HK40120249A - Radiopaque monomer and embolisation microspheres comprising same - Google Patents

Description

Radiopaque monomers and embolic microspheres containing them

Technical Field

This invention relates to a novel halogenated radiopaque monomer, particularly intended for use in cross-linked matrices contained in embolization microsphere compositions.

Background Technology

Therapeutic vascular occlusion (i.e., embolization) is used to prevent or treat certain pathological conditions in situ. It can be performed via catheter, allowing the placement of microparticle blocking agents (i.e., emboli or embolic agents) into the circulatory system under imaging control. It has a variety of medical applications, such as treating vascular malformations, bleeding processes, or tumors, including, for example, uterine fibroids and primary or secondary liver tumors. For example, vascular occlusion can induce tumor necrosis and avoid more invasive surgery. In the context of chemoembolization, this occlusion technique can also be combined with the delivery of anticancer agents. This allows for increased local drug concentration and its residence time in the tumor while limiting systemic drug exposure through targeted injection. In cases of vascular malformations, vascular occlusion allows for the normalization of blood flow to normal tissues, assisting surgery by limiting the risk of bleeding. During bleeding processes, vascular occlusion can help reduce flow velocity, thereby promoting arterial wound healing. Furthermore, depending on the pathology being treated, embolization can be used for temporary or permanent purposes.

Embolizing agents are routinely introduced into blood vessels via catheters, particularly microcatheters, with a diameter smaller than that of the vessel to be treated. Embolizing agents used for vascular occlusion include, for example, embolic fluids (acrylic adhesives, gels), mechanical devices, particles, and polymeric embolic microspheres. The choice of specific material depends on many factors, such as the type of lesion to be treated, the type of catheter to be used, and whether temporary or permanent embolization is required.

Polymer-based embolic microspheres are particularly useful for the aforementioned therapeutic purposes. They can be biodegradable for temporary embolization, as described in patent applications WO 2012/120139 and WO 2012/120138, or non-biodegradable for permanent embolization.

For example, the product (Biosphere Medical) corresponds to non-biodegradable microspheres based on tripropylene (N-acryloyl-2-amino-2-hydroxymethylpropane-1,3-diol) and gelatin. The use of non-biodegradable microspheres based on acrylic copolymers and polyvinyl alcohol (PVA) for permanent embolization has also been proposed (Osuga et al. (2002) J. Vasc. Interv. Radiol. [Journal of Vascular and Interventional Radiology] 13:929-34).

Furthermore, to make them visible in X-ray imaging, the embolization microspheres can be made radiopaque by adding radiopaque substances or monomers to the composition of the microspheres. Such radiopaque embolization microspheres are described in patent applications WO 2021/069527 and WO 2021/069528. The microspheres in these patent applications incorporate a radiopaque monomer called MAOETIB having the following formula:

Transmissivity refers to the fact that electromagnetic radiation, particularly X-rays, cannot penetrate dense materials described as "transmissive," appearing opaque/white in X-ray images. Given the complexity of the contents in X-ray or fluorescence fluoroscopy images, clinicians are sensitive to image quality in terms of the brightness or signal intensity of the material in the image. Two main factors influencing the importance of transmissivity are density and atomic number. Polymer-based medical devices requiring transmissivity typically use polymer blends incorporating small amounts (by weight percentage) of transmissive elements, such as heavy atoms like halogens, particularly iodine. The device's ability to be visualized by fluorescence microscopy depends on the amount or density of transmissive elements incorporated into the material. However, the addition of transmissive substances or monomers with halogenated groups appears to significantly reduce the material's hydrophilicity. Moreover, the increased density of microspheres incorporating one or more of these types of transmissive monomers or substances affects their suspension properties in the injection medium. In summary, prior art iodine-filled microspheres for X-ray visibility are typically more hydrophobic, denser, and rigid than non-X-ray visible microspheres and tend to form microsphere aggregates. Therefore, (1) they are difficult to keep suspended in the catheter during the duration of injection, and (2) they often clog the catheter, even when their diameter is smaller than the inner diameter of the catheter (Duran 2016), for example, because they are more likely to clump together, and (3) they tend to adhere to the catheter wall.

Therefore, it is preferable to include radiopaque substances or monomers in the composition of the embolic microspheres to ensure that the microspheres remain hydrophilic and flexible upon swelling in water. These microspheres are also expected to possess mechanical properties suitable for injection via catheters or microcatheters, particularly swelling capacity, elasticity, and compressibility. Furthermore, it is desirable that these microspheres remain suspended in the catheter within the injection mixture (a composite mixture of contrast agent product and aqueous phase) for the duration of injection. Specifically, for injectability and to allow physicians to track the injection under X-ray control, the microspheres are typically suspended in a mixture of nonionic iodinated contrast agent product and aqueous phase. For this purpose, radiologists typically use a contrast agent product solution and, optionally, saline, bicarbonate buffer, or phosphate buffer, advantageously a 100% contrast agent product solution. To ensure their injectability, the microspheres must remain uniformly suspended in this solution. If the microspheres settle or, conversely, float on the surface of the solution, the resulting suspension is non-uniform, unstable, and therefore cannot be injected into the patient.

Patent applications WO 2021/069527 and WO 2021/069528 describe halogenated radiopaque monomers that can satisfactorily meet these requirements. However, there remains a need for novel radiopaque monomers or substances intended for use in the preparation of embolic microspheres, which provide, for example, better performance in terms of the stability or injectability of suspensions containing said microspheres, while maintaining compatibility with iodinated contrast agents as described above.

Summary of the Invention

In this context, the inventors have developed a novel halogenated radiopaque monomer of formula (A) that improves the performance of embolic microspheres contained in their compositions. For example, this novel radiopaque monomer of formula (A) particularly prevents embolic microspheres containing it from agglomerating in catheters or microcatheters prior to injection. The presence of this novel halogenated radiopaque monomer of formula (A) in the embolic microspheres also prevents the microspheres from adhering to the walls of catheters or microcatheters prior to injection. Moreover, the suspension and injectability of these microspheres are improved by means of this novel radiopaque monomer.

For the purposes of this invention, the term "improved suspension" refers to the ability of the microspheres to form a suspension that is stable and uniform over a period of time compatible with the use of the microspheres, i.e., the microspheres have the same distribution at all points in the suspension volume.

For the purposes of this invention, the term "improved injectability" means the ability of a suspension to be injected via an injection system (such as a syringe or catheter) without creating a plug and without requiring a large amount of force from the physician's perspective.

