EP4041319A1

EP4041319A1 - Non degradable radio-opaque embolisation microsphere

Info

Publication number: EP4041319A1
Application number: EP20781605.9A
Authority: EP
Inventors: Anne BEILVERT; Emeline CORUS; Laurent Bedouet; Olivier FOUGERE
Original assignee: Guerbet SA
Current assignee: Guerbet SA
Priority date: 2019-10-07
Filing date: 2020-10-07
Publication date: 2022-08-17
Also published as: KR20220079600A; JP2022550957A; CN114555659A; WO2021069528A1; US20230285601A1

Abstract

The invention relates to a polymer comprising a crosslinked matrix, the matrix being based on at least: a) 20 to 90% hydrophilic monomer; b) 5 to 50% radio-opaque halogenated monomer; c) 1 to 15% non-biodegradable hydrophilic crosslinking agent; and d) 0.1 to 10% transfer agent chosen among the alkyl halides and cycloaliphatic or aliphatic thiols having, in particular, 2 to 24 carbon atoms, and optionally having another functional group chosen among the amino, hydroxy and carboxy groups. The invention further relates to a pharmaceutical composition comprising at least one polymer according to the invention, in association with a pharmaceutically acceptable vehicle, advantageously for a parenteral administration. The invention further relates to a kit comprising a pharmaceutical composition comprising the polymer according to the invention in association with a pharmaceutically acceptable vehicle for a parenteral administration, and an injection means.

Description

RADIO-OPAQUE NON-DEGRADABLE EMBOLIZATION MICROSPHERE

FIELD OF THE INVENTION

The present invention relates to a non-biodegradable radiopaque polymer, in particular suitable for being implanted in an individual and optionally for releasing active principles or macromolecules in a controlled manner. The non-biodegradable radiopaque polymer according to the invention in particular forms non-biodegradable radiopaque embolization microspheres intended to be injected into an individual. A subject of the present invention is also a pharmaceutical composition comprising the polymer according to the invention.

PRIOR ART

Therapeutic vascular occlusion (i.e., embolization) is used to prevent or treat certain pathological conditions in situ. It can be carried out by means of catheters allowing, under imaging control, to position particulate occlusion agents (that is to say emboli or embolic agents) in the circulatory system. It has a variety of medical applications such as the treatment of vascular malformations, hemorrhagic processes, or tumors, including, for example, uterine fibroids, primary or secondary tumors of the liver. For example, vascular occlusion can cause tumor necrosis and prevent a more invasive operation. This occlusion technique can also be coupled with the provision of an anticancer agent as part of chemoembolization. This increases the local drug concentration by targeted injection, as well as its residence time in the tumor. In the case of vascular malformations, vascular occlusion helps normalize blood flow to normal tissues, to aid in surgery by limiting the risk of bleeding. In hemorrhagic processes, vascular occlusion can lead to decreased flow, which promotes healing of the arterial wound. In addition, depending on the pathologies being treated, embolization can be used for temporary or permanent purposes.

Commercial embolic agents for vascular occlusion include embolization fluids (acrylic glues, gels), mechanical devices, and particles for embolization. The choice of a specific material depends on many factors, such as the type of lesion to be treated and the type of catheter to be used and the need for temporary or permanent embolization. The particles for embolization mainly include polymers, natural and synthetic. Polymer-type embolic agents have an advantage because they have, for the most part, good tissue biocompatibility.

They can be hydrophobic materials. However, the latter are used less and less in embolization because they are difficult or even impossible to inject into the catheters and involve a risk of obstruction of the catheter which forces the user to replace it, lengthens the duration of the procedure and increases the risks.

For example, dry polyvinyl alcohol (PVA) particles are injected into catheters after they are suspended in injectable fluids such as saline and iodinated contrast media. They remain quite hydrophobic even after being suspended and tend to form aggregates in the syringe, hub and lumen of the catheter, which occlude the injection catheters. Several technical devices (addition of collagen, albumin, dextran, gelatin sponge particles, alcohol, etc.) have been proposed without success to prevent these aggregates and obstruction (Derdeyn CP1, Moran CJ, Cross DT, Dietrich HH, Dacey RG Jr. Polyvinyl alcohol particle size and suspension characteristics. AJNR Am J Neuroradiol. 1995 Jun-Jul; 16 (6): 1335-43).

Hydrophilic materials have therefore been considered for embolization, such as trisacryl gelatin microspheres or gelatin sponges, as they are easier to suspend, injectable and less often cause obstruction of catheters than hydrophobic materials (CP Derdeyn, VB Graves, MS Salamat and A Rappe Collagen-coated acrylic microspheres for embolotherapy: in vivo and in vitro characteristics. American Journal of Neuroradiology April 1997, 18 (4) 647-653).

In order to verify the exact location of the embolic particles and to detect reflux in non-target organs, the embolic particles are made radio-opaque, that is, visible on X-ray images. opaque can thus be localized in order to detect whether the coverage of a chemotherapy is suitable or not, in order to observe whether the dispersion of the embolic particles in a target area is homogeneous or heterogeneous, complete or incomplete, or in order to detect whether particles are located outside the target area.

Embolic particles of radiopaque polymers are described in US Pat. No. 4,622,367 and in the publication Horak et al, Biomaterials, 1987, 8, 142. These particles are based on polymers and copolymers of acrylates and methacrylates and comprise a derivative of amino-triiodobenzoic acid which is distributed in the matrix network. However, the tri-iodinated molecule is too bulky to be easily diffused in the network and is therefore mainly grafted on the surface of the particle, limiting the transport. of water inside the particle, thereby causing the loss of the hydrophilic character of the material and hence the loss of the swelling properties in water. This drawback limits the medical applications of such materials, in particular by making their administration by injection very difficult or even impossible.

The publication Jayakn ^' shnan et al., J. Biomed Mat Res, 1990, 24, 993 _, describes microspheres of radiopaque hydrogel type based on PHEMA / iothalamic acid copolymers and PHEMA / iopanoic acid. However, these microspheres are very rigid, and therefore difficult to inject.

The publication Horak et al, J. Biomed Mat Res, 1997, 34, 183, describes particles of radiopaque hydrogel type based on PHEMA. The presence of an ionizable group within the structure improves the swelling properties of the microsphere, but these remain limited due to the porous structure of the microsphere. They therefore remain difficult to inject.

Patent application US 2009/0297612 describes particles of spherical, solid and homogeneous radiopaque copolymers, with controllable swelling properties and their use in embolization. These particles are based on at least one hydrophilic monomer and on at least one radiopaque monomer of general formula (CH2 = CR) -CO-RI. The examples of this application show that the swelling properties decrease as the content of iodinated monomer increases, thus stiffening the microspheres. Such embolization microspheres are marketed under the name “X-Spheres ^® ”. It is therefore difficult to obtain non-rigid microspheres comprising a sufficient quantity of iodinated monomer.

The patent application US 2015/0110722 and the publication Duran et al., Theranostics 2016, 6, 28, describe radiopaque particles based on crosslinked PVA and an iodine compound (triiodobenzyl). These particles nevertheless have a high density (density 1, 21 - 1, 36 g / cc) and a rigid structure, a reduced water content, causing difficulty in suspending them, very limited injectability or requiring the use of catheters with an internal diameter clearly greater than the diameter of the microspheres.

In all these examples, it is clearly observed that the addition of a radiopaque entity or monomer having halogenated groups considerably reduces the hydrophilic character of the material. In summary, current microspheres loaded with iodine to be visible in X-ray are hydrophobic, dense and rigid. As a result, (1) they are difficult to keep in suspension for the duration of the injection into the catheter, and (2) they often block the catheter, even when their diameter is smaller than the internal diameter of the catheter (Duran 2016). There is therefore a great need to prepare microspheres based on a radiopaque polymer which, while comprising halogens (about 5 to 50% by mole), remain hydrophilic and flexible when they are swollen with water. It is thus desired that these microspheres exhibit mechanical properties, in particular a rate of swelling, elasticity and compressibility, suitable for injection via a catheter or a microcatheter and be able to regain their initial shape after injection while avoiding embolization far from the body. targeted site.

It is also desired that these microspheres can be maintained in suspension in contrast medium - buffer solution mixtures for the duration of the injection into the catheter. Indeed, to be injectable, the microspheres are generally suspended in a mixture of nonionic iodinated contrast product and buffer solution. For this, radiologists generally use a contrast product solution and optionally physiological serum, bicarbonate buffer or phosphate buffer, advantageously a 100% contrast product solution. To ensure their injectability, the microspheres must be kept in homogeneous suspension in this solution. If the microspheres sediment or, conversely, float on the surface of the solution, the resulting suspension is inhomogeneous, unstable and therefore cannot be injected into the patient.

It is thus advantageous to have microspheres having an adequate density to allow their suspension in a homogeneous manner in a mixture comprising physiological serum, bicarbonate buffer or phosphate buffer with a contrast product in proportions of between 50/50 and 0/100.

They must also be able to be made visible by Magnetic Resonance Imaging (MRI) and be capable of loading active ingredients.

SUMMARY OF THE INVENTION

The present invention thus makes it possible to meet these needs and to propose a solution to the various drawbacks encountered in the prior art.

The main subject of the present invention is a polymer comprising a crosslinked matrix, said matrix being based on at least: a) 20% to 90% of hydrophilic monomer chosen from N-vinylpyrrolidone and a monomer of formula (I) below:

(CH ₂ = CRI) -CO-D (I) in which:

• D represents 0-1 or NH-Z, Z representing (CrC _ô ) alkyl, - (CR R) _m -CH, - (CH ₂ -CH ₂ -0) _m - H, - (CH ₂ -CH2-0 ) m-CH ₃ , -C (R OH) _m or - (CH2) _m -NR5R6 with m representing an integer from 1 to 30, preferably m is equal to 4 or 5

• Ri, R ₂ , R ₃ , R ₄ , R ₅ and R _Ô represent, independently of each other, H or a (Cr C _ô ) alkyl; b) 5% to 50% of halogenated radiopaque monomer of the following general formula (II):

(CH ₂ = CR ₇ ) -CO-Y (II) in which

• Y represents OW, (O-Rs) _p -W, (NH-Rs) _p -W or NH-W, W representing Ar, L-Ar, and p being an integer between 1 and 10, preferably between 1 and 4 in which:

• Ar represents a (Cs-C36) aryl or (Cs-C36) heteroaryl group, said group being substituted with one, two or three atom (s) of iodine and / or bromine, and optionally substituted with one to four, preferably two or three groups selected from (Cr Cio) alkyl, -NR _a Rb, -NR _c CORd, -COOR _e , -ORf, -OCOR _g , -CONRhR ,, -OCONRjRk, -NRCOOR, - NR _r CONRsRt , -OCOORu, and -COR _v ;

• L represents - (Chhj _n -, - (HCCH) _n -, -O-, -S-, -SO-, -SO ₂ -, -OSO ₂ , -NR ₉ -, -CO-, -COO-, - OCO-, -OCOO-, -CONR ₁₀ -, -NR ₁₁ CO-, -OCONR ₁₂ -, -NR ₁₃ COO- or -NR ₁₄ CONR ₁₅ -, n being an integer from 1 to 10;

• R9 to R15 and R _a to R _v represent, independently of each other, a hydrogen atom, a (CrCio) alkyl, said (C1-C10) alkyl being optionally substituted with 1 to 10 OH group (s), or a - (CH ₂ -CH ₂ -0) _q -R ', R' being a hydrogen atom or a - (Ci-C ₆ ) alkyl and q being an integer between 1 and 10, preferably between 1 and 5;

• R ₇ represents H or a (CrC ₆ ) alkyl;

• Rs represents a group chosen from (Ci-C3 _ô ) alkylene, (C3-C3 _ô ) cycloalkylene, (C ₂ - C3 _ô ) alkenylene, (C3-C3 _ô ) cycloalkenylene, (C2-C3 _ô ) alkynylene, (C3 -C3 _ô ) cycloalkynylene, (C5- C3 _ô ) arylene and (C5-C36) heteroarylene, c) 1% to 15% of linear or branched non-biodegradable hydrophilic crosslinking agent having (CH2 = (CRi6)) - groups at each of its ends, each R ₆ independently representing H or a (C 1 -C ₆ ) alkyl; and d) 0.1% to 10% of transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino groups , hydroxy and carboxy, the percentages of monomers a) to c) being cited in moles relative to the total number of moles of monomers and the percentages of compound d) being cited in moles relative to the number of moles of hydrophilic monomer a).

