WO2021069527A1 - Microsphere d'embolisation non degradable - Google Patents
Microsphere d'embolisation non degradable Download PDFInfo
- Publication number
- WO2021069527A1 WO2021069527A1 PCT/EP2020/078178 EP2020078178W WO2021069527A1 WO 2021069527 A1 WO2021069527 A1 WO 2021069527A1 EP 2020078178 W EP2020078178 W EP 2020078178W WO 2021069527 A1 WO2021069527 A1 WO 2021069527A1
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- WIPO (PCT)
- Prior art keywords
- microspheres
- monomer
- advantageously
- alkyl
- biodegradable
- Prior art date
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- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000006410 propenylene group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000011581 secondary neoplasm Diseases 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000007847 structural defect Effects 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 1
- 229960000909 sulfur hexafluoride Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229950010168 tauromustine Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229950005976 tivantinib Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
Classifications
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
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- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0476—Particles, beads, capsules, spheres
- A61K49/048—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
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- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
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- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
- C08F226/10—N-Vinyl-pyrrolidone
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- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
- C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/04—Acids; Metal salts or ammonium salts thereof
- C08F220/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F222/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof
- C08F222/10—Esters
- C08F222/1006—Esters of polyhydric alcohols or polyhydric phenols
- C08F222/102—Esters of polyhydric alcohols or polyhydric phenols of dialcohols, e.g. ethylene glycol di(meth)acrylate or 1,4-butanediol dimethacrylate
Definitions
- the present invention relates to non-biodegradable embolization microspheres comprising a crosslinked polymeric matrix advantageously intended to be injected into an individual, and optionally intended to release in a controlled manner active principles or macromolecules.
- Therapeutic vascular occlusion i.e., embolization
- embolization is used to prevent the flow of blood into an area of the body, which leads to ischemia. It can be administered through catheters to position particulate occluding agents in the circulatory system. It has a variety of medical applications such as the treatment of vascular malformations, hemorrhagic processes or tumors, including, for example, uterine fibroids, primary or secondary tumors of the liver.
- vascular occlusion can cause tumor necrosis and prevent a more invasive operation.
- This occlusion technique can also be coupled with the provision of an anticancer agent as part of chemoembolization. This increases the local drug concentration by targeted injection, as well as its residence time in the tumor.
- vascular occlusion helps normalize blood flow to normal tissue and aid in surgery by limiting the risk of bleeding.
- vascular occlusion can lead to decreased flow, which promotes healing of the arterial wound.
- embolic agents for vascular occlusion include embolization fluids (acrylic glues, gels), mechanical devices and particles for embolization.
- embolization agents are conventionally introduced into a blood vessel via a catheter, in particular a microcatheter, the diameter of which is smaller than that of the vessel to be treated.
- solid embolizing agents such as particles
- their shape must therefore allow them to circulate inside said catheter, then, once released, to occupy a volume sufficient to achieve occlusion of the vessel over its entire diameter.
- the shape and size of the embolic agents affect the accuracy of the target region.
- microspheres in the prior art whose development occurred in parallel with the development of increasingly fine microcatheters which allowed more distal arterial access.
- the practitioner can proceed with vascular targeting by performing a more or less distal occlusion.
- Embolization can be performed at selected levels. For example in the case of tumors, the tumor-intended vessels can also be more easily occluded while respecting the vessels intended for normal tissues.
- These microspheres can be biodegradable in order to achieve temporary embolizations.
- non-biodegradable embolization microspheres allow embolization for permanent purposes.
- Different non-biodegradable microspheres were tested in the 1960s, with the aim of carrying out embolizations (lead, stainless steel, silicone beads).
- embolizations lead, stainless steel, silicone beads.
- the small size of these microspheres and the large reflux into healthy non-target organs increased complication rates in patients.
- non-biodegradable microspheres made from a polymer, trisacryl (N-acryloyl-2-amino-2-hydroxymethylpropan-1,3-diol), and gelatin which may be of porcine origin.
- Embosphere® Biosphere Medical
- Non-biodegradable microspheres based on acrylic and PVA copolymers have also been proposed for permanent embolization (Osuga et al. (2002) J. Vase Interv Radiol. 13: 929-34).
- These are, for example, the Quadrasphere® microspheres from Biosphere Medical which are supplied in dry form and then swell after being mixed with physiological saline and / or iodinated contrast media before injection via a catheter.
- the term “calibrated” is understood to mean that the microspheres must be able to be classified according to their size after swelling. The practitioner then chooses the size microspheres corresponding to the size of the vessel or the malformation to be embolized (Laurent et al. 2007). Any morphological defect in these embolization microspheres can cause occlusion of the catheter or impair their embolization properties.
- the compressive strength and elasticity of the embolization microspheres are also important. Indeed, they must be able to be injected via a microcatheter with a diameter smaller than theirs, while regaining their original shape and size at the exit of the microcatheter, when they are injected into a blood vessel.
- the compressibility of the microspheres In order to target a specific embolization site, the compressibility of the microspheres must be controlled. Moreover, to be injectable, the microspheres are generally suspended in a mixture of nonionic iodinated contrast product and of buffer solution. For this, radiologists generally use a mixture of 50% contrast product and 50% physiological saline, bicarbonate buffer or phosphate buffer. To ensure their injectability, the microspheres must be kept in suspension of homogeneously in this 50/50 solution. If the microspheres sediment or, conversely, float on the surface of the solution, the resulting suspension is inhomogeneous, unstable and therefore cannot be injected into the patient.
- microspheres having an adequate density to allow their suspension in a homogeneous manner in a mixture comprising 50% of contrast product and 50% of physiological serum, bicarbonate buffer, phosphate buffer or tris buffer. (tris (hydroxymethyl) aminomethane.
- non-biodegradable embolization microspheres which are: - of calibrated size, - composed of biocompatible materials without risk of allergy, and exhibiting mechanical properties, in particular a of swelling, elasticity and compressibility, adequate for injection via a catheter or microcatheter and capable of recovering their original shape after injection while avoiding embolization far from the target site. active agents while retaining their mechanical properties SUMMARY OF THE INVENTION The present invention makes it possible to meet these needs.
- embolization microspheres comprising a hydrophilic, non-biodegradable, solid, calibrated, elastic, compressible polymeric crosslinked matrix with a controlled swelling rate sufficient for permanent and targeted embolization.
- the mechanical properties (swelling, elasticity, strength, compressive strength) of the microspheres of the invention allow them to be suitable for injection and capable of providing a sufficient and permanent level of embolization when they are injected into the. vascular tree of a mammal, preferably a human.
- transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino, hydroxy and carboxy groups, the percentages of monomers a) and b) being cited in moles relative to the number of total moles of monomers and the percentages of compound c) being cited in moles relative to number of moles of hydrophilic monomer a).
- transfer agent chosen from alkyl halides and cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino, hydroxy and carboxy groups, the percentages of monomers a) and b) being cited in moles relative to the number of total moles of monomers and the percentages of compound c) being cited in moles relative to number of moles of hydrophilic monomer a).
- the inventors have discovered that the addition of 1.5% to less than 6% by mole relative to the number of moles of the hydrophilic monomer a), preferably 1.5% to 4.5%, preferably 3%, of a transfer agent chosen from those mentioned above in the reaction mixture for the polymerization of a crosslinked matrix comprising a hydrophilic polymer makes it possible to improve the mechanical properties of the non-biodegradable embolization microspheres, that is to say to increase their swelling, elasticity, solidity and improve their compressive strength.
- the inventors have in particular discovered that the amount of transfer agent added to the reaction mixture must be strictly controlled to meet the needs mentioned above.
- the swelling rate, elasticity and compression of the microspheres are optimal from 1.5% of transfer agent by mole relative to the number of moles of hydrophilic monomer a) present in the reaction mixture.
- the microspheres obtained are not flexible enough to allow injection by microcatheter.
- the transfer agent is present in amounts of 6% or more in the reaction mixture, the non-biodegradable embolization microspheres are too compressible, are not strong enough, and will break. Elasticity is also an important parameter.
- the present invention also relates to embolization microspheres loaded with active substances, thus making it possible to combine vascular occlusion and the delivery of an active principle.
- the present invention further relates to a pharmaceutical composition comprising non-biodegradable embolization microspheres as defined above, in association with a pharmaceutically acceptable vehicle, advantageously for administration by injection.
- a subject of the present invention is also a kit comprising a pharmaceutical composition as defined above and at least one means of injecting said composition, for administration of said composition by the parenteral route.
- a subject of the present invention is also a kit comprising on the one hand a pharmaceutical composition as defined above and on the other hand a contrast agent for imaging by X-ray, by magnetic resonance or by ultrasound, and optionally in less an injection medium for parenteral administration.
