Radiopaque monomers and embolic microspheres comprising same

Abstract

The present invention relates to a compound having the following formula (A), which is primarily used as a radiopaque monomer: The present invention further relates to radiopaque embolic microspheres based at least on: 20% to 90% of a hydrophilic monomer; 5% to 50% of a compound having formula (A); from 1% to 15% of a non-biodegradable hydrophilic crosslinking monomer; and-0.1% to 10% of a transfer agent. The invention also relates to a pharmaceutical composition comprising at least one embolic microsphere according to the invention in combination with a pharmaceutically acceptable carrier advantageously for parenteral administration. The invention further relates to a kit comprising a pharmaceutical composition according to the invention in combination with a pharmaceutically acceptable carrier for parenteral administration, and to an injection device. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel halogenated radiopaque monomer, particularly intended for use in a cross-linked matrix contained in an embolic microsphere composition. Background Art

[0002] Therapeutic vascular occlusion (i.e., embolization) is used to prevent or treat certain pathological conditions in situ. It can be performed with the aid of a catheter so that particulate occlusive agents (i.e., emboli or embolic agents) are positioned in the circulatory system under imaging control. It has a variety of medical applications, such as the treatment of vascular malformations, bleeding processes or tumors, including, for example, uterine fibroids, and primary or secondary liver tumors. For example, vascular occlusion can induce tumor necrosis and avoid more invasive surgery. In the context of chemoembolization, the occlusion technique can also be combined with the provision of anticancer agents. This increases the local concentration of the drug and its residence time in the tumor while limiting systemic drug exposure by targeted injection. In the case of vascular malformations, vascular occlusion allows normalization of blood flow to normal tissues, assisting surgery by limiting the risk of bleeding. During bleeding, vascular occlusion can help reduce flow rate, thereby promoting arterial wound healing. In addition, depending on the pathology being treated, embolization can be used for temporary or permanent purposes.

[0003] Embolic agents are routinely introduced into a blood vessel via a catheter, particularly a microcatheter, whose diameter is smaller than that of the blood vessel to be treated. Embolic agents used for vascular occlusion include, for example, embolic liquids (acrylic adhesives, gels), mechanical devices, particles, and polymer embolic microspheres. The choice of a 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.

[0004] Polymer-based embolic microspheres are particularly useful for the above-mentioned 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.

[0005] For example, product (Biosphere Medical) corresponds to non-biodegradable microspheres based on triacryl (N-acryloyl-2-amino-2-hydroxymethylpropane-1,3-diol) and gelatin. Non-biodegradable microspheres based on acrylic acid copolymers and polyvinyl alcohol (PVA) have also been proposed for permanent embolization (Osuga et al. (2002) J. Vasc. Interv. Radiol. [Journal of Vascular and Interventional Radiology] 13: 929-34).

[0006] Moreover, in order to be visible in X-ray imaging, the embolic microspheres can be made radiopaque by adding a radiopaque substance or monomer to the composition of the embolic microspheres. Such radiopaque embolic 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:

[0007]

[0008] Radiopacity refers to the relative inability of electromagnetics, especially X-rays, to pass through dense materials described as "radio-opaque", which appear opaque / white in X-ray images. Given the complexity of the content in X-ray or fluoroscopic images, clinicians are sensitive to image quality in terms of brightness or signal intensity of materials in the image. The two main factors that affect the importance of radiopacity are density and atomic number. Polymer-based medical devices that require radiopacity typically use polymer mixtures that incorporate a small amount (by weight percentage) of radiopaque elements, such as heavy atoms, such as halogens, especially iodine. The ability of the device to be visualized by fluoroscopy depends on the amount or density of the radiopaque elements mixed into the material. However, the addition of radiopaque substances or monomeric substances with halogenated groups appears to significantly reduce the hydrophilicity of the material. Moreover, the density of microspheres incorporating one or more of these types of radiopaque monomers or substances increases, which affects their suspension characteristics in the injection medium. In summary, the iodine-filled microspheres for X-ray visibility in the prior art are typically more hydrophobic, dense and rigid than non-X-ray visible microspheres, and tend to form microsphere aggregates. Therefore, (1) they have difficulty staying suspended in the catheter for the duration of the 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 aggregate with each other, and (3) they tend to adhere to the catheter wall.

[0009] Therefore, it is preferred to include a radiopaque substance or monomer in the composition of the embolic microspheres so that the embolic microspheres remain hydrophilic and flexible when they swell in water. It is also expected that these microspheres have mechanical properties suitable for injection via a catheter or microcatheter, particularly swelling, elasticity and compressibility. It is also expected that these microspheres can remain suspended in the injection mixture (complex mixture of contrast medium product and aqueous phase) in the catheter for the duration of the injection. Specifically, in order to be injectable and enable physicians to track injections under X-ray control, the microspheres are usually suspended in a mixture of non-ionic iodinated contrast medium products and aqueous phases. For this purpose, radiologists usually use contrast medium product solutions and optionally physiological saline, bicarbonate buffer or phosphate buffer, advantageously 100% contrast medium product solutions. In order to ensure their injectability, the microspheres must remain uniformly suspended in the solution. If the microspheres settle or float on the surface of the solution, the resulting suspension is uneven, unstable, and therefore cannot be injected into the patient.

[0010] Patent applications WO 2021 / 069527 and WO 2021 / 069528 describe halogenated radiopaque monomers that can satisfactorily meet these requirements. However, there is still a need for new radiopaque monomers or substances intended for the preparation of embolic microspheres, which provide better properties, for example in terms of stability or injectability of suspensions containing said microspheres, while remaining compatible with iodinated contrast agents as described above. Summary of the invention

[0011] In this context, the inventors have developed a novel halogenated radiopaque monomer of formula (A) that improves the performance of embolic microspheres comprising the monomer in their compositions. For example, the novel radiopaque monomer of formula (A) prevents, in particular, the embolic microspheres comprising the monomer from aggregating together in a catheter or microcatheter prior to injection. The presence of the novel halogenated radiopaque monomer of formula (A) in the embolic microspheres also prevents the microspheres from adhering to the wall of the catheter or microcatheter prior to injection. Moreover, by means of the novel radiopaque monomer, the suspendability and injectability of these microspheres are improved.

