Non-degradable radiopaque embolic microspheres

Abstract

The invention relates to a polymer comprising a cross-linked matrix based on at least the following: a) from 20% to 90% of a hydrophilic monomer; b) from 5% to 50% of a radiopaque halogenated monomer; c) from 1% to 15% of a non-biodegradable hydrophilic cross-linking agent; and d) 0.1% to 10% of a transfer agent selected from alkyl halides and cycloaliphatic or aliphatic mercaptans, in particular these alkyl halides and cycloaliphatic or aliphatic mercaptans have 2 to 24 carbon atoms, and optionally have another functional group selected from amino, hydroxyl and carboxyl groups. The invention further relates to a pharmaceutical composition comprising at least one polymer according to the invention in combination with a pharmaceutically acceptable vehicle advantageously for parenteral administration. The invention further relates to a kit comprising a pharmaceutical composition comprising a polymer according to the invention in combination with a pharmaceutically acceptable vehicle for parenteral administration and an injection means.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of October 7, 2020, application number 202080070479.X, and invention name “Non-degradable Radiopaque Embolic Microspheres”. Technical Field

[0002] The present invention relates to non-biodegradable radiopaque polymers, particularly suitable for implantation in an individual and optionally for controlled release of active ingredients or macromolecules. The non-biodegradable radiopaque polymers according to the present invention are particularly formed into non-biodegradable radiopaque embolic microspheres intended for injection into an individual. The present invention also relates to a pharmaceutical composition comprising a polymer according to the present invention. Background Art

[0003] Therapeutic vascular occlusion (i.e., embolization) is used to prevent or treat certain pathological conditions in situ. It can be performed through a catheter, making it possible to place microparticle occlusive agents (i.e., emboli or embolic agents) into the circulatory system under imaging control. It has a variety of medical applications, such as the treatment of vascular malformations, bleeding processes, or tumors, including, for example, uterine fibroids, primary or secondary liver tumors. For example, vascular occlusion may lead to tumor necrosis and avoid more invasive surgery. This occlusion technique can also be combined with the delivery of anticancer agents in the case of chemoembolization. This makes it possible to increase the local concentration of the drug product and its residence time in the tumor by targeted injection. In the case of vascular malformations, vascular occlusion can normalize blood flow to normal tissues and assist surgery by limiting the risk of bleeding. In the process of bleeding, vascular occlusion may lead to reduced blood flow, thereby promoting the healing of arterial wounds. In addition, depending on the pathological condition being treated, embolization can be used for temporary or permanent purposes.

[0004] Commercial embolic agents for vascular occlusion include embolic liquids (acrylic adhesives, 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.

[0005] Particles used for embolization mainly contain natural and synthetic polymers. Polymer-type embolic agents have advantages because they generally have good biocompatibility with tissues.

[0006] They can be of hydrophobic material. However, the latter are increasingly used in embolization because they are difficult or even impossible to insert into the catheter and present a risk of catheter occlusion, which necessitates the user to replace the latter, prolonging the procedure and increasing its risks.

[0007] For example, dry particles of polyvinyl alcohol (PVA) are suspended in an injectable liquid (such as saline solution and iodinated contrast agent) and then injected into the catheter. Even after suspension, they are still quite hydrophobic and tend to form aggregates in the syringe, base and catheter lumen, thereby blocking the injection catheter. Some technical measures have been proposed (adding collagen, albumin, dextran, gelatin sponge particles, alcohol, etc.), but no success has been achieved in preventing these aggregations and blockages (Derdeyn CP1, Moran CJ, Cross DT, Dietrich HH, Dacey RG Jr. Polyvinyl alcohol particle size and suspension characteristics. [Particle size and suspension characteristics of polyvinyl alcohol] AJNR Am J Neuroradiol. [AJNR American Society of Neuroradiology] June-July 1995; 16 (6): 1335-43).

[0008] Therefore, hydrophilic materials such as triacyl gelatin or gelatin sponge have been considered for embolization because they are more easily suspended, injectable and cause less catheter occlusion than hydrophobic materials (CP Derdeyn, VB Graves, MS Salamat and A Rappe, Collagen-coated acrylic microspheres for embolotherapy: invivo and in vitro characteristics. American Journal of Neuroradiology April 1997, 18(4) 647-653).

[0009] To verify the exact location of the embolic particles and to detect backflow in non-target organs, the embolic particles are made radiopaque, i.e., visible in X-ray images. Thus, the radiopaque embolic particles can be positioned to detect whether the coverage of chemotherapy is adequate, to observe whether the dispersion of the embolic particles in the target area is uniform or uneven, complete or incomplete, or to detect whether the particles are located outside the target area.

[0010] Radiopaque polymer embolic particles are described in US Pat. No. 4,622,367 and in the work of Horak et al., Biomaterials, 1987, 8, 142. These particles form the basis of acrylate and methacrylate polymers and copolymers and contain derivatives of aminotriiodobenzoic acid, which are distributed in a matrix network. However, the triiodinated molecules are too bulky to diffuse easily in the network and are therefore mainly grafted to the particle surface, limiting the transport of water to the interior of the particle, resulting in a loss of the hydrophilic character of the material and therefore of the swelling properties in water. This drawback limits the medical application of this material and in particular makes its administration by injection very difficult or even impossible.

[0011] Jayakrishnan et al., J. Biomed Mat Res, 1990, 24, 993, describe hydrogel-type radiopaque microspheres based on PHEMA / iodopamine and PHEMA / iodopamine copolymers. However, these microspheres are very rigid and therefore difficult to inject.

[0012] Horak et al., J. Biomed Mat Res, 1997, 34, 183, describe radiopaque hydrogel-type particles based on PHEMA. The ionizable groups present in the structure improve the swelling properties of the microspheres, but these properties are still limited due to the porous structure of the microspheres. Therefore, they are still difficult to inject.

[0013] Patent application US2009 / 0297612 describes solid uniform spherical particles of radiopaque copolymers with controlled swelling properties and their use in embolization. These particles are based on at least one hydrophilic monomer and at least one radiopaque monomer with the general formula (CH2=CR)-CO-R1. The examples in this application show that when the content of iodinated monomer increases, the swelling properties decrease, making the microspheres more rigid. Such embolic microspheres are known under the name It is therefore difficult to obtain non-rigid microspheres containing sufficient amounts of iodinated monomers.

[0014] Patent application US2015 / 0110722 and Duran et al., Theranostics, 2016, 6, 28 describe radiopaque particles based on cross-linked PVA and iodinated compounds (triiodobenzyl). However, these particles have a high density (density of 1.21-1.36 g / cm 3 ) and rigid structure with reduced water content, resulting in difficulty in forming a suspension and very limited injectability or requiring the use of a catheter with an inner diameter much larger than the diameter of the microspheres.

[0015] In all of these examples, it has been clearly observed that the addition of radiopaque entities or monomers with halogenated groups significantly reduces the hydrophilic character of the material. In summary, the microspheres currently loaded with iodine to be visible in X-rays are hydrophobic, dense, and rigid. As a result, (1) they are difficult to keep suspended during intracatheter injection, and (2) they often block the catheter, even when their diameter is smaller than the inner diameter of the catheter (Duran 2016).

[0016] Therefore, it is highly desirable to prepare microspheres based on radiopaque polymers which, despite containing halogens (about 5 to 50 mol%), remain hydrophilic and flexible when swollen in water. It is therefore desirable that these microspheres possess mechanical properties, in particular a certain degree of swelling, elasticity and compressibility, be suitable for injection through a catheter or microcatheter, and be able to recover their original shape after injection while avoiding embolism away from the target site.

[0017] It is also desirable that these microspheres be able to remain suspended in a mixture of contrast medium and buffer solution during injection within the catheter. In fact, to facilitate injection, the microspheres are usually suspended in a mixture of non-ionic iodinated contrast medium and buffer solution. To this end, radiologists usually use a contrast medium solution and optionally a saline solution, a bicarbonate buffer or a phosphate buffer, advantageously a solution of 100% contrast medium. To ensure injectability, the microspheres must remain uniformly suspended in this solution. If the microspheres settle or otherwise float to the surface of the solution, the resulting suspension is not uniform and is unstable and therefore cannot be injected into the patient.

[0018] Therefore, it is advantageous to have microspheres with an appropriate density to allow homogeneous suspension in a mixture comprising saline solution, bicarbonate buffer or phosphate buffer and a contrast agent in a ratio of 50 / 50 to 0 / 100.

[0019] Furthermore, it is necessary to make them visible in magnetic resonance imaging (MRI) and capable of being loaded with active ingredients. Summary of the invention

[0020] Therefore, the present invention can meet these needs and provide solutions to various shortcomings encountered in the prior art.

[0021] The present invention is generally directed to polymers comprising a crosslinked matrix based on at least:

[0022] a) 20% to 90% of a hydrophilic monomer selected from N-vinylpyrrolidone and a monomer having the following formula (I):

[0023] (CH2=CR1)-CO-D(I)

[0024] in:

[0025] D represents OZ or NH-Z, Z represents (C1-C6) alkyl, -(CR2R3) m -CH3, -(CH2-CH2-O) m -H, -(CH2-CH2-O) m -CH3, -C(R4OH) m or -(CH2) m -NR5R6, wherein m represents an integer from 1 to 30, preferably m is equal to 4 or 5

[0026] R1, R2, R3, R4, R5 and R6 independently represent H or (C1-C6) alkyl;

[0027] b) 5% to 50% of a halogenated radiopaque monomer having the following general formula (II):

[0028] (CH2=CR7)-CO-Y(II)

[0029] in

[0030] ·Y stands for OW, (O-R8) p -W, (NH-R8) p -W or NH-W, W represents Ar, L-Ar, and p is an integer between 1 and 10, preferably between 1 and 4, wherein:

[0031] Ar represents (C5-C 36 )aryl or (C5-C 36 ) heteroaryl groups, which are substituted by one, two or three atoms of iodine and / or bromine, and are optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-OR f 、-OCOR g 、-CONR h R i 、-OCONR j R k 、-NR1COOR o 、-NRrCONR S R t 、-OCOOR u , and -COR v ;

[0032] ·L represents -(CH2) n -、-(HCCH) n-, -O-, -S-, -SO-, -SO2-, -OSO2 - , -NR9-, -CO-, -COO-, -OCO-, -OCOO-, -CONR 10 -、-NR 11 CO-、-OCONR 12 -、-NR 13 COO- or -NR 14 CONR 15 -, n is an integer from 1 to 10;

[0033] R9 to R 15 and R a To R v Each independently represents a hydrogen atom, (C1-C 10 )alkyl, or group -(CH2-CH2-O) q -R', the (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups, R' is a hydrogen atom or -(C1-C6)alkyl, and q is an integer between 1 and 10, preferably between 1 and 5;

[0034] R7 represents H or (C1-C6) alkyl;

[0035] R8 represents a group selected from the following: (C1-C 36 ) alkylene, (C3-C 36 )cycloalkylene, (C2-C 36 ) alkenylene, (C3-C 36 )cycloalkenylene, (C2-C 36 ) alkynylene, (C3-C 36 )cycloalkynylene, (C5-C 36 )arylene and (C5-C 36 ) heteroarylene,

[0036] c) 1% to 15% of a non-biodegradable linear or branched hydrophilic crosslinker having at each end a group (CH2=(CR 16 ))-, each R 16 independently represent H or (C1-C6)alkyl; and

[0037] d) 0.1% to 10% of a transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols, in particular these alkyl halides and cycloaliphatic or aliphatic thiols have 2 to 24 carbon atoms and optionally have another functional group chosen from amino, hydroxyl and carboxyl groups,

[0038] The percentages of monomers a) to c) are given in moles relative to the total moles of monomers and the percentage of compound d) is given in moles relative to the moles of hydrophilic monomer a).

