Compositions based on glycerol polyesters comprising a releasable ingredient

Abstract

The present invention relates to a composition based on a glycerol polyester and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid; a cyclic carboxylic polyanhydride A, the cyclic carboxylic polyanhydride A comprising at least two cyclic carboxylic anhydride groups, and not comprising a linear carboxylic anhydride function; and at least one releasable ingredient; and a process for the preparation thereof.

Description

[0001] DESCRIPTION

[0002] Glycerol-based polyester compositions comprising a leachable ingredient

[0003] FIELD OF INVENTION

[0004] The present invention relates to glycerol polyester-based compositions comprising a releasable ingredient.

[0005] STATE OF THE ART

[0006] 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. The degradability of these polyesters can sometimes limit their use as carriers for ingredients such as pharmaceutical, dermatological, or cosmetic active ingredients. In the field of controlled drug release, the release rate can play a crucial role depending on the objective and the type of delivery system considered.

[0007] Poly(glycerol-sebacate) (PGS) has the advantage of being both bioresorbable in the human physiological environment and highly biocompatible.

[0008] However, traditional PGS does not always meet the duration of action requirements of releasable ingredients and therefore treatment efficacy, which restricts its use as a vehicle for releasable ingredients, such as veterinary, pharmaceutical, dermatological or cosmetic active ingredients.

[0009] There is therefore a need to develop PGS-based compositions that improve the release rate of releasable ingredients, using simple and reproducible manufacturing processes, for better control of the diffusion of these ingredients.

[0010] It is preferable that the composition also be bioresorbable and / or biodegradable, particularly in aqueous environments, but retain mechanical properties suitable for the intended short-term uses.

[0011] We are also looking for compositions based on biodegradable and / or bio-based polyesters that allow for the controlled release of ingredients without the need to add toxic agents or that lead to the formation of "stable" bonds, such as urethane bonds in the polyester network. These stable bonds are more difficult to degrade / absorb than ester bonds, thus reducing the bioresorbable and / or biodegradable nature of the composition in aqueous media (compared to the same composition crosslinked without a crosslinking agent). Unexpectedly, the inventors demonstrated that a specific crosslinking agent slows the release of an active ingredient carried by crosslinked PGS in the presence of this agent, in vitro in an aqueous PBS buffer at a temperature of 37.5°C, compared to a PGS composition containing the same ingredient but crosslinked without this agent.Furthermore, the rigidity of the bioresorbable composition is maintained, or even improved. This offers the prospect of better control over the diffusion of a given active ingredient, thus better respecting the window of activity, particularly the therapeutic window, while also ensuring longer-lasting treatment for the user or patient and thereby improving their comfort.

[0012] DESCRIPTION OF THE INVENTION

[0013] The inventors demonstrated that the use of a cyclic carboxylic polyanhydride type crosslinking agent made it possible to overcome the problems of the prior art.

[0014] Thus, the present invention relates to a composition based on o 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, o 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, o 5 to 300 parts by weight of at least one leachable ingredient.

[0015] To the inventors' knowledge, there is no composition in the scientific literature or in the known prior art based on PGS crosslinked with a cyclic carboxylic polyanhydride that allows both the regulation of the diffusion of the releasable ingredient and the improvement of mechanical rigidity.

[0016] 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,

[0017] The representative -O- ; -S- ; -S(O)- ; -S(O)2- ; -C(O)- ; -NR n R n - with R n and R n 'independently chosen from H or an alkyl group in Ci-Ce, 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.

[0018] In particular, cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (I) or (II): in which

[0019] • Li represents a bond; -O- ; -S- ; -S(O)- ; -S(O)2- ; -NR n R n - with R n and R n'independently chosen from H or an alkyl group in Ci-Ce; -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-; -NR m - with R m chosen from H or an alkyl group in Ci-Ce, ; -P- ; -P(O)- ; -SiR a Rb- with R a and Rb independently representing a -OH, Ci-Ce alkyl or Ci-Ce alkoxy group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, Ci-Ce alkyl, Ci-Ce alkoxy, hydroxyl, nitro, cyano, halogen, or Ci-Ce haloalkyl groups,

[0020] • Zi is absent or represents a -CH2- (methylene) group

[0021] • Z2 is absent or represents a -CH2- (methylene) group

[0022] • X independently represents an alkyl group in Ci-Ce, a hydroxyl group, an alkoxy group in Ci-Ce, a nitro group, a cyano group, or a halogen atom,

