Use of poly(2-oxazoline) for improving the extensibility of crosslinked glycerol polyesters

Abstract

The present invention relates to the use of a poly(2-oxazoline) comprising units of formula (I), where R is a linear or branched alkyl radical comprising 1 to 18 carbon atoms or a substituted or unsubstituted cycloalkyl radical comprising 3 to 18 carbon atoms, which may contain, within or outside the main chain or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S), for improving the extensibility of a crosslinked glycerol polyester, in particular compared to a glycerol polyester crosslinked in the absence of such a poly(2-oxazoline) compound.

Description

[0001] Use of poly(2-oxazoline) for improving the extensibility of glycerol-crosslinked polyesters

[0002] FIELD OF INVENTION

[0003] The present invention relates to crosslinked polyesters of glycerol and a carboxylic diacid or diester exhibiting improved extensibility.

[0004] STATE OF THE ART

[0005] Biodegradable and / or bio-based polyesters, such as polylactic acid (PLA), polyglycolic acid (PGA), poly(glycerol sebacate) (PGS), polycaprolactone (PLGA), and their copolymers, are widely used in the manufacture of biomaterials, particularly in medical fields (implants, sutures, controlled release devices) and as coating materials for various industrial applications.

[0006] However, these materials sometimes have limitations in terms of extensibility. Their intrinsic rigidity, linked to their chemical structure and crystallinity, restricts their ability to withstand significant deformation without breaking. This limited extensibility can be a hindrance when a certain degree of elasticity is required for applications such as flexible medical devices, flexible packaging, or biodegradable technical textiles. Therefore, there is a need to develop formulations or structural modifications to improve the extensibility of biodegradable polyesters while preserving their biodegradability, biocompatibility, and suitability for industrial processing.

[0007] The inventors have unexpectedly demonstrated that adding poly(2-oxazoline) (POx) to a glycerol polyester, such as poly(glycerol sebacate), significantly improves the mechanical properties of the crosslinked glycerol polyester compared to the same polyester without this compound, particularly in terms of tensile strength and fracture behavior. Thus, this polymer combination unexpectedly confers increased extensibility to the resulting material. While not limiting the invention, the inventors suggest that this effect could be attributed to a high degree of compatibility between the two polymers, the glycerol polymer and poly(2-oxazoline); the poly(2-oxazoline) would act as a plasticizer in the mixture after curing.

[0008] Furthermore, the inventors have also demonstrated that the addition of poly(2-oxazoline) to glycerol polyester is likely to significantly improve bioresorbability at body temperature, compared to cross-linked glycerol polyester without this additive.

[0009] This improvement in mechanical properties, and in particular extensibility, opens the way to new applications for biodegradable polyester-based materials in various industrial sectors where bioresorbability is desired, notably in the field of medical biomaterials (implants, flexible devices, bioactive coatings) where greater flexibility can be an advantage. Thus, the present invention aims to use a poly(2-oxazoline) to improve the extensibility of a cross-linked glycerol polyester.

[0010] DESCRIPTION OF THE INVENTION

[0011] The present invention relates to the use of a poly(2-oxazoline) comprising units of formula (I) to improve the extensibility of a glycerol polyester and a crosslinked diacid or dicarboxylic acid aliphatic monomer.

[0012]

[0013] formula (I)

[0014] in which R is a linear or branched alkyl radical comprising 1 to 18 carbon atoms or a substituted or unsubstituted cycloalkyl radical comprising 3 to 18 carbon atoms, these same radicals being able to contain, within or outside the main chains or within a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S). Advantageously, in formula (I), R is a C1-C10 alkyl radical. Advantageously, in formula (I), R is a C1-C4 alkyl radical, preferably methyl or ethyl.

[0015] Advantageously, poly(2-oxazoline) is a copolymer of at least two different 2-alkyl-2-oxazolines.

[0016] Advantageously, poly(2-oxazoline) is a homopolymer of 2-alkyl-2-oxazoline.

[0017] Advantageously, poly(2-oxazoline) is poly(2-methyl-2-oxazoline) or poly(2-ethyl-2-oxazoline).

[0018] Advantageously, the crosslinked glycerol polyester is a crosslinked polyester of glycerol and a diacid or carboxylic diester whose diacid or carboxylic diester monomer has the formula [R'00C-(CH2) P -C00R'], in which R' is H or each of the R's represents, independently of the other, a linear or branched C1-C10 alkyl, preferably C1-C2, preferably C1-C4, p is a number from 1 to 30, preferably a number from 1 to 10.

[0019] Advantageously, the dicarboxylic acid monomer is sebacic acid.

[0020] Advantageously the carboxylic diester monomer is a sebacic acid diester, preferably dimethyl sebacate.

[0021] The invention also relates to a crosslinkable composition comprising

[0022] o 100 parts by weight of at least one polyester of glycerol and one aliphatic diacid or carboxylic diester monomer with a number molar mass Mn less than or equal to 10000 g / mol, and

[0023] o 0.1 to 100 parts by weight of at least one poly(2-oxazoline) comprising units of formula (I) above.