[0039] The inventors have found that the addition of a transfer agent during the polymerization of a radiopaque polymer can improve the hydrophilic properties of the microspheres formed from the polymer, thereby allowing them to be injected. When a transfer agent is not added to the polymer according to the invention, the microspheres obtained are not injectable, which limits their range of therapeutic applications. Thus, the polymer according to the invention makes it possible to obtain embolic microspheres that are easy to inject and meet all the above requirements.

[0040] The invention further relates to a pharmaceutical composition comprising at least one polymer according to the invention in combination with a pharmaceutically acceptable vehicle advantageously for administration by injection.

[0041] The invention also relates to a kit comprising a pharmaceutical composition as defined above and at least one injection means for administering said composition by the parenteral route.

[0042] The invention also relates to 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, magnetic resonance or ultrasonography and, optionally, at least one injection means for parenteral administration.

[0043] The present invention also relates to compounds having the following general formula (V):

[0044] (CH2=CR 28 )-CO-Y'(V)

[0045] in

[0046] ·R 28 represents H or (C1-C6) alkyl;

[0047] ·Y' represents (OR 29 ) t -W'-Ar', or NH-W'-Ar', t is an integer between 1 and 10, preferably between 1 and 4;

[0048] ·R 29 Representative selected from (C2-C 36 ) an alkylene group;

[0049] ·W' represents a single bond, -CONR 30 -, or -NR 31 CO-;

[0050] Ar' represents (C5-C 36) aryl group, which is substituted by one, two or three atoms of iodine and / or bromine, and is optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )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 ;

[0051] ·R 30 and R 31 independently represent a hydrogen atom or a (C1-C6) alkyl group;

[0052] ·R 32 To R 49 Each independently represents a hydrogen atom, (C1-C 10 )alkyl, or group -(CH2-CH2-O) t' -R", said (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups, R" is a hydrogen atom or -(C1-C6)alkyl, and t' is an integer between 1 and 10, preferably between 1 and 5.

[0053] The present invention also relates to the use of compounds of formula (V) as defined above as radiopaque halogenated monomers.

[0054] definition

[0055] The expression "matrix based on..." is to be understood as a matrix comprising a mixture and / or reaction products between heterogeneously polymerized base components for the matrix, preferably only comprising reaction products between different base components for the matrix, some of which may react or react easily together or with their close chemical environment at least partially in different steps of the matrix manufacturing process, in particular in the polymerization step. Thus, the base components are reactants that are intended to react together during the polymerization of the matrix. The base components are thus introduced into a reaction mixture, which optionally further comprises 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 transfer agent d) mentioned in the present description as essential components, optionally a polymerization initiator, such as, for example, tert-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also known as 4,4'-azobis(4-cyanovaleric) acid), AIBN (isobutyronitrile), or 1,1'-azobis(cyclohexanecarbonitrile), or one or more thermal initiators, such as 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (106797-53-9); 2-hydroxy-2-methylpropiophenone ( 1173, 7473-98-5); 2,2-dimethoxy-2-phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenylacetophenone ( 24650-42-8) or 2-methyl-4'-(methylthio)-2-morpholinopropiophenone ( 71868-10-5), and at least one solvent, preferably a solvent mixture comprising an aqueous solvent and an organic solvent, such as a non-polar aprotic solvent, for example a water / toluene mixture.

[0056] According to the invention, the matrix is ​​therefore based at least on the monomers a), b), c) and transfer agents d) mentioned in this description, these compounds therefore being the essential components.

[0057] Therefore, in the present description, expressions such as "[base component X] is added to the reaction mixture in an amount of YY% to YYY% in particular" and "the cross-linked matrix is ​​based in particular on [base component X] in an amount of YY% to YYY%" are interpreted similarly. In addition, expressions such as "the reaction mixture contains at least [base component X]" and "the cross-linked matrix is ​​based at least on [base component X]" are interpreted similarly.

[0058] In the sense of the present invention, the "organic phase" of the reaction mixture is taken to mean the phase which comprises the organic solvent and the compounds which are soluble in the organic solvent, in particular the monomers, the transfer agent and the polymerization initiator.

[0059] In the sense of the present invention, "(C X -C Y A ")alkyl" group is intended to mean a saturated, linear or branched, monovalent hydrocarbon-containing chain containing from X to Y carbon atoms, X and Y being integers between 1 and 36, preferably between 1 and 18, in particular between 1 and 6. By way of example, mention may be made of a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl group.

[0060] In the sense of the present invention, "(C X -C Y )Aryl" means an aromatic hydrocarbon-containing group, which preferably contains X to Y carbon atoms and contains one ring or several condensed rings, X and Y being integers between 5 and 36, preferably 5 and 18, in particular 5 and 10. As examples, phenyl or naphthyl groups may be mentioned.

[0061] In the sense of the present invention, "(C X -C Y The term "heteroaryl" refers to an aromatic group containing X to Y ring atoms, including one or more heteroatoms, advantageously 1 to 4, 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 integers between 5 and 36, preferably 5 and 18, in particular 5 and 10. Examples of heteroaryl groups are furanyl, thienyl, pyrrolyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or indolyl groups.

[0062] In the sense of the present invention, "(C X -C Y )alkylene group" means a linear or branched divalent hydrocarbon-containing chain containing from X to Y carbon atoms, X and Y being integers between 1 and 36, preferably between 1 and 18, in particular between 1 and 6. Mention may be made, by way of example, of methylene, ethylene, propylene, butylene, pentylene or hexylene groups.

[0063] In the sense of the present invention, "(C X -C Y ) Cycloalkylene group "is intended to mean a saturated, cyclic, divalent hydrocarbon-containing group containing from X to Y ring carbon atoms, X and Y being integers between 3 and 36, preferably between 3 and 18, in particular between 3 and 6. Mention may be made, by way of example, of cyclopropylene, cyclohexylene or cyclopentylene groups.

[0064] In the sense of the present invention, "(C X -C Y)Alkenylene group" means a linear or branched divalent hydrocarbon-containing chain containing 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. As examples, mention may be made of vinylene / ethenylene or propenylene groups.

[0065] In the sense of the present invention, "(C X -C Y )Cycloalkenylene group" means a saturated, cyclic, divalent hydrocarbon-containing group containing X to Y ring carbon atoms and at least one double bond, X and Y being integers between 3 and 36, preferably 3 and 18, especially 3 and 6.

[0066] In the sense of the present invention, "(C X -C Y The term "alkynylene group" means a linear or branched divalent hydrocarbon-containing chain containing X to Y carbon atoms and at least one triple bond, X and Y being integers between 2 and 36, preferably 2 and 18, especially 2 and 6.

[0067] In the sense of the present invention, "(C X -C Y )cycloalkynylene group" means a saturated, cyclic, divalent hydrocarbon-containing group containing X to Y ring carbon atoms and at least one triple bond, X and Y being integers between 3 and 36, preferably 3 and 18, especially 3 and 6.

[0068] In the sense of the present invention, "(C X -C Y )Arylene" means a divalent aromatic hydrocarbon-containing group containing X to Y carbon atoms and containing one or more fused rings, X and Y being integers between 5 and 36, preferably 5 and 18, especially 5 and 10. As an example, a phenylene group may be mentioned.

[0069] In the sense of the present invention, "(C X -C Y )Heteroarylene is intended to mean a divalent aromatic group containing X to Y ring atoms, these ring atoms include one or more heteroatoms, advantageously 1 to 4, 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 integers between 5 and 36, preferably 5 and 18, in particular 5 and 10.

[0070] In the sense of the present invention, a "divalent group" means a group having a valence of 2, ie having two covalent bonds, polar covalent bonds or ionic chemical bonds. The group may contain, for example, carbon atoms and / or oxygen atoms.

[0071] In the sense of the present invention, "dry extract" means the mass of dry microspheres contained in 1 ml of water-swollen microspheres. DETAILED DESCRIPTION

[0072] The present invention is generally directed to polymers comprising a crosslinked matrix based on at least:

[0073] a) 20% to 90% of a hydrophilic monomer selected from N-vinylpyrrolidone and a monomer having the following formula (I):

[0074] (CH2=CR1)-CO-D(I)

[0075] in:

[0076] D represents OZ or NH-Z, Z represents (C1-C6) alkyl, -(CR2R3) m -CH3, -(CH2-CH2-O) m -H, -(CH2-CH2-O) m -CH3, -C(R4OH) m or -(CH2) m -NR5R6, wherein m represents an integer from 1 to 30;

[0077] R1, R2, R3, R4, R5 and R6 independently represent H or (C1-C6) alkyl;

[0078] b) 5% to 50% of a halogenated radiopaque monomer having the following general formula (II):

[0079] (CH2=CR7)-CO-Y(II)

[0080] in

[0081] ·Y stands for OW, (O-R8) p -W, (NH-R8) p -W or NH-W, W represents Ar, L-Ar, and p is an integer between 1 and 10, preferably between 1 and 4, wherein:

[0082] Ar represents (C5-C 36 )aryl or (C5-C 36 ) heteroaryl groups, which are substituted by one, two or three atoms of iodine and / or bromine, and are optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-ORf 、-OCOR g 、-CONR h R i 、-OCONR j R k 、-NR l COOR o -、-NR r CONR S R t 、-OCOOR u , and -COR v ;

[0083] ·L represents -(CH2) n -、-(HCCH) n -, -O-, -S-, -SO-, -SO2-, -OSO2 - , -NR9-, -CO-, -COO-, -OCO-, -OCOO-, -CONR 10 -、-NR 11 CO-、-OCONR 12 -、-NR 13 COO- or -NR 14 CONR 15 -, n is an integer from 1 to 10;

[0084] R9 to R 15 and R a To R v Each independently represents a hydrogen atom; (C1-C 10 ) alkyl, the (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups; or a group -(CH2-CH2-O) q -R', R' is a hydrogen atom or -(C1-C6)alkyl, and q is an integer between 1 and 10, preferably between 1 and 5;

[0085] R7 represents H or (C1-C6) alkyl;

[0086] R8 represents a group selected from the following: (C1-C 36 ) alkylene, (C3-C 36 )cycloalkylene, (C2-C 36 ) alkenylene, (C3-C 36 )cycloalkenylene, (C2-C 36 ) alkynylene, (C3-C 36 )cycloalkynylene, (C5-C 36 )arylene and (C5-C 36 ) heteroarylene.

[0087] c) 1% to 15% of a non-biodegradable linear or branched hydrophilic crosslinker having at each end a group (CH2=(CR 16 ))-, each R 16 independently represent H or (C1-C6)alkyl; and

[0088] d) 0.1% to 10% of a transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols, in particular these alkyl halides and cycloaliphatic or aliphatic thiols have 2 to 24 carbon atoms and optionally have another functional group chosen from amino, hydroxyl and carboxyl groups,

[0089] The percentages of monomers a) to c) are given in moles relative to the total moles of monomers and the percentage of compound d) is given in moles relative to the moles of hydrophilic monomer a).

[0090] Preferably, the polymer according to the invention is present in the form of spherical particles. The spherical particles are preferably microspheres.

[0091] In the sense of the present invention, "microspheres" are meant 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, from 500 to 700 μm, from 700 to 900 μm or from 900 to 1200 μm, as determined by optical microscopy. Microspheres advantageously have a diameter small enough to be injected by means of a needle, catheter or microcatheter having an inner diameter ranging from a few hundred micrometers to more than one millimeter.

[0092] The expression "after swelling" means that the size of the microspheres is considered after the polymerization and sterilization steps in the preparation process. The sterilization step involves, for example, the passage of the microspheres after the polymerization step in an autoclave at elevated 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, i.e. the degree of swelling is controlled. The degree of swelling is defined as:

[0093]

[0094] Where m w is the weight of 1 mL of deposited microspheres in grams, and m d is the weight in grams of 1 ml of lyophilized deposited microspheres.