- a pharmaceutical composition as defined above
- a contrast agent for imaging by X-ray, by magnetic resonance or by ultrasound and optionally in less an injection medium for parenteral administration.
- matrix based on should of course be understood to mean a matrix comprising the mixture and / or the product of the reaction between the constituents of bases used for the polymerization in a heterogeneous medium of this matrix, preferably only.
- the basic constituents are the reagents intended to react together during the polymerization of the matrix.
- the basic constituents are therefore introduced into a reaction mixture optionally further comprising a solvent or a mixture of solvents and / or other additives such as at least one salt and / or at least one polymerization initiator and / or at least one. stabilizer such as PVA.
- the reaction mixture comprises at least the monomers a), b) and the transfer agent c) mentioned in the present description as basic constituents and at least one solvent, preferably a mixture solvents comprising an aqueous solvent and an organic solvent such as an apolar aprotic solvent, for example a water / toluene mixture.
- a mixture solvents comprising an aqueous solvent and an organic solvent such as an apolar aprotic solvent, for example a water / toluene mixture.
- the reaction mixture comprises a polymerization initiator such as for example t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also called 4,4′-Azobis (4-cyanopentanoic acid)), AIBN (azobisisobutyronitrile), 1,1 ’Azobis (cyclohexane carbonitrile) 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-phenyl acetophenone (Irgacure®, 24650-42-8) or 2-methyl-4 ′ - (methylthio) -2-morpholinopropiophenone (Irgacure®), 2-
- the matrix is at least based on the monomers a), b) and the transfer agent c) mentioned in the present description, these compounds therefore being basic constituents.
- the [basic component X] is in particular added to the reaction mixture in an amount of YY to YYY%” and to "the crosslinked matrix is in particular based on [component base X] in an amount of YY to YYY% ”are interpreted similarly.
- the reaction mixture comprises at least [the base component X]” and "the crosslinked matrix is based on at least [the base component X]” are interpreted similarly.
- organic phase of the reaction mixture is meant, within the meaning of the present invention, the phase comprising the organic solvent and the compounds soluble in said organic solvent, in particular the monomers, the transfer agent and the polymerization initiator.
- grouping "(C X -VS Y ) alkyl ”means within the meaning of the present invention, a monovalent saturated, linear or branched hydrocarbon chain, comprising X to Y carbon atoms, X and Y being whole numbers between 1 and 36, preferably 1 and 18 , in particular 1 and 6.
- (CX-CY) aryl is meant, within the meaning of the present invention, an aromatic hydrocarbon group, preferably comprising from X to Y carbon atoms, and comprising one ring or several joined rings, X and Y being integers between 5 and 36, preferably 5 and 18, in particular 5 and 10.
- (CX-CY) heteroaryl is meant, within the meaning of the present invention, an aromatic group comprising X to Y cyclic atoms including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as by example of sulfur, nitrogen or oxygen atoms, the other ring atoms being atoms of carbon.
- X and Y are whole numbers between 5 and 36, preferably 5 and 18, in particular 5 and 10.
- heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl groups or indyle.
- (CX-CY) alkylene group is meant, within the meaning of the present invention, a divalent, linear or branched hydrocarbon chain, comprising X to Y carbon atoms, X and Y being whole numbers between 1 and 36 , preferably 1 and 18, in particular 1 and 6.
- X-CY) cycloalkylene group is meant, within the meaning of the present invention, a cyclic divalent saturated hydrocarbon group comprising from X to Y cyclic carbon atoms, X and Y being integers between 3 and 36 , preferably 3 and 18, in particular 3 and 6.
- cyclopropylene cyclohexylene or also cyclopentylene groups.
- grouping "(C X -VS Y ) alkenylene ”means within the meaning of the present invention, a divalent, linear or branched hydrocarbon chain, comprising X to Y carbon atoms and at least one double bond, X and Y being whole numbers between 2 and 36, preferably 2 and 18, in particular 2 and 6.
- (CX-CY) cycloalkenylene means a cyclic divalent saturated hydrocarbon group comprising from X to Y cyclic carbon atoms and at least one double bond, X and Y being numbers integers between 3 and 36, preferably 3 and 18, in particular 3 and 6.
- (CX-CY) alkynylene is understood to mean, within the meaning of the present invention, a divalent linear or branched hydrocarbon chain, comprising X to Y carbon atoms and at least one triple bond, X and Y being whole numbers between 2 and 36, preferably 2 and 18, in particular 2 and 6.
- (C X -VS Y ) cycloalkynylene a cyclic divalent saturated hydrocarbon group comprising from X to Y cyclic carbon atoms and at least one triple bond, X and Y being whole numbers between 3 and 36, preferably 3 and 18, in particular 3 and 6.
- (CX-CY) arylene is meant, within the meaning of the present invention, a divalent aromatic hydrocarbon group, comprising from X to Y carbon atoms, and comprising a or several adjoining cycles, X and Y being integers between 5 and 36, of preferably 5 and 18, in particular 5 and 10.
- Park X -VS Y ) heteroarylene means, within the meaning of the present invention, a divalent aromatic group comprising from X to Y cyclic atoms including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as for example atoms sulfur, nitrogen or oxygen, the other ring atoms being carbon atoms.
- X and Y are integers between 5 and 36, preferably 5 and 18, in particular 5 and 10.
- divalent radical is meant, within the meaning of the present invention, a radical having a valence of 2, c that is, having two chemical bonds covalent, polar covalent or ionic. Said radical can comprise, for example, carbon and / or oxygen atoms.
- dry extract is meant, within the meaning of the present invention, the mass of dry microspheres contained in 1 ml of water-swollen microspheres.
- transfer agent is understood to mean a chemical compound having at least one weak chemical bond. This agent reacts with the radical site of a growing polymer chain and interrupts the growth of the chain. In the chain transfer process, the radical is temporarily transferred to the transfer agent which restarts growth by transferring the radical to another polymer or monomer.
- said chain transfer agent is chosen from the group consisting of monofunctional or polyfunctional thiols and alkyl halides.
- said chain transfer agent is a cycloaliphatic or aliphatic thiol typically having from 2 to about 24 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 6 carbon atoms, and optionally having a functional group additional selected from amino, hydroxy and carboxy groups.
- chain transfer agents are thioglycolic acid, 2-mercaptoethanol, dodecanethiol, hexanethiol, and mixtures thereof, preferably hexanethiol.
- the transfer agent is in particular present in the reaction mixture in an amount of 1.5% to less than 6%, preferably of 1.5% to 4.5% and in particular of 3% by mole, based on the number of moles of the hydrophilic monomer a).
- the matrix is in particular based on transfer agent in an amount of 1.5% to less than 6%, preferably from 1.5% to 4.5% and in particular by 3% by mole, relative to the number of moles of the hydrophilic monomer a).
- the matrix of the non-biodegradable embolization microspheres according to the invention is based on a transfer agent in amounts of 1.5% to 4.5% by mole relative to the number of moles.
- the microspheres according to the invention comprise a crosslinked matrix based on 1.5% to 3% of transfer agent, preferably 3%.
- a transfer agent to the reaction mixture in the abovementioned amounts, in particular between 1.5% and 3% by mole relative to the number of moles of hydrophilic monomer a), makes it possible in particular to avoid the presence of morphological defect on the microspheres of the invention after swelling and sterilization.
- the absence of morphological defects is defined as the absence of twin or Siamese microspheres; microspheres themselves contained in other microspheres (or bead in bead); fractured microspheres or residues of fractured microspheres; stack or cluster of microspheres; cracked microspheres; deformed microspheres (non-spherical in shape); microspheres of non-smooth surfaces or polymer debris under magnification up to 100 times; inclusions in microspheres; drops of water trapped in the microspheres.
- the embolization microspheres of the present invention advantageously exhibit Young's modulus values typically between 3000 Pa and 30,000 Pa, preferably between 3000 Pa and 25,000 Pa, more preferably between 3000 Pa and 10,000 Pa, preferably 5000 Pa at 10,000 Pa which testify to a high compressive strength of the microspheres, associated with a swelling rate and an optimal elasticity of said microspheres.
- the non-biodegradable embolization microspheres comprise a homogeneous crosslinked matrix.
- homogeneous crosslinked matrix is meant, within the meaning of the present invention, a matrix consisting of a three-dimensional polymer network in which the components are uniformly distributed. This limits the presence of structural defect and reinforces the strength of said network.
- a sphere is defined as a surface of which all the points are equidistant from a point called the center.
- microspheres is meant, within the meaning of the present invention, spherical particles having a diameter after swelling ranging from 20 to 1200 ⁇ m, for example from 20 to 100 ⁇ m, 40 to 150 ⁇ m, from 100 to 300 ⁇ m, from 300 to 500 ⁇ m, 500 to 700 ⁇ m, 700 to 900 ⁇ m, or 900 to 1200 ⁇ m, as determined by light microscopy.
