EP0591374A1 - Nanoparticles based on a polyoxyethylene and polylactic acid block copolymer - Google Patents

Nanoparticles based on a polyoxyethylene and polylactic acid block copolymer

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Publication number
EP0591374A1
EP0591374A1 EP92913934A EP92913934A EP0591374A1 EP 0591374 A1 EP0591374 A1 EP 0591374A1 EP 92913934 A EP92913934 A EP 92913934A EP 92913934 A EP92913934 A EP 92913934A EP 0591374 A1 EP0591374 A1 EP 0591374A1
Authority
EP
European Patent Office
Prior art keywords
nanoparticles
polymer
polylactic
copolymer
solution
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.)
Pending
Application number
EP92913934A
Other languages
German (de)
French (fr)
Inventor
Gilles Spenlehauer
Didier Bazile
Michel Veillard
Christian Prud'homme
Jean-Paul Michalon
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.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
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 Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0591374A1 publication Critical patent/EP0591374A1/en
Pending 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
    • A61K9/48—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
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/70—Nanostructure
    • Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/70—Nanostructure
    • Y10S977/788—Of specified organic or carbon-based composition
    • Y10S977/795—Composed of biological material
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/915—Therapeutic or pharmaceutical composition

Definitions

  • the present invention relates to new spherical particles of small dimensions, often less than 500 nm.
  • the new particles of the present invention also called nanoparticles have the advantage of being able to circulate in the blood stream without any problem of size at the level of the capillaries and also have the advantage of being able to avoid the reticuloendothelial system.
  • the invention also relates to the use of the new particles according to the invention in human or animal pharmacy.
  • Nanoparticles that can be used for injection into the living system must be biocompatible. Thus all polymer systems not containing biodegradable or bioresorbable polymer chains are not acceptable for such injections. It is also preferable when using such systems that the degradation products are compatible with living organisms. To date only two types of polymers are suitable; these are lactic or glycolic polymers or mixed lactic-glycolic copolymers.
  • the processes for preparing the nanoparticles can be divided into three types of process, the first consisting in polymerizing the monomers and in prprming the nanoparticles simultaneously, the other two consisting in dissolving the polymer and in forming the nanoparticles independently.
  • the first type of process consists in carrying out a polymerization of a monomer in a solution so as to obtain a micellar dispersion of the polymer in the solution.
  • This type of process is limited to monomers polymerizable in solution, it requires the elimination, after the polymerization step, of the polymerization catalyst, of low molecular weight oligomers, of the monomers and of surfactants necessary for the polymerization.
  • the polymer obtained has a random molecular weight distribution.
  • the second and third types of process consist in using preformed polymers, in solubilizing them in a solvent, in forming a precipitate or a dispersion from a solution of these polymers and of a non-solvent then in evaporating the solvent from way to recover them nanoparticles in the form of a colloidal suspension.
  • the solvent solution is generally an organic solution of the polymer, the non-solvent solution is often an aqueous solution.
  • the polymer is dissolved in an organic solvent miscible with water.
  • this solution is mixed with the aqueous phase, the polymer insoluble in the aqueous phase / organic solvent mixture precipitates in the form of nanoparticles.
  • the organic solvent containing the polymer, immiscible with water is emulsified in an aqueous phase and then the organic solvent is evaporated.
  • the present invention relates to new nanoparticles avoiding the reticuloendothelial system based on polymers comprising a majority of degradable units and possibly containing no additional surfactant. They are obtained from a copolymer consisting of a majority of polylactic units and a minority of ethylene oxide and / or propylene oxide units. This copolymer corresponds for the majority of its units preferably to the following formula (I):.
  • R represents in each of the ylene oxide units an identical or different group chosen from hydrogen or a methyl group
  • R ' represents hydrogen or an alkyl group containing 1 to 4 carbon atoms, preferably a methyl group n is an integer between 20 and 1000 m is an integer between 10 and 1500
  • the polylactic polymeric unit of this copolymer of formula (I) preferably has a molecular weight of between 700 and 100,000, the polyethylene oxide unit preferably has a molecular weight of between
  • the polylactic polymeric unit has a molecular weight between 1,000 and 60,000
  • the polyethylene oxide unit has a molecular weight between 1,000 and 6,000.
  • the polylactic polymer is a polymer containing 50% of lactic units of configuration D (PLA50) and the polyalkylene oxide is a polyethylene oxide.
  • This copolymer is preferably in a diblock form, that is to say that according to a practical manner of implementation, one starts with a monofunctional commercial polyethylene and / or propylene polyoxide of desired molecular weight, ie a molecular weight of between 1000 and 40,000 or else comprising 20 to 1000 ethylene or propylene oxide units, preferably comprising 20 to 150 ethylene oxide units or 20 to 100 propylene oxide units onto which lactide units are grafted until the desired molecular weight is obtained on the polylactic chain in the presence of an initiator such as in particular tin octoate.
  • a monofunctional commercial polyethylene and / or propylene polyoxide of desired molecular weight ie a molecular weight of between 1000 and 40,000 or else comprising 20 to 1000 ethylene or propylene oxide units, preferably comprising 20 to 150 ethylene oxide units or 20 to 100 propylene oxide units onto which lactide units are grafted until the desired molecular weight is obtained on the polylactic chain in the presence
  • polylactic blocks with a molecular weight of between 1,000 and 60,000 it is desirable to introduce between approximately 10 and 1,000 lactide units. It is very particularly preferred to use polyethylene oxide and / or polylactic propylene polyoxide copolymers whose chain contains between 10 and 150 lactic units.
  • These new nanoparticles avoiding the reticuloendothelial system can also consist of a mixture of one or more pure polylactic polymer (s) and the copolymer of formula (I).
  • This polylactic polymer is preferably a polymer comprising a 50/50 mixture of D and L isomers of lactic acid (PLA50).