The inventors have discovered that the addition of a transfer agent during the polymerization of a radiopaque polymer makes it possible to improve the hydrophilic properties of the microspheres formed by this polymer and thus allows their injection. When the transfer agent is not added to the polymer according to the invention, the microspheres obtained are non-injectable, which limits their field of therapeutic application. The polymer according to the invention thus makes it possible to obtain embolization microspheres which are easily injectable and which meet all the needs mentioned above.

The present invention further relates to a pharmaceutical composition comprising at least one polymer according to the invention, in association with a pharmaceutically acceptable vehicle, advantageously for administration by injection.

A subject of the present invention is also a kit comprising a pharmaceutical composition as defined above and at least one injection means for parenteral administration of said composition.

A subject of the present invention is also a kit comprising on the one hand a pharmaceutical composition as defined above and on the other hand a contrast agent for imaging by X-ray, by magnetic resonance or by ultrasound, and optionally in less an injection medium for parenteral administration. A subject of the present invention is also a compound of the following general formula (V):

(CH ₂ = CR ₂₈ ) -CO-Y '(V) in which

• R ₂₈ represents H or a (Ci-C ₆ ) alkyl;

• Y 'represents, (0-R ₂₉ ) _t -W'-Ar', or NH-W'-Ar ', t being an integer between 1 and 10, preferably between 1 and 4;

• R ₂ 9 represents a group selected from (C ₂ -C 3 _O) alkylene;

• W 'represents a single bond, -CONR ₃₀ -, or -NR ₃₁ CO-;

• Ar 'represents a (Cs-C ₃₆ ) aryl group, said group being substituted by one, two or three atom (s) of iodine and / or bromine, and optionally substituted by one to four, preferably two or three , groups selected from (CrCio) alkyl, -NR ₃₂ R ₃₃ , -NR34COR35, -COOR36, -OR37, -OCOR38, -CONR39R40, -OCONR4iR4 ₂ , -NR43COOR44, NR ₄₅ CONR ₄₆ R _47, -OCOOR ₄₈ , and - COR ₄₉ ;

• R ₃₀ and R ₃₁ represent, independently of one another, a hydrogen atom or a (CrC ₆ ) alkyl;

• R ₃₂ to R ₄₉ represent, independently of each other, a hydrogen atom, a (CrCio) alkyl, said (C1-C10) alkyl being optionally substituted by 1 to 10 OH group (s), or a - group (CH ₂ -CH ₂ -0) _t -R ”, R” being a hydrogen atom or a - (CrC ₆ ) alkyl and t 'being an integer between 1 and 10, preferably between 1 and 5.

A subject of the present invention is also the use of the compound of general formula (V) as defined above as a radiopaque halogenated monomer.

DEFINITIONS

The expression “matrix based on” should of course be understood to mean a matrix comprising the mixture and / or the product of the reaction between the constituents of bases used for the polymerization in a heterogeneous medium of this matrix, preferably only the product. of the reaction between the different basic constituents used for this matrix, some of them possibly intended to react or capable of reacting with each other or with their close chemical environment, at least in part, during the various phases of the manufacturing process of the matrix, in particular during a step of polymerization. Thus, the basic constituents are the reagents intended to react together during the polymerization of the matrix. The base constituents are therefore introduced into a reaction mixture optionally further comprising a solvent or a mixture of solvents and / or other additives such as at least one salt and / or at least one polymerization initiator and / or at least one. stabilizer such as PVA. In the context of the present invention, the reaction mixture comprises at least the monomers a), b), c) and the transfer agent d) mentioned in the present description as basic constituents, optionally a polymerization initiator as per example t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also called 4,4'-Azobis (4- cyanopentanoic acid)), AIBN (azobisisobutyronitrile), or 1, 1 '- Azobis (cyclohexane carbonitrile) or one or more thermal initiators such as 2-Hydroxy-4 '- (2-hydroxyethoxy) -2-methylpropiophenone (106797-53-9); 2-Hydroxy-2-methylpropiophenone (Darocur® 1173, 7473-98-5); 2,2-Dimethoxy-2-phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenyl acetophenone (Irgacure®, 24650-42-8) or 2-Methyl-4 '- (methylthio) -2-morpholinopropiophenone (Irgacure®, 71868-10- 5), and at least one solvent, preferably a solvent mixture comprising an aqueous solvent and an organic solvent such as an apolar aprotic solvent, for example a water / toluene mixture.

Thus, according to the present invention, the matrix is at least based on the monomers a), b), c) and the transfer agent d) mentioned in the present description, these compounds therefore being basic constituents.

Thus, in the present description, expressions similar to "the [basic constituent X] is in particular added to the reaction mixture in an amount of YY% to YYY%" and to "the crosslinked matrix is in particular based on [ base component X] in an amount of YY% to YYY% ^” are interpreted similarly. Likewise, expressions similar to "the reaction mixture comprises at least [the base component X]" and to "the crosslinked matrix is based on at least [the base component X]" are interpreted similarly.

By "organic phase" of the reaction mixture is meant, within the meaning of the present invention, the phase comprising the organic solvent and the compounds soluble in said organic solvent, in particular the monomers, the transfer agent and the polymerization initiator.

By “(Cx-Cy) alkyl” group is meant, within the meaning of the present invention, a monovalent saturated, linear or branched hydrocarbon chain, comprising X to Y carbon atoms, X and Y being integers between 1 and 36, preferably 1 and 18, in particular 1 and 6. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or even hexyl groups.

By “(Cx-C _Y ) aryl” is meant, within the meaning of the present invention, an aromatic hydrocarbon group, preferably comprising from X to Y carbon atoms, and comprising one ring or several joined rings, X and Y being integers between 5 and 36, preferably 5 and 18, in particular 5 and 10. By way of example, mention may be made of phenyl or naphthyl groups.

By "(Cx-C _Y ) heteroaryl" is meant, within the meaning of the present invention, an aromatic group comprising X to Y cyclic atoms including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as for example sulfur, nitrogen or oxygen atoms, the other ring atoms being carbon atoms. X and Y are whole numbers between 5 and 36, preferably 5 and 18, in particular 5 and 10. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl groups or indyle.

By “(Cx-C _Y ) alkylene” group is meant, within the meaning of the present invention, a divalent, linear or branched hydrocarbon chain, comprising X to Y carbon atoms, X and Y being whole numbers between 1 and 36, preferably 1 and 18, in particular 1 and 6. By way of example, mention may be made of methylene, ethylene, propylene, butylene, pentylene or even hexylene groups.

For the purposes of the present invention, the term “(Cx-C _Y ) cycloalkylene” group is understood to mean a cyclic divalent saturated hydrocarbon group comprising from X to Y cyclic carbon atoms, X and Y being integers between 3 and Y. 36, preferably 3 and 18, in particular 3 and 6. By way of example, mention may be made of cyclopropylene, cyclohexylene or also cyclopentylene groups.

By “(Cx-C _Y ) alkenylene” group is meant, within the meaning of the present invention, a divalent, linear or branched hydrocarbon chain, comprising X to Y carbon atoms and at least one double bond, X and Y being integers between 2 and 36, preferably 2 and 18, in particular 2 and 6. By way of example, mention may be made of the vinylene (ethenylene) or propenylene groups.

For the purposes of the present invention, the term “(Cx-C _Y ) cycloalkenylene” group is understood to mean a cyclic divalent saturated hydrocarbon group comprising from X to Y cyclic carbon atoms and at least one double bond, X and Y being integers between 3 and 36, preferably 3 and 18, in particular 3 and 6. By (Cx-C _Y ) alkynylene group is meant, within the meaning of the present invention, a divalent, linear or branched hydrocarbon chain, comprising X to Y carbon atoms and at least one triple bond, X and Y being whole numbers between 2 and 36, preferably 2 and 18, in particular 2 and 6.

By (Cx-C _Y ) cycloalkynylene group is meant, within the meaning of the present invention, a cyclic divalent saturated hydrocarbon group comprising from X to Y cyclic carbon atoms and at least one triple bond, X and Y being integers. between 3 and 36, preferably 3 and 18, in particular 3 and 6.

By (Cx-C _Y ) arylene is meant, within the meaning of the present invention, a divalent aromatic hydrocarbon group comprising from X to Y carbon atoms, and comprising one or more attached rings, X and Y being whole numbers including between 5 and 36, preferably 5 and 18, in particular 5 and 10. By way of example, mention may be made of the phenylene group.

By (Cx-C _Y ) heteroarylene is meant, within the meaning of the present invention, a divalent aromatic group, comprising from X to Y cyclic atoms including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as as for example sulfur, nitrogen or oxygen atoms, the other ring atoms being carbon atoms. X and Y are whole numbers between 5 and 36, preferably 5 and 18, in particular 5 and 10.

By divalent radical is meant, within the meaning of the present invention, a radical having a valence of 2, that is to say having two chemical bonds covalent, polar covalent or ionic. Said radical can comprise, for example, carbon and / or oxygen atoms.

For the purposes of the present invention, the term “dry extract” means the mass of dry microspheres contained in 1 ml of microspheres swollen with water.

DETAILED DESCRIPTION

The main subject of the present invention is a polymer comprising a crosslinked matrix, said matrix being based on at least: a) 20% to 90% of hydrophilic monomer chosen from N-vinylpyrrolidone, and a monomer of formula (I) below :

(CH ₂ = CRI) -CO-D (I) in which :

• D represents 0-1 or NH-Z, Z representing (CrC _ô ) alkyl, - (CR2R3) _m -CH3, - (CH ₂ -CH ₂ -0) _m - H, - (CH ₂ -CH2-0) m-CH ₃ , -C (R OH) _m or - (Chh m-NRsR6 with m representing an integer of 1 to 30;

• Ri, R2, R3, R4, R5 and R _O independently of one another, H or (Cr C _O) alkyl; b) 5% to 50% of halogenated radiopaque monomer of the following general formula (II):

(CH ₂ = CR ₇ ) -CO-Y (II) in which

• Ar represents a (Cs-C36) aryl or (Cs-C36) heteroaryl group, said group being substituted with one, two or three atom (s) of iodine and / or bromine, and optionally substituted with one to four, preferably two or three groups selected from (Cr Cio) alkyl, -NR _a Rb, -NR _c CORd, -COORe, -ORf, -OCOR _g , -CONRhR ,, -OCONRjRk, -NRiCOOR ₀ -, - NR _r CONRsRt, -OCOORu, and -COR _v ;

• L represents - (Chhj _n -, - (HCCH) _n -, -O-, -S-, -SO-, -SO2-, -OSO2, -NR9-, -CO-, -COO-, - OCO- , -OCOO-, -CONR10-, -NR11CO-, -OCONR12-, -NR13COO- or -NR14CONR15-, n being an integer of 1 to 10;

• R9 to R15 and R _a to R _v represent, independently of each other, a hydrogen atom; a (CrCio) alkyl, said (C1-C10) alkyl being optionally substituted with 1 to 10 OH group (s); or a group - (CH ₂ -CH ₂ -0) _q -R ', R' being a hydrogen atom or a - (Ci-C ₆ ) alkyl and q being an integer between 1 and 10, preferably between 1 and 5;

• R ₇ represents H or a (CrC ₆ ) alkyl;

• Rs represents a group chosen from ( _{C 1} -C _{3 6} ) alkylene, (C _{3 -C 3 6} ) cycloalkylene, (C ₂ - C 3 ₆ ) alkenylene, (C ₃ -C _{3 6} ) cycloalkenylene, (C ₂ -C 3 ₆ ) alkynylene , (C ₃ -C _3ô ) cycloalkynylene, (C ₅ - C _3ô ) arylene and (C ₅ -C ₃₆ ) heteroarylene. c) 1% to 15% of linear or branched non-biodegradable hydrophilic crosslinker having (CH2 = (CRi6)) - groups at each of its ends, each R _½ independently representing H or a (CrC ₆ ) alkyl; and d) 0.1% to 10% of transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino groups, hydroxy and carboxy, the percentages of monomers a) to c) being cited in moles relative to the total number of moles of monomers and the percentages of compound d) being cited in moles relative to the number of moles of hydrophilic monomer a).