- the microspheres advantageously have a diameter small enough to be injected by needles, catheters or microcatheters with an internal diameter varying from a few hundred micrometers to more than one millimeter.
- the expression "after swelling” means that the size of the microspheres is considered after the polymerization and sterilization steps which take place during their preparation.
- the sterilization step involves, for example, passing the microspheres after the polymerization step in an autoclave at high temperature, typically at a temperature above 100 ° C, preferably at a temperature between 110 ° C and 150 ° C, preferably 121 ° C. During this sterilization step, the microspheres continue to swell. According to the present invention, the overall swelling rate of the microspheres is controlled.
- the rate of swelling is defined as: Where m w is the weight in grams of 1 mL of sedimented microspheres and m d is the weight in grams of 1 ml of sedimented microspheres which were then lyophilized.
- controlled swelling rate is meant, within the meaning of the present invention, that the overall swelling rate of the microspheres is reproducible depending on the batches, in particular that it differs by less than 15% from one batch to the next. other.
- the term “sedimented microsphere” is understood to mean microspheres dissolved in a container and then left long enough without stirring so that they fall to the bottom of the container in which they are contained, the supernatant thus having been able to. be withdrawn.
- lyophilized microsphere is meant, within the meaning of the present invention, microspheres which have undergone freezing followed by dehydration by sublimation.
- hydrophilic monomer is meant, within the meaning of the present invention, a monomer having a strong affinity for water, that is to say tending to dissolve in water, to mix with water. , to be wetted by water, or capable of swelling in water after polymerization.
- the hydrophilic monomer a) according to the invention is chosen from the group consisting of N-vinylpyrrolidone, vinyl alcohol, 2-hydroxyethyl methacrylate, sec-butyl acrylate, n-butyl
- the hydrophilic monomer a) is poly (ethylene glycol) methyl ether methacrylate (m-PEGMA).
- the hydrophilic monomer a) is in particular present in the reaction mixture in an amount of 20% to 95%, preferably 30% to 95%, more preferably 45% to 95%, of preferably from 45% to 75%, in particular from 45% to 70%, more particularly from 45% to 65% by mole, relative to the total number of moles of monomers.
- crosslinking monomer is meant, within the meaning of the present invention, an at least bifunctional but also multifunctional monomer having a double bond at each polymerizable end.
- the crosslinking monomer in combination with the other monomers in the mixture, allows the formation of a crosslinked network.
- the structure and the amount of crosslinking monomer (s) in the mixture of monomers can be easily chosen by one skilled in the art to provide the desired crosslinking density.
- the crosslinker is also advantageous for the stability of the microspheres.
- the crosslinker prevents the microspheres from dissolving in any solvent.
- the crosslinker also improves the compressibility of the microspheres, which is favorable for embolization.
- non-biodegradable hydrophilic crosslinking agent is meant, within the meaning of the present invention, a crosslinking agent as defined above, having a strong affinity for water and which cannot be degraded under the physiological conditions of the body of a person.
- the biodegradation of a molecule is permitted when the latter contains sufficient functional sites which can be cleaved under physiological conditions, in particular by the endogenous enzymes of the body of a mammal, in particular of the human body, and / or in physiological pH (usually around 7.4).
- the functional sites cleavable under physiological conditions are in particular the amide bonds, the ester bonds and the acetals.
- a molecule comprising an insufficient number of said functional sites will therefore be considered as non-biodegradable.
- the crosslinking monomer contains less than 20 physiologically cleavable functional sites, preferably less than 15 sites, more preferably less than 10 sites, still more preferably less than 5 sites.
- the linear or branched non-biodegradable hydrophilic crosslinker according to the invention is in particular a non-biodegradable crosslinker soluble in organic solvent and comprising the polymerizable groups of diacrylate, methacrylate, acrylamide, and / or methacrylamide.
- R 7 and R 8 independently of one another H or a (C1-C6) alkyl such as a methyl group,
- A represents, alone or with au at least one of the atoms to which it is bonded, a (C1-C6) alkylene or a polyethylene glycol (PEG), preferably a polyethylene glycol (PEG).
- PEG polyethylene glycol
- the polyethylene glycol has a length varying from 200 to 10,000 g / mol, preferably from 200 to 2000 g / mol, more preferably from 500 to 1000 g / mol.
- crosslinking monomer which can be used within the framework of the present invention, there may be mentioned (without being limiting): 1,4-butanediol diacrylate, pentaerythritol tetraacrylate, methylenebisacrylamide, glycerol 1,3-diglycerolate diacrylate and poly (ethylene glycol) dimethacrylate (PEGDMA).
- the crosslinking monomer is poly (ethylene glycol) dimethacrylate (PEGDMA), the polyethylene glycol unit having a length varying from 200 to 10,000 g / mol, preferably from 200 to 2000 g / mol, more preferably from 500 to 1000 g / mol.
- the crosslinking monomer is in particular present in the reaction mixture in an amount of 1% to 15%, preferably 2% to 10%, in particular 2% to 7%, more particularly 2%. at 5%, in particular 5% by mole relative to the total number of moles of monomers.
- the crosslinked polymeric matrix of the microspheres is based on the basic constituents a), b) and c) as defined above only, in the aforementioned proportions, no other basic constituent not being added to the reaction medium. It is thus obvious that the sum of the proportions of monomers a) and b) mentioned above must be equal to 100%.
- formula (III): (CH 2 CR
- ionized or ionizable group is meant, within the meaning of the present invention, a charged group or which may be in charged form (in ion form), that is to say bearing at least one positive or negative charge, depending on the pH of the medium.
- the COOH group can be ionized in COO- form and the NH2 group can be in ionized NH3 form. + .
- the introduction of an ionized or ionizable monomer into the reaction mixture makes it possible to increase the hydrophilicity of the resulting microspheres, thus increasing the rate of swelling of said microspheres, further facilitating their injection via catheters and microcatheters.
- the ionized or ionizable monomer is a cationic monomer, advantageously chosen from the group consisting of (methacryloyloxy) ethylphosphorylcholine, 2- (dimethylamino) ethyl (meth) acrylate, 2- (diethylamino) (meth) acrylate ethyl) and 2 - ((meth) acryloyloxy) ethyl) - trimethylammonium chloride, advantageously the cationic monomer is diethylamino) ethyl (meth) acrylate.
- the crosslinked matrix of the microspheres according to the present invention can be obtained by adding to the reaction mixture between 1 and 40 mol% of a cationic monomer mentioned above on the basis of the total amount of monomers.
- the crosslinked matrix according to the invention is obtained by adding to the reaction mixture between 5% and 15%, preferably by adding 10%, in moles of ionized or ionizable monomer relative to the total number of moles of monomers when the microspheres results are not intended to be loaded with an active substance.
- the crosslinked matrix according to the invention is obtained by adding to the reaction mixture between 20% and 40%, preferably by adding to the reaction mixture 20% to 30%, preferably 30% by moles of ionized or ionizable monomer relative to the total number of moles of monomers.
- the ionized or ionizable monomer is an anionic monomer advantageously chosen from the group consisting of acrylic acid, methacrylic acid, 2-carboxyethyl acrylate, 2-acrylate oligomers.
- the crosslinked matrix of the non-biodegradable embolization microspheres according to the present invention can be obtained by adding to the reaction mixture between 1% and 40% by moles of an anionic monomer mentioned above on the basis of the total amount of monomers. , more preferably between 10% and 30% by moles.
- the ionized or ionizable monomer is methacrylic acid.
- the crosslinked matrix according to the invention is based on methacrylic acid (MA or AM) in amounts of between 10% and 30% by moles based on the total amount of monomers.
- the crosslinked matrix of the microspheres according to the invention is also based on at least one halogenated, preferably iodinated, monomer.
- a halogenated, preferably iodinated, monomer has the effect of increasing the density of the resulting microspheres.
- the inventors have discovered that when a halogenated monomer, typically iodinated, is used in the reaction mixture to obtain the crosslinked matrix of the invention, in amounts advantageously between 1% and 15% by moles relative to the total number of monomers, the resulting embolization microspheres form an optimal and stable suspension in a mixture comprising 50% physiological serum and 50% contrast agent.
- a halogenated monomer typically iodinated
- the introduction of a halogenated monomer, in particular iodine, in the aforementioned amounts makes it possible to prevent the microspheres from floating on the surface of such a mixture.
- the halogenated monomer is in particular added to the reaction mixture in an amount of 5% to 15%, preferably 5% to 10%, more particularly 5% to 7%, by mole relative to to the total number of moles of monomers. Further, by using 15% or less of the halogenated monomer by mole based on the total number of moles of the monomer, the resulting microspheres are not radiopaque. The halogenated monomer is introduced in an insufficient quantity to impart radiopacity to the microsphere.