  • PVA50 lactic acid
  • the final weight ratio in the polymer composition between the polyethylene ethylene and / or propylene unit and the polylactic units is preferably between 1 and 25% by weight. It is particularly preferred to use the composition obtained by mixing a polylactic polymer with a molecular weight of 60,000, a copolymer of formula (I) in which R represents hydrogen, n is equal to 48 and m is equal to 133 .
  • the desired polylactic-ethylene and / or propylene polyoxide copolymer optionally in admixture with the polylactic polymer, is dissolved in a solvent or in a mixture of solvents, then the organic solution is poured into an aqueous solution, so as to cause the formation of nanoparticles by precipitation.
  • no additional colloidal protective agent is optionally used.
  • colloidal protective agent is understood to mean the surfactants of which the surface-active agents which promote the formation of colloids are part.
  • the solvent or the mixture of solvents dissolving the copolymer is chosen from ketones such as acetone, cyclic ethers such as tetrahydrofuran, dioxanes; nitriles such as acetonitrile. We prefer to use acetone.
  • the solubility of the copolymer in these solvents is preferably greater than 10 g / l.
  • the aqueous solution can be pure water or a saline solution such as for example a buffer solution or also a glucose solution.
  • the volume ratio between the aqueous solution and the solution of the copolymer is preferably between 0.5 and 10, and very particularly between 1 and 10.
  • the amount of copolymer introduced into the solvent obviously depends on its solubility, but for better implementation of the invention, ie essentially to obtain an optimum yield of formed nanoparticles, an amount between 10 and 50 mg / ml is preferred.
  • the polylactic polyethylene oxide of ethylene and / or propylene is dissolved in an ester, preferably in ethyl acetate, then the organic solution is poured into the aqueous solution.
  • Nonoparticles are formed by the use of a microfluidizer.
  • the solvent of the copolymer is then evaporated by heating the colloidal solution of nanoparticles above the boiling temperature of the solvent in the case where the elimination is carried out at atmospheric pressure or at a lower temperature if the evaporation is carried out under reduced pressure .
  • the suspension of nanoparticles in water is filtered through a filter with a pore diameter of approximately 1 ⁇ m, so as to remove the aggregates and large particles.
  • the yield of nanoparticles obtained generally exceeds 50%.
  • nanoparticles can be carried out in the presence of a pharmaceutical active ingredient which can be introduced either in the solvent of the copolymer or in the precipitation solvent, it must preferably be soluble in the solvent of the polymer and not soluble in water , although it is always possible to form nanoparticles if the active principle is soluble in water, the yield will nevertheless be reduced.
  • the nanoparticles obtained contain only the copolymer of formula (I) or the mixture of polylactic polymers and of copolymer of formula (I) and optionally an active principle if the precipitation is carried out in the presence of an active principle. They have an average diameter between 50 and 500 nm and preferably an average diameter between 50 and 250 nm.
  • the nanoparticles obtained are used for injections into a living organism insofar as their essential advantage is to be able to avoid the reticuloendothelial system, thus their main application is found in human or animal pharmacy. Or for medical diagnosis.
  • These products are injectable intramuscularly, subcutaneously, intraarterially, intravenously, intraorganically or intracavities without anaphylactic risk.
  • Dl lactide 144 g polyethylene glycol 79.3 g are introduced into a 250 ml three-necked flask fitted with a paddle stirrer and an ascending cooler with circulation of dry nitrogen, the flask being heated by a regulated oil bath.
  • the lactide is recrystallized the day before from ethyl acetate, then washed the same day with ethyl ether. It is dried under vacuum. All the reagents are loaded and then heated under slight reflux (110-114 ° C) for 5 hours and a half. The solvent is then removed under vacuum using a rotary evaporator (40 mm Hg - 100 ° C).
  • the purification of the copolymer is carried out as follows:
  • Example 1.1 is reproduced by introducing the following compounds: dl lactide 48.6 g polyethylene glycol 10 g stannous octoate 0.085 g toluene distilled 90 g after reaction 63.6 g of concentrate are obtained which are purified by the following method: in solution 40 g of concentrate in 200 g of dichloromethane until a homogeneous solution is obtained. This solution is poured slowly into 800 ml of water maintained between 55 and 60 ° C. The polymer precipitates and the dichloromethane is evaporated, the unreacted lactide remains in aqueous solution, the polymer is centrifuged and then dried in an oven under vacuum at 40 ° C. 35 g of polymer are obtained, the analysis of which by nuclear magnetic resonance makes it possible to determine the molecular weight. The latter is 9600 for the lactic chain and 2100 for the polyethylene oxide chain, which represents 133 lactic units and 48 ethylene oxide units.
  • reaction medium is left to react for 5 hours at 140 ° C., at the end of the reaction, it is rapidly cooled and then part of the xylene is removed in vacuo.
  • the polymer is dissolved in dichloromethane and precipitated with methanol. It is dried in a vacuum oven at 65 ° C.
  • Each rat is injected with 400 ⁇ l of suspension, the rats are divided into batches of five, one for each concentration of polyethylene oxide.
  • the kinetics of particle capture by the reticuloendothelial system is represented by plotting the radioactivity remaining in the plasma as a% of the radioactivity present in the plasma at the end of the perfusion as a function of time.
  • the half-life of the particles as a function of the amount of polyethylene glycol introduced is indicated in the table below.
  • the curves of radioactivity remaining in the plasma are plotted in the appendix.
  • PLA50 9600 PEG 200 and 10 mg of poly (d, 1-lactic acid) of molecular weight 18000 labeled with C are used, which is dissolved in 1 ml of ethyl acetate. This solution is then dispersed using an ultraturrax in 10 ml of water. A coarse emulsion is obtained. It is then recycled for 2 minutes using a high pressure homogenizer type MICROFLUIDICS. The emulsion is freed from ethyl acetate using a rotary evaporator at a pressure of 50.5 cm of mercury at 20 ° C. The pseudolatex obtained consists of nanoparticles with an average diameter of 145 ⁇ 60 nm. The half-life of these nanoparticles in the blood is 1 hour.
