Radiopaque monomer and embolic microspheres containing the same

Abstract

The present invention relates to a compound of the following formula (A) for use mainly as a radiopaque monomer. The present invention further relates to radiopaque embolization microspheres based on at least 20% - 90% hydrophilic monomer, 5% - 50% compound of formula (A), 1% - 15% non - biodegradable hydrophilic cross - linking monomer, and - 0.1% - 10% migrating agent. The present invention also relates to a pharmaceutical composition comprising at least one embolization microsphere according to the invention, preferably with a pharmaceutically acceptable carrier for parenteral administration. The present invention further relates to a kit comprising a pharmaceutical composition according to the invention with a pharmaceutically acceptable carrier for parenteral administration and injection means. TIFF2025521863000019.tif20128

Description

Technical Field

[0001] Field of the Invention The present invention relates to novel radiopaque halogenated monomers, particularly intended for use within a crosslinked matrix related to the composition of embolization microspheres.

Background Art

[0002] Prior Art Therapeutic vascular occlusion (i.e., embolization) is used to prevent or treat specific pathological conditions in situ. It can be performed by a catheter that enables the positioning of particulate occluding agents (i.e., emboli or embolizing agents) within the circulatory system under imaging control. It has various medical applications such as the treatment of vascular malformations, bleeding processes, or tumors including uterine fibroids and primary or secondary liver tumors. For example, vascular occlusion can cause tumor necrosis and avoid more invasive surgery. This occlusion technique can also be associated with the delivery of anticancer agents regarding chemoembolization. This can suppress systemic drug exposure while increasing local concentration by targeted injection and also increase its residence time in the tumor. In the case of vascular malformations, vascular occlusion can normalize blood flow to normal tissues and assist surgery by suppressing the risk of bleeding. In bleeding processes, vascular occlusion can help reduce the flow rate and thus promote arterial wound healing. Depending on the lesion being treated, emboli can also be used for primary or permanent purposes.

[0003] Embolizing agents have conventionally been introduced into blood vessels via a catheter, particularly a microcatheter having a diameter smaller than the diameter of the blood vessel to be treated. Embolizing agents for vascular occlusion include, for example, embolizing liquids (acrylic adhesives, gels), mechanical devices, particles, and polymeric embolization microspheres. The specific material selection depends on many factors such as the type of lesion being treated, the type of catheter used, and the need for primary or permanent embolization.

[0004] Polymer-based embolic microspheres are particularly useful for the above therapeutic purposes. They can be biodegradable for primary embolization or non-biodegradable for permanent embolization, as described in International Patent Publication No. WO 2012 / 120139 and International Patent Publication No. WO 2012 / 120138.

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

[0006] In addition, embolic microspheres can be made radiopaque by adding a radiopaque monomer or entity to their composition so as to be visible by X-ray imaging. Such radiopaque embolic microspheres are described in International Patent Publication No. WO 2021 / 069527 and International Patent Publication No. WO 2021 / 069528. The microspheres in these patent applications incorporate a radiopaque monomer called MAOETIB, having the following formula: TIFF2025521863000002.tif32128.

[0007] Radiopacity refers to the relatively low ability of electromagnetic forces, particularly X-rays, to pass through high-density materials, which is described as "radiopaque / white" in X-ray images. Considering the complexity of the content in X-ray or fluoroscopy images, clinicians are sensitive to the quality of the images regarding the luminance or signal intensity of the materials in the images. The two main factors contributing to radiopacity are density and atomic number. Polymer-based medical devices that require radiopacity typically use a mixture of polymers incorporating a small amount of radiopaque elements, such as halogens, particularly heavy atoms like iodine, by weight percentage. The ability of the device to be visualized by fluoroscopy depends on the amount or density of the radiopaque elements mixed in the material. However, the addition of radiopaque monomers or entities with halogenated groups seems to significantly reduce the hydrophilicity of the material. Microspheres incorporating this type of radiopaque monomer or entity also have an increased density, which affects their suspension in the injection medium. In summary, iodine-filled microspheres for X-ray visibility in the prior art are typically more hydrophobic, denser, harder, and tend to form microsphere aggregates than X-ray invisible microspheres. As a result, (1) they are difficult to maintain in suspension during the period of injection within the catheter, (2) they often clog the catheter, for example, by tending to clump together even when their diameter is smaller than the inner diameter of the catheter (Duran 2016), and (3) they tend to adhere to the walls of the catheter.

[0008] Accordingly, it is preferred to provide available radiopaque monomers or entities related to the composition of embolic microspheres that allow them to remain hydrophilic and flexible when swollen with water. These microspheres preferably also have mechanical properties suitable for injection via a catheter or microcatheter, particularly a certain degree of swelling, elasticity, and compressibility. It is also desirable that these microspheres can be maintained in suspension in an injection mixture (a formulated mixture of a contrast agent and an aqueous phase) over the period of injection within the catheter. This is because the microspheres are generally suspended in a mixture of a non-ionic iodine contrast agent and an aqueous phase, both for injectability and for the operator to be able to track the injection under X-ray control. For this purpose, radiology technicians generally use a solution of a contrast agent and optionally a solution of physiological saline, bicarbonate buffer, or phosphate buffer, preferably a solution of a 100% contrast agent product. To ensure injectability, the microspheres must be kept uniformly suspended in this solution. If the microspheres sediment or, conversely, float on the surface of the solution, the resulting suspension is non-uniform and unstable and thus cannot be injected into the patient.

[0009] WO 2021 / 069527 and WO 2021 / 069528 describe radiopaque halogenated monomers that can fully meet these requirements. However, there is still a need for new radiopaque monomers or entities intended for the preparation of embolic microspheres that allow better performance in terms of, for example, the stability or injectability of suspensions containing said microspheres while maintaining compatibility with the above iodine contrast agents. SUMMARY OF THE INVENTION

[0010] In this regard, the inventors have developed a novel radiopaque halogenated monomer of formula (A) that provides improved performance of embolic microspheres containing this monomer in the composition. For example, this novel radiopaque monomer of formula (A) makes it possible, in particular, for embolic microspheres containing it to avoid aggregating together in a catheter or microcatheter before injection. The presence of this novel radiopaque halogenated monomer of formula (A) in the embolic microspheres also prevents the microspheres from adhering to the walls of the catheter or microcatheter before injection. In addition, the suspension and injectability of these microspheres are also improved by this novel radiopaque monomer.

[0011] For the purposes of the present invention, the term "improved suspension" is understood to mean the ability of microspheres to form a suspension that is stable and uniform over a predetermined period compatible with the use of the microspheres, i.e., having the same distribution of microspheres throughout the suspension liquid volume.