[0023] • n represents an integer from 0 to 3, preferably from 0 to 2,

[0024] • Y independently represents an alkyl group in Ci-Ce, a hydroxyl group, an alkoxy group in Ci-Ce, a nitro group, a cyano group, or a halogen atom,

[0025] • m represents an integer from 0 to 3, preferably from 0 to 2,

[0026] • Ai represents: o A CC bond or a C=C bond linking the four carbon atoms of the two carboxylic anhydride functions, o a saturated, instaurated or aromatic carbocycle, optionally bridged, said carbocycle comprising from 4 to 30 carbon atoms, and o a saturated, instaurated or aromatic heterocycle, 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-Ce alkyl group, a hydroxyl, a C1-Ce alkoxy, nitro, cyano, or halogen atom.Advantageously L1 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, -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-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0027] Advantageously, the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (III) or (IV): in which it represents a simple or double DC connection,

[0028] 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 C1-Ce alkyl group, a hydroxyl, a Ci-Ce alkoxy, nitro, cyano, or halogen atom.

[0029] Advantageously, the composition is obtained by crosslinking: o 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, o 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, o in the presence of 5 to 300 parts by weight of at least one leachable ingredient.

[0030] Advantageously, the polyester of glycerol and an aliphatic diacid or carboxylic diester monomer has a molar mass in number M n less than or equal to 10,000 g / mol.

[0031] 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 group, in the C1-C10 range, preferably in the C1-C4 range, preferably also methyl or ethyl. Advantageously, 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.

[0032] Advantageously, the releasable ingredient is chosen from a veterinary, pharmaceutical, dermatological or cosmetic active ingredient, preferably chosen from a pharmaceutical, dermatological or cosmetic active ingredient.

[0033] The invention also relates to a method for preparing a composition according to the invention, 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 above, a cyclic carboxylic polyanhydride A as defined above and the leachable ingredient; b) Crosslinking the mixture from step a).

[0034] Advantageously, step a) comprises the following steps: a1) Mixing 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) adding the leachable ingredient to the mixture obtained from step a1); a3) mixing the mixture obtained from step a2).

[0035] Advantageously, step b) comprises the following steps: b1) Pressurizing the mixture obtained following step a) to a target temperature T c ranging from 100°C to 200°C; then b2) maintenance at temperature T c and under pressure for a heating time under pressure sufficient to achieve crosslinking of the polyester; then b3) cooling to room temperature and recovery of the composition. Advantageously, the duration of step b2) varies from 12 hours to 120 hours.

[0036] 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 enabling the release of a releaseable ingredient.

[0037] DEFINITIONS

[0038] For the purposes of the present invention, the term “a” or “an” means “one or more” or “at least one”. 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 strictly greater than a to strictly less than b (that is, 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, including the strict bounds a and b.

[0039] In this description, "approximately" means that the value in question may be 10% lower or higher, in particular 5%, and especially 1% higher, than the stated value. The term "composition based on" means a composition comprising a mixture and / or the in situ reaction product of the various basic constituents used, some of which may react and / or are 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 implemented for the invention may differ in the uncrosslinked and crosslinked states.

[0040] The compounds mentioned in the description can be of fossil origin or bio-based. In the latter case, they may be partially or entirely derived from biomass or obtained from renewable raw materials derived from biomass. Similarly, the compounds mentioned may also come from the recycling of previously used materials; that is, they may be partially or entirely produced through a recycling process, or obtained from raw materials themselves derived from a recycling process. This includes, in particular, monomers, specifically glycerol, dicarboxylic acid monomers, and cyclic carboxylic polyanhydride.

[0041] Glycerol is a triol with the following formula:

[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 bonded 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 bonded 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 functional group and further comprising from 3 to 40 carbon atoms. The cyclic anhydride group may be multivalent or monovalent. 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 an alkyl group in the Ci-Ce group, an alkoxy group in the Ci-Ce group, a hydroxyl, nitro, cyano, halogen atom, or a haloalkyl group in the Ci-Ce group.

[0045] A "linear anhydride group" is understood, for the purposes of this invention, to be 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.

[0046] 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 C1-C40 configuration. Preferably, a monovalent hydrocarbon group is an alkyl, cycloalkyl, alkenyl, or cycloalkenyl group, substituted or unsubstituted, in the C1-C40 configuration.