  • the aqueous phase is a solution of sodium cholate at 10 gl -1 in water. Diameter of the nanoparticles: 105 ⁇ 45 nm. Half-life: 0.5 hour.

Abstract

Nanoparticles having an extended time of capture by the reticulo-endothelial (retothelial) system. They consist of a polylactic-polyoxyethylene and/or polyoxypropylene copolymer, optionally in a mixture with a polylactic polymer.

Description

Nanoparticules à base d' un copolymere à blocs de polyoxyéthylène et acide polylactique Nanoparticles based on a block copolymer of polyoxyethylene and polylactic acid
La présente invention concerne de nouvelles particules sphériques de petites dimensions, souvent inférieures à 500 nm. Les nouvelles particules de la présente invention, encore appelées nanoparticules présentent l'avantage de pouvoir circuler dans le flux sanguin sans problème de dimension au niveau des capillaires et présentent en plus l'avantage de pouvoir éviter le système réticulo endothélial. L'invention vise aussi l'utilisation des nouvelles particules selon l'invention en pharmacie humaine ou animale.The present invention relates to new spherical particles of small dimensions, often less than 500 nm. The new particles of the present invention, also called nanoparticles have the advantage of being able to circulate in the blood stream without any problem of size at the level of the capillaries and also have the advantage of being able to avoid the reticuloendothelial system. The invention also relates to the use of the new particles according to the invention in human or animal pharmacy.
Les nanoparticules qui peuvent être utilisées pour une injection dans le système vivant doivent être biocompatibles. Ainsi tous les systèmes polymériques ne contenant pas de chaînes polymériques biodégradables ou biorésorbables ne sont pas acceptables pour de telles injections. Il est d'autre part préférable lorsque l'on utilise de tels systèmes que les produits de dégradation soient compatibles avec les organismes vivants. A ce jour seulement deux types de polymères peuvent convenir; il s'agit des polymères lactiques ou glycoliques ou des copolymères mixtes lactique-glycolique.Nanoparticles that can be used for injection into the living system must be biocompatible. Thus all polymer systems not containing biodegradable or bioresorbable polymer chains are not acceptable for such injections. It is also preferable when using such systems that the degradation products are compatible with living organisms. To date only two types of polymers are suitable; these are lactic or glycolic polymers or mixed lactic-glycolic copolymers.
Les procédés de préparation des nanoparticules peuvent être divisés en trois types de procédé, le premier consistant à polymériser les monomères et à fprmer les nanoparticules simultanément, les deux autres consistant à solubiliser le polymère et à former les nanoparticules indépendamment.The processes for preparing the nanoparticles can be divided into three types of process, the first consisting in polymerizing the monomers and in prprming the nanoparticles simultaneously, the other two consisting in dissolving the polymer and in forming the nanoparticles independently.
Le premier type de procédé consiste à effectuer une polymérisation d'un monomère dans une solution de façon à obtenir une dispersion micellaire du polymère dans la solution. Ce type de procédé est limité à des monomères polymérisables en solution, il nécessite l'élimination après l'étape de polymérisation du catalyseur de polymérisation, des oligomères de bas poids moléculaire, des monomères et des agents surfactants nécessaires à la polymérisation. Le polymère obtenu présente une répartition de poids moléculaire aléatoire.The first type of process consists in carrying out a polymerization of a monomer in a solution so as to obtain a micellar dispersion of the polymer in the solution. This type of process is limited to monomers polymerizable in solution, it requires the elimination, after the polymerization step, of the polymerization catalyst, of low molecular weight oligomers, of the monomers and of surfactants necessary for the polymerization. The polymer obtained has a random molecular weight distribution.
Le deuxième et le troisième types de procédé consistent à utiliser des polymères préformés, à les solubiliser dans un solvant, à former un précipité ou une dispersion à partir d'une solution de ces polymères et d'un non solvant puis à évaporer le solvant de façon à récupérer les nanoparticules sous forme d'une suspension colloïdale. La solution solvante est généralement une solution organique du polymère, la solution non solvante est souvent une solution aqueuse.The second and third types of process consist in using preformed polymers, in solubilizing them in a solvent, in forming a precipitate or a dispersion from a solution of these polymers and of a non-solvent then in evaporating the solvent from way to recover them nanoparticles in the form of a colloidal suspension. The solvent solution is generally an organic solution of the polymer, the non-solvent solution is often an aqueous solution.
Selon le deuxième type de procédé, le polymère est solubilisé dans un solvant organique miscible à l'eau. Lorsque cette solution est mélangée à la phase aqueuse, le polymère insoluble dans le mélange phase aqueuse/solvant organique précipite sous forme de nanoparticules.According to the second type of process, the polymer is dissolved in an organic solvent miscible with water. When this solution is mixed with the aqueous phase, the polymer insoluble in the aqueous phase / organic solvent mixture precipitates in the form of nanoparticles.
Selon le troisième type de procédé on émulsionne le solvant organique contenant le polymère, non miscible à l'eau, dans une phase aqueuse puis on évapore le solvant organique.According to the third type of process, the organic solvent containing the polymer, immiscible with water, is emulsified in an aqueous phase and then the organic solvent is evaporated.
La formation du précipité ou de l'émulsion exige la présence d'une quantité d'agent surfactant loin d'être négligeable. Or lors de l'évaporation subséquente, il est très difficile d'éliminer l'agent surfactant qui subsiste dans la suspension colloïdale de nanoparticules obtenue, cet agent est souvent indésirable pour une bonne biocompatibilé. Ces deux dernières techniques ne sont donc pas utilisables pour la préparation de nanoparticules biocompatibles à cause de la présence de l'agent protecteur colloïdal.The formation of the precipitate or of the emulsion requires the presence of a quantity of surfactant far from being negligible. However, during subsequent evaporation, it is very difficult to remove the surfactant which remains in the colloidal suspension of nanoparticles obtained, this agent is often undesirable for good biocompatibility. These last two techniques cannot therefore be used for the preparation of biocompatible nanoparticles because of the presence of the colloidal protective agent.