Preferably, the polymer according to the invention is in the form of a spherical particle. The spherical particle is preferably a microsphere.

For the purposes of the present invention, the term “microspheres” is understood to mean spherical particles having a diameter after swelling ranging from 20 to 1200 μm, for example from 20 to 100 μm, from 40 to 150 μm, from 100 to 300 μm, from 300 to 500 µm, 500-700 µm, 700-900 µm, or 900-1200 µm, as determined by light microscopy. The microspheres advantageously have a diameter small enough to be injected by needles, a catheter or a microcatheter with an internal diameter varying from a few hundred micrometers to more than one millimeter.

The expression after swelling means that the size of the microspheres is considered after the polymerization and sterilization steps which take place during their preparation. The sterilization step involves, for example, passing the microspheres after the polymerization step in an autoclave at high temperature, typically at a temperature above 100 ° C, preferably at a temperature between 110 ° C and 150 ° C, preferably 121 ° C. During this sterilization step, the microspheres continue to swell in a controlled manner, that is to say with a controlled swelling rate. The rate of swelling is defined as: where m _w is the weight in grams of 1 ml of sedimented microspheres and m _d is the weight in grams of 1 ml of sedimented microspheres which were then lyophilized.

By controlled swelling rate is meant, within the meaning of the present invention, that the swelling rate is reproducible depending on the batches, in particular that it differs by less than 15% from one batch to another.

By sedimented microspheres is meant, within the meaning of the present invention, microspheres which are dissolved in a container and then left sufficiently a long time without agitation so that they fall to the bottom of the container in which they are contained, the supernatant thus having been able to be removed.

By "lyophilized microsphere" is meant, within the meaning of the present invention, microspheres which have undergone freezing followed by dehydration by sublimation.

By “hydrophilic monomer” is meant, within the meaning of the present invention, a monomer having a strong affinity for water, that is to say tending to dissolve in water, to mix with water. , to be wetted by water, or capable of swelling in water after polymerization.

The hydrophilic monomer a) of the present invention is chosen from N-vinylpyrrolidone, and a monomer of formula (I) below:

(CH ₂ = CRI) -CO-D (I) in which:

D represents Ol or NH-Z, Z representing (CrC ₆ ) alkyl, - (CR2R3) _m -CH3, - (CH ₂ -CH ₂ -0) _m -H, - (CH ₂ -CH2-0) m-CH ₃ , -C (R OH) _m or - (ChhJm-NRsR6 with m preferably representing an integer between 1 and 10, more preferably m is equal to 4 or 5;

Advantageously, the hydrophilic monomer a) according to the invention is chosen from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-methacrylate -butyl, methylmethacrylate, N-dimethylaminoethyl (methyl) acrylate, N, N-dimethylaminopropyl- (meth) acrylate, t-butylaminoethyl (methyl) acrylate, N, N-diethylaminoacrylate, poly (ethylene oxide) (meth) acrylate, ( meth) acrylate, methoxy poly (ethylene oxide), (meth) acrylate, butoxy poly (ethylene oxide), (meth) acrylate, poly (ethylene glycol), (meth) acrylate, methoxy poly (ethylene glycol), (meth) acrylate butoxy poly (ethylene glycol), methyl ether poly (ethylene glycol) methacrylate (m-PEGMA), and mixtures thereof.

More preferably, the hydrophilic monomer a) is poly (ethylene glycol) methyl ether methacrylate (m-PEGMA).

In the context of the present invention, the hydrophilic monomer a) is in particular added to the reaction mixture in an amount of 20% to 90%, preferably 30% to 80%, preferably 40% to 70%, in in particular from 45% to 65% by Mole, relative to the total number of moles of monomers. Thus, in the context of the present invention, the crosslinked matrix in particular based on the hydrophilic monomer a) in an amount of 20% to 90%, preferably 30% to 80%, preferably 40% to 70% , in particular from 45% to 65% by Mole, relative to the number of total moles of monomers. Radiopacity refers to the relative inability of electromagnetism, especially x-rays, to pass through dense materials, which are described as "radiopaque" appearing opaque / white in an x-ray image. Given the complexity of the content in an x-ray or fluoroscopic image, clinicians are sensitive to image quality in terms of the brightness or signal strength of the material in the image. The two main factors that contribute to the importance of radiopacity are density and atomic number. Polymer-based medical devices requiring radiopacity typically use a blend of polymers which incorporates a small amount, in weight percent, of a radiopaque element such as, for example, a heavy atom such as halogen, in particular. iodine. The ability of a device to be visualized by fluoroscopy depends on the amount or density of the radiopaque element mixed into the material. The amount of the radiopaque element in the mixture is generally limited to a small amount because it can adversely affect the material properties of the base polymer.

In the context of the present invention, the radiopaque monomer is advantageously a monomer of general formula (II) as defined above, in which Y represents NH-W, OW or (O-Rs) pW, advantageously NH- W or (O-Rs) pW, more preferably (O-Rs) _p -W, W representing Ar or L-Ar, p, Rs, L and Ar being as defined above. Preferably, Rs is a ( _{CrC 3 6} ) alkylene, in particular a (CrCis) alkylene, more particularly a (CrC ₆ ) alkylene; L represents -OCO-; and Ar represents a (Cs-C ₃₆ ) aryl, in particular a (Cs-Cio) aryl, more particularly a phenyl, substituted by one, two or three atom (s) of iodine and / or bromine, preferably d 'iodine, and optionally two or three, groups chosen from -NR _a Rb, -NR _c CORd, -COOR _e , -OCOR _g , -CONRhR ,, -OCONR _j Rk, - NRiCOORo- and -NR _r CONR _s R _t , preferably -NR _a Rb, -NR _c CORd.

Advantageously, the radiopaque monomer is a monomer of general formula (II) as defined above, in which Y represents NH-W or (O-Rs) _p -W, more advantageously (O-Rs) _p -W , W representing Ar or L-Ar, and p, Rs, L and Ar being as defined above. Preferably, Rs is a (C ₂ -C 3 ₆ ) alkylene, in particular a (C ₂ -Cis) alkylene, more particularly a (C ₂ -C ₆ ) alkylene; L represents -OCO-, -C (O) NRio-, or -NRnC (O) -; and Ar represents a (Cs-C ₃₆ ) aryl, in particular a (Cs-Cio) aryl, more particularly a phenyl, substituted by one, two or three atom (s) of iodine and / or bromine, preferably d 'iodine, and optionally two or three, groups chosen from - NR _a R _b , -NRcCORd, -COORe, -OCORg, -CONRhR ,, -OCONRjRk, -NRiCOORo- and -NR _r CONR _s R _t , preferably -NR _a R _b , -NR _c COR _d and -C (0) NR _h R ,. Advantageously, Ar represents a (Cs-Cio) aryl, more particularly a phenyl, substituted with three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (CrCio) alkyl, -NR _a Rb, -NR _c CORd, -COOR _e , -OCOR _g , -CONRhR ,, -OCONRjRk, -NRLCOOR _O - and -NR _r CONR _s R _t .

Advantageously, Ar represents a phenyl substituted with three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (Cr Cio) alkyl, -NR _a Rb, -NR _c CORd, -COORe, -OCORg, -CONRhR ,, -OCONRjRk, -NRiCOOR ₀ - and - NRrCONRsRt, advantageously among (CrCio) alkyl, -NR _a Rb, -NR _c CORd, -COOR _e , -CONRhR ,, - NRiCOORo- and -NR _r CONR _s R _t .

Advantageously, the radiopaque monomer is a monomer of general formula (II) as defined above, in which Y represents OC _ô hUI, OC _ô hh, OC _ô hhh, NH- C ₆ H ₄ I, NH-C ₆ H ₃ I ₂ , NH-C ₆ H ₂ I ₃ , 0-CH ₂ -CH ₂ -C (0) -C ₆ H l, 0-CH ₂ -CH ₂ -0-C (0) -C ₆ H ₃ l ₂ , O-CH ₂ -CH ₂ -O- C (0) -C ₆ H ₂ l ₃ , NH-CH ₂ -CH ₂ -C (0) -C ₆ H l, NH-CH ₂ - CH ₂ -0-C (0) -C ₆ H ₃ l ₂ , OR NH-CH ₂ -CH ₂ -0-C (0) - C ₆ H ₂ I ₃ , in particular 0-C ₆ H ₂ l ₃ , NH-C ₆ H ₂ I ₃ , 0-CH ₂ -CH ₂ -0-C (0) -C ₆ H ₂ l ₃ , or NH-CH ₂ -CH ₂ -0-C (0) - C ₆ H ₂ I ₃ .

Advantageously, the halogenated monomer is chosen from the compounds of general formula (V) below:

(CH ₂ = CR ₂₈ ) -CO-Y '(V) in which

• R ₂₈ represents H or a (CrC ₆ ) alkyl;

• R ₂ 9 represents a group selected from (C ₂ -C 3 _O) alkylene;

• W 'represents a single bond, -CONR ₃₀ -, or -NR ₃₁ CO-;

• R ₃₂ to R ₄₉ represent, independently of each other, a hydrogen atom, a (CrCio) alkyl, said (C1-C10) alkyl being optionally substituted by 1 to 10 OH group (s), or a - (CH ₂ -CH ₂ -0) _t -R ”group, R” being a hydrogen atom or a - (CrC _ô alkyl and t 'being an integer between 1 and 10, preferably between 1 and 5.

Advantageously, R ₂₈ represents a (Ci-C ₆ ) alkyl, more advantageously a (Cr C ₃ ) alkyl, more advantageously a methyl.

Advantageously, R29 represents a (C2-Ci ₈₎ alkylene, more preferably a (C2- C _O) alkylene, more preferably ethylene.

Advantageously, R30 and R31 represent, independently of each other, a hydrogen atom. Thus, W ′ advantageously represents a single bond, -C (0) NH-, or -NHC (O) -.

Advantageously, Ar 'represents a (Cs-Cio) aryl, more particularly a phenyl, substituted by one, two or three atom (s) of iodine and / or bromine, preferably of iodine, and optionally two or three, groups chosen from (CrCio) alkyl, -NR32R33, - NR ₃₄ C (0) R ₃ 5, -C (0) 0R ₃₆ , -OR37, -0C (0) R ₃₈ , -C (0) NR ₃₉ R ₄ O, -0C (0) NR ₄ IR ₄₂ , -NR ₄₃ C (0) 0R ₄₄ , - NR ₅ C (0) NR ₆ R _47, -0C (0) 0R ₈ , and -C (0) R ₉ .

Advantageously, Ar 'represents a (Cs-Cio) aryl, more particularly a phenyl, substituted by three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (CrCio) alkyl, -NR32R33 , -NR3 ₄ C (0) R35, -C (0) 0R36, -OR37, - 0C (0) R ₃₈ , -C (0) NR ₃₉ R ₄ O, -0C (0) NR IR ₂ , -NR ₃ C (0) 0R, -NR ₅ C (0) NR ₆ R _47, -0C (0) 0R ₈ , and - C (0) R ₄₉ .

Advantageously, Ar 'represents a phenyl substituted with three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (Cr Cio) alkyl, -NR32R33, -NR ₃₄ C (0) R ₃₅ , -C (0) 0R ₃₆ , -OR37, -0C (0) R ₃₈ , -C (0) NR ₃₉ R ₄ o, -0C (0) NR ₄ IR ₄ 2, -NR ₄₃ C (0) 0R ₄₄ , -NR ₄₅ C (0) NR ₄₆ R _47, -0C (0) 0R ₄₈ , and -C (0) R ₄₉ , advantageously among (Cr Cio) alkyl, -NR32R33, -NR ₃₄ C (0) R ₃₅ , -C (0) 0R ₃₆ , -OR37, -C (0) NR ₃₉ R ₄ o, -NR ₄₃ C (0) 0R ₄₄ ,

NR ₅ C (0) NR ₆ R _47, -0C (0) 0R ₈ , and -C (0) R ₉ .