Therefore, the present invention relates to a compound having the following formula (A):

In this specification, the compound is also referred to by the term MAETIP.

Another subject of the present invention relates to the use of compounds having formula (A) as defined above as radiopaque halide monomers.

Another subject of the invention relates to embolic microspheres comprising the halogenated radiopaque monomer having formula (A).

Therefore, the present invention also relates to the use of the compound having formula (I) in embolic microspheres.

The present invention also relates to pharmaceutical compositions comprising a combination of embolic microspheres as defined above and a pharmaceutically acceptable carrier, advantageously for administration by injection.

The subject of this invention is also a kit comprising a pharmaceutical composition as defined above and at least one device for injecting the composition for parenteral administration.

The subject of this invention is also a reagent kit, which firstly comprises a pharmaceutical composition as defined above, and secondly comprises a contrast agent for X-ray, magnetic resonance, or ultrasound imaging, and optionally at least one syringe for parenteral administration; advantageously, the syringe is a device as described in patent applications WO 2016/166346, WO 2016/166339, WO 2017/005914 and WO 2017/081178.

Detailed Implementation

Therefore, the main subject of this invention is compounds having the following formula (A):

In the compound having formula (A), iodine atoms are located at positions 2, 4, and 6 of the benzene ring. Due to the size of the iodine atoms and their uniform distribution on the phenyl ring, this compound provides reduced steric accessibility to the aromatic carbons (at positions 3 and 5 of the phenyl ring) compared to compound (Vb) in MAOETIB or patent application WO 2021/069528 (where iodine atoms are at positions 2, 3, and 5 of the phenyl ring and aromatic carbons are at positions 4 and 6 of the phenyl ring). The restricted accessibility of aromatic carbons in the compound having formula (A) appears to have a reducing effect on the lipophilicity of the molecule. Specifically, intermolecular or intramolecular interactions of these carbons are reduced or even absent, thereby limiting the stickiness of the molecule. In other words, the spatial configuration of the compound having formula (A) helps prevent embolic microspheres incorporated into the compound from agglomerating together.

According to the invention, the compound having formula (A) is advantageously used as a radiopaque halide monomer. Therefore, the subject matter of the invention remains the use of the compound having formula (A) as a radiopaque halide monomer, as defined above.

Furthermore, the present invention relates to embolic microspheres comprising the halogenated radiopaque monomer having formula (A). Specifically, the embolic microspheres comprise a cross-linked polymer matrix comprising the halogenated radiopaque monomer having formula (A).

In a particular embodiment, the crosslinked polymer matrix is as defined in patent application WO 2021/069528, except that the halogenated radiopaque monomer having general formula (II) is replaced by a compound having formula (A) according to the invention. In other words, the crosslinked polymer matrix is based at least on the following:

a) 20% to 90% hydrophilic monomers selected from N-vinylpyrrolidone and monomers having the following formula (I):

( _CH₂ ＝ _CR₁ )-CO-D(I)

in:

• D represents OZ or NH-Z, Z represents ( _C1 - _C6 ) _alkyl , -( _CR2R3 ) _mCH3 , -CH-( _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 , preferably, m equals 4 or 5.

_R1 , _R2 , _R3 , _R4 , _R5 and _R6 independently represent H or ( _C1 - _C6 ) alkyl;

b) 5% to 50% of compounds having the following formula (A):

c) 1% to 15% of non-biodegradable linear or branched hydrophilic crosslinked monomers, each terminal of which is attached with a ( _CH2 =( _CR16 ))- group, each _R16 independently representing an H or ( _C1 - _C6 ) alkyl group; and

d) 0.1% to 10% of a transfer agent selected from alkyl halides and alicyclic or aliphatic thiols, particularly containing 2 to 24 carbon atoms and optionally carrying another functional group selected from amino, hydroxyl, and carboxyl groups.

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

The hydrophilic monomer of formula (I), the crosslinking monomer (c) and the transfer agent (d) are advantageously as defined in patent application WO 2021/069528, particularly on pages 13 and 19-22.

For the purposes of this invention, the term "hydrophilic monomer" refers to a monomer that has a high affinity for water, that is, a monomer that tends to dissolve in water, mix with water, be wetted by water, or swell in water after polymerization.

For the purposes of this invention, the term "crosslinking monomer" refers to a monomer that is at least bifunctional, but also multifunctional, and has a double bond at each polymerizable end. Combinations of crosslinking monomers with other monomers in a mixture allow for the formation of a crosslinked network. Those skilled in the art can readily select the structure and amount of one or more crosslinking monomers in the monomer mixture to provide the desired crosslinking density. Crosslinking agents are also advantageous for the stability of the microspheres. Crosslinking agents prevent the microspheres from dissolving in any solvent. Crosslinking agents also allow for improved compressibility of the microspheres, which is advantageous for embolization.

For the purposes of this invention, the term "non-biodegradable hydrophilic crosslinking agent" means a crosslinking agent as defined above, which has a high affinity for water and cannot be degraded in mammals, particularly in humans, under physiological conditions. Specifically, when a molecule contains sufficient functional sites, biodegradation of the molecule is permitted; these functional sites can be cleaved under physiological conditions, particularly by endogenous enzymes in mammals, especially humans, and/or at physiological pH (typically about 7.4). Physiologically cleavable functional sites particularly include amide bonds, ester bonds, and acetals. Therefore, molecules containing insufficient numbers of these functional sites will be considered non-biodegradable. In the context of this invention, a crosslinking monomer contains fewer than 20 physiologically cleavable functional sites, preferably fewer than 15 sites, more preferably fewer than 10 sites, and even more preferably fewer than 5 sites.

In the context of this invention, the term "transfer agent" refers to a compound containing at least one weak chemical bond. This agent reacts with the radical sites of a growing polymer chain and interrupts chain growth. During chain transfer, the radical is temporarily transferred to the transfer agent, which restarts growth by transferring the radical to another polymer or monomer.