[0012] For purposes of the present invention, the term "improved suspensibility" means the ability of the microspheres to form a suspension that is stable over a period of time compatible with the use of the microspheres and is homogeneous, ie, the microspheres have the same distribution at all points in the volume of the suspension.

[0013] For the purposes of the present invention, the term "improved syringability" means the ability of a suspension to be injected via an injection system, such as a syringe or catheter, without creating occlusions and without requiring the application of significant force on the part of the physician.

[0014] Therefore, the present invention relates to a compound having the following formula (A):

[0015]

[0016] In the present specification, this compound is also represented by the term MAETIP.

[0017] Another subject of the present invention relates to the use of compounds of formula (A) as defined above as radiopaque halogenated monomers.

[0018] Another subject of the present invention relates to embolic microspheres comprising said halogenated radiopaque monomer of formula (A).

[0019] Therefore, the present invention also relates to the use of the compound of formula (I) in embolic microspheres.

[0020] The present invention also relates to a pharmaceutical composition comprising the embolic microspheres as defined above in combination with a pharmaceutically acceptable vehicle, advantageously for administration by injection.

[0021] A subject of the present invention is also a kit comprising a pharmaceutical composition as defined above and at least one device for injecting said composition, this device being intended for parenteral administration of said composition.

[0022] The subject of the present invention is also a kit comprising firstly a pharmaceutical composition as defined above and secondly a contrast medium for X-ray, magnetic resonance or ultrasound imaging and optionally at least one injection device for parenteral administration; advantageously, said injection device is Devices as described in patent applications WO 2016 / 166346, WO 2016 / 166339, WO 2017 / 005914 and WO 2017 / 081178. DETAILED DESCRIPTION

[0023] The main subject of the present invention is therefore the compound of the following formula (A):

[0024]

[0025] In the compound of formula (A), the 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, the compound provides reduced spatial accessibility to the aromatic carbon (at positions 3 and 5 of the phenyl ring) relative to MAOETIB or compound (Vb) of patent application WO 2021 / 069528 (wherein the iodine atoms are at positions 2, 3 and 5 of the phenyl ring and the aromatic carbon is at positions 4 and 6 of the phenyl ring). The restricted accessibility of aromatic carbon in the compound of formula (A) seems to have the effect of reducing the lipophilicity of the molecule. Specifically, the intermolecular or intramolecular interactions of these carbons are reduced or even absent, thereby limiting the viscosity of the molecule. In other words, the spatial configuration of the compound of formula (A) helps prevent the embolic microspheres incorporated with the compound from aggregating together.

[0026] According to the invention, the compound of formula (A) is advantageously used as radiopaque halogenated monomer.A subject of the present invention is therefore also the use of the compound of formula (A) as defined above as radiopaque halogenated monomer.

[0027] Furthermore, the present invention relates to embolic microspheres comprising the halogenated radiopaque monomer having formula (A). In particular, the embolic microspheres comprise a crosslinked polymer matrix comprising the halogenated radiopaque monomer having formula (A).

[0028] In a particular embodiment, the cross-linked polymer matrix is ​​as defined in patent application WO 2021 / 069528, except that the halogenated radiopaque monomer of general formula (II) is replaced by a compound of formula (A) according to the invention. In other words, the cross-linked polymer matrix is ​​based at least on:

[0029] a) 20% to 90% of a hydrophilic monomer selected from N-vinylpyrrolidone and a monomer having the following formula (I):

[0030] (CH2=CR1)-CO-D(I)

[0031] in:

[0032] ·D represents OZ or NH-Z, Z represents (C1-C6) alkyl, -(CR2R3) m CH3, -CH-(CH2-CH2-O) m -H, -(CH2-CH2-O) m -CH3, -C(R4OH) m or -(CH2) m -NR5R6, wherein m represents an integer from 1 to 30, preferably, m is equal to 4 or 5

[0033] R1, R2, R3, R4, R5 and R6 independently represent H or (C1-C6) alkyl;

[0034] b) 5% to 50% of a compound having the following formula (A):

[0035]

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

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

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

[0039] The hydrophilic monomer of formula (I), the crosslinking monomer c) and the transfer agent d) are advantageously as defined in patent application WO 2021 / 069528, in particular on pages 13 and 19-22.

[0040] For purposes of the present invention, the term "hydrophilic monomer" means a monomer that has a high affinity for water, ie, tends to dissolve in water, mix with water, be wetted by water, or is capable of swelling in water after polymerization.

[0041] For the purposes of the present invention, the term "crosslinking monomer" means a monomer that is at least difunctional, but also multifunctional and carries a double bond at each polymerizable end. The combination of the crosslinking monomer with the other monomers in the mixture allows the formation of a crosslinked network. A person skilled in the art can easily choose the structure and amount of one or more crosslinking monomers in the monomer mixture to provide the desired crosslinking density. The crosslinking agent is also advantageous for the stability of the microspheres. The crosslinking agent prevents the microspheres from dissolving in any solvent. The crosslinking agent also allows to improve the compressibility of the microspheres, which is advantageous for embolization.

[0042] For the purposes of the present invention, the term "non-biodegradable hydrophilic cross-linker" means a cross-linker as defined above, which has a high affinity for water and cannot be degraded under physiological conditions in a mammal, in particular in a human body. In particular, biodegradation of the molecule is allowed when the molecule contains sufficient functional sites that can be cleaved under physiological conditions, in particular by endogenous enzymes in a mammal, in particular in a human body, and / or at physiological pH (usually about 7.4). Functional sites that can be cleaved under physiological conditions include, in particular, amide bonds, ester bonds and acetals. Therefore, molecules containing an insufficient number of such functional sites will be considered non-biodegradable. In the context of the present invention, the cross-linking monomer contains less than 20 functional sites that can be cleaved under physiological conditions, preferably less than 15 sites, more preferably less than 10 sites, even more preferably less than 5 sites.

[0043] In the context of the present invention, the term "transfer agent" means a compound containing at least one weak chemical bond. The agent reacts with the free radical site of a growing polymer chain and interrupts the chain growth. During chain transfer, the free radical is temporarily transferred to the transfer agent, which restarts growth by transferring the free radical to another polymer or monomer.

