Crosslinked polyesters of glycerol and a dicarboxylic acid monomer exhibiting improved bioresorbability and / or degradation in aqueous media

Abstract

The present invention relates to the use of a cyclic polycarboxylic anhydride A, the cyclic polycarboxylic anhydride A comprising at least two cyclic carboxylic anhydride groups, and not comprising a linear carboxylic anhydride function, as a crosslinking agent of a glycerol polyester and a dicarboxylic acid, so as to increase the bioresorbability and / or degradation in aqueous media of a crosslinked glycerol polyester and a dicarboxylic acid, in particular compared to a thermally crosslinked glycerol polyester and a dicarboxylic acid in the absence of a crosslinking agent, and advantageously in the absence of cyclic polycarboxylic anhydride A.

Description

Title of the invention: Crosslinked polyesters of glycerol and a dicarboxylic acid monomer exhibiting improved bioresorbability and / or degradation in aqueous media. FIELD OF THE INVENTION

[0001] The present invention relates to crosslinked polyesters of glycerol and a dicarboxylic acid monomer exhibiting improved bioresorbability and / or degradation in aqueous media. STATE OF THE ART

[0002] Biodegradable and / or bio-based polyesters, such as polylactic acid (PLA), polyglycolic acid (PGA) and their copolymers, such as poly(glycerol sebacate) (PGS), are now ubiquitous in the preparation of biomaterials useful both as medical biomaterials and for surface coating for various fields of application.

[0003] These polyesters are generally poorly biodegradable, which limits their use as a resorbable biomaterial or for encapsulating an organic molecule.

[0004] There is therefore a need for crosslinked polyesters that are more bioresorbable, and / or with better biodegradability, particularly in aqueous media, but which retain mechanical properties suitable for the intended short-term uses. Description of the invention

[0005] The inventors have demonstrated that the use of a cyclic polycarboxylic anhydride type crosslinking agent made it possible to overcome the problems of the prior art.

[0006] Thus, the present invention relates to the use of a cyclic carboxylic polyanhydride A, the cyclic carboxylic polyanhydride A comprising at least two cyclic carboxylic anhydride groups, and not comprising a linear carboxylic anhydride function,

[0007] as a crosslinking agent of a glycerol and dicarboxylic acid polyester, so as to increase the bioresorbability and / or degradation in aqueous medium of a crosslinked glycerol and dicarboxylic acid polyester, in particular compared to a thermally crosslinked glycerol and dicarboxylic acid polyester in the absence of a crosslinking agent, and advantageously in the absence of cyclic carboxylic polyanhydride A.

[0008] Advantageously, the cyclic carboxylic anhydride groups of the cyclic polycarboxylic anhydride A are joined, linked together by at least one covalent bond or carried by a spacer group L,

[0009] L representing -O- ; -S- ; -S(O)- ; -S(O)2- ; -C(O)- ; -NRnRn- with Rn and Rn independent- pendally chosen from H or a Ci-C6 alkyl group, or a multivalent hydrocarbon group comprising 1 to 40 carbon atoms, cyclic or acyclic, saturated, unsaturated or aromatic, and which may contain one or more heteroatoms of O, S, Cl, Br, F, N, P or Si,

[0010] L being devoid of linear anhydride groups.

[0011] Preferably, the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (I) or (II): OO (I) or To JHU .L. cC 'z{ (X)n 9 9 ( n ) § ; A« ) S

[0012] in which • Li represents a bond; -O-; -S-; -S(O)-; -S(O)2-; -NRnRn- with Rn and Rn independently chosen from H or a Ci-C6 alkyl group; -C(O)-; or an aliphatic chain of 1 to 30 carbon atoms, in which 1 to 6 methylene unit(s) is / are optionally replaced by an arylene group, a heteroarylene group, -C(O)-; -O-; -S-; -S(O)-; -S(O)2-; -NRm- with Rm chosen from H or a Ci-C6 alkyl group, -P-; -P(O)-; -SiRaRb- with Ra and Rb independently representing a -OH, Ci-C6 alkyl or Ci-C6 alkoxy group,

[0013] said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, alkyl groups in C1-6, alkoxy group in C1-6, a hydroxyl, nitro, cyano, halogen atom, haloalkyl group in C1-6, • Zi is absent or represents a -CH2- (methylene) or -NH- group, • Z2 is absent or represents a -CH2- (methylene) or -NH- group, • X independently represents a C1-C6 alkyl group, a C1-C6 hydroxyl group, a C1-C6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • n represents an integer between 0 and 3, preferably between 0 and 2, • Y represents, independently of each other, an alkyl group in Ci-C6, a hydroxyl, alkoxy (Ci-C6), nitro, cyano, or a halogen atom, • m represents an integer between 0 and 3, preferably between 0 and 2, • Ai represents: • A C-C bond or a C=C bond linking the four carbon atoms of the two carboxylic anhydride functions, • a saturated, instituted or aromatic carbocycle, optionally bridged, said carbocycle comprising from 4 to 30 carbon atoms, and • a saturated, instaurated or aromatic heterocycle, optionally bridged,

[0014] said heterocycle comprising from 4 to 30 carbon atoms, and

[0015] said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, CrC6 alkoxy, nitro, cyano, or halogen atom.

[0016] In particular, Li represents an aliphatic bond or chain of 1 to 6 carbon atoms, in which one or two methylene units is / are optionally replaced by an arylene group, -C(O)-, -O-, -S-, -S(O)-, -S(O)2-,

[0017] said aliphatic chain being substituted or unsubstituted by a group preferably selected from a Ci-C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

[0018] Advantageously, the cyclic carboxylic polyanhydride A may comprise or consist of a compound of formula (III) or (IV): O o (III) b; jp V 'V O o p P (IV) ù Z / Q [ P ô b

[0019] in which represents a simple or double DC connection

[0020] L2 and L3 taken together with the carbon atoms to which they are linked represent a saturated, unsaturated or aromatic carbocycle or heterocycle, said carbocycle or heterocycle comprising from 4 to 30 carbon atoms, and said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, Ci-C6 alkoxy, nitro, cyano, or halogen atom.

[0021] The invention also relates to a crosslinked polyester obtained by crosslinking a polyester of glycerol and a dicarboxylic acid with at least one cyclic carboxylic polyanhydride A as defined herein, with a mass loss at 7 days after in vitro incubation at 37.5°C in a phosphate-buffered saline (PBS) solution and drying at 60°C of 5% or greater. The polyester can in particular be obtained by crosslinking: • 100 parts by weight of at least one polyester, glycerol, and a diacid because boxyl with a molar mass in number Mn less than or equal to 10,000 g / mol, • with 10 to 100, preferably 20 to 50, parts by weight of cyclic carboxylic polyanhydride A as defined herein.

[0022] In particular, the inventors have demonstrated that a polyester of glycerol and a dicarboxylic acid crosslinked with at least one cyclic polycarboxylic anhydride A as a crosslinking agent exhibited a significant increase in their mass loss at 7 days after in vitro incubation at 37.5°C in a phosphate saline buffer solution (PBS buffer) and drying at 60°C, in particular compared to the polyester of glycerol and a dicarboxylic acid thermally crosslinked in the absence of a crosslinking agent, and advantageously in the absence of cyclic polycarboxylic anhydride A.