The term "matrix based on..." should naturally be understood to include a matrix comprising a mixture of basic components and/or reaction products for heterogeneous medium polymerization of the matrix, preferably only including reaction products between different basic components for the matrix, some of which may be intended to react or readily react with each other or with their closely related chemical environment at least partially during various stages of the matrix manufacturing process, particularly during the polymerization step. Thus, the basic components are agents intended to react together during matrix polymerization. Therefore, the basic components are introduced into the reaction mixture, which optionally further comprises a solvent or solvent mixture 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 this invention, the reaction mixture comprises at least the monomers a), b), c) and transfer agent d) mentioned herein as base components, optionally with polymerization initiators such as tert-butyl peroxide, benzoyl peroxide, azobis(4-cyanopentanoic acid) (also known as 4,4′-azobis(4-cyanopentanoic acid)), AIBN (azobisisobutyronitrile), or 1,1′-azobis(cyclohexanecarboxynitrile), or one or more thermal initiators such as 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylphenylacetone (106797-5). 3-9); 2-hydroxy-2-methylphenylacetone (1173, 7473-98-5); 2,2-dimethoxy-2-phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenylacetophenone (24650-42-8) or 2-methyl-4′-(methylthio)-2-morpholinophenylacetone (71868-10-5), and at least one solvent, preferably a mixture of an aqueous solvent and an organic solvent (such as a nonpolar aprotic solvent), for example, an immiscible water/toluene system.

Therefore, according to the present invention, the matrix is based at least on the monomers a), b), c) and transfer agent d) mentioned in this specification, and these compounds are the basic components.

Therefore, in this specification, expressions such as "[base component X] is added to the reaction mixture in an amount of YY% to YYY%" and "the crosslinking matrix is based on an amount of YY% to YYY% of [base component X]" are interpreted similarly. Similarly, expressions such as "the reaction mixture contains at least [base component X]" and "the crosslinking matrix is based at least on [base component X]" are interpreted similarly.

For the purposes of this invention, the term "organic phase" in the reaction mixture means a phase comprising an organic solvent and compounds soluble in the organic solvent, particularly monomers, transfer agents, and polymerization initiators.

For the purposes of this invention, the term "(C_{_X}-C_{_Y})alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon chain containing X to Y carbon atoms, where X and Y are integers between 1 and 36, preferably between 1 and 18, and particularly between 1 and 6. By way of example, the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, or hexyl may be mentioned.

In the context of this invention, the compound having formula (A) is added to the reaction mixture in an amount of 5% to 50% molar relative to the total molar number of monomers, in an amount of greater than 7% and less than or equal to 50%, in an amount of greater than 10% and less than or equal to 50%, more particularly in an amount of greater than 15% and less than or equal to 50%, preferably in an amount of greater than 15% and less than or equal to 35%, and particularly in an amount of 20% to 30%.

Embolic microspheres comprising a cross-linked polymer matrix as defined above advantageously correspond to spherical particles with swollen diameters ranging from 20 to 1200 μm, for example 20 to 100 μm, 40 to 150 μm, 100 to 300 μm, 300 to 500 μm, 500 to 700 μm, 700 to 900 μm, or 900 to 1200 μm, as determined by optical microscopy. The microspheres advantageously have a sufficiently small diameter for injection via needles, catheters, or microcatheters with inner diameters ranging from several hundred micrometers to greater than one millimeter.

The phrase "after swelling" refers to the size of the microspheres after the polymerization and sterilization steps during microsphere preparation. The sterilization step involves, for example, placing the polymerized microspheres in a high-temperature autoclave, typically at a temperature above 100°C, preferably between 110°C and 150°C, and most preferably 121°C. During this sterilization step, the microspheres continue to swell in a controlled manner, i.e., exhibit a controlled degree of swelling. The degree of swelling is defined as:

Where _mw is the weight (in grams) of 1 ml of settled microspheres, and _md is the weight (in grams) of 1 ml of settled microspheres that were subsequently freeze-dried.

In a specific embodiment of the invention, the crosslinked polymer matrix of the microspheres is based solely on the basic components a), b), c), and d) as defined above in the proportions of the monomers and transfer agents described above, without adding any other basic components to the reaction mixture. Therefore, it is evident that the sum of the above proportions of monomers a), b), and c) must equal 100%.

Preferably, the hydrophilic monomer having formula (I) is selected from the group consisting of: N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, tert-butyl acrylate, tert-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl methacrylate, N,N-dimethylaminopropyl methacrylate, tert-butylaminoethyl methacrylate, N,N-diethylaminoacrylate, poly(ethylene oxide)(meth)acrylate, methoxy poly(ethylene oxide)(meth)acrylate, butoxy poly(ethylene oxide)(meth)acrylate, poly(ethylene glycol)(meth)acrylate, methoxy poly(ethylene glycol)(meth)acrylate, butoxy poly(ethylene glycol)(meth)acrylate, poly(ethylene glycol) methyl ether methacrylate, and mixtures thereof.

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

In the context of this invention, the hydrophilic monomer a) is added to the reaction mixture in an amount of 20% to 90%, preferably 30% to 80%, more preferably 40% to 70%, and particularly 45% to 65% relative to the total molar amount of the monomer. Therefore, in the context of this invention, the crosslinking matrix is specifically based on an amount of hydrophilic monomer a) in an amount of 20% to 90%, preferably 30% to 80%, more preferably 40% to 70%, and particularly 45% to 65% relative to the total molar amount of the monomer.

Advantageously, the straight-chain or branched non-biodegradable hydrophilic crosslinked monomer has at least two ( _CH2 =( _CR16 ))CO- or ( _CH2 =( _CR16 ))CO-O- groups at its two ends, wherein each _R16 independently represents H or ( _C1 - _C6 ) alkyl.

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

(CH ₂ =(CR ₁₆ ))CO-NH-A-HN-OC((CR ₁₆ )=CH ₂ )(IIIa),

(CH ₂ =(CR ₁₆ ))CO-OAO-OC((CR ₁₆ )=CH ₂ )(IIIb),

in

Each R ₁₆ independently represents H or (C ₁ -C ₆ ) alkyl; advantageously, the groups R ₁₆ are identical and represent H or (C ₁ -C ₆ ) alkyl; and

A alone or together with at least one of the atoms it is bonded to represents ( _C1 - _C6 ) alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A.

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

(CH ₂ =(CR ₁₆ ))CO-NH-A-HN-OC((CR ₁₆ )=CH ₂ )(IIIa),

(CH ₂ =(CR ₁₆ ))CO-OAO-OC((CR ₁₆ )=CH ₂ )(IIIb),

in,

Each R ₁₆ independently represents H or (C ₁ -C ₆ ) alkyl; advantageously, the groups R ₁₆ are identical and represent H or (C ₁ -C ₆ ) alkyl; and

Preferably, A, alone or together with at least one of the atoms it is bonded to, represents ( _C1 - _C6 ) alkyl or polyethylene glycol (PEG), preferably polyethylene glycol (PEG).

In the context of the definition of A above, polyethylene glycol has a length in the range of 200 to 10000 g/mol, preferably 200 to 2000 g/mol, and more preferably 500 to 1000 g/mol.