[0044] The term "matrix based on..." is naturally to be understood as a matrix comprising a mixture and / or reaction products between the base components for the heterogeneous medium polymerization of the matrix, preferably only comprising the reaction products between the different base components for the matrix, some of which may be intended to react or be susceptible to reaction at least partially with each other or with its close chemical environment during the various stages of the matrix manufacturing process, especially during the polymerization step. Therefore, the base components are reagents intended to react together during the polymerization of the matrix. Therefore, the base components are introduced into a reaction mixture, which optionally further comprises a solvent or a 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 the present invention, the reaction mixture comprises at least the monomers a), b), c) mentioned in the present description and the transfer agent d) as basic components, optionally a polymerization initiator, for example tert-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also known as 4,4′-azobis(4-cyanovaleric acid)), AIBN (azobisisobutyronitrile), or 1,1′-azobis(cyclohexanecarbonitrile), or one or more thermal initiators, such as 2-hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone (106797-53-9); 2-hydroxy-2-methylpropiophenone ( 1173, 7473-98-5); 2,2-dimethoxy-2-phenylacetophenone (24650-42-8); 2,2-dimethoxy-2-phenylacetophenone ( 24650-42-8) or 2-methyl-4′-(methylthio)-2-morpholinopropiophenone ( 71868-10-5), and at least one solvent, preferably a solvent mixture comprising an aqueous solvent and an organic solvent (such as a non-polar aprotic solvent), for example an immiscible water / toluene system.

[0045] According to the invention, the matrix is ​​therefore based at least on the monomers a), b), c) and transfer agents d) mentioned in this description, these compounds therefore being the essential components.

[0046] Therefore, in the present specification, expressions like "[base component X] is added to the reaction mixture, in particular in an amount of YY% to YYY%" and "the cross-linked matrix is ​​in particular based on [base component X] in an amount of YY% to YYY%" are interpreted similarly. Similarly, expressions like "the reaction mixture contains at least [base component X]" and "the cross-linked matrix is ​​based at least on [base component X]" are interpreted similarly.

[0047] For the purposes of the present invention, the "organic phase" of the reaction mixture is understood to mean the phase comprising the organic solvent and the compounds soluble in the organic solvent, in particular the monomers, the transfer agent and the polymerization initiator.

[0048] For the purposes of the present invention, the term “ X -C Y ")alkyl" means a saturated, linear or branched, monovalent hydrocarbon chain containing from X to Y carbon atoms, X and Y being integers between 1 and 36, preferably between 1 and 18, in particular between 1 and 6. Mention may be made, by way of example, of the radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

[0049] In the context of the present invention, the compound of formula (A) is especially added to the reaction mixture in an amount of 5% to 50% by mole, relative to the total moles of the monomers, especially in an amount of greater than 7% and less than or equal to 50%, especially in an amount of greater than 10% and less than or equal to 50%, more especially 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 especially in an amount of 20% to 30%.

[0050] Embolic microspheres comprising a crosslinked polymer matrix as defined above advantageously correspond to spherical particles having a diameter after swelling in the range of 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 diameter small enough to be injected through a needle, catheter or microcatheter having an inner diameter ranging from a few hundred micrometers to more than one millimeter.

[0051] The expression "after swelling" means that the size of the microspheres is considered after the polymerization and sterilization steps carried out during the preparation of the microspheres. The sterilization step involves, for example, sending the microspheres after the polymerization step to a high temperature autoclave, typically at a temperature above 100°C, preferably at a temperature between 110°C and 150°C, preferably at 121°C. During this sterilization step, the microspheres continue to swell in a controlled manner, i.e. with a controlled degree of swelling. The degree of swelling is defined as:

[0052]

[0053] Where m w is the weight (in grams) of 1 ml of settled microspheres, and m d is the weight (in grams) of 1 ml of settled microspheres which were subsequently lyophilized.

[0054] In a particular 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 above-mentioned proportions of monomers and transfer agents, without adding other basic components to the reaction mixture. It is therefore obvious that the sum of the above-mentioned proportions of monomers a), b) and c) must be equal to 100%.

[0055] 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 (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, tert-butylaminoethyl (meth)acrylate, N,N-diethylaminoacrylate, poly(ethylene oxide) (meth)acrylate, methoxypoly(ethylene oxide) (meth)acrylate, butoxypoly(ethylene oxide) (meth)acrylate, poly(ethylene glycol) (meth)acrylate, methoxypoly(ethylene glycol) (meth)acrylate, butoxypoly(ethylene glycol) (meth)acrylate, poly(ethylene glycol) methyl ether methacrylate, and mixtures thereof.

[0056] More advantageously, the hydrophilic monomer a) is poly(ethylene glycol) methyl ether methacrylate (m-PEGMA).

[0057] In the context of the present invention, the hydrophilic monomers a) are added to the reaction mixture in an amount of 20% to 90%, preferably 30% to 80%, more preferably 40% to 70%, in particular 45% to 65% by mole, relative to the total moles of the monomers. Thus, in the context of the present invention, the crosslinking matrix is ​​based in particular on hydrophilic monomers a) in an amount of 20% to 90%, preferably 30% to 80%, more preferably 40% to 70%, in particular 45% to 65% by mole, relative to the total moles of the monomers.

[0058] Advantageously, the linear or branched non-biodegradable hydrophilic cross-linking monomer carries (CH2=(CR 16 ))CO- or (CH2=(CR 16 ))CO-O-group, where each R 16 and (C1-C6)alkyl.

[0059] In particular, the crosslinking agent has the following general formula (IIIa) or (IIIb):

[0060] (CH2=(CR 16 ))CO-NH-A-HN-OC((CR 16 )=CH2)(IIIa),

[0061] (CH2=(CR 16 ))CO-OAO-OC((CR 16 )=CH2)(IIIb),

[0062] in

[0063] Each R 16 independently represents H or (C1-C6)alkyl; advantageously, the group R 16 are identical and represent H or (C1-C6)alkyl; and

[0064] A alone or together with at least one of the atoms to which it is bound represents (C1-C6)alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A.

[0065] Advantageously, the crosslinking agent has the following general formula (IIa) or (IIb):

[0066] (CH2=(CR 16 ))CO-NH-A-HN-OC((CR 16 )=CH2)(IIIa),

[0067] (CH2=(CR16 ))CO-OAO-OC((CR 16 )=CH2)(IIIb),

[0068] in,

[0069] Each R 16 independently represents H or (C1-C6)alkyl; advantageously, the group R 16 are identical and represent H or (C1-C6)alkyl; and

[0070] Preferably, A alone or together with at least one of the atoms to which it is bound represents (C1-C6)alkyl or polyethylene glycol (PEG), preferably polyethylene glycol (PEG).

