compositions based on glycerol polyesters comprising a leachable ingredient

Abstract

The present invention relates to a composition based on a polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid; 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; and of at least one leachable ingredient; and its preparation process.

Description

Title of the invention: Glycerol-based polyester compositions comprising a leachable ingredient FIELD OF INVENTION

[0001] The present invention relates to glycerol polyester-based compositions comprising a leachable ingredient. The nature of the crosslinking of the composition allows for prolonged release of the ingredient. 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 coatings in various fields of application. These polyesters are generally poorly biodegradable, which limits their use as a vehicle for ingredients such as a pharmaceutical, dermatological, or cosmetic active ingredient.

[0003] There is a need for compositions based on biodegradable and / or bio-based polyesters, such as PGS, that allow for the controlled release of ingredients such as active principles. It is preferable that the composition also be bioresorbable and / or have improved biodegradability, particularly in aqueous media, while retaining mechanical properties suitable for the intended short-term uses.

[0004] Compositions based on biodegradable and / or bio-based polyesters are also sought that allow controlled release of ingredients without the need to add toxic agents or leading to the formation of "permanent" bonds, such as urethane bonds, which are very difficult to degrade / absorb subsequently, thus reducing the bioresorbable and / or biodegradable nature of the composition (compared to the same crosslinked composition in the absence of a crosslinking agent). Description of the invention

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

[0006] Thus, the present invention relates to a composition based on a polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid; of a cyclic polycarboxylic anhydride A, the cyclic polycarboxylic anhydride A comprising at least two anhydride groups cyclic carboxylic, and not comprising a linear carboxylic anhydride function; and at least one leachable ingredient.

[0007] 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,

[0008] L representing -O- ; -S- ; -S(O)- ; -S(O)2- ; -C(O)- ; -NRnRn- with Rn and Rn independently 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,

[0009] L being devoid of linear anhydride groups.

[0010] In particular, the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (I) or (II):

[0011] 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 CrC6 alkoxy group,

[0012] 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) group • Z2 is absent or represents a -CH2- (methylene) group • X independently represents an alkyl group in Cr C6, a hydroxyl group, an alkoxy group in Ci-C6, a nitro group, a cyano group, or a halogen atom, • n represents an integer from 0 to 3, preferably from 0 to 2, • Y represents, independently of each other, an alkyl group in Cr C6, a hydroxyl, alkoxy in Ci-C6, nitro, cyano, or a halogen atom, • m represents an integer from 0 to 3, preferably from 0 to 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, instituted or aromatic heterocycle, optionally bridged,

[0013] said heterocycle comprising from 4 to 30 carbon atoms, and

[0014] said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, Cr C6 alkoxy, nitro, cyano, or halogen atom.

[0015] Advantageously 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-,

[0016] said aliphatic chain being substituted or unsubstituted by a group preferably selected from a CrC6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

[0017] Advantageously, the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (III) or (IV): O o (ni) XX QJ £ P £ p oo OO (IV) d [ b 6 o

[0018] in which represents a simple or double DC connection

[0019] 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, a Ci-C6 alkoxy, nitro, cyano, or halogen atom.

[0020] Advantageously, the composition is obtained by crosslinking: • 100 parts by weight of at least one polyester, glycerol, and one monomer aliphatic chosen from a dicarboxylic acid and a diester of a dicarboxylic acid, • 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, • in the presence of 5 to 300 parts by weight of at least one leachable ingredient.

[0021] Advantageously, the polyester of glycerol and an aliphatic diacid or carboxylic diester monomer has a number molar mass Mn less than or equal to 10,000 g / mol.

[0022] Advantageously, the dicarboxylic acid monomer or the carboxylic diester monomer corresponds to the general formula R'OOC-(CH2)p-COOR', in which p represents an integer from 1 to 30, preferably an integer from 1 to 10, preferably p=8, and R' represents H or each R' represents, independently of each other, a linear or branched alkyl, in C1-C10, preferably in C1-C4, preferably methyl or ethyl.

[0023] Advantageously, the Shore A hardness of the composition, measured according to ASTM D 2240:2021 at room temperature, varies from 70 to 100, typically from 80 to 100.

[0024] Advantageously, the releasable ingredient is chosen from a pharmaceutical, dermatological or cosmetic active ingredient.

[0025] The invention also relates to a method for preparing a composition according to the invention, comprising the following steps: a. Mix a polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid as defined above, a cyclic carboxylic polyanhydride A as defined above and the leachable ingredient; b. Crosslink the mixture from step a).

[0026] Advantageously, step a) comprises the following steps:

[0027] al) Mix the polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid and cyclic carboxylic polyanhydride A;

[0028] a2) add the leachable ingredient to the mixture obtained following step al);

[0029] a3) mix the mixture obtained following step a2).

[0030] Advantageously, step b) comprises the following steps:

[0031] bl) Pressurizing the mixture obtained following step a) to a target temperature Tc ranging from 100°C to 200°C; then

[0032] b2) maintaining temperature Tcet under pressure during a heating time under Sufficient pressure to achieve polyester crosslinking; then

[0033] b3) cooling to room temperature and recovery of the composition.

[0034] Advantageously, the duration of step b2) varies from 12 hours to 120 hours.

[0035] The invention also relates to the use of a cyclic carboxylic polyanhydride A, as defined above, as a crosslinking agent of a glycerol polyester and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid, for the preparation of a vehicle allowing the release of a releaseable ingredient. DEFINITIONS

[0036] For the purposes of the present invention, the term “a” or “an” means “one or more” or “at least one”.

[0037] 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.

[0038] 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.

[0039] The term "composition based on" should be understood as a composition comprising the mixture and / or the in situ reaction product of the various basic constituents used, some of these constituents being able to react and / or intended to react with each other, at least partially, during the various stages of manufacturing the composition, thereby modifying the composition as initially prepared. Thus, the compositions as implemented for the invention may differ in the uncrosslinked and crosslinked states.

[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 to say, they may be partially or totally derived from a recycling process, or obtained from raw materials themselves derived from a recycling process. This includes, in particular, monomers, specifically glycerol, dicarboxylic acid monomer, and cyclic polycarboxylic anhydride.

[0041] Glycerol is a triol with the following formula: HO^A^OH

[0042] In the present invention, a "cyclic polycarboxylic anhydride" means an organic compound comprising at least two cyclic carboxylic anhydride functional groups. A "cyclic carboxylic anhydride functional group" is linked to two carbons of the rest of the molecule, whether adjacent or not, so as to form a ring comprising a carboxylic anhydride functional group. In contrast, a "linear anhydride functional group" means a divalent carboxylic anhydride functional group that is linked to two carbons of the rest of the molecule but is not contained within a ring.

[0043] In the present invention, a "carboxylic anhydride function" corresponds to the formula -C(=O)-OC(=O)-. This function is divalent.

[0044] In the present invention, a "cyclic carboxylic anhydride group" means a group comprising a cyclic carboxylic anhydride function and further comprising from 3 to 40 carbon atoms. The cyclic anhydride group may be multivalent or monovalent.

[0045] 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.

[0046] A "linear anhydride group" is understood in the context of the invention to mean a group comprising a linear carboxylic anhydride function. Unlike a cyclic anhydride group, in a linear carboxylic anhydride group, the divalent carboxylic anhydride function is bonded to two carbons of the rest of the molecule, but is not contained within a ring.

[0047] In the present invention, a "monovalent hydrocarbon group" means a monovalent hydrocarbon chain, saturated, unsaturated, or aromatic, 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 Ci-C4O. Preferably, a monovalent hydrocarbon group is an alkyl, cycloalkyl, alkenyl, or cycloalkenyl group, substituted or unsubstituted, in the form CrC4O.

[0048] 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, Ci-C40 alkanediyl, alkenediyl, or alkynediyl groups. A divalent hydrocarbon group also covers substituted or unsubstituted cycloalkanediyl, cycloalkenediyl, or cycloalkynediyl groups, in the C1-C40 configuration. A divalent hydrocarbon group also covers a substituted or unsubstituted divalent aromatic group. Preferably, a monovalent hydrocarbon group is a substituted or unsubstituted C1-C40 alkanediyl (linear or branched), alkenediyl (linear or branched), cycloalkanediyl, or cycloalkenediyl group.