[0095] In the sense of the present invention, "controlled swelling degree" means that the swelling degree is reproducible from batch to batch, in particular differs from one batch to another by less than 15%.

[0096] In the sense of the present invention, "sedimenting the microspheres" means placing the microspheres in a solution in a container and then leaving them without stirring for a sufficient time to allow them to sink to the bottom of the container containing them so that the supernatant can be removed.

[0097] In the sense of the present invention, "lyophilized microspheres" refer to microspheres that have been dehydrated by freezing followed by sublimation.

[0098] In the sense of the present invention, "hydrophilic monomers" are taken to mean monomers which have a strong affinity for water, ie tend to dissolve in water, to mix with water or are capable of swelling in water after being wetted by water or after polymerization.

[0099] The hydrophilic monomer a) of the present invention is selected from N-vinylpyrrolidone and a monomer having the following formula (I):

[0100] (CH2=CR1)-CO-D(I)

[0101] in:

[0102] D represents OZ or NH-Z, Z represents (C1-C6) alkyl, -(CR2R3) m -CH3, -(CH2-CH2-O) m -H, -(CH2-CH2-O) m -CH3, -C(R4OH) m or -(CH2) m -NR5R6, wherein m preferably represents an integer between 1 and 10, more preferably m is equal to 4 or 5.

[0103] 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, tert-butyl acrylate, tert-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl-(meth)acrylate, tert-butylaminoethyl (meth)acrylate, N,N-diethylaminoacrylate, poly(ethylene oxide) (meth)acrylate, methoxypoly(ethylene oxide) (meth)acrylate, butoxypoly(ethylene oxide) (meth)acrylate, poly(ethylene glycol) (meth)acrylate, methoxypoly(ethylene glycol) (meth)acrylate, butoxypoly(ethylene glycol) (meth)acrylate, poly(ethylene glycol) methyl ether methacrylate (m-PEGMA), and mixtures thereof.

[0104] More advantageously, the hydrophilic monomer a) is poly(ethylene glycol) methyl ether methacrylate (m-PEGMA).

[0105] In the context of the present invention, the hydrophilic monomers a) are added to the reaction mixture in an amount of from 20% to 90%, preferably from 30% to 80%, preferably from 40% to 70%, in particular from 45% to 65% (mol %), relative to the total moles of the monomers. Thus, in the context of the present invention, the crosslinking matrix is ​​based in particular on hydrophilic monomers a) in an amount of from 20% to 90%, preferably from 30% to 80%, preferably from 40% to 70%, in particular from 45% to 65% (mol %), relative to the total moles of the monomers.

[0106] Radiopacity refers to the relative inability of electromagnetics, particularly X-rays, to pass through a dense material described as "radio-opaque," which appears as opaque / white in radiographic images. Given the complexity of the content in radiographic or fluoroscopic images, clinicians are very sensitive to image quality in terms of brightness or the power of the signal from the material in the image. The two main factors that affect the level of radiopacity are density and atomic number. Medical devices based on polymers that need to be radiopaque typically use a blend of polymers that incorporates small amounts (by weight percentage) of radiopaque elements, such as heavy atoms such as halogens, particularly iodine. The ability of the device to be observable via fluoroscopy depends on the amount or density of the radiopaque element mixed with the material. The amount of radiopaque element in the blend is typically limited to small amounts because it may adversely affect the properties of the base polymer material.

[0107] In the context of the present invention, the radiopaque monomer is advantageously a monomer having the general formula (II) as defined above, wherein Y represents NH—W, OW or (O—R8) p -W, advantageously NH-W or (O-R8) p -W, more advantageously (O-R8) p -W, W represents Ar or L-Ar, p, R8, L and Ar are as defined above. Preferably, R8 is (C1-C 36 ) alkylene, especially (C1-C 18 )alkylene, more particularly (C1-C6)alkylene; L represents -OCO-; and Ar represents (C5-C 36 ) aryl, especially (C5-C 10 ) aryl, more particularly phenyl, substituted by one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally two or three groups selected from: -NR a R b 、-NR c COR d 、-COOR e 、-OCOR g 、-CONR h R i、-OCONR j R k 、-NR1COOR o -and-NR r CONR S R t , preferably -NR a R b 、-NR c COR d .

[0108] Advantageously, the radiopaque monomer is a monomer having the general formula (II) as defined above, wherein Y represents NH—W or (O—R8) p -W, more advantageously (O-R8) p -W, W represents Ar or L-Ar, and p, R8, L and Ar are as defined above. Preferably, R8 is (C2-C 36 ) alkylene, especially (C2-C 18 )alkylene, more particularly (C2-C6)alkylene; L represents -OCO-, -C(O)NR 10 -, or -NR 11 C(O)-; and Ar represents (C5-C 36 ) aryl, especially (C5-C 10 ) aryl, more particularly phenyl, substituted by one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally two or three groups selected from: -NR a R b 、-NR c COR d 、-COOR e 、-OCOR g 、-CONR h R i 、-OCONR j R k 、-NR1COOR o -and-NR r CONR S R t , preferably -NR a R b 、-NR c COR d and -C(O)NR h R i .

[0109] Advantageously, Ar represents (C5-C 10 ) aryl, more particularly phenyl, substituted by three atoms of iodine and / or bromine, preferably iodine, and optionally two groups selected from: (C1-C 10)alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-OCOR g 、-CONR h R i 、-OCONR j R k 、-NR l COOR o -and-NR r CONR S R t .

[0110] Advantageously, Ar represents a phenyl group substituted by three atoms of iodine and / or bromine, preferably iodine, and optionally two groups selected from: (C1-C 10 )alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-OCOR g 、-CONR h R i 、-OCONR j R k 、-NR1COOR o -and-NR r CONR S R t , advantageously selected from (C1-C 10 )alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-CONR h R i 、-NR1COOR o -and-NR r CONR S R t .

[0111] Advantageously, the radiopaque monomer is a monomer of formula (II) as defined above, wherein Y represents O-C6H4I, O-C6H2I2, O-C6H2I3, NH-C6H4I, NH-C6H3I2, NH-C6H2I3, O-CH2-CH2-C(O)-C6H4I, O-CH2-CH2-OC(O)-C6H3I2, O-CH2-CH2-OC(O)- C6H2I3, NH-CH2-CH2-C(O)-C6H4I, NH-CH2-CH2-OC(O)-C6H3I2, or NH-CH2-CH2-OC(O)-C6H2I3, in particular O-C6H2I3, NH-C6H2I3, O-CH2-CH2-OC(O)-C6H2I3, or NH-CH2-CH2-OC(O)-C6H2I3.

[0112] Advantageously, the halogenated monomer is selected from compounds having the following general formula (V):

[0113] (CH2=CR 28 )-CO-Y'(V)

[0114] in

[0115] ·R 28 represents H or (C1-C6) alkyl;

[0116] ·Y' represents (OR 29 ) t -W'-Ar', or NH-W'-Ar', t is an integer between 1 and 10, preferably between 1 and 4;

[0117] ·R 29 Representative selected from (C2-C 36 ) an alkylene group;

[0118] ·W' represents a single bond, -CONR 30 -, or -NR 31 CO-;

[0119] Ar' represents (C5-C 36 ) aryl group, which is substituted by one, two or three atoms of iodine and / or bromine, and is optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 COR 35 、-COOR 36 、-OR 37 、-OCOR 38 、-CONR39 R 40 、-OCONR 41 R 42 、-NR 43 COOR 44 、-NR 45 CONR 46 R 47 、-OCOOR 48 , and -COR 49 ;

[0120] ·R 30 and R 31 independently represent a hydrogen atom or a (C1-C6) alkyl group;

[0121] ·R 32 To R 49 Each independently represents a hydrogen atom, (C1-C 10 )alkyl, or group -(CH2-CH2-O) t' -R", said (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups, R" is a hydrogen atom or -(C1-C6)alkyl, and t' is an integer between 1 and 10, preferably between 1 and 5.

[0122] Advantageously, R 28 represents a (C1-C6)alkyl group, more preferably a (C1-C3)alkyl group, more preferably a methyl group.

[0123] Advantageously, R 29 Representative (C2-C 18 )alkylene, more particularly (C2-C6)alkylene, more advantageously ethylene.

[0124] Advantageously, R 30 and R 31 Independently of one another, W' represents a hydrogen atom. Thus, W' advantageously represents a single bond, -C(O)NH-, or -NHC(O)-.

[0125] Advantageously, Ar' represents (C5-C 10 ) aryl, more particularly phenyl, substituted by one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally two or three groups selected from: (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-OC(O)R 38 、-C(O)NR39 R 40 、-OC(O)NR 41 R 42 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 .

[0126] Advantageously, Ar' represents (C5-C 10 ) aryl, more particularly phenyl, substituted by three atoms of iodine and / or bromine, preferably iodine, and optionally two groups selected from: (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-OC(O)R 38 、-C(O)NR 39 R 40 、-OC(O)NR 41 R 42 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 .

[0127] Advantageously, Ar' represents a phenyl group substituted by three atoms of iodine and / or bromine, preferably iodine, and optionally two groups selected from: (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-OC(O)R 38 、-C(O)NR 39 R 40 、-OC(O)NR 41 R 42 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46R 47 、-OC(O)OR 48 , and -C(O)R 49 , advantageously selected from (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-C(O)NR 39 R 40 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 .

[0128] Advantageously, the halogenated monomer is selected from the following compounds:

[0129]

[0130]

[0131] Advantageously, the halogenated monomer is selected from the following compounds:

[0132]

[0133]

[0134] More advantageously, the radiopaque monomer is (tri-iodobenzoyl)oxyethyl methacrylate (MAOETIB) having the following formula (IIa):

[0135]

[0136] or 2-(2-(2-(2,3,5-triiodobenzamide)ethoxy)ethyl methacrylate having the formula:

[0137]

[0138] In the context of the present invention, the radiopaque monomer is in particular added to the reaction mixture in an amount from 5% to 50%, in particular an amount greater than 7% and less than or equal to 50%, in particular an amount greater than 10% and less than or equal to 50%, more particularly an amount greater than 15% and less than or equal to 50%, preferably an amount greater than 15% and less than or equal to 35%, and in particular from 20% to 30% (mol %), relative to the total moles of the monomers.

[0139] In the sense of the present invention, "crosslinking monomer" means at least bifunctional but also multifunctional monomers having a double bond at each polymerizable end. The crosslinking monomer combines with other monomers in the mixture to allow the formation of a crosslinked network. A person skilled in the art can easily select the structure and amount of one or more crosslinking monomers in the monomer mixture to provide the desired crosslinking density. The crosslinking agent is also beneficial to the stability of the microspheres. The crosslinking agent prevents the microspheres from dissolving in any solvent. The crosslinking agent can also improve the compressibility of the microspheres, which is beneficial for embolization.

[0140] In the sense of the present invention, a "non-biodegradable hydrophilic cross-linker" means a cross-linker as defined above, which has a strong affinity for water and cannot be degraded under physiological conditions in a mammal, in particular in the human body. In fact, biodegradation of the molecule is allowed when the molecule contains sufficient functional sites that can be cleaved by endogenous enzymes under physiological conditions, in particular in a mammal, in particular in the human body, and / or at a physiological pH (usually about 7.4). Functional sites that can be cleaved under physiological conditions are in particular amide bonds, ester bonds and acetals. Therefore, molecules containing an insufficient number of said functional sites will be considered non-biodegradable. In the context of the present invention, the cross-linking monomer contains less than 20 functional sites that can be cleaved under physiological conditions, preferably less than 15 sites, more preferably less than 10 sites, even more preferably less than 5 sites.

