Non-degradable embolisation microsphere

Abstract

To provide non-biodegradable embolisation microspheres comprising a cross-linked matrix, and a pharmaceutical composition comprising the embolisation microspheres in conjunction with a pharmaceutically acceptable vehicle intended for parenteral administration, and further to provide a kit comprising the pharmaceutical composition and at least one injection means.SOLUTION: A cross-linked matrix is based on at least: a) from 20% to 95% of a hydrophilic monomer; b) from 1% to 15% of a non-biodegradable hydrophilic cross-linking monomer; and c) from 1.5% to less than 6% of a transfer agent selected from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group selected from amino, hydroxy, and carboxy groups.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to non-biodegradable embolization microspheres containing a crosslinked polymer matrix, which are advantageously intended to be injected into an individual and optionally intended for sustained release of an active substance or polymer.

Background Art

[0002] To impede blood flow within a region of the body, vascular occlusion therapy (i.e., embolization therapy) that causes ischemia is used. It may be administered using a catheter that enables the positioning of particulate occluding agents in the circulatory system. It has various medical applications such as the treatment of vascular malformations, bleeding processes or tumors, for example, uterine fibroids, primary or secondary liver tumors. For example, vascular occlusion can cause tumor necrosis and may avoid more invasive surgery. This occlusion procedure may also be related to the delivery of anticancer agents in the context of chemoembolization therapy. This makes it possible to increase the local concentration of the drug by targeted injection and further its residence time within the tumor. In the case of vascular malformations, vascular occlusion makes it possible to normalize blood flow to normal tissue, assist in surgery and limit the risk of bleeding. In bleeding processes, vascular occlusion may result in a decrease in flow rate and promote the healing of arterial injuries.

[0003] Commercially available embolization agents for vascular occlusion include embolization fluids (acrylic adhesives, gels), mechanical devices and embolization particles. The choice of specific materials depends on many factors, for example, the type of lesion to be treated, the type of catheter to be used and the need for temporary or permanent embolization therapy.

[0004] These embolization agents are usually introduced into the blood vessels via a catheter having a diameter less than the diameter of the blood vessel to be treated, particularly a microcatheter. Thus, in the case of solid embolization agents, such as particles, their shape enables them to occupy a volume sufficient to cause occlusion of the blood vessel over its entire diameter as they circulate within the catheter and are then once released.

[0005] The shape and size of the embolizing agent are elements in the accuracy of the target area. In the case of particles, when they are spherical and of a size suitable for the vascular lumen, they have been found to produce total embolization and to be present exclusively within the target tissue.

[0006] In the prior art, in parallel with the development of ever finer microcatheters that allow access to more distal arteries, the development of microspheres has taken place. Depending on the size of the microspheres used, the operator may promote vascular targeting and perform more or less distal occlusion. The embolization therapy may be set at a selected level. For example, in the case of tumors, the vessels defined for the tumor can be more easily occluded while avoiding the vessels intended for normal tissue.

[0007] These microspheres may be biodegradable for the purpose of performing temporary embolization. The main difficulties encountered in the case of these biodegradable microspheres are - the difficulty of controlling the rate of degradation, which may range from several hours to several months depending on the microspheres; - the control of the disappearance of the microspheres without residues or toxicity for the organism, and - the difficulty of loading these microspheres with therapeutic agents are.

[0008] Furthermore, unwanted chain transfer reactions inside the polymeric microspheres may cause irreversible crosslinking and result in the formation of non-absorbable polymers.

[0009] Thus, in the published International Patent Application No. WO 2012 / 120139 and International Patent Application No. WO 2012 / 120138, it is described that adding a transfer agent to the monomer solution during the preparation of biodegradable microspheres makes it possible to avoid these unwanted secondary reactions and thus retain the degradation characteristics of the embolizing microspheres.

[0010] In contrast to these biodegradable embolization microspheres, which have the advantage of providing temporary plugs, non - biodegradable embolization microspheres enable plugs for permanent purposes.

[0011] Various non - biodegradable microspheres were tested in the 1960s for the purpose of performing embolization therapy (lead, stainless steel, and silicone beads). However, their small size and significant back - flow in healthy, non - targeted organs increased the level of complications in patients.

[0012] There are non - biodegradable microspheres based on the polymer trisacryl (N - acryloyl - 2 - amino - 2 - hydroxymethylpropane - 1,3 - diol) and gelatin (which may be of porcine origin). This is the product Embosphere® (Biosphere Medical), one of whose drawbacks is the potential presence of gelatin, which may be of porcine origin.

[0013] Furthermore, non - biodegradable microspheres based on acrylic copolymers and PVA have been presented for permanent embolization (Osuga et al., (2002) J.Vase Interv Radiol.13:929 - 34). These are, for example, the Quadrasphere® microspheres manufactured by Biosphere Medical, which are provided in a dry form and then mixed with normal saline and / or iodinated contrast agent and swollen before injection via a catheter. Their final size after swelling varies as a function of the ionic charge of the medium (doubling or quadrupling compared to their initial size in saline or contrast agent respectively). However, their use in embolization therapy is limited because the swelling of the microspheres is not controlled and their volume after implantation is uncontrollable due to the excessive change in final size. In fact, it has been shown that there is a correspondence between the size of the microspheres and the diameter of the occluded blood vessel. In the accurate targeting of the blood vessel to be embolized, it is preferable to use microspheres of an appropriate size (Laurent et al., 2007).

[0014] Therefore, the embolization microspheres must be spherical and must be calibrated. "Calibrated" means that the microspheres must be classifiable according to their size after swelling. Next, the operator selects microspheres of a size corresponding to the size of the blood vessel or the malformation to be embolized (Laurent et al., 2007). Any morphological defect of these embolization microspheres may cause catheter occlusion or may have an adverse effect on their embolization properties.

[0015] The resistance to compression and elasticity of the embolization microspheres are also important. In fact, while they can be injected via a microcatheter having a diameter less than their diameter when injected into the blood vessel, they need to retain their shape and their initial size when released from the microcatheter. Low elasticity and low resistance to compression have been shown to reduce the level of occlusion in vivo (Laurent et al., 2007).

[0016] The Young's modulus represents the resistance to compression, or compressibility. It has been shown that the value of the Young's modulus of the microspheres is directly related to the fact that they are localized more or less distally in the blood vessel into which they are injected (Laurent A., Agents d’embo lisation [Embolization agents]. EMC - Radiologie et imagerie medicale - principes et technique - radioprotection 2014;9(1):1 - 11).

[0017] Microspheres with low compressibility will result in embolization near the injection site, while microspheres with high compressibility will result in embolization remote from the injection site.

[0018] According to in vitro tests, Embosphere® microspheres manufactured by Biosphere Medical have been shown to have low compressibility and cause embolization at the level of the proximal region of the blood vessels into which they are injected. Conversely, Contour SE® microspheres manufactured by Boston Scientific are easily deformable and embolize regions of blood vessels further remote from the injection site.

[0019] One of the problems encountered in the case of microspheres that are overly deformable due to being too compressible is that they may move inside the blood vessels under the pressure of the blood flow, which makes their localization uncertain. However, in the case of microspheres with insufficient deformability due to low compressibility, injection may be difficult or they may not return to their initial shape after injection.

[0020] The compressibility of the microspheres must be controlled in order to target a specific embolization site.

[0021] Furthermore, the microspheres are generally suspended in a mixture of a non-ionic iodinated contrast agent and a buffer so as to be injectable. For this reason, radiologists generally use a mixture of 50% contrast agent and 50% normal saline, bicarbonate buffer or phosphate buffer. In order to ensure their injectability, the microspheres must be uniformly suspended in this 50 / 50 solution. If the microspheres sediment or, conversely, float on the surface of the solution, the resulting suspension is heterogeneous and unstable and thus cannot be injected into the patient.

[0022] Therefore, it is advantageous for the microspheres to have a density suitable for enabling a uniform suspension in a mixture containing 50% contrast agent and 50% normal saline, bicarbonate buffer, phosphate buffer or Tris buffer (tris(hydroxymethyl)aminomethane). SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0023] Therefore, - a calibration size, - made of a biocompatible material with no allergy risk, and having mechanical properties suitable for injection via a catheter or microcatheter, particularly swelling degree, elasticity and compressibility, and returning to their initial shape after injection while avoiding embolization remotely from the target site, non - biodegradable embolization microspheres are highly sought after.

[0024] Furthermore, it is required that they have the ability to maintain their mechanical properties while being loaded with an active substance.

Means for Solving the Problems

[0025] The present invention presents embolization microspheres containing a hydrophilic cross - linked polymer matrix that is non - biodegradable, solid, calibrated, elastic, compressible, and has a controlled swelling degree sufficient for permanent targeted embolization therapy, thereby making it possible to meet these requirements.

[0026] The mechanical properties (swellability, elasticity, solidity, resistance to compression) of the microspheres of the present invention are suitable for injection and enable a sufficient permanent level of embolization therapy when they are injected into the vascular structure of mammals, preferably humans.

[0027] The present invention mainly relates to a cross - linked polymer matrix comprising at least: a) N - vinylpyrrolidone, and the following formula (I): (CH2 = CR1)-CO - D (I) (wherein, · D represents O - Z or NH - Z, and Z is (C1 - C6) alkyl, -(CR2R3) m - CH3, -(CH2 - CH2 - O) m - H, -(CH2 - CH2 - O) m - CH3, - C(R4OH) m or -(CH2) m-NR5R6, where m represents an integer from 1 to 30; · R1, R2, R3, R4, R5 and R6 each independently represent H or (C1 - C6) alkyl) 20% - 95% of hydrophilic monomers selected from the monomers of b) The following formula (IIa) or (IIb): (CH2=CR7)CO-NH-A-HN-OC(CR8=CH2) (IIa), or (CH2=CR7)CO-O-A-O-OC(CR8=CH2) (IIb) (wherein R7 and R8 each independently represent H or (C1 - C6) alkyl, and A, alone or together with at least one of the atoms to which it is attached, represents (C1 - C6) alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A) 1% - 15% of non - biodegradable linear or branched hydrophilic cross - linking monomers; and c) An alkyl halide and an alicyclic or aliphatic thiol, especially those having 2 - 24 carbon atoms, and optionally having another functional group selected from amino, hydroxy and carboxy groups, 1.5% - less than 6% of a migrating agent relates to non - biodegradable occlusive microspheres containing a cross - linked matrix based on the above, the percentages of monomers a) and b) are given in molar units compared to the total number of moles of monomers, and the percentage of compound c) is given in molar units compared to the number of moles of hydrophilic monomer a).

[0028] In connection with the present invention, the addition of a migrating agent during the polymerization of the crosslinked matrix of the microspheres according to the present invention makes it possible to increase the degree of swelling of the microspheres. The increase in the degree of swelling results in a decrease in the dry extract of the microspheres in a given volume and thus a higher proportion of water, facilitating their injection. Surprisingly, the presence of this migrating agent improves the elastic properties as well as the properties of swellability and resistance to compression. The inventors have found that the addition of a migrating agent selected from the above in the reaction mixture during the polymerization of a crosslinked matrix containing a hydrophilic polymer, in an amount of from 1.5 mol% to less than 6 mol%, preferably from 1.5% to 4.5%, preferably 3%, compared to the number of moles of hydrophilic monomer a), improves the mechanical properties of the non-biodegradable embolizing microspheres, i.e., enhances their swellability, their elasticity, their solidity and improves their resistance to compression.

[0029] These characteristics enable the injection of the microspheres of the present invention into an individual using a catheter or microcatheter and the formation of a target embolization that is total and radical.

[0030] The inventors have found in particular that the amount of migrating agent added to the reaction mixture must be precisely controlled so as to meet the above requirements.

[0031] Thus, the degree of swelling, elasticity and compressibility of the microspheres are optimal with a migrating agent in molar units of 1.5% or more compared to the number of moles of hydrophilic monomer a) present in the reaction mixture. Microspheres obtained at levels below 1.5% are not sufficiently mobile to allow injection by microcatheter.