[0049] 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.

[0050] By "aliphatic" is meant a linear, branched and / or cyclic hydrocarbon group, whether saturated or unsaturated but non-aromatic.

[0051] 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.

[0052] 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.

[0053] For the purposes of this invention, the term "alkenyl group" refers to 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.

[0054] For the purposes of this invention, the term "cycloalkenyl group" refers to a monovalent cyclic hydrocarbon chain comprising 3 to 40 cyclic carbon atoms and at least one cyclic double bond. A cycloalkenyl may be monocyclic, bicyclic, or polycyclic. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. A polycyclic cycloalkenyl is bicyclo[2.2.2]oct-7-ene.

[0055] 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.

[0056] 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.

[0057] 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 pyrenylene, advantageously pyrenylene.

[0058] 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, propanediyl, butanediyl, pentanediyl, or hexanediyl group.

[0059] 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.

[0060] By "alkenediyl" group, for the purposes of the present invention, means a divalent acyclic hydrocarbon chain, linear or branched, comprising from 2 to 40 carbon atoms and at least one double bond, such as, for example, a vinylene (ethenylene) or propenylene group.

[0061] By "cycloalkenidiyl" group, for the purposes of the present invention, is understood to mean a cyclic divalent hydrocarbon chain, linear or branched, 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.

[0062] By "alkynediyl" group, for the purposes of the present invention, is understood to be a divalent, linear or branched, acyclic hydrocarbon chain comprising from 2 to 40 carbon atoms and at least one triple bond.

[0063] 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.

[0064] By "C1-C6 alkoxy group," for the purposes of this invention, we mean a C1-C6 alkyl group, as defined above, linked to the rest of the molecule via an oxygen atom. Examples include the groups methoxy, ethoxy, n-propoxy, Lo-propoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, or even n-hexoxy.

[0065] By "halogen atom" or "halogen", for the purposes of the present invention, means the atoms of fluorine, chlorine, bromine and iodine, preferably the atoms of fluorine and chlorine.

[0066] For the purposes of this invention, the term "Ci-C6 haloalkyl group" refers to 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.

[0067] The hydroxy group is the -OH group. The cyano group is the -CN group. The nitro group is the -NO2 group.

[0068] 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.

[0069] When the carbocycle is aromatic, we will speak of an “aryl” group.

[0070] For the purposes of this invention, "heterocycle comprising 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 bonded rings), of which one or more, advantageously 1 to 4, 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, thiazolidine, isothiazolidine, oxazocane, thiazepane, and benzimidazolone.

[0071] 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, and oxadiazole. thiadiazole, pyridazine, pyrimidine, pyrazine, triazine, quinole, isoquinole, quinoxal or even indole.

[0072] An "arylene group" is understood to mean a divalent aromatic hydrocarbon group, preferably comprising 6 to 10 carbon atoms, and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group. Advantageously, this refers to phenylene.

[0073] 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.

[0074] According to the invention, an "orthophthalic group" is understood to be a group of formula: p, preferably of formula: p, this group being linked to the rest of the polyanhydride molecule by the P bond, or of a divalent group of formula: x O, this group being linked to the rest of the molecule of polyanhydride by the A bond, on the one hand, and by the - bond on the other. The orthophthalic group may be substituted or unsubstituted.

[0075] In the present invention, a "succinic group" means a monovalent group of formula: P, this group being linked to the rest of the molecule of polyanhydride by the bond and which may be substituted or unsubstituted, or of a divalent group of formula: O, this group being linked to the rest of the polyanhydride molecule by the -A bond on one side, and by the - bond on the other part. A succinic group is distinct from an orthophthalic group, so that in general, a divalent succinic group is not attached to a phenyl group.

[0076] In the present invention, a "maleic group" means a monovalent group of formula: p, this group being linked to the rest of the molecule O of polyanhydride by bonding and which may be substituted or unsubstituted, or of a divalent group of formula: p - ÿ, this group then being linked to the rest of D3 b the polyanhydride molecule by the bond on one side, and by the -p 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.

[0077] In the present invention, a "homo-phthalic group" means a group of formula: O, preferably of formula: O, this W 4 LJ 1 a group being linked to the rest of the polyanhydride molecule by the p bond, or a divalent group of formula: x O, this group being linked to the rest of the polyanhydride molecule by the .-U bond on the one hand, and by the bond - ■■ -on the other hand. The homophthalic group can be substituted or unsubstituted.

[0078] By "ambient temperature" we mean here a temperature generally ranging from 15°C to 40°C, preferably from 20°C to 30°C, in particular around 25°C.

[0079] A "releasable ingredient" is any molecule of interest, chemical (small molecule) or biological ("biological"), that is not intended to react with the other components of the composition, and that one wishes to trap within the composition, which then serves as a vehicle or reservoir for this ingredient. The composition will subsequently allow the more or less rapid release of this ingredient. The ingredient is advantageously a "pharmaceutical ingredient," a "dermatological ingredient," or a "cosmetic ingredient."

[0080] The term "cosmetic ingredient" means any substance that can be administered to humans or animals and that is added to a personal care or beauty product to improve its properties such as its effectiveness, texture, smell, or effects on the skin, hair, or nails.

[0081] In particular, this ingredient is a pharmaceutical, dermatological or cosmetic active ingredient.

[0082] The term "active ingredient" means any substance having biological activity in humans or animals, in particular enabling the restoration, correction, or modification of organic functions in humans or animals, especially possessing curative or preventive properties with regard to human or animal diseases or non-pathological conditions, or which may be administered to humans or animals for the purpose of establishing a diagnosis, whether therapeutic or not. The term "active ingredient" therefore includes cosmetic actives that have an effect on the skin, hair, or appendages.

[0083] 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 formation of lower molecular weight metabolites, particularly monomers.

[0084] As used here, the "degradation" of a polyester is understood to be a chemical process involving in particular the hydrolysis of ester bonds, generating polymeric molecules of lower molecular weight.

[0085] 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).

[0086] 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). The PBS buffer is therefore generally usable to reproduce the environment of a living organism.

[0087] “Release-out” refers to the process by which the ingredient is released or transferred from the composition to another medium. This may involve the release of the ingredient from the composition to a specific environment, often to achieve a desired effect, such as the controlled release of pharmaceutical, dermatological or cosmetic active ingredients.

[0088] 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 polyester and glycerol, when the crosslinking reaction is carried out. DETAILED DESCRIPTION OF THE INVENTION

[0089] The invention relates to a composition based on:

[0090] - of a polyester of glycerol and an aliphatic monomer selected from a diacid carboxylic and a diester of a dicarboxylic acid;

[0091] - of a cyclic carboxylic polyanhydride A, the carboxylic polyanhydride cyclic A comprising at least two cyclic carboxylic anhydride groups, and not comprising any linear carboxylic anhydride function; and

[0092] - of at least one releasable ingredient.

[0093] This composition may be crosslinked or not. The invention covers both non-crosslinked compositions, which can notably be compared to an intermediate product, and crosslinked compositions particularly suited for controlling the release of the ingredient. Advantageously, the composition is crosslinked. The crosslinking results both from the reaction of the polyester chains of glycerol with each other and from the reaction of the polyester of glycerol with polyanhydride A.

[0094] Starting glycerol polyester (i.e. before crosslinking)

[0095] 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.

[0096] The dicarboxylic acid monomer or the diester monomer of a dicarboxylic acid is aliphatic

[0097] The carboxylic diacid or diester preferably comprises from 3 to 36 carbon atoms.

[0098] According to preferred embodiments of the invention, the dicarboxylic acid monomer or the carboxylic diester monomer corresponds to the general formula R'OOC-(CH2)P-COOR', 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.

[0099] According to variants, the monomer is a dicarboxylic acid corresponding to the general formula [HOOC-(CH2)P-COOH] in which p is a number from 1 to 30, preferably a number from 1 to 10.

[0100] In particular, according to these variants, the dicarboxylic acid monomer can be chosen 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.

[0101] Preferably, the dicarboxylic acid monomer can 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.

[0102] 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.