[0024] Advantageously, glycerol polyester is a polyester of glycerol and a diacid or carboxylic diester whose diacid or carboxylic diester monomer has the formula [R'OOC-(CH2) P-COOR'], in which R' is H or each of the R's represents, independently of the other, a linear or branched alkyl in C1-C10, preferably in C1-C2, preferably in C1-C4, p is a number from 1 to 30, preferably a number from 1 to 10, most preferably p=8. Advantageously, in formula (I), R is an alkyl radical in C1-C10, preferably in C1-C4, preferably methyl or ethyl.

[0025] Advantageously, poly(2-oxazoline) is a homopolymer poly(2-alkyl-2-oxazoline), preferably poly(2-methyl-2-oxazoline) or poly(2-ethyl-2-oxazoline).

[0026] The invention also relates to a process for manufacturing a cross-linked glycerol polyester comprising the following steps:

[0027] a) contacting 100 parts by weight of a polyester of glycerol and aliphatic monomer of a diacid or carboxylic diester of number molar mass Mn less than or equal to 10000 g / mol, with 0.1 to 100 parts by weight, preferably 5 to 100 parts by weight, preferably still 10 to 70 parts by weight, preferably still 10 to 50 parts by weight, preferably 20 to 50 parts by weight, preferably 20 to 45 parts by weight, of a poly(2-oxazoline) comprising units of formula (I)

[0028]

[0029] formula (I)

[0030] wherein R is an alkyl radical, linear or branched, comprising 1 to 18 carbon atoms, or a cycloalkyl radical, substituted or unsubstituted, comprising 3 to 18 carbon atoms, these same radicals being able to contain, in or outside the main chains or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S); b) heating the mixture obtained in step a) to a target temperature Te between 100°C and 200°C, and holding (at temperature Te and under pressure) for a heating time tch sufficient to obtain a crosslinked polyester,

[0031] c) cooling and recovery of the crosslinked polyester.

[0032] The invention also relates to a crosslinked product based on, or obtained as a result of, a composition described above. This refers to a product comprising such a composition that has undergone a treatment, particularly a thermal treatment, aimed at crosslinking the composition.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] DEFINITIONS

[0035] For the purposes of this invention, the term “a” or “an” shall be interpreted as including “at least one” or “at least one”, unless otherwise indicated.

[0036] 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 (i.e. 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, i.e. including the strict bounds a and b.

[0037] 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 stated value.

[0038] For the purposes of this invention, the term "polymer compatibility" refers to the ability of two polymers to form a homogeneous mixture. This compatibility is characterized in particular by good miscibility, favorable interaction between the polymer chains, and synergy in mechanical properties.

[0039] This definition should not be confused with biocompatibility, which concerns the ability of a material to interact with a biological environment without causing an undesirable reaction.

[0040] 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 may also come from the recycling of already used materials; that is, they may be partially or totally derived from a recycling process, or obtained from raw materials themselves derived from a recycling process. Monomers are particularly concerned, namely glycerol and dicarboxylic acid monomers. In the present invention, a "glycerol polyester" means a "glycerol and dicarboxylic acid or diester polyester," that is, a glycerol and dicarboxylic acid monomer polyester or a glycerol and dicarboxylic acid diester polyester.

[0041] OH HO JL OH

[0042] Glycerol is a triol with the following formula:

[0043]

[0044] By "aliphatic" we mean a linear, branched and / or cyclic hydrocarbon group, whether saturated or unsaturated but non-aromatic.

[0045] For the purposes of this invention, the term "alkyl group" refers to a monovalent, saturated, linear or branched hydrocarbon chain comprising from 1 to 18 carbon atoms, preferably from 1 to 10 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups.

[0046] For the purposes of this invention, the term "cycloalkyl group" refers to a monovalent cyclic saturated hydrocarbon chain comprising 3 to 18 cyclic carbon atoms, preferably comprising 5 to 10 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.

[0047] For the purposes of this invention, "oxazoline" means a compound corresponding to formula (II)

[0048]

[0049] Formula (II)

[0050] wherein R is a linear or branched alkyl radical comprising 1 to 18 carbon atoms or a substituted or unsubstituted cycloalkyl radical comprising 3 to 18 carbon atoms, these same radicals being able to contain, within or outside the main chains or within a heterocycle, one or more heteroatoms chosen by oxygen (O), nitrogen (N), or sulfur (S). Advantageously, R is a C1-C10 alkyl radical, preferably a C1-C4 alkyl radical, preferably methyl or ethyl. "Room temperature" herein means a temperature generally between 15°C and 40°C, preferably between 20°C and 30°C, in particular about 25°C.

[0051] By "body temperature" we mean here a temperature typically between 32°C and 45°C, and essentially around 37°C to 38°C.

[0052] 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 both the 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 formation of metabolites with lower molecular weights.

[0053] As used here, the "degradation" of a polyester refers to a chemical process involving, in particular, the hydrolysis of ester bonds, generating polymer molecules of lower molecular weight. "Biodegradation" is such a process in which the degradation is carried out by the action of microorganisms. As used here, an "aqueous medium" refers to 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).