- the halogenated monomer is more advantageously a monomer of general formula (IV) as defined above, in which Y represents NH-W, O-W or (O-R 16 ) p -W, preferably NH-W or (O-R 16 ) p -W, more preferably (O-R 16 ) p -W, W representing Ar or L-Ar, p, R 16 , L and Ar being as defined above.
- Y represents NH-W, O-W or (O-R 16 ) p -W, preferably NH-W or (O-R 16 ) p -W, more preferably (O-R 16 ) p -W, W representing Ar or L-Ar, p, R 16 , L and Ar being as defined above.
- R 16 is a (C 1 -VS 36 ) alkylene, in particular a (C 1 -VS 18 ) alkylene, more particularly a (C 1 -VS 6 ) alkylene;
- L represents -OCO-;
- Ar represents a (C 5 -VS 36 ) aryl, in particular a (C5-C10) aryl, more particularly a phenyl, substituted with one, two or three atom (s) of iodine and / or bromine, preferably of iodine, and optionally two or three, groups chosen from -NR at R b , -NR vs HORN d , -COOR e , -OCOR g , -CONR h R i , -OCONR j R k , - NRlCOORo- and -NRrCONRsRt, preferably -NRaRb, -NRcCORd.
- the halogenated monomer is a monomer of general formula (IV) as defined above, in which Y represents NH-W or (O-R16) p-W, more advantageously (O-R 16 ) p -W, W representing Ar or L-Ar, and p, R 16 , L and Ar being as defined above.
- R 16 is a (C 2 -VS 36 ) alkylene, in particular a (C 2 - C18) alkylene, more particularly a (C 2 -VS 6 ) alkylene;
- L represents -OCO-, -C (O) NR17-, or -NR18C (O) -;
- Ar represents a (C5-C36) aryl, in particular a (C5-C10) aryl, more particularly a phenyl, substituted by one, two or three atom (s) of iodine and / or bromine, preferably of iodine, and optionally two or three, groups chosen from - NR at R b , -NR vs HORN d , -COOR e , -OCOR g , -CONR h R i , -OCONR j R k , -NR l COOR o - and -NR r CONR s R
- Ar represents a (C 5 -VS 10 ) aryl, more particularly a phenyl, substituted with three atoms of iodine and / or bromine, preferably iodine, and optionally two groups chosen from (C 1 -VS 10 ) alkyl, -NRaRb, -NRcCORd, -COORe, -OCORg, -CONRhRi, -OCONRjRk, -NRlCOORo- and -NRrCONRsRt.
- Ar represents a phenyl substituted with three atoms of iodine and / or bromine, preferably iodine, and optionally two groups chosen from (C 1 - VS 10 ) alkyl, -NR at R b , -NR vs HORN d , -COOR e , -OCOR g , -CONR h R i , -OCONR j R k , -NR l COOR o - and - NRrCONRsRt, advantageously among (C 1 -VS 10 ) alkyl, -NRaRb, -NRcCORd, -COORe, -CONRhRi, - NRlCOORo- and -NRrCONRsRt.
- the halogenated monomer is a monomer of general formula (IV) as defined above, in which Y represents O-C6H4I, O-C6H3I2, O-C6H2I3, NH-C6H4I, NH-C 6 H 3 I 2 , NH-C 6 H 2 I 3 , O-CH 2 -CH 2 -C (O) -C 6 H 4 I, O-CH 2 -CH 2 -O-C (O) -C 6 H 3 I 2 , O-CH 2 -CH 2 -O-C (O) - C 6 H 2 I 3 , NH-CH 2 -CH 2 -C (O) -C 6 H 4 I, NH-CH 2 -CH 2 -O-C (O) -C 6 H 3 I 2 , or NH-CH 2 -CH 2 -O-C (O) -C 6 H 2 I 3 , in particular O-C6H2I3, NH-C6H2I,
- R 29 represents a (C 1 -VS 6 ) alkyl, more preferably a (C 1 - VS 3 ) alkyl, more preferably methyl.
- R 30 represents a (C 2 -VS 18 ) alkylene, more particularly a (C 2 - VS 6 ) alkylene, more preferably ethylene.
- R31 and R32 represent, independently of each other, a hydrogen atom.
- W ’ advantageously represents a single bond, -C (O) NH-, or -NHC (O) -.
- Ar ' represents a (C5-C10) aryl, more particularly a phenyl, substituted with one, two or three atom (s) of iodine and / or bromine, preferably of iodine, and optionally two or three, groups chosen from (C 1 -VS 10 ) alkyl, -NR 33 R 34 , - NR 35 HORN 36 , -C (O) OR 37 , -GOLD 38 , -OC (O) R 39 , -C (O) NR 40 R 41 , -OC (O) NR 42 R 43 , -NR 44 C (O) OR 45 , - NR 46 C (O) NR 47 R 48 , -OC (O) OR 49 , and -C (O) R 50 .
- Ar ’ represents a (C 5 -VS 10 ) aryl, more particularly a phenyl, substituted with three atoms of iodine and / or bromine, preferably iodine, and optionally two groups chosen from (C 1 -VS 10 ) alkyl, -NR 33 R 34 , -NR 35 HORN 36 , -C (O) OR 37 , -GOLD 38 , - OC (O) R39, -C (O) NR40R41, -OC (O) NR42R43, -NR44C (O) OR45, -NR46C (O) NR47R48, -OC (O) OR49, and - C (O) R 50 .
- Ar ' represents a phenyl substituted with three atoms of iodine and / or bromine, preferably of iodine, and optionally two groups chosen from (C1-C10) alkyl, -NR33R34, -NR35C (O) R36, - C (O) OR37, -OR38, -OC (O) R39, -C (O) NR40R41, -OC (O) NR42R43, -NR44C (O) OR45, -NR46C (O) NR47R48, -OC (O) OR49 , and -C (O) R50, advantageously from (C1- C10) alkyl, -NR33R34, -NR35C (O) R36, -C (O) OR37, -OR38, -C (O) NR40R41, -NR44C (O) OR45, - NR 46 C (O) NR 47 R 48, and optionally two groups
- the halogenated monomer is chosen from the following compounds of general formula (VI):
- the halogenated monomer is chosen from the following compounds: More advantageously, the halogenated monomer is chosen from (tri-iodobenzoyl) oxo ethyl methacrylate (MAOETIB) of formula (IVa) below: or 2- (2- (2- (2- (2,3,5-triiodobenzamido) ethoxy) ethyl methacrylate of the following formula:
- the crosslinked matrix of the microspheres according to the invention is also based on at least one colored monomer to make them visible to the naked eye.
- the crosslinked matrix of the microspheres according to the invention is also based on at least one colored monomer of the following general formula (V): , in which, ⁇ Z1 and Z2 represent, independently of each other, H or OR26, R26 representing H or a (C1-C6) alkyl, advantageously Z1 and Z2 represent H; ⁇ X represents H or a halogen such as Cl, advantageously H; ⁇ R24 represents a group selected from (C1-C6) linear or branched alkylene, (C5- C36) arylene, (C5-C18) arylene-O-R27, (C5-C18) heteroarylene and (C5-C18) heteroarylene-O -R28, R27 and R28 representing a (C1-C6) alkyl or a (C1-C6) alky
- ⁇ R25 represents H or a (C1-C6) alkyl, advantageously a (C1-C6) alkyl, in particular a methyl.
- the colored monomer has the following formula (Va) or (Vb):
- the colored monomer is in particular added to the reaction mixture in an amount from 0% to 1%, preferably from 0% to 0.5%, more particularly from 0.01% to 0, 2%, more preferably from 0.02% to 0.2%, and even more particularly from 0.04% to 0.1% by mole, relative to the number of total moles of monomers.
- Magnetic Resonance Imaging MRI is used in the medical community to provide two-dimensional sectional images of the internal structures of a patient's body without exposing them to harmful radiation.
- the crosslinked matrix of embolization microspheres according to the invention may further be based on particles making it possible to make the microspheres visible on magnetic resonance imaging scans.
- the particles visible on MRI are advantageously added to the reaction mixture in an amount of 0% to 10%, preferably 0.1% to 10% by volume of organic phase.