[0032] When the migrating agent is present in the reaction mixture in an amount of 6% or more, the non-biodegradable embolizing microspheres are overly compressible, not sufficiently solid and break.

[0033] Elasticity is also an important parameter. Microspheres with low elasticity are not significantly deformed by the pressure of the blood vessel wall and remain localized within the proximal region of the blood vessel into which they are injected.

[0034] The present invention also relates to embolizing microspheres loaded with an active substance, thereby making it possible to combine blood vessel occlusion and delivery of the active substance.

[0035] The present invention further advantageously relates to a pharmaceutical composition comprising non-biodegradable embolizing microspheres as defined above, together with a pharmaceutically acceptable medium intended for administration by injection.

[0036] The present invention also relates to a kit comprising a pharmaceutical composition as defined above and at least one means for injecting said composition for parenteral administration of said composition.

[0037] The present 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 ultrasound examination, and optionally at least one means for injection for parenteral administration.

DETAILED DESCRIPTION OF THE INVENTION

[0038] The expression "matrix based on ~" of course means a matrix containing only the mixture and / or product of the reactions between the base components used for the non-uniform polymerization of this matrix, preferably the product of the reaction between different base components used for this matrix, many of which are intended to react with each other or have a high probability of reacting with a chemical environment that is at least partially close to each other or to them during different steps of the method for producing the matrix, especially during the polymerization step. Therefore, the base components are reactants intended to react with each other during the polymerization of the matrix. Therefore, the base components are optionally added to a reaction mixture further containing 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 contains at least the monomers a), b) and the transfer agent c) described in this description as base components, and at least one solvent, preferably an aqueous solvent and an organic solvent, such as a mixture of solvents containing a non-polar aprotic solvent, such as a water / toluene mixture. Optionally, the reaction mixture contains a polymerization initiator, such as t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also called 4,4'-azobis(4-cyanopentanoic acid)), AIBN (azobisisobutyronitrile), 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 (Darocur® 1173, 7473-98-5), 2,2-dimethoxy-2-phenylacetophenone (24650-42-8), 2,2-dimethoxy-2-phenylacetophenone (Irgacure®, 24650-42-8) or 2-methyl-4'-( methylthio)-2-morpholinopropiophenone (Irgacure®, 71868-10-5), etc.

[0039] Accordingly, according to the present invention, the matrix is based at least on the monomers a), b) and the migrating agent c) described in this description, and thus these compounds are base components.

[0040] Accordingly, in this description, expressions similar to "[base component X] is added to the reaction mixture in an amount of especially YY to YYY%" and "the crosslinked matrix is based especially on [base component X] in an amount of YY to YYY%" are to be interpreted in the same way. Furthermore, expressions similar to "the reaction mixture contains at least [base component X]" and "the crosslinked matrix is based at least on [base component X]" are to be interpreted in the same way.

[0041] The "organic phase" of the reaction mixture means, in the context of the present invention, the phase containing the organic solvent and the compounds soluble in said organic solvent, in particular monomers, migrating agents and polymerization initiators.

[0042] "(C X ~C Y ) alkyl group" means, in the context of the present invention, a linear or branched saturated monovalent hydrocarbon-containing chain having X to Y carbon atoms, where X and Y are integers between 1 and 36, preferably 1 and 18, especially 1 and 6. Examples may include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group or a hexyl group.

[0043] "(C X ~C Y ) aryl" means, in the context of the present invention, preferably a group containing X to Y carbon atoms, where X and Y are integers between 5 and 36, preferably 5 and 18, especially 5 and 10, and containing a ring or several fused rings, and is an aromatic hydrocarbon-containing group. Examples may include a phenyl group or a naphthyl group.

[0044] "(C X ~C Y"Heteroaryl" means, in the context of the present invention, an aromatic group in which the ring atoms from X to Y, for example, one or more, preferably 1 to 4 and even more preferably 1 or 2 heteroatoms, such as sulfur, nitrogen or oxygen atoms, etc., are included and the other ring atoms are carbon atoms. X and Y are integers between 5 and 36, preferably 5 and 18, particularly 5 and 10. Examples of heteroaryl groups include furyl group, thienyl group, pyrrolyl group, pyridinyl group, pyrimidinyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group or indyl group.

[0045] "(C X ~C Y ) alkylene group" means, in the context of the present invention, a linear or branched divalent hydrocarbon-containing chain consisting of carbon atoms from X to Y, where X and Y are integers between 1 and 36, preferably 1 and 18, particularly 1 and 6. Examples may include methylene group, ethylene group, propylene group, butylene group, pentylene group or hexylene group.

[0046] "(C X ~C Y ) cycloalkylene group" means, in the context of the present invention, a saturated divalent cyclic hydrocarbon-containing group consisting of ring carbon atoms from X to Y, where X and Y are integers between 3 and 36, preferably 3 and 18, particularly 3 and 6. Examples may include cyclopropylene group, cyclohexylene group or cyclopentylene group.

[0047] "(C X ~C Y ) alkenylene group" means, in the context of the present invention, a linear or branched divalent hydrocarbon-containing chain consisting of carbon atoms from X to Y, where X and Y are integers between 2 and 36, preferably 2 and 18, particularly 2 and 6 and including at least one double bond. Examples may include vinylene (ethenylene) group or propenylene group.

[0048] "(C X ~C Y ) cycloalkenylene group" means, in the context of the present invention, the ring carbon atoms from X to It means a saturated divalent cyclic hydrocarbon-containing group in which X and Y are integers between 3 and 36, preferably between 3 and 18, particularly between 3 and 6, and which contains at least one double bond.

[0049] “(C X ~C Y ) alkynylene group” means, in the context of the present invention, a linear or branched divalent hydrocarbon-containing chain having X to Y carbon atoms, where X and Y are integers between 2 and 36, preferably between 2 and 18, particularly between 2 and 6, and which contains at least one triple bond.

[0050] “(C X ~C Y ) cycloalkynylene group” means, in the context of the present invention, a saturated divalent cyclic hydrocarbon-containing group having X to Y ring carbon atoms, where X and Y are integers between 3 and 36, preferably between 3 and 18, particularly between 3 and 6, and which contains at least one triple bond.

[0051] “(C X ~C Y ) arylene” means, in the context of the present invention, a divalent aromatic hydrocarbon-containing group having X to Y carbon atoms, where X and Y are integers between 5 and 36, preferably between 5 and 18, particularly between 5 and 10, and which contains one or more fused rings. For example, a phenylene group may be mentioned.

[0052] “(C X ~C Y ) heteroarylene” means, in the context of the present invention, a divalent aromatic group in the case where the ring atoms X to Y include one or more, preferably 1 to 4 and more preferably 1 or 2 heteroatoms such as sulfur, nitrogen or oxygen atoms, and the other ring atoms are carbon atoms. X and Y are integers between 5 and 36, preferably between 5 and 18, particularly between 5 and 10.

[0053] “Divalent free radical” means, in the context of the present invention, a free radical having two valences, that is, a free radical having two covalent bonds, polar covalent bonds or ionic chemical bonds. The free radical may contain, for example, carbon atoms and / or oxygen atoms.

[0054] "Dry extract" means, in the context of the present invention, a mass of dry microspheres contained in 1 ml of water-swellable microspheres.

[0055] In the context of the present invention, "chain transfer agent" means a compound having at least one weak chemical bond. This agent reacts with the radical site of the growing polymer chain and stops the growth of the chain. In the chain transfer process, the radical is temporarily transferred to the chain transfer agent and the growth is restarted by transferring the radical to another polymer or monomer.

[0056] Advantageously, the chain transfer agent is selected from the group consisting of monofunctional or polyfunctional thiols and alkyl halides.

[0057] Alkyl halides that may serve as chain transfer agents include, in particular, bromotrichloromethane, carbon tetrachloride, and carbon tetrabromide.

[0058] Particularly advantageously, the chain transfer agent is typically an alicyclic or aliphatic thiol having from 2 to about 24 carbon atoms, preferably from 2 to 12 carbon atoms, more preferably 6 carbon atoms, and optionally further functional groups selected from amino, hydroxy, and carboxy groups.

[0059] Particularly preferred examples of chain transfer agents are thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof, preferably hexanethiol.

[0060] In the context of the present invention, the chain transfer agent is present in the reaction mixture, in particular, in an amount of from 1.5% to less than 6%, preferably from 1.5% to 4.5% and in particular 3% in molar units, compared to the number of moles of hydrophilic monomer a). Thus, in the context of the present invention, the matrix is based in particular on a chain transfer agent in an amount of from 1.5% to less than 6%, preferably from 1.5% to 4.5% and in particular 3% in molar units, compared to the number of moles of hydrophilic monomer a).

[0061] In a preferred embodiment, the matrix of the non-biodegradable embolization microspheres according to the invention is based on a migrating agent in an amount of 1.5 to 4.5 mol% compared to the number of moles of the hydrophilic monomer a).

[0062] Advantageously, the microspheres according to the invention comprise a crosslinked matrix based on 1.5% to 3%, preferably 3% of the migrating agent.

[0063] The addition of the above amount, in particular 1.5 to 3 mol%, of the migrating agent to the reaction mixture, compared to the number of moles of the hydrophilic monomer a), makes it possible to avoid the presence of morphological defects in the microspheres of the invention, especially after swelling and sterilization.

[0064] In the context of the present invention, the absence of morphological defects is defined as the absence of double or twin microspheres; the absence of the microspheres themselves contained in other microspheres (i.e., bead-in-bead); the absence of crushed microspheres or residues of crushed microspheres; the absence of stacks or clusters of microspheres; the absence of degraded microspheres; the absence of (non-spherical) deformed microspheres; the absence of microspheres with a non-smooth surface or residues of the polymer under a magnification of up to 100 times; the absence of inclusions in the microspheres; the absence of water droplets trapped in the microspheres.

[0065] The embolization microspheres of the invention advantageously have a Young's modulus value typically between 3000 Pa and 30000 Pa, preferably between 3000 Pa and 25000 Pa, more preferably between 3000 Pa and 10000 Pa, preferably between 5000 Pa and 10000 Pa, indicating high resistance to compression of the microspheres, which is related to the optimal degree of swelling and elasticity of said microspheres.

[0066] Advantageously, according to the invention, the non-biodegradable embolization microspheres comprise a uniform crosslinked matrix.

[0067] "Uniform crosslinked matrix" means, in the context of the present invention, a matrix consisting of a three-dimensional polymer network in which the components are uniformly distributed. This limits the presence of structural defects and strengthens the solidity of the said network. In fact, typically, in the absence of a uniform crosslinked matrix, the polymer network will break down at the level of its inhomogeneous regions under the action of compressive forces.

[0068] In the context of the present invention, a sphere is defined as a surface where all points are at an equal distance from a point called the center.

[0069] "Microsphere" means, in the context of the present invention, spherical particles having a diameter after swelling of 20 - 1200 μm, for example 20 - 100 μm, 40 - 150 μm, 100 - 300 μm, 300 - 500 μm, 500 - 700 μm, 700 - 900 μm or 900 - 1200 μm, as measured by an optical microscope. Microspheres preferably have a diameter small enough to be injected using needles, catheters or microcatheters having an inner diameter in the range of several hundred μm to 2 mm or more.

[0070] The expression "after swelling" means that the size of the microspheres is considered after the polymerization and sterilization steps included during their preparation. The sterilization step includes, for example, passing the microspheres through an autoclave at a high temperature, typically a temperature above 100°C, preferably a temperature between 110°C and 150°C, preferably 121°C, after the polymerization step. During this sterilization step, the microspheres continue to swell. According to the present invention, the overall degree of swelling of the microspheres is controlled. The degree of swelling is

Number

[0071] "Controlled degree of swelling" means, in the context of the present invention, that the degree of swelling can be reproduced as a function of the batch, and in particular that it varies by less than 15% between batches.

[0072] "Deposited microspheres" means, in the context of the present invention, microspheres that are placed in a solution within a blood vessel and then left for a sufficiently long period without stirring so that they sink to the bottom of the blood vessel in which they are contained, whereby it is possible to remove the supernatant.