[0054] As used here, a "PBS buffer," also called a "phosphate saline buffer," refers to 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. Generally, the concentration of these salts is that of the human body (isotonicity). Therefore, the PBS buffer is generally suitable for replicating the environment of a living organism. (Use of poly(2-oxazoline) to improve the extensibility of a cross-linked glycerol polyester)

[0055] The invention relates to the use of a poly(2-oxazoline) comprising units of formula (I) so as to increase the tensile strength and fracture behavior properties of the crosslinked glycerol polyester, in particular compared to the same starting glycerol polyester which has undergone thermal crosslinking in the absence of such an additive,

[0056]

[0057] formula (I)

[0058] in which R is an alkyl radical, linear or branched, comprising 1 to 18 carbon atoms or a cycloalkyl radical, substituted or unsubstituted, comprising 3 to 18 carbon atoms, these same radicals being able to contain in or out of the main chains or in a heterocycle, one or more heteroatoms chosen by oxygen (O), nitrogen (N) and sulfur (S).

[0059] In formula (I), the Rs are either identical or different.

[0060] The extensibility of the crosslinked polyesters obtained according to the invention, which is characterized in particular in the laboratory by measurements of the breaking properties, is improved.

[0061] It also turns out that the bioresorbability indicator, measured by the degradation in aqueous medium of crosslinked glycerol polyesters in the presence of a poly(2-oxazoline) 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°C, i.e. body temperature.

[0062] The indicator of bioresorbability and / or degradation in aqueous media is characterized in the context of the invention in the laboratory by the mass loss, up to 10 days after in vitro incubation at 37°C in PBS buffer and drying at 60°C. The mass loss is calculated relative to the total weight of the initial crosslinked polyester (i.e., on day 0). The mass loss is advantageously greater than or equal to 3%, or even greater than or equal to 5%. (Polyester of the starting glycerol (i.e., before crosslinking))

[0063] The starting glycerol polyester can be a polyester of glycerol and a dicarboxylic acid monomer or a polyester of glycerol and a diester monomer of a dicarboxylic acid.

[0064] The dicarboxylic acid monomer or the diester monomer of a dicarboxylic acid can be aliphatic, aromatic, or aliphatic / aromatic. An aliphatic / aromatic monomer comprises an aliphatic portion and an aromatic portion. The dicarboxylic acid or diester preferably comprises from 3 to 36 carbon atoms.

[0065] According to preferred embodiments of the invention, the carboxylic diacid or diester is aliphatic, in particular saturated, especially linear or branched. Preferably, it is a (C3-C20)alkanediyldiacid carboxylic acid, more preferably a (Cs-C15)alkanediyldiacid carboxylic acid, or one of its diesters. A (C) group x -C y )alkanediyl is a divalent, saturated, linear or branched hydrocarbon group, comprising x to y carbon atoms.

[0066] Advantageously, the dicarboxylic acid monomer or the carboxylic diester monomer corresponds to the general formula R'00C-(CH2) P-C00R' , in which p represents an integer from 1 to 30, preferably a number from 1 to 10, and R' represents H (hydrogen atom) or each R' represents, independently of each other, a linear or branched alkyl, in C1-C10, preferably in C1-C4, preferably also methyl or ethyl.

[0067] Depending on the variant, the monomer is a dicarboxylic acid corresponding to the general formula [H00C-(CH2) P -C00H] in which p is a number from 1 to 30, preferably a number from 5 to 10.

[0068] Specifically, according to these variants, the dicarboxylic acid monomer may 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. Preferably, the dicarboxylic acid monomer may be selected 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.

[0069] According to variations 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.

[0070] Preferably, the dicarboxylic acid monomer comprises or consists of sebacic acid.

[0071] According to preferred embodiments of the invention, the dicarboxylic acid monomer and glycerol are the only monomers during polycondensation.

[0072] According to other variants, the monomer is a diester of a dicarboxylic acid corresponding to the general formula R"00C-(CH2) n-C00R”, in which n represents an integer from 1 to 30, preferably a number from 1 to 10, and each R”, independently of each other, represents a linear or branched alkyl, in C1-C10, preferably in C1-C4, preferably also methyl or ethyl. In particular, according to these variants of the invention, the alkyl diester monomer of dicarboxylic acid can be chosen from the alkyl diesters corresponding to malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid or a mixture of two or more of these dicarboxylic acid diesters, more preferably the dicarboxylic acid diester is chosen from the group consisting of dimethyl malonate, dimethyl succinate, dimethyl glutarate, dimethyl adipate, dimethyl pimelate, dimethyl suberate, dimethyl azelate, dimethyl sebacate, and mixtures thereof.According to embodiments of the invention, the dicarboxylic acid diester monomer may be a mixture of at least two different dicarboxylic acid diesters. Preferably, the dicarboxylic acid diester monomer comprises dimethyl sebacate. According to preferred embodiments of the invention, the dicarboxylic acid diester monomer is dimethyl sebacate. According to preferred embodiments of the invention, the dicarboxylic acid diester monomer and glycerol are the only monomers. Most preferably, the dimethyl sebacate monomer and glycerol are the only monomers.

[0073] Advantageously, the molar ratio of glycerol / diacid or carboxylic diester monomer varies from 1 / 2 to 10 / 1, notably from 1 / 1 to 5 / 1, preferably from 1 / 1 to 2 / 1.