Advantageously, the halogenated monomer is chosen from the following compounds: (My),

Advantageously, the halogenated monomer is chosen from the following compounds: More advantageously, the radiopaque monomer is (tri-iodobenzoyl) oxo ethyl methacrylate (MAOETIB) of the following formula (IIa): or 2- (2- (2- (2,3,5-triiodobenzamido) ethoxy) ethyl methacrylate of the following formula: In the context of the present invention, the radiopaque monomer is in particular added to the reaction mixture in an amount of 5% to 50%, in particular in an amount greater than 7% and less than or equal to 50%, in particular in an amount greater than 10% and less than or equal to 50%, more particularly in an amount greater than 15% and less than or equal to 50%, preferably in an amount greater than 15% and less than or equal to 35%, and in particular from 20% to 30% by Mole, relative to the total number of moles of monomers.

By “crosslinking monomer” is meant, within the meaning of the present invention, an at least bifunctional but also multifunctional monomer having a double bond at each polymerizable end. The crosslinking monomer, in combination with the other monomers in the mixture, allows the formation of a crosslinked network. The structure and the amount of crosslinking monomer (s) in the mixture of monomers can be easily chosen by one skilled in the art to provide the desired crosslinking density. The crosslinker is also advantageous for the stability of the microspheres. The crosslinker prevents the microspheres from dissolving in any solvent. The crosslinker also improves the compressibility of the microspheres, which is favorable for embolization.

By “non-biodegradable hydrophilic crosslinking agent” is meant, within the meaning of the present invention, a crosslinking agent as defined above, having a strong affinity for water and which cannot be degraded under the physiological conditions of the body of a person. mammal, especially the human body. Indeed, the biodegradation of a molecule is permitted when the latter contains sufficient functional sites which can be cleaved under physiological conditions, in particular by the endogenous enzymes of the body of a mammal, in particular of the human body, and / or in physiological pH (usually around 7.4). The functional sites cleavable under physiological conditions are in particular the amide bonds, the ester bonds and the acetals. A molecule comprising an insufficient number of said functional sites will therefore be considered as non-biodegradable. In the context of the present invention, the crosslinking monomer contains less than 20 sites physiologically cleavable functional, preferably less than 15 sites, more preferably less than 10 sites, still more preferably less than 5 sites.

The linear or branched non-biodegradable hydrophilic crosslinker is in particular a non-biodegradable crosslinker soluble in an organic solvent and comprising the polymerizable diacrylate, methacrylate, acrylamide and / or methacrylamide groups.

Advantageously, the crosslinking _{agent has (CH 2} = (CRi ₆ )) CO- or (CH ₂ = (CRi ₆ )) C0-0- groups at its at least two ends, each R _½ independently representing H or one (CrC _ô ) alkyl, advantageously the radicals R _½ are identical and represent H or (Ci-C ₆ ) alkyl.

In particular, the crosslinking agent is of the following general formula (Ilia) or (IIIb):

(CH ₂ = (CRI ₆ )) CO-NH-A-HN-OC ((CRI ₆ ) = CH ₂ ) (Ilia),

(CH ₂ = (CRI ₆ )) C0-0-A-0-0C ((CRI ₆ ) = CH ₂ ) (IIIb), in which each R16 independently represents H or a (CrC ₆ ) alkyl, advantageously the radicals R16 are identical and represent H or (CrC ₆ ) alkyl; and

A represents, alone or with at least one of the atoms to which it is bonded, a ( _{CrC 6} alkylene, a polyethylene glycol (PEG), a polysiloxane, a poly (dimethylsiloxane) (PDMS), a poly-glycerol ester (PGE) or a bisphenol A.

Advantageously, the crosslinking agent is of the following general formula (IIa) or (Mb): (CH ₂ = (CRi6)) CO-NH-A-HN-OC ((CRi6) = CH ₂ ) (Ilia),

(CH ₂ = (CRI ₆ )) C0-0-A-0-0C ((CRI ₆ ) = CH ₂ ) (111 b), in which, each R _½ independently represents H or a (CrC ₆ ) alkyl, advantageously the radicals R16 are identical and represent H or (CrC ₆ ) alkyl; and

A preferably represents, alone or with at least one of the atoms to which it is bonded, a (Cr C ₆ ) alkylene or a polyethylene glycol (PEG), preferably a polyethylene glycol (PEG).

Within the framework of the definitions of A above, the polyethylene glycol has a length varying from 200 to 10,000 g / mol, preferably from 200 to 2,000 g / mol, more preferably from 500 to 1,000 g / mol. As an example of a crosslinking monomer that can be used in the context of the present invention, there may be mentioned (without being limiting): 1, 4-butanediol diacrylate, pentaerythritol tetraacrylate, methylenebisacrylamide, glycerol 1, 3-diglycerolate diacrylate and poly (ethylene glycol) di methacrylate (PEGDMA).

Advantageously, the crosslinking monomer is poly (ethylene glycol) dimethacrylate (PEGDMA), the polyethylene glycol unit having a length varying from 200 to 10,000 g / mol, preferably from 200 to 2,000 g / mol, more preferably from 500 to 1. 000 g / mol.

In the context of the present invention, the crosslinking monomer is in particular added to the reaction mixture in an amount of 1% to 15%, preferably 2% to 10%, in particular 2% to 7%, more particularly 2%. at 5% by Mole, relative to the total number of moles of monomers.

In the context of the present invention, the term “transfer agent” is understood to mean a chemical compound having at least one weak chemical bond. This agent reacts with the radical site of a growing polymer chain and interrupts the growth of the chain. In the chain transfer process, the radical is temporarily transferred to the transfer agent which restarts growth by transferring the radical to another polymer or monomer.

In the context of the present invention, the use of a transfer agent for obtaining the polymer according to the invention makes it possible to retain its hydrophilicity despite the addition of the radiopaque monomer, and thus allows the injection of the microspheres. . This allows a more homogeneous polymer network to be obtained, with improved elastic properties and thus improving the swelling properties.

Advantageously, said chain transfer agent is chosen from the group consisting of monofunctional or polyfunctional thiols, and alkyl halides.

Among the alkyl halides which can serve as transfer agent, there are in particular bromotn ^' chloromethane, tetrachloromethane and tetrabromomethane.

Particularly advantageously, said chain transfer agent is a cycloaliphatic or aliphatic thiol typically having from 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 6 carbon atoms, and optionally having a functional group additional selected from amino, hydroxy and carboxy groups.

Examples of particularly preferred chain transfer agents are thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof, preferably hexanethiol. In the context of the present invention, the transfer agent is in particular added to the reaction mixture in an amount of 0.1% to 10%, preferably 0.5% to 8%, more preferably 1.5. % to 6% and in particular from 1.5% to 4.5% by mole, and in particular from 3% by mole, relative to the number of moles of hydrophilic monomer a).

In a particular embodiment according to the invention, the crosslinked polymeric matrix of the microspheres is based solely on the basic constituents a), b), c) and d) as defined above, in the aforementioned proportions of monomers and transfer agent, no other basic constituent being added to the reaction medium. It is thus evident that the sum of the aforementioned proportions of monomers a), b) and c) must be equal to 100%.

According to a particular aspect of the invention, the polymer matrix according to the invention is also based on at least one ionized or ionizable monomer, of the following formula (IV):

(CH ₂ = CR _I7 ) -ME (IV) in which:

• R17 represents H or a (CrC ₆ ) alkyl;

• M represents a single bond or a divalent radical having 1 to 20 carbon atoms, preferably a single bond;

• E represents an ionized or ionizable group, E being advantageously chosen from the group consisting of -COOH, -COO-, -SO ₃ H, -SO ₃ , -PO ₄ H ₂ , -PO ₄ H, -PO ₄ ² , -NR ₁₈ R ₁₉ , and -

NR20R2I R ₂ 2 ⁺ ,

• Ris, R19, R20, R21 and R ₂₂ represent, independently of each other, H or a (Cr

C ₆ ) alkyl.

By ionized or ionizable group is meant, within the meaning of the present invention, a charged group or which may be in charged form (in ion form), that is to say bearing at least one positive or negative charge, depending on the pH of the medium. For example, the COOH group can be ionized in COO form and the NH ₂ group can be in ionized NH3 ^{+ form} .

The introduction of an ionized or ionizable monomer into the reaction mixture makes it possible to increase the hydrophilicity of the resulting microspheres, thus increasing the rate of swelling of said microspheres, further facilitating their injection via the catheters. and microcatheters. In addition, the presence of an ionized or ionizable monomer allows the loading of active substances within the microsphere.

Preferably, the ionized or ionizable monomer is a cationic monomer, advantageously chosen from the group consisting of (methacryloyloxy) ethylphosphorylcholine, 2- (dimethylamino) ethyl (meth) acrylate, 2- (diethylamino) (meth) acrylate ethyl) and 2 - ((meth) acryloyloxy) ethyl) - trimethylammonium chloride, advantageously the cationic monomer is diethylamino) ethyl (meth) acrylate. Advantageously, the crosslinked matrix according to the invention is based on a cationic monomer mentioned above in amounts of between 1% and 40% by moles relative to the total number of moles of monomers. Preferably, the crosslinked matrix according to the invention is based on ionized or ionizable monomer in amounts of between 5% and 15%, preferably 10% by moles relative to the total number of moles of monomers, when the resulting microspheres are not are not intended to be loaded with an active substance. According to another embodiment, when the microspheres are intended to be loaded with an active substance, the crosslinked matrix according to the invention is obtained by adding to the reaction mixture between 20% and 40%, preferably by adding to the reaction mixture 20% at 30 mol% of ionized or ionizable monomer relative to the total number of moles of monomers.

In another advantageous embodiment, the ionized or ionizable monomer is an anionic monomer advantageously chosen from the group consisting of acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-acrylate oligomers. carboxyethyl, 3-sulfopropyl (meth) acrylate, potassium salt and 2 - ((methacryloyloxy) ethyl) dimethyl- (3-sulfopropyl) ammonium hydroxide. Advantageously, the crosslinked matrix according to the invention is based on an anionic monomer mentioned above in amounts of between 1% and 40% by moles on the basis of the total amount of monomers. Preferably, the crosslinked matrix according to the invention is based on ionized or ionizable monomer in amounts of between 5% and 15%, preferably 10% by moles based on the total amount of monomers, when the resulting microspheres are not are not intended to be loaded with an active substance. According to another embodiment, when the microspheres are intended to be loaded with an active substance, the crosslinked matrix according to the invention is based on ionized or ionizable monomer in amounts of between 20% and 40%, preferably 20%. 30% ionized or ionizable monomer based on the total amount of monomers. In a particularly advantageous manner, the ionized or ionizable monomer is methacrylic acid (MA or AM). Advantageously, the crosslinked matrix according to the invention is based on methacrylic acid (MA) in amounts of between 10% and 30% by moles on the basis of the total amount of monomers.

In the context of the present invention, the crosslinked matrix according to the invention is also based on at least one colored monomer making it possible to improve its visibility to the naked eye. This allows in particular to check before injection that the polymer suspension is homogeneous in the syringe and to control the injection speed.

Thus, according to a particular embodiment, the matrix of the polymer according to the invention is also based on at least one colored monomer of the following general formula (VI): in which,

• Zi and Z2 represent, independently of one another, H or OR25, R25 representing H or a (CrC ₆ ) alkyl, advantageously Z1 and Z2 represent H;

X represents H or a halogen such as Cl, advantageously H;

R23 represents H or a (CrC ₆ ) alkyl, advantageously a (CrC ₆ ) alkyl, in particular a methyl; and

• R24 represents a group chosen from (CrC _ô ) linear or branched alkylene, (C5- C3ô) arylene, (Cs-C36) arylene-0-R26, (Cs-C36) heteroarylene and (C5-C3ô) heteroarylene-0- R27, R26 and R27 representing a (CrC ₆ ) alkyl or a (CrC ₆ ) alkylene, advantageously R24 represents a group -C 6hU-O-ÎChh - or -C (CH3) 2-CH2-.

Advantageously, the colored monomer is of the following formula (Via) or (Vlb): More preferably, the colored monomer is of formula (VIb) above.

