EP1082104A1 - Neue mikrosphären auf basis von poly(methylidenmalonat), deren herstellungsverfahren und diese enthaltende pharmazeutische zusammensetzungen - Google Patents

Neue mikrosphären auf basis von poly(methylidenmalonat), deren herstellungsverfahren und diese enthaltende pharmazeutische zusammensetzungen

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Publication number
EP1082104A1
EP1082104A1 EP99915856A EP99915856A EP1082104A1 EP 1082104 A1 EP1082104 A1 EP 1082104A1 EP 99915856 A EP99915856 A EP 99915856A EP 99915856 A EP99915856 A EP 99915856A EP 1082104 A1 EP1082104 A1 EP 1082104A1
Authority
EP
European Patent Office
Prior art keywords
microspheres
preparation
poly
solution
support material
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.)
Ceased
Application number
EP99915856A
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English (en)
French (fr)
Inventor
Nicole Bru-Magniez
Catherine Le Visage
Elias Fattal
Patrick Couvreur
Pascal Breton
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Virsol SNC
Original Assignee
Virsol SNC
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Filing date
Publication date
Application filed by Virsol SNC filed Critical Virsol SNC
Publication of EP1082104A1 publication Critical patent/EP1082104A1/de
Ceased 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • C08J3/14—Powdering or granulating by precipitation from solutions
    • 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
    • A61K9/14—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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2335/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical, and containing at least one other carboxyl radical in the molecule, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Derivatives of such polymers