[0074] Glycerol polyester and a diacid or carboxylic diester monomer (hereinafter referred to as non-crosslinked polyester) advantageously exhibits one or more of the following characteristics:

[0075] - an average number 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;

[0076] - an average number molar mass (Mn) of the non-crosslinked polyester less than 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;

[0077] - a polydispersity Ip (Mw / Mn) of the non-crosslinked polyester of less than 10, preferably less than or equal to 8.

[0078] The polyester of glycerol and a dicarboxylic acid monomer can be obtained, in particular, by implementing the processes described in EP3149067 and EP1448656. The polyester of glycerol and a carboxylic diester monomer can be obtained, in particular, by implementing the processes described in WO2021252554, or in FR2315383.

[0079] The number-average molar mass (Mn), the mass-average molar mass (Mw), and the dispersity (also called polydispersity and denoted D, which is the Mw / Mn ratio), can be measured in a known manner by size-exclusion chromatography (SEC) analysis, notably as described later in the examples.

[0080] Pol / (2-oxazoline)

[0081]

[0082] The structure of the Poly(2-alkyl-2-oxazoline) useful to the invention comprises units corresponding to the formula (I):

[0083]

[0084] Formula (I)

[0085] where R can be an aliphatic group, linear or branched, comprising 1 to 18 carbon atoms, a cyclic aliphatic group comprising 3 to 18 carbon atoms, these same groups being able to contain in or outside the main chains or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S).

[0086] Advantageously, in formula (I), R is an alkyl radical, linear or branched, preferably comprising 1 to 10 carbon atoms, and more preferably 1 to 4 carbon atoms. Most preferably, R designates a methyl or ethyl radical. According to a preferred embodiment of the invention, the poly(2-oxazoline) useful for the purposes of the invention is not modified. In other words, the poly(2-oxazoline) has not undergone any chemical and / or physical modifications after its synthesis, such as the addition of functional groups, crosslinking, copolymerization, or mixing with other substances.

[0087] According to one embodiment, the poly(2-oxazoline) useful for the purposes of the invention is a poly(2-alkyl-2-oxazoline) homopolymer. That is to say, the poly(2-oxazoline) is a homopolymer of a single 2-alkyl-2-oxazoline monomer. In other words, in the polymer chain, all the R groups are identical.

[0088] According to another embodiment, the poly(2-oxazoline) useful for the purposes of the invention is a poly(2-alkyl-2-oxazoline) copolymer. That is to say, the poly(2-oxazoline) is a copolymer of at least two different 2-alkyl-2-oxazoline monomers. In other words, the poly(2-oxazoline) consists of a repetition of at least two formula units (I), in which the Rs differ.

[0089] Advantageously, poly(2-oxazoline) is a poly(2-alkyl-2-oxazoline) homopolymer. Preferably, poly(2-oxazoline) is poly(2-methyl-2-oxazoline) or poly(2-ethyl-2-oxazoline). Poly(2-alkyl-2-oxazolines) are known compounds and can be obtained by cation ring-opening polymerization of a 2-alkyl-2-oxazoline monomer as represented by formula (II) described above. For example, see Kohlan, TB, Atespare, AE, Yildiz, M., Menceloglu, YZ, Unal, S., & Dizman, B. (2022), Synthesis and Structure-Property Relationship of Amphiphilic Poly(2-ethyl-co-2-(alkyl / aryl)-2-oxazoline) Copolymers. ACS Omega, 7(44), 40067-40077. https: / / doi.org / 10.1021 / acsomega.2c04809.

[0090] The poly(2-oxazoline) useful for the purposes of the invention advantageously has one or more of the following characteristics:

[0091] - an average number molar mass (Mn) greater than or equal to 500 g / mol, preferably ranging from 500 g / mol to 100,000 g / mol, preferably further ranging from 1,000 g / mol to 100,000 g / mol, preferably further ranging from 5,000 g / mol to 80,000 g / mol;

[0092] - an average molar mass by weight (Mw) less than or equal to 130,000 g / mol, preferably from 550 g / mol to 130,000 g / mol, from 550 g / mol to 100,000 g / mol, preferably still from 1,000 g / mol to 100,000 g / mol; - a dispersity D (Mw / Mn) from 1 to 5, and, according to some embodiments, from 1 to 2, preferably from 1.1 to 1.5, preferably still from 1.1 to 1.3, and, according to other embodiments, from 1.5 to 4, preferably still from 2 to 4.

[0093] The values ​​of Mn, Mw and D can be determined by SEC chromatography for example as described in the publication "Synthesis and Structure-Property Relationship of Amphiphilic Poly(2-ethyl-co-2-(alkyl / aryl)-2-oxazoline) Copolymers", when they are not given by the supplier.

[0094] Indeed, some poly(2-alkyl-2-oxazoline)s can be found commercially such as PetOx sold by Sigma-Aldrich [Cas 25805-17-8].

[0095] Composition réticu table

[0096] The invention also relates to a crosslinkable composition comprising 100 parts by weight of at least one polyester of glycerol and a carboxylic diacid or diester with a number molar mass Mn less than or equal to 10,000 g / mol,

[0097] o 0.1 to 100 parts by weight of at least one poly(2-oxazoline) comprising units of formula (I).

[0098]

[0099] formula (I)

[0100] in which R is an alkyl radical, linear or branched, comprising 1 to 18 carbon atoms or a cycloalkyl radical, substituted or unsubstituted, comprising 3 to 18 carbon atoms, these same radicals being able to contain in or out of the main chains or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S).