Examples of crosslinking monomers that can be used in the context of this invention may include (but are not limited to): 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylene bisacrylamide, glycerol 1,3-diglyceride diacrylate, and poly(ethylene glycol) dimethacrylate (PEGDMA).

Advantageously, the crosslinking monomer is poly(ethylene glycol) dimethacrylate (PEGDMA), and the polyethylene glycol unit has a length in the range of 200 to 10000 g/mol, preferably 200 to 2000 g/mol, more preferably 500 to 1000 g/mol.

In the context of this invention, the crosslinking monomer is added to the reaction mixture in an amount of 1% to 15%, preferably 2% to 10%, particularly 2% to 7%, and more particularly 2% to 5% relative to the total molar amount of the monomer.

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

Alkyl halides that can be used as chain transfer agents particularly include chloroform, tetrachloromethane, and tetrabromomethane. Particularly advantageously, the chain transfer agent is an alicyclic or aliphatic thiol that typically contains 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 6 carbon atoms, and optionally additional functional groups selected from amino, hydroxyl, and carboxyl groups.

Advantageously, the transfer agent is selected from mercaptoacetic acid, 2-mercaptoethanol, dodecyl mercaptan, hexamethylene mercaptan, and mixtures thereof.

In the context of this invention, the transfer agent is particularly added to the reaction mixture in the following amounts relative to the moles of the hydrophilic monomer a): 0.1 mol% to 10 mol%, preferably 0.5 mol% to 8 mol%, more advantageously 1.5 mol% to 6 mol%, and particularly 1.5 mol% to 4.5 mol%, and particularly 3 mol%.

In another specific embodiment of the invention, the crosslinked polymer matrix of the microspheres of the invention is further based on:

- Ionized or ionizable monomers, and/or

- Monomers with color to make them visible to the naked eye, so as to check, for example, whether the microsphere suspension is uniform in the syringe before injection and to control the injection speed, and/or

- At least one reagent that is visible through magnetic resonance imaging (MRI).

The colored ionized or ionizable monomers, and MRI-visible reagents, are defined, in particular, as in patent application WO 2021/069528, especially on pages 22-25.

In particular, the crosslinked polymer matrix of the embolic microspheres of the present invention can also be based on at least one ionized or ionizable monomer having the following formula (IV):

(CH ₂ ＝CR ₁₇ )-ME(IV)

in:

• R ₁₇ indicates H or (C ₁ -C ₆ ) alkyl;

•M represents a single bond or a divalent group containing 1 to 20 carbon atoms;

•E represents a charged or ionizable group containing no more than 100 atoms, and E _is advantageously selected from _the group consisting of: _-COOH ^{, -COO-} , _-SO3H , ^{-SO3- ,} _-PO3H2 , ^-PO3H- , _-PO32- , _{-NR18R19 , -NR20R21R22 + ;}

_R18 , _R19 , _R20 , _R21 , and _R22 independently represent H or ( _C1 - _C6 ) alkyl groups.

For the purposes of this invention, the term "ionized or ionizable group" means a group that is charged or can be in a charged form (as an ion), that is, carrying at least one positive or negative charge, depending on the pH of the medium. For example, a COOH group can be ionized to the form ^COO- , and an _NH2 group can be ionized to the form _NH3 ⁺ .

Introducing ionized or ionizable monomers into the reaction mixture allows for enhanced hydrophilicity of the resulting microspheres, thereby increasing their swelling degree and making them easier to inject via conduits and microcatheters. Furthermore, the presence of ionized or ionizable monomers allows for the loading of active substances into the microspheres.

According to preferred variants, the ionized or ionizable monomer has the following formula (IV-A):

(CH ₂ =CR ₁₇ )-C(O)-O-M'-E(IV)

in:

• R ₁₇ and E are as defined above, and

·M' is a hydrocarbon chain containing 1 to 20 atoms.

Preferably, the ionized or ionizable monomer is advantageously a cationic monomer selected from the group consisting of: methacrylic acid, (methacryloyloxy)ethyl phosphorylcholine, 2-(dimethylamino)ethyl (meth)acrylate, 2-(diethylamino)ethyl (meth)acrylate, 11-methacryloyloxyundecyl phosphoric acid, and 2-((meth)acryloyloxy)ethyl)trimethylammonium chloride; advantageously, the cationic monomer is (diethylamino)ethyl (meth)acrylate. Advantageously, the crosslinking matrix according to the invention is based on the aforementioned cationic monomers in an amount between 1 mol% and 40 mol% relative to the total molar number of monomers. Preferably, when the resulting microspheres are not intended to be filled with an active substance, the crosslinking matrix according to the invention is based on ionized or ionizable monomers in an amount between 5 mol% and 15 mol%, preferably 10 mol%, relative to the total molar number of monomers. According to another embodiment, when the microspheres are intended to be filled with an active substance, the crosslinking matrix according to the invention is obtained by adding between 20 mol% and 40 mol% of an ionized or ionizable monomer relative to the total molar amount of the monomer to the reaction mixture, preferably by adding between 20 mol% and 30 mol% of an ionized or ionizable monomer to the reaction mixture.

In another advantageous embodiment, the ionized or ionizable monomer is advantageously an anionic monomer selected from the group consisting of: acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-oligomers of carboxyethyl acrylate, 3-sulfopropyl (meth)acrylate, 2-((methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide and its potassium salt. Advantageously, the crosslinking matrix according to the invention is based on the aforementioned anionic monomers in an amount between 1 mol% and 40 mol% relative to the total amount of monomers. Preferably, when the resulting microspheres are not intended to be filled with an active substance, the crosslinking matrix according to the invention is based on ionized or ionizable monomers in an amount between 5 mol% and 15 mol%, preferably 10 mol%, relative to the total amount of monomers. According to another embodiment, when the microspheres are intended to be filled with an active substance, the crosslinking matrix according to the invention is based on ionized or ionizable monomers in an amount between 20% and 40%, preferably 20% to 30%, relative to the total amount of monomers.

In a particularly advantageous manner, the ionized or ionizable monomer is methacrylic acid (MA or AM). Advantageously, the crosslinking matrix according to the invention is based on an amount of methacrylic acid (MA) between 10 mol% and 30 mol% relative to the total amount of monomer.