[0047] As used here, a "divalent hydrocarbon group" refers to a saturated, unsaturated, or aromatic divalent hydrocarbon chain, cyclic or acyclic (linear or branched), containing from 1 to 40 carbon atoms. A divalent hydrocarbon group includes, in particular, substituted or unsubstituted, linear or branched, C1-C40 alkanediyl, alkenediyl, or alkynediyl groups. A divalent hydrocarbon group also includes substituted or unsubstituted, C1-C40 cycloalkanediyl, cycloalkenediyl, or cycloalkynediyl groups. A divalent hydrocarbon group also includes a substituted or unsubstituted divalent aromatic group. Preferably, a monovalent hydrocarbon group is an alkanediyl (linear or branched), alkenediyl (linear or branched), cycloalkanediyl, cycloalkenediyl, substituted or unsubstituted, C1-C40 group.

[0048] 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.

[0049] By "aliphatic" we mean a linear, branched and / or cyclic hydrocarbon group, whether saturated or unsaturated but non-aromatic.

[0050] For the purposes of this invention, an "alkyl" group is defined as a monovalent, saturated, linear or branched hydrocarbon chain comprising from 1 to 40 carbon atoms, preferably from 1 to 10 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups. A "cycloalkyl" group, for the purposes of this invention, is a monovalent, cyclic, saturated hydrocarbon chain comprising 3 to 40 cyclic carbon atoms. A cycloalkyl may be monocyclic, bicyclic, or polycyclic. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups. Adamantyl is an example of a polycyclic cycloalkyl.

[0051] For the purposes of this invention, an "alkenyl" group is defined as a monovalent, linear or branched hydrocarbon chain comprising at least one double bond and from 2 to 40 carbon atoms. Examples include ethenyl, propenyl, allyl, butenyl, pentenyl, and hexenyl groups.

[0052] For the purposes of this invention, a "cycloalkenyl" group is defined as a monovalent cyclic hydrocarbon chain comprising 3 to 40 cyclic carbon atoms and at least one cyclic double bond. A cycloalkenyl may be monocyclic, bicyclic, or polycyclic. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Bicyclo[2.2.2]oct-7-ene is an example of a polycyclic cycloalkenyl.

[0053] For the purposes of this invention, an "alkynyl" group is defined as a monovalent, linear or branched hydrocarbon chain comprising at least one triple bond and from 2 to 40 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.

[0054] 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 triple cyclic bond. A cycloalkynyl group may be monocyclic, bicyclic, or polycyclic. The cycloheptynyl group is an example.

[0055] For the purposes of this invention, "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, naphthyl, or pyrene, advantageously pyrene.

[0056] For the purposes of this invention, an "alkanediyl" group is defined as a linear or branched acyclic divalent hydrocarbon chain comprising 1 to 40 carbon atoms, such as, for example, a methylene, ethanediyl, propanediyl, butanediyl, pentanediyl, or hexanediyl group.

[0057] For the purposes of this invention, the term "cycloalkanediyl group" means a saturated divalent cyclic hydrocarbon group comprising 3 to 40 cyclic carbon atoms, such as, for example, a cyclobutylene, cyclohexylene or cyclopentylene group.

[0058] For the purposes of this invention, an "alkeniyl" group is defined as a linear or branched acyclic divalent hydrocarbon chain comprising 2 to 40 carbon atoms and at least one double bond, such as, for example, a vinylene (ethenylene) or propenylene group.

[0059] For the purposes of this invention, a "cycloalkeniyl" group is defined as a linear or branched cyclic divalent hydrocarbon chain comprising 3 to 40, preferably 4 to 40 or even 5 to 40 carbon atoms and at least one double bond, such as, for example, a cyclopentenylene group.

[0060] For the purposes of this invention, an "alkynediyl" group is defined as a divalent, linear or branched, acyclic hydrocarbon chain comprising 2 to 40 carbon atoms and at least one triple bond.

[0061] 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.

[0062] For the purposes of this invention, an "alkoxy Ci-Ce group" is defined as an alkyl Ci-Ce group, as defined above, linked to the rest of the molecule via an oxygen atom. Examples include methoxy, ethoxy, n-propoxy, / so-propoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, and n-hexoxy.

[0063] For the purposes of this invention, "halogen atom" or "halogen" means fluorine, chlorine, bromine, and iodine atoms, preferably fluorine and chlorine atoms. For the purposes of this invention, "haloalkyl Ci-Ce group" means a Ci-Ce 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. An example is the trifluoromethyl (-CF3) group.