[0073] "Lyophilized microspheres" means, in the context of the present invention, microspheres that have undergone freezing followed by dehydration by sublimation.

[0074] "Hydrophilic monomer" means, in the context of the present invention, a monomer that has a strong affinity for water, i.e., a monomer that dissolves in water, mixes with water, tends to be wetted by water, or can swell with water after polymerization.

[0075] The hydrophilic monomer a) of the present invention is N-vinylpyrrolidone and the following formula (I): (CH2=CR1)-CO-D (I) (wherein, D represents O-Z or NH-Z, and Z is (C1-C6) alkyl, -(CR2R3) m -CH3, -(CH2-CH2-O) m -H, -(CH2-CH2-O) m -CH3, -C(R4OH) m or -(CH2) m -NR5R6, where m preferably represents an integer between 1 and 10, and more preferably m is equal to 4 or 5) and is selected from the monomers of.

[0076] Advantageously, the hydrophilic monomer a) according to the present invention is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl (methyl) acrylate, N,N-dimethylaminopropyl (meth) acrylate, t-butylaminoethyl (methyl) 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.

[0077] More advantageously, the hydrophilic monomer a) is poly(ethylene glycol) methyl ether methacrylate (m-PEGMA).

[0078] In the context of the present invention, the hydrophilic monomer a) is present in the reaction mixture, in particular, in an amount of 20% to 95%, preferably 30% to 95%, more preferably 45% to 95%, preferably 45% to 75%, in particular 45% to 70%, more particularly 45% to 65% in molar units, compared to the total number of moles of the monomers.

[0079] "Crosslinking monomer" means, in the context of the present invention, a monomer that is at least bifunctional but may also be polyfunctional and has a double bond at each polymerizable end. The crosslinking monomer, in combination with other monomers in the mixture, enables the formation of a crosslinked network. The structure and amount of the crosslinking monomer in the monomer mixture can be readily selected by one skilled in the art to provide the desired crosslink density. The crosslinking agent is also advantageous for the stability of the microspheres. The crosslinking agent prevents the microspheres, whatever they may be, from being soluble in any solvent. The crosslinking agent also makes it possible to improve the compressibility of the microspheres, which is preferred for embolization therapy.

[0080] "Non-biodegradable hydrophilic crosslinking agent" means, in the context of the present invention, a crosslinking agent as defined above that has a strong affinity for water and cannot be decomposed under the physiological conditions of the mammalian body, particularly the human body. In fact, biodegradation of a molecule is tolerated when the latter has sufficient functional sites that can be cleaved under physiological conditions and / or at physiological pH (generally about 7.4) by endogenous enzymes of the mammalian body, particularly the human body. Functional sites that can be cleaved under physiological conditions are, in particular, amide bonds, ester bonds and acetals. Therefore, a molecule containing an insufficient number of said functional sites will be considered non-biodegradable. In the context of the present invention, the crosslinking monomer has less than 20 functional sites that can be cleaved under physiological conditions, preferably less than 15 such sites, more preferably less than 10 such sites, and even more preferably less than 5 such sites.

[0081] The non-biodegradable linear or branched hydrophilic crosslinking agent according to the present invention is, in particular, a non-biodegradable crosslinking agent that is soluble in an organic solvent and contains polymerizable groups of diacrylate, methacrylate, acrylamide, and / or methacrylamide.

[0082] Advantageously, the crosslinking agent has the following general formula (IIa) or (IIb): (CH2=CR7)CO-NH-A-HN-OC(CR8=CH2) (IIa), (CH2=CR7)CO-O-A-O-OC(CR8=CH2) (IIb) and wherein R7 and R8, independently of one another, represent H or (C1-C6) alkyl, for example a methyl group, preferably R7 and R8 represent H, and A preferably represents alone or in combination with at least one of the atoms to which it binds, such as (C1-C6) alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A.

[0083] Even more preferably, A represents alone or in combination with at least one of the atoms to which it binds, such as (C1-C6) alkylene or polyethylene glycol (PEG), preferably polyethylene glycol (PEG).

[0084] In connection with the above definition of A, the polyethylene glycol has a length in the range of 200 to 10,000 g / mol, preferably 200 to 2,000 g / mol, more preferably 500 to 1,000 g / mol.

[0085] Examples of crosslinking monomers that can be used in connection with the present invention include, without limitation, 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylene bisacrylamide, gly cerol 1,3-diglycerolate diacrylate and poly(ethylene glycol) dimethacrylate (PEGDMA).

[0086] Advantageously, the crosslinking monomer is poly(ethylene glycol) dimethacrylate (PEGDMA) of polyethylene glycol units having a length in the range of 200 to 10,000 g / mol, preferably 200 to 2,000 g / mol, more preferably 500 to 1,000 g / mol.

[0087] In connection with the present invention, the crosslinking monomer is present in the reaction mixture in an amount of 1% to 15%, preferably 2% to 10%, particularly 2% to 7%, more particularly 2% to 5%, especially 5 mol%, in particular compared to the total number of moles of the monomer.

[0088] In a particular embodiment of the invention, the crosslinked polymer matrix of the microspheres is based solely on the base components a), b) and c) as defined above in the above ratios, and no other base components are added to the reaction mixture. Therefore, it is clear that the sum of the above ratios of monomers a) and b) must be equal to 100%.

[0089] According to a particular aspect of the invention, the crosslinked matrix of the microspheres according to the invention further has the following formula (III): (CH2=CR9)-M-E (III) (wherein, ·R9 represents H or (C1-C6) alkyl; ·M represents a single bond or a divalent free radical having 1 to 20 carbon atoms, preferably a single bond; ·E represents an ionized or ionizable group, and E is preferably -COOH, -COO-, -SO3H, -SO3 - , -PO4H2, -PO4H - , -PO4 2- , -NR 10 R 11 , -NR 12 R 13 R 14 + selected from the group consisting of, ·R 10 , R 11 , R 12 , R 13 and R 14 each independently represents H or (C1-C6) alkyl) is based on at least one ionized or ionizable monomer.

[0090] "Ionized or ionizable groups" in the context of the present invention mean groups that are charged or may be in a charged form (ionic form), i.e., depending on the pH of the medium, having at least one positive or negative charge. For example, the COOH group may be ionized in the form of COO−, and the NH2 group may be in the ionized form of NH3 + +.

[0091] The introduction of ionized or ionizable monomers into the reaction mixture enables enhancement of the hydrophilicity of the resulting microspheres and thus enhancement of the degree of swelling of said microspheres, further facilitating their injection via catheters and microcatheters. The presence of ionized or ionizable monomers particularly facilitates loading of the active substance inside the microspheres.

[0092] Preferably, the ionized or ionizable monomer is advantageously a cationic monomer selected from the group consisting of (methacryloyloxy)ethyl phosphorylcholine, 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 of the microspheres according to the invention may be obtained by adding to the reaction mixture the above cationic monomer in an amount between 1 and 40 mol% based on the total amount of monomers. Preferably, the crosslinked matrix according to the invention is added to the reaction mixture , in molar units of the ionizable or ionizable monomer, it is obtained by adding between 5% and 15%, preferably by adding 10%, compared to the total number of moles of the monomer when it is not intended that the resulting microspheres be loaded with the active substance. According to another embodiment, when it is intended that the microspheres be loaded with the active substance, the crosslinked matrix according to the invention is obtained by adding the ionizable or ionizable monomer to the reaction mixture between 20% and 40%, preferably between 20% and 30%, preferably 30 mol%, compared to the total number of moles of the monomer.

[0093] In another advantageous embodiment, the ionizable or ionizable monomer is preferably an anionic monomer selected from the group consisting of acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-oligomer of carboxyethyl acrylate, 3-sulfopropyl (meth) acrylate, potassium salt and hydroxide of 2-((methacryloyloxy) ethyl) dimethyl-(3-sulfopropyl) ammonium. Advantageously, the crosslinked matrix of the non-biodegradable embolizing microspheres according to the invention may be obtained by adding to the reaction mixture the above anionic monomer between 1 and 40 mol%, more advantageously between 10 and 30 mol%, based on the total amount of the monomer.

[0094] Particularly preferably, the ionizable or ionizable monomer is methacrylic acid. Advantageously, the crosslinked matrix according to the invention is based on an amount of methacrylic acid (MA) between 10 and 30 mol% based on the total amount of the monomer.

[0095] According to a preferred embodiment of the invention, the crosslinked matrix of the microspheres according to the invention is further based on at least one halogenated monomer, preferably an iodinated monomer.

[0096] The introduction of a halogenated monomer, preferably an iodinated monomer, has the effect of increasing the density of the resulting microspheres. Unexpectedly, the inventors have found that when the halogenated monomer, typically an iodinated monomer, is advantageously used in an amount between 1 and 15 mol% compared to the total number of monomers in the reaction mixture for obtaining the cross-linked matrix of the present invention, the resulting plug microspheres form an optimally stable suspension in a mixture containing 50% normal saline and 50% contrast agent. In other words, the introduction of the halogenated monomer, particularly the iodinated monomer, in the above amount makes it possible to prevent the microspheres from floating on the surface of the mixture.

[0097] In the context of the present invention, the halogenated monomer is added to the reaction mixture, in particular, in an amount of 5% to 15%, preferably 5% to 10%, more particularly 5% to 7% in molar units compared to the total number of moles of monomers.

[0098] Furthermore, when using a halogenated monomer in an amount of 15% or less in molar units compared to the total number of moles of monomers, the resulting microspheres are not radiopaque. The halogenated monomer is introduced in an amount insufficient to impart radiopacity to the microspheres.

[0099] Advantageously, the halogenated monomer has the following general formula (IV): (CH2=CR 15 )-CO-Y (IV) (wherein, ·Y represents O-W, (O-R 16 ) p -W, (NH-R 16 ) p -W or NH-W, W represents Ar, L-Ar, p is an integer between 1 and 10, preferably between 1 and 4, where: ·Ar represents a (C5-C 36 ) aryl group or a (C5-C 36 ) heteroaryl group, said groups being substituted with one, two or three atoms of iodine and / or bromine, and optionally, (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 , -N r CONR s R t , -OCOOR u , and -COR v is substituted with one to four, preferably two or three groups selected from; ·L is -(CH2) n -, -(HCCH) n -, -O-, -S-, -SO-, -SO2-, -OSO2 - , -NR 17 -, -CO-, -COO-, -OCO-, -OCOO-, -CONR 18 , -NR 19 CO-, -OCONR 20 , -NR 21 COO- or -NR 22 CONR 23 -, where n is an integer from 1 to 10; ·R 17 ~R 23 and R a ~R v are, independently of each other, a hydrogen atom, (C1 - C 10 )alkyl, and the (C1 - C 10 )alkyl is optionally substituted with 1 to 10 OH groups, or -(CH2 - CH2 - O) q -R' group, where R' is a hydrogen atom or (C1 - C6)alkyl, and q is an integer between 1 and 10, preferably between 1 and 5; ·R 15 represents H or (C1 - C6)alkyl; ·R 16 is (C1 - C 36 )alkylene, (C3 - C 36 )cycloalkylene, (C2 - C 36) An alkylene, (C3 - C 36 ) A cycloalkylene, (C2 - C 36 ) An alkynylene, (C3 - C 36 ) A cycloalkynylene, (C5 - C 36 ) An arylene and (C5 - C 36 ) A heteroarylene (representing a group selected from) is as follows.

[0100] In the context of the present invention, the halogenated monomer is more preferably a monomer of general formula (IV) as defined above, where Y is NH - W, O - W or (O - R 16 ) p - W, preferably NH - W or (O - R 16 ) p - W, more preferably (O - R 16 ) p - W, where W represents Ar or L - Ar, and p, R 16 , L and Ar are as defined above. Preferably, R 16 is (C1 - C 36 ) alkylene, especially (C1 - C 18 ) alkylene, more particularly (C1 - C6) alkylene; L represents - OCO -; and Ar is one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally, - 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 - N r CONR s R t , preferably - NR a R b , - NR c COR d selected from two or three groups of, a (C5 - C 36 ) aryl, especially (C5 - C10 ) represents aryl, more particularly phenyl.