[0071] In the context of the definition of A above, the polyethylene glycol 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.

[0072] Examples of crosslinking monomers that may be used in the context of the present invention may include, but are not limited to: 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylenebisacrylamide, glycerol 1,3-diglyceride diacrylate, and poly(ethylene glycol) dimethacrylate (PEGDMA).

[0073] Advantageously, the crosslinking monomer is poly(ethylene glycol) dimethacrylate (PEGDMA), the polyethylene glycol unit having a length in the range of 200 to 10000 g / mol, preferably 200 to 2000 g / mol, more preferably 500 to 1000 g / mol.

[0074] In the context of the present invention, the crosslinking monomer is especially added to the reaction mixture in an amount of 1 to 15%, preferably 2 to 10%, especially 2 to 7%, more especially 2 to 5% by mole relative to the total moles of monomers.

[0075] Advantageously, the chain transfer agent is selected from the group consisting of monofunctional or polyfunctional mercaptans and alkyl halides.

[0076] The alkyl halides that can be used as transfer agents include in particular bromotrichloromethane, tetrachloromethane and tetrabromomethane. Particularly advantageously, the chain transfer agent is an alicyclic or aliphatic mercaptan, which typically contains 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 6 carbon atoms and optionally carries additional functional groups selected from amino, hydroxyl and carboxyl groups.

[0077] Advantageously, the transfer agent is selected from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof.

[0078] In the context of the present invention, the transfer agent is added to the reaction mixture in an amount of 0.1 mol% to 10 mol%, preferably 0.5 mol% to 8 mol%, more advantageously 1.5 mol% to 6 mol% and in particular 1.5 mol% to 4.5 mol% and in particular 3 mol%, relative to the moles of hydrophilic monomer a).

[0079] In another particular embodiment of the present invention, the crosslinked polymer matrix of the microspheres of the present invention is also based on:

[0080] - ionizable or ionizable monomers, and / or

[0081] - monomers with a color to make them visible to the naked eye, for example to check whether the microsphere suspension is homogeneous in the syringe before injection and to control the injection speed, and / or

[0082] - At least one agent visible by magnetic resonance imaging (MRI).

[0083] The colored ionized or ionizable monomers, and the MRI-visible agents are in particular as defined in patent application WO 2021 / 069528, in particular on pages 22-25.

[0084] In particular, the crosslinked polymer matrix of the embolic microspheres of the present invention may also be based on at least one ionized or ionizable monomer having the following formula (IV):

[0085] (CH2=CR 17 )-ME(IV)

[0086] in:

[0087] ·R 17 represents H or (C1-C6) alkyl;

[0088] M represents a single bond or a divalent group containing 1 to 20 carbon atoms;

[0089] E represents a charged or ionizable group containing not more than 100 atoms, E is advantageously selected from the group consisting of: -COOH, -COO - 、-SO3H、-SO3 - 、-PO3H2、-PO3H - 、-PO3 2- 、-NR 18 R 19 、-NR 20 R 21 R 22 + ;

[0090] ·R 18 , R 19 , R 20 , R 21 , and R 22 Each independently represents H or (C1-C6)alkyl.

[0091] For the purposes of the present invention, the term "ionized or ionizable group" means a group that is or can be in a charged form (as an ion), i.e., carries at least one positive or negative charge, depending on the pH of the medium. For example, a COOH group can be ionized to COO - in the form of NH2, and the NH2 group can be in the ionized form NH3 + .

[0092] The introduction of ionized or ionizable monomers into the reaction mixture allows to enhance the hydrophilicity of the resulting microspheres, thereby increasing the swelling degree of said microspheres, making them easier to inject via catheters and microcatheters. Furthermore, the presence of ionized or ionizable monomers allows to load active substances into the microspheres.

[0093] According to a preferred variant, the ionizing or ionizable monomer has the following formula (IV-A):

[0094] (CH2=CR 17 )-C(O)-O-M'-E(IV)

[0095] in:

[0096] ·R 17 and E are as defined above, and

[0097] • M' is a hydrocarbyl chain containing 1 to 20 atoms.

[0098] Preferably, the ionizing or ionizable monomer is a cationic monomer advantageously chosen from the group consisting of methacrylic acid, (methacryloyloxy)ethylphosphorylcholine, 2-(dimethylamino)ethyl (meth)acrylate, 2-(diethylamino)ethyl (meth)acrylate), 11-methacryloyloxyundecylphosphoric 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 above-mentioned cationic monomers in an amount of between 1 mol% and 40 mol% relative to the total number of moles of monomers. Preferably, when the resulting microspheres are not intended to be filled with active substances, the crosslinking matrix according to the invention is based on ionizing or ionizable monomers in an amount of between 5 mol% and 15 mol%, preferably 10 mol%, relative to the total number of moles of monomers. According to another embodiment, when the microspheres are intended to be filled with active substances, the crosslinked matrix according to the invention is obtained by adding to the reaction mixture between 20 and 40 mol %, preferably by adding to the reaction mixture 20 to 30 mol % of ionized or ionizable monomers relative to the total moles of monomers.

[0099] In another advantageous embodiment, the ionized or ionizable monomer is an anionic monomer advantageously chosen from the group consisting of acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-oligomers of carboxyethyl acrylate, 3-sulfopropyl (meth)acrylate, 2-((methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide and potassium salt. Advantageously, the crosslinked matrix according to the invention is based on the above-mentioned 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 active substances, the crosslinked 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 active substances, the crosslinked 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.

[0100] In a particularly advantageous manner, the ionizable or ionizable monomer is methacrylic acid (MA or AM). Advantageously, the crosslinking matrix according to the invention is based on methacrylic acid (MA) in an amount of between 10 and 30 mol % relative to the total amount of monomers.