[0012] For the purposes of the present invention, the term "improved injectability" is understood to mean the ability of a suspension to be injected through an injection system such as a syringe or catheter without clogging and without requiring great effort on the part of the practitioner.

[0013] Accordingly, the present invention relates to a compound of the following formula (A): TIFF2025521863000003.tif20128

[0014] This compound is also denoted herein by the term MAETIP.

[0015] Another subject of the present invention relates to the use of a compound of formula (A) as defined above as a radiopaque halogenated monomer.

[0016] Another subject of the present invention relates to embolic microspheres containing said radiopaque halogenated monomer of formula (A).

[0017] Accordingly, the present invention also relates to the use of a compound of formula (A) in embolization microspheres.

[0018] The present invention further relates to a pharmaceutical composition comprising the embolization microspheres as defined above, in combination with a pharmaceutically acceptable vehicle, preferably for administration by injection.

[0019] Another subject of the present invention is a kit comprising the pharmaceutical composition as defined above and at least one means for injecting the composition for parenteral administration of the composition.

[0020] Another subject of the present invention is a kit comprising, on the one hand, the pharmaceutical composition as defined above, and on the other hand, a contrast agent for imaging by X-ray, magnetic resonance or ultrasound, and optionally at least one injection means for parenteral administration, preferably, the injection means is the Vectorio® device described in WO 2016 / 166346, WO 2016 / 166339, WO 2017 / 005914 and WO 2017 / 081178. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description Accordingly, a main subject of the present invention is a compound of the following formula (A): TIFF2025521863000004.tif20128

[0022] In the compound of formula (A), the iodine atoms are located at the 2, 4, and 6 positions of the phenyl ring. Due to the size of the iodine atoms and their uniform distribution in the phenyl ring, this compound provides reduced steric accessibility to aromatic carbons (at the 3 and 5 positions of the phenyl ring) compared to MAOETIB or compound (Vb) of WO 2021 / 069528 pamphlet, where the iodine atoms are at the 2, 3, and 5 positions of the phenyl ring and the aromatic carbons are at the 4 and 6 positions of the phenyl ring. The restricted accessibility of the aromatic carbons in the compound of formula (A) seems to have the effect of reducing the lipophilicity of the molecule. The reason for this is that the intermolecular or intramolecular interactions of these carbons are reduced so as to suppress the adhesiveness of the molecule, and rather, they even disappear. In other words, the configuration of the compound of formula (A) helps to prevent the embolic microspheres incorporating the said compound from aggregating together.

[0023] According to the present invention, this compound of formula (A) is advantageously used as a radiopaque halogenated monomer. Thus, another main subject of the present invention is the use of the compound of formula (A) as defined above as a radiopaque halogenated monomer.

[0024] Furthermore, the present invention relates to embolic microspheres comprising the radiopaque halogenated monomer of formula (A). In particular, the embolic microspheres comprise a crosslinked polymer matrix comprising the radiopaque halogenated monomer of formula (A).

[0025] In a particular embodiment, the crosslinked polymer matrix is as defined in WO 2021 / 069528 pamphlet, except that the radiopaque halogenated monomer of general formula (II) is replaced by the compound of formula (A) according to the present invention. In other words, the crosslinked polymer matrix comprises at least (a) N-vinylpyrrolidone and the following formula (I): (CH2=CR1)-CO-D (I) (wherein, · D represents O-Z or NH-Z, and Z 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, preferably m is equal to 4 or 5, · R1, R2, R3, R4, R5 and R6 each independently represent H or (C1-C6) alkyl) selected from monomers of, 20% to 90% hydrophilic monomers, (b) 5% to 50% of the following formula (A): TIFF2025521863000005.tif20128 compound, (c) 1% to 15% of a linear or branched non-biodegradable hydrophilic crosslinking monomer, each of its ends showing a (CH2=(CR 16 ))- group, each R 16 independently represents H or (C1-C6) alkyl, a linear or branched non-biodegradable hydrophilic crosslinking monomer, and (d) 0.1% to 10% of a migrating agent selected from halogenated alkyls and alicyclic or aliphatic thiols having specifically 2 to 24 carbon atoms and optionally having another functional group selected from amino, hydroxyl and carboxyl groups based on, the percentages of monomers (a) to (c) are shown in moles relative to the total number of moles of monomers, and the percentage of compound (d) is shown in moles relative to the number of moles of hydrophilic monomer (a).

[0026] The hydrophilic monomer, crosslinking monomer (c) and migrating agent (d) of formula (I) are preferably as defined in International Patent Application Publication No. WO 2021 / 069528, especially on pages 13 and 19-22.

[0027] For the purposes of the present invention, the term "hydrophilic monomer" is understood to mean a monomer that has a high affinity for water, i.e., a tendency to dissolve in water, mix with water, be wetted by water, or swell in water after polymerization.

[0028] For the purposes of the present invention, the term "crosslinking monomer" is understood to mean not only at least bifunctional monomers but also polyfunctional monomers having double bonds at each polymerizable end. Crosslinking monomers enable the formation of a crosslinked network structure in combination with other monomers in a mixture. The structure and amount of crosslinking monomers in a monomer mixture to obtain a desired crosslink density can be readily selected by those skilled in the art. Crosslinking agents are also advantageous for the stability of the microspheres. Crosslinking agents prevent the microspheres from dissolving in any solvent. Crosslinking agents also make it possible to improve the compressibility of the microspheres, which is favorable for the plugs.

[0029] For the purposes of the present invention, the term "non-biodegradable hydrophilic crosslinking agent" is understood to mean a crosslinking agent as defined above that has a high affinity for water and is non-degradable under the physiological conditions of the mammalian body, particularly the human body. This is because biodegradation of the molecule becomes possible when it contains sufficient functional sites that can be cleaved under physiological conditions, particularly by endogenous enzymes of the mammalian body, particularly the human body, and / or at a physiological pH (generally about 7.4). Functional sites that can be cleaved under physiological conditions particularly include amide bonds, ester bonds, and acetals. Thus, molecules containing an insufficient number of said functional sites will be considered non-biodegradable. With respect to the present invention, the crosslinking 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, and even more preferably less than 5 sites.

[0030] Regarding the present invention, the term "transfer agent" is understood to mean a chemical compound containing at least one weak chemical bond. This agent reacts with the radical site of the growing polymer chain and interrupts the chain growth. In the chain transfer process, the radical temporarily transfers to the transfer agent, and the transfer agent resumes growth by transferring the radical to another polymer or monomer.