[0101] Advantageously, the halogenated monomer is a monomer of general formula (IV) as defined above, where Y is NH-W or (O-R 16 ) p -W, more advantageously (O-R 16 ) p -W, where W represents Ar or L-Ar, and p, R 16 , L and Ar are as defined above. Preferably, R 16 is (C2-C 36 ) alkylene, especially (C2-C 18 ) alkylene, more particularly (C2-C6) alkylene; L represents -OCO-, -C(O)NR 17 -, or -NR 18 C(O)-; and Ar is one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally, -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 -N r CONR s R t -, preferably -NR a R b -, -NR c COR d and -C(O)NR h R i selected from two or three groups selected from, (C5-C 36 ) aryl, especially (C5-C 10 ) aryl, more particularly phenyl.

[0102] Advantageously, Ar is one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally, (C1-C 10Alkyl, -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 -N r CONR s R t represents (C5 - C 10 ) aryl, more particularly phenyl, substituted with two groups selected from the following.

[0103] Advantageously, Ar is phenyl substituted with three atoms of iodine and / or bromine, preferably iodine, and optionally and selectively, (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 -N r CONR s R t selected from, advantageously, (C1 - C 10 ) alkyl, -NR a R b 、-NR c COR d 、-COOR e 、-CONR h R i 、-NR l COOR o - and -N r CONR s R t represents phenyl substituted with two groups selected from the following.

[0104] Advantageously, the halogenated monomer is a monomer of general formula (IV) as defined above, where Y is O-C6H4I, O-C6H3I2, O-C6H2I3, NH-C6H4I, NH-C6H3I2, NH-C6H2I3, O-CH2-CH2-C(O)-C6H4I, O-CH2-CH2-O-C(O)-C6H3I2, O-CH2-CH2-O-C(O)-C6H2I3, NH-CH2-CH2-C(O)-C6H4I, NH-CH2-CH2-O-C(O)-C6H3I2, or NH-CH2-CH2-O-C(O)-C6H2I3, in particular O-C6H2I3, NH-C6H2I3, O-CH2-CH2-O-C(O)-C6H2I3, or NH-CH2-CH2-O-C(O)-C6H2I3.

[0105] In another embodiment, the halogenated monomer is of the following general formula (VI): (CH2=CR 29 )-CO-Y’ (VI) (wherein ·R 29 represents H or (C1-C6) alkyl; ·Y’ represents (O-R 30 )t-W’-Ar’, or NH-W’-Ar’ (t is an integer between 1 and 10, preferably between 1 and 4); ·R 30 represents a group selected from (C2-C 36 ) alkylene; ·W’ represents a single bond, -CONR 31 -, or -NR 32 CO-; ·Ar’ represents a (C5-C 36 ) aryl group, said group being substituted with one, two or three atoms of iodine and / or bromine, and optionally (C1-C 10 ) alkyl, -NR 33 R 34 、-NR 35 COR 36 、-COOR 37 、-OR 38 、-OCOR 39 、-CONR 40 R 41 、-OCONR42 R 43 、 -NR 44 COOR 45 、 NR 46 CONR 47 R 48 、 -OCOOR 49 、 and -COR 50 substituted with one to four, preferably two or three groups selected from; ·R 31 and R 32 each independently represents a hydrogen atom or (C1 - C6) alkyl; ·R 33 ~R 50 each independently represents a hydrogen atom, (C1 - C 10 ) alkyl, and the (C1 - C 10 ) alkyl is optionally substituted with 1 to 10 OH groups, or -(CH2 - CH2 - O) t’ -R” groups (where R” is a hydrogen atom or -(C1 - C6) alkyl, and t’ is an integer between 1 and 10, preferably between 1 and 5)) is.

[0106] Advantageously, R 29 represents (C1 - C6) alkyl, more advantageously (C1 - C3) alkyl, more advantageously methyl.

[0107] Advantageously, R 30 represents (C2 - C 18 ) alkylene, more particularly (C2 - C6) alkylene, more advantageously ethylene.

[0108] Advantageously, R 31 and R 32 each independently represents a hydrogen atom. Thus, W’ advantageously represents a single bond, -C(O)NH-, or -NHC(O)-.

[0109] Advantageously, Ar’ is one, two or three atoms of iodine and / or bromine, preferably iodine, and optionally (C1 - C 10 ) alkyl, -NR 33 R 34 、 -NR 35C(O)R 36 、 -C(O)OR 37 、 -OR 38 、 -OC(O)R 39 、 -C(O)NR 40 R 41 、 -OC(O)NR 42 R 43 、 -NR 44 C(O)OR 45 、 -NR 46 C(O)NR 47 R 48 、 -OC(O)OR 49 、 and -C(O)R 50 selected from two or three groups, (C5 - C 10 ) aryl, more particularly phenyl.

[0110] Advantageously, Ar’ is iodine and / or bromine, preferably three atoms of iodine, and optionally, (C1 - C 10 ) alkyl, -NR 33 R 34 、 -NR 35 C(O)R 36 、 -C(O)OR 37 、 -OR 38 、 -OC(O)R 39 、 -C(O)NR 40 R 41 、 -OC(O)NR 42 R 43 、 -NR 44 C(O)OR 45 、 -NR 46 C(O)NR 47 R 48 、 -OC(O)OR 49 、 and -C(O)R 50 selected from two groups, (C5 - C 10 ) aryl, more particularly phenyl.

[0111] Advantageously, Ar’ is iodine and / or bromine, preferably three atoms of iodine, and optionally, (C1 - C 10 ) alkyl, -NR 33 R 34 、 -NR 35C(O)R 36 、 -C(O)OR 37 、 -OR 38 、 -OC(O)R 39 、 -C(O)NR 40 R 41 、 -OC(O)NR 42 R 43 、 -NR 44 C(O)OR 45 、 -NR 46 C(O)NR 47 R 48 、 -OC(O)OR 49 、 and -C(O)R 50 from, preferably (C1 - C 10 ) alkyl, -NR 33 R 34 、 -NR 35 C(O)R 36 、 -C(O)OR 37 、 -OR 38 、 -C(O)NR 40 R 41 、 -NR 44 C(O)OR 45 、 -NR 46 C(O)NR 47 R 48 、 -OC(O)OR 49 、 and -C(O)R 50 represents phenyl substituted with two groups selected from.

[0112] Preferably, the halogenated monomer is a compound of the following general formula (VI):

Chemical formula

[0113] Preferably, the halogenated monomer is the following compound:

Chemical formula

[0114] More preferably, the halogenated monomer is the following formula (IVa):

Chemical formula

Chemical formula

[0115] In the context of the present invention, the crosslinked matrix of the microspheres according to the present invention is further based on at least one coloring monomer for visualizing them with the naked eye. This makes it possible in particular to verify that the suspension of microspheres is properly homogeneous in the syringe before injection and to monitor the injection rate.

[0116] Thus, according to a particular embodiment, the crosslinked matrix of the microspheres according to the present invention is further of the following general formula (V):

Chemical formula

[0117] Preferably, the colored monomer is of the following formula (Va) or (Vb):

Chemical formula

[0118] In the context of the present invention, the colored monomer is added to the reaction mixture, in particular, in an amount of 0% to 1%, preferably 0% to 0.5%, more particularly 0.01% to 0.2%, more preferably 0.02% to 0.2%, and even more particularly 0.04% to 0.1% in molar units, compared to the total number of moles of the monomers.

[0119] Magnetic resonance imaging (MRI) is used in the medical field to provide two-dimensional cross-sectional images of the internal structure of a patient's body without exposing the patient to harmful radiation. The crosslinked matrix of the embolization microspheres according to the present invention may further be based on particles for visualizing the microspheres during scanning from magnetic resonance imaging. spheres.

[0120] Thus, preferably, the crosslinked matrix of the microspheres according to the present invention further comprises an agent visible by magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, preferably iron oxide nanoparticles, such as USPIO (ultrasmall superparamagnetic iron oxide or ultrasmall paramagnetic iron oxide = magnetic particles based on iron compounds exhibiting superparamagnetic properties that are visible by MRI).

[0121] In the context of the present invention, the particles visible by MRI are preferably added to the reaction mixture in an amount of 0% to 10%, preferably 0.1% to 10%, based on the volume of the organic phase.

[0122] In the context of the present invention, when the crosslinked matrix of the microspheres does not contain ionized or ionizable monomers as base components, it preferably has: - 94.5% to 98%, preferably 94.5% to 96%, preferably 94.96% of hydrophilic monomer a); - 2% to 5%, preferably 3% to 5%, preferably 5% of non - biodegradable hydrophilic crosslinked monomer b); - 1% to 3%, preferably 3% of migration agent c); - 0% to 0.5%, preferably 0.02% to 0.1%, preferably 0.04% of coloring monomer; and - 0% to 10%, preferably 0% to 5%, preferably 1% of particles visible by MRI based on, where the nature of each of the above monomers and their associated percentages are as defined above in this description. It is clear that the sum of the above percentages of the monomers must equal 100%.

[0123] According to another embodiment of the present invention, the microspheres according to the present invention not loaded with an active substance preferably have - 79.5% to 93%, preferably 80% to 90%, preferably 84.96% of hydrophilic monomer a); - 2% to 5%, preferably 3% to 5%, preferably 5% of non - biodegradable hydrophilic crosslinked monomer b); - 1% to 3%, preferably 3% of migration agent c); - 5% to 15%, preferably 8% to 12%, preferably 10% of ionized or ionizable monomer; - 0% to 0.5%, preferably 0.02% to 0.1%, preferably 0.04% of coloring monomer; and - 0% to 10%, preferably 0% to 5%, preferably 1% of particles visible by MRI and contain a crosslinked matrix based on, where the nature of each of the above monomers and their associated percentages are as defined above in this description. It is clear that the sum of the above percentages of the monomers must equal 100%.

[0124] According to a preferred embodiment of the present invention, the microspheres according to the present invention not loaded with an active substance preferably have -63% to 95%, preferably 70% to 90%, preferably 75% to 80%, preferably 79.96% of hydrophilic monomer a); -2% to 5%, preferably 3% to 5%, preferably 5% of non-biodegradable hydrophilic crosslinking monomer b); -1% to 3%, preferably 3% of migration agent c); -5% to 15%, preferably 8% to 12%, preferably 10% of ionized or ionizable monomer; -5% to 7%, preferably 5% to 6%, preferably 5% of halogenated monomer; -0% to 0.5%, preferably 0.02% to 0.1%, preferably 0.04% of coloring monomer; and -0% to 10%, preferably 0% to 5%, preferably 1% of particles visible by MRI and contain a crosslinked matrix based on the above, and the nature of each of the above monomers and their related percentages is as defined above in this description. It is clear that the sum of the above percentages of the monomers must equal 100%.

[0125] In connection with the present invention, the microspheres according to the present invention loaded with an active substance preferably have -45% to 65%, preferably 50% to 65%, preferably 55% to 65%, preferably 64.96% of hydrophilic monomer a); -2% to 5%, preferably 3% to 5%, preferably 5% of non-biodegradable hydrophilic crosslinking agent b); -1% to 3%, preferably 3% of migration agent c); -20% to 40%, preferably 30% to 40%, preferably 30% of ionized or ionizable charged monomer; -0% to 0.5%, preferably 0.02% to 0.1%, preferably 0.04% of coloring monomer; and -0% to 10%, preferably 0% to 5%, preferably 1% of particles visible by MRI It contains a cross-linked matrix based on the above, and the properties of each of the above monomers and their related percentages are as defined above in this description. It is obvious that the total of the above percentages of the monomers must be equal to 100%.