Definitions

  • New microspheres based on polyfmethylidene malonate their preparation process and pharmaceutical compositions containing them.
  • the present invention relates to new microspheres in particular useful in the pharmaceutical field as particulate vectors intended for the transport of biologically active substances, in particular hydrophilic substances (peptides or proteins), for oral administration.
  • biologically active substances in particular hydrophilic substances (peptides or proteins)
  • the invention also relates to a process for manufacturing these microspheres and to pharmaceutical compositions containing them.
  • microspheres is intended to denote substantially spherical particles, with an average diameter of between 1 ⁇ m and 100 ⁇ m, and preferably between 5 and 100 ⁇ m formed from a continuous network, more or less dense, of a support material.
  • microspheres are different from microcapsules which consist of a wall surrounding a cavity. It should however be noted that the microspheres prepared in multiple emulsion can comprise a set of globules dispersed in the continuous network constituting them.
  • the total volume of these globules will generally represent a fraction between 1:20 and 1: 2 of the total volume of the microspheres.
  • particulate polymer systems can be used to modify the release profile of a therapeutically active substance.
  • microspheres based on synthetic polymers such as, for example, poly (lactic acid), poly (lactic-co-glycolic acid), polystyrene, polyepsilonecaprolactone, polymethylmethacrylate, or even methylcellulose or ethylcellulose have been prepared, by various techniques.
  • synthetic polymers such as, for example, poly (lactic acid), poly (lactic-co-glycolic acid), polystyrene, polyepsilonecaprolactone, polymethylmethacrylate, or even methylcellulose or ethylcellulose have been prepared, by various techniques.
  • microspheres thus obtained are generally non-biodegradable, and when they are, they are characterized by a degradation very delayed in time.
  • the degradation is not progressive and occurs all at once after a significant time interval.
  • lactic polymers degrade, releasing strongly acidic products which not only cause the autocatalysis of the degradation of the polymer, but are at the origin of the induction of incompatibilities with the encapsulated substances.
  • the microspheres exhibit an extremely low degradation rate, or even zero.
  • the persistence time in the body of such particles can limit the repeated application in humans.
  • microspheres are characterized, for the most part, by a significant hydrophobicity which promotes strong and often denaturing interactions with the substance to be encapsulated, in particular when the latter is of protein or peptide nature.
  • the present application relates to microspheres consisting of a continuous network of a support material in which a substance is optionally dispersed, characterized in that said support material contains at least 70% by weight of a homopolymer consisting of repeating units corresponding to the following general formula (I):
  • R represents an alkyl group having from 1 to 6 carbon atoms or a group (CH 2 ) m - COOR 3 in which m is an integer between 1 and 5 and R 3 represents an alkyl group having from 1 to 6 carbon atoms;
  • R_ represents an alkyl group having from 1 to 6 carbon atoms
  • - n is an integer between 1 and 5.
  • microspheres can induce a stimulation of the immune response, when they are associated with an antigen
  • This polymeric material is essentially formed of a homopolymer consisting of recurring units of general formula (I).
  • Such polymers have the remarkable property of being biocompatible and bioerodible, that is to say that they are capable of degrading chemically or biochemically, by cutting the lateral substituents.
  • the erosion rate of the microspheres according to the invention being dependent on the molecular weight of the support material, it can therefore be modulated simply, by using a support material having a molecular weight adapted to the desired erosion rate.
  • microspheres according to the present invention therefore exhibit a modulated and progressive bioerosion allowing, for example, the transport of a biologically active substance, dispersed in the support material, to the place in the body where its action will be most effective. .
  • the bioerosion of microspheres also prevents their accumulation in the body; their use is therefore no longer limited.
  • the above-mentioned homopolymer consists of repeating units corresponding to the general formula (I) in which: R represents an alkyl group having from 1 to 6 carbon atoms; R 2 represents an alkyl group having from 1 to 6 carbon atoms; and n is a number equal to 1; and preferably in which R, and R_ represent a CH 2 -CH 3 group .
  • polymers from the poly (methylidene-malonate) family are particularly suitable for the encapsulation of substances hydrophilic, in particular of biological origin, and possibly biologically active.
  • biologically active molecule means without limitation any molecule having a prophylactic or curative biological activity, in vitro or in vivo, in particular an anti-infectious agent, in particular an antiseptic, antibiotic, antiviral, antiparasitic or antimitotic agent, especially anticancer.
  • Antibiotic or antiseptic agents which can be used can be, for example, rifampicin and colistin.
  • antiviral agents non-limiting mention may be made of didanosine, ribavirin, zidovudine, acyclovir, ganciclovir, foscarnet, vidarabine and zalcitabine.
  • the support material for the microspheres contains:
  • a copolymer comprising at least one block having a hydrophilic character and at least one block having a hydrophobic character, said block of hydrophobic character preferably comprising at least one repeating unit corresponding to the general formula (I).
  • the hydrophilic block of the abovementioned copolymer is chosen from a poly (oxyethylene), a poly (vinyl alcohol), a poly (vinylpyrrolidone), a poly (N-2-hydroxypropyl methacrylamide), a poly (hydroxyethylmethacrylate), a poly hydrophilic (amino acid) such as a polylysine, a polysaccharide, and will preferably be a poly (oxyethylene).
  • the copolymer may have a block structure, preferably diblock or triblock, or a grafted structure.
  • the addition of such copolymers in the support material makes it possible to obtain a homogeneous dispersion of the substance to be encapsulated inside each of the microspheres. It also makes it possible to modulate the hydrophilicity / hydrophobicity ratio of the surface of the microspheres, which makes it possible to avoid or limit the strong and often denaturing interactions with the substance to be encapsulated.
  • these copolymers are particularly advantageous for the implementation of the currently preferred process for preparing the microspheres as will be explained in more detail later.
  • microspheres in accordance with the present invention can be obtained by implementing a process comprising:
  • This multiple emulsion can be obtained in a conventional manner by dispersing a primary emulsion of the water-in-oil type in a second aqueous phase containing a stabilizing agent. This multiple emulsion can also be obtained by a process