[0064] The hydroxy group is the -OH group. The cyano group is the -CN group. The nitro group is the -NO2 group.

[0065] A "carbocycle comprising 4 to 30 carbon atoms" is understood to be a cyclic (monovalent) hydrocarbon group comprising 4 to 30 carbon atoms. A carbocycle can 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 can be saturated (i.e., containing no unsaturation or multiple bonds), unsaturated (i.e., containing at least one double bond or possibly one triple bond, without being aromatic), or aromatic. When the carbocycle is aromatic, it is referred to as an "aryl" group.

[0066] For the purposes of this invention, a "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, and more advantageously 1 or 2, atoms of the ring are heteroatoms, such as, for example, sulfur, nitrogen, or oxygen atoms, the other cyclic atoms being carbon atoms. Examples of saturated or unsaturated heterocycles include: pyrrolidine, piperidine, piperazine, morpholine, pyrazolidinyl, imidazolidine, azepane, thiazolidine, isothiazolidine, oxazocane, thiazepane, and benzimidazolone.

[0067] 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 sulfur, nitrogen, or oxygen atoms, the other ring atoms being carbon atoms. Examples of heteroaryl groups are furan, thiophene, pyrrole, pyridine, imidazole, triazolyl, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, oxadiazole, thiadiazole, pyridazine, pyrimidine, pyrazine, triazine, quinole, isoquinole, quinoxal, and indole.

[0068] An "arylene group" is understood to be a divalent aromatic hydrocarbon group, preferably comprising 6 to 10 carbon atoms, and including one or more attached rings, such as a phenyl or naphthyl group. Advantageously, this refers to phenylene.

[0069] A "heteroarylene group" is understood to be a divalent aromatic heterocycle, comprising 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 is an example.

[0070] According to the invention, an "orthophthalic group" is understood to be a group with the formula:

[0071] ° , preferably of formula: ° , this group being linked to the rest of the polyanhydride molecule by the i bond, or of a divalent group of formula: This group is linked to the rest of the polyanhydride molecule by the i-bond on one side, and by the i-bond on the other. The orthophthalic group can be substituted or unsubstituted.

[0072] In the present invention, a "succinic group" is understood to be a monovalent group of formula group being linked to the rest of the polyanhydride molecule by the bond 1 and can be substituted or unsubstituted, or of a divalent group of formula: O

[0073] °, this group being linked to the rest of the polyanhydride molecule by the i bond on one side, and by the l bond on the other. A succinic group is distinct from an orthophthalic group, so that, generally, a divalent succinic group is not attached to a phenyl group. In the present invention, a "maleic group" is understood to be a monovalent group of formula a group being linked to the rest of the polyanhydride molecule by the i bond and which may be substituted or unsubstituted, or a divalent group of formula: , this group then being linked to the rest of the polyanhydride molecule by the bond 1 on the one hand, and by the link 1 On the other hand. 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.

[0074] In the present invention, a "homo-phthalic group" is understood to mean a group of formula formula preference grouping being connected to the rest of the polyanhydride molecule by the i bond, or of a divalent group of formula: , this group being linked to the rest of the molecule of polyanhydride by bonding 1 on the one hand, and by the I bond on the other hand. The homophthalic group can be substituted or unsubstituted.

[0075] By "room temperature" we mean here a temperature generally ranging from 15°C to 40°C, preferably from 20°C to 30°C, especially around 25°C.

[0076] 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 which 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 an "ingredient."

[0077] "

[0078] By "cosmetic ingredient" we mean any substance that can be administered to humans or animals and that is added to a care or beauty product to improve its properties such as its effectiveness, texture, smell, or effects on the skin, hair, or appendages.

[0079] In particular, this ingredient is a pharmaceutical, dermatological or cosmetic active ingredient.

[0080] The term "active ingredient" refers to any substance with biological activity in humans or animals, particularly one that restores, corrects, or modifies organic functions in humans or animals, especially one possessing curative or preventive properties with regard to human or animal diseases or non-pathological conditions, or one that can 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 nails.

[0081] As used here, "bioresorbability" refers to the ability of a material, particularly a polymer such as polyester, to be naturally broken down (digested) within a living organism. Bioresorbability depends on both the capacity to be degraded and the rate of digestion of the product in the biological environment. Chemically, bioresorption is 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. As used here, the "degradation" of a polyester refers to a chemical process involving the hydrolysis of ester bonds, generating lower molecular weight polymer molecules.