The crosslinked polymer matrix can also be based on at least one colored monomer having the following general formula (VI):

in,

• _Z1 and _Z2 independently represent H or OR ₂₅ , where R ₂₅ represents H or ( _C1 - _C6 ) alkyl; advantageously, _Z1 and _Z2 represent H;

·X represents H or Cl, with H being preferable;

• R ₂₃ represents H or ( _C1 - _C6 ) alkyl, advantageously ( _C1 - _C6 ) alkyl, particularly methyl; and

• R ₂₄ represents a group selected from: straight-chain or branched ( _C1 - _C6 ) alkylene, ( _C5 - _C36 ) arylene, ( _C5 - _C36 ) arylene-OR ₂₆ , (C5-C36) heteroarylene and ( _C5 - _C36 ) heteroarylene-OR ₂₇ , _where R ₂₆ and R ₂₇ represent ( _{C1 - C6} ) alkyl or ( _C1 - _C6 ) alkylene; advantageously, R ₂₄ represents the group _{-C6H4 -} O-( _CH2 ) ₂ -O or -C( _CH3 ) ₂ - _CH2 -O.

For the purposes of this invention, the term "(C _X - C _Y ) alkylene" refers to a divalent, straight-chain or branched hydrocarbon chain containing X to Y carbon atoms, where X and Y are integers between 1 and 36, preferably between 1 and 18, and particularly between 1 and 6. By way of example, the groups methylene, ethylene, propylene, butylene, pentylene, or hexylene may be mentioned.

For the purposes of this invention, the term "(C_{_X}-C_{_Y})heteroaryl" refers to a divalent aromatic group containing X to Y ring atoms, which include one or more heteroatoms, advantageously 1 to 4, and even more advantageously 1 or 2, 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, and particularly between 5 and 10.

For the purposes of this invention, the term "divalent group" refers to a group having a 2-valent charge, that is, having two covalent bonds, polar covalent bonds, or ionic chemical bonds. The group may contain, for example, carbon and/or oxygen atoms.

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

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

In the context of this invention, the colored monomer is particularly added to the reaction mixture in an amount of 0 mol% to 1 mol%, preferably 0 mol% to 0.5 mol%, more particularly 0.02 mol% to 0.2 mol%, and even more particularly 0.04 mol% to 0.1 mol% relative to the total moles of the monomer.

The cross-linked polymer matrix can also be based on elements visible in magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates, or magnesium chelates, with iron oxide nanoparticles being advantageous.

In the context of this invention, the MRI-visible component is advantageously added to the reaction mixture in an amount of 0% to 0.5%, preferably 0.025% to 0.4%, more preferably 0.025% to 0.25%, and especially 0.05% based on the mass of the MRI-visible component per volume of organic phase, in order to obtain MRI-visible and quantifiable microspheres.

The cross-linked polymer matrix of the embolic microspheres of the present invention can be readily synthesized by many methods well known to those skilled in the art. For example, it can be obtained by suspension polymerization as described, particularly on pages 27-29, in patent application WO 2021/069528.

In certain embodiments, the embolic microspheres according to the invention are filled with an active substance, thereby allowing combined vascular occlusion and delivery of the active ingredient. The active substance may be selected from pharmaceuticals, diagnostic agents, and macromolecules, as defined in patent application WO 2021/069528, particularly on pages 29-31.

Preferably, the microspheres according to the invention can be filled with active substances selected from: anticancer agents, anti-inflammatory agents, local anesthetics, analgesics, antibiotics, steroids, preservatives, and mixtures thereof.

The preferred anticancer agents are anthracyclines (such as doxorubicin, epirubicin, or idarubicin), platinum complexes, anthracycline-related compounds (such as mitoxantrone and nemorubicin), antibiotics (such as mitomycin C, bleomycin, and actinomycin D), and other antitumor compounds (such as irinotecan, 5-fluorouracil, sorafenib, sunitinib, regorafenib, brinibril, olatinib, lincitinib, erlotinib, cabozantinib, faritinib, tivantinib, formustin, tauromustine (TCNU), carmustine, cytosine C, cyclophosphamide, cytosine arabinoside (or cytarabine), paclitaxel, docetaxel, methotrexate, and erythromycin). Vimolox PEG-arginine deiminase, tegafur/gemeracil/oteracil combination moparfostat, peretinoin, gemcitabine, bevacizumab, ramucirumab, fluorouridine, immunostimulants such as GM-CSF (granulocyte-macrophage colony-stimulating factor) and their recombinant forms: morastatin or saxaglastin OK-432, interleukin-2, interleukin-4 and tumor necrosis factor-α (TNFα), antibodies, radioactive elements, complexes of these radioactive elements with chelates, nucleic acid sequences, and one or more of these compounds (preferably mixtures of one or more anthracyclines).

Preferably, the anticancer agent is selected from anthracyclines, immunostimulants, platinum complexes, antitumor agents, and mixtures thereof.

Even more preferably, the anticancer agent is selected from anthracyclines, antibodies, antitumor agents, and mixtures thereof.

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

Anti-PD-1 drugs include, for example, nivolumab and pembrolizumab.

Anti-PD-L1 agents include, for example, avelumumab, durvalumab, and atezolizumab.

Anti-CTLA-4 agents include, for example, ipilimumab and trimemumab.

Even more advantageously, anticancer agents are selected from the group consisting of: paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (granulocyte-macrophage colony-stimulating factor), tumor necrosis factor-α (TNFα), antibodies, and mixtures thereof.

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

Anti-inflammatory agents can be selected from ibuprofen, niflunic acid, dexamethasone, naproxen, and mixtures thereof.

In the context of this invention, microspheres can be filled, in particular, by temporary adsorption with macromolecules selected from the group consisting of: enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNases (also known as DNAzymes), aptamers, anti-inflammatory proteins, bone morphogenetic protein (BMP), pro-angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, angiogenesis inhibitors or antityrosine kinases, and mixtures thereof.

Anti-inflammatory proteins include, for example, infliximab or linacicept, and mixtures thereof.

Angiogenic factors include, for example, fibroblast growth factor (FGF) and mixtures thereof.

Angiogenesis inhibitors include, for example, bevacizumab, ramucirumab, nevasuzumab, olarumab, vanucizumab, rituximab, imatozumab, aflibercept, felatuzumab, pilgatanib, and mixtures thereof.

Antityrosine kinases include, for example, lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motraceneib, sildenafil, sofatinib, dovirtinib, linivanib, and mixtures thereof.

Advantageously, the microspheres can be filled with macromolecules selected from antityrosine kinases, TGF-β, angiogenesis inhibitors, and mixtures thereof.

The active material is typically adsorbed onto the cross-linked matrix via non-covalent interactions, optionally in the presence of one or more pharmaceutically acceptable excipients well known to those skilled in the art. This particular method of capturing the active material is referred to as physical encapsulation. There are no particular requirements for the active material to be encapsulated.