  • the present invention relates to a process for obtaining microspheres as previously described, comprising: a) the preparation of a first solution of the above-mentioned polymer (s) constituting the support material in a volatile organic solvent optionally containing a surfactant, b) the preparation of a second solution immiscible with the solution obtained in a), optionally containing said substance to be dispersed and optionally a surfactant, c) the preparation of a primary emulsion by dispersion of the second solution in the first solution, the continuous phase consisting of the solution of polymer (s), d) the preparation of a secondary emulsion: - either by dispersing, under stirring, the primary emulsion obtained in c) in a dispersing medium immiscible with said primary emulsion, said dispersing medium optionally containing a stabilizing agent;
  • the aforementioned method further comprises: f) isolation of the microspheres by centrifugation g) one or more successive washings of said microspheres h) lyophilization of said microspheres.
  • the first step of the process for preparing the microspheres according to the invention therefore comprises the production of an emulsion of the water-in-oil type preferably in the presence of an appropriate surfactant, the oily or organic phase containing the or polymers intended to constitute the support material of said microspheres.
  • a solution of the polymer (s) constituting the support material is prepared using an appropriate volatile organic solvent optionally in the presence of a surfactant.
  • preformed polymers will be used insofar as the homopolymers essentially constituting the support material for the microspheres can be obtained under conditions allowing good characterization in terms of molar mass and mass dispersity.
  • Homopolymers made up of repeating units corresponding to general formula (I) can be prepared from monomers, for example, by following the process described in patent EP 283 346 corresponding to patents US 4,931,584 and US 5,142,098 incorporated here. by reference, said monomers being generally degassed under a vane pump vacuum to constant weight to remove the polymerization inhibitor (SO 2 ).
  • These homopolymers will however advantageously be prepared anionically in an aprotic medium, for example by dispersion of the monomer in acetone, followed by the addition of sodium hydroxide with stirring, again followed by evaporation of the acetone and drying of the polymer thus got.
  • Other aprotic organic solvents such as acetonitrile, dioxane and tetrahydrofuran can be used in place of acetone.
  • the molecular mass of the homopolymer capable of being obtained by the implementation of this process can be perfectly controlled by a judicious choice of the conditions of implementation, and in particular of the concentration of monomer in the organic phase, of the pH and the molarity of the polymerization initiator (sodium hydroxide).
  • homopolymers having an average molar mass of 1,000 to 100,000, and preferably 5,000 to 80,000 will be used in the context of the present invention.
  • the volatile organic solvent capable of being used for the preparation of the first solution containing the polymer or polymers constituting the support material will generally be chosen so that its boiling point is lower than that of water. This solvent can therefore be easily removed during the final evaporation step, allowing precipitation of the polymer.
  • Ethyl acetate is a particularly suitable volatile organic solvent for this purpose.
  • the surfactants capable of being used for the stabilization of the primary emulsion can be of various nature and will be added to the organic phase containing the polymer (s) (first solution) and / or to the aqueous phase ( second solution) constituting the dispersed phase.
  • This can be for example a poloxamer such as the product sold under the name Pluronic ® F68, or even an alcohol
  • (R) poly vinyl such as the product sold under the name Mowiol 40-88, or else a polysorbate, or even a surfactant copolymer whose hydrophobic sequence has a chemical nature identical to that of homopolymer consisting of recurring units corresponding to the general formula (I). It has been shown that such surface-active copolymers and in particular the copolymers of poly (methylidene malonate) and of polyoxyethylene are particularly advantageous insofar as they allow, on the one hand, to obtain a very stable primary emulsion and on the other hand, to obtain a good anchoring of the surfactant in the matrix after evaporation of the solvent.
  • surfactant copolymers can be prepared by conventional polymerization techniques well known to those skilled in the art. Among these techniques, use will preferably be made of anionic polymerization, radical polymerization, or else the technique of coupling the precursor sequences of the copolymer, these sequences having previously been functionally functionalized at the end of the chain.
  • the anionic polymerization is more particularly suitable for the preparation of block copolymers.
  • a block copolymer can thus be obtained:
  • the initiating agents capable of being used in the context of these anionic polymerizations will generally be:
  • organometallic derivatives such as butyllithium and in particular diphenylhexyllithium;
  • alcoholates and in particular macromolecular alcoholates such as a POE alcoholate which can be generated by activation of a hydroxy function using cumylpotassium, diphenylmethylpotassium, naphthalene potassium.
  • the anionic polymerization will generally be carried out in a solvent compatible with the various blocks of the copolymer.
  • the block copolymers will preferably be prepared by successive anionic polymerization of the ethylene oxide followed by methylidene malonate or by activation of a polyoxyethylenated precursor commercial monohydroxylate and subsequent anionic polymerization of the poly (methylidene malonate) sequence.
  • tetrahydrofuran will preferably be used as the polymerization solvent, this product making it possible to work in a homogeneous medium and favorably influencing the polymerization kinetics.
  • the monomers used for the preparation of the hydrophilic blocks will generally be commercial products.
  • the coupling technique is also more particularly suitable for the preparation of block copolymers.
  • This reaction is generally carried out from presynthesized and functionalized homopolymers, in the presence of a coupling agent and optionally an activating agent, in an appropriate solvent.
  • the homopolymer of poly (oxyethylene) functionalized with an ⁇ -carboxy group can be obtained for example by transformation with succinic anhydride of a poly (oxyethylene) functionalized with a commercial ⁇ -hydroxy group.
  • the homopolymer of poly (methylidene malonate) functionalized with an ⁇ -hydroxy group can be obtained directly by anionic synthesis in an aqueous medium or by anionic synthesis in a solvent using an aqueous sodium hydroxide solution as initiator of the polymerization.
  • DCCI dicyclohexylcarbodiimide
  • Radical polymerization is more particularly suitable for the preparation of graft copolymers.
  • This polymerization is generally carried out from a macromonomer, that is to say from an oligomer carrying at one of its ends an ethylenic group which can be polymerized by radical means and capable of reacting with a monomer to form a copolymer with grafted structure .
  • This polymerization will generally be carried out in the presence of an initiator in an appropriate solvent.
  • Such a product may be commercial (Aldrich) and will consist, for example, of a poly (oxyethylene) chain with a molar mass of between 308 and 440 g / mol, or will be prepared from a commercial poly (ethylene glycol) monomethyl ether by coupling with methacrylic acid in dichloromethane to form a methoxy terminal function.