[0126] Preferably, the microspheres according to the invention loaded with the active substance are advantageously - 47.5% to 73%, preferably 50% to 70%, preferably 59.96% of hydrophilic monomer a); - 2% to 5%, preferably 3% to 5%, preferably 5% of non-biodegradable hydrophilic cross-linking agent b); - 1% to 3%, preferably 3% of migration agent c); - 20% to 40%, preferably 30% to 40%, preferably 30% of ionized or ionizable charged monomers; - 5% to 7%, preferably 5% to 6%, preferably 5% of halogenated monomers; - 0% to 0.5%, preferably 0.02% to 0.1%, preferably 0.04% of coloring monomers; and - 0% to 10%, preferably 0% to 5%, preferably 1% of particles visible by MRI It contains a cross-linked matrix based on the above, and the properties of each of the above monomers and their related percentages are as defined above in this description.

[0127] The cross-linked matrix of the microspheres according to the invention can be easily synthesized by many methods with which those skilled in the art are familiar. As an example, the cross-linked matrix according to the invention may typically be obtained by direct or inverse suspension polymerization as described below or in the examples.

[0128] Direct suspension may be carried out as follows. (a)(i) At least one hydrophilic monomer a) as defined above, at least one non-biodegradable hydrophilic cross-linking agent b) as defined above, and at least one migration agent c) as defined above; (ii) A polymerization initiator present in an amount in the range of 0.1 to about 2 parts by weight per 100 parts by weight of the monomer; (iii) a surfactant in an amount of about 5 parts by weight or less, preferably about 3 parts by weight or less, and most preferably in the range of 0.2 to 1.5 parts by weight per 100 parts by weight of the aqueous phase; and (iv) water for forming an oil-in-water suspension; Mix or stir a reaction mixture containing (b) polymerize the base component

[0129] In this direct suspension process, the surfactant may be selected from the group consisting of hydroxyethyl cellulose, polyvinyl alcohol (PVA), polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, and polysorbate 20 (Tween (registered trademark) 20); preferably PVA.

[0130] Next, the microspheres thus obtained are washed and calibrated by techniques well known to those skilled in the art.

[0131] Inverse suspension may be carried out as follows. (a)(i) at least one hydrophilic monomer a) as defined above, at least one non-biodegradable hydrophilic cross-linking agent b) as defined above, and at least one transfer agent c) as defined above; (ii) a polymerization initiator present in an amount in the range of 0.1 to about 2 parts by weight per 100 parts by weight of the monomer; (iii) a surfactant in an amount of about 10 parts by weight or less, preferably about 8 parts by weight or less, and most preferably in the range of 3 to 7 parts by weight per 100 parts by weight of the oil phase; and (iv) an oil for forming a water-in-oil suspension; Mix or stir a reaction mixture containing (b) polymerize the base component

[0132] In the above method, the polymerization initiator is, in particular, t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also known as 4,4'-azobis(4-cyanopentanoic acid), 1,1'-azobis(cyclohexanecarbonitrile) or AIBN (azobisisobutyronitrile) or one or more thermal initiators, for example, 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone (106797-53-9); 2-hydroxy-2-methylpropiophenone (Darocur® 1173, 7473-98-5), 2,2-dimethoxy-2-phenylacetophenone (24650-42-8), 2,2-dimethoxy-2-phenylacetophenone (Irgacure®, 24650-42-8) or 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (Irgacure®, 71868-10-5).

[0133] In this inverse suspension process, the surfactant may be selected from the group consisting of sorbitan esters, for example, sorbitan monolaurate (Span® 20), sorbitan monopalmitate (Span® 40), sorbitan monooleate (Span® 80) and sorbitan trioleate (Span® 85), hydroxyethyl cellulose, a mixture of glyceryl stearate and PEG stearate (Arlacel®), and cellulose acetate.

[0134] The oil used in the above method may be selected from paraffin oil, silicone oil, and organic solvents such as hexane, cyclohexane, ethyl acetate or butyl acetate.

[0135] When the crosslinked matrix according to the invention is obtained by the polymerization of at least one ionized or ionizable monomer, further a drug, an active substance, a diagnostic agent or a polymer may be loaded onto the microspheres, i.e., adsorbed onto the crosslinked matrix, by non-covalent interactions, optionally in the presence of pharmaceutically acceptable excipients well known to those skilled in the art. A drug or an active This particular method of capturing substances is referred to as physical encapsulation. No specific requirements are imposed on the agent or active substance to be loaded.

[0136] Loading can be carried out by many methods familiar to those skilled in the art, such as passive adsorption (swelling of the crosslinked matrix in the drug solution) or ionic interactions. These methods are described, for example, in WO 2012 / 120138 pamphlet, especially on pages 22, line 20 to page 26, line 7. The efficiency of encapsulation mainly depends on the compatibility and / or favorable interactions between the two structures.

[0137] In the context of the present invention, the microspheres may be loaded with an agent, active substance or diagnostic agent, and thus enable their release at target sites present inside the body of a mammal, especially inside the human body. Thus, the crosslinked matrix of the microspheres according to the present invention may be loaded with an agent, active substance or diagnostic agent having a molecular weight preferably less than 5000 Da, typically less than 1000 Da, and the agent or active substance is preferably selected from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anti-cancer agents, steroids, disinfectants and mixtures thereof.

[0138] Preferably, the polymer according to the present invention may be loaded with an anti-cancer agent.

[0139] 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 (Ametycine®), bleomycin and actinomycin D, other antineoplastic compounds such as irinotecan, 5-fluorouracil (Adrucil®), sorafenib (Nevaxar®), sunitinib (Sutent®), regorafenib, brivanib, orantinib, linifanib, erlotinib, cabozantinib, foretinib, tibatinib, fotemustine, temozolomide (TCNU), carmustine, cytosine C, cyclophosphonamide, cytarabine (or cytarabine), paclitaxel, docetaxel, methotrexate, everolimus (Afinitor®), PEG - arginin deiminase, the combination of tegafur / gimeracil / oteracil (Teysuno®), muparfostat, peletinoin, gemcitabine, bevacizumab (Avastin®), ramucirumab, floxuridine, immunostimulants such as GM - CSF (granulocyte - macrophage colony - stimulating factor) and its recombinant forms: molgramostim or sargramostim (Leukin®), OK - 432 (Picibanil®), interleukin 2, interleukin 4 and tumor necrosis factor α (TNFα), 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).

[0140] Preferably, the anticancer agent is selected from anthracyclines, immunostimulants, platinum complexes, antineoplastic drugs and mixtures thereof.

[0141] Even more preferably, the anticancer agent is selected from anthracyclines, antibodies, antineoplastic drugs and mixtures thereof.

[0142] The antibody is selected from, for example, anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CEA (carcinoembryonic antigen), or a mixture thereof.

[0143] Anti-PD-1 is, for example, nivolumab or pembrolizumab.

[0144] Anti-PD-L1 is, for example, avelumab, durvalumab, or atezolizumab.

[0145] Anti-CTLA-4 is, for example, ipilimumab or tremelimumab.

[0146] Even more preferably, the anticancer drug is selected from the group consisting of paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (granulocyte-macrophage colony-stimulating factor), tumor necrosis factor α (TNFα), an antibody, and a mixture thereof.

[0147] Preferably, the local anesthetic is selected from lidocaine, bupivacaine, and a mixture thereof.

[0148] The anti-inflammatory drug may be selected from ibuprofen, niflumic acid, dexamethasone, naproxen, and a mixture thereof.

[0149] In connection with the present invention, the polymer may be loaded with a polymer selected from the group consisting of an enzyme, an antibody, a cytokine, a growth factor, a coagulation factor, a hormone, a plasmid, an antisense oligonucleotide, siRNA, a ribozyme, a DNA enzyme (also referred to as a DNAzyme), an aptamer, an anti-inflammatory protein, a bone morphogenetic protein (BMP), an angiogenesis promoter, a vascular endothelial growth factor (VEGF) and TGFβ, and an angiogenesis inhibitor or an anti-tyrosine kinase, and a mixture thereof, particularly by immediate adsorption.

[0150] The anti-inflammatory protein is, for example, infliximab or rilonacept and a mixture thereof.

[0151] The angiogenesis promoting factors are, for example, fibroblast growth factors (FGF) and mixtures thereof.

[0152] The angiogenesis inhibitors are, for example, bevacizumab, ramucirumab, nesvacumab, olaparatumab, vanucizumab, rilotumumab, emibetuzumab, aflibercept, ficlatuzumab, pegaptanib, and mixtures thereof.

[0153] The anti-tyrosine kinases are, for example, lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, sulfatinib, dovetinib, linifanib, and mixtures thereof.

[0154] Advantageously, the polymer may be loaded with a polymer selected from anti-tyrosine kinases, TGFβ, angiogenesis inhibitors, and mixtures thereof.

[0155] In a second aspect, the present invention relates to a pharmaceutical composition comprising non-biodegradable embolization microspheres according to the present invention, advantageously accompanied by a pharmaceutically acceptable medium intended for administration by injection.

[0156] Examples of pharmaceutically acceptable media include, but are not limited to, water for injection, physiological saline, also referred to as normal saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, esters of hyaluronic acid, plasma, contrast agents for imaging by X-ray, magnetic resonance or ultrasound examination, buffers, preservatives, gelling agents and / or surfactants. Advantageously, the pharmaceutically acceptable medium is normal saline, water for injection, a contrast agent for imaging by X-ray, magnetic resonance or ultrasound examination, or a mixture thereof. More advantageously, the pharmaceutically acceptable medium is normal saline, a contrast agent for imaging by X-ray, magnetic resonance or ultrasound examination, or a mixture of normal saline and a contrast agent for imaging by X-ray, magnetic resonance or ultrasound examination.

[0157] According to the present invention, the contrast agent is preferably a contrast agent for X-ray imaging. Advantageously, it is a non-ionic iodinated water-soluble contrast agent, such as iobitridol (Xenetix®), iopamidol (Iopamiron®, Isovue®), iomeprol (Iomeron®), ioversol (Optiray®, Optiject®), iohexol (Omnipaque®), iopentol (Imagopaque®), ioxitol (Oxilan®), iopromide (Ultravist®), metrizamide (Amipaque®), iosarcol (Melitrast®), iotrolan (Isovist®), iodixanol (Visipaque®), ioximenol and ioximid (Univist®), and mixtures thereof.

[0158] According to another embodiment, the contrast agent is a contrast agent for magnetic resonance imaging (MRI). Advantageously, it is gadolinium chelate (Dotarem®).

[0159] According to another embodiment, the contrast agent is a contrast agent for imaging by ultrasound examination. Advantageously, it is sulfur hexafluoride (Sonovue®).

[0160] In a particular embodiment of the present invention, the pharmaceutical composition comprises non-biodegradable embolizing microspheres according to the present invention together with normal saline, and the composition is intended to be mixed with at least one contrast agent for imaging by X-ray, magnetic resonance or ultrasound examination, in particular for X-ray imaging, as defined above, before administration by injection, and said mixing comprises preparing a suspension of the microspheres according to the present invention.

[0161] The pharmaceutical composition advantageously has an acceptable injection viscosity.

[0162] In certain embodiments according to the invention, a pharmaceutical composition according to the invention comprises non-biodegradable embolizing microspheres according to the invention together with a mixture of normal saline and a contrast agent as defined above, the normal saline and the contrast agent being present in a ratio of 70 / 30 to 20 / 80, preferably 50 / 50 to 20 / 80, more preferably 50 / 50.

[0163] Advantageously, when a pharmaceutical composition according to the invention comprises microspheres obtained by polymerization of a reaction mixture comprising 5% to 10%, more preferably 5% to 7% of a halogenated monomer as described in this description, the pharmaceutical composition comprises the microspheres together with a mixture of normal saline and a contrast agent in a ratio between 80 / 20 and 0 / 100, preferably between 70 / 30 and 40 / 60, in particular 50 / 50. Preferably, the microspheres have a size of 500 to 700 μm, 700 to 900 μm or 900 to 1200 μm. In this way, the suspension of microspheres in the solution is uniform and stable over the time required for injection.