[0031] The term "matrix based on ~" is naturally understood to include a matrix that contains a mixture of the basic components used in the polymerization of this matrix in a heterogeneous medium and / or the product of the reaction between these basic components, preferably only the product of the reaction between the various basic components used in this matrix. Some of these basic components may be intended to react or be capable of reacting with each other or their adjacent chemical environment during various stages of the matrix manufacturing process, especially during the polymerization step. Therefore, the basic components are the reactants intended to react together during the polymerization of the matrix. Thus, the basic components are introduced into the reaction mixture, which may optionally further contain a solvent or a mixture of a solvent 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. For the present invention, the reaction mixture contains, as at least basic components, the monomers (a), (b), (c) and the transfer agent (d) described herein, optionally a polymerization initiator, such as t-butyl peroxide, benzoyl peroxide, azobisisovaleronitrile (also called 4,4'-azobis(4-cyanopentanoic 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 (Darocur® 1173, 7473-98-5), 2,2-dimethoxy-2-phenylacetophenone (24650-42-8), 2,2-dimethoxy-2-phenylacetophenone (Irgacure®, 24650-42-8) or 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (Irgacure®, 71868-10-5) and at least one solvent, preferably a solvent mixture containing an aqueous solvent and an organic solvent, such as a nonpolar aprotic solvent, such as a non-miscible water / toluene system.

[0032] Accordingly, according to the present invention, the matrix is based at least on the monomers (a), (b), (c) and the mobile agent (d) described herein, and accordingly, these compounds are basic components.

[0033] Accordingly, in this specification, expressions such as "[basic component X] is particularly added to the reaction mixture in an amount of YY% to YYY%" and "the crosslinked matrix is particularly based on [basic component X] in an amount of YY% to YYY%" are interpreted in the same way. Similarly, expressions such as "the reaction mixture contains at least [basic component X]" and "the crosslinked matrix is based at least on [basic component X]" are interpreted in the same way.

[0034] For the purposes of the present invention, the "organic phase" of the reaction mixture is understood to mean the phase containing the organic solvent and the compounds soluble in said organic solvent, in particular the monomers, the mobile agent and the polymerization initiator.

[0035] For the purposes of the present invention, the term " X ~C Y ) alkyl" group is understood to mean a saturated, straight-chain or branched monovalent hydrocarbon-based chain containing from X to Y carbon atoms, where X and Y are integers from 1 to 36, preferably from 1 to 18, in particular from 1 to 6. By way of example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl groups may be mentioned.

[0036] With respect to the present invention, the compound of formula (A) is particularly added to the reaction mixture in an amount of 5% to 50% on a molar basis, in particular more than 7% and up to 50%, in particular more than 10% and up to 50%, more particularly more than 15% and up to 50%, preferably more than 15% and up to 35%, in particular 20% to 30% based on the total molar number of the monomers.

[0037] The embolization microspheres containing the cross-linked polymer matrix defined above preferably correspond to spherical particles having a post-swelling diameter in the range of 20 to 1200 μm, such as 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 preferably have a diameter small enough to be injected by a needle, catheter or microcatheter having an inner diameter in the range of several hundred micrometers to over 1 millimeter.

[0038] The expression "post-swelling" means that the size of the microspheres is considered after the polymerization and sterilization steps carried out during their preparation. The sterilization step includes, for example, passing the microspheres through an autoclave at a high temperature, typically a temperature above 100 °C, preferably 110 °C to 150 °C, preferably 121 °C, after the polymerization step. 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 TIFF2025521863000006.tif10128, where m w is the weight (grams) of 1 ml of sedimented microspheres, and m d is the weight (grams) of 1 ml of microspheres freeze-dried after sedimentation.

[0039] In a particular embodiment of the present invention, the cross-linked polymer matrix of the microspheres is based only on the basic components (a), (b), (c) and (d) defined above, in the above proportions of monomers and mobile agents, and no other basic components are added to the reaction medium. Thus, it is clear that the sum of the above proportions of monomers (a), (b) and (c) must be equal to 100%.

[0040] Preferably, the hydrophilic monomer of formula (I) is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, t-butylaminoethyl (meth)acrylate, Ν,Ν-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.

[0041] More preferably, the hydrophilic monomer (a) is poly(ethylene glycol)methyl ether methacrylate (m-PEGMA).

[0042] With respect to the present 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%, particularly 45% to 65% on a molar basis relative to the total molar number of monomers. Therefore, with respect to the present invention, the crosslinked matrix is particularly based on the hydrophilic monomer (a) in an amount of 20% to 90%, preferably 30% to 80%, more preferably 40% to 70%, particularly 45% to 65% on a molar basis relative to the total molar number of monomers.

[0043] Advantageously, the linear or branched non-biodegradable hydrophilic crosslinking monomer has at least two ends with (CH2=(CR 16 ))CO- or (CH2=(CR 16 ))CO-O- groups, and each R 16 independently represents H or (C1-C6)alkyl.

[0044] In particular, the crosslinking agent is of the following general formula (IIIa) or (IIIb): (CH2=(CR 16 ))CO-NH-A-HN-OC((CR 16 )=CH2) (IIIa), (CH2=(CR 16 ))CO-O-A-O-OC((CR 16 )=CH2) (IIIb) wherein each R 16 independently represents H or (C1-C6) alkyl, and preferably, the R 16 radicals are the same and represent H or (C1-C6) alkyl, A, alone or together with at least one of the atoms to which it is attached, represents (C1-C6) alkylene, polyethylene glycol (PEG), polysiloxane, poly(dimethylsiloxane) (PDMS), polyglycerol ester (PGE) or bisphenol A.

[0045] Preferably, the crosslinking agent is of the following general formula (IIa) or (IIb): (CH2=(CR 16 ))CO-NH-A-HN-OC((CR 16 )=CH2) (IIIa), (CH2=(CR 16 ))CO-O-A-O-OC((CR 16 )=CH2) (IIIb) wherein each R 16 independently represents H or (C1-C6) alkyl, and preferably, the R 16 radicals are the same and represent H or (C1-C6) alkyl, A preferably, alone or together with at least one of the atoms to which it is attached, represents (C1-C6) alkylene or polyethylene glycol (PEG), preferably polyethylene glycol (PEG).

[0046] Regarding the above definition of A, polyethylene glycol has a length in the range of 200 to 10,000 g / mol, preferably 200 to 2,000 g / mol, more preferably 500 to 1,000 g / mol.

[0047] Examples of crosslinking monomers that can be used in the present invention include, but are not limited to, 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylene bisacrylamide, glyceryl 1,3-diglycerolate diacrylate, and poly(ethylene glycol) dimethacrylate (PEGDMA).

[0048] Advantageously, the crosslinking monomer is poly(ethylene glycol) dimethacrylate (PEGDMA), and the polyethylene glycol units have a length in the range of 200 to 10,000 g / mol, preferably 200 to 2,000 g / mol, more preferably 500 to 1,000 g / mol.