[0103] Preferably, the dicarboxylic acid monomer comprises or consists of sebacic acid.

[0104] According to preferred embodiments of the invention, the dicarboxylic acid monomer and glycerol are the only monomers during polycondensation.

[0105] According to other variants, the monomer is a diester of a dicarboxylic acid corresponding to the general formula R"OOC-(CH2)n-COOR'', in which n represents an integer from 1 to 30, preferably a number from 1 to 10 and each R" represents, independently of each other, a linear or branched alkyl, in CrCio, preferably in Ci-C4, preferably also methyl or ethyl.

[0106] 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 variations 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.

[0107] According to preferred embodiments of the invention, the dicarboxylic acid diester monomer is dimethyl sebacate.

[0108] 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.

[0109] Advantageously, the molar ratio of glycerol / diacid or carboxylic diester monomer varies from 1 / 2 to 10 / 1, in particular from 1 / 1 to 5 / 1, preferably from 1 / 1 to 2 / 1.

[0110] The polyester of glycerol and an aliphatic diacid or carboxylic diester monomer advantageously has one or more of the following characteristics:

[0111] - an average number-average molar mass (Mn) greater than or equal to 1500 g / mol, of preference greater than or equal to 2000 g / mol;

[0112] - an average number-average molar mass (Mn) less than or equal to 10,000 g / mol, of preferably less than or equal to 7,000 g / mol, preferably less than or equal to 5,000 g / mol;

[0113] - a polydispersity Ip (Mw / Mn) less than 10, preferably less than or equal to 8.

[0114] 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.

[0115] The polyester of glycerol and an aliphatic dicarboxylic acid monomer can be obtained in particular by implementing the processes described in EP3149067 and EP1448656. The polyester of glycerol and an aliphatic diester carboxylic acid monomer can be obtained in particular by implementing the processes described in FR2315383. Cyclic carboxylic polyanhydride A

[0116] Preferably, the cyclic carboxylic polyanhydride comprises two cyclic carboxylic anhydride functions, that is to say, it is a cyclic bis-carboxylic anhydride.

[0117] In the present invention, the cyclic carboxylic anhydride groups of the cyclic carboxylic polyanhydride A are preferably independently selected from orthophthalic, succinic, maleic and homophthalic groups.

[0118] 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.

[0119] Advantageously, the cyclic carboxylic anhydride groups are independent of the orthophthalic, succinic or maleic groups.

[0120] 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,

[0121] L representing -O- ; -S- ; -S(O)- ; -S(O)2- ; -NRn- with Rn selected from H or a Ci-C6 alkyl group; -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

[0122] L being devoid of linear anhydride groups.

[0123] 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(Cr-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.

[0124] The valence of the L group is even (since L carries cyclic carboxylic anhydride groups, which are monovalent or divalent), and generally of 4 or 6, preferably of 4.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] According to particular embodiments, L represents a saturated or unsaturated acyclic multivalent hydrocarbon group comprising 1 to 10 atoms of carbon, in which one or more carbon atoms can be replaced by one or more oxygen (O) atoms or a -C(O)-, -S-, -S(O)-, -S(O)2- group, and possibly by one or more heteroatoms of Cl, Br, F, N, P or Si.

[0129] 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.

[0130] In particular embodiments, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (I) or preferably of formula (la): 9 9 .A .JL vJ L vA .K o- z; x -J 'Z2 vo / Xi DO (the) .4' d P ,j Cj. 4 y-' My" ''■'.-v'- "-y d ( ^ n d

[0131] 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 CrC6 alkoxy group,

[0132] 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) group • Z2 is absent or represents a -CH2- (methylene) group • X independently represents a CrC6 alkyl group, a CrC6 hydroxyl group, a CrC6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • n represents an integer from 0 to 3, preferably from 0 to 2, • Y represents, independently of each other, an alkyl group in Cr C6, a hydroxyl, alkoxy in CrC6, nitro, cyano, or a halogen atom, • m represents an integer from 0 to 3, preferably from 0 to 2.

[0133] Preferably, Zi and Z2 are identical. Advantageously, Zi and Z2 both represent a link.

[0134] 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.

[0135] 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-,

[0136] 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.

[0137] 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 from a Ci-C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

[0138] 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 group, -C(O)-, -O-, -S-, -S(O)-, -S(O)2-,

[0139] said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two group(s) preferably selected from a Cr C6 alkyl, Ci-C6 alkoxy, or Ci-C6 haloalkyl.

[0140] 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, wherein 1 to 2 methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene, -C(O)-, -O- group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two Ci-C6 alkyl, Ci-C6 alkoxy, hydroxyl, nitro, cyano, halogen atom, Ci-C6 haloalkyl group, typically substituted or unsubstituted by a Ci-C6 alkyl, Ci-C6 alkoxy, halogen atom, or Ci-C6 haloalkyl group.

[0141] In particular, X can independently represent a Ci-C6 alkyl group, a hydroxyl group, or a halogen atom.

[0142] Advantageously, n represents 0 or 1.

[0143] Preferably, Y represents, independently of each other, a Ci-C6 alkyl group, a hydroxyl group, or a halogen atom,

[0144] Advantageously, m represents 0 or 1.

[0145] 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.

[0146] In other particular embodiments, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (II) or preferably of formula (lia): OO (II) or s To Al > : OO (lia) \ -'''A, of A1 1 P d 'b

[0147] in which

[0148] Zi is absent or represents a -CH2- (methylene) group,

[0149] Z2 is absent or represents a -CH2- (methylene) group,

[0150] 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

[0151] 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, a Ci-C6 alkoxy, nitro, cyano, or a halogen atom.

[0152] 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.

[0153] According to variants, Ai represents an aromatic carbocycle comprising 6 to 10 carbon atoms, such as a phenyl or a naphthalene.

[0154] 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 carbocycle comprising from 4 to 6 carbon atoms.

[0155] 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 (ni) XX mii '° £ 'P OO

[0156] in which represents a simple or double DC connection

[0157] 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

[0158] said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-C6 alkyl group, a hydroxyl, Cr C6 alkoxy, nitro, cyano, or halogen atom.

[0159] Preferably, L2 and L3 taken together with the carbon atoms to which they are bonded represent a saturated, instaurated or aromatic carbocycle, optionally bridged,

[0160] said carbocycle comprising from 4 to 10 carbon atoms, and

[0161] 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.

[0162] 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.

[0163] 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.

[0164] According to variants, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (IV): O p (IV) co 6b

[0165] in which represents a single or double DC connection.

[0166] According to preferred embodiments, the cyclic carboxylic polyanhydride of formula (I) is chosen from the group consisting of:

[0167] and a mixture of these.

[0168] [Tables 1] Pyromellitic acid bis-anhydride (PMDA) 0 0 0 0 1,2,3,4-cyclopentanetetracarboxylic acid bis-anhydride 0 0 AA \—(, p—4 OO 1,2,3,4-cyclobutanetetracarboxylic acid bis-anhydride O 0 .KA o J__! o 0 0 Benzophenone-3,3 / ,4,4'-tetracarboxylic acid bis-anhydride (BTDA) 4,4'-(4,4'-Isopropylidenediphenoxy)phthalic acid bis-anhydride (BPADA) 9. ... P q : •: < < ... 0 0 4,4'-Diphthalic acid bis-anhydride (BPDA) 0 0 V A.xx vCAOO ü 0 4,4'-Oxydiphthalic acid bis-anhydride (ODPA) Q od TJ y A> db 4,4'-Hexafluoroisopropyldenediphthalic acid bis-anhydride (6FDA) o F,C Cr\ 0 yU AJ- / C 0 4,4'-Isopropyldenediphthalic acid bis-anhydride o s-îjï e AAJ / / 1 ATA y- 3,3'A4'-Diphenylsulfonetetracarboxylic acid bis-anhydride (DSDA) 0 o O 0 V s. V yji .X? A " ' AO 0 . 1,4,5,8-Naphthalenetetracarboxylic acid bisanhydride O p—y O Ô Ethylenetetracarboxylic acid bisanhydride O KA i P r ' AOO Bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic acid bisanhydride q Q i

[0169] Preferably, the cyclic carboxylic polyanhydride is BTDA, BPADA, BPDA and ODPA, or a mixture of these, more particularly BTDA, BPADA or a mixture of these.