[0023] Advantageously, the crosslinked polyester obtained by crosslinking a polyester of glycerol and a dicarboxylic acid with at least one cyclic carboxylic polyanhydride A as defined herein as a crosslinking agent exhibits a mass loss at 7 days after in vitro incubation at 37.5°C in PBS buffer and drying at 60°C greater than or equal to 5%.

[0024] Preferably, the crosslinked polyester has a Shore A hardness measured according to ASTM D 2240 at room temperature between 20 and 80, typically between 20 and 50.

[0025] Advantageously, the crosslinked polyester has a number molar mass Mn less than or equal to 10,000 g / mol.

[0026] Typically, the dicarboxylic acid has the formula [HOOC-(CH2)P-COOH], in which p is a number from 1 to 30, preferably a number from 1 to 10, advantageously sebacic acid (p=8). DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

[0027] For the purposes of the present invention, the term “a” or “an” means “one or more” or “at least one”.

[0028] For the purposes of the present invention, a range of values ​​designated by the expression "between a and b" represents the range of values ​​from greater than strictly a, to less than strictly b (that is to say excluding the bounds a and b), while any range of values ​​designated by the expression "from a to b" represents the range of values ​​from a to b, that is to say including the strict bounds a and b.

[0029] In this description, "approximately" means that the value in question may be 10% lower or higher, in particular 5%, and especially 1% higher, than the value indicated.

[0030] The compounds mentioned in the description may be of fossil origin or bio-based. In the latter case, they may be, partially or totally, derived from biomass or obtained from renewable raw materials derived from biomass. Similarly, the compounds mentioned can also come from the recycling of previously used materials; that is, they can be partially or totally derived from a recycling process, or obtained from raw materials themselves derived from a recycling process. This includes monomers, specifically glycerol, dicarboxylic acid monomer, and cyclic carboxylic polyanhydride.

[0031] Glycerol is a triol with the following formula: Q|q HO^Jx^OH

[0032] In the present invention, a "cyclic polycarboxylic anhydride" means an organic compound comprising at least two cyclic carboxylic anhydride functional groups. Each functional group is selected from either a carboxylic anhydride or a nitrogen anhydride functional group. A "cyclic carboxylic anhydride (nitrogen or non-nitrogen) functional group" is bonded to two carbons of the rest of the molecule, whether adjacent or not, so as to form a ring comprising a carboxylic anhydride or a nitrogen anhydride functional group. In contrast, a "linear anhydride (nitrogen or non-nitrogen) functional group" means a divalent carboxylic anhydride functional group (nitrogen or non-nitrogen) that is bonded to two carbons of the rest of the molecule but is not part of a ring.

[0033] In the present invention, a "carboxylic anhydride function" corresponds to the formula -C(=O)-OC(=O)-. This function is divalent.

[0034] In the present invention, a "nitrogenous carboxylic anhydride function" corresponds to the formula -C(=O)-OC(=O)-NH-. This function is divalent.

[0035] In the present invention, a "cyclic carboxylic anhydride group" means a group comprising a cyclic carboxylic anhydride function (nitrogenous or non-nitrogenous) and further comprising from 3 to 40 carbon atoms. The cyclic anhydride group may be multivalent or monovalent. When the cyclic anhydride group is an isatotic group, then the cyclic anhydride group comprises a nitrogenous anhydride function.

[0036] When the group is further substituted, it comprises from 1 to 4, preferably from 1 to 2, substituents. The substituent(s) is / are, independently, preferably a Ci-C6 alkyl group, a Ci-C6 alkoxy group, a hydroxyl, nitro, cyano, halogen atom, or a Ci-C6 haloalkyl group.

[0037] A "linear anhydride group" in the context of the invention means a group comprising a linear carboxylic anhydride function (nitrogenous or not). Unlike a cyclic anhydride group, in a linear carboxylic anhydride group, the divalent carboxylic anhydride function (nitrogenous or not) is linked to two carbons of the rest of the molecule, but is not part of a ring.

[0038] In the present invention, a "monovalent hydrocarbon group" means a monovalent saturated, unsaturated, or aromatic hydrocarbon chain, cyclic or acyclic (linear or branched), comprising from 1 to 40 carbon atoms. A monovalent hydrocarbon group includes, in particular, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkynyl groups, substituted or unsubstituted, in the form C1-C40. Preferably, a monovalent hydrocarbon group is an alkyl, cycloalkyl, alkenyl, or cycloalkenyl group, substituted or unsubstituted, in the form C1-C40.

[0039] As used herein, a "divalent hydrocarbon group" means a saturated, unsaturated, or aromatic divalent hydrocarbon chain, cyclic or acyclic (linear or branched), comprising from 1 to 40 carbon atoms. A divalent hydrocarbon group includes, in particular, substituted or unsubstituted, linear or branched, C1-C40 alkanediyl, alkenediyl, or al-cynediyl groups. A divalent hydrocarbon group also includes substituted or unsubstituted, C1-C40 cycloalkanediyl, cycloalcenediyl, or cycloalkynediyl groups. A divalent hydrocarbon group also includes a substituted or unsubstituted divalent aromatic group. Preferably, a monovalent hydrocarbon group is an alkanediyl (linear or branched), alkenediyl (linear or branched), cycloalkanediyl, cycloalkenediyl, substituted or unsubstituted, Ci-C40 group.

[0040] In the present invention, a "multivalent hydrocarbon group" means a hydrocarbon chain with a valence of four or more, saturated, unsaturated (i.e. comprising at least one double or possibly one triple C-C bond) or aromatic, cyclic or acyclic (linear or branched), comprising from 1 to 40 carbon atoms.

[0041] By "aliphatic" is meant a linear, branched and / or cyclic hydrocarbon group, whether saturated or unsaturated but non-aromatic.

[0042] For the purposes of this invention, the term "alkyl group" means a monovalent, saturated, linear or branched hydrocarbon chain comprising from 1 to 40 carbon atoms, preferably comprising from 1 to 10 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups.

[0043] For the purposes of this invention, the term "cycloalkyl group" refers to a monovalent cyclic saturated hydrocarbon chain comprising 3 to 40 cyclic carbon atoms. A cycloalkyl group may be monocyclic, bicyclic, or polycyclic. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups. Adamantyl is an example of a polycyclic cycloalkyl group.

[0044] For the purposes of this invention, an "alcenvle" group is defined as a monovalent, linear or branched hydrocarbon chain comprising at least one double bond and from 2 to 40 carbon atoms. Examples include ethenyl, propenyl, allyl, butenyl, pentenyl, and hexenyl groups.

[0045] For the purposes of this invention, a "cycloalcenyl" group is defined as a monovalent cyclic hydrocarbon chain comprising 3 to 40 cyclic carbon atoms and at least one cyclic double bond. A cycloalkenyl can be monocyclic, bicyclic, or polycyclic. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. A polycyclic cycloalkenyl is bicyclo[2.2.2]oct-7-ene.

[0046] For the purposes of this invention, the term "aie y ny le" refers to a monovalent hydrocarbon chain, linear or branched, comprising at least one triple bond and consisting of 2 to 40 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.

[0047] For the purposes of this invention, a "cycloalkynyl group" is defined as a monovalent cyclic hydrocarbon chain comprising 5 to 40, preferably 7 to 40, cyclic carbon atoms and at least one cyclic triple bond. A cycloalkynyl group may be monocyclic, bicyclic, or polycyclic. The cycloheptynyl group is an example.