In the context of the present invention, the colored monomer is in particular added to the reaction mixture in an amount from 0% to 1%, preferably from 0% to 0.5%, more particularly from 0.02% to 0, 2%, and even more particularly from 0.04% to 0.1% by Mole, relative to the total number of moles of monomers.

Magnetic Resonance Imaging (MRI) is used in the medical community to provide two-dimensional sectional images of the internal structures of a patient's body without exposing them to harmful radiation. The polymer matrix according to the invention can in particular be based on particles making it possible to make the polymer visible using magnetic resonance imaging (MRI).

Thus, advantageously, the matrix of the polymer according to the invention is also based on at least one agent visible in magnetic resonance imaging (MRI) such as iron oxide nanoparticles, gadolinium chelates or chelates of magnesium, advantageously iron oxide nanoparticles such as USPIOs (Ultra Small Super Paramagnetic Iron Oxide or Ultra Small Paramagnetic Iron Oxides, ie magnetic particles based on an iron compound exhibiting superparamagnetic characteristics which make them visible in MRI ).

In the context of the present invention, the particles visible on MRI are advantageously added to the reaction mixture in an amount from 0% to 10%, preferably from 0.5% to 8%, more preferably from 0.5% to 5. %, in particular 1%, by volume of organic phase.

In the context of the present invention, when the polymer matrix does not comprise an ionized or ionizable monomer as basic constituent, it is advantageously based on:

34.5% to 84%, preferably 64.9% to 77.98% of hydrophilic monomer a);

More than 15% to 50%, preferably 20% to 30% of radiopaque monomer b);

1% to 15%, preferably 2% to 5% of non-biodegradable hydrophilic crosslinker c);

1.5% to 4.5% transfer agent d), preferably 3%;

0% to 0.5% colored monomer, preferably 0.02% to 0.1%; and

0% to 10% of particles visible on MRI, preferably 1% to 5%, each of the monomers mentioned and the nature of their associated percentages being as defined above in the present description. It is obvious that the sum of the above mentioned percentages of monomers must be equal to 100%.

74.5% to 78% hydrophilic monomer a)

20% of radiopaque monomer b);

2% to 5% non-biodegradable hydrophilic crosslinker c);

1.5% to 4.5% transfer agent d);

0% to 0.5% colored monomer; and

0% to 10% of particles visible on MRI, each of the mentioned monomers and the nature of their associated percentages being as defined above in the present description. It is obvious that the sum of the above mentioned percentages of monomers must be equal to 100%.

In the context of the present invention, when the polymer matrix comprises at least one ionized or ionizable monomer as basic constituent, it is advantageously based on:

34.9% to 67.98%, preferably 34.96% to 67.96%, of hydrophilic monomer a)

20% to 30% radiopaque monomer b);

2% to 5% non-biodegradable hydrophilic crosslinker c);

1.5% to 3% transfer agent d);

10% to 30% charged or ionizable monomer;

0.02% to 0.1%, preferably 0.04%, of colored monomer; and

The polymer according to the invention can be easily synthesized by numerous methods well known to those skilled in the art. By way of example, the polymer according to the invention can be obtained by suspension polymerization as described below and in the examples. A direct suspension can proceed as follows:

(a) kneading or stirring a reaction mixture comprising:

(i) at least one hydrophilic monomer a) as defined above, at least one radiopaque monomer b) as defined above, at least one non-biodegradable hydrophilic crosslinker c) as defined above, and at least one transfer agent d) as defined above;

(ii) a polymerization initiator present in amounts ranging from 0.1 to about 2 parts by weight per 100 parts by weight of the monomers;

(iii) a surfactant in an amount of not more than about 5 parts by weight per 100 parts by weight of aqueous phase, preferably not more than about 3 parts by weight and most preferably in the range of 0.2 to 1.5 parts by weight; and

(iv) water to form an oil-in-water suspension; and

(b) polymerize the basic constituents.

In such a direct suspension process, the surfactant can be selected from the group consisting of hydroxyethyl cellulose, polyvinylalcohol (PVA), polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol and Polysorbate 20 (Tween® 20); preferably it is PVA.

The microspheres thus obtained are then washed and calibrated according to techniques well known to those skilled in the art.

A reverse suspension can proceed as follows:

(a) kneading or stirring a reaction mixture comprising:

(iii) a surfactant in an amount of not more than about 10 parts by weight per 100 parts by weight of the oil phase, preferably not more than about 8 parts by weight per 100 parts by weight of the oil phase and most preferably in the range of 3 to 7 parts by weight per 100 parts by weight of the oil phase; and

(iv) oil to form a water-in-oil suspension; and

(b) polymerize the basic constituents.

In the processes mentioned above, the polymerization initiator may in particular be t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also called 4,4'-Azobis (4-cyanopentanoic acid)), GAIBN (azobisisobutyronitrile), or 1, 1 'Azobis (cyclohexane carbonitrile) or one or more thermal initiators such as 2- Hydroxy-4' - (2-hydroxyethoxy) -2-methylpropiophenone (106797-53-9); 2-Hydroxy-2-methylpropiophenone (Darocur® 1173, 7473-98-5); 2,2-Dimethoxy-2-phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenyl acetophenone (Irgacure®, 24650-42-8) or 2-Methyl-4 '- (methylthio) -2-morpholinopropiophenone (Irgacure®, 71868-10-5).

In such a reverse suspension process, the surfactant can be chosen from the group consisting of sorbitan esters such as sorbitan monolaurate (Span ^® 20), sorbitan monopalmitate (Span ^® 40), sorbitan monooleate (Span ^® 80), and sorbitan trioleate (Span ^® 85), hydroxyethyl cellulose, a mixture of glyceryl stearate and PEG stearate (Arlacel ^® ) and cellulose acetate.

The oil used in the process described above can be chosen from paraffin oil, silicone oil and organic solvents such as hexane, cyclohexane, ethyl acetate or acetate. butyl.

When the polymer according to the invention is obtained from the polymerization of at least one ionized or ionizable monomer, a drug, an active substance, a diagnostic agent or macromolecules, can / can also be loaded on the polymer, that is to say adsorbed on the polymer by non-covalent interactions, optionally in the presence of pharmaceutically acceptable excipient (s) well known to those skilled in the art. This particular way of trapping drugs or active substances is called physical encapsulation. No special requirements are imposed on the drug or active substance to be loaded.

Loading can be done by many methods well known to those skilled in the art such as passive adsorption (swelling of the polymer in a drug solution) or by ionic interaction. These methods are for example described in the request international WO 2012/120138, in particular from page 22, line 20 to page 26, line 7. The efficiency of the encapsulation depends mainly on the compatibility between the two structures and / or the favorable interactions.

In the context of the present invention, the polymer can be loaded with a drug, an active substance or a diagnostic agent and thus allow their release on a target site, said target site being inside of. a body of a mammal, particularly within a human body. Monitoring the loaded polymer by X-ray or MRI ensures that the release of the drug / active substance / diagnostic agent is carried out at the specific desired site. The polymer according to the invention can therefore be loaded with a drug or an active substance or a diagnostic agent, advantageously having a molar mass of less than 5000 Da, typically less than 1000 Da, the drug or the active substance. being advantageously chosen from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, antiseptics and a mixture thereof.

Preferably, the polymer according to the invention can be loaded with an anticancer agent.

The anticancer agent is preferably chosen from anthracyclines such as doxorubicin, epirubicin or idarubicin, platinum complexes, compounds related to anthracyclines such as mitoxantrone and nemorubicin, antibiotics such as mitomycin C (Ametycine ®), bleomycin and actinomycin D, other anti-neoplastic compounds such as irinotecan, 5-Fluoro-Uracil (Adrucil®), sorafenib (Nevaxar®), sunitinib (Sutent®), regorafenib , bn ^' vanib, orantinib, linsitinib, erlotinib, cabozantinib, foretinib, tivantinib, fotemustine, tauromustine (TCNU), carmustine, cytosine C, cyclophosphonamide, cytosine arabinoside (or cytarabine), paclitaxel, docetaxel, methotrexate, everolimus (Afinitor®), PEG- arginine deiminase, tegafur / gimeracil / oteracil (Teysuno®), muparfostat, peretinine, gemcitabine, bevacizab (bevaciz Avastin®), ramucirumab, floxuridine, immunostimulants such as GM-CSF (Granulocyte-macrophage colony-stimulating factor) and its recombinant forms: molgramostim or sargramostim (Leukine®), OK-432 (Picibanil®), interleukin-2, interleukin-4 and Tumor necrosing Factor-alpha (TNFalpha), antibodies, radio elements, complexes of these radio elements with chelates, nucleic acid sequences and a mixture of one or more of these compounds (preferably a mixture of 'one or more anthracyclines). Preferably, the anticancer agent is chosen from anthracyclines, immuno-stimulants, platinum complexes, anti-neoplastics and their mixtures.

Even more preferably, the anticancer agent is chosen from anthracyclines, antibodies, anti-neoplastics and their mixtures.

The antibodies are for example chosen from anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CEA (CarcinoEmbryonic Antigen) or a mixture of these.

Anti-PD-1s are, for example, nivolumab or pembrolizumab.

Anti-PD-L1s are, for example, avelumab, durvalumab or atezolizumab.

Anti-CTLA-4s are, for example, ipilimumab or tremelimumab.

Even more advantageously, the anticancer drug is selected from the group consisting of paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (Granulocyte-macrophage colony-stimulating factor), tumor necrosing Factor-alpha (TNFalpha), antibodies, and their mixtures.

Preferably, the local anesthetic is chosen from lidocaine, bupivacaine and their mixtures.

The anti-inflammatory can be selected from ibuprofen, niflumic acid, dexamethasone, naproxen and mixtures thereof.

In the context of the present invention, the polymer can be loaded, in particular by extemporaneous adsorption, with macromolecules chosen from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones. , plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzyme (also called DNAzyme), aptamers, anti-inflammatory proteins, bone morphogenic proteins (BMP), pro-angiogenic factors, factors vascular endothelial growth (VEGF) and TGF-beta, and angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof.

The anti-inflammatory proteins are, for example, infliximab or rilonacept and their mixture. The proangiogenic factors are, for example, fibroblast growth factors (FGFs) and their mixture.

Angiogenesis inhibitors are, for example, bevacizumab, ramucirumab, nesvacumab, olaratumab, vanucizumab, rilotumumab, emibetuzumab, aflibercept, ficlatuzumab, pegaptanib and mixtures thereof.

Anti-tyrosine kinases are, for example, lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, sulfatinib, dovetinib, linifanib and their mixtures.

Advantageously, the polymer can be loaded with macromolecules chosen from anti-tyrosine kinases, TGF-beta, angiogenesis inhibitors and their mixtures.

In a second aspect, the invention relates to a pharmaceutical composition comprising at least one polymer according to the invention, in association with a pharmaceutically acceptable vehicle, advantageously for administration by injection.

An example of a pharmaceutically acceptable vehicle includes, but is not limited to, water for injection, saline also referred to as physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, ester of hyaluronic acid, plasma, a contrast agent for X-ray, magnetic resonance or ultrasound imaging, a buffering agent, a preservative, a gelling agent, a surfactant, or a mixture thereof. this. Advantageously, the pharmaceutically acceptable vehicle is physiological serum, water for injection, a contrast agent for imaging by X-ray, by magnetic resonance or by echography, or a mixture thereof. More advantageously, the pharmaceutically acceptable vehicle is a contrast agent for X-ray, magnetic resonance or ultrasound imaging, physiological saline, or a mixture of physiological saline and a contrast agent for ray imaging. X, by magnetic resonance or by ultrasound.

According to the present invention, the contrast agent is preferably a contrast agent for X-ray imaging. It is advantageously one or more nonionic iodinated water-soluble contrast agents, such as for example iobitridol ( Xenetix ^® ), iopamidol (lopamiron ^® , Isovue ^® ), iomeprol (lomeron ^® ), ioversol (Optiray ^® , Optiject ^® ), iohexol (Omnipaque ^® ), iopentol (Imagopaque ^® ), ioxitol ( Oxilan®) 1'iopromide (Ultravist ^®), metrizamide (Amipaque ^®), iosarcol (Melitrast ^®), iotrolan (ISOVIST ^®), iodixanol (Visipaque ^®), iosimenol and iosimide (Univist ^® ) and a mixture of these.