[0101] The crosslinked polymer matrix may also be based on at least one colored monomer having the following general formula (VI):

[0102]

[0103] in,

[0104] Z1 and Z2 independently represent H or OR 25 , R 25 represents H or (C1-C6)alkyl; advantageously, Z1 and Z2 represent H;

[0105] X represents H or Cl, advantageously H;

[0106] ·R 23 represents H or (C1-C6)alkyl, advantageously (C1-C6)alkyl, in particular methyl; and

[0107] ·R 24 represents a group selected from the following: straight chain or branched (C1-C6) alkylene, (C5-C 36 ) arylene, (C5-C 36 )Arylene-OR 26 、(C5-C 36 )heteroarylene and (C5-C 36 )heteroarylene-OR 27 , R 26 and R 27 represents (C1-C6)alkyl or (C1-C6)alkylene; advantageously, R 24 It represents the group -C6H4-O-(CH2)2-O or -C(CH3)2-CH2-O.

[0108] For the purposes of the present invention, the term “ X -C Y ")Alkylene" means a divalent, linear or branched hydrocarbon chain containing from X to Y carbon atoms, X and Y being integers between 1 and 36, preferably between 1 and 18, in particular between 1 and 6. Mention may be made, by way of example, of the radicals methylene, ethylene, propylene, butylene, pentylene or hexylene.

[0109] For the purposes of the present invention, the term “ X -C Y )Heteroarylene "means a divalent aromatic group containing X to Y ring atoms, these ring atoms include one or more heteroatoms, advantageously 1 to 4, and even more advantageously 1 or 2, such as sulfur, nitrogen or oxygen atoms, the other ring atoms being carbon atoms. X and Y are integers between 5 and 36, preferably between 5 and 18, in particular between 5 and 10.

[0110] For the purposes of the present invention, the term "divalent group" means a group having a valence of 2, ie having two covalent bonds, polar covalent bonds or ionic chemical bonds. The group may contain, for example, carbon and / or oxygen atoms.

[0111] Advantageously, the colored monomer has the following formula (VIa) or (VIb):

[0112]

[0113] More advantageously, the colored monomer has the above formula (VIb).

[0114] In the context of the present 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 monomers.

[0115] The crosslinked polymer matrix may also be based on elements visible in magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, advantageously iron oxide nanoparticles.

[0116] In the context of the present 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%, in particular 0.05%, by mass of the MRI-visible component per volume of the organic phase, in order to obtain MRI-visible and quantifiable microspheres.

[0117] The cross-linked polymer matrix of the embolic microspheres of the present invention can be easily synthesized via many methods well known to those skilled in the art. As an example, it can be obtained by suspension polymerization as described in patent application WO 2021 / 069528, in particular pages 27-29.

[0118] In a particular embodiment, the embolic microspheres according to the invention are filled with an active substance, thereby allowing combined vascular occlusion and delivery of an active principle. The active substance may be selected from drugs, diagnostic agents and macromolecules, as defined in patent application WO 2021 / 069528, in particular on pages 29-31.

[0119] Preferably, the microspheres according to the present invention may be filled with an active substance selected from the group consisting of anticancer agents, anti-inflammatory agents, local anesthetics, analgesics, antibiotics, steroids, preservatives, and mixtures thereof.

[0120] The anticancer agent is preferably selected from anthracyclines (such as doxorubicin, epirubicin or idarubicin), platinum complexes, anthracycline-related compounds (such as mitoxantrone and nemorubicin) and antibiotics (such as mitomycin C Bleomycin and actinomycin D), other antitumor compounds (such as irinotecan, 5-fluorouracil Sorafenib Sunitinib Regorafenib, brivanib, olantinib, lincitinib, erlotinib, cabozantinib, foretinib, tivantinib, fotemustine, tauromustine (TCNU), carmustine, cytosine C, cyclophosphamide, cytosine arabinoside (or cytarabine), paclitaxel, docetaxel, methotrexate, everolimus PEG-arginine deiminase, tegafur / gimeracil / oteracil combination Muparfostat, peretinoin, gemcitabine, bevacizumab Ramucirumab, floxuridine), immunostimulants such as GM-CSF (granulocyte-macrophage colony-stimulating factor) and its recombinant forms: molaspostim or sargramostim 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 mixtures of one or more of these compounds (preferably mixtures of one or more anthracyclines).

[0121] Preferably, the anticancer agent is selected from anthracyclines, immunostimulants, platinum complexes, antitumor agents, and mixtures thereof.

[0122] Even more preferably, the anticancer agent is selected from anthracyclines, antibodies, anti-tumor agents, and mixtures thereof.

[0123] The antibody is selected from, for example, anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CEA (carcinoembryonic antigen), or a mixture thereof.

[0124] Anti-PD-1 drugs include, for example, nivolumab and pembrolizumab.

[0125] Anti-PD-L1 agents include, for example, avelumab, durvalumab, and atezolizumab.

[0126] Anti-CTLA-4 agents include, for example, ipilimumab and tremelimumab.

[0127] Even more advantageously, the anticancer agent is selected from the group consisting of paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (granulocyte-macrophage colony stimulating factor), tumor necrosis factor-α (TNFα), antibodies, and mixtures thereof.

[0128] Preferably, the local anesthetic is selected from lidocaine, bupivacaine, and mixtures thereof.

[0129] The anti-inflammatory agent may be selected from ibuprofen, niflumic acid, dexamethasone, naproxen, and mixtures thereof.

[0130] In the context of the present invention, the 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, DNA enzymes (also known as DNAzymes), aptamers, anti-inflammatory proteins, bone morphogenetic proteins (BMPs), pro-angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, angiogenesis inhibitors or anti-tyrosine kinases, and mixtures thereof.

[0131] Anti-inflammatory proteins are for example infliximab or rilonacept, and mixtures thereof.

[0132] Pro-angiogenic factors are, for example, fibroblast growth factor (FGF) and mixtures thereof.

[0133] Angiogenesis inhibitors include, for example, bevacizumab, ramucirumab, nevacuzumab, olaratumab, vanucezumab, rilotumumab, imatuzumab, aflibercept, filatuzumab, pegaptanib, and mixtures thereof.

[0134] Anti-tyrosine kinases include, for example, lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cedicidinib, surufatinib, dovitinib, linifanib, and mixtures thereof.

[0135] Advantageously, the microspheres may be filled with macromolecules selected from anti-tyrosine kinases, TGF-β, angiogenesis inhibitors, and mixtures thereof.