[0141] In particular, the non-biodegradable linear or branched hydrophilic cross-linking agent is a non-biodegradable cross-linking agent that is soluble in an organic solvent and comprises a diacrylate, methacrylate, acrylamide, and / or methacrylamide polymerizable group.

[0142] Advantageously, the cross-linking agent has (CH2=(CR 16 ))CO- or (CH2=(CR 16 ))CO-O-group, each R 16 independently represent H or (C1-C6) alkyl; advantageously, the group R 16 are the same and represent H or (C1-C6)alkyl.

[0143] In particular, the crosslinking agent has the following general formula (IIIa) or (IIIb):

[0144] (CH2=(CR 16 ))CO-NH-A-HN-OC((CR 16 )=CH2)(IIIa),

[0145] (CH2=(CR 16 ))CO-OAO-OC((CR16 )=CH2)(IIIb),

[0146] in

[0147] Each R 16 independently represents H or (C1-C6) alkyl, advantageously, the group R 16 are the same and represent H or (C1-C6)alkyl; and

[0148] A alone or together with at least one atom to which it is bonded represents (C1-C6)alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A.

[0149] Advantageously, the crosslinking agent has the following general formula (IIa) or (IIb):

[0150] (CH2=(CR 16 ))CO-NH-A-HN-OC((CR 16 )=CH2)(IIIa),

[0151] (CH2=(CR 16 ))CO-OAO-OC((CR 16 )=CH2)(IIIb),

[0152] in,

[0153] Each R 16 independently represents H or (C1-C6) alkyl, advantageously, the group R 16 are the same and represent H or (C1-C6)alkyl; and

[0154] Preferably, A alone or together with at least one atom to which it is bonded represents (C1-C6)alkylene or polyethylene glycol (PEG), preferably polyethylene glycol (PEG).

[0155] In the context of the definition of A given above, the length of the polyethylene glycol ranges from 200 to 10000 g / mol, preferably from 200 to 2000 g / mol, more preferably from 500 to 1000 g / mol.

[0156] As examples of crosslinking monomers useful in the context of the present invention, mention may be made, without limitation, of 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylenebisacrylamide, glycerol 1,3-diglycerate diacrylate and poly(ethylene glycol) dimethacrylate (PEGDMA).

[0157] Advantageously, the crosslinking monomer is poly(ethylene glycol) dimethacrylate (PEGDMA), the length of the polyethylene glycol unit ranging from 200 to 10000 g / mol, preferably from 200 to 2000 g / mol, more preferably from 500 to 1000 g / mol.

[0158] In the context of the present invention, the crosslinking monomer is added to the reaction mixture in an amount of from 1 to 15%, preferably from 2 to 10%, in particular 2 to 7%, more particularly 2 to 5% (mol %) relative to the total moles of monomers.

[0159] In the context of the present invention, "transfer agent" means a chemical compound with at least one weak chemical bond. The agent reacts with the free radical site of a growing polymer chain and arrests the growth of the chain. During chain transfer, the free radical is temporarily transferred to the transfer agent, which restarts growth by transferring the free radical to another polymer or monomer.

[0160] In the context of the present invention, the use of a transfer agent to obtain a polymer according to the invention allows the polymer to maintain its hydrophilicity even with the addition of radiopaque monomers, thus allowing the microspheres to be injected. This makes it possible to obtain a more homogeneous polymer network with improved elastic properties and thus improved swelling characteristics.

[0161] Advantageously, the chain transfer agent is selected from the group consisting of monofunctional or polyfunctional mercaptans, and alkyl halides.

[0162] Specifically, alkyl halides useful as transfer agents include bromotrichloromethane, tetrachloromethane, and tetrabromomethane.

[0163] Particularly advantageously, the chain transfer agent is an aliphatic or cycloaliphatic mercaptan, which mercaptan generally has from 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 6 carbon atoms, and optionally has additional functional groups selected from amino, hydroxyl and carboxyl groups.

[0164] Examples of particularly preferred chain transfer agents are thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof, preferably hexanethiol.

[0165] In the context of the present invention, the transfer agent is added to the reaction mixture in an amount of from 0.1% to 10%, preferably from 0.5% to 8%, more advantageously from 1.5% to 6%, in particular from 1.5% to 4.5% (mol %), and in particular 3 mol %, relative to the moles of the hydrophilic monomer a).

[0166] In a particular embodiment according to the invention, the crosslinked polymer matrix of the microspheres is based solely on the basic components a), b), c) and d) as defined above in the above-mentioned proportions of monomers and transfer agents, without adding other basic components to the reaction mixture. It is therefore obvious that the sum of the above-mentioned proportions of monomers a), b) and c) must be equal to 100%.

[0167] According to a particular aspect of the invention, the matrix of the polymer according to the invention is further based on at least one ionized or ionizable monomer of the following formula (IV):

[0168] (CH2=CR 17 )-ME(IV)

[0169] in:

[0170] ·R 17 represents H or (C1-C6) alkyl;

[0171] M represents a single bond or a divalent group having 1 to 20 carbon atoms, preferably a single bond;

[0172] E represents an ionized or ionizable group, advantageously, E is selected from the group consisting of: -COOH, -COO-, -SO3H, -SO3 - 、-PO4H2、-PO4H - ,-PO4 2- 、-NR 18 R 19 and-NR 20 R 21 R 22 + ,

[0173] ·R 18 , R 19 , R 20 , R 21 and R 22 Independently of each other represent H or (C1-C6) alkyl.

[0174] In the sense of the present invention, an "ionized or ionizable group" is understood to mean a group which is or may be charged (in the form of an ion), i.e., carries at least one positive or negative charge, depending on the pH value of the medium. - ionized, and the NH2 group can be ionized as NH3 + form.

[0175] The introduction of ionized or ionizable monomers into the reaction mixture can increase the hydrophilicity of the resulting microspheres, thereby increasing the swelling of the microspheres, further facilitating their injection through catheters and microcatheters. In addition, the presence of ionized or ionizable monomers allows for loading of active substances within the microspheres.

[0176] 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)ethyl)(meth)acrylate 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 the above cationic monomers in an amount of between 1 and 40 mol % (relative to the total moles of monomers). Preferably, when the resulting microspheres are not intended to be loaded with active substances, the crosslinked matrix according to the invention is based on ionized or ionizable monomers in an amount of between 5% and 15%, preferably 10 mol % (relative to the total moles of monomers). According to another embodiment, when the microspheres are intended to be loaded with active substances, the crosslinked matrix according to the invention is obtained by adding to the reaction mixture between 20% and 40% of ionized or ionizable monomers, preferably by adding to the reaction mixture 20% to 30 mol % of ionized or ionizable monomers relative to the total moles of monomers.

[0177] 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-oligomers of carboxyethyl acrylate, 3-sulfopropyl (meth) acrylate, potassium salt and hydroxide of 2-((methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium. Advantageously, the crosslinked matrix according to the invention is based on the above cationic monomers in an amount of between 1% and 40 mol % (based on the total amount of monomers). Preferably, when the resulting microspheres are not intended to be loaded with active substances, the crosslinked matrix according to the invention is based on ionized or ionizable monomers in an amount of between 5% and 15%, preferably 10 mol % (based on the total amount of monomers). According to another embodiment, when the microspheres are intended to be loaded with active substances, the crosslinked matrix according to the invention is based on ionized or ionizable monomers in an amount of between 20% and 40%, preferably 20 to 30% of ionized or ionizable monomers (based on the total amount of monomers).

[0178] Particularly advantageously, the ionized or ionizable monomer is methacrylic acid (MA). Advantageously, the crosslinking matrix according to the invention is based on methacrylic acid (MA) in an amount of between 10 and 30 mol % (based on the total amount of monomers).

[0179] In the context of the present invention, the crosslinked matrix according to the invention is further based on at least one colored monomer to improve its visibility to the naked eye. This makes it possible in particular to check whether the polymer suspension is homogeneous in the syringe before injection and to control the injection rate.

[0180] Thus, according to a particular embodiment, the matrix of the polymer according to the invention is further based on at least one colored monomer having the following general formula (VI):

[0181]

[0182] in,

[0183] Z1 and Z2 independently represent H or OR 25 , R 25 represents H or (C1-C6) alkyl, advantageously Z1 and Z2 represent H;

[0184] X represents H or a halogen such as Cl, advantageously H;

[0185] ·R 23 represents H or (C1-C6)alkyl, advantageously (C1-C6)alkyl, in particular methyl; and

[0186] ·R 24 represents a group selected from the following: straight chain or branched (C1-C6) alkylene, (C5-C 36 ) arylene, (C5-C 36 )Arylene-OR 26 、(C5-C 36 )heteroarylene and (C5-C 36 )heteroarylene-OR 27 , R 26 and R 27 represents (C1-C6) alkyl or (C1-C6) alkylene, preferably R 24 Represents a -C6H4-O-(CH2)2- or -C(CH3)2-CH2- group.

[0187] Advantageously, the colored monomer has the following formula (VIa) or (VIb):

[0188]

[0189] More advantageously, the colored monomer has the above formula (VIb).

[0190] 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% (mol %) relative to the total moles of monomers.

[0191] Magnetic resonance imaging (MRI) is used in medical settings to provide two-dimensional cross-sectional images of the internal structures of a patient's body without exposing it to harmful radiation. The matrix of the polymer according to the invention may in particular be based on particles allowing the polymer to be visualized using magnetic resonance imaging (MRI).

[0192] Thus, advantageously, the matrix of the polymer according to the invention is further based on at least one agent visible in magnetic resonance imaging (MRI), such as nanoparticles of iron oxide, gadolinium chelates or magnesium chelates, advantageously nanoparticles of iron oxide such as USPIO (ultrasmall superparamagnetic iron oxide or ultrasmall paramagnetic iron oxide, i.e. magnetic particles based on iron compounds having superparamagnetic characteristics making them visible in MRI).

[0193] In the context of the present invention, particles visible in MRI are advantageously added to the reaction mixture in an amount of from 0 to 10%, preferably from 0.5 to 8%, more preferably from 0.5 to 5%, in particular 1% by volume of the organic phase.

[0194] In the context of the present invention, when the polymer matrix does not contain ionized or ionizable monomers as an essential component, it is advantageously based on:

[0195] - 34.5% to 84%, preferably 64.9% to 77.98% of hydrophilic monomers a);

[0196] - more than 15% to 50%, preferably 20% to 30% of radiopaque monomers b);

[0197] - 1% to 15%, preferably 2% to 5%, of a non-biodegradable hydrophilic crosslinker c);

[0198] - 1.5 to 4.5%, preferably 3%, of a transfer agent d);

[0199] - 0% to 0.5%, preferably 0.02% to 0.1% of a colored monomer; and

[0200] - 0% to 10%, preferably 1% to 5% of particles visible on MRI,

[0201] The nature of each monomer mentioned and its relative percentages are as defined above in this specification. Obviously, the sum of the percentages of the above monomers must equal 100%.

[0202] In the context of the present invention, when the polymer matrix does not contain ionized or ionizable monomers as an essential component, it is advantageously based on:

[0203] - 74.5% to 78% hydrophilic monomer a)

[0204] - 20% radiopaque monomer b);

[0205] - 2 to 5% of a non-biodegradable hydrophilic crosslinker c);

[0206] - 1.5 to 4.5% of transfer agent d);

[0207] - 0% to 0.5% of a colored monomer; and

[0208] -0% to 10% of particles visible on MRI,

[0209] The nature of each monomer mentioned and its relative percentages are as defined above in this specification. Obviously, the sum of the percentages of the above monomers must equal 100%.