According to another embodiment, the contrast agent is a contrast agent for magnetic resonance imaging (MRI). These are advantageously gadolinium chelates (Dotarem®).

According to another embodiment, the contrast agent is a contrast agent for ultrasound imaging. It is advantageously sulfur hexafluoride (Sonovue®).

In a particular embodiment of the present invention, the pharmaceutical composition comprises the polymer according to the invention, in combination with physiological serum, said composition being intended to be mixed with at least one contrast agent for X-ray imaging. , by magnetic resonance or by echography as defined above, in particular for X-ray imaging, before administration by injection, such a mixture causing the suspension of the microspheres obtained from the polymer according to the invention.

In a particular embodiment according to the invention, the pharmaceutical composition according to the invention comprises the polymer according to the invention, in combination with a mixture of physiological serum and of a contrast agent as defined above, the serum physiological and the contrast agent being present in proportions 50/50 to 0/100, advantageously from 40/60 to 0/100, preferably 30/70 to 0/100.

In another particular embodiment according to the invention, the pharmaceutical composition according to the invention comprises the polymer according to the invention, in combination with only one or more contrast agent (s) as defined above, in particular a or more contrast agent (s) for X-ray imaging as defined above.

The pharmaceutical composition should have an acceptable viscosity for injection.

The fields of application of the radiopaque polymer according to the invention include in particular embolization and chemoembolization.

The polymer according to the invention can, as indicated above, be used for various biomedical purposes, which means that it must be compatible with the body of a mammal and in particular with the human body. More particularly, suitable biomedical materials do not possess hemolytic properties. The present invention further relates to the specific use of a transfer agent in the polymerization of a radiopaque polymer to allow injection of said radiopaque polymer, in particular injection into a catheter or microcatheter of internal diameter. varying from a few hundred micrometers to more than a millimeter. The present invention also relates to the specific use of a transfer agent in the polymerization of a radiopaque polymer for improving the hydrophilicity and the water-swelling properties of said polymer and thus promoting its injection. Said transfer agent being in particular as defined above and in the contents as defined above, and in particular chosen from cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group selected from amino, hydroxy and carboxy groups.

A subject of the present invention is also a kit comprising a pharmaceutical composition as defined above and at least one means of injecting said composition, for administration of said composition by the parenteral route. According to the present invention, the term “injection means” means any means allowing parenteral administration. Advantageously, said injection means is one or more syringes, which can be pre-filled, and / or one or more catheters or microcatheters.

Advantageously, the pharmaceutical composition present in said kit comprises the polymer according to the present invention in combination with physiological serum, one or more contrast agent (s) as defined above, in particular one or more contrast agent (s) for X-ray imaging as defined above, or a mixture thereof. More advantageously, said pharmaceutical composition comprises the polymer according to the present invention in combination with a mixture of physiological serum and of one or more contrast agent (s) as defined above, in particular one or more agent (s) of contrast for X-ray imaging as defined above, in proportions of between 50/50 and 0/100, advantageously between 40/60 and 0/100, preferably 30/70 to 0/100.

Advantageously, the injection means (s) present in the kit according to the invention is (are) suitable for parenteral administration of the pharmaceutical composition according to the invention. Thus, the size of the syringe (s) or of the (micro) catheter (s) will be adapted as a function of the size of the microspheres obtained from the polymer according to the invention and of the volume to be injected for the embolization, the size of the microspheres itself being chosen as a function of the size of the vessel to be embolized. Those skilled in the art will know how to choose the suitable size of the microspheres and therefore the suitable injection means.

A subject of the present invention is also a kit comprising on the one hand a pharmaceutical composition as defined above and on the other hand at least one contrast agent for imaging by X-ray, by magnetic resonance or by echography, and optionally at least one injection means for parenteral administration. The injection means is as defined above.

In said kit, the pharmaceutical composition and the contrast agent are packaged separately and are intended to be mixed just before administration by injection.

In said kit, at least one contrast agent is as defined above in the description. In particular, the at least one contrast agent is a contrast agent for X-ray imaging as defined above in the description.

In said kit, the pharmaceutical composition advantageously comprises the polymer according to the present invention in association with a pharmaceutically acceptable vehicle for administration by injection. Said pharmaceutically acceptable vehicle may be, for example, but not limited to, water for injection, physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, ester. hyaluronic acid and / or plasma. Preferably, in said kit, the pharmaceutical composition advantageously comprises the polymer according to the present invention in combination with physiological saline or water for injection.

In said kit, the pharmaceutical composition is advantageously packaged directly in an injection means, in particular in a syringe, suitable for the injection of parenteral embolization microspheres.

In said kit, the contrast agent is advantageously packaged in a vial or directly in an injection means, in particular a syringe, in particular suitable for the injection of parenteral embolization microspheres.

In said kit, the pharmaceutically acceptable vehicle / contrast agent proportions are between 50/50 and 0/100, advantageously between 40/60 and 0/100, preferably 30/70 to 0/100.

A subject of the present invention is also a compound of the following general formula (V): (CH ₂ = CR ₂₈ ) -CO-Y '(V) in which

• R ₂₈ represents H or a (Ci-C ₆ ) alkyl;

• R ₂ 9 represents a group selected from (C ₂ -C 3 _O) alkylene;

• W 'represents a single bond, -CONR ₃₀ -, or -NR ₃₁ CO-;

• R30 and R31 represent, independently of one another, a hydrogen atom or a (CrC ₆ ) alkyl;

• R3 ₂ to R49 represent, independently of each other, a hydrogen atom, a (CrCio) alkyl, said (C1-C10) alkyl being optionally substituted by 1 to 10 OH group (s), or a - ( CH ₂ -CH ₂ -0) _t -R ”, R” being a hydrogen atom or a - (CrC ₆ ) alkyl and t 'being an integer between 1 and 10, preferably between 1 and 5.

Advantageously, R ₂ s represents a (Ci-C ₆ ) alkyl, more advantageously a (Cr C3) alkyl, more advantageously a methyl.

Advantageously, R _¾ represents a (C ₂ -Cis) alkylene, more particularly a (C ₂ - C ₆ ) alkylene, more advantageously an ethylene.

Advantageously, Ar 'represents a (Cs-Cio) aryl, more particularly a phenyl, substituted by one, two or three atom (s) of iodine and / or bromine, preferably of iodine, and optionally two or three, groups chosen from (CrCio) alkyl, -NR3 ₂ R33, -

Advantageously, Ar 'represents a (Cs-Cio) aryl, more particularly a phenyl, substituted with three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (CrCio) alkyl, -NR3 ₂ R33, -NR34C (0) R35, -C (0) 0R36, -OR37, - 0C (0) R ₃₈ , -C (O) NR ₃₉ R ₀ , -0C (0) NR _I R ₄₂ , -NR ₃ C (0) 0R, -NR ₅ C (0) NR ₆ R _47, -0C (0) 0R ₈ , and - C (0) R ₄₉ .

Advantageously, Ar 'represents a phenyl substituted with three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (Cr Cio) alkyl, -NR ₃₂ R ₃₃ , -NR ₃₄ C (0 ) R ₃₅ , -C (0) 0R ₃₆ , -OR ₃₇ , -0C (0) R ₃₈ , -C (O) NR ₃₉ R ₄₀ , -0C (0) NR _4i R ₄₂ , -NR ₄₃ C (0 ) 0R ₄₄ , -NR ₄₅ C (0) NR ₄₆ R _47, -0C (0) 0R ₄₈ , and -C (0) R ₄₉ , advantageously from (Cr Cio) alkyl, -NR ₃₂ R ₃₃ , -NR ₃₄ C (0) R ₃₅ , -C (0) 0R ₃₆ , -OR ₃₇ , -C (0) NR ₃₉ R ₄ o, -NR ₄₃ C (0) 0R ₄₄ , NR ₅ C (0) NR ₆ R _{47 ,} -0C (0) 0R ₈ , and -C (0) R ₉ . Advantageously, the compound of general formula (V) is chosen from the following compounds: In the context of the present invention, the compound of general formula (V) as defined above is advantageously used as radiopaque halogenated monomer. Thus, a subject of the present invention is also the use of the compound of general formula (V) as defined above as a radiopaque halogenated monomer.

The examples which follow aim to illustrate the present invention. In the following, the word "microsphere", whether singular or plural, will most often be abbreviated by "MS".

EXAMPLES

Example 1a: synthesis of a tri-iodinated monomer, 2-methacryloyloxyethyl (2,3,5-triiodobenzoate) (MAOETIB)

40 g (80 mmol) of 2,3,5-triiodobenzoic acid are added in small portions to a solution at 0 ° C of di-ethyl ether (400 mL) containing 11.46 g (88 mmol, 1, 1 eq. ) of 2-hydroxyethyl methacrylate, 18.17 g (88 mmol, 1.1 eq.) of 1, 3-dicyclohexylcarbodiimide and 1.19 g (8 mmol, 0.1 eq.) of 4-pyrrolidinopyridine. The solution is stirred for one hour at 0 ° C. then for 18 h at 25 ° C. The solid formed is filtered through a frit and washed with diethyl ether several times. The ether solution is then washed with hydrochloric acid solution (2N) and then with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After filtration, the solvent is removed on a rotary evaporator to give an orange solid. The crude product is then purified on silica gel, eluting with a solution of petroleum ether / ethyl acetate (9/1). After evaporation of the solvent, an orangeish solid is obtained and re-purified by recrystallization by slow diffusion in a mixture of ethyl acetate in petroleum ether at 4 ° C overnight. After filtration, washing with the cold solution and drying under vacuum, 31.1 g of pure white flakes of MAOETIB are obtained (yield = 64%).

¹ H NMR (CDCh) 1.97 (s, 3H, CH ₃ ), 4.57 and 4.48 (m, 4H, 0CH ₂ CH ₂ 0), 5.61 (s, 1H, olefinic), 6.16 (s, 1H, olefinic), 7.33 (d, 1H), 8.30 (d, 1H). Example 1b: synthesis of a tri-iodinated monomer, 2- (2- (2- (2,3,5- triiodobenzamido) ethoxy) ethyl methacrylate (formula Vb)

Step 1 :

20.0 g (40.0 mmol) of 2,3,5-triiodobenzoic acid are dissolved in dichloromethane (60 mL), to which are added dimethylformamide (a few drops). The reaction medium is then placed under argon and cooled to a temperature of 0 ° C. 17.15 mL (200 mmol) of oxalyl chloride are then added dropwise over a period of 5 to 10 min while maintaining the temperature of the reaction medium close to 0 ° C. The solution is stirred until it returns to room temperature and then heated to reflux (70 ° C) for 30 h. The reaction medium is then evaporated under vacuum. The solid obtained is coevaporated with dichloromethane 3 to 4 times, so as to eliminate the traces of oxalyl chloride still present. An orange-brown solid is obtained. At this stage, the product is not isolated and is directly involved in the rest of the synthesis.

2nd step :

13.44 g (90 mmol) of 2- [2- (2-aminoethoxy) ethoxy] ethan-1 -ol are dissolved in 235 mL of anhydrous tetrahydrofuran (THF) at 60 ° C. The medium is dried under MgS0 ₄ , filtered then poured into a tricolor. 12.6 mL (90.4 mmol) of triethylamine (TEA) are added to the medium. The medium is then placed under argon and then cooled to a temperature of 0 ° C. 20.74 g (40 mmol) of 2,3,5-triiodobenzoyl chloride are dissolved in 60 ml of anhydrous THF and added dropwise over a period of 5 minutes in the reaction medium, while maintaining a temperature close to 0 ° C. The solution is stirred for 4 hours at 0 ° C. then overnight at room temperature (AT). The reaction medium is then suspended in 1.8 L of water for one hour. The mixture is poured into a separating funnel, and 235 mL of dichloromethane (DCM) is added. The aqueous phase is washed 3 times with 115 ml of DCM. The organic phases are combined and then dried under MgSO4. Evaporated in vacuo until a brown oil is obtained. 23.4 g of this oil are obtained. The yield of this step is 92.7%.