[0082] As used here, an "aqueous medium" refers to an aqueous solution, generally saline, and typically buffered (notably with a PBS buffer). The aqueous medium of the invention advantageously aims to reproduce the environment of the living organism (pH, saline concentration).

[0083] 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 field and are commercially available. They typically consist of a solution containing sodium chloride, disodium phosphate, monopotassium phosphate, and possibly potassium chloride. Generally, the concentration of these salts is that of the human body (isotonicity). Therefore, PBS buffers are generally suitable for replicating the environment of a living organism.

[0084] "Release-release" refers to the process by which an ingredient is released or transferred from the formulation to another medium. This can involve releasing the ingredient from the formulation into a specific environment, often to achieve a desired effect, such as the controlled release of active pharmaceutical, dermatological, or cosmetic ingredients.

[0085] A "crosslinking agent" is an agent designed to form one or more three-dimensional networks, chemically, within 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.

[0086] DETAILED DESCRIPTION OF THE INVENTION

[0087] The invention relates to a composition based on:

[0088] - of 100 parts by weight of at least one polyester of glycerol and an aliphatic monomer chosen from a dicarboxylic acid and a diester of a dicarboxylic acid;

[0089] - from 5 to 100, preferably from 10 to 60 parts by weight of a cyclic carboxylic polyanhydride A, the cyclic carboxylic polyanhydride A comprising at least two cyclic carboxylic anhydride groups, and not comprising a linear carboxylic anhydride function; and

[0090] - from 5 to 300 parts by weight of at least one releasable ingredient.

[0091] According to a particular embodiment, the composition comprises from 10 to 80 parts, preferably 10 to 60 parts, more preferably 15 to 60 parts by weight of a cyclic carboxylic polyanhydride A. According to a particular embodiment, the composition comprises from 5 to 200 parts, preferably 10 to 150 parts, and more preferably 10 to 130 parts by weight of at least one leachable ingredient.

[0092] This composition may be crosslinked or non-crosslinked. The invention covers both non-crosslinked compositions, which can 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 from both the reaction of the glycerol polyester chains with each other and the reaction of the glycerol polyester with polyanhydride A.

[0093] Polyester of the starting glycerol (i.e., before crosslinking)

[0094] 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. The dicarboxylic acid monomer or the diester monomer of a dicarboxylic acid is aliphatic.

[0095] The carboxylic diacid or diester preferably comprises from 3 to 36 carbon atoms.

[0096] 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.

[0097] Depending on the variant, 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.

[0098] 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.

[0099] 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. According to embodiments 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.

[0100] Preferably, the dicarboxylic acid monomer comprises or consists of sebacic acid. According to preferred embodiments of the invention, the dicarboxylic acid monomer and glycerol are the only monomers during polycondensation.

[0101] 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 C1-C10, preferably in Ci-C4, preferably also methyl or ethyl.

[0102] 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.

[0103] According to preferred embodiments of the invention, the dicarboxylic acid diester monomer is dimethyl sebacate.

[0104] 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.

[0105] Advantageously, the molar ratio of glycerol / diacid or carboxylic diester monomer varies from 1 / 2 to 10 / 1, notably from 1 / 1 to 5 / 1, preferably from 1 / 1 to 2 / 1.

[0106] The polyester of glycerol and an aliphatic diacid or carboxylic diester monomer advantageously exhibits one or more of the following characteristics:

[0107] - an average number molar mass (Mn) greater than or equal to 1,500 g / mol, preferably greater than or equal to 2,000 g / mol;

[0108] - a number-average molar mass (Mn) less than or equal to 10,000 g / mol, preferably less than or equal to 7,000 g / mol, preferably less than or equal to 5,000 g / mol; - a polydispersity Ip (Mw / Mn) less than 10, preferably less than or equal to 8.

[0109] The number-average molar mass (Mn), the mass-average molar mass (Mw), and the dispersity (also called polydispersity and denoted D, which is the Mw / Mn ratio), can be measured in a known manner by size-exclusion chromatography (SEC) analysis, notably as described below.

[0110] 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 monomer can be obtained in particular by implementing the processes described in FR2315383.

[0111] Cyclic carboxylic polyanhydride A

[0112] Preferably, the cyclic carboxylic polyanhydride comprises two cyclic carboxylic anhydride functions, that is to say, it is a cyclic bis-carboxylic anhydride.

[0113] 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.

[0114] 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.

[0115] Advantageously, the cyclic carboxylic anhydride groups are independent of the orthophthalic, succinic, or maleic groups.