[0170] Cyclic polycarboxylic anhydrides, 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 polycarboxylic anhydrides containing homophthalic groups, the syntheses described in US 6,797,838 may be used or adapted.

[0171] Polyanhydrides as crosslinking agents offer the following advantages:

[0172] - Polyanhydrides allow the creation of an elastic network with crosslinking points containing hydrolyzable ester groups. The resulting material remains equally biodegradable within the human body, as it fully preserves the degradation properties of glycerol polyester, in particular glycerol and sebacic acid polyester, poly(glycerol sebacate).

[0173] -The reaction does not lead to the formation of by-products that can cause hydrolysis of the polyester chains of glycerol, unlike acid polychlorides which generate hydrogen chloride during the reaction.

[0174] - Another major advantage of polyanhydrides lies in the crosslinking process itself. Unlike polyacids, other possible crosslinking agents for poly(glycerol sebacate), which react with hydroxyl groups by esterification, the alcohol anhydride reaction requires less energy, thus favoring a reduction in crosslinking time or temperature. Furthermore, this reaction does not lead to the formation of water as This is a by-product, unlike the polyacid-alcohol reaction. This characteristic promotes efficient crosslinking in closed molds, limiting the risk of loss of water-soluble ingredients such as certain leachable ingredients or the formation of bubbles during crosslinking.

[0175] -In comparison with di-isocyanates, the use of which is described as crosslinking agents, forming methane bonds that are little or not hydrolyzable, polyanhydrides represent a more advantageous alternative because they reduce toxicological risks.

[0176] In addition to the advantages mentioned above, the inventors noted that the use of a cyclic carboxylic polyanhydride A as a crosslinking agent unexpectedly allows for prolonged ingredient release times, thus placing it in superiority over the use of crosslinked poly(glycerol sebacate) alone, i.e. in particular in the absence of crosslinking agents such as cyclic carboxylic polyanhydrides A. This characteristic reinforces the advantage of the polyanhydride in prolonging and thus more easily modulating the release time of active ingredients according to the duration of the cosmetic or therapeutic treatments desired for the user, patient or practitioner.

[0177] The use of cyclic carboxylic polyanhydride A allows for the controlled release of ingredients by a simple process that does not involve a step modifying the polyester of glycerol and a diacid aliphatic monomer or carboxylic diester. Releaseable ingredient

[0178] The releasable ingredient is advantageously a pharmaceutical, dermatological or cosmetic active ingredient.

[0179] Cosmetic active ingredients can be classified into several categories including in particular antioxidant agents, anti-aging agents, moisturizing agents, soothing agents, healing agents, brightening or depigmenting agents, antimicrobial agents, firming agents, and combinations thereof.

[0180] By way of representative and illustrative example of a cosmetic active ingredient, the following may be cited in particular:

[0181] - C-glycoside compounds, in particular C-beta-D-xylopyranoside-n-propane-2- one, C-alpha-D-xylopyranoside-n-propane-2-one, C-beta-D-xylopyranoside-2-hydroxy-propane, C-alpha-D-xylopyranoside-2-hydroxy-propane, 1-(C-beta-D-glucopyranosyl)-2-hydroxy-propane, l-(C-alpha-D-glucopyranosyl)-2-hydroxy-propane, l-(C-beta-D-glucopyranosyl)-2-amino-propane, l-(C-alpha-D-glucopyranosyl)-2-amino-propane, 3'-(acetamido-C-beta-D-glucopyranosyl)-propane-2'-one, 3'-(acetamido-C-alpha-D-glucopyranosyl)-propane-2'-one, 1-(acetamido-C-beta-D-glucopyranosyl)-2-hydroxyl-propane, the l-(acetamido-C-beta-D-glucopyranosyl)-2-amino-propane;

[0182] - cucurbic acid derivatives, such as the sodium salt of 3-hydroxy-2- pentylcyclopentylacetic acid;

[0183] - retinoids, in particular retinol (also known as vitamin A) and esterified retinol derivatives;

[0184] - niacinamide (also known as Vitamin B3) and its derivatives such as N,N-diethylniacinamide, Npicolylniacinamide, N-allylniacinamide;

[0185] - adenosine and its analogues such as 2'-deoxyadenosine, 2',3'-isopropoylidene adenosine, toyocamycin, 1-methyladenosine; N-6-Methyladenosine, adenosine N-oxide, 6-Methylmercaptopurine riboside, 6-Chloropurine riboside, 5'-Adenosine monophosphate, 5'-Adenosine diphosphate and 5'-Adenosine triphosphate, phenylisopropyladenosine (PIA), 1-Methylisoguanosine, N-6-Cyclohexyladenosine (CHA), N-6-Cyclopentyladenosine (CPA), 2-Chloro-N-6-Cyclopentyladenosine, 2-Chloroadenosine, N-6-Phenylaminoadenosine, N6-Phenethyladenosine, 2-p-(2-Carboxethyl)phenethylamino-5'-Nethylcarboxamidoadenosine (CGS-21680), N10-ethylcarboxamido-adenosine (NECA), 5'(N-cyclopropyl)-carboxamidoadenosine, metrifudil, erythro-9-(2-hydroxy3-nonyl) adenine (EHNA) and iodotubercidin;

[0186] - ascorbic acid (also known as Vitamin D), its salts such that sodium ascorbate, magnesium or sodium ascorbyl phosphate, glycosylated ascorbic acid, its sugar esters, in particular glycosylated, mannosylated, fructosylated, fucosylated, galactosylated derivatives of N-acetylglucosamine, N-acetylmuramic ascorbic acid, and its derivatives such as 5,6-di-O-dimethylsilylascorbate, potassium salt of dl-alpha-tocopheryl-dl-ascorbyl-phosphate, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl glucoside;

[0187] - hyaluronic acid or one of its derivatives;

[0188] - salicylic acid compounds, such as n-octanoyl-5-salicylic acid (or capryloyl salicylic acid), n-decanoyl-5-salicylic acid, n-dodecanoyl-5-salicylic acid, n-heptanoyl-5-salicylic acid, and their corresponding salts;

[0189] - extracts of algae, fungi, plants, yeasts and bacteria;

[0190] - proteins, protein hydrolysates and peptides, in particular of origin vegetable;

[0191] - amino acids and their derivatives such as betaine (trimethylglycine), the proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, P-alanine, threonine, glutamic acid, glutamine, aspartic acid, cysteine, cystine, methionine, leucine, isoleucine, valine, histidine, threonine, tyrosine, taurine, α-aminobutyric acid, α-amino-P-hydroxybutyric acid, carnitine, carnosine, creatine, epsilon aminocaproic acid, tryptophan and similar;

[0192] - ceramides, sphingolipids, cholesterols, sphingosines, polyphenols, flavones, flavonoids, stilbenoids, tannins, phenolic acids;

[0193] - luteolin, quercetin, myricetin, rutin, hesperidin, narirutin, alpha-glycosyl rutin, quercitrin, isoquercitrin, morin, hesperetin, chrysin, apigenin, luteolin-7-O-glucoside, 6-hydroxyflavone, 7,8-dihydroxyflavone or tropoflavin;

[0194] - essential oils and vegetable oils;

[0195] - sugars, in particular monosaccharides, oligosaccharides, polysaccharides, organic acids such as AHAs and / or BHAs;

[0196] - Dl-α-tocopherol acetate, tocopherol nicotinate, glucosyl hesperidin, hesperidin, caffeine, y-oryzanol, capsaicin, nicotinic acid benzyl ester, and similar substances;

[0197] - vitamins and their derivatives, in particular their esters, such as in particular the provitamin B 5 also known as panthenol, tocopherol (vitamin E) and its esters (such as tocopherol acetate), ascorbic acid and its derivatives (vitamin C);

[0198] - enzymes, such as coenzyme Q10, ubiquinone;

[0199] - resorcinol derivatives such as phenyl ethyl resorcinol, 4-n-butylresorcinol and 4-(tetrahydro-2H-pyran-4-yl)benzene-1,3-diol;

[0200] - urea, hydroxyureas, glycerol, polyglycerols, glycerol glucoside, the diglycerol glucoside, polyglyceryl glucoside, xylityl glucoside, glycerol, collagen, glycerin

[0201] - alpha-hydroxy acids such as lactic acid or glycolic acid and their derivatives,

[0202] - hydroxycinnamate derivatives such as ferulic acid, vitamin C;

[0203] - allantoin;

[0204] - guaiazulene and derivatives thereof;

[0205] - bisabolol;

[0206] - sunscreens and sun filters, in particular triazine derivatives, cinnamic derivatives, benzophenone derivatives such as benzophenone-4, aminobenzoic acid (PABA), polyethoxyethyl ester of 4-Bis(polyethoxy)-para-aminobenzoic acid (PEG-25 PABA), benzylidene camphor derivatives, benzalkonium camphor methosulfate, methylene bis-benzotriazolyl tetramethylbutylphenol (Bisoctrizole), disodium phenyl dibenzimidazole tetrasulfonate (Bisdisulizole disodium), methylene bis-benzotriazolyl tetramethylbutylphenol; and

[0207] - their mixtures.