La présente invention concerne de nouvelles nanoparticules évitant le système réticulo endothélial à base de polymères comportant une majorité de motifs dégradables et ne contenant éventuellement pas d'agent tensioactif additionnel. Elle sont obtenues à partir d'un copolymère constitué d'une majorité de motifs polylactiques et d'une minorité de motifs oxyde d'éthylène et/ou oxyde de propylene. Ce copolymère répond pour la majorité de ses motifs de préférence à la formule (I) suivante :.The present invention relates to new nanoparticles avoiding the reticuloendothelial system based on polymers comprising a majority of degradable units and possibly containing no additional surfactant. They are obtained from a copolymer consisting of a majority of polylactic units and a minority of ethylene oxide and / or propylene oxide units. This copolymer corresponds for the majority of its units preferably to the following formula (I):.
dans laquelle R représente dans chacun des motifs oxyde d'al ylène un groupe identique ou différent choisi parmi l'hydrogène ou un groupe méthyle in which R represents in each of the ylene oxide units an identical or different group chosen from hydrogen or a methyl group
R' représente l'hydrogène ou un groupe alkyle contenant 1 à 4 atomes de carbone, de préférence un groupe méthyle n est un nombre entier compris entre 20 et 1000 m est un nombre entier compris entre 10 et 1500R 'represents hydrogen or an alkyl group containing 1 to 4 carbon atoms, preferably a methyl group n is an integer between 20 and 1000 m is an integer between 10 and 1500
Le motif polymérique polylactique de ce copolymère de formule (I) a de préférence un poids moléculaire compris entre 700 et 100 000, le motif polyoxyde d'éthylène a lui de préférence un poids moléculaire compris entreThe polylactic polymeric unit of this copolymer of formula (I) preferably has a molecular weight of between 700 and 100,000, the polyethylene oxide unit preferably has a molecular weight of between
1 000 et 40 000. D'une façon encore plus préférentielle le motif polymérique polylactique a un poids moléculaire compris entre 1 000 et 60 000, le motif polyoxyde d'éthylène a un poids moléculaire compris entre 1 000 et 6000.1,000 and 40,000. Even more preferably, the polylactic polymeric unit has a molecular weight between 1,000 and 60,000, the polyethylene oxide unit has a molecular weight between 1,000 and 6,000.
Selon une dernière préférence le polymère polylactique est un polymère contenant 50 % de motifs lactique de configuration D (PLA50) et le polyoxyde d'alkylène est un polyoxyde d'éthylène.According to a final preference, the polylactic polymer is a polymer containing 50% of lactic units of configuration D (PLA50) and the polyalkylene oxide is a polyethylene oxide.
Ce copolymère se présente de préférence sous une forme dibloc, c'est à dire que selon une manière pratique de mise en oeuvre on part d'un polyéthylène et/ou polyoxyde de propylene commercial monofonctionnel de poids moléculaire désiré c'est à dire d'un poids moléculaire compris entre 1000 et 40 000 ou encore comportant 20 à 1000 motifs oxyde d'éthylène ou de propylene, de préférence comportant 20 à 150 motifs oxyde d'éthylène ou 20 à 100 motifs oxyde de propylene sur lequel on greffe des motifs lactides jusqu'à obtenir le poids moléculaire désiré sur la chaîne polylactique en présence d'un initiateur tel que notamment l'octoate d'étain.This copolymer is preferably in a diblock form, that is to say that according to a practical manner of implementation, one starts with a monofunctional commercial polyethylene and / or propylene polyoxide of desired molecular weight, ie a molecular weight of between 1000 and 40,000 or else comprising 20 to 1000 ethylene or propylene oxide units, preferably comprising 20 to 150 ethylene oxide units or 20 to 100 propylene oxide units onto which lactide units are grafted until the desired molecular weight is obtained on the polylactic chain in the presence of an initiator such as in particular tin octoate.
On peut préciser que pour obtenir des blocs polylactiques d'un poids moléculaire compris entre 1 000 et 60 000, il est souhaitable d'introduire entre environ 10 et 1000 motifs lactide. On préfère tout particulièrement utiliser des copolymères polyoxyde d'éthylène et/ou polyoxyde de propylene polylactique dont la chaîne contient entre 10 et 150 motifs lactiques.It can be specified that in order to obtain polylactic blocks with a molecular weight of between 1,000 and 60,000, it is desirable to introduce between approximately 10 and 1,000 lactide units. It is very particularly preferred to use polyethylene oxide and / or polylactic propylene polyoxide copolymers whose chain contains between 10 and 150 lactic units.
On préfère encore plus particulièrement partir d'un polyéthylène glycol commercial comportant 48 motifs oxyde d'éthylène d'un poids moléculaire de 2100 que l'on fait réagir avec 40 à 150 motifs lactide.It is still more particularly preferred to start from a commercial polyethylene glycol comprising 48 ethylene oxide units with a molecular weight of 2100 which is reacted with 40 to 150 lactide units.
Ces nouvelles nanoparticules évitant le système réticulo endothélial peuvent aussi être constituées d'un mélange d'un ou de plusieurs polymère(s) polylactique pur et du copolymère de formule (I).These new nanoparticles avoiding the reticuloendothelial system can also consist of a mixture of one or more pure polylactic polymer (s) and the copolymer of formula (I).