[0116] 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,

[0117] The representative -O- ; -S- ; -S(O)- ; -S(O)2- ; -NR n - with R n chosen from H or an alkyl group in Ci-Ce; -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

[0118] L being devoid of linear anhydride groups.

[0119] 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(alkyl Ci-Ce)- or -N(alkyl Ci-Ce)-N(alkyl Ci-Ce) 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.

[0120] 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.

[0121] Advantageously, L represents a multivalent hydrocarbon group comprising 1 to 40 carbon atoms, cyclic or acyclic, saturated, unsaturated or aromatic, and capable of containing 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.

[0122] Phosphorus (P), sulfur (S), nitrogen (N) and silicon (Si) atoms can be in oxidized form (notably P(O), SO, SO2), and / or substituted - notably by an alkyl group in Ci-Ce - depending on the valence of the atom.

[0123] Most 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.

[0124] According to particular embodiments, L represents a multivalent acyclic hydrocarbon group, saturated or unsaturated, comprising 1 to 10 carbon atoms, 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 optionally by one or more heteroatoms of Cl, Br, F, N, P or Si.

[0125] 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 atoms (O) 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. In particular embodiments, the cyclic polycarboxylic anhydride comprises or is composed of a compound of formula (I) or preferably of formula (la): in which

[0126] • Li represents a bond; -O- ; -S- ; -S(O)- ; -S(O)2- ; -NR n R n - with R n and Rn 'independently chosen from H or an alkyl group in Ci-Ce; -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-; -NR m - with R m chosen from H or an alkyl group in Ci-Ce, ; -P- ; -P(O)- ; -SiR a Rb- with R a and Rb independently representing a -OH, Ci-Ce alkyl or Ci-Ce alkoxy group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, Ci-Ce alkyl, Ci-Ce alkoxy, hydroxyl, nitro, cyano, halogen, or Ci-Ce haloalkyl groups,

[0127] • Zi is absent or represents a -CH2- (methylene) group

[0128] • Z2 is absent or represents a -CH2- (methylene) group

[0129] • X independently represents an alkyl group in Ci-Ce, a hydroxyl group, an alkoxy group in Ci-Ce, a nitro group, a cyano group, or a halogen atom,

[0130] • n represents an integer from 0 to 3, preferably from 0 to 2,

[0131] • Y independently represents an alkyl group in Ci-Ce, a hydroxyl group, an alkoxy group in Ci-Ce, a nitro group, a cyano group, or a halogen atom,

[0132] • m represents an integer from 0 to 3, preferably from 0 to 2. Preferably, Z1 and Z2 are identical. Advantageously, Z1 and Z2 both represent a link.

[0133] Preferably, L1 represents a bond of -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-, or -NR m - with R m chosen from H or a Ci-Ce alkyl group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, Ci-Ce alkyl, Ci-Ce alkoxy, hydroxyl, nitro, cyano, halogen atoms, or Ci-Ce haloalkyl groups. Preferably, Li represents a bond; -O-; -S(O)2-; -C(O)-; or an aliphatic chain of

[0134] 1 to 20 carbon atoms, wherein 1 to 4 (preferably 1 to 2) methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene, -C(O)-, -O-, -S-, -S(O)-, or -S(O)2- group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, substituents preferably selected from a Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl group. In particular, Li may comprise one or two divalent aromatic groups, such as phenylenes.

[0135] In particular, Li represents a G1-G2-G3 radical where G1 and G3 are independently chosen from O, -S(O)2, -C(O)- ; G2 is a divalent hydrocarbon group of 4 to 15 carbon atoms which may include one or two divalent aromatic groups, such as phenylenes, and may be substituted by one or more, in particular one or two, preferably chosen from a Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0136] Advantageously, L1 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

[0137] 2 methylene unit(s) (preferably non-adjacent) 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 one or more, in particular one or two group(s) preferably selected from a Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl.

[0138] Advantageously, L1 represents a bond ; -O- ; -S(O)2- ; -C(O) ; or an aliphatic chain of 1 to 10 carbon atoms, in particular of 1 to 6 carbon atoms, in which 1 to 2 methylene unit(s) (preferably non-adjacent) is / are optionally replaced by an arylene, -C(O)-, -O- group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two Ci-Ce alkyl, Ci-Ce alkoxy, hydroxyl, nitro, cyano, halogen atom, Ci-Ce haloalkyl group, typically substituted or unsubstituted by a Ci-Ce alkyl, Ci-Ce alkoxy, halogen atom, or Ci-Ce haloalkyl group.