Filling can be achieved through many methods well known to those skilled in the art, such as passive adsorption (swelling of the cross-linked matrix in a drug solution) or ionic interactions. These methods are described, for example, in International Patent Application WO 2012/120138, particularly on page 22, line 20 to page 26, line 7. The effectiveness of filling depends primarily on the compatibility and/or favorable interactions between the two structures.

Another subject of the invention relates to pharmaceutical compositions comprising a combination of embolic microspheres according to the invention and a pharmaceutically acceptable carrier, advantageously for administration by injection.

Examples of pharmaceutically acceptable mediators include, but are not limited to, water for injection, saline solutions (also known as physiological saline), starch, hydrogels, polyvinylpyrrolidone, polysaccharides, hyaluronic acid esters, plasma, contrast agents for X-ray, magnetic resonance, or ultrasound imaging, buffers, preservatives, gelling agents, glucose, and/or surfactants. Advantageously, pharmaceutically acceptable mediators are physiological saline, water for injection, contrast agents for X-ray, magnetic resonance, or ultrasound imaging, or mixtures thereof. More advantageously, pharmaceutically acceptable mediators are physiological saline, contrast agents for X-ray, magnetic resonance, or ultrasound imaging, or mixtures of physiological saline and contrast agents for X-ray, magnetic resonance, or ultrasound imaging.

According to the invention, the contrast agent is preferably a contrast agent for X-ray imaging. Advantageously, the contrast agent for X-ray imaging is a water-soluble iodinated nonionic contrast agent, such as iodipylenol, ... and mixtures thereof.

According to another embodiment, the contrast agent is a magnetic resonance imaging (MRI) contrast agent. Advantageously, these are gadolinium chelates (gadopiclenol).

According to another embodiment, the contrast agent is an ultrasound imaging contrast agent. Advantageously, the ultrasound imaging contrast agent is sulfur hexafluoride.

In a particular embodiment of the invention, the pharmaceutical composition comprises a combination of embolic microspheres according to the invention and physiological saline, the composition being intended to be mixed with at least one contrast agent for X-ray, magnetic resonance or ultrasound imaging as defined above, particularly for X-ray imaging, prior to administration by injection, such mixing producing a suspension of the microspheres according to the invention.

In a specific embodiment of the invention, the pharmaceutical composition according to the invention comprises a combination of embolic microspheres according to the invention, and a mixture of saline and a contrast agent as defined above, wherein the saline and the contrast agent are present in a ratio of 70/30 to 20/80, advantageously 50/50 to 20/80, preferably 50/50.

The pharmaceutical composition must have an injection-acceptable viscosity.

As described above, the embolic microspheres according to the present invention can be used for a variety of biomedical purposes, which means that they must be compatible with the human or mammalian body. More specifically, suitable biomedical materials do not have hemolytic properties.

The subject of this invention is also a reagent kit comprising a pharmaceutical composition as defined above and at least one device for injecting said composition, the device being used for parenteral administration of said composition. According to the invention, the term "syringe" means any device capable of parenteral administration. Advantageously, said syringe 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.

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

Advantageously, the syringe element present in the kit according to the invention is suitable for parenteral administration of the pharmaceutical composition according to the invention. Therefore, the size of one or more syringes or (micro)catheters will be adjusted according to the size of the microspheres according to the invention and the injection volume for embolization. Those skilled in the art will be able to select the most suitable syringe element. According to a preferred embodiment, the syringe element is a device as described in patent applications WO 2016/166346, WO 2016/166339, WO 2017/005914 and WO 2017/081178.

The subject of this invention is also a reagent kit, which firstly comprises a pharmaceutical composition as defined above, and secondly comprises at least one contrast agent for X-ray, magnetic resonance, or ultrasound imaging, and optionally at least one syringe for parenteral administration. The syringe is as defined above.

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

In the kit, the at least one contrast agent is as defined above in the specification. Specifically, the at least one contrast agent is an X-ray imaging contrast agent as defined above in the specification.

In the kit, the pharmaceutical composition advantageously comprises a combination of microspheres according to the invention and a pharmaceutically acceptable medium for administration by injection. The pharmaceutically acceptable medium may be, for example, but not limited to, water for injection, physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharides, hyaluronic acid esters, glucose, and/or plasma. Preferably, in the kit, the pharmaceutical composition advantageously comprises a combination of microspheres according to the invention and physiological saline or water for injection.

In the kit, the pharmaceutical composition is advantageously packaged directly in an injection device, particularly a syringe, suitable for parenteral injection of embolic microspheres.

In the kit, the contrast agent is advantageously packaged in a vial or directly in an injection device, particularly a syringe, that is particularly suitable for parenteral injection of embolic microspheres.

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

Example

Example 1: Synthesis of MAETIP (a compound having formula (A) according to the present invention)

Materials and Methods

Chemical products :

- Magnesium sulfate ( _MgSO4 , anhydrous, 98%, Sigma-Aldrich, reference: 230391, CAS: 10034-99-8)

-2,4,6-Triiodophenol (95-98%, BLDpharm, Reference: A17145, CAS: 609-23-4)

-2-[2-(2-chloroethoxy)ethoxy]ethanol (95-98%, Tokyo Chemical Industry Co., Ltd. (TCI), reference: QF-8470, CAS: 5197-62-6)

- Sodium iodide (NaI, >99%, Oakwood Chemical, Reference: QE-0904, CAS: 7681-82-5)

- Sodium hydroxide (NaOH, anhydrous, >98%, Sigma-Aldrich, Reference: S8045, CAS: 1310-73-2)

-Methacrylic anhydride (MA, >94%, Sigma-Aldrich, Reference: 276685, CAS: 760-93-0)

- Triethylamine (TEA, >99.5%, Sigma-Aldrich, Reference: 471283, CAS: 121-44-8)

Solvent :

- Anhydrous ethanol (EtOH, 99.96%, VWR, Reference: 20821.310, CAS: 64-17-5)

- Ethyl acetate (anhydrous, 99.8%, Sigma-Aldrich, Reference: 270989, CAS: 141-78-6)

-Heptane (>99%, Sigma-Aldrich, Reference: 34873, CAS: 142-82-5)

- Dichloromethane (DCM, anhydrous, >99.8%, Sigma-Aldrich, Reference: 270997, CAS: 75-09-2)

- Distilled water (Grade 2)

equipment :

- Magnetic plate (Heidoplh, MR Hei-Standard)

- Rotary evaporator (Büchi Rotavapor R-215)

- Precision balance (d = 0.1 mg, Sartorius)

- Silica pillars: ChromatoFlash (Büchi)

1. O-alkylation

In a 10 mL round-bottom flask, triiodophenol (200 mg; 0.42 mmol) was dissolved in 2.2 mL of ethanol. NaOH (15 mg; 0.375 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After stirring, the mixture was evaporated under vacuum until a pale yellow solid was obtained.