[0048] For the purposes of this invention, the term "aromatic group" means an aromatic hydrocarbon group, preferably comprising 6 to 40 carbon atoms, and including one or more fused rings. Examples of monovalent aromatic groups include phenyl, naphthyl, or pyrene, advantageously phenyl. Examples of divalent aromatic groups include phenylene, naphthylene, or pyrene, advantageously pyrene.

[0049] By "alkanediyl" group, for the purposes of the present invention, means a divalent acyclic hydrocarbon chain, linear or branched, comprising from 1 to 40 carbon atoms, such as, for example, a methylene, ethanediyl, pro-panediyl, butanediyl, pentanediyl, or hexanediyl group.

[0050] By "cycloalkanediyl" group, in the context of the present invention, we mean a saturated divalent cyclic hydrocarbon group, comprising from 3 to 40 cyclic carbon atoms, such as for example a cyclobutylene, cyclohexylene or cyclopentylene group.

[0051] By "alkenediyl" group, for the purposes of the present invention, means a linear or branched acyclic divalent hydrocarbon chain comprising from 2 to 40 carbon atoms and at least one double bond, such as, for example, a vinylene (ethenylene) or propenylene group.

[0052] By "cvcloalcenedivle" group, for the purposes of the present invention, means a cyclic, linear or branched divalent hydrocarbon chain comprising from 3 to 40 atoms, preferably from 4 to 40 or even from 5 to 40 carbon atoms and at least one double bond, such as, for example, a cyclopentenylene group.

[0053] By "alcvnedivle" group, for the purposes of the present invention, we mean a divalent, linear or branched, acyclic hydrocarbon chain comprising from 2 to 40 carbon atoms and at least one triple bond.

[0054] For the purposes of this invention, a "cycloalkyndiyl" group is defined as a monovalent cyclic hydrocarbon chain comprising 5 to 40, preferably 7 to 40 or even 8 to 40, cyclic carbon atoms and at least one cyclic triple bond. A cycloalkyndiyl group may be monocyclic, bicyclic, or polycyclic.

[0055] For the purposes of this invention, the term "C-C6 alkoxy group" refers to a Ci-C6 alkyl group, as defined above, linked to the rest of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, Ao-propoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, and n-hexoxy.

[0056] For the purposes of this invention, "halogen atom" or "halogen" means fluorine, chlorine, bromine and iodine atoms, preferably fluorine and chlorine atoms.

[0057] For the purposes of this invention, the term “haloalkyl group in CQ” means a Ci-C6 alkyl group, as defined above, in which one or more hydrogen atoms are replaced by a halogen atom, in particular a chlorine, bromine, iodine, or fluorine atom, preferably a fluorine atom. The trifluoromethyl (-CF3) group is an example.

[0058] The hydroxy group is the -OH group. The cyano group is the -CN group. The nitro group is the -NO2 group.

[0059] A "carbocycle comprising from 4 to 30 carbon atoms" means a cyclic (monovalent) hydrocarbon group comprising from 4 to 30 carbon atoms. A carbocycle may be monocyclic or polycyclic, optionally bridged (including bridged and / or fused rings). When the carbocycle is polycyclic, it comprises at least 2, advantageously 2 or 3, fused or bridged rings. The carbocycle may be saturated (i.e., comprising no unsaturation or multiple bonds), unsaturated (i.e., comprising at least one double bond or possibly one triple bond, without being aromatic), or aromatic.

[0060] When the carbocycle is aromatic, we will speak of an “aryl” group.

[0061] For the purposes of this invention, "heterocycle comprising from 4 to 30 carbon atoms" means a (monovalent) ring of 4 to 30 carbon atoms, saturated, unsaturated, or aromatic, monocyclic or polycyclic, optionally bridged (including bridged and / or fused rings), of which one or more, advantageously 1 to 4, even more advantageously 1 or 2, atom(s) of the ring is / are a heteroatom, such as, for example, sulfur, nitrogen, or oxygen atoms, the other cyclic atoms being carbon atoms. Examples of saturated or unsaturated heterocycles are: pyrrolidine, piperidine, piperazine, morpholine, pyrazolidinyl, imidazolidine, azepane, thia-zolidine, isothiazolidine, oxazocane, thiazepane, benzimidazolone.

[0062] An aromatic heterocycle, also called a heteroaryl (monovalent) group, comprises 5 to 10 ring atoms, one or more of which are heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as, for example, sulfur, nitrogen, or oxygen atoms, the other ring atoms being carbon atoms. Examples of heteroaryl groups are furan, thiophene, pyrrole, pyridine, imidazole, triazolyl, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, oxadiazole, thiadiazole, pyridazine, pyrimidine, pyrazine, triazine, quinole, isoquinole, quinoxal, or indole.

[0063] An "arylene group" is understood to mean a divalent aromatic hydrocarbon group, preferably comprising 6 to 10 carbon atoms, and including one or more fused rings, such as, for example, a phenyl or naphthyl group. Advantageously, this refers to phenylene.

[0064] A "heteroarylene group" is understood to mean a divalent aromatic heterocycle, comprising from 5 to 10 ring atoms, one or more of which are heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as, for example, sulfur, nitrogen or oxygen atoms, the other ring atoms being carbon atoms. Pyridinylene may be cited as an example.

[0065] According to the invention, an "orthophthalic group" is understood to be a group of formula: O, preferably of formula: p, this group OO being linked to the rest of the polyanhydride molecule by the Av bond, or of a divalent group of formula: p, this group being linked to the rest of the molecule b ô b of polyanhydride via the A-bond on one side, and via the -y bond on the other. The The orthophthalic group can be substituted or unsubstituted.

[0066] In the present invention, a "succinic grouping" is understood to mean a mo- group O, this group being linked to the rest of the polyanhydride molecule by the b b o y-bond, and which may be substituted or unsubstituted, or a divalent group of formula: p, this group being linked to the rest of the polyanhydride molecule

[0067]

[0068] by the bond on the one hand, and by the ■ y bond on the other hand. A succinic group is distinct from an orthophthalic group, so that in general, a divalent succinic group is not attached to a phenyl group. In the present invention, a "maleic group" is understood to be a monovalent group of formula: p, this group being bonded to the rest of the molecule of 'yp oh polyanhydride by the .4 bond and which may be substituted or unsubstituted, or of a divalent group of formula: O -, this grouping then being linked to the rest of the b polyanhydride molecule by the U bond on one side, and by the - ~ bond on the other part. A maleic group is distinct from an orthophthalic group, so that in general, a cyclic anhydride group of divalent maleic nature is not attached to a phenyl group. In the present invention, a "homo-phthalic group" is understood to be a group of formula: O, preferably of formula: O, this « aÆ >FTTA TF J k il 4 k group being linked to the rest of the polyanhydride molecule by the "U" bond, or of a divalent group with the formula: O, this grouping being linked to AiT the remainder of the polyanhydride molecule by the bond on one hand, and by the bond - On the other hand, the homophthalic group can be substituted or unsubstituted.

[0069] In the present invention, an "isato group" means a group of formula: O, preferably of formula: O or TC A T ( ,-TT K 'o N' "o HH Q, this group being linked to the rest of the polyanhydride molecule by the .xL link, or a divalent group of formula The group is linked to the rest of the polyanhydride molecule by a bond on one side, and by a • ■ bond on the other. The isato group may be substituted or unsubstituted.