[0210] In the context of the present invention, when the polymer matrix comprises as basic components ionized or ionizable monomers, it is advantageously based on:

[0211] - 34.9% to 67.98%, preferably 34.96% to 67.96% of hydrophilic monomers a)

[0212] - 20% to 30% radiopaque monomer b);

[0213] - 2 to 5% of a non-biodegradable hydrophilic crosslinker c);

[0214] - 1.5 to 3% of transfer agent d);

[0215] - 10% to 30% ionizable or charged monomers;

[0216] - 0.02% to 0.1%, preferably 0.04% of a colored monomer; and

[0217] -0% to 10% of particles visible on MRI,

[0218] The nature of each monomer mentioned and its relative percentages are as defined above in this specification. Obviously, the sum of the percentages of the above monomers must equal 100%.

[0219] The polymers according to the invention can be readily synthesized by a number of methods with which the skilled person will be familiar. As an example, the polymers according to the invention can be obtained by suspension polymerization as described below and in the examples.

[0220] Direct suspension can be performed as follows:

[0221] (a) mixing or stirring a reaction mixture comprising:

[0222] (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 cross-linking agent c) as defined above, and at least one transfer agent d) as defined above;

[0223] (ii) a polymerization initiator present in an amount of from 0.1 to about 2 parts by weight per 100 parts by weight of the monomer;

[0224] (iii) a surfactant in an amount no greater than about 5 parts by weight per 100 parts by weight of the aqueous phase, preferably no greater than about 3 parts by weight, and most preferably in the range of from 0.2 to 1.5 parts by weight; and

[0225] (iv) water to form an oil-in-water suspension;

[0226] as well as

[0227] (b) Polymerizing the base component.

[0228] In the direct suspension method, the surfactant may be selected from the group consisting of hydroxyethyl cellulose, polyvinyl alcohol (PVA), polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol and polysorbate 20 ( 20); preferably it is PVA.

[0229] The microspheres thus obtained are then washed and calibrated by techniques familiar to those skilled in the art.

[0230] The reverse suspension can be prepared as follows:

[0231] (a) mixing or stirring a reaction mixture comprising:

[0232] (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 cross-linking agent c) as defined above, and at least one transfer agent d) as defined above;

[0233] (ii) a polymerization initiator present in an amount of from 0.1 to about 2 parts by weight per 100 parts by weight of the monomer;

[0234] (iii) a surfactant in an amount no greater than about 10 parts by weight per 100 parts by weight of the oil phase, preferably no greater than about 8 parts by weight per 100 parts by weight of the oil phase, and most preferably in the range of from 3 to 7 parts by weight per 100 parts by weight of the oil phase; and

[0235] (iv) oil, to form a water-in-oil suspension;

[0236] as well as

[0237] (b) Polymerizing the base component.

[0238] In the above method, the polymerization initiator can be, in particular, tert-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also known as 4,4'-azobis(4-cyanovaleric acid), AIBN (azobisisobutyronitrile), or 1,1'-azobis(cyclohexanenitrile) or one or more thermal initiators, such as 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (106797-53-9); 2-hydroxy-2-methylpropiophenone ( 1173, 7473-98-5); 2,2-dimethoxy-2-phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenylacetophenone ( 24650-42-8) or 2-methyl-4'-(methylthio)-2-morpholinopropiophenone ( 71868-10-5).

[0239] In the reverse suspension method, the surfactant may be selected from the group consisting of: sorbitan esters, such as sorbitan monolaurate ( 20) Sorbitan monopalmitate ( 40) Sorbitan monooleate ( 80), and sorbitan trioleate ( 85), hydroxyethylcellulose, glyceryl stearate and PEG stearate mixture and cellulose acetate.

[0240] The oil used in the above method can be selected from paraffin oil, silicone oil and organic solvents such as hexane, cyclohexane, ethyl acetate or butyl acetate.

[0241] When the polymer according to the invention is obtained based on the polymerization of at least one ionized or ionizable monomer, the drug product, active substance, diagnostic agent or macromolecule can also be loaded on the polymer, i.e. adsorbed on the polymer by non-covalent interactions, optionally in the presence of one or more pharmaceutically acceptable excipients familiar to the person skilled in the art. This particular way of capturing the drug product or active substance is called physical encapsulation. There are no particular requirements for the drug product or active substance to be loaded.

[0242] Loading can be carried out by many methods familiar to those skilled in the art, such as passive adsorption (swelling of the polymer in the drug product solution) or by ionic interaction. These methods are described, for example, in the international application 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 and / or favorable interaction between the two structures.

[0243] In the context of the present invention, polymers can be loaded with drug products, active substances or diagnostic agents, thereby allowing them to be released at a target site, which is located in a mammal, particularly in a human body. Monitoring the loaded polymer by X-ray or MRI can ensure that the release of the drug product / active substance / diagnostic agent occurs at the desired specific site. Therefore, polymers according to the present invention can be loaded with drug products or active substances or diagnostic agents advantageously having a molecular weight lower than 5000Da, typically lower than 1000Da, and the drug product or active substance is advantageously selected from the group consisting of: anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, preservatives and mixtures thereof.

[0244] Preferably, the polymers according to the present invention may be loaded with anti-cancer agents.

[0245] The anticancer agent is preferably selected from anthracyclines, such as doxorubicin, epirubicin or idarubicin, platinum complexes, compounds related to anthracyclines, such as mitoxantrone and nemorubicin, antibiotics, such as mitomycin C Bleomycin and actinomycin D, other antineoplastic compounds such as irinotecan, 5-fluorouracil Sorafenib Sunitinib Regorafenib, brivanib, oantitinib, linsetinib, erlotinib, cabozantinib, foretinib, tivantinib, fotemustine, tauromustine (TCNU), carmustine, cytosine C, cyclophosphamide, cytosine arabinoside (or cytarabine), paclitaxel, docetaxel, methotrexate, everolimus PEG-arginine deiminase, fluazifop / gimeracil / oteracil combination muparfostat, peretinoine, gemcitabine, bevacizumab Ramucirumab, floxuridine, immunostimulants such as GM-CSF (granulocyte macrophage colony-stimulating factor) and the recombinant forms: molgramostim or sargramostim OK-432 Interleukin-2, interleukin-4 and tumor necrosis factor-alpha (TNFalpha), antibodies, radioactive elements, complexes of these radioactive elements with chelates, nucleic acid sequences and mixtures of one or more of these compounds (preferably mixtures of one or more anthracyclines).

[0246] Preferably, the anticancer agent is selected from anthracyclines, immunostimulants, platinum complexes, antineoplastic drugs and mixtures thereof.

[0247] Even more preferably, the anticancer agent is selected from the group consisting of anthracyclines, antibodies, antineoplastic drugs, and mixtures thereof.

[0248] The antibody is, for example, selected from anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CEA (carcinoembryonic antigen), or a mixture thereof.

[0249] Anti-PD-1 is, for example, nivolumab or pembrolizumab.

[0250] Anti-PD-L1 is, for example, avelumab, durvalumab or atezolizumab.

[0251] Anti-CTLA-4 is, for example, ipilimumab or tremelimumab.

[0252] Even more advantageously, the anticancer agent is selected from the group consisting of paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (granulocyte macrophage colony stimulating factor), tumor necrosis factor-α (TNFalpha), antibodies, and mixtures thereof.

[0253] Preferably the local anesthetic is selected from lidocaine, bupivacaine and mixtures thereof.

[0254] The anti-inflammatory agent may be selected from the group consisting of: ibuprofen, niflumic acid, dexamethasone, naproxen, and mixtures thereof.

[0255] In the context of the present invention, the polymer can be loaded with macromolecules, in particular by temporary adsorption, which are selected from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzymes (also known as DNAzymes), aptamers, anti-inflammatory proteins, bone morphogenetic proteins (BMPs), pro-angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, as well as angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof.

[0256] Anti-inflammatory proteins are, for example, infliximab or rilonacept and mixtures thereof.

[0257] Angiogenic factors are, for example, fibroblast growth factor (FGF) and mixtures thereof.

[0258] Angiogenesis inhibitors are for example bevacizumab, ramucirumab, nesvacumab, olatumumab, vanucizumab, rilotumumab, emibetuzumab, aflibercept, felatuzumab, pegaptanib and mixtures thereof.

[0259] Anti-tyrosine kinases are, for example, lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, surufatinib, dovetinib, linifanib and mixtures thereof.

[0260] Advantageously, the polymer may be loaded with macromolecules selected from anti-tyrosine kinases, TGF-β, angiogenesis inhibitors and mixtures thereof.

[0261] In a second aspect, the present invention relates to a pharmaceutical composition comprising at least one polymer according to the invention in combination with a pharmaceutically acceptable vehicle, advantageously for administration by injection.

[0262] Examples of pharmaceutically acceptable vehicles include, but are not limited to, water for injection, saline solution (also known as physiological serum), starch, hydrogel, polyvinyl pyrrolidone, polysaccharide, hyaluronate, plasma, contrast agents for X-ray, magnetic resonance or ultrasonography, buffers, preservatives, gelling agents, surfactants or mixtures thereof. Advantageously, the pharmaceutically acceptable vehicle is saline solution, water for injection, contrast agents for X-ray, magnetic resonance or ultrasonography or mixtures thereof. More advantageously, the pharmaceutically acceptable vehicle is a contrast agent for X-ray, magnetic resonance or ultrasonography, saline solution, or a mixture of saline solution and a contrast agent for X-ray, magnetic resonance or ultrasonography.

[0263] According to the invention, the contrast agent is preferably a contrast agent for X-ray imaging. It is advantageously one or more non-ionic iodinated water-soluble contrast agents, such as iodine alcohol. Iopamidol Iomeprol Ioversol Iohexol Iodine pentol Ioxiline Iopromide Mepane Iodoxacol Iodtrolan Iodixanol Iosimenol and iodoxime and mixtures thereof.

[0264] According to another embodiment, the contrast agent is a contrast agent for magnetic resonance imaging (MRI). It is advantageously a gadolinium chelate

[0265] According to another embodiment, the contrast agent is a contrast agent for imaging by ultrasonography. It is advantageously sulfur hexafluoride.

[0266] In a particular embodiment of the invention, the pharmaceutical composition comprises a polymer according to the invention in combination with a saline solution, said composition being intended to be mixed with at least one contrast agent for X-ray, magnetic resonance or ultrasonography imaging, in particular for X-ray imaging, as defined above, and then administered by injection, said mixing leading to a suspension of microspheres obtained from the polymer according to the invention.

[0267] In a particular embodiment according to the invention, the pharmaceutical composition according to the invention comprises a polymer according to the invention in combination with a mixture of a saline solution as defined above and a contrast agent, the saline solution and the contrast agent being present in a ratio of from 50 / 50 to 0 / 100, advantageously from 40 / 60 to 0 / 100, preferably from 30 / 70 to 0 / 100.

[0268] In another particular embodiment according to the present invention, the pharmaceutical composition according to the present invention comprises the polymer according to the present invention solely in combination with one or more contrast agents as defined above, in particular one or more contrast agents for X-ray imaging as defined above.

[0269] The pharmaceutical composition must have an acceptable viscosity for injection.

[0270] Fields of application of the radiopaque polymers according to the invention include in particular embolization and chemoembolization.

[0271] As mentioned above, the polymer according to the invention can be used for various biomedical purposes, which means that it must be compatible with the mammalian body, in particular with the human body. More particularly, suitable biomedical materials do not have hemolytic properties.

[0272] The 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 in catheters or microcatheters with an inner diameter ranging from a few hundred micrometers to more than one millimeter. The invention also relates to the specific use of a transfer agent in the polymerization of a radiopaque polymer to improve the hydrophilicity and swelling properties of said polymer in water, thereby facilitating its injection. The transfer agent is in particular as defined above and in the context of the above definition, and is in particular chosen from cycloaliphatic thiols or aliphatic thiols, in particular having from 2 to 24 carbon atoms and optionally having another functional group chosen from amino, hydroxyl and carboxyl.