- the crosslinked matrix of the microspheres does not comprise an ionized or ionizable monomer as basic constituent, it is advantageously based on: - 94.5% to 98%% of hydrophilic monomer a) , preferably 94.5% to 96%, more preferably 94.96%; - 2% to 5% of non-biodegradable hydrophilic crosslinking monomer b), preferably 3% to 5%, preferably 5%; - 1% to 3% of transfer agent c), preferably 3%; - 0% to 0.5% of colored monomer, preferably 0.02% to 0.1%, preferably 0.04%; and - 0% to 10% of particles visible on MRI, preferably 0% to 5%, preferably 1%, each of the monomers mentioned and the nature of their associated percentages being as defined above
- the microspheres according to the invention not loaded with an active substance comprise a crosslinked matrix advantageously based on: - 79.5% to 93% of hydrophilic monomer a), preferably 80% 90%, preferably 84.96%; - 2% to 5% of non-biodegradable hydrophilic crosslinking monomer b), preferably 3% to 5%, preferably 5%; - 1% to 3% of transfer agent c), preferably 3%; - 5% to 15% of ionized or ionizable monomer, preferably 8% to 12%, preferably 10%; - 0% to 0.5% of colored monomer, preferably 0.02% to 0.1%, preferably 0.04%; and - 0% to 10% of particles visible on MRI, preferably 0% to 5%, preferably 1%, each of the monomers mentioned and the nature of their associated percentages being as defined above in the present description.
- the microspheres according to the invention not loaded with an active substance comprise a crosslinked matrix advantageously based on: - 63% to 95% of hydrophilic monomer a), preferably 70% to 90 %, preferably 75% to 80%, preferably 79.96%; - 2% to 5% of non-biodegradable hydrophilic crosslinking monomer b), preferably 3% to 5%, preferably 5%; - 1% to 3% of transfer agent c), preferably 3%; - 5% to 15% of ionized or ionizable monomer, preferably 8% to 12%, preferably 10%; - 5% to 7% of halogenated monomer, preferably 5% to 6%, preferably 5%; - 0% to 0.5% of colored monomer, preferably 0.02% to 0.1%, preferably 0.04%; and - 0% to 10% of particles visible in MRI
- the microspheres according to the invention loaded with an active substance comprise a crosslinked matrix advantageously based on: - 45% to 65% of hydrophilic monomer a), preferably 50% to 65%, preferably 55% to 65%, preferably 64.96%; - 2% to 5% of non-biodegradable hydrophilic crosslinking agent b), preferably 3% to 5%, preferably 5%; - 1% to 3% of transfer agent c), preferably 3%; - 20% to 40% of ionized or ionizable charged monomer, preferably 30% to 40%, preferably 30%; - 0% to 0.5% of colored monomer, preferably 0.02% to 0.1%, preferably 0.04%; and - 0% to 10% of particles visible on MRI, preferably 0% to 5%, preferably 1%, each of the monomers mentioned and the nature of their associated percentages being as defined above in the present description.
- the microspheres according to the invention loaded with an active substance comprise a crosslinked matrix advantageously based on: - 47.5% to 73% of hydrophilic monomer a), preferably 50% to 70%, preferably 59, 96%; - 2% to 5% of non-biodegradable hydrophilic crosslinking agent b), preferably 3% to 5%, preferably 5%; - 1% to 3% of transfer agent c), preferably 3%; - 20% to 40% of ionized or ionizable charged monomer, preferably 30% to 40%, preferably 30%; - 5% to 7% of halogenated monomer, preferably 5% to 6%, preferably 5%; - 0% to 0.5% of colored monomer, preferably 0.02% to 0.1%, preferably, preferably 0.04%; and - 0% to 10% of particles visible on MRI, preferably 0% to 5%, preferably 1%, each of the
- the crosslinked matrix of the microspheres according to the invention can be easily synthesized by numerous methods well known to those skilled in the art.
- the crosslinked matrix according to the invention can typically be obtained by suspension polymerization, direct or reverse, as described below and in the examples.
- a direct suspension can take place as follows: (a) kneading or stirring a reaction mixture comprising: (i) at least one hydrophilic monomer a) as defined above, at least one non-biodegradable hydrophilic crosslinker b) as defined above above, and at least one transfer agent c) as defined above; (ii) a polymerization initiator present in amounts ranging from 0.1 to about 2 parts by weight per 100 parts by weight of monomers; (iii) a surfactant in an amount of not more than about 5 parts by weight per 100 parts by weight of aqueous phase, preferably not more than about 3 parts by weight and most preferably in the range of 0.2 to 1.5 parts by weight of aqueous phase; and (iv) water to form an oil-in-water suspension; and (b) polymerizing the basic constituents.
- the surfactant can be selected from the group consisting of hydroxyethyl cellulose, polyvinylalcohol (PVA), polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol and Polysorbate 20 (Tween ® 20); preferably it is PVA.
- PVA polyvinylalcohol
- Tween ® 20 polyvinylpyrrolidone
- the microspheres thus obtained are then washed and calibrated according to techniques well known to those skilled in the art.
- Inverse suspension can proceed as follows: (a) kneading or stirring a reaction mixture comprising: (i) at least one hydrophilic monomer a) as defined above, at least one non-biodegradable hydrophilic crosslinker b) as defined above, and at least one transfer agent c) as defined above; (ii) a polymerization initiator present in amounts ranging from 0.1 to about 2 parts by weight per 100 parts by weight of monomers; (iii) a surfactant in an amount of not more than about 10 parts by weight per 100 parts by weight of the oil phase, preferably not more than about 8 parts by weight and most preferably in the range of 3 to 7 parts by weight ; and (iv) the oil to form a water-in-oil suspension; and (b) polymerizing the basic constituents.
- a reaction mixture comprising: (i) at least one hydrophilic monomer a) as defined above, at least one non-biodegradable hydrophilic crosslinker b) as defined above, and at
- the polymerization initiator may in particular be t-butyl peroxide, benzoyl peroxide, azobiscyanovaleric acid (also called 4,4′-Azobis (4-cyanopentanoic acid), 1,1 'Azobis (cyclohexane carbonitrile) or AIBN (azobisisobutyronitrile) 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-phenyl acetophenone (Irgacure®, 24650- 42-8) or 2-methyl-4 ′ - (methylthio) -2-morpholinopropiophenone (Irgacure®, 718
- the surfactant can be selected from the group consisting of esters sorbitan such as sorbitan monolaurate (Span ® 20), sorbitan monopalmitate (Span ® 40), sorbitan monooleate (Span ® 80) and sorbitan trioleate (Span ® 85), hydroxyethyl cellulose, a mixture of glyceryl stearate and PEG stearate (Arlacel ® ) and cellulose acetate.
- the oil used in the process described above can be chosen from paraffin oil, silicone oil and organic solvents such as hexane, cyclohexane, ethyl acetate or acetate. butyl.
- a drug, an active substance, a diagnostic agent or macromolecules can / can also be loaded on microspheres, that is to say adsorbed on the crosslinked matrix by non- interactions covalent, optionally in the presence of pharmaceutically acceptable excipient (s) well known to those skilled in the art.
- This particular way of trapping drugs or active substances is called physical encapsulation. No special requirements are imposed on the drug or active substance to be loaded. Loading can be done by many methods well known to those skilled in the art such as passive adsorption (swelling of the crosslinked matrix in a drug solution) or by ionic interaction.
- the microspheres can be loaded with a drug, an active substance or a diagnostic agent and thus allow their release on a target site, said target site being inside the body. of a mammal, in particular within a human body.
- the crosslinked matrix of the microspheres according to the invention can therefore be loaded with a drug or an active substance or a diagnostic agent, advantageously having a molar mass of less than 5000 Da, typically less than 1000 Da, the drug or the active substance being advantageously chosen from the group consisting of anti-inflammatory agents, local anesthetics, analgesics, antibiotics, anticancer agents, steroids, antiseptics and a mixture of these .
- the polymer according to the invention can be loaded with an anticancer agent.
- the anticancer agent is preferably chosen from anthracyclines such as doxorubicin, epirubicin or idarubicin, platinum complexes, compounds related to anthracyclines such as mitoxantrone and nemorubicin, antibiotics such as mitomycin C (Ametycine ® ), bleomycin and actinomycin D, other anti-neoplastic compounds such as irinotecan, 5-Fluoro-Uracil (Adrucil®), sorafenib (Nevaxar ® ), sunitinib (Sutent ® ), regorafenib, brivanib, orantinib, linsitinib, erlotinib, cabozantinib, foretinib, tivantinib, fotemustine, tauromustine (TCNU), carmustine, cytosine C, cyclophosphonamide, cytosine arabinoside
- the anticancer agent is chosen from anthracyclines, immuno-stimulants, platinum complexes, anti-neoplastics and their mixtures. Even more preferably, the anticancer agent is chosen from anthracyclines, antibodies, anti-neoplastics and their mixtures.
- the antibodies are for example chosen from anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-CEA (CarcinoEmbryonic Antigen) or a mixture of these.
- Anti-PD-1s are, for example, nivolumab or pembrolizumab.
- Anti-PD-L1s are, for example, avelumab, durvalumab or atezolizumab.