[0049] Regarding the present 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%, more particularly 2% to 5% on a molar basis with respect to the total number of moles of the monomers.

[0050] Advantageously, the chain transfer agent is selected from the group consisting of monofunctional or polyfunctional thiols and alkyl halides.

[0051] Examples of alkyl halides that can be used as the transfer agent include, in particular, bromotrichloromethane, carbon tetrachloride, and carbon tetrabromide. Particularly advantageously, the chain transfer agent is an alicyclic or aliphatic thiol typically having 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferentially 6 carbon atoms, and optionally having an additional functional group selected from amino, hydroxyl, and carboxyl groups.

[0052] Advantageously, the transfer agent is selected from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof.

[0053] Regarding the present invention, the migrating 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 preferably 1.5 mol% to 6 mol%, particularly 1.5 mol% to 4.5 mol%, and especially 3 mol%, based on the number of moles of the hydrophilic monomer (a).

[0054] In another specific embodiment of the present invention, the crosslinked polymer matrix of the microspheres of the present invention further comprises - an ionized or ionizable monomer, and / or - for example, a monomer colored so as to be visible to the naked eye, such as to confirm that the microsphere suspension is homogeneous in the syringe before injection and to control the injection rate, and / or - at least one agent visible by magnetic resonance imaging (MRI). is based on

[0055] The ionized or ionizable monomer, the colored monomer, and the MRI visualization agent are as specifically defined in Pamphlet of International Publication No. WO 2021 / 069528, particularly on pages 22 to 25.

[0056] In particular, the crosslinked polymer matrix of the embolizing microspheres of the present invention further comprises the following formula (IV): (CH2=CR 17 )-M-E (IV) (wherein ·R 17 represents H or (C1-C6) alkyl, ·M represents a single bond or a divalent radical having 1 to 20 carbon atoms, ·E represents a charged or ionizable group having 100 or fewer atoms, and E is preferably -COOH, -COO - , -SO3H, -SO3 - , -PO3H2, -PO3H - , -PO3 2- , -NR 18 R 19 , and -NR20 R 21 R 22 + selected from the group consisting of ·R 18 R 19 R 20 R 21 and R 22 each independently represent H or (C1-C6) alkyl) may be based on at least one ionized or ionizable monomer of

[0057] For the purposes of the present invention, the term "ionized or ionizable group" is understood to mean a group that is charged or can be in a charged form (ionic form), i.e., has at least one positive or negative charge depending on the pH of the medium. For example, the COOH group can be ionized in the form of COO - and the NH2 group can be in the ionized form NH3 +

[0058] The introduction of an ionized or ionizable monomer into the reaction mixture increases the hydrophilicity of the resulting microspheres, and thus increases the degree of swelling of said microspheres, facilitating their injection via catheters and microcatheters. Furthermore, the presence of an ionized or ionizable monomer allows the active substance to be loaded into the microspheres.

[0059] According to a preferred variant, the ionized or ionizable monomer is of the following formula (IV-A): (CH2=CR 17 )-C(O)-O-M'-E (IV) wherein ·R 17 and E are as defined above, ·M' is a hydrocarbon-based chain containing 1 to 20 atoms.

[0060] ​Preferably, the ionized or ionizable monomer is a cationic monomer preferably selected from the group consisting of methacrylic acid, (methacryloyloxy)ethyl phosphorylcholine, 2-(dimethylamino)ethyl (meth)acrylate, 2-(diethylamino)ethyl (meth)acrylate, 11-methacryloyloxyundecylphosphonic acid, and 2-((meth)acryloyloxy)ethyl)trimethylammonium chloride, and preferably, the cationic monomer is (diethylamino)ethyl (meth)acrylate. Preferably, the crosslinked matrix according to the present invention is based on the above cationic monomer in an amount of 1 mol% to 40 mol% relative to the total number of moles of the monomer. Preferably, when it is not intended to fill the resulting microspheres with an active substance, the crosslinked matrix according to the present invention is based on the ionized or ionizable monomer in an amount of 5 mol% to 15 mol%, preferably 10 mol%, relative to the total number of moles of the monomer. According to another embodiment, when it is intended to fill the microspheres with an active substance, the crosslinked matrix according to the present invention is obtained by adding 20 mol% to 40 mol% to the reaction mixture, preferably by adding the ionized or ionizable monomer in an amount of 20 mol% to 30 mol% relative to the total number of moles of the monomer to the reaction mixture.

[0061] In another advantageous embodiment, the ionized or ionizable monomer is an anionic monomer preferably selected from the group consisting of acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-oligomer of carboxyethyl acrylate, 3-sulfopropyl (meth) acrylate, hydroxide and potassium salt of 2-((methacryloyloxy) ethyl) dimethyl-(3-sulfopropyl) ammonium. Advantageously, the crosslinked matrix according to the present invention is based on the anionic monomer in an amount of 1 mol% to 40 mol% relative to the total number of monomers. Preferably, when it is not intended to fill the obtained microspheres with an active substance, the crosslinked matrix according to the present invention is based on the ionized or ionizable monomer in an amount of 5 mol% to 15 mol%, preferably 10 mol% relative to the total number of monomers. According to another embodiment, when it is intended to fill the microspheres with an active substance, the crosslinked matrix according to the present invention is based on the ionized or ionizable monomer in an amount of 20% to 40%, preferably 20% to 30% relative to the total number of monomers.

[0062] In a particularly advantageous method, the ionized or ionizable monomer is methacrylic acid (MA or AM). Advantageously, the crosslinked matrix according to the present invention is based on methacrylic acid (MA) in an amount of 10 mol% to 30 mol% relative to the total number of monomers.

[0063] The crosslinked polymer matrix further has the following general formula (VI): TIFF2025521863000007.tif31128(wherein, ·Z1 and Z2 are, independently of each other, H or OR 25 represents, 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, particularly methyl, and ·R 24 represents a group selected from linear or branched (C1-C6) alkylene, (C5-C 36 ) arylene, (C5-C 36 ) arylene-O-R 26 , (C5-C 36 ) heteroarylene and (C5-C 36 ) heteroarylene-O-R 27 , and 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). can be based on at least one colored monomer of .

[0064] For the purposes of the present invention, the term "(C X -C Y ) alkylene group" is understood to mean a linear or branched divalent hydrocarbon chain containing X to Y carbon atoms, where X and Y are integers from 1 to 36, preferably from 1 to 18, particularly from 1 to 6. By way of example, methylene, ethylene, propylene, butylene, pentylene or hexylene groups may be mentioned.