[0273] The invention also relates to a kit comprising a pharmaceutical composition as defined above and at least one means of injecting the composition for parenteral administration. According to the invention, "injection means" means any means allowing administration by a parenteral route. Advantageously, the injection means is one or more syringes, which may be prefilled, and / or one or more catheters or microcatheters.

[0274] Advantageously, the pharmaceutical composition contained in the kit comprises a polymer according to the invention in combination with a saline solution, one or more contrast agents as defined above, in particular one or more contrast agents for X-ray imaging as defined above, or a mixture thereof. More advantageously, the pharmaceutical composition comprises a polymer according to the invention in combination with a saline solution and one or more contrast agents as defined above, in particular one or more contrast agents for X-ray imaging as defined above, in a mixture in a ratio of between 50 / 50 and 0 / 100, advantageously between 40 / 60 and 0 / 100, preferably from 30 / 70 to 0 / 100.

[0275] Advantageously, the one or more injection means contained in the kit according to the invention are suitable for parenteral administration of the pharmaceutical composition according to the invention. Thus, the size of the one or more syringes or (micro)catheters will be adjusted according to the size of the microspheres obtained from the polymer according to the invention and the volume injected for embolization, the size of the microspheres themselves being chosen as a function of the size of the vessel to be embolized.

[0276] One skilled in the art will know how to select microspheres of appropriate size and thus the appropriate means of injection.

[0277] The invention also relates to a kit comprising, on the one hand, a pharmaceutical composition as defined above, and, on the other hand, at least one contrast agent for X-ray, magnetic resonance or ultrasonography imaging, and optionally at least one injection means for parenteral administration. The injection means are as defined above.

[0278] In the kit, the pharmaceutical composition and the contrast agent are packaged separately and are intended to be mixed before administration by injection.

[0279] In the kit, at least one contrast agent is as defined in the specification above. In particular, at least one contrast agent is a contrast agent for X-ray imaging as defined in the specification above.

[0280] In the kit, the pharmaceutical composition advantageously comprises a polymer according to the invention in combination with a pharmaceutically acceptable vehicle for administration by injection. The pharmaceutically acceptable vehicle may be, for example, but not limited to, water for injection, saline solution, starch, hydrogel, polyvinyl pyrrolidone, polysaccharide, hyaluronate and / or plasma. Preferably, in the kit, the pharmaceutical composition advantageously comprises a polymer according to the invention in combination with saline solution or water for injection.

[0281] In the kit, the pharmaceutical composition is advantageously packaged directly in an injection means, in particular a syringe, suitable for injecting the embolic microspheres by the parenteral route.

[0282] In said kit, the contrast agent is advantageously packaged in a vial or directly in an injection means, in particular a syringe, particularly suitable for the injection of the embolic microspheres by the parenteral route.

[0283] In the kit, the ratio of pharmaceutically acceptable vehicle / contrast agent is between 50 / 50 and 0 / 100, advantageously between 40 / 60 and 0 / 100, preferably from 30 / 70 to 0 / 100.

[0284] The present invention also relates to compounds having the following general formula (V):

[0285] (CH2=CR 28 )-CO-Y'(V)

[0286] in

[0287] ·R 28 represents H or (C1-C6) alkyl;

[0288] ·Y' represents (OR 29 ) t -W'-Ar', or NH-W'-Ar', t is an integer between 1 and 10, preferably between 1 and 4;

[0289] ·R 29 Representative selected from (C2-C 36 ) an alkylene group;

[0290] ·W' represents a single bond, -CONR 30 -, or -NR 31 CO-;

[0291] Ar' represents (C5-C 36 ) aryl group, which is substituted by one, two or three atoms of iodine and / or bromine, and is optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )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 ;

[0292] ·R 30 and R 31 independently represent a hydrogen atom or a (C1-C6) alkyl group;

[0293] ·R 32 To R 49 Each independently represents a hydrogen atom, (C1-C 10 )alkyl, or group -(CH2-CH2-O) t' -R", said (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups, R" is a hydrogen atom or -(C1-C6)alkyl, and t' is an integer between 1 and 10, preferably between 1 and 5.

[0294] Advantageously, R 28 represents a (C1-C6)alkyl group, more preferably a (C1-C3)alkyl group, more preferably a methyl group.

[0295] Advantageously, R 29 Representative (C2-C 18 )alkylene, more particularly (C2-C6)alkylene, more advantageously ethylene.

[0296] Advantageously, R 30 and R 31 Independently of one another, W' represents a hydrogen atom. Thus, W' advantageously represents a single bond, -C(O)NH-, or -NHC(O)-.

[0297] Advantageously, Ar' represents (C5-C 10 ) aryl, more particularly phenyl, substituted by one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally two or three groups selected from: (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-OC(O)R 38 、-C(O)NR 39 R 40 、-OC(O)NR 41 R 42 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 .

[0298] Advantageously, Ar' represents (C5-C 10 ) aryl, more particularly phenyl, substituted by three atoms of iodine and / or bromine, preferably iodine, and optionally two groups selected from: (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-OC(O)R 38 、-C(O)NR 39 R 40 、-OC(O)NR 41 R 42 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 .

[0299] Advantageously, Ar' represents a phenyl group substituted by three atoms of iodine and / or bromine, preferably iodine, and optionally two groups selected from: (C1-C 10 )alkyl, -NR 32R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-OC(O)R 38 、-C(O)NR 39 R 40 、-OC(O)NR 41 R 42 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 , advantageously selected from (C1-C 10 )alkyl, -NR 32 R 33 、-NR 34 C(O)R 35 、-C(O)OR 36 、-OR 37 、-C(O)NR 39 R 40 、-NR 43 C(O)OR 44 、-NR 45 C(O)NR 46 R 47 、-OC(O)OR 48 , and -C(O)R 49 .

[0300] Advantageously, the compound of general formula (V) is selected from the following compounds:

[0301]

[0302] In the context of the present invention, the compounds of formula (V) as defined above are advantageously used as radiopaque halogenated monomers. Therefore, the present invention also relates to the use of compounds of formula (V) as defined above as radiopaque halogenated monomers.

[0303] The following examples are given to illustrate the present invention. Hereinafter, the term "microspheres", whether singular or plural, will generally be abbreviated as "MS".

[0304] Examples

[0305] Example 1a: Synthesis of tri-iodinated monomer, 2-methacryloyloxyethyl (2,3,5-triiodobenzoate) (MAOETIB)

[0306]

[0307] 40 g (80 mmol) of 2,3,5-triiodobenzoic acid was added in small portions to a 0°C solution of diethyl 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-pyrrolidinepyridine. The solution was stirred for one hour at 0°C and then stirred for 18 h at 25°C. The solid formed was filtered on a glass frit and washed several times with diethyl ether. The ether solution was then washed with a hydrochloric acid solution (2N) and then with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate. After filtration, the solvent was removed in a rotary evaporator to give an orange solid. The crude product was then purified on silica gel, eluting with a petroleum ether / ethyl acetate (9 / 1) solution. After evaporation of the solvent, an orange solid was obtained, which was purified again by recrystallization (by slow diffusion in a mixture of ethyl acetate in petroleum ether at 4° C. overnight). After filtration, washing with ice-cold solution and drying under vacuum, 31.1 g of pure white flaky MAOETIB were obtained (yield = 64%).

[0308] 1 H NMR (CDCl3) 1.97 (s, 3H, CH3), 4.57 and 4.48 (m, 4H, OCH2CH2O), 5.61 (s, 1H, olefinic), 6.16 (s, 1H, olefinic), 7.33 (d, 1H), 8.30 (d, 1H).

[0309] Example 1b: Synthesis of tri-iodinated monomer, 2-(2-(2-(2,3,5-triiodobenzamide)ethoxy)ethyl methacrylate (Formula Vb)

[0310]

[0311] Step 1:

[0312] 20.0g (40.0mmol) of 2,3,5-triiodobenzoic acid was dissolved in dichloromethane (60mL), to which dimethylformamide (a few drops) was added. The reaction mixture was then placed under argon and cooled to a temperature of 0°C. 17.15mL (200mmol) of oxalyl chloride was then added dropwise over a time range of 5 to 10min, while keeping the temperature of the reaction mixture close to 0°C. The solution was kept stirring until it returned to room temperature and then heated at reflux (70°C) for 30h. The reaction mixture was then evaporated under vacuum. The solid obtained was co-evaporated with dichloromethane 3 to 4 times to remove traces of oxalyl chloride that were still present. An orange-brown solid was obtained. The product was not isolated in this step, but was directly used in the remainder of the synthesis.

[0313] Step 2:

[0314] At 60 ° C, 13.44g (90mmol) of 2-[2-(2-aminoethoxy)ethoxy]ethane-1-ol was dissolved in 235mL of anhydrous tetrahydrofuran (THF). The mixture was dried over MgSO4, filtered, and then poured into a three-necked flask. 12.6mL (90.4mmol) of triethylamine (TEA) was added to the mixture. The mixture was then placed under argon and cooled to a temperature of 0 ° C. 20.74g (40mmol) of 2,3,5-triiodobenzoyl chloride was dissolved in 60mL of anhydrous THF, and added dropwise to the reaction mixture within 5 minutes, keeping the temperature close to 0 ° C. The solution was stirred at 0 ° C for 4 hours, then overnight at room temperature (RT). The reaction mixture was then suspended in 1.8L of water for one hour. The mixture was poured into a separatory funnel, and 235mL of dichloromethane (DCM) was added. The aqueous phase was washed 3 times with 115mL of DCM. The organic phases were combined and then dried over MgSO4. Vacuum evaporation was carried out until a brown oil was obtained. 23.4 g of this oil were obtained. The yield of this step was 92.7%.

[0315] Step 3:

[0316] 23.4 g (37 mmol) of N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)-2,3,5-triiodobenzamide was dissolved in 235 mL of anhydrous THF. 26 mL (186.5 mmol) of triethylamine was added to the mixture. The reaction mixture was cooled to T = 0°C. 27.5 mL (185.5 mmol) of methacrylate anhydride was added dropwise to the mixture, keeping the temperature close to 0°C. At 0°C, the mixture was stirred for 3 hours and then refluxed (80°C) overnight. The reaction mixture was then suspended in 1.5 L of water for one hour and then decanted. 350 mL of DCM was added, and the aqueous phase was washed 3 times with DCM (120 mL). The organic phases were combined and then dried over MgSO4. After evaporation under vacuum, 32.64 g of a brown oil was recovered. The crude product was then passed through Purification on a silica gel column (330 g, Si40-60) eluting the mixture with DCM / acetonitrile (9 / 1) After evaporation of the solvent, 11.31 g of a white solid were obtained.

[0317] The total yield was 40.4%.

[0318] HPLC-MS analysis conditions :

[0319] BEH C18 Column No. 516

[0320] T 炉 =30℃

[0321] Mobile phase composition: water-HCO2H 0.5% (v / v) / MeCN

[0322] Isocratic gradient 55 / 45

[0323] Flow rate 0.7mL / min

[0324] Injection volume = 1 μL

[0325] λ=235nm

[0326] result :

[0327] Retention time: 2.2min

[0328] Mass m / z: 699.89

[0329] Purity UV: 82.3%

[0330] 1H NMR (acetone) 1.97 (s, 3H, CH3), 2.93 (t, 2H, NCH2), 3.57 (m, 10H, CH2OCH2CH2OCH2), 4.32 (t, 2H, CH2O), 5.65 (s, 1H, olefinic), 6.15 (s, 1H, olefinic), 7.65 (d, 2H, benzyl and NH), 8.38 (d, 1H, benzyl).