[0136] The active substance is typically adsorbed onto the cross-linked matrix by non-covalent interactions, optionally in the presence of one or more pharmaceutically acceptable excipients well known to those skilled in the art. This particular way of capturing the active substance is called physical encapsulation. There are no particular requirements for the active substance to be filled.

[0137] Filling can be carried out by many methods well known to those skilled in the art, such as passive adsorption (swelling of the cross-linked matrix in the drug solution) or ionic interaction. These methods are described, for example, in international patent application WO 2012 / 120138, especially on page 22, line 20 to page 26, line 7. The filling efficacy depends mainly on the compatibility and / or favorable interaction between the two structures.

[0138] Another subject of the present invention relates to a pharmaceutical composition comprising the embolic microspheres according to the invention in combination with a pharmaceutically acceptable vehicle, advantageously for administration by injection.

[0139] The example of pharmaceutically acceptable vehicle includes but is not limited to water for injection, saline solution (also referred to as normal saline), starch, hydrogel, polyvinyl pyrrolidone, polysaccharide, hyaluronate, blood plasma, contrast agent for X-ray, magnetic resonance or ultrasonic imaging, buffer, preservative, gelling agent, glucose and / or surfactant. Advantageously, pharmaceutically acceptable vehicle is normal saline, water for injection, contrast agent for X-ray, magnetic resonance or ultrasonic imaging or its mixture. More advantageously, pharmaceutically acceptable vehicle is normal saline, contrast agent for X-ray, magnetic resonance or ultrasonic imaging or a mixture of normal saline and contrast agent for X-ray, magnetic resonance or ultrasonic imaging.

[0140] According to the present 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 non-ionic contrast agent, such as iodine Iopamidol Iomeprol Ioversol Iohexol Iodine pentol Ioxiline Iopromide Mepane Iodoxacol Iodtrolan Iodixanol Iomethol and iodoxamide and mixtures thereof.

[0141] According to another embodiment, the contrast agents are magnetic resonance imaging (MRI) contrast agents. Advantageously, these are gadolinium chelates ( Gadopiclenol).

[0142] According to another embodiment, the contrast agent is an ultrasound imaging contrast agent. Advantageously, the ultrasound imaging contrast agent is sulfur hexafluoride.

[0143] In a particular embodiment of the invention, the pharmaceutical composition comprises the embolic microspheres according to the invention in combination with physiological saline, said composition being intended to be mixed with at least one contrast agent for X-ray, magnetic resonance or ultrasound imaging, in particular for X-ray imaging, as defined above, before administration by injection, such mixing producing a suspension of the microspheres according to the invention.

[0144] In a particular embodiment according to the invention, the pharmaceutical composition according to the invention comprises the embolic microspheres according to the invention in combination with a mixture of physiological saline and a contrast agent as defined above, the physiological saline and the contrast agent being present in a ratio of 70 / 30 to 20 / 80, advantageously 50 / 50 to 20 / 80, preferably 50 / 50.

[0145] The pharmaceutical composition must have a viscosity acceptable for injection.

[0146] As mentioned above, the embolic microspheres according to the invention can be used for a variety of biomedical purposes, which means that they must be compatible with the human or mammalian body. More particularly, suitable biomedical materials do not have hemolytic properties.

[0147] The subject of the present invention is also a kit comprising a pharmaceutical composition as defined above and at least one device for injecting said composition, which is used for parenteral administration of said composition. According to the present invention, the term "injection device" means any device capable of parenteral administration. Advantageously, said injection device is one or more syringes and / or one or more syringes that can be prefilled and / or one or more catheters or microcatheters for administering said composition by injection.

[0148] Advantageously, the pharmaceutical composition present in the kit comprises a combination of the microspheres according to the invention with saline, a contrast agent or a mixture thereof. More advantageously, the pharmaceutical composition comprises a combination of the microspheres according to the invention with a mixture of saline and a contrast agent in a ratio between 80 / 20 and 0 / 100, advantageously between 70 / 30 and 40 / 60, preferably 50 / 50.

[0149] Advantageously, the injection device 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 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. A person skilled in the art will be able to select the most suitable injection device. According to a preferred embodiment, the injection device is Devices as described in patent applications WO 2016 / 166346, WO 2016 / 166339, WO 2017 / 005914 and WO 2017 / 081178.

[0150] The subject of the invention is also a kit comprising firstly a pharmaceutical composition as defined above and secondly at least one contrast medium for X-ray, magnetic resonance or ultrasound imaging and optionally at least one injection device for parenteral administration. The injection device is as defined above.

[0151] In said kit, the pharmaceutical composition and the contrast agent are packaged separately and are intended to be mixed just prior to administration by injection.

[0152] In said kit, the at least one contrast agent is as defined above in the description. In particular, the at least one contrast agent is an X-ray imaging contrast agent as defined above in the description.

[0153] In the kit, the pharmaceutical composition advantageously comprises a combination of the microspheres according to the present invention and a pharmaceutically acceptable vehicle for administration by injection. The pharmaceutically acceptable vehicle may be, for example, but not limited to, water for injection, saline, starch, hydrogel, polyvinyl pyrrolidone, polysaccharide, hyaluronate, glucose and / or plasma. Preferably, in the kit, the pharmaceutical composition advantageously comprises a combination of the microspheres according to the present invention and saline or water for injection.

[0154] In the kit, the pharmaceutical composition is advantageously packaged directly in an injection device, especially a syringe, suitable for parenteral injection of the embolic microspheres.

[0155] In the kit, the contrast agent is advantageously packaged in a bottle or directly in an injection device, in particular a syringe, which is particularly suitable for parenteral injection of embolic microspheres.

[0156] In the kit, the ratio of the pharmaceutically acceptable vehicle to the contrast agent is between 50 / 50 and 0 / 100, advantageously between 40 / 60 and 0 / 100, preferably 30 / 70 to 0 / 100.