[0065] For the purposes of the present invention, the term "(C X -C Y ) heteroarylene" is understood to mean a divalent aromatic group containing X to Y ring atoms, advantageously 1 to 4, more preferably 1 or 2, of one or more heteroatoms, such as sulfur, nitrogen or oxygen atoms, the other ring atoms being carbon atoms. X and Y are integers from 5 to 36, preferably from 5 to 18, particularly from 5 to 10.

[0066] For the purposes of the present invention, the term "divalent radical" is understood to mean a radical having a valency of 2, i.e. having two covalent, polar covalent or ionic chemical bonds. Said radical may contain, for example, carbon and / or oxygen atoms.

[0067] Advantageously, the coloring monomer is of the following formula (VIa) or (VIb): It is that of TIFF2025521863000008.tif45157.

[0068] More advantageously, the coloring monomer is of the above formula (VIb).

[0069] Regarding the present invention, the coloring monomer is 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% based on the total molar amount of the monomers.

[0070] The crosslinked polymer matrix further includes components visible by magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelates or magnesium chelates, and advantageously may also be based on iron oxide nanoparticles.

[0071] Regarding the present invention, the MRI visualization component is advantageously added to the reaction mixture in an amount of 0% to 0.5%, preferably 0.025% to 0.4%, more preferentially 0.025% to 0.25%, and particularly 0.05% based on the mass of the MRI visualization component with respect to the volume of the organic phase in order to obtain microspheres that can be visualized and quantified by MRI.

[0072] The crosslinked polymer matrix of the embolization microspheres of the present invention can be easily synthesized by several processes well known to those skilled in the art. As an example, it can be obtained by suspension polymerization as described in International Patent Application Publication No. WO 2021 / 069528 pamphlet, particularly on pages 27 to 29.

[0073] In a specific embodiment, the embolization microspheres according to the present invention are filled with an active substance, thereby enabling combined vascular occlusion and delivery of the active ingredient. The active substance can be selected from drugs, diagnostic agents and polymers as defined in International Patent Application Publication No. WO 2021 / 069528 pamphlet, particularly on pages 29 to 31.

[0074] Preferably, the microspheres according to the present invention can be filled with an active substance selected from an anticancer agent, an anti-inflammatory agent, a local anesthetic, an analgesic, an antibiotic, a steroid, a bactericide, and mixtures thereof.

[0075] The anticancer agent is preferably an anthracycline such as doxorubicin, epirubicin or idarubicin, a platinum complex, an anthracycline-related compound such as mitoxantrone and nemorubicin, and an antibiotic such as mitomycin C (Ametycine®), bleomycin and actinomycin D, irinotecan, 5-fluorouracil (Adrucil®), sorafenib (Nevaxar®), sunitinib (Sutent®), regorafenib, brivanib, orantinib, linifanib, erlotinib, cabozantinib, foretinib, tibantineb, fotemustine, tauromustine (TCNU), carmustine, cytosine C, cyclophosphonamide, cytosine arabinoside (or cytarabine), paclitaxel, docetaxel, methotrexate, everolimus (Afinitor®), PEG - arginine deiminase, tegafur / gimeracil / oteracil combination (Teysuno®), muparfostat, peletinoin, gemcitabine, bevacizumab (Avastin®), ramucirumab, floxuridine and other antitumor compounds, GM - CSF (granulocyte - macrophage colony - stimulating factor) and its recombinant forms: immunostimulants such as molgramostim or sargramostim (Leukine®), OK - 432 (Picibanil®), interleukin - 2, interleukin - 4 and tumor necrosis factor - α (TNFα), antibodies, radioactive elements, complexes of these radioactive elements with chelates, nucleic acid sequences, and mixtures of one or more of these compounds (preferably mixtures of one or more anthracyclines).

[0076] Preferably, the anticancer agent is selected from anthracyclines, immunostimulants, platinum complexes, anti - neoplastic agents, and mixtures thereof.

[0077] Even more preferably, the anticancer agent is selected from anthracyclines, antibodies, anti-neoplastic agents, and mixtures thereof.

[0078] The antibody is selected from, for example, anti-PD-1 substances, anti-PD-L1 substances, anti-CTLA-4 substances, anti-CEA (carcinoembryonic antigen) substances, or mixtures thereof.

[0079] Examples of the anti-PD-1 substance include nivolumab and pembrolizumab.

[0080] Examples of the anti-PD-L1 substance include avelumab, durvalumab, and atezolizumab.

[0081] Examples of the anti-CTLA-4 substance include ipilimumab and tremelimumab.

[0082] Even more preferably, 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.

[0083] Preferably, the local anesthetic is selected from lidocaine, bupivacaine, and mixtures thereof.

[0084] The anti-inflammatory agent may be selected from ibuprofen, niflumic acid, dexamethasone, naproxen, and mixtures thereof.

[0085] Regarding the present invention, the microspheres can be filled, particularly by immediate adsorption, with a polymer 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), angiogenesis promoters, vascular endothelial growth factor (VEGF) and TGF-β, angiogenesis inhibitors, or anti-tyrosine kinases, and mixtures thereof.

[0086] The anti-inflammatory protein is, for example, infliximab or rilonacept and mixtures thereof.

[0087] The angiogenesis promoter is, for example, fibroblast growth factor (FGF) and mixtures thereof.

[0088] Examples of angiogenesis inhibitors include bevacizumab, ramucirumab, nesvacumab, olaparatumab, bavituximab, lirilumab, emibetuzumab, aflibercept, ficlatuzumab, pegaptanib, and mixtures thereof.

[0089] Examples of anti-tyrosine kinases include lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, sulfatinib, dovitinib, linifanib, and mixtures thereof.

[0090] Advantageously, the microspheres can be filled with a polymer selected from anti-tyrosine kinases, TGF-β substances, angiogenesis inhibitors, and mixtures thereof.

[0091] The active substance is typically adsorbed to the crosslinked matrix by non-covalent interactions, optionally in the presence of pharmaceutically acceptable excipients well known to those skilled in the art. This particular method of capturing the active substance is called physical encapsulation. No specific requirements are imposed on the active substance to be filled.

[0092] The filling can proceed by several processes well known to those skilled in the art, such as passive adsorption (swelling of the crosslinked matrix in the drug solution) or ionic interactions. These methods are described, for example, in International Patent Application Publication No. WO 2012 / 120138, particularly on pages 22, line 20 to page 26, line 7. The efficiency of filling mainly depends on the compatibility between two structures and / or favorable interactions.

[0093] Another subject of the present invention relates to a pharmaceutical composition comprising the embolization microspheres according to the invention, in combination with a pharmaceutically acceptable vehicle, advantageously for administration by injection.