Afin de préparer ces dernières nouvelles nanoparticules selon l'invention il est nécessaire de mélanger le copolymère de formule (I) avec une quantité utile d'un polymère polylactique. Ce polymère polylactique est de préférence un polymère comportant un mélange 50/50 d'isomère D et L de l'acide lactique (PLA50). On préfère utiliser un mélange contenant entreIn order to prepare the latter new nanoparticles according to the invention, it is necessary to mix the copolymer of formula (I) with a useful quantity of a polylactic polymer. This polylactic polymer is preferably a polymer comprising a 50/50 mixture of D and L isomers of lactic acid (PLA50). We prefer to use a mixture containing
10 et 80 % en poids de copolymère de formule (I) par rapport au polymère polylactique. Le rapport pondéral final dans la composition polymérique entre le motif polyoxyde d'éthylène et/ou de propylene et les motifs polylactique est de préférence compris entre 1 et 25 % en poids. On préfère tout particulièrement utiliser la composition obtenue par mélange d'un polymère polylactique de poids moléculaire de 60 000, d'un copolymère de formule (I) dans lequel R représente l'hydrogène, n est égal à 48 et m est égal à 133.10 and 80% by weight of copolymer of formula (I) relative to the polylactic polymer. The final weight ratio in the polymer composition between the polyethylene ethylene and / or propylene unit and the polylactic units is preferably between 1 and 25% by weight. It is particularly preferred to use the composition obtained by mixing a polylactic polymer with a molecular weight of 60,000, a copolymer of formula (I) in which R represents hydrogen, n is equal to 48 and m is equal to 133 .
Selon une première méthode de préparation des nanoparticules, le copolymère polylactique-polyoxyde d'éthylène et/ou de propylene désiré, éventuellement en mélange avec le polymère polylactique est mis en solution dans un solvant ou dans un mélange de solvants, puis la solution organique est versée dans une solution aqueuse, de façon à provoquer la formation des nanoparticules par précipitation. Dans ce procédé, on n'utilise éventuellement pas d'agent protecteur colloïdal additionnel. On entend par agent protecteur colloïdal, les agents de surface dont font partie les agents tensioactifs qui favorisent la formation de colloïdes.According to a first method for preparing the nanoparticles, the desired polylactic-ethylene and / or propylene polyoxide copolymer, optionally in admixture with the polylactic polymer, is dissolved in a solvent or in a mixture of solvents, then the organic solution is poured into an aqueous solution, so as to cause the formation of nanoparticles by precipitation. In this process, no additional colloidal protective agent is optionally used. The term “colloidal protective agent” is understood to mean the surfactants of which the surface-active agents which promote the formation of colloids are part.
Le solvant ou le mélange de solvants solubilisant le copolymère est choisi parmi les cétones telle que l'acétone, les éthers cycliques tels que le tétrahydrofurane, les dioxanes; les nitriles tels que l'acétonitrile. On préfère utiliser l'acétone. La solubilité du copolymère dans ces solvants est de préférence supérieure à 10 g/l.The solvent or the mixture of solvents dissolving the copolymer is chosen from ketones such as acetone, cyclic ethers such as tetrahydrofuran, dioxanes; nitriles such as acetonitrile. We prefer to use acetone. The solubility of the copolymer in these solvents is preferably greater than 10 g / l.
La solution aqueuse peut être de l'eau pure ou une solution saline telle par exemple une solution tampon ou également.une solution de glucose.The aqueous solution can be pure water or a saline solution such as for example a buffer solution or also a glucose solution.
Le rapport volumique entre la solution aqueuse et la solution du copolymère est compris de préférence entre 0,5 et 10, et tout particulièrement entre 1 et 10. La quantité de copolymère introduite dans le solvant dépend bien entendu de sa solubilité, mais pour une meilleure mise en oeuvre de l'invention, c'est à dire essentiellement pour obtenir un rendement optimum en nanoparticules formées, une quantité comprise entre 10 et 50 mg/ml est préférée. Selon une deuxième méthode de préparation des nanoparticules, le polymère polylactique polyoxyde d'éthylène et/ou de propylene est mis en solution dans un ester, de préférence dans l'acétate d'éthyle puis la solution organique est versée dans la solution aqueuse. Les nonoparticules sont formées par l'utilisation d'un microfluidiseur.The volume ratio between the aqueous solution and the solution of the copolymer is preferably between 0.5 and 10, and very particularly between 1 and 10. The amount of copolymer introduced into the solvent obviously depends on its solubility, but for better implementation of the invention, ie essentially to obtain an optimum yield of formed nanoparticles, an amount between 10 and 50 mg / ml is preferred. According to a second method for preparing the nanoparticles, the polylactic polyethylene oxide of ethylene and / or propylene is dissolved in an ester, preferably in ethyl acetate, then the organic solution is poured into the aqueous solution. Nonoparticles are formed by the use of a microfluidizer.
Le solvant du copolymère est ensuite évaporé en chauffant la solution colloïdale de nanoparticules au dessus de la température d'ébullition du solvant dans le cas où l'élimination est effectuée à pression atmosphérique ou à une température inférieure si l'évaporation est effectuée sous pression réduite. Après que le solvant ait été éliminé, la suspension de nanoparticules dans l'eau est filtrée sur un filtre de diamètre de pores d'environ 1 μm, .de façon à éliminer les agrégats et les grosses particules. Le rendement en nanoparticules obtenues dépasse généralement 50 %.The solvent of the copolymer is then evaporated by heating the colloidal solution of nanoparticles above the boiling temperature of the solvent in the case where the elimination is carried out at atmospheric pressure or at a lower temperature if the evaporation is carried out under reduced pressure . After the solvent has been removed, the suspension of nanoparticles in water is filtered through a filter with a pore diameter of approximately 1 μm, so as to remove the aggregates and large particles. The yield of nanoparticles obtained generally exceeds 50%.