[0164] In another embodiment according to the invention, when a pharmaceutical composition according to the invention comprises microspheres obtained by polymerization of a reaction mixture that does not contain a halogenated monomer as described in this description, the pharmaceutical composition comprises the microspheres together with a mixture of normal saline and a contrast agent in a ratio between 80 / 20 and 0 / 100.

[0165] The field of application of the non-biodegradable embolizing microspheres according to the invention is in particular vascular embolization therapy, especially in cases of uterine fibroids and chemoembolization, for example in cases of liver cancer such as hepatocellular carcinoma (HCC) or primary liver cancer, which consists of removing a tumor by combining vascular occlusion with the delivery of one or more active substances or polymers loaded with embolizing microspheres. This technique makes it possible to concentrate the loaded drug at the tumor level and thus reduce any undesirable effects while simultaneously reducing the systemic concentration.

[0166] As described above, the non-biodegradable embolizing microspheres according to the present invention may be used for various biomedical purposes, which means that they must be compatible with the human body or the body of a mammal. More specifically, suitable biomedical materials do not have hemolytic properties.

[0167] The present invention further relates to the specific use of a migrating agent in the polymerization of a crosslinked matrix contained in a non-biodegradable embolizing microsphere to enable injection of said microspheres, particularly injection in a catheter or microcatheter having an inner diameter in the range of several hundred microns to 2 mm or more. The present invention also relates to the specific use of a migrating agent in the polymerization of a crosslinked matrix to improve mechanical properties (swellability, elasticity, solidity, resistance to compression). Said migrating agent is selected in particular from alicyclic or aliphatic thiols having from 2 to 24 carbon atoms, optionally having another functional group selected from amino, hydroxy and carboxy groups.

[0168] The present invention also relates to a pharmaceutical composition as defined above and to a kit comprising at least one injection means for parenteral administration of said composition. According to the present invention, "injection means" means any means enabling parenteral administration. Advantageously, said injection means is one or more syringes and / or one or more pre-filled syringes and / or one or more catheters or microcatheters for administering said composition by injection.

[0169] Advantageously, the pharmaceutical composition present in said kit comprises microspheres according to the present invention together with normal saline, a contrast agent, or a mixture thereof. More advantageously, said pharmaceutical composition comprises microspheres according to the present invention together with a mixture of normal saline and a contrast agent in a ratio between 80 / 20 and 0 / 100, advantageously between 70 / 30 and 40 / 60, preferably 50 / 50.

[0170] Advantageously, when the microspheres according to the invention are obtained by polymerization of a reaction mixture comprising 5% to 10%, more preferably 5% to 7% of a halogenated monomer as described in the present description, the pharmaceutical composition comprises said microspheres together with a mixture of normal saline and a contrast agent in a ratio between 60 / 40 and 0 / 100, advantageously 50 / 50.

[0171] According to another embodiment of the invention, when the microspheres according to the invention are obtained by polymerization of a reaction mixture not comprising a halogenated monomer as described in the present description, the pharmaceutical composition comprises said microspheres together with a mixture of normal saline and a contrast agent in a ratio between 80 / 20 and 0 / 100.

[0172] Advantageously, the injection means present in the kit according to the invention is suitable for parenteral administration of the pharmaceutical composition according to the invention. Thus, the size of the syringe or (micro) catheter will be adapted as a function of the size of the microspheres according to the invention and the volume to be injected into the plug. A person skilled in the art will be able to select a suitable injection means.

[0173] The present invention relates, on the one hand, to a pharmaceutical composition as defined above, and on the other hand, to at least one contrast agent for imaging by X-ray, magnetic resonance or ultrasound examination, and optionally at least one injection means intended for non- oral administration. The injection means is as defined above.

[0174] In said kit, the pharmaceutical composition and the contrast agent are packaged separately and are intended to be mixed immediately before administration by injection.

[0175] In said kit, at least one contrast agent is as defined above in the present description. In particular, at least one contrast agent is a contrast agent for imaging by X-ray as defined above in the present description.

[0176] In the kit, the pharmaceutical composition preferably comprises the microspheres according to the invention together with a pharmaceutically acceptable medium intended for administration by injection. The pharmaceutically acceptable medium may be, for example but not limited to, water for injection, normal saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, ester of hyaluronic acid and / or plasma. Preferably, in the kit, the pharmaceutical composition preferably comprises the microspheres according to the invention together with normal saline or water for injection.

[0177] In the kit, the pharmaceutical composition is preferably directly packaged within an injection means suitable for injection of the embolizing microspheres by a parenteral route, in particular within a syringe.

[0178] In the kit, the contrast agent is preferably directly packaged within a vial or within an injection means suitable for injection of the embolizing microspheres by a parenteral route, in particular within a syringe.

[0179] In the kit, the ratio of the pharmaceutically acceptable medium to the contrast agent is between 80 / 20 and 0 / 100, preferably between 70 / 30 and 40 / 60, and preferably 50 / 50. Advantageously, when the microspheres according to the invention are obtained by polymerization of a reaction mixture comprising 5% to 10%, preferably 5% to 7% of halogenated monomer as described in this description, the ratio of the pharmaceutically acceptable medium to the contrast agent is between 70 / 30 and 0 / 100, preferably between 60 / 40 and 20 / 80, and preferably 50 / 50. According to another embodiment of the invention, when the microspheres according to the invention are obtained by polymerization of a reaction mixture not comprising halogenated monomer as described in this description, the ratio of the pharmaceutically acceptable medium to the contrast agent is between 80 / 20 and 0 / 100.

Brief Description of the Drawings

[0180]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

[0181] The examples presented below are intended to illustrate the present invention. Hereinafter, the term "microsphere" will generally be abbreviated as MS, regardless of singular or plural form.

Example

[0182] - Materials and Methods · Materials 2,2'-Azobis(2-methylpropionitrile) (AIBN), poly(ethylene glycol) methacrylate (M n = 300 g·mol -1 )(PEG), 1-hexanethiol (95%), methacrylic acid (99%), polyvinyl alcohol (M n = 30000 - 70000 g·mol -1 )(PVA), thioglycolic acid (99%), 1-dodecanethiol (98%) were purchased from Sigma-Aldrich. Toluene and acetone were purchased from VWR. NaCl was purchased from Merck. Polyethylene glycol dimethacrylate (M n = 1000 g·mol -1 )(PEGDMA-1000) was purchased from Polysciences Inc. Violet dye and iodinated monomer were synthesized at Guerbet's R&D center. All materials were used as received without any further purification. · Method

[0183] Morphology The morphological characteristics of the obtained MS were characterized by a Morphologi 4 apparatus (Malvern Instruments, United Kingdom). The Morphologi 4 apparatus can be used to create a database of MS images. It can show the size distribution of the MS being measured. Twenty-six different morphological parameters could be determined by the Morphologi 4 apparatus. The diameter (μm) was the main parameter under consideration.

[0184] The MS was deposited on the sample holder of the Morphologi 4 apparatus. For a more thorough analysis, 500 MS were imaged and stored in the software database. Standard operating procedures (SOP) were used in the imaging process to ensure the uniformity of the measurements.

[0185] After each measurement, defective MS were excluded from the total number of MS (500 MS). The most reliable method consisted of visually testing each MS and removing or storing them in the image database as a function of their defects and their integrity. Furthermore, for defect-free MS, histograms, average values and standard deviations of the diameter were obtained.

[0186] Analysis of defects: There are various classes of defects in the microspheres (MS), which are listed here. - Class 1: MS without defects - Class 2: Sham twin MS - Class 3: Double-core MS - Class 4: Isolated and fragmented MS - Class 5: Residue or residue of fragmented MS - Class 6: MS pile after sterilization - Class 7: MS core without USPIO - Class 8: Very transparent MS (phantom MS) - Class 9: Stack of MS in Polymer Fragment - Class 10: Cracked MS - Class 11: Oval Object Containing Several Small MS - Class 12: Deformed MS

[0187] In the examination of defects based on 500 tested MS, defective MS were excluded. Therefore, the percentage of non - defective MS was calculated:

Number

[0188] Dry Extract, Swelling Degree by Weight The dry extract is measured as follows: Place 1 ml of deposited MS into a 5 - ml Eppendorf vial, freeze it at - 80 °C, and lyophilize it overnight in a lyophilizer (Heto PowerDry LL1500, Thermo Scientific). Next, measure the weight of the lyophilized MS.

[0189] The measurement was carried out on three samples, and the average value was obtained as the final value of the dry weight of the MS.

[0190] Swelling Degree: To calculate the swelling degree by the weight of the MS, the same sample preparation as in the above case was used.

Number

[0191] Rheology and Compressibility The rheological properties of the MS were measured with an HR2 Discovery rheometer (TA Instruments, USA). The Young's modulus was measured using the uniaxial compression mode.

[0192] A plate with a diameter of 50 mm and an initial spacing of 1600 μm was used with a plane-plane type geometry. The temperature of the sample was maintained at 25 °C by the Peltier effect. Before measurement, the vertical force was set to 0 by software. Next, a uniform bed with a single layer of microspheres was deposited on the plate.

[0193] A first measurement was performed to measure the contact point with the MS and the linear deformation conditions.

[0194] For this purpose, the gap between the plates was reduced from 1600 μm to 700 μm at a rate of 16.7 μm / s (1 mm / min), and the vertical force was measured. The contact point corresponds to the gap between the plates when the vertical force begins to be exerted. When continuing to reduce this gap between the plates, the vertical force follows a linear state as a function of the applied deformation up to a specific point. The gap between the plates during this divergence corresponds to the exit from the linear state.

[0195] Next, the second measurement was performed three times continuously to measure the average value and the measurement error of the Young's modulus. This second measurement consists of directly placing the upper plate at the contact point and applying the axial strain up to the maximum value of the exit from the linear state. Therefore, the measured vertical force changes linearly as a function of the applied strain. The slope of this curve corresponds to the Young's modulus.

[0196] Other method (Method No. 2) used to measure the Young's modulus The compression test is carried out on a single microsphere using a compressor (Synergy 800, MTS, France) with a 3D printed piston having a diameter of 15.3 mm. By measuring the exerted force with a 2N force sensor, accurate and reproducible measurement values starting from 1mN are provided. The software TestWorks4 is an interface for controlling the piston and recording the data measured by the sensor. It is necessary to use a lamp (100W bulb) to irradiate the cells containing the microsphere to be analyzed and to enable the camera to clearly visualize the microsphere and the piston. Image processing software ImageJ is used to measure the exact size of the microsphere by measuring the number of pixels in the image. The speed of the piston is fixed at 1 mm / min and the test starts with the piston positioned approximately 100 μm above the microsphere.

[0197] Together with the collected data (measurements of force, time and displacement), the Young's modulus is calculated using the Hertz model applicable to the compression of the sphere between two flat plates.

[0198] Injection of MS MS was injected via a microcatheter and its mechanical properties during injection were tested. A solution consisting of 30 vol% of the contrast agent Xenetix® with 350 mg of iodine / ml and 70 vol% of normal saline was prepared. 20 mL of this solution was obtained using a 20 mL syringe, and 2 mL of MS deposited in parallel was obtained from the sterilized bottle as described above using a 3 mL syringe.

[0199] Two syringes (3 mL and 20 mL) are connected to a three-way stopcock. The MS is suspended in the above mixture by making approximately 15 alternating movements between the two syringes.

[0200] The 3 ml syringe is used to inject the solution of MS in the suspension into a microcatheter of the Progreat® 2.8F (Terumo) or GlideCath® 4F or 5F (Terumo) type.