[0208] The active pharmaceutical ingredient may be an active molecule.

[0209] In the context of the invention, small molecules refer to pharmaceutical active ingredients obtained by chemical synthesis and whose molecular weight is usually less than approximately 1500-2000 g / mol. SMALL MOLECULES

[0210] In the context of the invention, "small molecules" or synthetic molecules, for the treatment of blood and hematopoietic organ diseases, include vitamin K antagonists (dicoumarol, phenindione, warfarin, clorinidione, acenocoumarol, diphenadione, fluindione), the heparin group (heparin, enoxaparin, dalleparin, antithrombin III, parnaparin, revilparin, bemiparin, tinzaparin), platelet aggregation inhibitors (ditazole, picotamia, ticlopidine, dipyridamole, indobufen, aloxiprine, tirofiban), thrombin inhibitors (argatroban, melagatran, ximelagatran, bivalirudin, dabigatran elexilate), and direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban).

[0211] For the treatment of cardiovascular diseases, we should also mention non-selective beta-blockers (alprenolol, propranolol, thnolol, sotalol, carteolol, bopindolol), selective beta-blockers (meloprolol, atenolol, betaxolol, bisoprolol, esmolol, nebivolol), calcium channel blockers (amlodipine, nicardipine, nifedipine, nimodipine, nisoldipine, lacidipine, bernidipine, clevidipine, lercanidipine, nitrendipine), and serum lipid reducers (simvastatin, lovastatin, fluvastatin, cerivastatin, rovustatin, clofibrate, bezafibrate, fenofibrate, ciprofibrate, cholestyramine, nicotinic acid derivatives, meglutol, ezetimibe, lomitapide).

[0212] For treatments with sex hormones, we will also mention progestins alone, estrogens alone and progestins combined with estrogens (Group G).

[0213] Among systemic anti-infectives, mention should be made of the group of systemic antibacterials such as tetracyclines, phenicols, penicillins, beta-lactamase-sensitive penicillins, beta-lactamase-resistant penicillins, beta-lactamase inhibitors, first-generation cephalosporins, second-generation cephalosporins, third-generation cephalosporins, fourth-generation cephalosporins, monobactams, carbapenems, trimethoprim and derivatives, short-acting sulfonamides, intermediate-acting sulfonamides, long-acting sulfonamides, sulfonamides, macrolides, lincosamides, streptogramins, streptomycins, aminoglycosides, fluoroquinolones, quinoxalines, glycopeptide antibacterials, polymyxins, derivatives of nitrofurans and pleuromutilins.Among systemic anti-infectives, we should also mention the group of systemic antifungals such as amphotericin B, hempsin, miconazole, ketoconazole, and clotrimazole. Among systemic anti-infectives, we should also mention the group... antimycobacterial drugs such as aminosalicylic acid, cycloserine, rifampicin, rifamycin, rifabutin, rifapentine, capreomycin, isoniazid, protionamide, tiocarlide, ethionamide, pyrazinamide, ethambutol, terizidone, morinamide, bedaquiline, delamanid, amithiozone, clofazimine, dapsone or aldesulfone sodium.Finally, among systemic anti-infectives, we should also mention the group of antivirals such as thiosemicarbazones (metisazone), nucleosides, nucleotides and reverse transcriptase inhibitors (acyclovir, ganciclovir, famiclovir, valganciclovir), cyclic amines (rimantadine, tromantadine), phosphonic acid derivatives (foscamet, fosfonet), protease inhibitors (saquinavir, ritonavir, nelfinavir, atazanavir), nucleoside and nucleotide reverse transcriptase inhibitors (zidovudine, zalcitabine, lamivudine), non-nucleoside transcriptase inhibitors (nevirapine, delavirdine, ripivirine), neuraminidase inhibitors (zanamivir, oseltamivir), and antivirals against... HCV infection (ribavirin, boceprevir, daclatasvir, sofosbuvir and their combinations), antivirals against HIV infections and other antivirals (lysozyme, enfuvirtide, reltegravir, umifenovir).

[0214] Among the anti-inflammatory drugs, mention should be made of the group of non-steroidal anti-inflammatory drugs such as phenylbutazone, diclofenac, ketorolac, piroxicam, meloxicam, ibuprofen, ketoprofen, oxaprozin, mefenamic acid, rofecoxib, etoricoxib, niflumic acid, and nabumetone. Also mentioned is the group of steroidal anti-inflammatory drugs such as fludrocortisone, triamcinolone, betamethasone, dexamethasone, methylprednisolone, prednisone, hydrocortisone, rimexolone, and cortivazol.

[0215] Also to be mentioned among the analgesics are the natural alkaloids of opium, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphane derivatives, oripavine derivatives, morphinane derivatives, acetylsalicylic acid and its derivatives, pyrazolones and anilides.

[0216] Antiepileptics should also be mentioned, including barbiturates and their derivatives, hydantoin and its derivatives, oxazolidine derivatives, succinimide, benzodiazepines and carboxamide.

[0217] Among the anti-parkinsonian agents, we will mention the anticholinergic agents (biperiden, tropatepine, benzotropine) the dopaminergic agents (levodopa, amantadine, bromocriptine, ropinirole, rotigotine, selegiline, tolcapone, budipine).

[0218] Finally, we will also mention among the psycholeptics aliphatic chain phenothiazines, piperazine structure phenothiazines, piperidine structure phenothiazines, butyrophenone derivatives, indole derivatives, diphenylbutypiperidine derivatives, benzamides, benzodiazepine derivatives, diphenylmethane derivatives, carbamates and piperidinedione derivatives.

[0219] Other systemic antihistamines include aminoalkyl ethers, substituted alkylamines, substituted ethylenediamines, phenothiazine derivatives, piperazine derivatives, and other compounds such as cyproheptadine, triprolidine, loratadine, acrivastine, and mizolastine.

[0220] Among the active pharmaceutical ingredients for ophthalmic use, we should also mention anti-infectives such as antibiotics, sulfonamides, antivirals, and fluoroquinolones. We should also mention anti-inflammatories such as uncombined corticosteroids and non-steroidal anti-inflammatory drugs. Among the antiglaucoma and miotic agents, we should also mention sympathomimetic antiglaucoma agents, parasympathomimetics, carbonic anhydrase inhibitors, beta-blockers, and prostaglandin analogues. Among the mydriatics and cycloplegics, we should also mention anticholinergics and sympathomimetics. Finally, among the decongestants and anti-allergics, we should mention sympathomimetics and other anti-allergics. Finally, among the agents for ocular vascular disorders, we should mention antineovascularizing agents.

[0221] The active pharmaceutical ingredient may be a biological molecule.