[0070] By "ambient temperature" we mean here a temperature generally between 15°C and 40°C, preferably between 20°C and 30°C, in particular about 25°C.

[0071] As used here, "bioresorbability" refers to the ability of a material, particularly a polymer such as polyester, to be naturally broken down (digested) within a living organism. Bioresorbability depends on the material's capacity to be degraded and the rate of digestion of the product in the biological environment. Chemically, bioresorption is characterized by a process of progressive deconstruction of the polymer's (polyester's) chemical structure, notably resulting in the production of metabolites with lower molecular weights.

[0072] As used here, the "degradation" of a polyester is understood to mean a chemical process involving in particular the hydrolysis of ester bonds, generating polymeric molecules of lower molecular weight.

[0073] As used here, an "aqueous medium" means an aqueous solution, generally saline, and typically buffered (in particular with a PBS buffer). The aqueous medium of the invention advantageously aims to reproduce the environment of the living organism (pH, saline concentration).

[0074] As used herein, a "PBS buffer," also called a "phosphate saline buffer," means a saline solution buffered with a phosphate buffer. PBS buffers are well known in the art and are commercially available. They are typically a solution containing sodium chloride, disodium phosphate, Monopotassium phosphate and possibly potassium chloride are present. Generally, the concentration of these salts is that of the human body (isotonicity). The PBS buffer is therefore generally usable to replicate the environment of a living organism.

[0075] Use of a cyclic carboxylic polyhydroxyl A as a crosslinking agent to increase bioresorbability and / or degradation in aqueous media

[0076] The invention relates to the use of a cyclic polycarboxylic anhydride A, the cyclic polycarboxylic anhydride A comprising at least two cyclic carboxylic anhydride groups, and not comprising a linear carboxylic anhydride function, as a crosslinking agent of a glycerol polyester and a dicarboxylic acid, so as to increase the bioresorbability and / or degradation in aqueous media of the crosslinked glycerol polyester and dicarboxylic acid, in particular compared to the crosslinked glycerol polyester and dicarboxylic acid alone, i.e. compared to the glycerol polyester and a starting dicarboxylic acid monomer which has undergone purely thermal crosslinking, in particular in the absence of a crosslinking agent, and advantageously in the absence of cyclic polycarboxylic anhydride A.The polyester of glycerol and a thermally crosslinked dicarboxylic acid monomer can be prepared by the same process as that of the invention, but without the addition of polyanhydride. An example of implementation is given in the examples.

[0077] The bioresorbability measured by the degradation in aqueous medium of the crosslinked polyesters obtained according to the invention is improved in particular at a temperature between 20°C and 70°C, in particular between 25°C and 50°C, typically at 37.5°C, i.e. body temperature.

[0078] The bioresorbability and / or degradation in aqueous media of the crosslinked polyesters obtained according to the invention is characterized, in particular in the laboratory, by a mass loss, 7 days after in vitro incubation at 37.5°C in PBS buffer and drying at 60°C, greater than or equal to 5%, typically at atmospheric pressure. The mass loss is calculated relative to the total weight of the initial crosslinked polyester (i.e., on day 0).

[0079] A “crosslinking agent” is understood to be an agent intended to form one or more three-dimensional networks, chemically, in polyester. Thus, the crosslinking agent aims to create chemical bonds (called bridges) between the macromolecular chains of the polyester, when the crosslinking reaction is carried out.

[0080] Thus, the invention also relates to a crosslinked polyester obtained by crosslinking a polyester of glycerol and a dicarboxylic acid with as crosslinking agent at least one cyclic carboxylic polyanhydride A as defined below, with a mass loss at 7 days after in vitro incubation at 37.5°C in a PBS buffer and drying at 60°C greater than or equal to 5%, or preferably greater than or equal to 7%.

[0081] Advantageously, the crosslinked polyester has a Shore A hardness measured according to the ASTM D 2240 standard at ambient temperature between 20 and 80, typically between 20 and 50.

[0082] Crosslinked polyester can be obtained by the process of the invention.

[0083] Crosslinked polyester is typically obtained by crosslinking: • 100 parts by weight of at least one polyester, glycerol, and a diacid because boxyl, advantageously with a number-molecular-weight molar mass (Mn) less than or equal to 10,000 g / mol, • 10 to 100, preferably 20 to 50, parts by weight of cyclic carboxylic polyanhydride A.

[0084] Polyester of glycerol and a starting dicarboxylic acid monomer (i.e., before crosslinking)

[0085] The dicarboxylic acid monomer can be aliphatic, aromatic, or aliphatic / aromatic. An aliphatic / aromatic dicarboxylic acid monomer comprises an aliphatic portion and an aromatic portion. The dicarboxylic acid monomer preferably comprises from 4 to 36 carbon atoms.

[0086] According to preferred embodiments of the invention, the dicarboxylic acid monomer is aliphatic, in particular saturated, especially linear or branched, preferably a (C3-C2o)alkanediyldiacid carboxylic acid, more preferably a (C8-Ci5)alkanediyldiacid carboxylic acid. A (Cx-Cy)alkanediyl group is a divalent, saturated, linear or branched hydrocarbon group comprising x to y carbon atoms.

[0087] Advantageously, the dicarboxylic acid monomer comprises or consists of a diacid of general formula [HOOC-(CH2)P-COOH] in which p is a number from 1 to 30, preferably a number from 5 to 10.

[0088] In particular, the dicarboxylic acid monomer can be selected from malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, dodecanedioic acid, hexadecanedioic acid, octadecanedioic acid and a mixture of two or more of these dicarboxylic acids.

[0089] Preferably, the dicarboxylic acid monomer can be chosen from malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid and a mixture of two or more of these dicarboxylic acids.

[0090] According to variants of the invention, the dicarboxylic acid monomer can be a mixture of at least two dicarboxylic acids. Preferably, the dicarboxylic acid monomer comprises sebacic acid.

[0091] Preferably, the dicarboxylic acid monomer comprises or consists of sebacic acid.

[0092] According to preferred embodiments of the invention, the dicarboxylic acid monomer and glycerol are the only monomers during polycondensation.

[0093] Advantageously, the molar ratio of glycerol / dicarboxylic acid monomer varies from 1 to 10 / 1, in particular from 1 / 1 to 5 / 1, preferably from 1 / 1 to 2 / 1.

[0094] Glycerol polyester and a dicarboxylic acid monomer (hereinafter referred to as non-crosslinked polyester) advantageously has one or more of the following characteristics:

[0095] - an average number-average molar mass (Mn) of the non-crosslinked polyester greater than or equal to 1500 g / mol, preferably greater than or equal to 2000 g / mol;

[0096] - an average number-average molar mass (Mn) of the non-crosslinked polyester lower or equal to 10,000 g / mol, preferably less than or equal to 7,000 g / mol, preferably less than or equal to 5,000 g / mol;

[0097] - a polydispersity Ip (Mw / Mn) of the uncrosslinked polyester less than 10, of preference less than or equal to 8.

[0098] The polyester of glycerol and a dicarboxylic acid monomer can be obtained in particular by implementing the processes described in EP3149067 and EP1448656.

[0099] The number-average molar mass (Mn), the mass-average molar mass (Mw), and the dispersity (also called polydispersity and denoted D, which is the ratio Mw / Mn), can be measured in a known manner by size exclusion chromatography (SEC) analysis, in particular as described below.