- Anti-CTLA-4s are, for example, ipilimumab or tremelimumab.
- the anticancer drug is selected from the group consisting of paclitaxel, doxorubicin, epirubicin, idarubicin, irinotecan, GM-CSF (Granulocyte-macrophage colony-stimulating factor), tumor necrosing Factor-alpha (TNFalpha), antibodies, and their mixtures.
- the local anesthetic is chosen from lidocaine, bupivacaine and their mixtures.
- the anti-inflammatory can be selected from ibuprofen, niflumic acid, dexamethasone, naproxen and mixtures thereof.
- the polymer can be loaded, in particular by extemporaneous adsorption, with macromolecules chosen from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones. , plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzyme (also called DNAzyme), aptamers, anti-inflammatory proteins, bone morphogenic proteins (BMP), pro-angiogenic factors, factors of vascular endothelial growth (VEGF) and TGF-beta, and angiogenesis inhibitors or anti-tyrosine kinases and mixtures thereof.
- macromolecules chosen from the group consisting of enzymes, antibodies, cytokines, growth factors, coagulation factors, hormones. , plasmids, antisense oligonucleotides, siRNA, ribozymes, DNA enzyme (also called DNAzyme), aptamers, anti-inflammatory proteins, bone morphogenic proteins (BMP), pro-angi
- Anti-inflammatory proteins are, for example, infliximab or rilonacept and their mixture.
- the proangiogenic factors are, for example, fibroblast growth factors (FGFs) and their mixture.
- Angiogenesis inhibitors are, for example, bevacizumab, ramucirumab, nesvacumab, olaratumab, vanucizumab, rilotumumab, emibetuzumab, aflibercept, ficlatuzumab, pegaptanib and mixtures thereof.
- Anti-tyrosine kinases are, for example, lenvatinib, sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, fruquintinib, nintedanib, anlotinib, motesanib, cediranib, sulfatinib, dovetinib, linifanib and their mixtures.
- the polymer can be loaded with macromolecules chosen from anti-tyrosine kinases, TGF-beta, angiogenesis inhibitors and their mixtures.
- the invention in a second aspect, relates to a pharmaceutical composition comprising non-biodegradable embolization microspheres according to the invention, in association with a pharmaceutically acceptable vehicle, advantageously for administration by injection.
- a pharmaceutically acceptable vehicle includes, but is not limited to, water for injection, saline also referred to as physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, ester of hyaluronic acid, plasma, a contrast agent for X-ray, magnetic resonance or ultrasound imaging, a buffering agent, a preservative, a gelling agent and / or a surfactant.
- the pharmaceutically acceptable vehicle is physiological serum, water for injection, a contrast agent for imaging by X-ray, by magnetic resonance or by echography, or their mixtures. More advantageously, the pharmaceutically acceptable vehicle is physiological saline, a contrast agent for imaging by X-ray, by magnetic resonance or by ultrasound, or a mixture of physiological saline and a contrast agent for imaging by X-ray, for example magnetic resonance or ultrasound.
- the contrast agent is preferably a contrast agent for X-ray imaging.
- nonionic iodinated water-soluble contrast agent such as, for example, 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 ® ), iosimenol and iosimide (Univist ® ) and a mixture
- the contrast agent is a contrast agent for magnetic resonance imaging (MRI). These are advantageously gadolinium chelates (Dotarem®).
- the contrast agent is a contrast agent for ultrasound imaging. It is advantageously sulfur hexafluoride (Sonovue®).
- the pharmaceutical composition comprises non-biodegradable embolization microspheres according to the invention, in combination with physiological serum, said composition being intended to be mixed with at least one contrast agent for X-ray, magnetic resonance or ultrasound imaging as defined above, in particular for X-ray imaging, before administration by injection, such a mixture causing the microspheres according to the invention to be suspended.
- the pharmaceutical composition advantageously has an acceptable viscosity for injection.
- the pharmaceutical composition according to the invention comprises non-biodegradable embolization microspheres according to the invention, in combination with a mixture of physiological serum and a contrast agent as defined herein.
- physiological serum and the contrast being present in proportions 70/30 to 20/80, advantageously from 50/50 to 20/80, preferably 50/50.
- the pharmaceutical composition according to the invention comprises microspheres obtained by polymerization of a reaction mixture comprising from 5% to 10%, more preferably from 5% to 7% of halogenated monomer as described in the present description
- said composition pharmaceutical comprises said microspheres in combination with a mixture of physiological serum and a contrast agent in proportions of 80/20 and 0/100, preferably 70/30 and 40/60, in particular 50/50.
- said microspheres have a size of 500 to 700 ⁇ m, 700 to 900 ⁇ m or 900 to 1200 ⁇ m. In this way, the suspension of microspheres in the solution is homogeneous and stable for the time required for injection.
- the pharmaceutical composition according to the invention comprises microspheres obtained by polymerization of a reaction mixture not comprising halogenated monomer as described in the present description
- said pharmaceutical composition comprises said microspheres in combination with a mixture of physiological serum and a contrast agent in proportions of between 80/20 and 0/100.
- the fields of application of the non-biodegradable embolization microspheres according to the invention include in particular vessel embolization, in particular in the case of uterine fibroids and of chemoembolization, for example in the case of hepatocarcinoma also called hepatocellular carcinoma ( HCC) or primary liver cancer, which consists of eliminating a tumor by combining vascular occlusion with the delivery of one or more active ingredients or macromolecules loaded into embolization microspheres.
- HCC hepatocellular carcinoma
- HCC hepatocellular carcinoma
- This technique makes it possible to concentrate the drug load at the level of the tumor and therefore to reduce the systemic concentration and at the same time the undesirable effects.
- the non-biodegradable embolization microspheres according to the invention can, as indicated above, be used for various biomedical purposes, which means that they must be compatible with the human body or the body of a mammal. More particularly, suitable biomedical materials do not possess hemolytic properties.
- the present invention further relates to the specific use of a transfer agent in the polymerization of a crosslinked matrix comprised in non-biodegradable embolization microspheres to allow injection of said microspheres, in particular injection into a catheter or a tube. microcatheter with an internal diameter varying from a few hundred micrometers to more than one millimeter.
- the present invention also relates to the specific use of a transfer agent in the polymerization of a crosslinked matrix to improve the mechanical properties (swelling, elasticity, strength, compressive strength).
- Said transfer agent is in particular chosen from cycloaliphatic or aliphatic thiols having in particular from 2 to 24 carbon atoms, and optionally having another functional group chosen from amino, hydroxy and carboxy groups.
- a subject of the present invention is also a kit comprising a pharmaceutical composition as defined above and at least one means of injecting said composition, for administration of said composition by the parenteral route.
- injection means means any means allowing parenteral administration.
- said injection means is one or more syringes and / or one or more syringe (s) which can be pre-filled and / or one or more catheter (s) or microcatheter (s) for administration of said composition by injection.
- the pharmaceutical composition present in said kit comprises the microspheres according to the present invention in combination with physiological serum, a contrast agent, or a mixture thereof. More advantageously, said pharmaceutical composition comprises the microspheres according to the present invention in combination with a mixture of physiological serum and of a contrast agent in proportions of between 80/20 and 0/100, advantageously of between 70/30 and 40 / 60, preferably 50/50.
- said pharmaceutical composition comprises said microspheres in combination with a mixture of physiological serum and of a contrast agent in proportions of between 60/40 and 0/100, advantageously 50/50.
- said pharmaceutical composition comprises said microspheres in combination with a mixture of physiological serum and a contrast agent in proportions of between 80/20 and 0/100.
- the injection means present in the kit according to the invention is suitable for parenteral administration of the pharmaceutical composition according to the invention.
- the size of the syringe (s) or of the (micro) catheter (s) will be adapted according to the size of the microspheres according to the invention and the volume to be injected for embolization.
- a subject of the present invention is also a kit comprising on the one hand a pharmaceutical composition as defined above and on the other hand at least one contrast agent for imaging by X-ray, by magnetic resonance or by echography, and optionally at least one injection means for parenteral administration.
- the injection means is as defined above.
- the pharmaceutical composition and the contrast agent are packaged separately and are intended to be mixed just before administration by injection.
- at least one contrast agent is as defined above in the description.
- the at least one contrast agent is a contrast agent for X-ray imaging as defined above in the description.
- the pharmaceutical composition advantageously comprises the microspheres according to the present invention in association with a pharmaceutically acceptable vehicle for administration by injection.
- Said pharmaceutically acceptable vehicle may be, for example, but not limited to, water for injection, physiological saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, ester. hyaluronic acid and / or plasma.
- the pharmaceutical composition advantageously comprises the microspheres according to the present invention in combination with physiological saline or water for injection.