[0222] In the context of the invention, "biological molecules" include peptides, polypeptides, antisense nucleotides (ASOs), proteins, and monoclonal antibodies (conjugated or unconjugated). PEPTIDES, POLYPEPTIDES AND PROTEINS

[0223] The term “peptide” or “polypeptide” should be interpreted in the sense generally understood in the art, that is, as referring to any covalently linked polymer of amino acids, irrespective of length or post-translational modification. The term preferably refers to polymers of amino acid residues comprising at least six amino acids covalently linked by peptide bonds. Generally, the term refers to both short polymers (generally referred to in the art as peptide or protein fragment) and longer polymers (generally referred to in the art as polypeptide or protein). By way of general indication and without limitation, if the amino acid polymer contains more than 50 amino acid residues, it is preferably called a polypeptide or protein, whereas if the polymer consists of 50 amino acids or fewer, it is preferably called a “peptide”.

[0224] Examples of peptides for pharmaceutical use include exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, pramlintide, abarelix, degarelix, carfilzomib, mifamurtide, teriparatide, abaloparatide, enfuvirtide, peginesatide, setmelanotide.

[0225] For polypeptides or pharmaceutical proteins, examples include immunostimulants such as growth factors (filgrastim, ancestim), interferons (natural alfa and beta interferons, peginterferon alfa-2b), interleukins (adelsleukin, oprelvekin) as well as other immunostimulants (pedademase, tasonermin, immunocyanine) or even insulin, etanercept and trombine. OLIGONUCLEOTIDES

[0226] The term "polynucleotide" should be interpreted in the sense generally understood in the art, that is, as referring to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or their analogs. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. Where appropriate, modifications to the nucleotide structure may be made before or after polymer assembly. The term polynucleotide refers indiscriminately to both double-stranded and single-stranded molecules. In particular, it is possible to synthesize nucleotides with sufficiently short sequences (oligosequences) specific to blocking certain disease-causing proteins.This synthetic nucleic acid sequence is called an antisense oligonucleotide because its base pair sequence is complementary to that of the gene's messenger RNA, which is called the sense sequence. Examples of antisense oligonucleotides include fomivirsen, nusinersen, eteplirsen, inotersen, volanesorsen, patisiran, golodirsen, givosiran, viltolarsen, prexigebersen, vupanorsen, cobomarsen, atesidorsen, apatorsen, alicaforsen, casimersen, pelacarsen, sepofarsen, tominersen, and tofersen. MONOCLONAL ANTIBODIES.

[0227] Regarding monoclonal antibodies, examples include rituximab, trastuzumab, infliximab, ripilimumab, pertuzumab, novlumab, ramucirumab, olaratumab, avelumab or atezolizumab).

[0228] The ingredient is advantageously intended for administration by systemic route, advantageously by enteral route such as the oral route; by parenteral route such as the intravenous, intramuscular, subcutaneous or vitreous route.

[0229] The ingredient may also be intended for local administration, in particular topically. Composition

[0230] The composition may be non-crosslinked or crosslinked.

[0231] The composition advantageously comprises a product of the crosslinking of polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid and cyclic carboxylic polyanhydride A.

[0232] The composition is advantageously obtained by crosslinking of: • 100 parts by weight of at least one polyester, glycerol, and one monomer aliphatic diacid or carboxylic diester, as described previously; • 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, as described above; • in the presence of 5 to 300 parts by weight of at least one leachable ingredient, as described above.

[0233] Advantageously, the product of the crosslinking of glycerol polyester and an aliphatic diacid or carboxylic diester monomer and cyclic carboxylic polyanhydride A comprises only ester functions.

[0234] Advantageously, the Shore A hardness of the composition, measured according to ASTM D 2240:2021 at room temperature, ranges from 50 to 100, typically from 70 to 100.

[0235] An advantage of the invention is that the vehicle for the leachable ingredient can be of natural origin, biodegradable, and / or biocompatible. The term "vehicle" refers to the mixture of polyester, glycerol, and cyclic carboxylic polyanhydride A. This mixture of polyester, glycerol, and cyclic carboxylic polyanhydride A is advantageously cross-linked.

[0236] The degree of crosslinking of the composition, and thus of the vehicle, is adapted according to the desired release time for the ingredient and / or the ingredient content.

[0237] Advantageously, the vehicle is also bioresorbable. Advantageously, the vehicle degrades in an aqueous environment at a temperature ranging from 20°C to 70°C, in particular from 25°C to 50°C, typically at 37.5°C, i.e., body temperature in humans.

[0238] The bioresorbability and / or degradation in aqueous media of the vehicle according to the invention is characterized, in particular in the laboratory, by a mass loss, at least 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 vehicle (i.e., on day 0). crosslinking process

[0239] The invention also relates to a method for preparing a composition according to the invention, at least partially crosslinked, comprising the following steps: a. Mixing a polyester of glycerol and an aliphatic diacid or carboxylic diester monomer as defined above, a cyclic carboxylic polyanhydride A as defined above and a leachable ingredient as defined above; b. Crosslink the mixture from step a).

[0240] Preferably, step a) of mixing is carried out in the absence of solvent, diluent or other additive.

[0241] Step a) advantageously comprises mixing:

[0242] - 100 parts by weight of at least one polyester, glycerol, and a monomer aliphatic diacid or carboxylic diester, as defined previously with

[0243] - from 5 to 100, in particular from 10 to 60, parts by weight of at least one polyanhydride cyclic carboxylic acid A as defined previously and

[0244] - from 5 to 300 parts by weight of at least one leachable ingredient as defined previously.

[0245] Advantageously, step a) comprises the following steps:

[0246] al) Mix the polyester of glycerol and an aliphatic diacid or carboxylic diester monomer and the cyclic carboxylic polyanhydride A;

[0247] a2) add the leachable ingredient to the mixture obtained following step al);

[0248] a3) mix the mixture obtained following step a2).

[0249] Step a1) advantageously comprises the following steps:

[0250] al 1) heat the polyester of glycerol and of an aliphatic diacid or carboxylic diester monomer to a temperature Ta allowing the melting of the polyester of glycerol, advantageously at a temperature Ta ranging from 20°C to 100°C, more advantageously ranging from 30°C to 80°C;

[0251] al2) add the cyclic carboxylic polyanhydride A to the molten glycerol polyester obtained following step al 1);

[0252] al3) homogenize, preferably by manual or mechanical stirring, the mixture obtained following step al2).

[0253] During step al2), the cyclic carboxylic polyanhydride A can be introduced in solid form.

[0254] Step a2) consists, after homogenization obtained at the end of step a113), of incorporating the releasable ingredient at a temperature Ta ranging from 20 to 120°C, more advantageously ranging from 30 to 110°C.

[0255] The purpose of step a3) is to homogenize, preferably by manual or mechanical stirring, the mixture obtained following step a2).

[0256] Advantageously, step a) also includes a step a4) of cooling, to room temperature, the mixture obtained following step a3).

[0257] At the end of step a), the non-crosslinked composition is obtained.

[0258] Advantageously, step b), also called the crosslinking step, comprises the following steps:

[0259] bl) Pressurizing the mixture obtained following step a) in a mold at a target temperature Tc ranging from 100°C to 200°C; then

[0260] b2) maintaining temperature Tcet under pressure during a heating time under Sufficient pressure to achieve polyester crosslinking; then

[0261] b3) cooling to room temperature and recovery of composition cross-linked.

[0262] Advantageously, in steps bl) and b2), a platen press will be used, the plates of which have been preheated to temperature Tc.

[0263] The temperature Tc advantageously varies from 10°C to 175°C, preferably from 120°C to 160°C.

[0264] Advantageously, the overpressure applied by the press (relative to atmospheric pressure) varies from 0.5 bar to 8 bar (equivalent to 50 kPa to 800 kPa), in particular from 1 to 6 bar.

[0265] The heating time is determined by the duration between the moment the press is closed and the moment it is opened. Advantageously, the heating time tch varies from 12 hours to 120 hours.

[0266] The invention also relates to the use of a cyclic carboxylic polyanhydride A, as defined above, as a crosslinking agent of a glycerol polyester and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid, for the preparation of a vehicle allowing the release of a releaseable ingredient.

[0267] The vehicle advantageously allows the release of the ingredient at a temperature ranging from 35°C to 42°C in an aqueous medium, advantageously buffered as defined above. Thus, the vehicle advantageously allows the release of the ingredient in vivo, in humans or animals, advantageously after systemic or local administration.

[0268] The vehicle may be of natural origin, may be biodegradable and / or biocompatible.