[0331] Example 2: Synthesis of polymers according to the invention containing MAOETIB in the form of microspheres with a size of 700-900 μm with varying monomer concentrations by direct suspension polymerization

[0332] The aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride was poured into the reactor and then heated to 50°C. The organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye and AIBN (initiator) dissolved in toluene was then fed into the reactor. A propeller stirrer was used to stir at an appropriate speed to obtain droplets of the desired diameter. The temperature was then increased to 80°C and stirring was continued for 8 hours. The mixture was then filtered and the microspheres were washed with acetone, then with water, then sieved, and sterilized by autoclaving.

[0333] Table 1 below summarizes the main parameters and composition of the organic phase.

[0334]

[0335] Table 1.

[0336] Example 3: Synthesis of polymers in the form of microspheres containing different concentrations of MAOETIB according to the present invention by direct suspension polymerization

[0337] The aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride was poured into the reactor and then heated to 50°C. The organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye and AIBN (initiator) dissolved in toluene was then fed into the reactor. A propeller stirrer was used to stir at an appropriate speed to obtain droplets of the desired diameter. The temperature was then increased to 80°C and stirring was continued for 8 hours. The mixture was then filtered and the microspheres were washed with acetone, then with water, then sieved, and sterilized by autoclaving.

[0338] Table 2 below summarizes the main parameters and composition of the organic phase.

[0339]

[0340] Table 2.

[0341] Example 4: Synthesis of polymers in the form of microspheres containing USPIO according to the present invention by direct suspension polymerization

[0342] The aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride was poured into the reactor and then heated to 50°C. The organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye, USPIO and AIBN (initiator) dissolved in toluene was then fed into the reactor. A propeller stirrer was used to stir at an appropriate speed to obtain droplets of the desired diameter. The temperature was then increased to 80°C and stirring was continued for 8 hours. The mixture was then filtered and the microspheres were washed with acetone and then with water, then sieved and sterilized by autoclaving.

[0343] Table 3 below summarizes the main parameters and composition of the organic phase.

[0344]

[0345] Table 3

[0346] Example 5: Synthesis of polymers in the form of microspheres with sizes of 300-500 μm and 700-900 μm according to the invention containing MAOETIB and without methacrylic acid (MA) by direct suspension polymerization

[0347] An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride was poured into the reactor and then heated to 50°C. An organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye and AIBN (initiator) dissolved in toluene was then fed into the reactor. A propeller stirrer was used to stir at an appropriate speed to obtain droplets of the desired diameter. The temperature was then increased to 80°C and stirring was continued for 8 hours. The mixture was then filtered and the microspheres were washed with acetone and then with water, then sieved and sterilized by autoclave. Two fractions were recovered, microspheres of 300-500 μm in size and microspheres of 500-700 μm in size.

[0348] Table 4 below summarizes the main parameters and composition of the organic phase.

[0349]

[0350] Table 4.

[0351] Characterization:

[0352] The dry extract (dry weight) was determined as follows: 1 ml of the sedimented MS was placed in a 5 ml Eppendorf vial, frozen at -80°C and placed in a lyophilizer (Heto The microspheres were freeze-dried overnight in a LL 1500 (Thermo Scientific). The mass of the freeze-dried microspheres was then measured. Three samples were measured and the average value was taken as the final value of MS dry matter.

[0353] The average diameter was measured by analyzing microscopic images of 2000 microspheres (Morphologi 4, Malvern).

[0354] Use iodinated contrast medium (70% The injectability in the microcatheter was tested by depositing 1 mL of microspheres in a 300 mL syringe (30% saline solution). The uniform suspension of microspheres in a 3 mL syringe was then injected into the microcatheter. The microcatheter provided by Terumo was selected so that its inner diameter was slightly larger than the average diameter of the microspheres. The resistance during the injection of the microspheres into the microcatheter was recorded (Table 4Bis). Blockage during the injection process would mean a failed injection. After injection, the microspheres were observed under a microscope to check whether the microspheres have regained their spherical shape.

[0355] result:

[0356]

[0357] Table 4Bis.

[0358] Example 6: Synthesis of other polymers according to the invention in the form of microspheres by direct suspension polymerization

[0359] The aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into the reactor and then heated to 50°C. The organic phase containing the main hydrophilic monomer, crosslinker, radiopaque monomer, optionally ionizable monomer, transfer agent, (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye and AIBN (initiator) dissolved in toluene is then fed into the reactor. A propeller stirrer is used to stir at a suitable speed to obtain droplets with the desired diameter. The temperature is then increased to 80°C and stirring is continued for 8 hours. The mixture is then filtered and the microspheres are washed with acetone, then with water, then sieved, and sterilized by autoclaving.

[0360] Table 5 below summarizes the main parameters and composition of the organic phase.

[0361]

[0362] Table 5.

[0363] The average diameters of microspheres of batches L2 and L4 were 731±53 and 652±39, respectively.

[0364] Example 7: Synthesis of polymers in the form of microspheres containing different concentrations of transfer agents according to the present invention by direct suspension polymerization

[0365] The aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride was poured into the reactor and then heated to 50°C. The organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), MAOETIB (radiopaque monomer), hexanethiol (transfer agent), (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye and AIBN (initiator) dissolved in toluene was then fed into the reactor. A propeller stirrer was used to stir at an appropriate speed to obtain droplets of the desired diameter. The temperature was then increased to 80°C and stirring was continued for 8 hours. The mixture was then filtered and the microspheres were washed with acetone, then with water, then sieved, and sterilized by autoclaving.

[0366] Table 6 below summarizes the main parameters and composition of the organic phase.

[0367]

[0368] Table 6.

[0369] Characterization:

[0370] Characterization was performed in the same manner as in Example 5 and the results are listed in Table 6bis.

[0371] result:

[0372]

[0373] Table 6bis.

[0374] Therefore, these results demonstrate the effect of adding transfer agent on the injectability of microspheres and the advantage of the selected concentration range. If the amount of transfer agent is much higher than this range, no microspheres can be obtained.

[0375] Example 8: Synthesis of a polymer in the form of microspheres according to the invention containing the compound from Example 1b) as radiopaque halogenated monomer of formula (Vb) by direct suspension polymerization

[0376] The aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride was poured into the reactor and then heated to 50°C. The organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), methacrylic acid (MA) (ionizable monomer), the compound from Example 1b) (radiopaque monomer), bromotrichloromethane (transfer agent), (1-(4-((2-methacryloyloxyethyl)oxy)phenylamino)-anthraquinone) violet dye and AIBN (initiator) dissolved in toluene was then fed into the reactor. A propeller stirrer was used to stir at an appropriate speed to obtain droplets of the desired diameter. The temperature was then increased to 80°C and stirring was continued for 8 hours. The mixture was then filtered and the microspheres were washed with acetone and then with water, then sieved and sterilized by autoclaving.

[0377] Table 7 below summarizes the main parameters and composition of the organic phase.

[0378]

[0379] Table 7.

[0380] Example 9: Effect of transfer agents on the injectability of 700-900 μm microspheres comprising a polymer according to the invention in a microcatheter

[0381] Microspheres were prepared as described in Example 2 for batches 4, 5, 6 and L6. The synthesis of batches 1, 2 and 3 was equivalent, but no transfer agent was added. 1 mL of the microspheres pre-suspended in 10 mL of iodinated contrast medium (70% 300, Bracco, 30% saline solution or for batch L6: 70% 300, Guerbet , 30% saline solution) for microcatheterization ( 2.8Fr, Terumo Corporation, inner diameter 700μm). The uniform suspension of microspheres in a 3mL syringe was then injected into the microcatheter. The average diameter of the microspheres was selected to be larger than the inner diameter of the catheter to show the flexibility of the microspheres. The resistance during the injection of the microspheres into the microcatheter was recorded (Table 8). Blockage during the injection process means injection failure. After injection, the microspheres were observed under a microscope to check whether the microspheres have regained their spherical shape.

[0382]

[0383] (1) ID = inner diameter of the microcatheter

[0384] * Due to the high ratio of MAOETIB, the MS gel was too hydrophobic to swell and reach the desired size.

[0385] **Microspheres are sticky and they can clump together, preventing proper injection.

[0386] Table 8. Injectability of 700-900 μm microspheres comprising polymers according to the invention in microcatheters

[0387] After injection, the microspheres prepared with the transfer agent according to the present invention maintained their spherical shape and did not break up.

[0388] In the absence of a diverting agent, the microspheres would block the microcatheter.

[0389] In the presence of a transfer agent, microspheres comprising the polymer according to the invention are easily injectable, ie they offer only a low resistance to injection and do not block the microcatheter.

[0390] Example 10: Visibility of microspheres according to the present invention to X-rays in vivo

[0391] After 3 months of implantation, the visibility of the microspheres according to Example 3 implanted subcutaneously in rabbits was analyzed. The animals (n=2) were euthanized, the backs were shaved and a 26G needle was placed in the skin at the microsphere injection site as a reference. A fluoroscopy / radiography mobile device (GE Healthcare-OEC 9900Elite) was used to take pictures of the animal's back (X-ray beam energy of 63 kV, current intensity of 1.3 mA). Quantification of radiopacity in Hounsfield units (HU) was performed using ANALYZE 11.0 software (Table 9).

[0392]

[0393] Table 9: X-ray imaging of microspheres injected into rabbit skin

[0394] Radiopaque microspheres implanted in the dermis of rabbit skin were visible to X-rays (Table 9). The intensity of the microspheres was close to that observed for the animal's ribs. Microspheres without iodine It is not visible under X-rays.

[0395] Example 11: Loading and releasing active ingredients on radiopaque microspheres according to the present invention

[0396] The loading and controlled release of anticancer drugs were tested on 100-300 μm radiopaque microspheres sterilized by autoclaving and containing or not containing ionized or ionizable monomers such as methacrylic acid.

[0397] The microspheres with methacrylic acid were microspheres from batch 13, the composition of which is given in Example 3. The microspheres without methacrylic acid had the same composition as the microspheres from batches L1 and L1Bis described in Example 5.

[0398] Loading doxorubicin: The loading target was 37.5 mg doxorubicin / ml microspheres. To this end, 3.8 mL of doxorubicin-HCl ( Pfizer (Pfizer) aqueous solution was added to 250 μL of wet microsphere sediment at 2.5 mg / mL. After mixing by inversion, the suspension was supplemented to 6 mM with sodium bicarbonate (Lavoisier). Loading was performed at room temperature and stirred for one hour. The residual amount of doxorubicin in the supernatant (absorbance at 490 nm) was measured to determine the drug loading on the microspheres.

[0399] To study the release of doxorubicin from the microspheres, the sediment was washed in 10 mL of water and then 50 mL of buffer (50 mM Tris-HCl, 0.9% NaCl, pH 7.4) was added. The incubation was carried out at 37° C. with stirring. The release of doxorubicin was measured at 490 nm at different times.

[0400] Loading irinotecan: The loading target was 50 mg irinotecan / mL microspheres. The sediment of radiopaque microspheres was incubated in excess sodium bicarbonate (1.4%, Lavoisier) for 30 minutes without stirring. The supernatant was then removed and 625 μL of a 20 mg / mL irinotecan solution (Campto, Pfizer) was added. After 30 minutes, the residual amount of irinotecan in the supernatant was measured (absorbance at 370 nm) to determine the loading on the microspheres.

[0401] To study the release of irinotecan, the microspheres were washed in 10 mL of water and then 50 mL of PBS (10 mM Na2HPO4, 1.8 mM KH2PO4, 138 mM NaCl, 2.7 mM KCl, pH 7.4) equilibrated at 37° C. was added. The drug release over time was measured by reading the absorbance at 370 nm.