La formation de nanoparticules peut être effectuée en présence d'un principe actif pharmaceutique qui peut être introduit soit dans le solvant du copolymère soit dans le solvant de précipitation, il doit de préférence être soluble dans le solvant du polymère et non soluble dans l'eau, bien qu'il soit toujours possible de former des nanoparticules si le principe actif est soluble dans l'eau, le rendement en sera néanmoins amoindri. Les nanoparticules obtenues ne contiennent que le copolymère de formule (I) ou le mélange de polymères polylactiques et de copolymère de formule (I) et éventuellement un principe actif si la précipitation est effectuée en présence d'un principe actif. Elles présentent un diamètre moyen compris entre 50 et 500 nm et de préférence un diamètre moyen compris entre 50 et 250 nm.The formation of nanoparticles can be carried out in the presence of a pharmaceutical active ingredient which can be introduced either in the solvent of the copolymer or in the precipitation solvent, it must preferably be soluble in the solvent of the polymer and not soluble in water , although it is always possible to form nanoparticles if the active principle is soluble in water, the yield will nevertheless be reduced. The nanoparticles obtained contain only the copolymer of formula (I) or the mixture of polylactic polymers and of copolymer of formula (I) and optionally an active principle if the precipitation is carried out in the presence of an active principle. They have an average diameter between 50 and 500 nm and preferably an average diameter between 50 and 250 nm.
Les nanoparticules obtenues sont utilisées pour des injections dans un organisme vivant dans la mesure où leur avantage essentiel est de pouvoir éviter le système réticulo endothélial, ainsi leur application principale se trouve en pharmacie humaine ou animale.ou pour le diagnostic médical. Ces produits sont injectables par voie intramusculaire, sous cutanée, intraartérielle, intraveineuse, intraorgane ou intracavités sans risque anaphylactique L'invention sera plus complètement décrite à l'aide des exemples suivants qui ne doivent pas être considérés comme limitatifs de l'invention.The nanoparticles obtained are used for injections into a living organism insofar as their essential advantage is to be able to avoid the reticuloendothelial system, thus their main application is found in human or animal pharmacy. Or for medical diagnosis. These products are injectable intramuscularly, subcutaneously, intraarterially, intravenously, intraorganically or intracavities without anaphylactic risk The invention will be more fully described with the aid of the following examples which should not be considered as limiting the invention.
EXEMPLE 1 Préparation de copoiymères polylactique polyéthylène glycolEXAMPLE 1 Preparation of Polylactic Polyethylene Glycol Copolymers
1.1) polymère PLA2900. PEG21001.1) PLA2900 polymer. PEG2100
Dans un ballon tricol de 250 ml muni d'un agitateur à palettes et d'un réfrigérant ascendant avec circulation d'azote sec, le ballon étant chauffé par un bain d'huile régulé, on introduit : dl lactide 144 g polyéthylène glycol 79.3 g octoate stanneux 0.256 g toluène distillé 335 gDl lactide 144 g polyethylene glycol 79.3 g are introduced into a 250 ml three-necked flask fitted with a paddle stirrer and an ascending cooler with circulation of dry nitrogen, the flask being heated by a regulated oil bath. stannous octoate 0.256 g distilled toluene 335 g
Le lactide est recristallisé la veille dans l'acétate d'éthyle, puis lavé le jour même à l'éther éthylique. On le sèche sous vide. On charge tous les réactifs puis on chauffe sous léger reflux (110-114°C) pendant 5 heures et demi. Le solvant est ensuite éliminé sous vide à l'aide d'un évaporateur rotatif (40 mm de Hg - 100°C).The lactide is recrystallized the day before from ethyl acetate, then washed the same day with ethyl ether. It is dried under vacuum. All the reagents are loaded and then heated under slight reflux (110-114 ° C) for 5 hours and a half. The solvent is then removed under vacuum using a rotary evaporator (40 mm Hg - 100 ° C).
On obtient 226.3 g de concentrât.226.3 g of concentrate are obtained.
La purification du copolymère est effectuée de la façon suivante :The purification of the copolymer is carried out as follows:
On charge : concentrât 215 g dichlorométhane 280 gLoad: concentrate 215 g dichloromethane 280 g
On agite jusqu'à formation d'une solution homogène. Cette solution est coulée lentement dans 900 ml d'hexane à froid. Le polymère précipite sous forme d'une pâte qui est séparée par décantation. Le catalyseur de polymérisation est éliminé dans la phase hexanique. Après séparation du polymère il est mis à sécher dans une étuve sous vide à 40 °C. On obtient 188.4 g de copolymère dont la masse est analysée par résonnance magnétique nucléaire, la masse de polyéthylène glycol est de 2100 et celle de polylactique de 2900, ce qui représente 40 motifs lactique et 48 motifs oxyde d'éthylène 1.2) polymère PLA9600.PEG2100Stir until a homogeneous solution is formed. This solution is poured slowly into 900 ml of cold hexane. The polymer precipitates in the form of a paste which is separated by decantation. The polymerization catalyst is removed in the hexane phase. After separation of the polymer, it is put to dry in an oven under vacuum at 40 ° C. 188.4 g of copolymer are obtained, the mass of which is analyzed by nuclear magnetic resonance, the mass of polyethylene glycol is 2100 and that of polylactic is 2900, which represents 40 lactic units and 48 ethylene oxide units. 1.2) PLA9600 polymer. PEG 2100
On reproduit l'exemple 1.1 en introduisant les composés suivants : dl lactide 48.6 g polyéthylène glycol 10 g octoate stanneux 0.085 g toluène distillé 90 g après réaction on obtient 63,6 g de concentrât que l'on purifie par la méthode suivante : on met en solution 40 g de concentrât dans 200 g de dichlorométhane jusqu'à l'obtention d'une solution homogène. Cette solution est versée lentement dans 800 ml d'eau maintenu entre 55 et 60°C. Le polymère précipite et le dichlorométhane est évaporé, le lactide non réagi reste en solution aqueuse, le polymère est centrifugé puis séché à l'étuve sous vide à 40°C. On obtient 35g de polymère dont l'analyse par résonnance magnétique nucléaire permet de déterminer le poids moléculaire. Ce dernier est de 9600 pour la chaîne lactique et de 2100 pour la chaîne polyoxyde d'éthylène, ce qui représente 133 motifs lactique et 48 motifs oxyde d'éthylène.Example 1.1 is reproduced by introducing the following compounds: dl lactide 48.6 g polyethylene glycol 10 g stannous octoate 0.085 g toluene distilled 90 g after reaction 63.6 g of concentrate are obtained which are purified by the following method: in solution 40 g of concentrate in 200 g of dichloromethane until a homogeneous solution is obtained. This solution is poured slowly into 800 ml of water maintained between 55 and 60 ° C. The polymer precipitates and the dichloromethane is evaporated, the unreacted lactide remains in aqueous solution, the polymer is centrifuged and then dried in an oven under vacuum at 40 ° C. 35 g of polymer are obtained, the analysis of which by nuclear magnetic resonance makes it possible to determine the molecular weight. The latter is 9600 for the lactic chain and 2100 for the polyethylene oxide chain, which represents 133 lactic units and 48 ethylene oxide units.