[0201] Example 1: Synthesis by direct suspension polymerization of microspheres (MS) (900 - 1200 μm) according to the present invention An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50°C. Next, an organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinking agent), a coloring monomer, methacrylic acid (ionizable or ionizable monomer), a transfer agent, and AIBN (initiator) dissolved in toluene is fed into the reactor. Stirring is applied using a propeller-type stirrer at a speed suitable for obtaining droplets of the desired diameter. Next, the temperature is increased to 80°C and stirring is continued for 12 hours. Next, the mixture is filtered through a 40-μm sieve and the MS is collected. Next, the MS retained by the sieve is washed three times with acetone and then three times with water. Next, these washed MS are sieved between a 900-μm sieve and a 710-μm sieve. Next, the MS collected between these two sieves is sterilized in an autoclave at 121°C for 20 minutes, which will have the effect of swelling the MS to obtain the desired size, i.e., MS of 900 - 1200 μm in this case.

[0202] Next, the microspheres synthesized by the above method have the following compositions (Table 1 and Table 1-2).

[0203]

Table 1

[0204]

Table 1-2

[0205] Example 2: Size of microspheres from Example 1 For each of batches 1 - 9 and L9, the average diameter of the microspheres is measured after sterilization and the effect of the concentration of the transfer agent on the size of the MS is evaluated.

[0206] The MS was sterilized according to the above procedure.

[0207] The average diameter (900 - 1200) of the calibrated and sterilized MS for each batch is shown in Figure 1.

[0208] The diameter of the MS after sterilization increases from 923 μm to 1259 μm as the concentration of HT increases (batches 1, 2, 3, 4, 5, 6, and 7). Increasing the mobile agent contained in the microspheres makes their size larger.

[0209] Example 3: Percentage of defect - free microspheres from Example 1 For samples of MS (batches 1 - 9 and L9) having a size of 900 - 1200 μm and containing different concentrations of HT as one or more different types of mobile agents, the percentage of defective MS was calculated by the above method. The results are shown in Figure 2.

[0210] From 0% - 1.5% of HT (batches 1 - 4), the percentage of defect - free MS varies from 89% - 91%. This percentage increases from 1.5% of the mobile agent and reaches a maximum (over 95%) with 3% of the mobile agent (batches 5, 8, 9, and L9).

[0211] The type of defect varies depending on the concentration of the mobile agent in the microspheres. Figure 3 shows two examples of the most frequently observed morphological defects. At concentrations between 0% - 1.5% of HT, the MS is either mostly decomposed (B) or deformed (C).

[0212] At a concentration of 6% or more of HT in the MS, a very large number of ruptured MS are present (see Figure 3).

[0213] Example 4: Dry extract of microspheres from Example 1 Figure 4 shows the dry extract (mg / ml) of MS calculated by the above method as a function of the concentration or nature of the mobile agent. The dry extract (mg) for a given volume of MS decreases linearly, and the concentration of HT increases (batches 1, 2, 3, 4, 5, 6, and 7). The dry extract of MS in batch L9 is about 101 mg / mL. Without the mobile agent, the dry mass of 1 mL of deposited MS is about 159 mg. With 6% HT, this dry extract is only about 52 mg.

[0214] Example 5: Swelling degree of microspheres from Example 1 The swelling degree of the microspheres was determined by the above method for batches 1 to 9 and L9, and the effects of the concentration and nature of the mobile agent were evaluated. The results are shown in Figure 5. It can be observed that as the concentration of HT increases, the resulting swelling degree increases.

[0215] For HT concentrations between 0% and 6%, the swelling degree by weight increases from 7 g / g to 26 g / g. It is about 8.88% in the case of MS in batch L9.

[0216] Therefore, MS without the mobile agent does not swell much and has a very high dry mass. These data indicate that the various mobile agents tested impart a suitable swelling degree.

[0217] Example 6: Rheology and compressibility of microspheres from Example 1 The compressibility of the microspheres can be characterized by measuring the Young's modulus by the above method. The Young's modulus of batches 1 to 9 is shown in Figure 6. The results obtained by method No. 2 for the measurement of the Young's modulus gave fairly similar results.

[0218] As the concentration of HT increases from 0% to 3%, the Young's modulus decreases from about 13 kPa to about 6 kP a, and then it can be observed that it reaches a plateau at about 6 kPa for higher concentrations (4.5% and 6%).

[0219] MS (batches 1 - 4) containing HT between 0% and 0.5% are more solid and rigid and not suitable for injection. The value of the Young's modulus of MS is below 10 kPa, which is the target limit of the present invention, after 1.5% HT and thus is softer and more mobile. MS becomes softer and more mobile after a concentration of 3%.

[0220] All MS with equal concentration of the mobilizing agent, here 3%, have the same plateau value of about 6 kPa.

[0221] When the concentration of the mobilizing agent is between 1.5% and less than 6%, the compressibility of MS makes them suitable for injection by microcatheter.

[0222] Example 7: Injection of microspheres from Example 1 in a microcatheter Each of the MS of batches 1 - 9 and L9 was injected with 4Fr and 5Fr microcatheters. No occlusion was observed.

[0223] In the case of batch 7 (6% HT), the MS did not allow for injection preparation and all were destroyed. Thus, the mechanical properties of MS obtained with 6% mobilizing agent are not compatible with injection by microcatheter.

[0224] Example 8: Synthesis by direct suspension polymerization of microspheres (100 - 300 μm) intended to be loaded according to the present invention Pour an aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride into a reactor and heat it to 50 °C. Next, supply an organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinking agent), methacrylic acid (MA) (ionizable monomer), hexanethiol (HT) (transfer agent), violet dye (1-(4-((2-methacryloxyethyl)oxy)phenylamino)anthraquinone), a suspension agent for iron nanoparticles, and AIBN (initiator) dissolved in toluene to the reactor. Apply stirring using a propeller-type stirrer at a speed suitable for obtaining droplets of a desired diameter. Next, increase the temperature to 80 °C and continue stirring for 8 hours. Next, filter the mixture, wash the microspheres with acetone and then with water, sieve them, and then autoclave them.

[0225] Table 2 below presents the main parameters and compositions of the organic and aqueous phases.

[0226] [Table 2]

[0227] Example 8-2: Synthesis by direct suspension polymerization and evaluation of loading capacity of microspheres (MS) (900 - 1200 μm) without an ionizable monomer according to the present invention Synthesis of microspheres of 900 - 1200 μm Pour an aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride into a reactor and heat it to 50 °C. Next, feed an organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinking agent), colored monomer, hexanethiol (migration agent), and AIBN (initiator) dissolved in toluene into the reactor. Apply stirring using a propeller-type stirrer at a speed suitable for obtaining droplets of a desired diameter. Next, increase the temperature to 80 °C and continue stirring for 12 hours. Next, filter the mixture through a 40 μm sieve and collect the microspheres. Next, wash the microspheres retained by the sieve three times with acetone and then three times with water. Next, sieve these washed microspheres between a 900 μm sieve and a 710 μm sieve. Next, sterilize the microspheres collected between these two sieves in an autoclave at 121 °C for 20 minutes, which will have the effect of swelling the microspheres to obtain microspheres of a desired size, i.e., 900 - 1200 μm in this case. Next, the microspheres synthesized by the above method have the following composition:

[0228] Table 3 below presents the main parameters and compositions of the organic and aqueous phases.

[0229] [Table 3]

[0230] Characterization: The dry extract (dry weight) is determined as follows: Place 1 ml of the deposited MS in a 5 ml Eppendorf vial, freeze it at -80 °C, and lyophilize it overnight in a lyophilizer (Heto PowerDry® LL1500, Thermo Scientific). Next, measure the weight of the microspheres after lyophilization. The measurement was performed on three samples, and the average value was obtained as the final value of the dry mass of the MS.

[0231] The average diameter is measured by analyzing microscopic images of 2000 microspheres (Morphologi 4, Malvern).

[0232] The injectability test in the microcatheter is carried out using 1 mL of a sediment of microspheres pre-suspended in 10 mL of an iodinated contrast agent (70% Optiray® 300, Guerbet, 30% normal saline). Next, a homogeneous suspension of microspheres in a 3 mL syringe is injected with the microcatheter. Microcatheters supplied by Terumo are selected and their inner diameters are made just slightly larger than the average diameter of the microspheres. The resistance felt during the injection of the microspheres with the microcatheter is recorded (Table 3-2). If an occlusion occurs during the injection, it will indicate a failed injection. After injection, the microspheres are observed under a microscope to verify whether the microspheres recover their spherical shape.

[0233]

Table 3-2

[0234] Furthermore, microspheres of 100 - 300 μm are synthesized without methacrylic acid (the same composition as the microspheres in Example 8 having 0% methacrylic acid (MA) and 94.96% m-PEGMA), and then sterilized by autoclaving. Their ability for doxorubicin loading is evaluated and compared with the case of microspheres synthesized as per Example 8.

[0235] Doxorubicin loading: The target of loading is 37.5 mg of doxorubicin per 1 ml of microspheres. Therefore, 3.8 mL of 2.5 mg / mL doxorubicin-HCl (Adriblastine®, Pfizer) in an aqueous solution is added to 250 μL of the wet sediment of microspheres. After mixing by inversion, the suspension is made up to 6 mM with sodium bicarbonate (Lavoisier). The loading is carried out at room temperature and stirred for 1 hour. Measurement of the residual amount of doxorubicin present in the supernatant (absorbance at 490 nm) helps to determine the amount of drug loaded onto the microspheres.

[0236]

Table 4

[0237] The loading efficiency is calculated from the following formula:

Equation

[0238] The loading efficiency in the absence of methacrylic acid is 82.6% compared to 99.6% in the presence of 30% methacrylic acid. The ability of microspheres in the absence of ionizable monomers for doxorubicin loading can be explained by the establishment of hydrophobic or van der Waals bonds. In the presence of ionizable monomers, in addition to these bonds, doxorubicin is loaded by electrostatic bonds. Thereby, the kinetics and loading capacity are improved.

[0239] Example 9: Synthesis by direct suspension polymerization of a polymer containing 5% MAOETIB according to the invention in the form of microspheres with a size of 700 - 900 μm An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 °C. Next, an organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinking agent), methacrylic acid (MA) (ionizable monomer), MAOETIB (halogenated monomer), hexanethiol (transfer agent), violet dye (1-(4-((2-methacryloxyethyl)oxy)phenylamino)anthraquinone), and AIBN (initiator) dissolved in toluene is fed into the reactor. Stirring is applied using a propeller-type stirrer at a speed suitable to obtain droplets of the desired diameter. Next, the temperature is increased to 80 °C and stirring is continued for 12 hours. Next, the mixture is filtered, and the microspheres are washed with acetone and then with water, sieved, and then autoclaved.

[0240] Table 5 below presents the main parameters and composition of the organic phase.

[0241] [Table 5]

[0242] Example 10: Suspension of the microspheres from Example 9 in a 50 / 50 mixture of contrast agent and normal saline, and comparison with the corresponding microspheres in the absence of MAOETIB 2 mL of the bead sediment is added to 10 mL of a 50 / 50 mixture of normal saline / contrast agent (5 mL of Optiray® 300 mg / mL and 5 mL of normal saline). Using a 20 mL syringe, the mixture is passed through a three-way stopcock 5 times.

[0243] Next, position the syringe containing the mixture vertically and observe the destabilization of the mixture; then raise the microspheres to the surface. Measure the time corresponding to the case where the destabilization interface reaches the middle height of the syringe.

[0244] In the case of particles sized 700 - 900 μm without MAOETIB, this time is 20 seconds, while in the case of particles containing 5% MAOETIB, it is 120 seconds. This destabilization time further increases to 220 seconds when 7% MAOETIB is added.

[0245] The presence of MAOETIB enables the suspension to be stabilized.

[0246] Example 11: Synthesis by direct suspension polymerization of various species of polymers in the form of microspheres sized 700 - 900 μm Synthesis Pour an aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride into the reactor and heat it to 50°C. Next, feed an organic phase containing a hydrophilic monomer, a crosslinking agent, a coloring monomer, a migrating agent, a halogenated monomer if applicable, an ionizable monomer if applicable, and AIBN (initiator) dissolved in toluene into the reactor. Apply stirring using a propeller-type stirrer at a speed suitable for obtaining droplets of the desired diameter. Then, increase the temperature to 80°C and continue stirring for 12 hours. Next, filter the mixture through a 40 μm sieve and collect the microspheres. Then, wash the microspheres retained by the sieve three times with acetone and then three times with water. Next, sieve these washed microspheres between a 900 μm sieve and a 710 μm sieve. Then, sterilize the microspheres collected between these two sieves in an autoclave at 121°C for 20 minutes, which will have the effect of swelling the microspheres and obtaining microspheres of the desired size, i.e., 700 - 900 μm in this case. Table 6 below presents the main parameters and composition of the organic phase.