[0100] Cyclic carboxylic polyanhydride (before crosslinking)

[0101] Preferably, the cyclic carboxylic polyanhydride comprises two functions cyclic carboxylic anhydride, that is to say, it is a cyclic bis-carboxylic anhydride.

[0102] In the present invention, the cyclic carboxylic anhydride groups of the cyclic polycarboxylic anhydride A are preferably independently selected from orthophthalic, succinic, maleic, homophthalic and isatoic groups.

[0103] The cyclic carboxylic polyanhydride may comprise identical or different cyclic carboxylic anhydride groups. Preferably, the cyclic carboxylic anhydride groups of the cyclic carboxylic polyanhydride are identical.

[0104] Advantageously, the cyclic carboxylic anhydride groups are independent of the orthophthalic, succinic or maleic groups.

[0105] Advantageously, the cyclic carboxylic anhydride groups of the cyclic polycarboxylic anhydride A are joined or linked to each other by at least one covalent bond or carried by a spacer group L,

[0106] L representing -O- ; -S- ; -S(O)- ; -S(O)2- ; -NRn- with Rn chosen from H or a alkyl group in Ci-C6; -C(O)-; or a multivalent hydrocarbon group comprising 1 to 40 carbon atoms, cyclic or acyclic, saturated, unsaturated or aromatic, and which may contain one or more heteroatoms of O, S, Cl, Br, F, N, P or Si, and

[0107] L being devoid of linear anhydride groups.

[0108] L is chemically stable. Thus, an oxygen atom cannot be bonded to another oxygen atom and a nitrogen atom cannot be bonded to another nitrogen atom. Therefore, L is preferably devoid of peroxide (-OO-) or hydrazine (-NH-NH- or -NH-N(Ci-C6 alkyl)- or -N(Ci-C6 alkyl)-N(Ci-C6 alkyl) groups. Similarly, an ester (C(O)O) function cannot be bonded to another ester function. Furthermore, L is advantageously devoid of readily hydrolyzable groups. In particular, L is devoid of linear anhydride groups, especially linear (divalent) carboxylic anhydride groups of the formula -OC(=O)-O-. Advantageously, L is also devoid of ester (-OC(=O)-) or amide (-OC(=O)-NR-) functions, with R representing H or a substituent such as a hydrocarbon chain.

[0109] The valence of the L group is even (since L carries cyclic carboxylic anhydride groups, which are divalent), and generally of 4 or 6, preferably of 4.

[0110] Advantageously, L represents a multivalent hydrocarbon group comprising 1 to 40 carbon atoms, cyclic or acyclic, saturated, unsaturated or aromatic, and able to contain one or more heteroatoms of O, S, Cl, Br, F, N, P or Si, which means that L then represents a cyclic or acyclic, saturated, unsaturated or aromatic multivalent hydrocarbon group, comprising 1 to 40 carbon atoms, in which one or more carbon atoms can be replaced by one or more heteroatoms of O, S, Cl, Br, F, N, P or Si or by a -C(O)- group.

[0111] Phosphorus (P), sulfur (S), nitrogen (N) and silicon (Si) atoms can be in oxidized form (in particular P(O), SO, SO2), and / or substituted - in particular by an alkyl group in Ci-C6 - depending on the valence of the atom.

[0112] Particularly advantageously, L represents a cyclic or acyclic, saturated, unsaturated or aromatic multivalent hydrocarbon group, comprising 1 to 40 carbon atoms, in which one or more carbon atoms can be replaced by one or more oxygen (O) atoms or a -C(O)- or -S(O)2- group, and optionally by one or more heteroatoms of Cl, Br, F, N, P or Si.

[0113] According to particular embodiments, L represents a saturated or unsaturated acyclic multivalent hydrocarbon group comprising 1 to 10 carbon atoms, in which one or more carbon atoms may be replaced by one or more oxygen (O) atoms or a -C(O)-, -S-, -S(O)-, -S(O)2-, and possibly by one or more heteroatoms of Cl, Br, F, N, P or Si.

[0114] According to other particular embodiments, L represents a saturated, unsaturated, or aromatic cyclic multivalent hydrocarbon group comprising 3 to 40 carbon atoms, wherein one or more carbon atoms may be replaced by one or more oxygen (O) atoms or a -C(O)- group, and optionally by one or more heteroatoms of S, Cl, Br, F, N, P, or Si, preferably a heteroatom of Cl, Br, or F. In these embodiments, the multivalent group may be monocyclic, bicyclic, or polycyclic. When L is bicyclic or polycyclic, it advantageously comprises one or more fused rings.

[0115] In particular embodiments, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (I) or preferably of formula (la):

[0116] in which • Li represents a bond; -O-; -S-; -S(O)-; -S(O)2-; -NRnRn- with Rn and Rn independently chosen from H or a Ci-C6 alkyl group; -C(O)-; or an aliphatic hydrocarbon chain of 1 to 30 carbon atoms, in which 1 to 6 methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene group; a heteroarylene group; -C(O)-; -O-; -S-; -S(O)-; -S(O)2-; -NRm- with Rm chosen from H or a Ci-C6 alkyl group; -P-; -P(O)-; -SiRaRb- with Ra and Rb independently representing a -OH, Ci-C6 alkyl or Ci-C6 alkoxy group,

[0117] said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, C6-alkyl, C6-alkoxy, hydroxyl, nitro, cyano, halogen, or C6-haloalkyl groups, • Zi is absent or represents a -CH2- (methylene) or -NH- group, • Z2 is absent or represents a -CH2- (methylene) or -NH- group, • X independently represents a C1-C6 alkyl group, a C1-C6 hydroxyl group, a C1-C6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • n represents an integer between 0 and 3, preferably between 0 and 2, • Y represents, independently of each other, an alkyl group in Ci-C6, a hydroxyl, alkoxy (Ci-C6), nitro, cyano, or a halogen atom, • m represents an integer between 0 and 3, preferably between 0 and 2.

[0118] Preferably, Zi and Z2 are identical. Advantageously, Zi and Z2 both represent a link.

[0119] Preferably, Li represents a bond ; -O- ; -S- ; -S(O)- ; -S(O)2- ; -C(O)- ; or an aliphatic chain of 1 to 30 carbon atoms, in which 1 to 6 methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene group, a heteroarylene group, -C(O)-, -O-, -S-, -S(O)-, -S(O)2-, -NRm- with Rm selected from H or a Ci-C6 alkyl group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, Ci-C6 alkyl groups, Ci-C6 alkoxy groups, a hydroxyl, nitro, cyano, halogen atom, a Ci-C6 haloalkyl group.

[0120] Preferably, Li represents a bond ; -O- ; -S(O)2- ; -C(O)- ; or an aliphatic chain of 1 to 20 carbon atoms, in which 1 to 4 (preferably 1 to 2) methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene group, -C(O)-, -O-, -S-, -S(O)-, -S(O)2-,

[0121] said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, substituents preferably selected from a Ci-C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl. In particular, Li may comprise one or two divalent aromatic groups, such as phenylenes.