  • copolymers with grafted structures can also be prepared by transesterification of a poly (oxyethylene) monomethyl ether on side ester chains of a pre-synthesized poly (methylidene malonate). This transesterification will generally be carried out with alcohol in the presence of a catalyst at high temperature.
  • Copolymers whose total molecular weight of the hydrophobic blocks is between 1,000 and 80,000 g / mol, and preferably between 1,000 and 50,000 g / mol are particularly suitable in the context of the present invention.
  • the primary emulsion used for the preparation of the microspheres according to the invention can be obtained by means of a shearing homogenizer, for example of the Ultraturrax type (13,500 rpm - 5 min).
  • the substance to be encapsulated is generally added to the dispersed aqueous phase of the primary emulsion. 11 5309 PCT / FR99 / 01005
  • the second step of the process for preparing the microspheres in accordance with the invention comprises the preparation of a secondary emulsion:
  • the dispersing medium which is immiscible with the primary emulsion is an aqueous phase into which the primary emulsion is preferably introduced drop by drop and the emulsion is also produced for example using a homogenizer of the Ultraturrax type ( 8,000 rpm; 5 mins).
  • Polyvinyl alcohol constitutes a stabilizing agent which is particularly suitable for the preparation of the secondary emulsion.
  • this second step can be followed by an additional step of displacement of the organic solvent.
  • the third essential step of the process for preparing the microspheres in accordance with the invention consists in evaporating the volatile organic solvent which was used for the preparation of the solution of the polymer (s). In the particular case where this solvent is ethyl acetate, this evaporation takes place for a period of approximately 12 hours at room temperature, with mechanical stirring (1,400 rpm).
  • these microspheres will have an average diameter of between 1 ⁇ m and 100 ⁇ m, preferably between 5 ⁇ m and 50 ⁇ m for their application as vectors in the pharmaceutical field.
  • the microspheres obtained at the end of the third step will be isolated by centrifugation, washed and possibly lyophilized.
  • the present invention also relates to pharmaceutical compositions containing the microspheres which have just been described. These compositions will generally be suitable for a 12 5309 PCT / FR99 / 01005
  • oral administration and will be presented, for example, in the form of tablets, capsules, powders or granules.
  • PMM 2.1.2 polymer consisting of recurring monomer units corresponding to the formula
  • microspheres thus obtained have an average diameter of 6 microns and 14.2% of the ovalbumin used in the preparation are encapsulated in the microspheres of PMM 2.1.2, which corresponds to an encapsulation of 2.5% (w / w).
  • This preparation is administered orally to C3H mice at a dose of 100 micrograms of encapsulated ovalbumin (per mouse and per day) for 5 consecutive days. The last force-feeding takes place 7 days before the 14 55309 PCT / FR99 / 01005
  • a POE-PMM 2.1.2 block copolymer was used. This copolymer was obtained by successive polymerization of the two monomers, starting with the preparation of the POE block, by the implementation of the following experimental protocol.
  • the reactor in which the polymerization is carried out 250 ml is connected to a vacuum ramp allowing to work under high vacuum and to get rid of protic impurities.
  • the solvent (THF, 150 ml) purified of any trace of moisture is cryodistilled in the reactor at -70 ° C.
  • the initiator (potassium Terbutanolate (0.1N / THF); 10 ml) is then added using a syringe through a septum.
  • the ethylene oxide (5 g) is then introduced by cryodistillation.
  • the polymerization is carried out at room temperature for 48 hours. After this period, a sample makes it possible to control, by gel permeation chromatography, the molar mass (4,000 g / mol) and the polymolecularity index (1.13) of the first sequence.
  • the MM 2.1.2 (0.5 ml) freshly degassed under vacuum to remove the SO 2 used as a polymerization inhibitor, is then added quickly and all at once at room temperature. 15 5309 PCT / FR99 / 01005
  • the copolymer is deactivated by adding methanol and precipitated in diethyl ether.
  • the procedure described in example 1 is followed, but the ovalbumin (60 mg) is replaced by 2 mg of the peptide V3 28 of the V3 BRU loop of HIV gp 120 (sequence NNTRKSIHI GPGRAFYATGDIIGDIRQA).
  • the microspheres obtained have an average size of 5.8 microns and 70% of the V3 28 peptide used is encapsulated in the microspheres, which corresponds to an encapsulation of 0.48% w / w.
  • the study carried out in scanning electron microscopy reveals smooth and spherical particles.
  • the procedure is as in Example 4, but Pluronic F 68 is added to the aqueous phase containing the peptide at a concentration of 2%.
  • the microspheres obtained have a size of 7.0 microns and 70% of the V3 28 peptide used is encapsulated in the microspheres.
  • Example 2 The procedure is as in Example 1, but the internal aqueous phase consists of 1 ml of 0.5M acetic acid containing 3 mg of type IL collagen.
  • the microspheres thus obtained have an average diameter of 6 microns and 66.6% of the collagen put in in the preparation are encapsulated in the microspheres of PMM2.1.2, which corresponds to an encapsulation of 0.7% (w / w).
  • Example 2 The procedure is as in Example 1, but the internal aqueous phase consists of 1 ml of distilled water.
  • the microspheres thus obtained do not contain a biologically active substance. Their average diameter is 7.0 microns.
  • Example 2 The procedure described in Example 1 is followed, but the ovalbumin (60 mg) is replaced by the plasmid pCDNA3 (5 mg).
  • the microspheres obtained have an average size of 7 ⁇ m and 9.8% of plasmid used are encapsulated in the microspheres which corresponds to an encapsulation of 0.17% (w / w).
  • microspheres thus obtained have an average diameter of 7 ⁇ m and 12% of the plasmid used are encapsulated in the microspheres which corresponds to an encapsulation of 0.22% (w / w).
  • Example 2 The procedure described in Example 1 is followed, but the ovalbumin (60 mg) is replaced by the oligonucleotide (pdT16) (2 mg).
  • the microspheres obtained have an average size of 4.8 ⁇ m and 20.6% of oligonucleotide used are encapsulated in the microspheres which corresponds to an encapsulation of 0.19% (w / w).
  • microspheres obtained have an average diameter of 5.7 ⁇ m and 23% of oligonucleotide used are encapsulated in the microspheres which corresponds to an encapsulation of 0.21% (w / w).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
EP99915856A 1998-04-29 1999-04-28 Neue mikrosphären auf basis von poly(methylidenmalonat), deren herstellungsverfahren und diese enthaltende pharmazeutische zusammensetzungen Ceased EP1082104A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9805424 1998-04-29
FR9805424A FR2778100B1 (fr) 1998-04-29 1998-04-29 Nouvelles microspheres a base de poly(methylidene malonate), leur procede de preparation et compositions pharmaceutiques les contenant
PCT/FR1999/001005 WO1999055309A1 (fr) 1998-04-29 1999-04-28 Nouvelles microspheres a base de poly(methylidene malonate), leur procede de preparation et compositions pharmaceutiques les contenant