[0269] Adjusting the degree of crosslinking of the vehicle allows control of the release time of the ingredient. METHODS

[0270] Measurement of the size distribution of the ingredient:

[0271] The volume distribution of particle size can be measured by laser granulometry on a Malvern Mastersizer 3000 instrument. The measurement is performed using a dry method: the particles are dispersed through a venturi using compressed air. The particles are then drawn, by vacuum, into the measuring cell of the Mastersizer 3000. The measurement is carried out in accordance with ISO 13320-1 and, based on the determination of the laser diffraction angles by the ingredient particles, allows the determination of, in particular, the D10 and D50 values, i.e. the diameter below which respectively 10% by volume and 50% by volume of the total particle population is present Shore A hardness measurement:

[0272] Shore A hardness measurements were performed using a portable Shore durometer according to ASTM D2240:2021 at room temperature (23°C ± 2°C). In vitro release measurement:

[0273] Discs of the composition, 10 mm in diameter and 2 mm thick, are prepared and weighed. They are then incubated individually in 200 ml of aqueous PBS buffer at a temperature of 37.5°C. The amount of ingredient to be released (caffeine in the examples) was measured in the aqueous phase of the PBS buffer over time, according to the samples taken. The time (in hours) after which all the ingredient contained in the discs had been released into the liquid phase was determined. Measurement of in vitro degradation:

[0274] Crosslinked polyester discs with a diameter of 10 mm and a thickness of 2 mm are prepared and weighed. They are then individually incubated in aseptic 30-liter bottles containing 20 ml of phosphate-buffered saline (PBS) solution at a temperature of 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). Macrostructure analysis: SEC RI

[0275] 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.

[0276] 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.

[0277] Size exclusion chromatography analyses were performed using a Viscotek instrument (Malvem Instruments) equipped with 4 columns, a guard column, and 3 detectors (differential refractometer and viscometer, and light scattering). The samples were dissolved at a concentration of 1 mg.mL-1 in unstabilized THF, then stirred for 2 hours before injection.

[0278] 1 mL of a solution of the sample was filtered through a 0.45 µm PTFE membrane. 100 pL of this solution were eluted in THF using a flow rate of 1 mL.min-1 at a temperature of 35 °C. OmniSEC software was used for data acquisition and analysis.

[0279] The technique used is size exclusion chromatography (SEC) with a column set optimized for the separation of low-mass species.

[0280] The analytical conditions used in the study are described in the following table: THF eluent without antioxidant. Injection volume 100 pL. Temperature 35 °C. Detector RI Waters. Mobile phase flow rate 1 mL / min. Columns: 2 Mixed D + 2 Mixed E

[0281]

[0282] The calibration used for the Moore calculation is a PS calibration, covering a range from 2,520,000 to 162 g.mol-1.

[0283] The calibration used is a mixed low and medium weight PS calibration of PSS Standards. The mass range extends from 162 to 66,000 g.mol-1. The calibration allows the determination of the Mn (g.mol-1), Mw (g.mol-1), and D (Mw / Mn) values ​​in PS equivalent.

[0284] Measurement of caffeine content by liquid chromatography

[0285] The analytical technique used is HPLC liquid chromatography. A UV detector is used because caffeine contains chromophores. The calibration curve is as follows: S1: 100 mg of caffeine in 100 mL of DCM, S2: 50 mg in 100 mL, S3: 20 mg in 100 mL, S4: 16 mL S3 in 4 mL DCM, S5: 12 mL S3 in 8 mL DCM, S6: 8 mL S3 in 12 mL DCM, S7: 4 mL S3 in 16 mL DCM, S8: 2 mL S3 in 18 mL DCM, S9: 0.2 mL S3 in 19.8 mL DCM. The analysis performed by HPLC-UV uses the Waters C18 Xbridge 150 mm x 4.6 mm x 5 µm column, which is placed in a column oven at 25°C. The mobile phases used were %A: ACN and %B: Water + 500 mg / L ammonium bicarbonate + 0.5 mL / L acetic acid, with a flow rate of 0.7 mL / min. A gradient was used for the analysis (%A-%B): 10⁻⁹ (0-10 min); 90⁻⁹ (15-20 min); 10⁻⁹ (20.1-35 min). Caffeine exhibited a retention time of 7.4 min under these conditions.

[0286] - Initial caffeine content in crosslinked PGS: Caffeine is extracted from a known mass sample of caffeine-loaded PGS. 100 mg of the sample is weighed and placed in a cellulose cartridge. 250 mL of dichloromethane (DCM) is added to a 500 mL round-bottom flask with 3 to 4 boiling chips. The flask is fitted with a Soxhlet and refluxed for 6 h. The solution is evaporated under a stream of nitrogen until approximately 10 to 20 mL is obtained. This solution is transferred to a 125 mL flask and the flask is rinsed with 10 mL of DCM. The DCM is then evaporated under nitrogen to obtain a dry extract. The extract is reconstituted with 10 mL of DCM and filtered through 0.45 µm H-PTFE. The extract is then transferred to a vial for subsequent analysis by HPLC.

[0287] - Caffeine content during the release test: At time t, a sample of the PBS solution used in the release test described above in the section "In vitro release measurement" is taken. The samples are analyzed by liquid chromatography coupled with a UV detector. Caffeine quantification is performed by external calibration. This method consists of preparing a series of standard solutions with known caffeine concentrations, which are then analyzed to establish a calibration curve. A plot is created from the areas of the chromatographic peaks as a function of the concentrations. The resulting line allows the relationship between the peak area and the caffeine concentration to be determined. When analyzing unknown samples, the peak area obtained is plotted on the calibration curve to deduce the caffeine concentration present in the samples.From the calculated concentration (in mg / L), it is possible to determine the mass of caffeine released using the total volume of the sampled solution. This allows us to obtain the mass of caffeine released for each sample. The cumulative amount of caffeine released can be calculated by summing the masses of caffeine released from each sample. The percentage of cumulative caffeine released corresponds to the cumulative mass of caffeine released divided by the theoretical mass of caffeine initially introduced into the sample. This percentage is plotted against the degradation time to observe the changes over time.

[0288] Preparation of the phosphate saline buffer (PBS) solution for the external calibration curve: 1 PBS pellet in 200 mL of ultrapure water. The calibration curve prepared is as follows: SM: 20 mg of caffeine in 100 mL of PBS, S1: 400 mg of SM in 20000 mg of PBS, S2: 2000 mg of SM in 18000 mg of PBS, S3: 4000 mg of SM in 16000 mg of PBS, S4: 8000 mg of SM in 12000 mg of PBS, S5: 12000 mg of SM in 8000 mg of PBS, S6: 16000 mg of SM in 4000 mg of PBS. The analysis performed by HPLC-UV uses the Waters C18 Xbridge column (150 mm x 4.6 mm x 3.5 µm) which is placed in a column oven at 25°C. The mobile phases used are %A: ACN and %B: Water + 0.1% formic acid and the The applied flow rate is 0.7 mL / min. A gradient is used for the analysis (%A-%B): 30-70 (0-1 min); 90-10 (7-8 min); 30-70 (9-10 min). Caffeine has a retention time of 2.6 min. The injected sample volume is 1 OpL, and the working wavelength for quantifying caffeine is 283 nm. Examples

[0289] The following example is given by way of illustration, but shall in no way be considered as limiting the present invention. Caffeine (a low molecular weight molecule, i.e., a "small molecule") is used as a model compound for a leachable ingredient in the present invention. 1. Materials and methods

[0290] The compositions studied are based on the following compounds:

[0291] [Tables2] CO Cl C2 PGS (%) 43.3 35.8 30.8 BTDA (%) 0 7.5 0 BPADA (%) 0 0 12.5 Caffeine (%) 56.7 56.7 56.7

[0292] Percentages are expressed as a percentage of the total mass of the composition.