[0139] In particular, X can independently represent a C1-C6 alkyl group, a hydroxyl group, or a halogen atom.

[0140] Advantageously, n represents 0 or 1.

[0141] Preferably, Y independently represents a Ci-Ce alkyl group, a hydroxyl group, or a halogen atom. Advantageously, m represents 0 or 1.

[0142] In particular embodiments, n and m independently represent 0 or 1, and X and Y independently represent a Ci-Ce alkyl group, a hydroxyl group, or a halogen atom. In other particular embodiments, the cyclic carboxylic polyanhydride comprises or is composed of a compound of formula (II) or preferably of formula (Ha): in which

[0143] Zi is absent or represents a -CH2- (methylene) group

[0144] Z2 is absent or represents a -CH2- (methylene) group

[0145] Ai represents: o a CC bond or a C=C bond linking the four carbon atoms of the two carboxylic anhydride functions, o a saturated, instaurated or aromatic carbocycle, said carbocycle comprising from 4 to 30 carbon atoms, and o a saturated, instaurated or aromatic heterocycle, said heterocycle comprising from 4 to 30 carbon atoms, and said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents, including a Ci-Ce alkyl group, a Ci-Ce haloalkyl group, a hydroxyl, a Ci-Ce alkoxy, nitro, cyano, or halogen atom.

[0146] In some variations, Ai represents a polycyclic carbocycle or heterocycle of 10 to 30 members. In these variations, the polycyclic group may include fused rings. Advantageously, Ai represents a polycyclic aromatic carbocycle or heterocycle of 10 to 30 members, comprising two or more fused rings. It may, in particular, be a naphthalene group.

[0147] Depending on the variant, Ai represents an aromatic carbocycle comprising 6 to 10 carbon atoms, such as a phenyl or a naphthalene.

[0148] According to other variants, 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.

[0149] Depending on variants, at least one of at least one cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (III): in which it represents a simple or double DC connection,

[0150] 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 said carbocycle or heterocycle being substituted or unsubstituted by one or more substituents selected from a Ci-Ce alkyl group, a hydroxyl, Ci-Ce alkoxy, nitro, cyano, or halogen atom.

[0151] Preferably, L2 and L3 taken together with the carbon atoms to which they are bonded represent a saturated, instaurated or aromatic carbocycle, optionally bridged, said carbocycle comprising from 4 to 10 carbon atoms, and said carbocycle being substituted or unsubstituted by one or more (in particular 1 or 2) substituents selected from a Ci-Ce alkyl group or a halogen atom.

[0152] Advantageously, L2 and L3 taken together with the carbon atoms to which they are bonded represent:

[0153] • 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-Ce alkyl group, halogen atom, or

[0154] • 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 C1-C6, halogen atom.

[0155] 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 phenyl.

[0156] Depending on the variant, the cyclic carboxylic polyanhydride comprises or is made up of a compound of formula (IV): in which 'I represents a single or double DC connection.

[0157] According to preferred embodiments, the cyclic carboxylic polyanhydride of formula (I) is chosen from the group consisting of: and a mixture thereof. [Table 1]

[0158] 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.

[0159] Cyclic carboxylic polyanhydrides, particularly the cyclic bis-carboxylic anhydrides of the invention, are well known to those skilled in the art (see especially US 7,425,650). They can be obtained by condensation of the corresponding tetracarboxylic acids, and some are commercially available. More specifically, for the synthesis of cyclic carboxylic polyanhydrides containing homophthalic groups, the syntheses described in US 6,797,838 may be used or adapted.

[0160] Polyanhydrides as crosslinking agents offer the following advantages:

[0161] -Polyanhydrides allow the creation of an elastic network with crosslinking points using hydrolyzable ester groups. The resulting material remains fully biodegradable within the human body, as it fully preserves the degradation properties of glycerol polyester, particularly glycerol and sebacic acid polyester, poly(glycerol sebacate).

[0162] -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.

[0163] Another major advantage of polyanhydrides lies in the crosslinking process itself. Unlike polyacids, other potential crosslinking agents for poly(glycerol sebacate), which react with hydroxyl groups via esterification, the alcohol-anhydride reaction requires less energy, thus reducing the crosslinking time or temperature. Furthermore, this reaction does not lead to the formation of water as a byproduct, 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.