[0094] Examples of pharmaceutically acceptable vehicles include, but are not limited to, water for injection, saline solution also known as physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, plasma, contrast agents for X-ray, magnetic resonance or ultrasonic imaging, buffer agents, bactericides, gelling agents, glucose and / or surfactants. Advantageously, the pharmaceutically acceptable vehicle is physiological saline, water for injection, a contrast agent for X-ray, magnetic resonance or ultrasonic imaging or a mixture thereof. More advantageously, the pharmaceutically acceptable vehicle is physiological saline, a contrast agent for X-ray, magnetic resonance or ultrasonic imaging or a mixture of physiological saline and a contrast agent for X-ray, magnetic resonance or ultrasonic imaging.

[0095] According to the present invention, the contrast agent is preferably a contrast agent for X-ray imaging. Advantageously, it is a water-soluble iodine non-ionic contrast agent such as iobitridol (Xenetix®), iopamidol (Iopamiron®, Isovue®), iomeprol (Iomeron®), ioversol (Optiray®, Optiject®), iohexol (Omnipaque®), iopentol (Imagopaque®), ioxitol (Oxilan®), iopromide (Ultravist®), metrizamide (Amipaque®), iosarcol (Melitrast®), iotrolan (Isovist®), iodixanol (Visipaque®), iocimenol and iocimide (Univist®) and mixtures thereof.

[0096] According to another embodiment, the contrast agent is a magnetic resonance imaging (MRI) contrast agent. Advantageously, these are gadolinium chelates (Dotarem®, Gadopiclenol).

[0097] According to another embodiment, the contrast agent is an ultrasound imaging contrast agent. It is advantageously sulfur hexafluoride (Sonovue®).

[0098] In a particular embodiment of the invention, the pharmaceutical composition comprises the embolization microspheres according to the invention in combination with physiological saline, and the composition is intended to be mixed with at least one contrast agent for imaging by X-ray, magnetic resonance or ultrasound as defined above, in particular X-ray imaging, before administration by injection, such mixing resulting in a suspension of the microspheres according to the invention.

[0099] In a particular embodiment according to the invention, the pharmaceutical composition according to the invention comprises the embolization microspheres according to the invention in combination with a mixture of physiological saline and the 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.

[0100] The pharmaceutical composition must have a viscosity acceptable for injection.

[0101] The embolization microspheres according to the invention can be used for various biomedical purposes, as described above, which means that they must be compatible with the human or mammalian body. More particularly, suitable biomedical materials do not have hemolytic properties.

[0102] Another subject of the present invention is a kit comprising the pharmaceutical composition defined above and at least one means for injecting said composition for parenteral administration of said composition. According to the present invention, the term "injecting means" is understood to mean any means enabling parenteral administration. Advantageously, said injecting means is one or more syringes for administration of said composition by injection, and / or one or more syringes that can be pre-filled, and / or one or more catheters or microcatheters.

[0103] Advantageously, the pharmaceutical composition present in said kit comprises the microspheres according to the invention in combination with physiological saline, a contrast agent or a mixture thereof. More advantageously, said pharmaceutical composition comprises the microspheres according to the invention in combination with a mixture of physiological saline and a contrast agent in a ratio of 80 / 20 to 0 / 100, advantageously 70 / 30 to 40 / 60, preferably 50 / 50.

[0104] Advantageously, the injecting means present in the kit according to the invention is suitable for parenteral administration of the pharmaceutical composition according to the invention. Thus, the size of the syringe or (micro)catheter is adapted according to the size of the microspheres according to the invention and the volume to be injected for embolization. A person skilled in the art will be able to select the most suitable injecting means. According to a preferred embodiment, said injecting means is the Vectorio® device described in WO 2016 / 166346, WO 2016 / 166339, WO 2017 / 005914 and WO 2017 / 081178.

[0105] Another subject of the present invention is a kit comprising, on the one hand, the pharmaceutical composition defined above, and on the other hand, at least one contrast agent for imaging by X-ray, magnetic resonance or ultrasound, and optionally at least one injecting means for parenteral administration. The injecting means is as defined above.

[0106] In the kit, the pharmaceutical composition and the contrast agent are separately packaged and are intended to be mixed immediately before administration by injection.

[0107] In the kit, at least one contrast agent is as defined above herein. In particular, at least one contrast agent is an X-ray imaging contrast agent as defined above herein.

[0108] In the kit, the pharmaceutical composition preferably contains the microspheres according to the invention in combination with a pharmaceutically acceptable vehicle for administration by injection. The pharmaceutically acceptable vehicle can be, for example, but not limited to, water for injection, physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, glucose and / or plasma. Preferably, in the kit, the pharmaceutical composition preferably contains the microspheres according to the invention in combination with physiological saline or water for injection.

[0109] In the kit, the pharmaceutical composition is preferably directly packaged in an injection device, particularly a syringe, suitable for parenteral injection of the embolizing microspheres.

[0110] In the kit, the contrast agent is preferably packaged in a bottle or directly packaged in an injection device, particularly a syringe, particularly suitable for parenteral injection of the embolizing microspheres.

[0111] In the kit, the ratio of the pharmaceutically acceptable vehicle / contrast agent is 50 / 50 to 0 / 100, preferably 40 / 60 to 0 / 100, and more preferably 30 / 70 to 0 / 100.

Example

[0112] Example 1: Synthesis of MAETIP (compound of formula (A) according to the invention) Materials and Methods Chemicals: - Magnesium sulfate (MgSO4, anhydrous, 98%, Sigma-Aldrich, ref: 230391, CAS: 10034-99-8) - 2,4,6-Triiodophenol (95-98%, BLDpharm, ref: A17145, CAS: 609-23-4) - 2-[2-(2-Chloroethoxy)ethoxy]ethanol (95~98%, TCI, ref: QF-8470, CAS: 5197-62-6) - Sodium iodide (NaI, >99%, Oakwood Chemical, ref: QE-0904, CAS: 7681-82-5) - Sodium hydroxide (NaOH, anhydrous, >98%, Sigma-Aldrich, ref: S8045, CAS: 1310-73-2) - Methacrylic acid anhydride (AM, >94%, Sigma-Aldrich, ref: 276685, CAS: 760-93-0) - Triethylamine (TEA, >99.5%, Sigma-Aldrich, ref: 471283, CAS: 121-44-8).

[0113] Solvent: - Absolute ethanol (EtOH, 99.96%, VWR, ref: 20821.310, CAS: 64-17-5) - Ethyl acetate (anhydrous, 99.8%, Sigma-Aldrich, ref: 270989, CAS: 141-78-6) - Heptane (>99%, Sigma-Aldrich, ref: 34873, CAS: 142-82-5) - Dichloromethane (DCM, anhydrous, >99.8%, Sigma-Aldrich, ref: 270997, CAS: 75-09-2) - Distilled water (Grade 2).