- the pharmaceutical composition is advantageously packaged directly in an injection means, in particular in a syringe, suitable for the injection of parenteral embolization microspheres.
- the contrast agent is advantageously packaged in a vial or directly in an injection means, in particular a syringe, in particular suitable for the injection of parenteral embolization microspheres.
- the pharmaceutically acceptable vehicle / contrast agent proportions are between 80/20 and 0/100, advantageously between 70/30 and 40/60, preferably 50/50.
- the pharmaceutically acceptable vehicle proportions / contrast agent are between 70/30 and 0/100, advantageously between 60/40 and 20/80, preferably 50/50.
- the proportions of pharmaceutically acceptable vehicle / contrast agent are between 80/20 and 0/100. Description of the figures Figure 1: Average diameter of the microspheres (MS) after sterilization as a function of the concentration of transfer agent.
- Figure 2 Percentage of defect-free microspheres as a function of transfer agent concentration.
- Figure 3 Example of microspheres: A: flawless with 0% hexanethiol; B: fractured with 0% hexanethiol; C: deformed with 0% hexanethiol; D: flawless with 6% hexane thiol; E: fractured with 6% hexanethiol.
- Figure 4 Dry extract as a function of the transfer agent concentration.
- Figure 5 Swelling rate as a function of the transfer agent concentration.
- Figure 6 Young's modulus as a function of the transfer agent concentration.
- MS were deposited on a sample holder of the Morphology instrument 4,500 MS were imaged and stored in the software database for further analysis.
- a standard operating procedure (SOP) was used in the imaging process to ensure consistency of measurements. After each measurement, the defective MS were excluded from the total MS (500 MS). The most reliable method was to visually examine each MS and delete or keep them in image databases based on their defect and integrity. Histogram, mean diameter and standard deviation were also obtained for intact MS.
- MS microsphere
- the percentage of MS without defect was calculated accordingly: Dry extract, mass swelling rate
- the dry extract is produced as follows: 1 ml of sedimented DM is placed in a 5 ml Eppendorf flask, frozen at -80 ° C and lyophilized by a lyophilizer (Heto PowerDry LL 1500, Thermo Scientific) overnight. The mass of the MS after lyophilization is then measured. The measurement was carried out for three samples and the average was taken as the final value of the dry mass of the DM.
- Swelling rate The same sample preparation as described above was used to calculate the mass swelling rate of MS: where (mw) is the weight in grams of 1 mL of sedimented DM and (md) is the weight in grams of 1 ml of sedimented microspheres which have been lyophilized. The measurement was carried out for three samples and the average was taken as the final value of the rate of mass swelling. Rheology and compressibility The rheological properties of the MS were measured on an HR2 Discovery rheometer (TA Instruments, USA). Young's modulus is measured using a uniaxial compression mode. A plane-plane geometry with 50mm diameter plates and an initial spacing of 1600 ⁇ m was used. The temperature of the samples is maintained at 25 ° C. by the Peltier effect.
- the normal force is zeroed by the software.
- a homogeneous bed of a single layer of microspheres is then deposited on the plate.
- a first measurement is carried out in order to determine the point of contact with the MS as well as the linear strain regime.
- the gap between the plates is reduced from 1600 ⁇ m to 700 ⁇ m with a speed of 16.7 ⁇ m / s (1 mm / min) and the normal force is measured.
- the point of contact is the distance between the plates at which a normal force begins to be exerted.
- the normal force follows a linear regime according to the applied strain, up to a point.
- the gap between the plates during this divergence corresponds to the output of the linear regime.
- a second measurement is then carried out 3 times in a row in order to measure the mean as well as the measurement error of the Young's modulus.
- This second measurement consists of placing the top plate directly at the point of contact and applying an axial strain up to the maximum output value of the linear regime. The measured normal force then evolves linearly as a function of the applied strain. The slope of this curve corresponds to the Young's modulus.
- Another method used to measure Young's modulus (method n ° 2) Compression tests are carried out on single microspheres using a compression machine (Synergie 800, MTS, France), using a 15.3 piston. mm diameter printed in 3D. The exerted force is measured by a 2 N force transducer, which provides accurate and repeatable measurements from 1 mN.
- TestWorks4 software is an interface for directing the piston and recording data measured by the sensor.
- the use of a lamp (100 W bulb) is necessary in order to illuminate the cell containing the analyzed microsphere, and to allow the camera to clearly see the microsphere and the piston.
- Image processing software, ImageJ is used to measure the exact size of microspheres by measuring the number of pixels in the image.
- the piston speed is set at 1 mm / min and the test starts with the piston positioned approximately 100 ⁇ m above the microsphere.
- Young's modulus is calculated using the Hertz model, applicable to the compression of a sphere between two planes. Injection of MS MSs were injected through a microcatheter in order to test their mechanical properties during injections.
- a solution composed of 30% by volume of Xenetix® contrast product 350 mg of iodine / ml and 70% by volume of physiological saline was prepared. 20 mL of this solution was withdrawn using a 20 mL syringe, and in parallel 2 mL of sedimented MS were withdrawn into the sterilized vial as described above using a 3 mL syringe .
- the two syringes (3mL and 20mL) are connected to a three-way stopcock.
- the MS are suspended in the above mixture by performing about 15 back-and-forth movements between the two syringes.
- Example 1 Synthesis by direct suspension polymerization of microspheres (DM) according to the invention (900-1200 ⁇ m) An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C.
- the organic phase containing poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinking), coloring monomer, methacrylic acid (ionized or ionizable monomer) ), the transfer agent and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and stirring is maintained for 12 hours. The mixture is then filtered through a 40 ⁇ m sieve in order to collect the DM.
- the DM retained by said sieve are then washed 3 times with acetone and then 3 times with water. These washed MS are then sieved between a 900 ⁇ m sieve and a 710 ⁇ m sieve. The DM collected between these two sieves are then sterilized by autoclave at 121 ° C for 20 minutes which will have the effect of swelling the DM and obtaining DM of the desired size, that is to say here 900 to 1200 ⁇ m.
- the microspheres synthesized according to the method described above therefore have the following composition (Tables 1 and 1a): Table 1 HT: 1-hexanethiol, TGA: thioglycolic acid, DODEC: 1-dodecanethiol, BTCM: bromotrichloromethane Table 1bis
- Example 2 Size of the microspheres from Example 1 The average diameter of the microspheres is measured after sterilization, for each of lots 1 to 9 and L9 to assess the impact of the concentration of the transfer agent on the size of the MS. The MS were sterilized according to the procedure described above. The mean diameter after sterilization of the calibrated MS (900-1200) for each of the lots is shown in Figure 1.
- Example 3 Percentage of non-defective microspheres obtained from example 1 The percentage of defective MS was calculated according to the method described above on a sample of MS of size 900-1200 ⁇ m comprising different concentrations of HT as transfer agent or transfer agents of a different nature (lots 1 to 9 and L9). The results are shown in Figure 2. From 0% to 1.5% HT (lots 1 to 4), the percentage of defect-free DM varies from 89% to 91%.
- Example 4 Dry extract of the microspheres obtained from Example 1 Figure 4 shows the dry extract of the DM (mg / ml), calculated according to the method described above, depending on the concentration or the nature of the transfer agent.
- the dry extract (mg) for a given volume of DM decreases linearly when the concentration of HT increases (lots 1, 2, 3, 4, 5, 6 and 7).
- the dry extract of the DM in lot L9 is approximately 101 mg / mL. Without transfer agent, the dry mass of 1mL of sedimented DM is approximately 159 mg. At 6% HT, this dry extract is only about 52 mg.
- Example 5 Swelling rate of the microspheres from Example 1 The swelling rate of the microspheres was determined according to the method described above on batches 1 to 9 and L9) in order to assess the influence of the concentration and the nature of the transfer agent. The results are illustrated in FIG. 5. It is observed that the higher the concentration of HT, the higher the rate of swelling obtained.
- Example 6 Rheology and compressibility of the microspheres from Example 1
- the compressibility of the microspheres can be characterized by measuring the Young's modulus according to the method described above. The Young's moduli of lots 1 to 9 are shown in FIG. 6. The results obtained with method No. 2 for measuring the Young's modulus gave fairly similar results.
- the Young's modulus decreases from about 13 kPa to about 6 kPa as the concentration of HT goes from 0% to 3% and then reaches a plateau at about 6 kPa for the higher concentrations (4.5 % and 6%).
- DM containing between 0% and 0.5% HT (lots 1 to 4) are more solid and rigid and unsuitable for injection. From 1.5% HT, the values of the Young's modulus of the DM fall below 10 kPa, which is the limit targeted by the present invention, and are therefore softer and more flexible. From a concentration of 3%, the DM becomes softer and more flexible. At the same concentration of transfer agent, here 3%, all the DM have the same plateau value of about 6 kPa.