1.3) polymère PLA400001.3) polymer PLA40000
Dans un réacteur d'un litre chauffé par un bain d'huile et muni d'un agitateur sous forme d'une ancre et d'un réfrigérant ascendant et maintenu sous azote, on introduit 180 g de xylène distillé avant emploi et 0,180 g d'octoate d'étain, on chauffe, puis on introduit 120 g de dl lactide S de la société Boehringer préalablement recristallisé dans l'acétate d'éthyle et lavé à l'éther sulfurique.In a liter reactor heated by an oil bath and provided with a stirrer in the form of an anchor and an ascending cooler and maintained under nitrogen, 180 g of xylene distilled before use and 0.180 g d octoate of tin, the mixture is heated and then 120 g of dl lactide S from the company Boehringer, previously recrystallized from ethyl acetate and washed with sulfuric ether, are introduced.
On laisse réagir 5 heures à 140°C , en fin de réaction, on refroidit rapidement puis on élimine une partie du xylène sous vide. On dissout le polymère dans le dichlorométhane et on le précipite par le méthanol. On le sèche dans une étuve à vide à 65°C. EXEMPLE 2The reaction medium is left to react for 5 hours at 140 ° C., at the end of the reaction, it is rapidly cooled and then part of the xylene is removed in vacuo. The polymer is dissolved in dichloromethane and precipitated with methanol. It is dried in a vacuum oven at 65 ° C. EXAMPLE 2
Préparation de nanoparticules à partir de ces polymères par la première méthode de préparationPreparation of nanoparticles from these polymers by the first method of preparation
On utilise 50 mg d'un mélange selon le tableau suivant de copolymère préparé en 1.1, de polymère polylactique selon 1.3 et d'un polymère polylactique de poids moiéculaire 18 000 marqué au carbone 14 que l'on dissout dans 5 ml d'acétone. Un essai comparatif est effectuée en utilisant des nanoparticules préparées selon l'art antérieur à partir du même polymère polylactique mais en présence d'un agent protecteur colloïdal qui est le Pluronic F68 ou Poloxamer 188. Les nanoparticules sont préparées par précipitation en versant lentement ce volume dans 5 ml de tampon phosphate 0,13 molaire (pH 7,4). La suspension colloïdale obtenue est évaporée 30 minutes au rotavapor à température ambiante et sous une pression de 3 mm de .Hg. La suspension est alors filtrée sur un filtre de 1,2 μm afin d'éliminer les grosses particules et les aggrégats.50 mg of a mixture according to the following table of copolymer prepared in 1.1, of polylactic polymer according to 1.3 and of a polylactic polymer of molecular weight 18,000 marked with carbon 14 are used, which is dissolved in 5 ml of acetone. A comparative test is carried out using nanoparticles prepared according to the prior art from the same polylactic polymer but in the presence of a colloidal protective agent which is Pluronic F68 or Poloxamer 188. The nanoparticles are prepared by precipitation by slowly pouring this volume in 5 ml of 0.13 molar phosphate buffer (pH 7.4). The colloidal suspension obtained is evaporated for 30 minutes on a rotary evaporator at room temperature and under a pressure of 3 mm . Hg. The suspension is then filtered through a 1.2 μm filter in order to remove large particles and aggregates.
On injecte à chaque rat 400 μl de suspension, les rats sont répartis en lots de cinq, un pour chaque concentration en polyoxyde d'éthylène. La cinétique de capture des particules par le système réticulo endothélial est représentée en portant la radioactivité restant dans le plasma en % de la radioactivité présente dans le plasma en fin de perfusion en fonction du temps. La demi vie des particules en fonction de la quantité de polyéthylène glycol introduite est indiquée dans le tableau ci-dessous. Les courbes de radioactivité restante dans le plasma sont tracées en annexe. Each rat is injected with 400 μl of suspension, the rats are divided into batches of five, one for each concentration of polyethylene oxide. The kinetics of particle capture by the reticuloendothelial system is represented by plotting the radioactivity remaining in the plasma as a% of the radioactivity present in the plasma at the end of the perfusion as a function of time. The half-life of the particles as a function of the amount of polyethylene glycol introduced is indicated in the table below. The curves of radioactivity remaining in the plasma are plotted in the appendix.
Préparation des nanoparticules à partir de ces polymères par la deuxième méthode de préparationPreparation of nanoparticles from these polymers by the second method of preparation
Sans agent tensio-actif .Without surfactant.