NaI (57 mg; 0.375 mmol) and 2-[(2-chloroethoxy)ethoxy]ethanol (55 μL; 0.375 mmol) were placed in a three-necked flask equipped with a condenser and placed under nitrogen. The mixture was dissolved in 1.7 mL of ethanol until the NaI was completely dissolved. Then, a triiodophenol derivative pre-dissolved in 0.7 mL of ethanol was added. The reaction medium was heated under reflux for 2.5 days, ensuring a sufficiently high water flow rate in the condenser to observe rapid ethanol condensation.

The reaction process was monitored by TLC (thin-layer chromatography): 5/5 heptane/ethyl acetate.

At the end of the reaction, the reaction medium was evaporated under pressure, and the obtained solid was then dissolved in 6 mL of NaOH solution (6 M). The aqueous phase was then washed with DCM (dichloromethane) (3 × 7 mL). The organic phase was dried over _MgSO4 . A pale yellow solid was obtained. Purification was performed on a silica column using a heptane/ethyl acetate co-elution system. After purification, 0.133 mg of a white solid was obtained.

Molar yield: 85%.

UV purity: 96%

2. Esterification of alcohols

Intermediate 1

In a 25 mL three-necked flask equipped with a condenser, intermediate 1 (0.133 mg; 0.22 mmol) was dissolved in 12 mL of anhydrous THF. TEA (triethylamine) (0.10 mL; 0.66 mmol) was added dropwise. The reaction medium was cooled to below 5 °C, and then methacrylic anhydride (0.11 mL; 0.66 mmol) was added dropwise over 5 minutes. Finally, the reaction medium was stirred at below 5 °C for one hour and then refluxed overnight.

The reaction process was monitored by TLC: 5/5 heptane/ethyl acetate.

At the end of the reaction, the reaction medium was allowed to reach room temperature and then suspended in 90 mL of water for one hour. The mixture was washed with dichloromethane (3 × 20 mL). The organic phase was dried over _MgSO₄ and then evaporated under pressure to produce an orange oil, which was then purified using a heptane/ethyl acetate co-elution system on a silica column. After purification, 89.7 mg of a clear oil was obtained.

Molar yield: 74.5%.

UV purity: 96.6%

3. Conclusion

MAETIP was synthesized in approximately 54% yield (comparable to the yield of MAOETIB synthesis), with a final molecular purity of approximately 97%.

Example 2: Synthesis of MAETIP-based microspheres according to the present invention with sizes of 100-300 μm, 300-500 μm, and 700-900 μm via oil-in-water suspension polymerization (direct phase).

The synthesis parameters are suitable for the desired microsphere size (see Table 1).

a) Preparation of the aqueous phase

Prepare an aqueous solution of hydrolyzed polyvinyl alcohol (PVA) and sodium chloride according to the following scheme:

i) Dissolve PVA in 5L of calorific value water and stir overnight at 50°C.

ii) Add NaCl and stir at room temperature for 4 hours.

b) Preparation of organic phase

v) Weigh each reagent and toluene.

w) Dissolve AIBN in one volume of toluene.

x) Dissolve poly(ethylene glycol) methyl ether methacrylate (m-PEG ₃₀₀ MA) (hydrophilic monomer), poly(ethylene glycol) dimethacrylate (PEG ₁₀₀₀ DMA) (crosslinking agent), methacrylic acid (AM or MA) (ionizable monomer), MAETIP (radiosensitive monomer), and colorant in one volume of toluene (in separate containers), then add hexamethylenetetramine (transfer agent).

y) Add the AIBN solution obtained in step w) to the monomer solution in step x).

c) Synthesis of microspheres according to the present invention

The aqueous solution of PVA and NaCl prepared in step a) was poured into a reactor and heated to 50°C. Then, the organic phase obtained in step b) was introduced into the reactor. Stirring was applied using an impeller stirrer to obtain droplets of dispersed phase with the desired diameter. The temperature was then increased to 80°C and stirring continued for 8 hours. The mixture was then filtered through a 50 μm sieve, and the microspheres were washed with acetone, then ethanol, then water, and then sieved using sieves of sizes 50 μm, 100 μm, 300 μm, 500 μm, 700 μm, 900 μm, and 1200 μm.

Table 1 below summarizes the main synthesis parameters based on the microsphere size.

*n = number of moles

Table 1

Example 3: Measurement of the suspension time of the MS according to the present invention and comparison with the MS containing a monomer other than MAETIP.

The suspension time of the MS synthesized in Example 1 according to the invention in the injection medium (50/50 saline/iodinated contrast agent) was studied and compared with the suspension time of the control MS containing radiopaque monomers other than MAETIP.

The control MS was synthesized using the same scheme as in Example 1, with the same components except for the radiopaque monomers. The following radiopaque monomers were used in the control MS:

• MAOETIB has the following formula:

The compound Vb with the following formula is described in patent application WO 2021/069528:

Hovering is achieved using the "Falcon" method:

Falcon method

Add 1 mL of radiopaque microspheres to 15 mL of a polypropylene-lined (or polystyrene) tube, then “fill” the tube with a 50/50 mixture of distilled water and contrast agent (to observe edge effects and expel as much air as possible from the tube).

-Then the microspheres are suspended by continuously flipping the tube for 3 minutes.

- Let the tube stand and measure the settling (or emulsification) time of the microspheres.

Results and discussion:

a) The first microsphere suspension test was conducted in a tube using the previously described protocol. The results obtained are as follows:

Table 2: MS suspension time in tubes using the Falcon method

It should be noted that in each case, the microspheres settle at the end of their suspension in the injection medium.

b) The second test was performed in the tube using the same parameters. The results obtained are as follows:

Table 3: MS suspension time in tubes using the Falcon method

In each case, the microspheres settled at the end of their suspension in the injection medium.

In both tests, the suspension time of the MS according to the present invention was significantly longer than that of the control MS.

Results marked with "*" correspond to suspension times greater than 600 seconds. This is considered irrelevant to measuring suspension times exceeding 600 seconds, as the results obtained using a suspension containing MS according to the invention are far superior to those observed using control microspheres.

