 below show a release of insulin up to 12 hours (solid line) and a significant hypoglycaemic effect which extends up to 20 hours (broken line) after the injection.
  • This example demonstrates the non-denaturation of insulin in the presence of PV according to the invention.

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EP01974417A 2000-10-06 2001-10-01 Kolloidale suspension submikronischer teilchen der vektorisation aktiver hydrophiler prinzipien (insulin) und deren herstellung Withdrawn EP1322296A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0012836A FR2814951B1 (fr) 2000-10-06 2000-10-06 Suspension colloidale de particules submicroniques de vectorisation de principes actifs hydrophiles (insuline) et leur mode de preparation
FR0012836 2000-10-06
PCT/FR2001/003028 WO2002028374A1 (fr) 2000-10-06 2001-10-01 Suspension colloidale de particules submicroniques de vectorisation de principes actifs hydrophiles (insuline) et leur mode de preparation

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EP1322296A1 true EP1322296A1 (de) 2003-07-02

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US (1) US20040048782A1 (de)
EP (1) EP1322296A1 (de)
JP (1) JP2004510729A (de)
KR (1) KR20030048419A (de)
CN (1) CN1468095A (de)
AU (1) AU2001293939A1 (de)
BR (1) BR0114513A (de)
CA (1) CA2424981A1 (de)
FR (1) FR2814951B1 (de)
MX (1) MXPA03002977A (de)
WO (1) WO2002028374A1 (de)

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WO2002028374A1 (fr) 2002-04-11
FR2814951B1 (fr) 2003-01-17
CA2424981A1 (fr) 2002-04-11
JP2004510729A (ja) 2004-04-08
BR0114513A (pt) 2003-10-21
AU2001293939A1 (en) 2002-04-15
MXPA03002977A (es) 2004-12-06
FR2814951A1 (fr) 2002-04-12
CN1468095A (zh) 2004-01-14
KR20030048419A (ko) 2003-06-19
US20040048782A1 (en) 2004-03-11

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