- Example 7 Injection of the microspheres from Example 1 into a microcatheter Each of batches 1 to 9 and L9 of MS was injected into 4Fr and 5Fr microcatheters. No blockages were observed. For batch 7 (6% HT), the DM did not tolerate the preparation for injection, and all broke. The mechanical properties of the MS obtained with 6% transfer agent are therefore not compatible for injection by microcatheter.
- Example 8 Synthesis by direct suspension polymerization of microspheres intended to be charged according to the invention (100-300 ⁇ m) An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C.
- m-PEGMA hydrophilic monomer
- PEGDMA poly (ethylene glycol) dimethacrylate
- AM methacrylic acid
- HT hexanethiol
- violet dye (1- (4 - ((2- methacryloxye
- Example 8Bis Synthesis by direct suspension polymerization of microspheres (MS) without ionizable monomer according to the invention (900-1200 ⁇ m) and evaluation of the loading capacity Synthesis of the microspheres 900 - 1200 ⁇ m An aqueous solution of polyvinyl alcohol hydrolyzed and sodium chloride is poured into a reactor and heated to 50 ° C.
- the organic phase containing poly (ethylene glycol) methyl ether methacrylate (m-PEGMA) (hydrophilic monomer), poly (ethylene glycol) dimethacrylate (PEGDMA) (crosslinker), coloring monomer, hexanethiol (transfer agent) and AIBN (initiator) dissolved in toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C and stirring is maintained for 12 hours. The mixture is then filtered through a 40 ⁇ m sieve in order to collect the microspheres.
- microspheres retained by said sieve are then washed 3 times with acetone and then 3 times with water. These washed microspheres are then sieved between a 900 ⁇ m sieve and a 710 ⁇ m sieve. The microspheres collected between these two sieves are then sterilized by autoclave at 121 ° C for 20 minutes which will have the effect of swelling the microspheres and obtaining microspheres of the desired size, that is to say here 900 to 1200 ⁇ m.
- the microspheres synthesized according to the method described above therefore have the following composition: Table 3 below summarizes the main parameters and the composition of the organic phase and of the aqueous phase:
- the dry extract (dry weight) is produced as follows: 1 ml of sedimented MS is placed in a 5 ml Eppendorf flask, frozen at -80 ° C and lyophilized by a lyophilizer (Heto PowerDry® LL 1500, Thermo Scientific) overnight. The mass of the microspheres after lyophilization is then measured. The measurement was carried out for three samples and the average was taken as the final value of the dry mass of the DM. The average diameter is measured by analysis of microscopy images on 2000 microspheres (Morphologi 4, Malvern).
- the injectability test in microcatheters is carried out with 1 ml of microsphere sediment suspended beforehand in 10 ml of iodinated contrast medium (70% of Optiray® 300, Guerbet, 30% of physiological serum). A homogeneous suspension of microspheres in a 3 mL syringe is then injected into the microcatheter.
- the microcatheters the supplier of which is the company Terumo, were chosen such that their internal diameter is just slightly greater than the average diameter of the microspheres.
- the resistance felt during the injection of the microspheres into the microcatheter is recorded (Table 3Bis). A blockage during the injection would mean a failure of the injection.
- microspheres After injection, the microspheres are observed under a microscope in order to check whether the microspheres regain their spherical shape. Characterization results: Table 3bis 100-300 ⁇ m microspheres are also synthesized without methacrylic acid (same composition as the microspheres of Example 8 with 0% methacrylic acid (MA) and 94.96% m-PEGMA) then sterilized by autoclaving. Their loading capacity of doxorubicin is evaluated and compared with that of microspheres as synthesized according to Example 8. Loading of doxorubicin: the loading objective is 37.5 mg of doxorubicin per mL of microspheres.
- doxorubicin-HCl Adriblastine®, Pfizer
- doxorubicin-HCl Adriblastine®, Pfizer
- the suspension is made up to 6 mM of sodium bicarbonate (Lavoisier). Loading is carried out at room temperature and with stirring for one hour. Measurement of the residual amount of doxorubicin (absorbance at 490 nm) present in the supernatants is used to determine the amount of drug loaded on the microspheres.
- LC Loading capacity
- LE Initial MDrug loading efficiency: Amount of drug solubilized
- CDrug_sur Drug concentration in the supernatant after loading
- Vsur Supernatant volume
- VMS Volume of microspheres
- the loading efficiency without methacrylic acid is 82.6%, compared to 99 , 6% in the presence of 30% methacrylic acid.
- the ability of microspheres without ionizable monomers to charge doxorubicin is explained by the establishment of hydrophobic or van der Waals bonds. In the presence of ionizable monomer, in addition to these bonds, doxorubicin is charged by electrostatic bonds. Kinetics and loading capacities are improved.
- Example 9 Synthesis by direct suspension polymerization of polymers containing 5% of MAOETIB according to the invention in the form of microspheres of size 700-900 ⁇ m An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated at 50 ° C.
- Example 10 Suspension in a 50/50 mixture of contrast agent and physiological serum of the microspheres of Example 9 and comparison with equivalent microspheres without MAOETIB 2 mL of bead sediment are added to a mixture of 10 mL 50/50 physiological serum / contrast agent (5 mL of Optiray® 300 mgI / mL and 5 mL of physiological serum). The mixture is passed 5 times through a three-way stopcock using 20 mL syringes. The syringe containing the mixture is then placed vertically and the destabilization of the mixture is observed; the microspheres then rise to the surface. The time corresponding to a destabilization interface arriving at mid-height of the syringe is measured.
- Example 11 Synthesis by direct suspension polymerization of polymers of different natures in the form of microspheres of size 700-900 ⁇ m Synthesis An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured into a reactor and heated to 50 ° C.
- the organic phase containing the hydrophilic monomer, the crosslinking agent, the coloring monomer, the transfer agent, the halogenated monomer if applicable, the ionizable monomer if applicable and the AIBN (initiator) dissolved in the toluene is then introduced into the reactor. Agitation is applied with a propeller-type stirrer at the appropriate speed so as to obtain droplets of the desired diameter. The temperature is then increased to 80 ° C. and stirring is maintained for 12 hours. The mixture is then filtered through a 40 ⁇ m sieve in order to collect the microspheres. The microspheres retained by said sieve are then washed 3 times with acetone and then 3 times with water.
- microspheres are then sieved between a 900 ⁇ m sieve and a 710 ⁇ m sieve.
- the microspheres collected between these two sieves are then sterilized by autoclave at 121 ° C for 20 minutes which will have the effect of swelling the microspheres and obtaining microspheres of the desired size, that is to say here 700 to 900 ⁇ m.
- Table 6 summarizes the main parameters and the composition of the organic phase.
- Example 12 Synthesis by direct suspension polymerization of polymers containing different amounts of MAOETIB according to the invention in the form of microspheres of size 100-300 ⁇ m
- Synthesis An aqueous solution of hydrolyzed polyvinyl alcohol and sodium chloride is poured in in a reactor and heated to 50 ° C.
- Example 13 Suspension in a 50/50 mixture of contrast agent and physiological serum of the microspheres of Example 12 with different levels of MAOETIB 2 mL of bead sediment are added to a mixture of 10 mL 50/50 physiological saline / contrast agent (5 mL of Xenetix® 350 mgI / mL and 5 mL of physiological saline). The mixture is passed 5 times through a three-way stopcock using 20 mL syringes. The syringe containing the mixture is then placed vertically and the destabilization of the mixture is observed, either by creaming or by sedimentation depending on the MAOETIB concentration.
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Abstract
Description
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KR1020227014952A KR20220081358A (ko) | 2019-10-07 | 2020-10-07 | 비분해성 색전술 미소구체 |
US17/754,531 US20230272142A1 (en) | 2019-10-07 | 2020-10-07 | Non-degradable embolisation microsphere |
EP20781603.4A EP4041318A1 (fr) | 2019-10-07 | 2020-10-07 | Microsphere d'embolisation non degradable |
JP2022520764A JP2022551118A (ja) | 2019-10-07 | 2020-10-07 | 非分解性の塞栓ミクロスフェア |
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Cited By (2)
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EP4299080A1 (fr) | 2022-06-28 | 2024-01-03 | Guerbet | Monomère radio-opaque et microsphères d'embolisation le comprenant |
WO2024003184A1 (fr) | 2022-06-28 | 2024-01-04 | Guerbet | Monomère radio-opaque et microsphères d'embolisation le comprenant |
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JP2022551118A (ja) | 2022-12-07 |
CN114555139A (zh) | 2022-05-27 |
KR20220081358A (ko) | 2022-06-15 |
EP4041318A1 (fr) | 2022-08-17 |
US20230272142A1 (en) | 2023-08-31 |
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