[0114] Apparatus: - Magnetic plate (Heidoplh, MR Hei-Standard) - Rotary evaporator (Buchi Rotavapor R-215) - Precision balance (d = 0.1mg, Sartorius) - Silica column: ChromatoFlash (Buchi).

[0115] 1. O-alkylation TIFF2025521863000009.tifDissolve triiodophenol (200 mg, 0.42 mmol) in 2.2 mL of ethanol in a 3213110 mL round-bottom flask. Add NaOH (15 mg, 0.375 mmol), and then stir the mixture at room temperature for 30 minutes. After stirring, perform evaporation under reduced pressure until a pale yellow solid is obtained.

[0116] Place NaI (57 mg, 0.375 mmol) and 2-[(2-chloroethoxy)ethoxy]ethanol (55 μL, 0.375 mmol) into a three-necked flask equipped with a condenser and placed under nitrogen. Dissolve the mixture in 1.7 mL of ethanol until NaI is completely dissolved. Next, add the triiodophenol derivative previously dissolved in 0.7 mL of ethanol. Heat the reaction medium under reflux for 2.5 days while ensuring a sufficiently high water flow rate in the condenser so that rapid ethanol condensation is observed.

[0117] Monitor the progress of the reaction by TLC (thin-layer chromatography): 5 / 5 heptane / ethyl acetate.

[0118] At the end of the reaction, evaporate the reaction medium under pressure, and then dissolve the resulting solid in 6 mL of NaOH (6 M) solution. Next, wash the aqueous phase with DCM (dichloromethane) (3 × 7 mL). Dry the organic phase over MgSO4. A yellowish solid is obtained. Purify by silica column using a heptane / ethyl acetate co-elution system. After purification, 0.133 mg of a white solid is obtained. Molar yield: 85%. U.V. purity: 96%.

[0119] 2. Esterification of alcohol Dissolve Intermediate 1 (0.133 mg, 0.22 mmol) in 12 mL of anhydrous THF in a 25 mL three-necked flask equipped with a condenser. Add dropwise TEA (triethylamine) (0.10 mL, 0.66 mmol). Cool the reaction medium to below 5 °C, and then add dropwise anhydrous methacrylic acid (0.11 mL, 0.66 mmol) over 5 minutes. Finally, stir the reaction medium at a temperature below 5 °C for 1 hour and then reflux overnight.

[0120] Monitor the reaction progress by TLC: 5 / 5 heptane / ethyl acetate.

[0121] At the end of the reaction, bring the reaction medium to room temperature and then suspend it in 90 mL of water for 1 hour. Wash with dichloromethane (3 × 20 mL). Dry the organic phase over MgSO4 and then evaporate under pressure to produce an orange oil, which is then purified by silica column using a heptane / ethyl acetate co-elution system. After purification, 89.7 mg of a clear oil is obtained. Molar yield: 74.5%. U.V. purity: 96.6%.

[0122] 3. Conclusion MAETIP was synthesized with a synthetic yield of approximately 54% (equivalent to the yield of MAOETIB synthesis) and a final molecular purity of approximately 97%.

[0123] Example 2: Synthesis of MAETIP-based microspheres of the present invention having sizes of 100 - 300 μm, 300 - 500 μm, and 700 - 900 μm by oil-in-water suspension polymerization (direct phase) Adapt the synthesis parameters to the desired microsphere size (see Table 1).

[0124] a) Preparation of the aqueous phase Prepare an aqueous solution of hydrolyzed polyvinyl alcohol (PVA) and sodium chloride according to the following protocol: i) Dissolve PVA in 5 L of non-heating water with stirring overnight at 50 °C. ii) Addition of NaCl while stirring at room temperature for 4 hours.

[0125] b) Preparation of the organic phase v) Weighing of each reactant and toluene w) Dissolution of AIBN in one volume of toluene x) Dissolution of 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 (radiopaque monomer), and colorant in one volume of toluene (in separate containers), followed by addition of hexanethiol (transfer agent) y) Addition of the AIBN solution obtained in step w) to the monomer solution of step x).

[0126] c) Synthesis of the microspheres according to the present invention Pour the aqueous solution of PVA and NaCl prepared in step a) into the reactor and heat to 50 °C. Next, introduce the organic phase obtained in step b) into the reactor. Apply stirring using a turbine-type stirrer to obtain droplets of the dispersed phase of the desired diameter. Next, raise the temperature to 80 °C and continue stirring for 8 hours. Next, filter the mixture using a 50 μm sieve, wash the microspheres with acetone, then ethanol, and then water, and then sieve using sieves of sizes 50 μm, 100 μm, 300 μm, 500 μm, 700 μm, 900 μm, and 1200 μm.

[0127] Table 1 below summarizes the main synthesis parameters according to the microsphere size.

[0128] (Table 1) TIFF2025521863000011.tif159159 * n = number of moles

[0129] Example 3: Measurement of the suspension time of the MS according to the present invention and comparison with MS containing a radiopaque monomer other than MAETIP In an injected medium (50 / 50 physiological saline / iodine contrast agent), the suspension time of the MS according to the present invention synthesized in Example 1 was examined and compared with the suspension time of a control MS containing a radiopaque monomer other than MAETIP.

[0130] The control MS is synthesized according to the same protocol as in Example 1 using the same components except for the radiopaque monomer. The following radiopaque monomers are used in the control MS. · MAOETIB of the following formula: TIFF2025521863000012.tif32128 · Compound Vb described in Pamphlet of International Patent Application Publication No. 2021 / 069528 of the following formula: TIFF2025521863000013.tif20128

[0131] The suspension was carried out using the "Falcon" method: Falcon method - 1 mL of radiopaque microspheres was added to a Falcon® (or Axygen®) tube whose inner coating consists of 15 mL of polypropylene (polystyrene), and then the tube was made into a "water flower" (observing the edge effect to discharge as much air as possible from the tube) using a 50 / 50 mixture of distilled water and contrast agent. - Next, the microspheres were suspended by continuously inverting the tube for 3 minutes. - The tube was allowed to stand, and the sedimentation (or creaming) time of the microspheres was measured.

[0132] Results and explanations: a) The first microsphere suspension test was carried out in an Axygen® tube using the protocol described above. The results obtained were as follows.

[0133] (Table 2) Suspension time of MS using the Falcon method in an Axygen® tube TIFF2025521863000014.tif62137

[0134] In each case, it should be noted that the microspheres settle at the end of suspension in the injection medium.

[0135] b) The second test was carried out using the same parameters in Falcon® tubes. The results obtained were as follows.