Step 3:

23.4 g (37 mmol) of N- (2- (2- (2-hydroxyethoxy) ethoxy) ethyl) -2,3,5-triiodobenzamide are dissolved in 235 mL of anhydrous THF. 26 mL (186.5 mmol) of triethylamine are added to the medium. The reaction medium is cooled to T = 0 ° C. 27.5 mL (185.5 mmol) of methacrylate anhydride are added dropwise to the medium, while maintaining a temperature close to 0 ° C. The medium is stirred for 3 hours at 0 ° C., then at reflux (80 ° C.) overnight. The reaction medium is then suspended in 1.5 L of water for one hour, then allowed to settle. 350 mL of DCM are added and the aqueous phase washed 3 times with DCM (120 mL). The organic phases are combined and then dried under MgSO4. After evaporation under vacuum, 32.64 g of a brown oil are recovered. The crude product was then purified by puriFlash ^®, on a silica column (330g, SÎ40-60), eluting with a mixture of DCM / acetonitrile (9/1). After evaporation of the solvent, 11.31 g of a white solid are obtained.

The total yield is 40.4%.

Conditions of the HPLC-MS analysis method:

Column BEH C18 n ° 516

Tfour ⁼ 30 ° C

Mobile phase composition: Water-HC0 ₂ H 0.5% (v / v) / MeCN Isocratic gradient 55/45 Flow rate 0.7 mL / min.

Volume injected = 1 pL l = 235 nm

Results:

Retention time: 2.2 min Mass m / z: 699.89 UV purity: 82.3% ¹ H NMR (Acetone) 1.97 (s, 3H, CH ₃ ), 2.93 (t, 2H, NCH ₂ ), 3.57 (m, 10H, CH2OCH2CH2OCH2), 4.32 (t, 2H, CH ₂ 0), 5.65 (s, 1H, olefinic), 6.15 (s, 1H, olefinic), 7.65 (d, 2H, benzyl and NH), 8.38 (d, 1H, benzyl). Example 2 Synthesis by direct suspension polymerization of polymers containing MAOETIB according to the invention in the form of microspheres of size 700-900 μm by varying the concentration of monomers

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), the poly (ethylene glycol) di methacrylate (PEGDMA) (crosslinking agent), methacrylic acid (AM or MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), violet dye (1 - (4 - ((2-methacryloxyethyl) oxy) phenylamino) -anthraquinone) and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved.

Table 1 below summarizes the main parameters and the composition of the organic phase.

Table 1.

Example 3: Synthesis by direct suspension polymerization of polymers containing different concentrations of MAOETIB according to the invention in the form of microspheres

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), the poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), violet dye (1 - (4 - ((2-methacryloxyethyl) oxy) phenylamino) -anthraquinone) and AIBN (initiator) dissolved in toluene is then introduced into the reactor. A commotion is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C. and stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved. Table 2 below summarizes the main parameters and the composition of the organic phase.

Table 2.

Example 4: Synthesis by direct suspension polymerization of polymers containing USPIOs according to the invention in the form of microspheres

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), the poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), violet dye (1 - (4 - ((2-methacryloxyethyl) oxy) phenylamino) -anthraquinone), USPIO and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved.

Table 3 below summarizes the main parameters and the composition of the organic phase.

Table 3

Example 5: Synthesis by direct suspension polymerization of polymers according to the invention containing MAOETIB and not comprising methacrylic acid (MA), in the form of microspheres of size 300 - 500 pm and 700 - 900 pm

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), the poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), violet dye (1 - (4 - ((2-methacryloxyethyl) oxy) phenylamino ) -anthraquinone) and AIBN (initiator) dissolved in the toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C. and stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved. Two fractions are recovered, microspheres of size 300 - 500 µm and microspheres of size 500 - 700 µm.

Table 4 below summarizes the main parameters and the composition of the organic phase.

Table 4.

Characterizations:

The dry extract (dry weight) is produced as follows: 1 ml of sedimented MS is placed in a 5 ml Eppendorf flask, frozen at -80 ° C and lyophilized by a lyophilizer (Heto PowerDry® LL 1500, Thermo Scientific ) overnight. The mass of the microspheres after lyophilization is then measured. The measurement was carried out for three samples and the mean was taken as the final value of the dry mass of the DM.

The average diameter is measured by analysis of microscopy images on 2000 microspheres (Morphologi 4, Malvern).

The injectability test in microcatheters is carried out with 1 ml of microsphere sediment suspended beforehand in 10 ml of iodinated contrast medium (70% of Optiray® 300, Guerbet, 30% of physiological serum). A homogeneous suspension of microspheres in a 3 mL syringe is then injected into the microcatheter. The microcatheters, the supplier of which is the company Terumo, were chosen such that their internal diameter is just slightly greater than the average diameter of the microspheres. The resistance felt during the injection of the microspheres into the microcatheter is recorded (Table 4Bis). A blockage during the injection would mean a failure of the injection. After injection, the microspheres are observed under a microscope to check if the microspheres return to their spherical shape.

Results:

Table 4Bis.

Example 6: Other syntheses by direct suspension polymerization of polymers according to the invention in the form of microspheres

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the main hydrophilic monomer, the crosslinking agent, the radiopaque monomer, optionally the ionizable monomer, the transfer agent, the violet dye (1 - (4 - ((2-methacryloxyethyl) oxy) phenylamino) -anthraquinone) and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and the stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved.

Table 5 below summarizes the main parameters and the composition of the organic phase.

Table 5.

The average diameters of the microspheres of lots L2 and L4 are respectively 731 +/- 53 and 652 +/- 39.

Example 7: Synthesis by direct suspension polymerization of polymers containing different concentrations of transfer agent according to the invention in the form of microspheres

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), the poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), violet dye (1 - (4 - ((2-methacryloxyethyl) oxy) phenylamino) -anthraquinone) and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved.

Table 6 below summarizes the main parameters and the composition of the organic phase.

Table 6.

Characterizations:

The characterization is carried out in the same way as in Example 5 and the results are collated in Table 6bis.

Results:

Table 6bis. These results thus demonstrate the effect of adding a transfer agent on the injectability of the microspheres and the value of the range of concentrations chosen. A quantity of transfer agent clearly above this range does not allow microspheres to be obtained. Example 8 Synthesis by direct suspension polymerization of polymers containing the compound of Example 1b) (of formula (Vb)) as radiopaque halogenated monomer according to the invention in the form of microspheres

An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C. The organic phase containing the poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), the poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinking agent), methacrylic acid (MA) (ionizable monomer), the compound of Example 1b) (radiopaque monomer), bromotrichloromethane (the transfer agent), violet dye (1- (4 - ((2-methacryloxyethyl) oxy) phenylamino) -anthraquinone) and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and stirring is maintained for 8 hours. The mixture is then filtered and the microspheres are washed with acetone and then with water before being sieved and then autoclaved.

Table 7 below summarizes the main parameters and the composition of the organic phase.

Table 7.

Example 9: Effect of the transfer agent on the injectability of microspheres of 700-900 μm comprising polymers according to the invention in a microcatheter The microspheres are prepared as indicated in Example 2 for batches 4, 5,

6 and L6. Lots 1, 2 and 3 are synthesized in an equivalent manner but without the addition of transfer agent. Injectability into a microcatheter (Progreat ^® 2.8 Fr, Terumo, internal diameter 700 μm) is carried out on 1 ml of microsphere sediment previously suspended in 10 ml of iodinated contrast medium (70% of lopamiron ^® 300, Bracco , 30% physiological serum or for batch L6: 70% Optiray ^® 300, Guerbet, 30% physiological serum). A homogeneous suspension of microspheres in a 3 mL syringe is then injected into the microcatheter. The average diameter of the microspheres was chosen to be greater than the internal diameter of the catheter, so as to demonstrate the flexibility of the microspheres. The resistance felt during the injection of the microspheres into the microcatheter is recorded (Table 8). A blockage during the injection means an injection failure. After injection, the microspheres are observed under a microscope in order to check whether the microspheres regain their spherical shape.

^(1> ID = internal diameter of the microcatheter

* Due to the high proportion of MAOETIB, the MS gel is too hydrophobic to swell and reach the desired size. ** The microspheres are sticky and clump together, preventing proper injection. Table 8. Injectability of 700-900 μm microspheres comprising polymers according to the invention in a microcatheter

After injection, the microspheres prepared with the transfer agent according to the invention retain their spherical shape and are not broken. In the absence of a transfer agent, the microspheres block the microcatheter.

In the presence of the transfer agent, the microspheres comprising the polymers according to the invention are easily injectable, that is to say they have only low resistance to injection and do not block the microcatheter.

Example 10 Visibility to X-rays in Vivo of the Microspheres According to the Invention The visibility of the microspheres according to Example 3 implanted subcutaneously in the rabbit is analyzed 3 months after implantation. The animals (n = 2) are euthanized, the back is shaved and a 26G needle is placed in the skin at the point of injection of the microspheres to serve as a landmark. A mobile fluoroscopic / radiographic unit (GE Healthcare - OEC 9900 Elite) is used to take pictures of the backs of animals (X-ray beam energy 63kV, intensity 1.3mA). The quantification of the radiopacity in Hounsfield units (HU) was performed using the ANALYZE 11.0 software (Table 9).

Table 9: X-ray visualization of microspheres injected into rabbit skin

The radiopaque microspheres implanted in the dermis of the rabbit skin are visible on X-rays (Table 9). The intensity of the microspheres is close to that observed for the ribs of animals. Microspheres without iodine (Embosphere ^® ) are not visible to X-rays.

Example 11 Loading and release of active ingredients on the radiopaque microspheres according to the invention

The loading tests and the controlled release of anti-cancer drugs were carried out on radiopaque microspheres of 100-300 µm sterilized by autoclaving and including or not comprising an ionized or ionizable monomer such as meth acrylic acid. The microspheres with methacrylic acid are microspheres from batch 13, the composition of which is given in Example 3. The microspheres without methacrylic acid have the same composition as the microspheres from batches L1 and L1 Bis described in Example 5.

Doxorubicin loading: The loading target is 37.5 mg doxorubicin per mL of microspheres. For this, 3.8 mL of doxorubicin-HCl (Adriblastine ^®, Pfizer) dissolved in water at 2.5 mg / mL are added to 250 pL of wet sediment microspheres. After mixing by inversion, the suspension is made up to 6 mM of sodium bicarbonate (Lavoisier). Loading is carried out at room temperature and with stirring for one hour. Measurement of the residual amount of doxorubicin (absorbance at 490 nm) present in the supernatants is used to determine the amount of drug loaded on the microspheres.

For the study of the release of doxorubicin from the microspheres, the sediments are washed in 10 mL of water, before the addition of 50 mL of 50 mM Tris-HCl buffer, 0.9% NaCl, pH 7.4. Incubation takes place at 37 ° C with agitation. The release of doxorubicin is measured at various times at 490 nm.

Irinotecan loading: The loading target is 50 mg irinotecan per mL of microspheres. The sediments of the radiopaque microspheres are incubated for 30 minutes in excess sodium bicarbonate (1.4%, Lavoisier) without being stirred. Then the supernatant is removed, and 625 µL of 20 mg / mL irinotecan solution (Campto, Pfizer) is added. After 30 minutes, measurement of the residual amount of irinotecan (absorbance at 370 nm) in the supernatant is used to determine the amount loaded on the microspheres.

For the study of the release of irinotecan, the microspheres are washed in 10 mL of water, then 50 mL of PBS (10 mM Na ₂ HP0, 1, 8 mM KH ₂ P0 ₄ , 138 mM NaCl, 2, 7 mM KCl, pH 7.4) equilibrated at 37 ° C are added. Drug release over time is measured by reading the absorbance at 370 nm.

Loading of sunitinib: The sediments of the radiopaque microspheres are incubated for 1 h at room temperature in 10 mL of sunitinib in the form of malate (LC laboratories) at 1 mg / mL in water. The final sodium bicarbonate concentration is 4 mM. After 1 hour of stirring on a wheel, measurement of the residual amount of sunitinib (absorbance at 405 nm) in the supernatant is used to determine the amount loaded on the microspheres.