[0122] In particular, Li represents a GrG2-G3 radical where Gi and G3 are independently selected from O, -S(O)2, -C(O)- ; G2 is a divalent hydrocarbon group of 4 to 15 carbon atoms which may comprise one or two divalent aromatic groups, such as phenylenes, and which may be substituted by one or more, in particular one or two, preferably selected groups from a Ci-C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

[0123] Advantageously, Li represents a bond ; -O- ; -S(O)2- ; -C(O) ; or an aliphatic chain of 1 to 10 carbon atoms, in particular of 1 to 6 carbon atoms, in which 1 to 2 methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene, -C(O)-, -O-, -S-, -S(O)-, -S(O)2- group,

[0124] said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two group(s) preferably selected from a Ci-C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

[0125] Advantageously, Li represents a bond ; -O- ; -S(O)2- ; -C(O) ; or an aliphatic chain of 1 to 10 carbon atoms, in particular of 1 to 6 carbon atoms, in which 1 to 2 methylene unit(s) (preferably non-adjacent) is / are optionally- nemally replaced by an arylene group, -C(O)-, -O-, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two Ci-C6 alkyl group(s), Ci-C6 alkoxy group(s), a hydroxyl, nitro, cyano, halogen atom, a Ci-C6 haloalkyl group, typically substituted or unsubstituted by a Ci-C6 alkyl group, a Ci-C6 alkoxy group, a halogen atom, or a Ci-C6 haloalkyl group.

[0126] In particular, X can independently represent a Ci-C6 alkyl group, a hydroxyl group, or a halogen atom.

[0127] Advantageously, n represents 0 or 1.

[0128] Preferably, Y represents an alkyl group independently of each other in Ci-C6, a hydroxyl group, or a halogen atom,

[0129] Advantageously, m represents 0 or 1.

[0130] According to particular variants, n and m independently represent 0 or 1, and X and Y independently represent a Ci-C6 alkyl group, a hydroxyl, or a halogen atom.

[0131] In other particular embodiments, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (II) or preferably of formula (lia): O"'""' Zf O p (Ha) O fpdo

[0132] in which

[0133] Zi is absent or represents a -CH2- (methylene) or -NH- group,

[0134] Z2 is absent or represents a -CH2- (methylene) or -NH- group,

[0135] Ai represents: • a C-C bond or a C=C bond linking the four carbon atoms of the two carboxylic anhydride functions, • a saturated, established or aromatic carbocycle, said carbocycle comprising from 4 to 30 carbon atoms, and • a saturated, instituted or aromatic heterocycle, said heterocycle comprising from 4 to 30 carbon atoms, and

[0136] said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents, in particular a Ci-C6 alkyl group, a Ci-C6 haloalkyl group, a hydroxyl, alkoxy in Ci-C6, nitro, cyano, or a halogen atony.

[0137] According to some embodiments, Aire represents a polycyclic carbocycle or heterocycle of 10 to 30 members. In these embodiments, the polycyclic group may include fused rings. Advantageously, Aire represents a polycyclic aromatic carbocycle or heterocycle of 10 to 30 members, comprising two or more fused rings. This may, in particular, be a naphthalene group.

[0138] According to variants, Ai represents an aromatic carbocycle comprising 6 to 10 carbon atoms, such as a phenyl or a naphthalene.

[0139] According to other embodiments, Ai represents a saturated carbocycle (monocyclic or bicyclic) comprising from 4 to 10, preferably from 4 to 6, carbon atoms. Preferably, it is a saturated monocyclic carbocyclic comprising from 4 to 6 carbon atoms.

[0140] According to variants, at least one of at least one cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (III): O o (III) 'P; O o

[0141] in which represents a simple or double DC connection

[0142] L2 and L3 taken together with the carbon atoms to which they are bonded represent a saturated, instaurated or aromatic carbocycle or heterocycle, optionally bridged, said carbocycle or heterocycle comprising from 4 to 30 carbon atoms, and

[0143] said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, CrC6 alkoxy, nitro, cyano, or halogen atom.

[0144] Preferably, L2 and L3 taken together with the carbon atoms to which they are bonded represent a saturated, instaurated or aromatic carbocycle, optionally bridged,

[0145] said carbocycle comprising from 4 to 10 carbon atoms, and

[0146] said carbocycle being substituted or not substituted by one or more (in particular 1 or 2) substituents chosen from a Ci-C6 alkyl group or a halogen atom.

[0147] Advantageously, L2 and L3 taken together with the carbon atoms to which they are bonded represent: • a saturated or established carbocycle, optionally bridged, comprising 4 to 8 carbon atoms, substituted or unsubstituted by one or more (in particular 1 or 2) substituents selected from a Ci-C6 alkyl group, halogen atom, or • an aromatic carbocycle of 6 to 10 carbon atoms, substituted or unsubstituted by one or more (in particular 1 or 2) substituents chosen from an alkyl group in Ci-C6, halogen atom.

[0148] In particular, L2 and L3 taken together with the carbon atoms to which they are bonded can represent a cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]oct-2-enyl, or a phenyl.

[0149] According to variants, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (IV): O p (IV) 6b

[0150] in which represents a single or double DC connection.

[0151] According to preferred embodiments, the cyclic carboxylic polyanhydride of formula (I) is chosen from the group consisting of:

[0152] and a mixture of these.

[0153] [Tables 1] Pyromellitic acid bisanhydride (PMDA) q P vCÏC fs 0 0 1,2,3,4-cyclopentanetetracarboxylic acid bisanhydride OO AA o )—ro $ 'aa 4 0 0 1,2,3,4-cyclobutanetetracarboxylic acid bisanhydride 0 ofm Y 0 0 ^0 0 Benzophenone-3,3 / ,4,4'-tetracarboxylic acid bisanhydride (BTDA) "X, X. $ \ 4,4'-(4,4'-Isopropylidene-diphenoxy) phthalic acid bisanhydride (BPADA) G I. 1' G j 1 i:} •G 4,4'-diphthalic acid bisanhydride (BPDA) / S 0 / / o-1" C- / G 4,4'-Oxydiphthalic acid bis-anhydride (ODPA) 0 Ci b 0 L îs P x--' b 4,4'-Hexafluoroisopropyldenediphthalic acid bis-anhydride (6FDA) 0 V, CF, K --.-. X .-a A n "ï 1 4 0 w Q 4,4'-Isopropyldenediphthalic acid bis-anhydride A 4 JO > S o 3,3',4,4'-Diphenylsulfonetetracarboxylic acid bisanhydride (DSDA) OO, OO bj J bbb 1,4,5,8-Naphthalenetetracarboxylic acid bisanhydride c< JL Js. Ethylenetetracarboxylic acid bisanhydride OOK d F b FF OO Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic acid bisanhydride O, yo yf° dj bF O

[0154] Preferably, the cyclic carboxylic polyanhydride is BDTA, DPADA, BPDA and ODPA, or a mixture of these.

[0155] Cyclic carboxylic polyanhydrides, particularly the cyclic bis-carboxylic anhydrides of the invention, are well known to those skilled in the art (see, in particular, US 7,425,650). They can be obtained by condensation of the corresponding tetracarboxylic acids, and some are commercially available. More specifically, for the synthesis of cyclic carboxylic polyanhydrides comprising groups:

[0156] Homophthalic: the syntheses described in US 6,797,838 may be used or adapted;

[0157] Isotaoic: the syntheses described in "Sonochimie ultrasonique", Volume 14, Number 5, July 2007, pages 497-501, may be used or adapted. Crosslinking

[0158] Advantageously, the crosslinking step comprises the following steps: a. contacting 100 parts by weight of at least one polyester of glycerol and a dicarboxylic acid monomer, with 10 to 100, preferably 20 to 50, parts by weight of at least one cyclic carboxylic polyanhydride as defined herein, to obtain a mixture of crosslinking precursors, b. pressurizing the mixture obtained in the crosslinking precursor step of step a) to a target temperature Tc between 100°C and 200°C, and maintenance (at temperature Tcet under pressure) for a heating time under pressure tch sufficient to obtain a crosslinked polyester, c. cooling and recovery of the crosslinked polyester.