Publications (1)

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EP1082104A1 true EP1082104A1 (de) 2001-03-14

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Country Status (15)

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US (1) US6440461B1 (de)
EP (1) EP1082104A1 (de)
JP (1) JP2002513042A (de)
KR (1) KR20010043060A (de)
CN (1) CN1146408C (de)
AR (1) AR019114A1 (de)
AU (1) AU752644B2 (de)
BR (1) BR9910016A (de)
CA (1) CA2330481A1 (de)
FR (1) FR2778100B1 (de)
HU (1) HUP0101649A3 (de)
PL (1) PL343687A1 (de)
RU (1) RU2227018C2 (de)
SK (1) SK16312000A3 (de)
WO (1) WO1999055309A1 (de)

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AU752644B2 (en) 2002-09-26
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AU3428899A (en) 1999-11-16
FR2778100B1 (fr) 2001-05-04
WO1999055309A1 (fr) 1999-11-04
JP2002513042A (ja) 2002-05-08
HUP0101649A2 (hu) 2002-03-28
US6440461B1 (en) 2002-08-27
CN1146408C (zh) 2004-04-21
HUP0101649A3 (en) 2002-10-28
PL343687A1 (en) 2001-08-27
CN1303274A (zh) 2001-07-11
KR20010043060A (ko) 2001-05-25
BR9910016A (pt) 2001-01-09
RU2227018C2 (ru) 2004-04-20
CA2330481A1 (en) 1999-11-04
AR019114A1 (es) 2001-12-26

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