For the study of the release of sunitinib, the microspheres are washed in 10 mL of water, then 50 mL of PBS equilibrated at 37 ° C is added. Drug release over time is measured by reading the absorbance at 405 nm.

Loading of vandetanib: The sediments of the radiopaque microspheres are incubated for 2 h at room temperature in 10 mL of a water / DMSO mixture (1/1) containing 5 mg of vandetanib (LC Laboratories). The residual amount of vandetanib in the supernatants is measured at 254 nm in order to calculate the amount loaded on the microspheres. For the study of the release of vandetanib, the microspheres are washed in 10 ml of water, then 50 ml of PBS equilibrated at 37 ° C. are added. Drug release over time is measured by reading the absorbance at 254 nm.

Table 10. Loading of anti-cancer drugs onto radiopaque microspheres and their release in vitro

Loading of different anti-cancer drugs (cytotoxic and anti-angiogenic drugs) is possible on the radiopaque microspheres with a diameter of 100-300 µm. Loading of drugs onto the microspheres is rapid (less than 2 h). Elution in PBS depends on the drugs loaded. The release of irinotecan is rapid (50% in 1 h), the release of doxorubicin, sunitinib and vandetanib is slower, it takes place over several days.

The loading efficiency is calculated according to the following equation: LE: Charging efficiency

Initial MDrug: Amount of drug solubilized

CDrug_sur: Drug concentration in the supernatant after loading Vsur: Volume of the supernatant VMS: Volume of microspheres

The charging efficiency without methacrylic acid is 83.5%, compared to 99.7% in the presence of 20% methacrylic acid. Studies have shown that loading efficiency is lower for microspheres without methacrylic acid than for those containing methacrylic acid.

The ability of microspheres without ionizable monomers to charge doxorubicin is explained by the establishment of hydrophobic or van der Waals bonds. In the presence of ionizable monomer, in addition to these bonds, doxorubicin is charged by electrostatic bonds. The kinetics and loading capacities are thus improved.

Example 12: Modification of the signal by in vitro MRI of the microspheres according to the invention loaded with USPIO: measurement of T2

The microspheres according to Example 4 were suspended in a 2% 50/50 vol / vol agarose gel. The microsphere inserts were included in a 2% agarose gel plate. The plate was imaged using a 1.5 T MRI (Phillips). The sequence used for this imaging is as follows: T2 sequence: TR = 2000 ms, TE from 10 ms to 310 ms in steps of 20 ms. Voxel = 0.5 * 0.5 * 2 mm, treatment with Matlab to obtain T2. The size of the voxels is 0.5 * 0.5 * 1mm. The FOV (Field of View) is 150 * 150mm.

Table 11a: Comparison of loaded microspheres with increasing amounts of USPIOs

Table 11b: comparison of microspheres loaded with USPIOs of 10, 20 or 30 nm

Table 11. MRI measurement of T2 in microspheres The decrease in signal intensity is consistent with the T2 effect of USPIOs. The intensity of the signal increases with the amount of USPIO in the microspheres. It also believes with the decrease in size of USPIOs (from 30 nm to 10 nm).

Claims

1. Polymer comprising a crosslinked matrix, said matrix being based on at least: a) 20% to 90% of hydrophilic monomer chosen from N-vinylpyrrolidone, and a monomer of formula (I) below:

(CH ₂ = CR _I ) -CO-D (I) in which:

• D represents 0-1 or NH-Z, Z representing (CrC _ô ) alkyl, - (CR ₂ R ₃ ) _m -CH ₃ , - (CH ₂ -CH ₂ -0) _m - H, - (CH ₂ - CH2-0) m-CH ₃ , -C (R OH) _m or - (CH2) _m -NR5R6 with m representing an integer of 1 to 30;

(CH ₂ = CR ₇ ) -CO-Y (II) in which

• Ar represents a (Cs-C36) aryl or (Cs-C36) heteroaryl group, said group being substituted with one, two or three atom (s) of iodine and / or bromine, and optionally substituted with one to four, preferably two or three groups selected from (Cr Cio) alkyl, -NR _a Rb, -NR _c CORd, -COOR _e , -ORf, -OCOR _g , -CONRhR ,, -OCONRjRk, -NRiCOOR ₀ -, - NR _r CONRsRt, -OCOORu, and -COR _v ;

• R9 to R15 and R _a to R _v represent, independently of each other, a hydrogen atom, a (CrCio) alkyl, said (C1-C10) alkyl being optionally substituted with 1 to 10 OH group (s), or a - (CH ₂ -CH ₂ -0) _q -R ', R' being a hydrogen atom or a - (CrC ₆ ) alkyl and q being an integer between 1 and 10, preferably between 1 and 5 ;

• R ₇ represents H or a (CrC ₆ ) alkyl; • Rs represents a group chosen from (Ci-C3 _ô ) alkylene, (C3-C3 _ô ) cycloalkylene, (C2- C3 _ô ) alkenylene, (C3-C3 _ô ) cycloalkenylene, (C2-C3 _ô ) alkynylene, (C3- C3 _ô ) cycloalkynylene, (C5- C3 _ô ) arylene and (C5-C3 _ô ) heteroarylene, c) 1% to 15% of non-biodegradable linear or branched hydrophilic crosslinker with groups (CH2 = (CRi6)) - to each at its ends, each R _½ independently representing H or a (CrC ₆ ) alkyl; and d) 0.1% to 10% of transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino groups , hydroxy and carboxy, the percentages of monomers a) to c) being cited in moles relative to the total number of moles of monomers and the percentages of compound d) being cited in moles relative to the number of moles of hydrophilic monomer a).

2. Polymer according to claim 1, wherein said matrix is based on a halogenated radiopaque monomer of general formula (II) in an amount greater than 7% and less than or equal to 50%, advantageously in an amount greater than 10%. and less than or equal to 50%, advantageously in an amount greater than 15% and less than or equal to 50%, more advantageously in an amount greater than 15% and less than or equal to 35%, and in particular from 20% to 30% per Mole, relative to the number of total moles of monomers.

3. Polymer according to claim 1 or 2, wherein the hydrophilic monomer a) is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, t acrylate. - butyl, t-butyl methacrylate, methyl methacrylate, N- dimethylaminoethyl (methyl) acrylate, N, N-dimethylaminopropyl- (meth) acrylate, t- butylaminoethyl (methyl) acrylate, N, N-diethylaminoacrylate, poly (meth) acrylate (ethylene oxide), methoxy poly (ethylene oxide) (meth) acrylate, (meth) acrylate poly (ethylene oxide), (meth) acrylate poly (ethylene glycol), (meth) acrylate methoxy poly (ethylene glycol) ), butoxy poly (ethylene glycol) (meth) acrylate, poly (ethylene glycol) methyl ether methacrylate and mixtures thereof, advantageously the monomer a) is poly (ethylene glycol) methyl ether methacrylate.

4. Polymer according to any one of claims 1 to 3, in which the radiopaque monomer is of general formula (II) as defined in claim 1, in which Y represents OC _Ô HW, O-Côhh, O- Côhhh, NH-C _Ô HW, NH-Côhh, NH-Côhhh, 0- CH ₂ -CH ₂ -C (0) -C ₆ H4l, 0-CH2-CH ₂ -0-C (0) -C ₆ H3l2 , 0-CH2-CH2-0-C (0) -C ₆ H ₂ l ₃ , NH-CH ₂ -CH ₂ -C (0) - C ₆ HI, NH-CH2-CH2-0-C (0) -C ₆ H ₃ l2, NH-CH2-CH2 -O-C (0) -C ₆ H ₂ l ₃ .

5. Polymer according to any one of claims 1 to 4, in which the radiopaque monomer is (tri-iodobenzoyl) oxo ethyl methacrylate of the following formula (IIa):

6. Polymer according to any one of claims 1 to 5, in which the non-biodegradable linear or branched hydrophilic crosslinker has (CH ₂ = (CRi ₆ )) CO- OR (CH ₂ = (CRi ₆ )) C0- groups. 0- at its at least two ends, each R _½ independently representing H or a (CrC ₆ ) alkyl.

7. Polymer according to any one of claims 1 to 6 wherein the transfer agent is selected from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol and mixtures thereof.

8. Polymer according to any one of claims 1 to 7, wherein said matrix is further based on at least one ionized or ionizable monomer of the following formula (IV):

(CH ₂ = CR _I7 ) -ME (IV) in which:

• R ₁₇ represents H or a (CrC ₆ ) alkyl; • M represents a single bond or a divalent radical having 1 to 20 carbon atoms;

• E represents a charged or ionizable group having 100 atoms at most, E being advantageously chosen from the group consisting of -COOH, -COO, -SO ₃ H, -SO ₃ , -PO ₄ H ₂ , -PO4H, -PO4 ² , -NR18R19, NR20R2I R22 ⁺ ,

• Ris, R19, R20, R21 and R22 represent independently of each other H or a (Cr C ₆ ) alkyl.

9. Polymer according to any one of claims 1 to 8, wherein said matrix is further based on at least one colored monomer of the following general formula (VI): in which,

• X represents H or Cl, advantageously H;

• R23 represents H or a (CrC ₆ ) alkyl, advantageously a (CrC ₆ ) alkyl, in particular a methyl; and

• R24 represents a group chosen from (CrC6) linear or branched alkylene, (C ₅ - C3 6) arylene, (Cs-C36) arylene-0-R26, (C5-C36) heteroarylene and (C5-C36) heteroarylene-0- R27, R26 and R27 representing a (CrC ₆ ) alkyl or a (CrC ₆ ) alkylene, advantageously R24 represents a group -C ₆ hU-O-ÎChh -O or -C (CH3) 2-CH2-0.

10. Polymer according to any one of claims 1 to 9, wherein said matrix is further based on particles visible by magnetic resonance imaging (MRI) such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, advantageously iron oxide nanoparticles.

11. Polymer according to any one of claims 8 to 10, loaded with a drug or an active substance or a diagnostic agent, advantageously having a molar mass of less than 5000 Da, typically less than 1000 Da, the drug or the active substance being advantageously chosen from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents , steroid, antiseptic and a mixture of these.

12. Polymer according to any one of claims 8 to 10, loaded with macromolecules chosen from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzyme, aptamers, anti-inflammatory proteins, bone morphogenic proteins (BMP), pro-angiogenic factors, vascular endothelial growth factors (VEGF) and TGFs -beta, and angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof.

13. Pharmaceutical composition comprising at least one polymer according to any one of claims 1 to 12, in association with a pharmaceutically acceptable vehicle, advantageously for parenteral administration.

14. Kit comprising a pharmaceutical composition as defined in claim 13, in association with a pharmaceutically acceptable vehicle for parenteral administration, and at least one means of injection.

15. Kit comprising on the one hand a pharmaceutical composition as defined in claim 13 and on the other hand at least one contrast agent for imaging by X-ray, by magnetic resonance or by ultrasound, and optionally at least one means. injection for parenteral administration, the pharmaceutical composition and the at least one contrast agent being packaged separately.

16. Compound of the following general formula (V):

(CH ₂ = CR ₂₈ ) -CO-Y '(V) in which

• R ₂₈ represents H or a (Ci-C ₆ ) alkyl;

• Y 'represents, (0-R ₂₉ ) _t -W'-Ar', or NH-W'-Ar ', t being an integer between

1 and 10, preferably between 1 and 4;

• R ₂ 9 represents a group selected from (C ₂ -C 3 _O) alkylene; • W 'represents a single bond, -CONR ₃₀ -, or -NR ₃₁ CO-;

• Ar 'represents a (Cs-C ₃₆ ) aryl group, said group being substituted by one, two or three atom (s) of iodine and / or bromine, and optionally substituted by one to four, preferably two or three , groups selected from (CrCio) alkyl, -NR ₃₂ R ₃₃ , -NR ₃₄ COR ₃₅ , -COOR ₃₆ , -OR ₃₇ , -OCOR ₃₈ , -CONR ₃₉ R ₄₀ , -OCONR ₄₁ R ₄₂ , -NR ₄₃ COOR ₄₄ , NR ₄₅ CONR ₄₆ R _47, -OCOOR ₄₈ , and -COR ₄₉ ;

17. Use of the compound of general formula (V) as defined in claim 16 as radiopaque halogenated monomer.