[0293] Characteristics of starting products

[0294] [Tables3] Polyester Mn (g.mol Mw (g.mol 1) IP Poly glycerol sebacate 3140 21035 6.7

[0295] [Tables4] Bis-Anhydride Abbreviation M (g.mol 1) Benzophenone-3,3',4,4'-tetracarboxylic acid bis-anhydride BTDA 322.23 4,4'-(4,4'-Isopropylidediphenoxy)phthalic acid bis-anhydride BPADA 520.49

[0296] [Tables5] Ingredient Supplier D50 CAS number M (g / mol) caffeine Sigma Aldrich 330 microns 58-08-2 196

[0297] Procedure for the synthesis of glycerol and sebacic acid polyester:

[0298] In a 10 L 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 (2.8 kg, 1 mol equiv.) is mixed with water (0.81 kg) at 40 °C under a nitrogen flow (0.5 L / min). Gentle stirring is applied (20 rpm) for 5 min. After the glycerol has dissolved, sebacic acid (6.15 kg, 1 mol equiv.) is added to the aqueous mixture in the reactor. Finally, the remaining water (0.81 kg) is added to the medium. The reactor vessel is then gradually heated following a progressive temperature ramp with intermediate plateaus, until a shell temperature of 170 °C is reached after 5 hours, corresponding to a surrounding medium temperature of 162 °C, measured using a immersion probe. Agitation is increased to 80 rpm when the surrounding medium temperature exceeds 90 °C.The medium is left under reflux at the start of the test. When the vapor temperature at the top of the distillation column reaches 98°C, and after a 15-minute equilibration time, 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 21 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. Subsequently, a vacuum system is connected to the distillation condenser, and a pressure below atmospheric pressure is applied to the reactor contents. The pressure is reduced slowly and in steps (approximately 10–15% per step) over approximately 30 minutes until a target value of less than 30 mbar is reached. The temperature setpoint is 130°C.Once the pressure in the reaction vessel stabilizes at 28 mbar, the medium is allowed to react for 2 hours, then the temperature setpoint is increased to 140 °C for an additional 7 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. Composition preparation protocol Step a)

[0299] The compounds are mixed according to the following successive steps:

[0300] Place a 100mL beaker on a hot plate equipped with a PT 100 probe to control the temperature;

[0301] Introduce the poly(glycerol sebacate);

[0302] Heat the polymer to 50°C while mixing it with a spatula;

[0303] Introduce the bis-anhydride;

[0304] Mix with a spatula until a homogeneous mixture is obtained;

[0305] Add the ingredient;

[0306] Mix with a spatula until a homogeneous mixture is obtained;

[0307] Cool to room temperature. Step b): crosslinking

[0308] Crosslinked compositions are prepared according to the following successive steps:

[0309] Place 15g of the mixture of the desired formulation in the middle of a 2mm thick mold, between two sheets of silicone;

[0310] Place under platen press at 140°C (no humidity control);

[0311] Crosslink the materials for the desired time tch (24h, 48h or 72h);

[0312] Cool to room temperature;

[0313] Demold and cut discs of 10 mm in diameter and 2 mm in thickness to be used for the release test. 2. Results

[0314] The discs were weighed and incubated in 200 ml of aqueous PBS buffer at a temperature of 37.5°C. The amount of caffeine released was measured in the aqueous phase of the PBS buffer over time, based on the samples taken. The time (in hours) after which all the caffeine contained in the discs had been completely released into the liquid phase was determined.

[0315] This release test was conducted for the crosslinked compositions C0, Cl and C2 for 24h, 48h and 72h. Even in the absence of a crosslinking agent, composition C0 is crosslinked.

[0316] [Tableauxô] CO Cl C2 Crosslinking time at 140°C (in hours) 24 Shore A 20.6 88.0 96.8 Total release time (hours) 18 54 72

[0317] [Tables7] CO Cl C2 Crosslinking time at 140°C (in hours) 48 Shore A 67.8 96.9 96.7 Total release time (hours) 48 63 64

[0318] [Tables8] CO Cl C2 Crosslinking time at 140°C (in hours) 72 Shore A 73.6 95.9 97.6 Total release time (hours) 48 54 75 3. Discussion

[0319] It is clear that the compositions according to the invention and comprising poly(glycerol sebacate), a bis-anhydride and caffeine (Cl and C2) have total caffeine release times greater than those of the composition comprising only poly(glycerol sebacate) and caffeine (CO), regardless of the crosslinking time applied.

[0320] This characteristic may in particular be used or exploited to better respect the window of activity, in particular the therapeutic window, for a given active ingredient while having the possibility of guaranteeing a longer treatment duration for the user or patient and thus improving their comfort.

Claims

Demands

1. Composition based on a polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid; 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; and of at least one leachable ingredient.

2. Composition 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 R„ 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 which may contain one or more heteroatoms of O, S, Cl, Br, F, N, P or Si, L being devoid of linear anhydride groups.

3. Composition 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): 0 0 (I) or o 0 (H) A Li- --- AK .......x Jl 0' Y " KY 0 O' Y . Y 0 ih Y sj U kit Al 1 cY x Y\ 'z£ <y>(Ÿ)m 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(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, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, alkyl groups in the form of Ci-C6, alkoxy groups in the form of Ci-C6, a hydroxyl group, a nitro group, a cyano group, a halogen atom, a haloalkyl group in the form of CrC6, • Zi is absent or represents a -CH2- (methylene) group • Z2 is absent or represents a -CH2- (methylene) group • X independently represents a Ci-C6 alkyl group, a hydroxyl group, a Cr C6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • n represents an integer from 0 to 3, preferably from 0 to 2, • Y independently represents a Ci-C6 alkyl group, a hydroxyl group, a Cr-C6 alkoxy group, a nitro group, a cyano group, or a halogen atom, • m represents an integer from 0 to 3, preferably from 0 to 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, a Ci-C6 alkoxy, nitro, cyano, or halogen atom.

4. Composition 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. Composition 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): 0 o (III) 0 0 (IV) b | fp QJP " L3 F"" '"b ô' " bbb in which j 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. Composition according to any one of the preceding claims, obtained by crosslinking of: • 100 parts by weight of at least one polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid, • 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, • in the presence of 5 to 300 parts by weight of at least one leachable ingredient.

7. Composition according to the preceding claim, wherein the polyester of glycerol and of an aliphatic diacid or carboxylic diester monomer has a number molar mass Mn less than or equal to 10,000 g / mol.

8. Composition according to any one of the preceding claims, wherein the dicarboxylic acid monomer or the carboxylic diester monomer corresponds to the general formula R'OOC-(CH2)P-COOR', in which p represents an integer from 1 to 30, preferably an integer from 1 to 10, preferably p=8, and R' represents H or each R' represents, independently of each other, a linear or branched alkyl, in Ci-CiO, preferably in Ci-C4, preferably methyl or ethyl.

9. Composition according to any one of claims 6 to 8, characterized in that the Shore A hardness of the composition, measured according to ASTM D 2240:2021 at room temperature, ranges from 70 to 100, typically from 80 to 100.

10. Composition according to any one of the preceding claims, wherein the leachable ingredient is selected from a pharmaceutical, dermatological or cosmetic active ingredient.

11. A method for preparing a composition according to any one of the preceding claims, comprising the following steps: a) Mixing a polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid as defined in any one of the preceding claims, a cyclic carboxylic polyanhydride A as defined in any one of the preceding claims and the leachable ingredient; b) Crosslinking the mixture from step a).

12. A method according to the preceding claim, characterized in that step a) comprises the following steps: a1) Mix the polyester of glycerol and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid and cyclic carboxylic polyanhydride A; a2) add the leachable ingredient to the mixture obtained following step a1); a3) mix the mixture obtained following step a2).

13. A process according to claim 11 or 12, characterized in that step b) comprises the following steps: b1) Pressurizing the mixture obtained following step a) to a target temperature Tc ranging from 100°C to 200°C; then b2) maintaining the temperature Tc under pressure for a heating time under pressure tch sufficient to obtain the crosslinking of the polyester; then b3) cooling to ambient temperature and recovery of the composition.

14. A method according to the preceding claim, characterized in that the duration of step b2) varies from 12 hours to 120 hours.

15. Use of a cyclic carboxylic polyanhydride A, as defined in any one of claims 1 to 5, as a crosslinking agent of a glycerol polyester and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid, for the preparation of a vehicle enabling the release of a releaseable ingredient.< / y>