[0159] Typically, step a) includes contacting 100 parts by weight of at least one polyester of glycerol and a dicarboxylic acid, with 10 to 100, in particular 15 to 90, parts by weight of at least one cyclic carboxylic polyanhydride.

[0160] Preferably, step a) of contacting is carried out in the absence of solvent, diluent or other additive.

[0161] Step a) comprises a mixture of at least one glycerol polyester and a dicarboxylic acid and at least one cyclic polycarboxylic anhydride, preferably at a temperature Ta allowing the melting of the glycerol polyester and a dicarboxylic acid monomer, and preferably a homogeneous dispersion of the cyclic polycarboxylic anhydride. Thus, Ta is typically between 20°C and 100°C, in particular between 30°C and 80°C.

[0162] To promote homogenization, agitation can be implemented in a known manner. Thus, step a) is typically carried out under agitation.

[0163] According to particulars of the invention, the contact is made by introducing the cyclic carboxylic polyanhydride in solid form.

[0164] Advantageously, in step b), a platen press will be used, the plates of which have been preheated to temperature Tc.

[0165] In step b), the temperature Tc is typically between 110°C and 175°C, preferably between 120°C and 160°C.

[0166] Advantageously, the overpressure applied by the press (relative to atmospheric pressure) in the heating step b) varies from 0.5 to 5 bar (equivalent to 50 to 500 kPa), in particular from 1 to 4 bar.

[0167] The heating time is determined by the duration between the moment the press is closed and the moment it is opened.

[0168] Generally, the heating time tch is between 10 and 2000 min.

[0169] During step c), the crosslinked polyester is typically cooled and recovered at room temperature and atmospheric pressure. METHODS Shore A hardness measurement:

[0170] Shore A hardness measurements were carried out using a portable Shore durometer according to ASTM D2240 at room temperature (23°C±2°C). Measurement of in vitro degradation:

[0171] Crosslinked polyester discs with a diameter of 10 mm and a thickness of 2 mm are prepared and then weighed. They are then incubated individually in aseptic flasks (TP30) containing 20 ml of phosphate-buffered saline (PBS) solution at a temperature of 37.5°C. Discs are taken at different dates. For each weighing, the sample is first dried in an oven at 60°C for 3 days prior to weighing. The percentage weight loss for each measurement is calculated from the initial dry weight (i.e., at t = 0). Macrostructure analysis: SEC RI

[0172] The SEC (Size Exclusion Chromatography) technique allows the separation of macromolecules in solution according to their size through columns filled with a porous gel. The macromolecules are separated according to their hydrodynamic volume, with the largest being eluted first.

[0173] While not an absolute method, SEC allows for the determination of the molar mass distribution of a polymer. From commercial standard products, the various number-average (Mn) and weight-average (Mw) molar masses can be determined, and the polydispersity index (Ip = Mw / Mn), also called "dispersity," can be calculated.

[0174] The "macrostructure" of polyesters is analyzed by size-exclusion chromatography with differential refractometer detection (SEC RI), using low-weight polystyrene (PS) calibration with medium-weight standards. Samples are dissolved at a concentration of approximately 1 g / L in THF without butylated hydroxytoluene (BHT), then stirred for two hours before injection. The analysis temperature is 35°C, with a mobile phase flow rate of 1 µL / minute on 2 Mixed E + 2 Mixed 2 columns (commercially available from Agilent). EXAMPLES

[0175] The following examples are given for illustrative purposes only, but should in no way be considered as limiting the present invention. 1. Materials and methods

[0176] Characteristics of the starting products

[0177] [Tables2] Polyester Mn (g.mol1' Mw (g.mol1) IP Polyglycerol sebacate 2656 16520 6.2

[0178] Procedure for the synthesis of the starting glycerol and sebacic acid polyester (non-crosslinked):

[0179] In a 10L double-walled stainless steel reactor fitted with an instrumented distillation column configured for total reflux and a condenser connected to a distillate recovery vessel, glycerol (1.94 kg, 1 molar equivalent) is mixed with Water (0.56 kg) is heated to 40 °C under a nitrogen flow (0.5 L / min). Gentle stirring is applied (20 rpm) for 5 minutes. After the glycerol dissolves, sebacic acid (4.25 kg, 1 molar equivalent) is added to the aqueous mixture in the reactor. Finally, the remaining water (0.56 kg) is added to the medium. The reactor vessel is then gradually heated, following a progressive temperature ramp with intermediate plateaus, until a body temperature of 172 °C is reached after 5 hours, corresponding to a medium temperature of 170 °C, measured using an immersion probe. Stirring is increased to 80 rpm when the medium temperature exceeds 90 °C. The medium is left under reflux at the beginning of the test.When the vapor temperature at the top of the distillation column reaches 98°C, and after a 15-minute equilibration period, the column configuration is switched to total draw-off to selectively recover the water produced during the reaction. Esterification of the medium is carried out over a total duration of 8.5 hours, starting from the moment distillation begins, approximately 30 minutes after the introduction of the reagents. The water distilled during the test is collected in a dedicated, heat-insulated recovery vessel. A vacuum system is then connected to the distillation condenser, and a pressure below atmospheric pressure is applied to the reactor contents. The pressure is reduced slowly and incrementally (approximately 10–15% per increment) over approximately 30 minutes until a target value of less than 30 mbar is reached.Once the pressure in the reaction vessel stabilizes at 28 mbar, the medium is allowed to react at 170 °C for an additional 4 hours. During this polycondensation step, the stirring speed is maintained at 80 rpm. The produced PGS is transferred from the reactor vessel to a container and allowed to cool to room temperature. The product is then transferred to a freezer for storage, where it is frozen for at least approximately 24 hours before analysis.

[0180] [Tables3] Bis Anhydride Abbreviation M (g.mol1) Benzophenone-3,3',4,4'-tetracarboxylic acid bis-anhydride BTDA 322.23 4,4'-(4,4'-Isopropylidene-diphenoxy)phthalic acid bis-anhydride BPADA 520.49 4,4'-Oxydiphthalic acid bis-anhydride ODPA 310.21 3,3',4,4'-Biphenyltetracarboxylic acid bis-anhydride BPDA 294.22 2. Results 2.1. Tested Formulations

[0181] The compositions studied are presented below. The contents are expressed in pce (parts per percent of polymer, i.e. of polyester, glycerol and dicarboxylic acid).

[0182] The so-called "reference" mixture for each comparison is a high molecular weight poly(glycerol sebacate) polymer used alone (i.e., crosslinked in the absence of a crosslinking agent, particularly a cyclic polycarboxylic anhydride). The preparation protocol used is the same as that described in section 2.2, but without the cyclic polycarboxylic anhydride. The heat treatment is then 2880 min at 140°C in the platen press. The reference mixture has a Mn = 2656 g / mol and a Mw = 16520 g / mol.