[0101] The polyester of glycerol and a diacid or carboxylic diester is as described above, according to all its variants.

[0102] Poly(2-oxazoline) is as described above, according to all its variants.

[0103] For 100 parts by weight polyester of glycerol, the proportion of poly(2-oxazoline) is preferably 5 to 100 parts by weight, preferably 5 to 70 parts by weight, preferably 10 to 70 parts by weight, preferably 10 to 50 parts by weight, preferably again 20 to 50 parts by weight, preferably again 20 to 45 parts by weight.

[0104] The composition may further include an additive selected from the group consisting of colorants, stabilizers, crosslinkers, organic fillers and mixtures thereof, advantageously at a content ranging from 1% to 50% by mass relative to the total mass of the composition.

[0105] According to embodiments, the composition may further include a molecule of interest, in particular active substances or chemical compounds which have a specific use in the fields of human, animal or plant health.

[0106] According to one embodiment of the invention, the composition comprises glycerol polyester as the major component, that is, the component that represents the largest quantity by mass among the components of the composition. Preferably, "major component" means a component present at more than 50%, and even more preferably, a component present at more than 60% by weight.

[0107] Polyester manufacturing process of cross-linked glycerol

[0108] The invention also relates to a method for manufacturing a crosslinked glycerol polyester comprising crosslinking a glycerol polyester in the presence of poly(2-oxazoline) according to the following steps:

[0109] a) contacting 100 parts by weight of a polyester of glycerol with 0.1 to 100, preferably 5 to 100 parts by weight, preferably 5 to 70 parts by weight, preferably still 10 to 70 parts by weight, preferably still 10 to 50 parts by weight, preferably still 20 to 50 parts by weight, preferably still 20 to 45 parts by weight, of a poly(2-oxazoline) comprising units of formula (I) as defined above;

[0110] b) raising the temperature of the mixture obtained in step a) to a target temperature T c between 100°C and 200°C, and maintenance at temperature T c during a heating time t C h sufficient to obtain a crosslinked glycerol polyester,

[0111] c) cooling and recovery of the crosslinked polyester.

[0112] Glycerol polyester is as described above, in all its variants. Poly(2-oxazoline) is as described above, in all its variants.

[0113] Thus, according to embodiments of the invention, glycerol polyester is a polyester of glycerol and a dicarboxylic acid monomer or carboxylic diester corresponding to the general formula R'OOC-(CH2) P -COOR', R' being as defined above. Preferably, the glycerol polyester is a polyester of glycerol and sebacic acid or dimethyl sebacate. Thus, according to embodiments of the invention, poly(2-oxazoline) is a poly(2-alkyl-2-oxazoline) homopolymer. Preferably, poly(2-oxazoline) is poly(2-methyl-2-oxazoline) or poly(2-ethyl-2-oxazoline).

[0114] These implementation methods can be combined.

[0115] Preferably, step a) of contacting is carried out in the absence of solvent, diluent or other additive.

[0116] Step a) comprises mixing a glycerol polyester and a poly(2-alkyl-2-oxazoline), preferably at a temperature T a allowing the fusion of the polyester from the glycerol and, preferably also, a homogeneous dispersion of the poly(2-alkyl-2-oxazoline). Thus, T a is typically between 20°C and 100°C, particularly between 30°C and 80°C.

[0117] To promote homogenization, agitation can be implemented in a known manner. Thus, step a) is typically carried out under agitation.

[0118] According to particular embodiments of the invention, contact is made by introducing a poly(2-alkyl-2-oxazoline) in solid form.

[0119] At the end of step a) and prior to the temperature rise of step b), the mixture obtained can be shaped in particular in a mold (for example a Teflon mold).

[0120] In step b), the temperature T c is typically between 110°C and 175°C, preferably between 120°C and 160°C.

[0121] Generally, the heating time t C h is between 10 and 2000 min.

[0122] According to one embodiment, in step b), the mixture is heated in a chamber heated to temperature T c at atmospheric pressure, for example in an oven, or by any other means known to those skilled in the art. According to another embodiment, in step b), the mixture is pressurized. For example, a platen press, the plates of which have been preheated to temperature T, may be used. cIn this case, the heating time is determined by the duration between the moment the press is closed and the moment it is opened. Advantageously, according to this embodiment, the overpressure applied (relative to atmospheric pressure) in heating step b), for example by a press, varies from 0.5 to 5 bar (equivalent to 50 to 500 kPa), in particular from 1 to 4 bar. During step c), the crosslinked polyester is typically cooled and recovered at ambient temperature and atmospheric pressure.

[0123] This process improves the extensibility of the manufactured cross-linked glycerol polyester. It also improves the bioresorbability and / or degradation of the cross-linked glycerol polyester in aqueous media.

[0124] cross-linked product

[0125] The invention also relates to the crosslinked product based on a composition as described above, obtained by implementing the process described above. The following examples are given by way of illustration, but shall in no way be considered as limiting the present invention.