[0157] Examples

[0158] Example 1: Synthesis of MAETIP (compound of formula (A) according to the present invention)

[0159] Materials and Methods

[0160] Chemical products :

[0161] -Magnesium sulfate (MgSO4, anhydrous, 98%, Sigma-Aldrich, Ref: 230391, CAS: 10034-99-8)

[0162] -2,4,6-Triiodophenol (95-98%, BLDpharm, Ref: A17145, CAS: 609-23-4)

[0163] -2-[2-(2-chloroethoxy)ethoxy]ethanol (95-98%, Tokyo Chemical Industry Co., Ltd. (TCI), reference: QF-8470, CAS: 5197-62-6)

[0164] -Sodium iodide (NaI, >99%, Oakwood Chemical, Ref: QE-0904, CAS: 7681-82-5)

[0165] -Sodium hydroxide (NaOH, anhydrous, >98%, Sigma-Aldrich, Ref: S8045, CAS: 1310-73-2)

[0166] -Methacrylic anhydride (MA, >94%, Sigma-Aldrich, Ref: 276685, CAS: 760-93-0)

[0167] -Triethylamine (TEA, >99.5%, Sigma-Aldrich, Ref: 471283, CAS: 121-44-8)

[0168] Solvents :

[0169] - Anhydrous ethanol (EtOH, 99.96%, VWR, Ref: 20821.310, CAS: 64-17-5)

[0170] -Ethyl acetate (anhydrous, 99.8%, Sigma-Aldrich, Ref: 270989, CAS: 141-78-6)

[0171] -Heptane (>99%, Sigma-Aldrich, Ref: 34873, CAS: 142-82-5)

[0172] - Dichloromethane (DCM, anhydrous, >99.8%, Sigma-Aldrich, Ref: 270997, CAS: 75-09-2)

[0173] - Distilled water (grade 2)

[0174] equipment :

[0175] -Magnetic plates (Heidoplh, MR Hei-Standard)

[0176] -Rotary evaporator (Büchi Rotavapor R-215)

[0177] - Precision balance (d = 0.1 mg, Sartorius)

[0178] -Silica column: ChromatoFlash (Büchi)

[0179] 1. O-alkylation

[0180]

[0181] 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 then stirred at room temperature for 30 minutes. After stirring, evaporation was performed under vacuum until a light yellow solid was obtained.

[0182] NaI (57 mg; 0.375 mmol) and 2-[(2-chloroethoxy)ethoxy]ethanol (55 μL; 0.375 mmol) are placed in a three-necked flask equipped with a condenser and placed under nitrogen. The mixture is dissolved in 1.7 mL of ethanol until the NaI is completely dissolved. The triiodophenol derivative previously dissolved in 0.7 mL of ethanol is then added. The reaction medium is heated under reflux for 2.5 days, ensuring a sufficiently high water flow rate in the condenser so that rapid ethanol condensation is observed.

[0183] The progress of the reaction was monitored by TLC (thin layer chromatography): 5 / 5 heptane / ethyl acetate.

[0184] At the end of the reaction, the reaction medium was evaporated under pressure, and the solid obtained 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 carried out on a silica column via a heptane / ethyl acetate co-elution system. After purification, 0.133 mg of a white solid was obtained.

[0185] Molar yield: 85%.

[0186] UV purity: 96%

[0187] 2. Esterification of alcohol

[0188]

[0189] Intermediate 1

[0190] 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 a temperature below 5° C. for one hour and then refluxed overnight.

[0191] The progress of the reaction was monitored by TLC: 5 / 5 heptane / ethyl acetate.

[0192] 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. 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 on a silica column using a heptane / ethyl acetate co-elution system. After purification, 89.7 mg of a transparent oil was obtained.

[0193] Molar yield: 74.5%.

[0194] UV purity: 96.6%

[0195] 3. Conclusion

[0196] MAETIP was synthesized in about 54% synthetic yield (comparable to the yield of MAOETIB synthesis) with a final molecular purity of about 97%.

[0197] Example 2: Synthesis of MAETIP-based microspheres according to the invention of sizes 100-300 μm, 300-500 μm and 700-900 μm by oil-in-water suspension polymerization (direct phase)

[0198] The synthesis parameters were adapted to the desired microsphere size (see Table 1).

[0199] a) Preparation of aqueous phase

[0200] An aqueous solution of hydrolyzed polyvinyl alcohol (PVA) and sodium chloride was prepared according to the following protocol:

[0201] i) PVA was dissolved in 5 L of pyrogen-free water while stirring at 50°C overnight.

[0202] ii) NaCl was added while stirring at room temperature for 4 hours.

[0203] b) Preparation of organic phase

[0204] v) Weigh each reagent and toluene

[0205] w) Dissolve AIBN in one volume of toluene

[0206] x) Poly(ethylene glycol) methyl ether methacrylate (m-PEG 300 MA) (hydrophilic monomer), poly (ethylene glycol) dimethacrylate (PEG 1000 DMA) (crosslinker), methacrylic acid (AM or MA) (ionizable monomer), MAETIP (radiopaque monomer) and colorant were dissolved in one volume of toluene (in separate containers), then hexanethiol (transfer agent) was added

[0207] y) adding the AIBN solution obtained in step w) to the monomer solution in step x)

[0208] c) Synthesis of microspheres according to the invention

[0209] The aqueous solution of PVA and NaCl prepared in step a) is poured into a reactor and heated to 50°C. The organic phase obtained in step b) is then introduced into the reactor. Stirring is applied with an impeller stirrer to obtain droplets of dispersed phase with a desired diameter. The temperature is then raised to 80°C and stirring is continued for 8 hours. The mixture is then filtered through a 50 μm sieve, and the microspheres are washed with acetone, then ethanol, then water, and then sieved with sieves of 50 μm, 100 μm, 300 μm, 500 μm, 700 μm, 900 μm and 1200 μm.

[0210] Table 1 below summarizes the main synthesis parameters according to the size of the microspheres.

[0211]

[0212]

[0213] *n = number of moles

[0214] Table 1

[0215] Example 3: Measurement of the suspension time of the MS according to the present invention and comparison with MS containing radiopaque monomers other than MAETIP

[0216] The suspension time of the MS according to the invention synthesized in Example 1 in the injection medium (50 / 50 saline / iodinated contrast medium) was studied and compared with the suspension time of a control MS comprising a radiopaque monomer other than MAETIP.

[0217] Control MS was synthesized according to the same protocol as in Example 1 with the same ingredients except for the radiopaque monomers. The following radiopaque monomers were used in the control MS:

[0218] MAOETIB having the following formula:

[0219]

[0220] Compound Vb described in patent application WO 2021 / 069528 and having the following formula:

[0221]

[0222] Suspension is performed using the "Falcon" method:

[0223] Falcon Method

[0224] - Add 1 mL of radiopaque microspheres to 15 mL of polypropylene-lined (or ) tube (polystyrene), and then "fill" the tube with a 50 / 50 mixture of distilled water and contrast medium (observe the edge effect so as to expel as much air as possible from the tube);

[0225] - The microspheres were then suspended by continuously inverting the tube for 3 minutes;

[0226] - The tube was allowed to sit and the sedimentation (or creaming) time of the microspheres was measured.