[0247]

Table 6

[0248] Characterization and results: Perform the characterization in the same manner as in Example 8-2 and present the results in Table 7.

[0249] [Table 7]

[0250] Example 12: Synthesis by direct suspension polymerization of polymers containing different amounts of MAOETIB according to the present invention in the form of microspheres with a size of 100 - 300 μm Synthesis: Pour an aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride into the reactor and heat to 50 °C. Next, an organic phase containing poly(ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEGDMA) (crosslinking agent), methacrylic acid (MA) (ionizable monomer), MAOETIB (halogenated monomer), hexanethiol (transfer agent), violet dye (1-(4-((2-methacryloxyethyl)oxy)phenylamino)anthraquinone), and AIBN (initiator) dissolved in toluene is fed into the reactor. Apply stirring using a propeller-type stirrer at a speed suitable for obtaining droplets of the desired diameter. Next, increase the temperature to 80 °C and continue stirring for 12 hours. Next, filter the mixture, wash the microspheres with acetone and then with water, sieve them, and then autoclave them.

[0251] The following Table 8 presents the main parameters and composition of the organic phase.

[0252] [Table 8]

[0253] Example 13: Suspension of microspheres from Example 12 having different levels of MAOETIB in a 50 / 50 mixture of contrast agent and normal saline Add 2 mL of the bead sediment to 10 mL of a 50 / 50 mixture of normal saline / contrast agent (5 mL of Xenetix® 350 mg / mL and 5 mL of normal saline). Using a 20 mL syringe, pass the mixture through a three-way stopcock five times. Next, position the syringe containing the mixture vertically and observe the destabilization of the mixture either through foaming or sedimentation, depending on the concentration of MAOETIB. Measure the time corresponding to the case where the destabilization interface reaches the mid-height of the syringe. Present the results in Table 9.

[0254] [Table 9]

[0255] The addition of a small amount of MAOETIB makes it possible to delay foaming by bringing the density of the microspheres closer to the density of the suspension medium. However, beyond a certain concentration, the density of the microspheres increases excessively and they sediment rapidly.

Claims

1. A crosslinked polymer matrix comprising at least: a) N-vinylpyrrolidone and 20% to 95% of a hydrophilic monomer selected from the monomers of the following formula (I): (CH ２ =CR １ )-CO-D (I) (wherein - D represents O-Z or NH-Z, and Z is (C １ ~C ６ ), alkyl, -(CR ２ R ３ ), ｍ -CH ３ , -(CH ２ -CH ２ -O) ｍ -H, -(CH ２ -CH ２ -O) ｍ -CH ３ , -C(R ４ OH) ｍ or -(CH ２ ), ｍ -NR ５ R ６ , where m represents an integer from 1 to 30; ・R １ 、R ２ 、R ３ 、R ４ 、R ５ and R ６ are, independently of each other, H or (C １ ~C ６ ) alkyl). 20% to 95% of a hydrophilic monomer selected from the monomers b) 1% to 15% of a non-biodegradable linear or branched hydrophilic crosslinking monomer of the following formula (IIa) or (IIb): (CH ２ = (CR ７ ))CO-NH-A-HN-OC(CR ８ = CH ２ )(IIa), (CH ２ = (CR ７ ))CO-O-A-O-OC(CR ８ = CH ２ )(IIb) (wherein, R ７ and R ８ are each independently H or (C １ - C ６ ) alkyl; and A, alone or together with at least one of the atoms to which it is bonded, represents (C １ -C ６ ) alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A) and c) 1.5% to less than 6% of a mobile agent selected from alkyl halides and alicyclic or aliphatic thiols, particularly those having 2 to 24 carbon atoms, and optionally having another functional group selected from amino groups, hydroxy groups and carboxy groups A non-biodegradable embolic microsphere comprising a crosslinked matrix based on the above, wherein the percentages of the monomers a) and b) are given in molar units compared to the total number of moles of the monomers, and the percentage of the compound c) is given in molar units compared to the number of moles of the hydrophilic monomer a).

2. The non-biodegradable embolic microsphere according to claim 1, wherein the crosslinked matrix is based on 1.5% to 4.5%, preferably 1.5% to 3%, more preferably 3% of a mobile agent in molar units compared to the number of moles of the hydrophilic monomer a).

3. The hydrophilic monomer a) is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl (methyl) acrylate, N,N-dimethylaminopropyl (meth) acrylate, t-butylaminoethyl (methyl) 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 and mixtures thereof, and advantageously the monomer a) is poly(ethylene glycol) methyl ether methacrylate. The non-biodegradable embolic microsphere according to any one of claims 1 to 2.

4. ​ The non-biodegradable embolization microspheres according to any one of claims 1 to 3, wherein the moving agent is selected from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof.

5. The matrix further has the following formula (II): (CH ２ =CR ９ ) - M - E (III) (wherein, ・R ９ represents H or (C １ ~C ６ ) alkyl; - M represents a single bond or a divalent free radical having 1 to 20 carbon atoms, preferably a single bond; - E represents an ionized or ionizable group, and E is preferably COOH, COO−, SO ３ H, SO ３ － , PO ４ H ２ , PO ４ H － , PO ４ ２－ , NR １０ R １１ , NR １２ R １３ R １４ ＋ selected from the group consisting of ·R １０ 、R １１ 、R １２ 、R １３ and R １４ are, independently of one another, H or (C １ ~C ６ ) alkyl). The non-biodegradable embolization microspheres according to any one of claims 1 to 4, based on at least one ionized or ionizable monomer of.

6. The non-biodegradable embolization microspheres according to claim 5, which are loaded with a drug, an active substance, a diagnostic agent, or a polymer, and the drug, the active substance, and the diagnostic agent preferably have a molecular weight of less than 5000 Da, preferably less than 1000 Da.

7. The non-biodegradable embolization microspheres containing the crosslinked matrix according to claim 6, wherein the drug or the active substance is selected from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anti-cancer agents, steroids, disinfectants, and mixtures thereof.

8. The polymer is an enzyme, an antibody such as anti-PD-1 such as nivolumab or pembrolizumab, anti-PD-L1 such as avelumab, durvalumab, or atezolizumab, anti-CTLA-4 such as ipilimumab or tremelimumab, cytokine, growth factor, coagulation factor, hormone, plasmid, antisense oligonucleotide, siRNA, ribozyme, DNA enzyme, aptamer, anti-inflammatory protein such as infliximab and rilonacept, bone morphogenetic protein (BMP), angiogenesis promoting factor such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), TGFβ, and angiogenesis inhibitors such as bevacizumab, ramucirumab, nesvacumab, olaparib, vanucizumab, rilotumumab, emibetuzumab, aflibercept, ficlatuzumab, pegaptanib, or anti-tyrosine kinase such as lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, sulfatinib, dovetinib, linifanib, and mixtures thereof. The non-biodegradable embolization microspheres according to claim 6, selected from the group consisting of.

9. The matrix further has the following general formula (V): 【Chemical 1】 (In the formula, ·Z １ and Z ２ each independently represents H or OR ２６ wherein R ２６ represents H or (C １ ~C ６ alkyl), and preferably Z １ and Z ２ represent H; - X represents H or a halogen such as Cl, preferably H; ・R ２４ is a linear or branched group selected from (C １ ~C ６ ) alkylene, (C ５ ~C ３６ ) arylene, (C ５ ~C １８ ) arylene - O - R ２７ 、(C ５ ~C １８ ) heteroarylene and (C ５ ~C １８ ) heteroarylene - O - R ２８ , where R ２７ and R ２８ represent (C １ ~C ６ ) alkyl or (C １ ~C ６ ) alkylene. Advantageously, R ２４ represents - C ６ H ４ -O-(CH ２ ) ２ - group or - C(CH ３ ) ２ -CH ２ - group, ・R ２５ is H or (C １ ~C ６ )alkyl, preferably (C １ ~C ６ )alkyl, especially methyl). is based on at least one coloring monomer, and preferably, the coloring monomer has the formula (Vb): [[Chemical Formula 2]] The non-biodegradable embolization microspheres according to any one of claims 1 to 8, corresponding to

10. The matrix further has 5% to 15%, preferably 5% to 7% of a halogenated monomer, preferably an iodinated monomer, particularly of the formula (IV): (CH ２ =CR １５ )-CO-Y (IV) (In the formula, - Y is O-W, (O-R １６ ) ｐ - W, (NH-R １６ ) ｐ - W or NH-W, where W represents Ar, L-Ar, p is an integer between 1 and 10, preferably between 1 and 4, and where: ・ Ar is a (C ５ ~C ３６ ) aryl group or a (C ５ ~C ３６ ) heteroaryl group, said group being substituted with one, two or three atoms of iodine and / or bromine, and optionally substituted with one to four, preferably two or three groups selected from (C １ ~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 、-N ｒ CONR ｓ R ｔ 、-OCOOR ｕ 、and -COR ｖ ; ・ L is, -(CH ２ ) ｎ -, -(HCCH)-, -O-, -S-, -SO-, -SO ｎ -, -OSO ２ ２ － １７ -, -CO-, -COO-, -OCO-, -OCOO-, -CONR １８ -, -NR １９ CO-, -OCONR ２０ -, -NR ２１ COO- or -NR ２２ CONR ２３ -, and n is an integer from 1 to 10;​​ ・R １７ ~R ２３ and R ａ ~R ｖ are, independently of one another, a hydrogen atom, (C １ ~C １０ )alkyl, and the (C １ ~C １０ )alkyl is optionally substituted with 1 to 10 OH' groups, or -(CH ２ -CH ２ -O) ｑ -R' group, where R' is a hydrogen atom or -(C １ ~C ６ )alkyl, and q is an integer between 1 and 10, preferably between 1 and 5; ・R １５ represents H or (C １ ~C ６ ) alkyl; ・R １６ is a group selected from (C １ ~C ３６ ) alkylene, (C ３ ~C ３６ ) cycloalkylene, (C ２ ~C ３６ ) alkenylene, (C ３ ~C ３６ ) cycloalkenylene, (C ２ ~C ３６ ) alkynylene, (C ３ ~C ３６ ) cycloalkynylene, (C ５ ~C ３６ ) arylene and (C ５ ~C ３６ ) heteroarylene) is based on the monomer of, and the percentage of the halogenated monomer is given in molar units compared to the total number of moles of the monomers. The non-biodegradable embolization microspheres according to any one of claims 1 to 9 heres.

11. The halogenated monomer has the following formula: [Chemical 3] The non-biodegradable embolization microspheres containing a crosslinked matrix containing at least one halogenated monomer according to claim 10, corresponding to (triiodobenzoyl) oxoethyl methacrylate (MAOETIB) of

12. The matrix further has particles visible by magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, preferably based on iron oxide nanoparticles. The non-biodegradable embolization microspheres containing a crosslinked matrix according to any one of claims 1 to 11

13. A pharmaceutical composition containing the non-biodegradable embolization microspheres according to any one of claims 1 to 12, preferably accompanied by a pharmaceutically acceptable medium intended for parenteral administration, a pharmaceutical composition.

14. A kit containing the pharmaceutical composition as defined in claim 13, accompanied by a pharmaceutically acceptable medium intended for parenteral administration and at least one injection means, a kit.

15. On the one hand, a pharmaceutical composition as defined in claim 13, and on the other hand, a kit containing at least one contrast agent for imaging by X-ray, magnetic resonance or ultrasound examination, and optionally at least one injection means intended for parenteral administration, wherein the pharmaceutical composition and the at least one contrast agent are packaged separately, a kit.

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