[0126] EXAMPLES

[0127] Measurement methods used

[0128] Extensibility: elongation and breaking strength:

[0129] Tensile tests determine elastic stresses and fracture properties; these measurements are performed on cross-linked mixtures. Mechanical tensile tests are carried out on an Instron extensometer equipped with a 1 kN load cell, using dumbbell-shaped specimens conforming to ASTM D1708 (thickness = 2 ± 0.5 mm) at a speed of 50 mm / min at ambient temperature (23°C ± 2°C) and under normal humidity conditions (50% relative humidity). Elongations at break (in %) at 23°C and moduli at break (in MPa) are measured.

[0130] Measurement of the glass transition by DSC thermal analysis (Tg):

[0131] The glass transition temperature is determined using Differential Scanning Calorimetry (DSC) according to ISO 11357-1 or ASTM D3418. DSC measures the heat flow required to heat or cool a sample relative to an inert reference. Differences in heat flow indicate structural or physical changes such as melting (endothermic), recrystallization (exothermic) of crystalline domains, or glass transition (endothermic) of amorphous domains. The glass transition of a material results in a change in its specific heat capacity (Cp).

[0132] The calorimeter is pre-calibrated with an indium standard. A 6 to 20 mg sample of the material to be characterized is placed in a crimped 40 lp aluminum crucible. Two diametrically opposed holes are made in the lid to allow for purging with an inert gas.

[0133] Under nitrogen flow, a temperature ramp of 10°C / min is applied between -110°C and +150°C. A first heating cycle is applied to eliminate the material's thermal history and any traces of water present. The second heating cycle is used to determine the Tg. Tangents to the baseline are plotted before and after the transition to extract the midpoint Tg. The resulting Tg values ​​are expressed in °C.

[0134] Measurement of in vitro degradation:

[0135] Cross-linked polyester discs with a diameter of 10 mm and a thickness of 2 mm are manufactured and weighed. They are then individually incubated in aseptic 30-liter bottles containing 20 ml of phosphate-buffered saline (PBS) solution at 37.5 °C. Discs are sampled at different times. 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). This percentage weight loss is an indicator of the material's bioresorbability.

[0136] Macrostructure analysis of PGS polymers: SEC RI

[0137] The SEC (Size Exclusion Chromatography) technique separates macromolecules in solution according to their size using columns filled with a porous gel. Macromolecules are separated according to their hydrodynamic volume, with the largest being eluted first.

[0138] While not an absolute method, SEC allows us to understand the molar mass distribution of a polymer. From commercial standard products, the various number-average molar masses (Mn) and weight-average molar masses (Mw) can be determined, and the polydispersity index (Ip = Mw / Mn), also called "dispersity," can be calculated.

[0139] Size exclusion chromatography analyses were performed using a Viscotek instrument (Malvern Instruments) equipped with four columns, a guard column, and three detectors (differential refractometer, differential viscometer, and light scattering). Samples were dissolved at a concentration of 1 mg / mL in unstabilized THF and then stirred for two hours before injection. One mL of the sample solution was filtered through a 0.45 µm PTFE membrane.

[0140] 100 pL of this solution were eluted in THF using a flow rate of 1 mL.min- / at a temperature of 35 °C. OmniSEC software was used for data acquisition and analysis.

[0141] The technique used is size exclusion chromatography (SEC) with a column set optimized for the separation of low-mass species.

[0142] The analytical conditions used in the study are described in the following table:

[0143] THF eluent without antioxidant

[0144] Injection volume 100 pL

[0145] Temperature 35 °C

[0146] Waters RI Detector

[0147] Mobile phase flow rate 1 mL / min

[0148] Columns 2 Mixed D + 2 Mixed E

[0149] The calibration used for Moore's calculation is a PS calibration, covering a range from 2,520,000 to 162 g.mol- / .

[0150] The calibration used is a mixed low and medium weight PS calibration from PSS Standards. The mass range extends from 162 to 66000 g·mol⁻¹. The calibration allows the determination of Mn (g·mol⁻¹), Mw (g·mol⁻¹), and D (Mw / Mn) values ​​in PS equivalent.

[0151] Materials

[0152] Characteristics of the starting products: Polyester Mn (g.mol -1) Mw (g.mol -1) IP Tg Poly glycerol sebacate 2656 16520 6.2 -28°C

[0153]

[0154] Poly(2-oxazoline) Mw (g.mol -1 ) Tg

[0155] Poly(2-ethyl-2-oxazoline)*

[0156] -50,000** 69 °C**

[0157] (PEtOx)

[0158]

[0159] * sold by Sigma-Aldrich [Cas 25805-17-8] and ** Sigma-Aldrich data.

[0160] Procedure for the synthesis of the starting (i.e., non-crosslinked) glycerol and sebacic acid polyester:

[0161] In a 10L double-walled stainless steel reactor equipped 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) at 40 °C under a nitrogen flow (0.5 L / min). Gentle stirring is applied (20 rpm) for 5 minutes. After the glycerol has dissolved, 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. The reactor vessel is then gradually heated, following a progressive temperature ramp with intermediate stops, until a shell temperature of 172 °C is reached after 5 hours, corresponding to a medium temperature of 170 °C, measured using an immersion probe. Agitation is increased to 80 rpm when the temperature of the medium 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 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 resulting 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.