[0227] Results and Discussion:

[0228] a) The first microsphere suspension test was performed using the previously described protocol. The results obtained are as follows:

[0229]

[0230]

[0231] Table 2: MS using Falcon method Suspension time in tube

[0232] It should be noted that in each case the microspheres settled at the end of their suspension placement in the injection medium.

[0233] b) The second test was performed using the same parameters The results obtained are as follows:

[0234]

[0235] Table 3: MS using Falcon method Suspension time in tube

[0236] In each case, the microspheres settled at the end of their suspension placement in the injection medium.

[0237] In both tests, the suspension time of the MS according to the invention was significantly longer than that of the control MS.

[0238] Results marked with "*" correspond to suspension times greater than 600 seconds. This is not considered relevant for measuring suspension times exceeding 600 seconds, since the results obtained with the suspensions comprising the MS according to the invention are far superior to those observed with the control microspheres.

Claims

1. A compound having the following formula (A):

2. Use of the compound of formula (A) as claimed in claim 1 as a radiopaque halogenated monomer.

3. A radiopaque embolic microsphere comprising a cross-linked matrix based at least on: a) 20% to 90% of a hydrophilic monomer selected from N-vinylpyrrolidone and a monomer 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, wherein m represents an integer from 1 to 30, and preferably, m is equal to 4 or 5 R1, R2, R3, R4, R5 and R6 independently represent H or (C1-C6) alkyl; b) 5% to 50% of a compound having the following formula (A): c) 1% to 15% of a non-biodegradable linear or branched hydrophilic cross-linking monomer having (CH2=(CR 16 ))-group, each R 16 independently represent H or (C1-C6)alkyl; and d) 0.1% to 10% of a transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols, in particular containing 2 to 24 carbon atoms and optionally carrying another functional group chosen from amino, hydroxyl and carboxyl, The percentages of monomers a) to c) are given in moles relative to the total moles of monomers and the percentage of compound d) is given in moles relative to the moles of hydrophilic monomer a).

4. The embolic microspheres according to claim 3, wherein: The matrix comprises, by mole, a quantity greater than 7% and less than or equal to 50%, advantageously greater than 10% and less than or equal to 50%, advantageously greater than 15% and less than or equal to 50%, more advantageously greater than 15% and less than or equal to 35%, and in particular 20% to 30% of the compound of formula (A), relative to the total moles of the monomers.

5. The embolic microsphere 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 (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, tert-butylaminoethyl (meth)acrylate, N,N-diethylaminoacrylate, poly(ethylene oxide) (meth)acrylate, methoxypoly(ethylene oxide) (meth)acrylate, butoxypoly(ethylene oxide) (meth)acrylate, poly(ethylene glycol) (meth)acrylate, methoxypoly(ethylene glycol) (meth)acrylate, butoxypoly(ethylene glycol) (meth)acrylate, poly(ethylene glycol) methyl ether methacrylate, and mixtures thereof; advantageously, monomer a) is poly(ethylene glycol) methyl ether methacrylate.

6. The embolic microsphere according to any one of claims 3 to 5, wherein: The linear or branched non-biodegradable hydrophilic cross-linking monomer c) has (CH2=(CR 16 ))CO- or (CH2=(CR 16 ))CO-O-group, each R 16 and (C1-C6)alkyl.

7. The embolic microsphere according to any one of claims 3 to 6, wherein: The transfer agent d) is selected from the group consisting of thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof.

8. The embolic microsphere according to any one of claims 3 to 7, wherein: The matrix is ​​also based on at least one ionizing or ionizable monomer having the following formula (IV): (CH2=CR 17 )-M-E(IV) in ·R 17 represents H or (C1-C6) alkyl; M represents a single bond or a divalent group containing 1 to 20 carbon atoms; E represents a charged or ionizable group containing not more than 100 atoms, E is advantageously selected from the group consisting of: -COOH, -COO - 、-SO3H、-SO3 - 、-PO3H2、-PO3H - 、-PO3 2- -、-NR 18 R 19 、-NR 20 R 21 R 22 + , ·R 18 , R 19 , R 20 , R 21 , and R 22 Each independently represents H or (C1-C6)alkyl.

9. The embolic microsphere according to any one of claims 3 to 8, wherein: The matrix is ​​also based on at least one colored monomer having the following general formula (VI): in, Z1 and Z2 independently represent H or OR 25 , R 25 represents H or (C1-C6)alkyl, advantageously, Z1 and Z2 represent H; X represents H or Cl, advantageously H; ·R 23 represents H or (C1-C6)alkyl, advantageously (C1-C6)alkyl, in particular methyl; and ·R 24 represents a group selected from the following: straight chain or branched (C1-C6) alkylene, (C5-C 36 ) arylene, (C5-C 36 )Arylene-OR 26 、(C5-C 36 )heteroarylene and (C5-C 36 )heteroarylene-OR 27 , R 26 and R 27 represents (C1-C6)alkyl or (C1-C6)alkylene; advantageously, R 24 It represents the group -C6H4-O-(CH2)2-O or -C(CH3)2-CH2-O.

10. The embolic microsphere according to any one of claims 3 to 9, wherein: The matrix is ​​also based on components visible in magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, advantageously iron oxide nanoparticles.

11. Microspheres according to any one of claims 8 to 10, 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 of any one of claims 8 to 10, filled with macromolecules selected from a combination consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzymes, aptamers, anti-inflammatory proteins, bone morphogenetic proteins (BMPs), pro-angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, and angiogenesis inhibitors or anti-tyrosine kinases, and mixtures thereof.

13. A pharmaceutical composition comprising at least one embolic microsphere according to any one of claims 3 to 12 in combination with a pharmaceutically acceptable vehicle, advantageously for parenteral administration.

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

15. A kit comprising firstly a 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 injection device for parenteral administration, the pharmaceutical composition and the at least one contrast agent being packaged separately.

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