[0402] Loading of Sunitinib: The deposit of radiopaque microspheres was incubated in 10 mL of 1 mg / mL aqueous solution of sunitinib in the malate form (LC Laboratories) at room temperature for 1 h. The final concentration of sodium bicarbonate was 4 mM. After stirring on a rotating wheel for 1 h, the residual amount of sunitinib in the supernatant was measured (absorbance at 405 nm) to determine the loading on the microspheres.

[0403] To study the release of sunitinib, the microspheres were washed in 10 mL of water and then 50 mL of PBS equilibrated at 37° C. was added. The drug release over time was measured by reading the absorbance at 405 nm.

[0404] Loading of Vandetanib: The deposit of radiopaque microspheres was incubated for 2 h at room temperature in 10 mL of a water / DMSO (1 / 1) mixture containing 5 mg of Vandetanib (LC Laboratories). The residual amount of Vandetanib in the supernatant was measured at 254 nm to calculate the amount loaded on the microspheres.

[0405] To study the release of vandetanib, the microspheres were washed in 10 mL of water and then 50 mL of PBS equilibrated at 37° C. was added. The drug release over time was measured by reading the absorbance at 254 nm.

[0406]

[0407] Table 10. Anticancer drug loading on radiopaque microspheres and their in vitro release

[0408] Radiopaque microspheres with a diameter of 100-300 μm can be loaded with various anticancer drugs (cytotoxic and antiangiogenic drugs). Drug loading on microspheres is rapid (less than 2 h). Elution in PBS depends on the loaded drug. Irinotecan is released rapidly (50% within 1 h); doxorubicin, sunitinib, and vandetanib are released more slowly and last for several days.

[0409] The loading efficiency is calculated by the following formula:

[0410]

[0411] LC: Loading capacity

[0412] LE: Loading Efficiency

[0413] M 药物初始 :Drug dissolution amount

[0414] C 药物_上清液 : Drug concentration in the supernatant after loading

[0415] V 上清液 : Volume of supernatant

[0416] V MS : Volume of microspheres

[0417] The loading efficiency without methacrylic acid was 83.5%, compared to 99.7% in the presence of 20% methacrylic acid. Studies conducted have shown that the loading efficiency of microspheres without methacrylic acid is lower than that of microspheres with methacrylic acid.

[0418] The ability of microspheres without ionizable monomers to load doxorubicin can be explained by the establishment of hydrophobic or van der Waals bonds. In the presence of ionizable monomers, doxorubicin is loaded via electrostatic bonds in addition to these bonds. The kinetics and loading capacity are thus improved.

[0419] Example 12: Signal changes of USPIO-loaded microspheres according to the present invention in in vitro MRI: Measurement of T2

[0420] The microspheres according to Example 4 were suspended in 2% agarose gel (50 / 50 v / v). The microsphere inserts were embedded in agarose gel plates at 2%. The plates were imaged using a 1.5T MRI (Phillips). The sequence used for the imaging was as follows: Sequence T2: TR = 2000ms, TE from 10ms to 310ms, 20ms steps. Stereo pixels = 0.5*0.5*2mm, processed under Matlab to obtain T2. ​​The size of the stereo pixels was 0.5*0.5*1mm. The FOV (field of view) was 150*150mm.

[0421]

[0422] Table 11a: Comparison of USPIO microspheres loaded with increasing amounts

[0423]

[0424] Table 11b: Comparison of microspheres loaded with 10, 20 or 30 nm USPIO

[0425] Table 11. MRI measurements of T2 of microspheres

[0426] The decrease in signal intensity is consistent with the T2 effect of USPIO. The signal intensity increases with the amount of USPIO in the microspheres. It also increases with decreasing USPIO size (from 30 nm to 10 nm).

Claims

1. A polymer comprising a crosslinked matrix based on at least: a) 20% to 90% of a hydrophilic monomer selected from N-vinylpyrrolidone and a monomer having the following formula (I): (CH2=CR1)-CO-D(I) in: D represents OZ or NH-Z, Z represents (C1-C6) alkyl, -(CR2R3) m -CH3, -(CH2-CH2-O) m -H, -(CH2-CH2-O) m -CH3, -C(R4OH) m or -(CH2) m -NR5R6, wherein m represents an integer from 1 to 30; R1, R2, R3, R4, R5 and R6 independently represent H or (C1-C6) alkyl; b) 5% to 50% of a halogenated radiopaque monomer having the following general formula (II): (CH2=CR7)-CO-Y(II) in ·Y stands for OW, (O-R8) p -W, (NH-R8) p -W or NH-W, W represents Ar, L-Ar, and p is an integer between 1 and 10, preferably between 1 and 4, wherein: Ar represents (C5-C 36 )aryl or (C5-C 36 ) heteroaryl groups, which are substituted by one, two or three atoms of iodine and / or bromine, and are optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-OR f 、-OCOR g 、-CONR h R i 、-OCONR j R k 、-NR l COOR o -、-NR r CONR S R t 、-OCOOR u , and -COR v ; ·L represents -(CH2) n -、-(HCCH) n -, -O-, -S-, -SO-, -SO2-, -OSO2 - , -NR9-, -CO-, -COO-, -OCO-, -OCOO-, -CONR 10 -、-NR 11 CO-、-OCONR 12 -、-NR 13 COO- or -NR 14 CONR 15 -, n is an integer from 1 to 10; R9 to R 15 and R a To R v Each independently represents a hydrogen atom, (C1-C 10 )alkyl, or group -(CH2-CH2-O) q -R', the (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups, R' is a hydrogen atom or -(C1-C6)alkyl, and q is an integer between 1 and 10, preferably between 1 and 5; R7 represents H or (C1-C6) alkyl; R8 represents a group selected from the following: (C1-C 36 ) alkylene, (C3-C 36 )cycloalkylene, (C2-C 36 ) alkenylene, (C3-C 36 )cycloalkenylene, (C2-C 36 ) alkynylene, (C3-C 36 )cycloalkynylene, (C5-C 36 )arylene and (C5-C 36 ) heteroarylene, c) 1% to 15% of a non-biodegradable linear or branched hydrophilic crosslinker having at each end a group (CH2=(CR 16 ))-, each R 16 independently represent H or (C1-C6)alkyl; and d) 0.1% to 10% of a transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols, in particular these alkyl halides and cycloaliphatic or aliphatic thiols have 2 to 24 carbon atoms and optionally have another functional group chosen from amino, hydroxyl and carboxyl groups, The percentages of monomers a) to c) are given in moles relative to the total moles of monomers and the percentage of compound d) is given in moles relative to the moles of hydrophilic monomer a).

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

3. The polymer of 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, tert-butyl acrylate, tert-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl-(meth)acrylate, tert-butylaminoethyl (meth)acrylate, N,N-diethylaminoacrylate, poly(ethylene oxide) (meth)acrylate, methoxypoly(ethylene oxide) (meth)acrylate, butoxypoly(ethylene oxide) (meth)acrylate, poly(ethylene glycol) (meth)acrylate, methoxypoly(ethylene glycol) (meth)acrylate, butoxypoly(ethylene glycol) (meth)acrylate, poly(ethylene glycol) methyl ether methacrylate and mixtures thereof, advantageously monomer a) is poly(ethylene glycol) methyl ether methacrylate.

4. The polymer of any one of claims 1 to 3, wherein the radiopaque monomer has the general formula (II) as defined in claim 1, wherein Y represents O-C6H4I, O-C6H3I2, O-C6H2I3, NH-C6H4I, NH-C6H3I2, NH-C6H2I3, O-CH2-CH2-C(O)-C6H4I, O-CH2-CH2-OC(O)-C6H3I2, O-CH2-CH2-OC(O)-C6H2I3, NH-CH2-CH2-C(O)-C6H4I, NH-CH2-CH2-OC(O)-C6H3I2, NH-CH2-CH2-OC(O)-C6H2I3.

5. The polymer of any one of claims 1 to 4, wherein the radiopaque monomer is (tri-iodobenzoyl)oxyethyl methacrylate having the following formula (IIa):

6. The polymer according to any one of claims 1 to 5, wherein the linear or branched, non-biodegradable hydrophilic crosslinker has at least two ends thereof a group (CH2=(CR 16 ))CO- or (CH2=(CR 16 ))CO-O-, each R 16 Independently represents H or (C1-C6) alkyl.

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

8. The polymer of any one of claims 1 to 7, wherein the matrix is ​​further based on at least one ionized or ionizable monomer having the following formula (IV): (CH2=CR 17 )-M-E(IV) in: ·R 17 represents H or (C1-C6) alkyl; M represents a single bond or a divalent group having 1 to 20 carbon atoms; E represents a charged or ionizable group having up to 100 atoms, advantageously, E is selected from the group consisting of: -COOH, -COO - 、-SO3H、-SO3 - 、-PO4H2、-PO4H - ,-PO4 2- 、-NR 18 R 19 、-NR 20 R 21 R 22 + , ·R 18 , R 19 , R 20 , R 21 and R 22 Independently of each other represent H or (C1-C6) alkyl.

9. The polymer of any one of claims 1 to 8, wherein the matrix is ​​further based on at least one colored monomer having the following general formula (VI): in Z1 and Z2 independently represent H or OR 25 , R 25 represents H or (C1-C6) alkyl, advantageously Z1 and Z2 represent H; X represents H or Cl, advantageously H; ·R 23 represents H or (C1-C6)alkyl, advantageously (C1-C6)alkyl, in particular methyl; and ·R 24 represents a group selected from the following: straight chain or branched (C1-C6) alkylene, (C5-C 36 ) arylene, (C5-C 36 )Arylene-OR 26 、(C5-C 36 )heteroarylene and (C5-C 36 )heteroarylene-OR 27 , R 26 and R 27 represents (C1-C6) alkyl or (C1-C6) alkylene, preferably R 24 Represents the group -C6H4-O-(CH2)2-O or -C(CH3)2-CH2-O.

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

11. A polymer as claimed in any one of claims 8 to 10, loaded with a drug or an active substance or a diagnostic agent, advantageously having a molecular weight below 5000 Da, typically below 1000 Da, the drug or the active substance advantageously being selected from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, preservatives and mixtures thereof.

12. The polymer of any one of claims 8 to 10 loaded with macromolecules selected from the group consisting of: Enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzymes, aptamers, anti-inflammatory proteins, bone morphogenetic proteins (BMPs), pro-angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, as well as angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof.

13. A pharmaceutical composition comprising at least one polymer as claimed in any one of claims 1 to 12 in combination with a pharmaceutically acceptable vehicle advantageously for administration by the parenteral route.

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

15. A 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, magnetic resonance or ultrasonography, and optionally at least one injection means for parenteral administration, the pharmaceutical composition and the at least one contrast agent being packaged separately.

16. A compound having the following general formula (V): (CH2=CR 28 )-CO-Y'(V) in ·R 28 represents H or (C1-C6) alkyl; ·Y' represents (OR 29 ) t -W'-Ar', or NH-W'-Ar', t is an integer between 1 and 10, preferably between 1 and 4; ·R 29 Representative selected from (C2-C 36 ) an alkylene group; ·W' represents a single bond, -CONR 30 -, or -NR 31 CO-; Ar' represents (C5-C 36 ) aryl group, which is substituted by one, two or three atoms of iodine and / or bromine and is optionally substituted by one to four, preferably two or three groups selected from the group consisting of: (C1-C 10 )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 ; ·R 30 and R 31 independently represent a hydrogen atom or a (C1-C6) alkyl group; ·R 32 To R 49 Each independently represents a hydrogen atom, (C1-C 10 )alkyl, or group -(CH2-CH2-O) t' -R", said (C1-C 10 )alkyl is optionally substituted by 1 to 10 OH groups, R" is a hydrogen atom or -(C1-C6)alkyl, and t' is an integer between 1 and 10, preferably between 1 and 5.

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

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