[0162] Results

[0163] Tested compositions

[0164] The compositions studied are presented below in Table 1. The contents are expressed in pce (parts per percent of polymer, i.e. of polyester, glycerol and sebacic acid) and in mass percentage (w / w).

[0165] The control composition T is a poly(glycerol sebacate) polymer used alone. The preparation protocol is the same as that described in section 3.2, but without poly(2-oxazoline). The heat treatment is then 72 hours in an oven at 140°C.

[0166] Table 1:

[0167] Composition T C1 C2 C3 C4

[0168] PGS (pc) 100 100 100 100

[0169] 100

[0170] (92.5p / p) (85p / p) (70p / p) (50p / p) Poly(2-ethyl- 100

[0171] 17.7 42.9

[0172] 2-oxazoline 0 8.1 (7.5p / p) (50p / p) (15p / p) (30p / p)

[0173] (pc)

[0174]

[0175] Process for preparing crosslinked polyesters

[0176] Step a)

[0177] Poly(2-ethyl-2-oxazoline) is ground using zirconium balls in a planetary mixer: o In a 75 mL pot, put 24 g of PEtOx + 2 balls of 16 mm diameter and then run 4 grinding cycles (300 rpm / 15s + 700 rpm / 15s + 1400 rpm / 60s + 700 rpm / 15s + 300 rpm / 10s).

[0178] o Remove the 16 mm balls, then add 8g of 5 mm balls and run 4 cycles (300 rpm / 15s + 700 rpm / 15s + 1400 rpm / 60s + 700 rpm / 15s +300 rpm / 10s).

[0179] o Ensure that the tank temperature does not exceed 30°C.

[0180] Step b)

[0181] Place a 100mL beaker. Introduce the poly(glycerol sebacate) and place it in an oven at 50°C until softened.

[0182] Step c): Preparation of the crosslinkable composition

[0183] In a bowl of the planetary mixer, mix the quantity of ground PETOx then the quantity of preheated PGS.

[0184] Run 3 cycles (350 rpm / 10 s + 1500 rpm / 15 s + 2500 rpm / 2 min + 1500 rpm / 15 s + 350 rpm / 10 s) in the planetary mixer until a homogeneous mixture is obtained, then place in a water bath (100°C) for one hour.

[0185] Step d): crosslinking

[0186] After the planetary mixer and water bath treatment, pour the formulation into 2mm deep Teflon molds, either to obtain plates or directly into the dumbbell-shaped test tube used for extensometry measurements. Place in an oven at 140°C for 72 hours.

[0187] Characterization of crosslinked polyesters

[0188] The results of measurements performed on crosslinked polyesters according to the protocols described above are presented in Table 2, along with a summary of crosslinkable compositions. Table 2:

[0189] Compositions T C1 C2 C3 C4 PGS %p / p 100 92.5 85 70 50 PEtOx %p / p 0 7.5 15 30 50 Properties

[0190] Elongation at break (%) 23 °C 18 23 30 79 246 Tensile strength (MPa) 23 °C 0.7 0.7 0.7 1.0 1.4 Calculated Tg Fox NA -24 -18 -6 12 Measured Tg DSC -29 -25 -19 -7 8 Loss at 2 days of incubation

[0191] 0.1 1 3 4 25 (%)

[0192] Loss at 4 days of incubation

[0193] 0.3 2 2 5 31 (%)

[0194] Loss at 7 days of incubation

[0195] 1.1 3 3 8 31 (%)

[0196] Loss at 10 days of incubation

[0197] 1.5 4 4 10 32 (%)

[0198]

[0199] Discussion

[0200] 5. It is noted that the use of poly(2-ethyl-2-oxazoline) significantly increases the elongation at break and, to a lesser extent, the tensile strength of the crosslinked composition. This phenomenon is even more pronounced when poly(2-ethyl-2-oxazoline) is used in proportions exceeding 15% w / w.

[0201] ,o

[0202] It is also observed that the Tg of the compositions (C1 to C4) according to the invention increases monotonically with increasing amounts of poly(2-ethyl-2-oxazoline). This evolution is consistent with the predictions of Fox's law, characteristic of compatible polymer systems, which is expressed in a known manner according to the following relationship:

[0203] 1 wi

[0204] Tg 2-iTgi

[0205] in which:

[0206] • Tg is the glass transition temperature of the mixture in Kelvin,

[0207] • Tgi is the glass transition temperature of polymers i in Kelvin, • wi is the mass fraction of polymers i in the mixture.

[0208] The presence of a unique Tg value for each composition confirms the miscibility of the poly(2-ethyl-2-oxazoline) polymer with the poly(glycerol sebacate) polymer, indicating good compatibility between their macromolecular chains. This trend, correlated with the improvement in mechanical fracture properties, reflects the expected behavior of a compatible diluent acting synergistically with the poly(glycerol sebacate) polymer.

[0209] Thus, the use of poly(2-ethyl-2-oxazoline) through the improvement of the breaking properties of the crosslinked poly(glycerol sebacate) polymer, makes it possible to improve its extensibility.

[0210] Furthermore, it is observed that after only 2 days of incubation, the composition according to the invention exhibits significantly higher mass losses compared to the reference composition T. It is thus noted that the use of poly(2-ethyl-2-oxazoline), although strengthening the cohesion within the composition comprising poly(glycerol sebacate), makes it possible to significantly reduce the in vitro degradation time of a poly(glycerol sebacate) polymer in a PBS type buffer at 37°C.