[0136] (Table 3) Suspension time of MS using the Falcon method in Falcon® tubes TIFF2025521863000015.tif62137

[0137] In each case, the microspheres settle at the end of suspension in the injection medium.

[0138] In both tests, the suspension time of the MS according to the present invention was considerably longer than that of the control MS.

[0139] 「 * 」-marked results correspond to suspension times exceeding 600 seconds. Since the results obtained with the suspension containing the MS according to the present invention were far superior to those observed with the control microspheres, it was not considered important to measure suspension times exceeding 600 seconds.

Claims

1. The following formula (A): A compound of [unclear].

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

3. Contains a crosslinking matrix, The matrix mentioned above includes at least, (a) N-vinylpyrrolidone and the following formula (I): (CH ２ =CR １ )-CO-D (I) (In the formula, - D represents O-Z or NH-Z, and Z represents (C １ ~C ６ ), alkyl, -(CR ２ R ３ ), ｍ -CH ３ , -(CH ２ -CH ２ -O) ｍ , -(CH ２ -CH ２ -O) ｍ -CH ３ , -C(R ４ OH) ｍ or -(CH ２ ), <o000019>-NR ５ R ６ where m represents an integer from 1 to 30, preferably, m is equal to 4 or 5. It should be noted that there may be a small error in the original text where "o000019" should probably be " ｍ ". This has been left as is in the translation to maintain consistency with the original. ・R １ , R ２ , R ３ , R ４ , R ５ and R ６ These are H or (C) independently of each other. １ ~C ６ (Represents alkyl) 20% to 90% hydrophilic monomers selected from the monomers, (b) For 5% to 50%, the following formula (A): The compound, (c) 1% to 15% linear or branched non-biodegradable hydrophilic crosslinked monomers, each of which has (CH ２ = (CR １６ )) - Indicates a group, each R １６ H or (C １ ~C ６ ) A linear or branched non-biodegradable hydrophilic crosslinked monomer representing an alkyl group, and (d) 0.1% to 10% of a transfer agent selected from alkyl halides and alicyclic or aliphatic thiols, which particularly have 2 to 24 carbon atoms and optionally have another functional group selected from amino, hydroxyl, and carboxyl groups. Based on, The percentages of monomers (a) to (c) are expressed in moles relative to the total number of moles of the monomers, and the percentage of compound (d) is expressed in moles relative to the number of moles of the hydrophilic monomer (a). Radiopaque embolic microspheres.

4. The embolic microsphere according to claim 3, wherein the matrix is ​​based on the compound of general formula (A) in an amount of more than 7% and 50% or less on a molar basis, preferably more than 10% and 50% or less, preferably more than 15% and 50% or less, more preferably more than 15% and 35% or less, and particularly 20% to 30% on a molar basis, relative to the total number of moles of monomers.

5. The hydrophilic monomer (a) is selected from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl acrylate, t-butyl acrylate, t-butyl methacrylate, methyl methacrylate, N-dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylate, t-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, and advantageously, monomer (a) is poly(ethylene glycol)methyl ether methacrylate, according to claim 3.

6. The linear or branched non-biodegradable hydrophilic crosslinked monomer (c) has at least two terminals (CH ２ = (CR １６ )) CO- or (CH ２ = (CR １６ )) CO-O- group, each R １６ H or (C １ ~C ６ ) The embolic microsphere according to claim 3, representing an alkyl group.

7. The embolic microsphere according to claim 3, wherein the transfer agent (d) is selected from thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof.

8. The matrix is ​​further expressed by the following formula (IV): (CH ２ =CR １７ )-M-E (IV) (In the formula, ・R １７ is H or (C １ ~C ６ ) Represents alkyl, M represents a single bond or a divalent radical having 1 to 20 carbon atoms. E represents a charged group or ionizable group having 100 or fewer atoms, and E is preferably -COOH, -COO － , -SO ３ H, -SO ３ － , -PO ３ H ２ , -PO ３ H － , -PO ３ ２－ , -NR １８ R １９ , and -NR ２０ R ２１ R ２２ ＋ Selected from the group consisting of, ・R １８ , R １９ , R ２０ , R ２１ and R ２２ These are H or (C) independently of each other. １ ~C ６ (Represents alkyl) The embolic microsphere according to claim 3, wherein the microsphere is based on at least one ionized or ionizable monomer.

9. The aforementioned matrix is ​​further expressed by the following general formula (VI): (In the formula, ・Z １ and Z ２ These are H or OR, independently of each other. ２５ Represents R ２５ is H or (C １ ~C ６ ) Represents alkyl, and advantageously, Z １ and Z ２ This represents H, X represents either H or Cl, preferably H. ・R ２３ is H or (C １ ~C ６ ) alkyl, advantageously (C １ ~C ６ ) Represents alkyl, especially methyl, and ・R ２４ is a linear or branched (C １ ~C ６ ) alkylene, (C ５ ~C ３６ ) arylene, (C ５ ~C ３６ ) arylene - O - R ２６ , (C ５ ~C ３６ ) heteroarylene and (C ５ ~C ３６ ) heteroarylene - O - R ２７ represents a group selected from, R ２６ and R ２７ are (C １ )]]~C ６ ) alkyl or (C １ ~C ６ ) alkylene, and preferably, R ２４ is the group - C ６ H ４ -O-(CH ２ ) ２ -O or -C(CH ３ ) ２ -CH ２ -O (represented)) The embolic microsphere according to claim 3, based on at least one colored monomer.

10. The matrix further comprises components visible by magnetic resonance imaging (MRI), such as iron oxide nanoparticles, gadolinium chelate, or magnesium chelate, preferably based on iron oxide nanoparticles, according to claim 3.

11. The microsphere according to claim 8, which is filled with an active substance advantageously selected from the group consisting of anti-inflammatory drugs, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, bactericides, and mixtures thereof.

12. The embolic microsphere according to claim 8, which is filled with a polymer selected from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones, plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzymes, aptamers, anti-inflammatory proteins, bone morphogenetic proteins (BMPs), angiogenic factors, vascular endothelial growth factor (VEGF) and TGF-β, and angiogenic 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, which is advantageous for parenteral administration.

14. A kit comprising the pharmaceutical composition according to claim 13, in combination with a pharmaceutically acceptable vehicle for parenteral administration, and at least one infusion means.

15. A kit comprising, on the one hand, the pharmaceutical composition according to claim 13, and on the other hand, at least one contrast agent for imaging by X-ray, magnetic resonance, or ultrasound, and optionally, at least one infusion means for parenteral administration, wherein the pharmaceutical composition and the at least one contrast agent are packaged separately.

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