Claims (15)

1. A compound having the following formula (A): 2. Use of the compound having formula (A) as claimed in claim 1 as a radiopaque halide monomer. 3. A radiopaque embolic microsphere comprising a crosslinked matrix, said matrix being at least based on: a) 20% to 90% hydrophilic monomers selected from N-vinylpyrrolidone and monomers having the following formula (I): (CH＝CR ₂₁ )-CO-D(I) in: • D represents OZ or NH-Z, Z represents ( _C1 - _C6 )alkyl, -( _CR2R3 ) _{m - CH3} , -( _CH2 - _CH2 -O) _m -H, -( _CH2 - _CH2 -O) _m - _CH3 , -C( _R4OH ) _m or -( _CH2 ) _m - _NR5R6 , where m represents an integer from 1 to ₃₀ , and preferably, m equals 4 or 5. _R1 , _R2 , _R3 , _R4 , _R5 and _R6 independently represent H or ( _C1 - _C6 ) alkyl; b) 5% to 50% of compounds having the following formula (A): c) 1% to 15% of non-biodegradable linear or branched hydrophilic crosslinked monomers, each terminal of which is attached with a ( _CH2 =( _CR16 ))- group, each _R16 independently representing an H or ( _C1 - _C6 ) alkyl group; and d) 0.1% to 10% of a transfer agent selected from alkyl halides and alicyclic or aliphatic thiols, particularly containing 2 to 24 carbon atoms and optionally carrying another functional group selected from amino, hydroxyl, and carboxyl groups. The percentages of monomers a) to c) are given in moles relative to the total number of moles of monomers, and the percentage of compound d) is given in moles relative to the number of moles of hydrophilic monomer a). 4. The embolic microspheres of claim 3, wherein the matrix comprises, based on the total molar amount of the monomer, an amount greater than 7% and less than or equal to 50%, advantageously greater than 10% and less than or equal to 50%, advantageously greater than 15% and less than or equal to 50%, more advantageously greater than 15% and less than or equal to 35%, and particularly 20% to 30% of the compound having general formula (A). 5. The embolic microspheres according to claim 3 or 4, wherein the hydrophilic monomer a) is selected from the group consisting of: N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, tert-butyl acrylate, tert-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl methacrylate, N,N-dimethylaminopropyl methacrylate, tert-butylaminoethyl methacrylate, N,N-diethylaminoacrylate, poly(ethylene oxide)(meth)acrylate, methoxy poly(ethylene oxide)(meth)acrylate, butoxy poly(ethylene oxide)(meth)acrylate, poly(ethylene glycol)(meth)acrylate, methoxy poly(ethylene glycol)(meth)acrylate, butoxy poly(ethylene glycol)(meth)acrylate, poly(ethylene glycol) methyl ether methacrylate, and mixtures thereof; advantageously, monomer a) is poly(ethylene glycol) methyl ether methacrylate. 6. The embolic microspheres according to any one of claims 3 to 5, wherein the straight-chain or branched non-biodegradable hydrophilic crosslinking monomer (c) has at least two ( _CH2 =( _CR16 ))CO- or ( _CH2 =( _CR16 ))CO-O- groups at its two ends, each _R16 independently representing H or ( _C1 - _C6 ) alkyl. 7. The embolization microspheres according to any one of claims 3 to 6, wherein the transfer agent d) is selected from mercaptoacetic acid, 2-mercaptoethanol, dodecyl mercaptan, hexamethylene mercaptan, and mixtures thereof. 8. The embolic microspheres according to any one of claims 3 to 7, wherein the matrix is further based on at least one ionized or ionizable monomer having the following formula (IV): (CH ₂ ＝CR ₁₇ )-ME(IV) in • R ₁₇ indicates H or (C ₁ -C ₆ ) alkyl; •M represents a single bond or a divalent group containing 1 to 20 carbon atoms; •E represents a charged or ionizable group containing no more than 100 atoms, ^and _E is advantageously selected from ^the group consisting of: -COOH ^{, -COO-} , _-SO3H , _-SO3- , _-PO3H2 , ^-PO3H- _{, -PO32-} , _{-NR18R19 , -NR20R21R22 + . R18} , _R19 , _R20 , _R21 , and _R22 independently represent H or ( _C1 - _C6 ) alkyl groups. 9. The embolic microspheres according to any one of claims 3 to 8, wherein the matrix is further based on at least one colored monomer having the following general formula (VI): in, • _Z1 and _Z2 independently represent H or OR ₂₅ , where R ₂₅ represents H or ( _C1 - _C6 ) alkyl, and advantageously, _Z1 and _Z2 represent H; ·X represents H or Cl, with H being preferable; • R ₂₃ represents H or ( _C1 - _C6 ) alkyl, advantageously ( _C1 - _C6 ) alkyl, particularly methyl; and • R ₂₄ represents a group selected from: straight-chain or branched ( _C1 - _C6 ) alkylene, ( _C5 - _C36 ) arylene, ( _C5 - _C36 ) arylene-OR ₂₆ , (C5-C36) heteroarylene and ( _C5 - _C36 ) heteroarylene-OR ₂₇ , _where R ₂₆ and R ₂₇ represent ( _{C1 - C6} ) alkyl or ( _C1 - _C6 ) alkylene; advantageously, R ₂₄ represents the group _{-C6H4 -} O-( _CH2 ) ₂ -O or -C( _CH3 ) ₂ - _CH2 -O. 10. The embolic microspheres according to any one of claims 3 to 9, wherein the matrix is further based on a component visible in magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, advantageously iron oxide nanoparticles. 11. The microspheres according to any one of claims 8 to 10, wherein the microspheres are filled with an active substance advantageously selected from the group consisting of: anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, preservatives, and mixtures thereof. 12. The embolic microspheres according to any one of claims 8 to 10, wherein the microspheres are filled with macromolecules selected from combinations of: enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNases, aptamers, anti-inflammatory proteins, bone morphogenetic protein (BMP), pro-angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, and angiogenesis inhibitors or antityrosine kinases, and mixtures thereof. 13. A pharmaceutical composition comprising at least one embolic microsphere as described in any one of claims 3 to 12 and a pharmaceutically acceptable carrier—advantageously for parenteral administration. 14. A kit comprising a combination of the pharmaceutical composition of claim 13 and a pharmaceutically acceptable medium for parenteral administration, and at least one syringe. 15. A kit comprising, firstly, the pharmaceutical composition as claimed in claim 13, and secondly, at least one contrast agent for X-ray, magnetic resonance, or ultrasound imaging, and optionally at least one syringe for parenteral administration, wherein the pharmaceutical composition and the at least one contrast agent are packaged separately.