[0183] [Tables4] PGS reference BTDA BPADA ODPA BPDA PGS (pc) 100 100 100 100 83 Polyanhydride (pc) 0 22 30 23.5 20.5

[0184] 2.2. Protocol for the preparation of crosslinked polyesters Step a)

[0185] Place a 100mL beaker on a hot plate equipped with a PT100 probe to control the temperature.

[0186] Introduce poly(glycerol sebacate)

[0187] Heat the polymer to 50°C while mixing it with a spatula.

[0188] Using a spatula, mix the cyclic carboxylic polyanhydride with the poly(glycerol sebacate) until a homogeneous mixture is obtained.

[0189] Cool to room temperature. Step b): crosslinking

[0190] Place the mixture in the middle of a 2mm thick mold, between two silicone sheets, 15g of the desired formulation.

[0191] Platen press at 140°C (no humidity control)

[0192] Crosslink the materials for the desired and previously determined time tc. according to the crosslinking kinetics measurement method described in point 1. The applied time tch is the time required for the elastic modulus to reach the value of IMPa, according to the crosslinking kinetics measurement method.

[0193] Cool to room temperature. Remove from mold and cut out the desired number of discs with a diameter of 10 mm and a thickness of 2 mm. 2.3. Characterization of crosslinked polyesters

[0194] [Tables5] PGS BTDA BPADA ODPA BPDA PGS (pc) 100 100 100 100 83 Polyanhydride (pc) 0 22 30 23.5 20.5 Crosslinking time at 140°C (min) 2880 150 200 350 150 Shore A 29 24 28 24 25 Loss at 7 days incubation (%) 6.7 15.8 8.7 15.3 11.2 3. Discussion

[0195] It is observed that after 7 days of incubation, practically all the compositions according to the invention exhibit significantly to significantly higher mass losses compared to the reference composition.

[0196] Furthermore, it is noted that the use of cyclic carboxylic polyanhydride as a crosslinking agent makes it possible to significantly reduce the in vitro degradation time of a poly(glycerol sebacate) polymer in a PBS type buffer at 37.5°C, while maintaining Shore A hardness values ​​similar to the reference PGS.

Claims

Demands

1. Use of a cyclic polycarboxylic anhydride A, the cyclic polycarboxylic anhydride A comprising at least two cyclic carboxylic anhydride groups, and not comprising a linear carboxylic anhydride function, as a crosslinking agent of a glycerol polyester and a dicarboxylic acid, so as to increase the bioresorbability and / or degradation in aqueous media of a crosslinked glycerol polyester and a dicarboxylic acid, in particular compared to a thermally crosslinked glycerol polyester and a dicarboxylic acid in the absence of a crosslinking agent, and advantageously in the absence of cyclic polycarboxylic anhydride A.

2. Use according to claim 1, characterized in that the cyclic carboxylic anhydride groups of the cyclic polycarboxylic anhydride A are joined, linked together by at least one covalent bond or carried by a spacer group L, L representing -O- ; -S- ; -S(O)- ; -S(O)2- ; -C(O)- ; -NRnRn- with Rn and Rn independently selected from H or a Ci-C6 alkyl group, or a multivalent hydrocarbon group comprising 1 to 40 carbon atoms, cyclic or acyclic, saturated, unsaturated or aromatic, and able to contain one or more heteroatoms of O, S, Cl, Br, F, N, P or Si, L being devoid of linear anhydride groups.

3. Use according to any one of the preceding claims, characterized in that the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (I) or (II): O p (I) or pp (H) _A Li. A x A J. 1 » J il \A k À L s 1 i O'' Zi Y' -.4- -Z£ Y O-' XZ{ Y) / U yy in which • Li represents a bond ; -O- ; -S- ; -S(O)- ; -S(O)2- ; -NRnRn' - with Rn and R„ independently chosen from H or a Ci-C6 alkyl group; -C(O)-; or an aliphatic chain of 1 to 30 carbon atoms, in which 1 to 6 methylene unit(s) is / are optionally replaced by an arylene group, a heteroarylene group, -C(O)-; -O-; -S-; - S(0)- ; -S(0)2- ; -NRm- with Rm chosen from H or a Ci-C6 alkyl group, ; -P- ; -P(O)- ; -SiRaRb- with Ra and Rb independently representing a -OH, Ci-C6 alkyl or Ci-C6 alkoxy group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, alkyl groups in the C1-6 group, alkoxy group in the C1-6 group, a hydroxyl group, a nitro group, a cyano group, a halogen atom, a haloalkyl group in the C1-6 group 6- • Zi is absent or represents a -CH2- (methylene) or -NH- group, • Z2 is absent or represents a -CH2- (methylene) or -NH- group, • X independently represents a Ci-C6 alkyl group, a Ci-C6 hydroxyl group, a Ci-C6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • n represents an integer between 0 and 3, preferably between 0 and 2, • Y independently represents a C1-C6 alkyl group, a C1-C6 hydroxyl group, a C1-C6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • m represents an integer between 0 and 3, preferably between 0 and 2, • Ai represents: • A C-C bond or a C=C bond linking the four carbon atoms of the two carboxylic anhydride functions, • a saturated, established or aromatic carbocycle, optionally bridged, said carbocycle comprising from 4 to 30 carbon atoms, and • a saturated heterocycle, established or aromatic, optionally bridged, said heterocycle comprising from 4 to 30 carbon atoms, and said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, alkoxy in Ci-C6, nitro, cyano, or halogen atom.

4. Use according to claim 3, characterized in that Li represents an aliphatic bond or chain of 1 to 6 carbon atoms, wherein one or two methylene units is / are optionally replaced by an arylene, -C(O)-, -O-, -S-, -S(O)-, -S(O)2- group, said aliphatic chain being substituted or unsubstituted by a group preferably selected from a Ci-C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

5. Use according to any one of the preceding claims, characterized in that the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (III) or (IV): O o (III) 0 O (IV) ...4 ^.-4 b 0 F oa J b / "'«'A «..........t 0 0 o O in which represents a single or double C-C bond, L2 and L3 taken together with the carbon atoms to which they are bonded represent a saturated, unsaturated or aromatic carbocycle or heterocycle, said carbocycle or heterocycle comprising from 4 to 30 carbon atoms, and said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, Ci-C6 alkoxy, nitro, cyano, or halogen atom.

6. Crosslinked polyester obtained by crosslinking a polyester of glycerol and a dicarboxylic acid with at least one cyclic carboxylic polyanhydride A as defined in any one of claims 1 to 5 as the crosslinking agent, with a mass loss at 7 days after in vitro incubation at 37.5°C in PBS buffer and drying at 60°C greater than or equal to 5%.

7. Crosslinked polyester according to claim 6, characterized in that the crosslinked polyester has a Shore A hardness measured according to ASTM D 2240 at room temperature between 20 and 80, typically between 20 and 50.

8. Crosslinked polyester according to claim 6 or 7, obtained by crosslinking: 100 parts by weight of at least one polyester of glycerol and of a dicarboxylic acid, • from 10 to 100, preferably from 20 to 50 parts by weight of the cyclic polycarboxylic anhydride A.

9. Crosslinked polyester according to claim 8, wherein the polyester of glycerol and a dicarboxylic acid has a number molar mass Mn less than or equal to 10,000 g / mol.

10. Crosslinked polyester according to claim 8 or 9, wherein the dicarboxylic acid has the formula [HOOC-(CH2)P-COOH], in which p is a number from 1 to 30, preferably a number from 1 to 10, advantageously sebacic acid (p=8).