On utilise 100 mg de PLA5o9600PEG2 00 et 10 mg de poly(d,l-acide lactique) de poids moléculaire 18000 marqué au ^C que l'on dissout dans 1 ml d'acétate d'éthyle. Cette solution est ensuite dispersée à l'aide d'un ultraturrax dans 10 ml d'eau. Une émulsion grossière est obtenue. Elle est ensuite recyclée pendant 2 minutes à l'aide d'un homogénéisateur haute pression type MICROFLUIDICS. L'émulsion est débarrassée de l'acétate d'éthyle à l'aide d'un évaporateur rotatif à une pression de 50.5 cm de mercure à 20°C. Le pseudolatex obtenu est constitué de nanoparticules d'un diamètre moyen de 145 ± 60 nm. La demi-vie de ces nanoparticules dans le sang est de 1 heure.100 mg of PLA50 9600 PEG 200 and 10 mg of poly (d, 1-lactic acid) of molecular weight 18000 labeled with C are used, which is dissolved in 1 ml of ethyl acetate. This solution is then dispersed using an ultraturrax in 10 ml of water. A coarse emulsion is obtained. It is then recycled for 2 minutes using a high pressure homogenizer type MICROFLUIDICS. The emulsion is freed from ethyl acetate using a rotary evaporator at a pressure of 50.5 cm of mercury at 20 ° C. The pseudolatex obtained consists of nanoparticles with an average diameter of 145 ± 60 nm. The half-life of these nanoparticles in the blood is 1 hour.
Avec un agent tensio-actif.With a surfactant.
On procède de même que dans l'exemple précédent en dissolvant 50 mg de PLA96O0PEG2100> 50 mg de et 10 mg deThe procedure is the same as in the previous example by dissolving 50 mg of PLA96O0PEG2100 > 50 m g of and 10 mg of
PLAdjtβOOO marqué au 14C que l'on dissout dans 1 ml d'acétate d'éthyle.PLAdjt β OOO labeled with 14 C which is dissolved in 1 ml of ethyl acetate.
La phase aqueuse est une solution de cholate de sodium à 10 g.l"1 dans l'eau. Diamètre des nanoparticules : 105 ± 45 nm. Demie-vie : 0.5 heure. The aqueous phase is a solution of sodium cholate at 10 gl -1 in water. Diameter of the nanoparticles: 105 ± 45 nm. Half-life: 0.5 hour.

Claims

REVENDICATIONS
- 1 - Nanoparticules évitant le système réticulo endothélial caractérisées en ce qu'elles sont constituées d'un copolymère polylactique polyoxyde d'éthylène et/ou de propylene comportant une majorité de motifs de formule :- 1 - Nanoparticles avoiding the reticuloendothelial system, characterized in that they consist of a polylactic copolymer of ethylene and / or propylene oxide comprising a majority of units of formula:
dans laquelle : R représente dans chacun des motifs oxyde d'alkylène un groupe identique ou différent choisi parmi l'hydrogène ou un groupe méthyle R' représente l'hydrogène ou un groupe alkyle contenant 1 à 4 atomes de carbone n est un nombre entier compris entre 20 et 1000 m est un nombre entier compris entre 10 et 1500. in which: R represents in each of the alkylene oxide units an identical or different group chosen from hydrogen or a methyl group R 'represents hydrogen or an alkyl group containing 1 to 4 carbon atoms n is an integer included between 20 and 1000 m is an integer between 10 and 1500.
- 2 - Nanoparticules selon la revendication 1 caractérisées en ce qu'elles sont constituées d'un mélange d'un copolymère selon la revendication 1 et d'un ou plusieurs polymère(s) polylactique.- 2 - Nanoparticles according to claim 1 characterized in that they consist of a mixture of a copolymer according to claim 1 and one or more polylactic polymer (s).
- 3 - Nanoparticules selon la revendication 2 caractérisées en ce qu'elles sont constituées d'un mélange de polymères selon la revendication 2 et d'un principe actif pharmaceutique.- 3 - Nanoparticles according to claim 2 characterized in that they consist of a mixture of polymers according to claim 2 and a pharmaceutical active ingredient.
- 4 - Nanoparticules selon l'une quelconque des revendications précédentes caractérisées en ce que dans la formule (I)- 4 - Nanoparticles according to any one of the preceding claims, characterized in that in formula (I)
R représente l'hydrogène R' représente un groupe méthyle n est compris entre 20 et 150 m est compris entre 10 et 150.R represents hydrogen R 'represents a methyl group n is between 20 and 150 m is between 10 and 150.
- 5 - Nanoparticules selon l'une quelconque des revendications précédentes caractérisées en ce qu'elles présentent une dimension moyenne comprise entre 50 et 500 nm - 6 - Nanoparticules selon la revendication 5 caractérisées en ce qu'elles présentent une dimension moyenne comprise entre 50 et 250 nm.- 5 - Nanoparticles according to any one of the preceding claims, characterized in that they have an average dimension of between 50 and 500 nm - 6 - Nanoparticles according to claim 5 characterized in that they have an average size between 50 and 250 nm.
- 7 - Utilisation des nanoparticules selon l'une quelconque des revendications précédentes en pharmacie humaine ou animale ou en diagnostic médical (imagerie). - 7 - Use of nanoparticles according to any one of the preceding claims in human or animal pharmacy or in medical diagnosis (imaging).
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DK0520888T3 (en) 2001-11-12
FI935868A0 (en) 1993-12-27
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FR2678168B1 (en) 1993-09-03
ES2162793T3 (en) 2002-01-16
FI935868A (en) 1993-12-27
JPH06508831A (en) 1994-10-06
EP0520888B1 (en) 2001-09-19
NO934358L (en) 1993-12-01
FI109576B (en) 2002-09-13
CA2102186A1 (en) 1992-12-29
GR3036773T3 (en) 2002-01-31
JP3465260B2 (en) 2003-11-10
NO934358D0 (en) 1993-12-01
US5683723A (en) 1997-11-04
CA2102186C (en) 2005-09-13
DE69232062T2 (en) 2002-04-25
WO1993000101A1 (en) 1993-01-07
EP0520888A1 (en) 1992-12-30
ATE205718T1 (en) 2001-10-15
DE69232062D1 (en) 2001-10-25
MX9203353A (en) 1992-12-01
PT520888E (en) 2002-02-28
FR2678168A1 (en) 1992-12-31
IE922110A1 (en) 1992-12-30

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