Claims

DEMANDS 1. Use of a poly(2-oxazoline) comprising units of formula (I) to improve the extensibility of a glycerol polyester and a crosslinked diacid or carboxylic diester formula (I) in which R is an alkyl radical, linear or branched, comprising 1 to 18 carbon atoms or a cycloalkyl radical, substituted or unsubstituted, comprising 3 to 18 carbon atoms, these same radicals being able to contain in or out of the main chains or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S).

2. Use according to claim 1, wherein, in formula (I), R is a linear or branched C1-C10 alkyl radical.

3. Use according to claim 2, wherein, in formula (I), R is a linear or branched C1-C4 alkyl radical, preferably methyl or ethyl.

4. Use according to any one of claims 1 to 3, wherein poly(2-oxazoline) is a copolymer of at least two different 2-alkyl-2-oxazoline monomers.

5. Use according to any one of claims 1 to 3, wherein poly(2-oxazoline) is a poly(2-alkyl-2-oxazoline) homopolymer.

6. Use according to claim 5, wherein poly(2-oxazoline) is poly(2-methyl-2-oxazoline) or poly(2-ethyl-2-oxazoline).

7. Use according to any one of the preceding claims, wherein the crosslinked glycerol polyester is a crosslinked glycerol and diacid or carboxylic diester polyester whose diacid or carboxylic diester monomer has the formula [R'00C-(CH2) P -C00R'], in which p is a number from 1 to 30, preferably a number from 1 to 10, preferably p=8, and R' represents H or each R' represents independently of each other, an alkyl, linear or branched, in C1-C10, preferably in C1-C2, preferably in C1-C4.

8. Use according to claim 7, wherein the dicarboxylic acid monomer is sebacic acid.

9. Use according to claim 7, wherein the carboxylic diester monomer is a diester of sebacic acid, preferably dimethyl sebacate.

10. Crosslinkable composition comprising o 100 parts by weight of a polyester of glycerol and a diacid or carboxylic diester of number molar mass Mn less than or equal to 10,000 g / mol, o 0.1 to 100 parts by weight, preferably 5 to 100 parts by weight, preferably 10 to 70 parts by weight, preferably 10 to 50 parts by weight, preferably 20 to 50 parts by weight, preferably 20 to 45 parts by weight, of a poly(2-oxazoline) comprising units of formula (I) formula (I) wherein R is an alkyl radical, linear or branched, comprising 1 to 18 carbon atoms, or a cycloalkyl radical, substituted or unsubstituted, comprising 3 to 18 carbon atoms, which may contain in or out of the main chain or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S), preferably R is a C1-C10 alkyl radical, preferably C1-C4, preferably methyl or ethyl.

11. Crosslinkable composition according to claim 10, wherein the glycerol polyester is a glycerol polyester and a diacid or carboxylic diester having the diacid or carboxylic diester having the formula [R'OOC- (CH2) P -COOR'], in which p is a number from 1 to 30, preferably a number from 1 to 10, very preferably p=8, and R' is H or each of the R's represents, independently of the other, a linear or branched alkyl in C1-C10, preferably in C1-C2, preferably in C1-C4.

12. Crosslinkable composition according to claim 10 or 11, wherein the glycerol polyester is a poly(glycerol-sebacate).

13. Crosslinkable composition according to any one of claims 10 to 12, wherein poly(2-oxazoline) is a poly(2-alkyl-2-oxazoline homopolymer, preferably poly(2-methyl-2-oxazoline) or poly(2-ethyl-2-oxazoline).

14. A process for manufacturing a crosslinked glycerol polyester comprising the following steps: a) contacting 100 parts by weight of a polyester of glycerol and a diacid or carboxylic diester of number molar mass Mn less than or equal to 10,000 g / mol, with 0.1 to 100 parts by weight, preferably 5 to 100 parts by weight, preferably 10 to 70 parts by weight, preferably 10 to 50 parts by weight, preferably 20 to 50 parts by weight, preferably 20 to 45 parts by weight, of a poly(2-oxazoline) comprising units of formula (I) formula (I) in which R is an alkyl radical, linear or branched, comprising 1 to 18 carbon atoms, or a cycloalkyl radical, substituted or unsubstituted, comprising 3 to 18 carbon atoms, these same radicals being able to contain in or out of the main chains or in a heterocycle, one or more heteroatoms selected from oxygen (O), nitrogen (N) and sulfur (S); b) raising the temperature of the mixture obtained in step a) to a target temperature T c between 100°C and 200°C, and maintenance at temperature T c during a heating time t C h sufficient to obtain a crosslinked polyester; c) cooling and recovery of the crosslinked polyester, which diacid or carboxylic diester preferably has the formula [R'00C-(CH2)p-COOR'], in which p is a number from 1 to 30, preferably a number from 1 to 10, most preferably p=8, and R' is H or each of the R's represents, independently of the other, a linear or branched alkyl in C1-C10, preferably in C1-C6, preferably in C1-C4.

15. Crosslinked product based on a crosslinkable composition according to any one of claims 10 to 13 or obtained at the end of the process according to claim 14.

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