[0164] -In comparison with di-isocyanates, whose use is described as crosslinking agents, forming urethane bonds that are little or not hydrolyzable, polyanhydrides represent a more advantageous alternative because they reduce toxicological risks.

[0165] In addition to the previously mentioned advantages, 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.

[0166] The use of cyclic carboxylic polyanhydride A allows controlled release of ingredients by a simple process which does not include a step of modifying the polyester of glycerol and an aliphatic diacid monomer or carboxylic diester.

[0167] Although the invention has been described in relation to certain embodiments, the inventors believe that the observed technical effect is independent of the leachable ingredient used. Indeed, the inventors, without limiting themselves to this interpretation, consider that the observed technical effect could be attributed to the formation of specific ester bonds between the cyclic polycarboxylic anhydride and the hydroxyl groups of the PGS during crosslinking. This interaction could promote an ester-bonded network of the polymer, contributing both to improved network rigidity and to better-controlled release of the ingredient in aqueous media. Thus, the nature of the incorporated leachable ingredient would not significantly influence the observed technical effect, compared to a PGS composition comprising the same leachable ingredient but crosslinked without the cyclic polycarboxylic anhydride A crosslinking agent.

[0168] The leachable ingredient is advantageously a veterinary, pharmaceutical, dermatological, or cosmetic active ingredient, preferably a pharmaceutical, dermatological, or cosmetic active ingredient. Generally, the leachable ingredient has a molecular weight less than or equal to 2000 g / mol, preferably less than or equal to 1500 g / mol.

[0169] Cosmetic active ingredients can be classified into several categories including antioxidants, anti-aging agents, moisturizing agents, soothing agents, healing agents, brightening or depigmenting agents, antimicrobial agents, firming agents, and combinations thereof.

[0170] As representative and illustrative examples of cosmetic active ingredients, we can notably mention:

[0171] - 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, 1-(C-alpha-D-glucopyranosyl)-2-hydroxy-propane, 1-(C-beta-D-glucopyranosyl)-2-amino-propane, 1-(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, 1-(acetamido-C-beta-D-glucopyranosyl)-2-amino-propane;

[0172] - cucurbic acid derivatives, such as the sodium salt of 3-hydroxy-2-pentylcyclopentyl)acetic acid;

[0173] - retinoids, in particular retinol (also known as vitamin A) and esterified retinol derivatives;

[0174] - niacinamide (also known as Vitamin B3) and its derivatives such as N,N-diethylniacinamide, N-picolylniacinamide, N-allylniacinamide;

[0175] - adenosine and its analogues such as 2'-deoxyadenosine, 2',3'-isopropoylidene adenosine, toyocamycin, 1-methyladenosine; N-6-Methyladenosine, adenosine dioxide, 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-Phenyladenosine, 2-Phenylaminoadenosine, N6-Phenethyladenosine, 2-P-(2-Carboxethyl)phenethylamino-5'-Nethylcarboxamidoadenosine (CGS-21680), N10-ethylcarboxamido-adenosine (NECA), 5'(N-cyclopropy1)-carboxamidoadenosine, metrifudil, erythro-9-(2-hydroxy3-nonyl) adenine (EHNA) and iodotubercidin;

[0176] - ascorbic acid (also known as Vitamin D), its salts such as 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;

[0177] - hyaluronic acid or one of its derivatives;

[0178] - salicylic acid compounds, such as n-octanoyl-5-salicylic acid (or capryloyl salicylic acid), n-decanoyl-1-5-salicylic acid, n-dodecanoyl-5-salicylic acid, n-heptanoyl-5-salicylic acid, and their corresponding salts;

[0179] - extracts of algae, fungi, plants, yeasts and bacteria;

[0180] - proteins, protein hydrolysates and peptides, in particular of plant origin;

[0181] - amino acids and their derivatives such as betaine (trimethylglycine), 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 the like;

[0182] - ceramides, sphingolipids, cholesterols, sphingosines, polyphenols, flavones, flavonoids, stilbenoids, tannins, phenolic acids;

[0183] - 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;

[0184] - essential oils and vegetable oils;

[0185] - sugars, in particular monosaccharides, oligosaccharides, polysaccharides, organic acids such as AHAs and / or BHAs;

[0186] - Dl-a-tocopherol acetate, tocopherol nicotinate, glucosyl hesperidin, hesperidin, caffeine, y-oryzanol, capsaicin, nicotinic acid benzyl ester, and similar substances;

[0187] - vitamins and their derivatives, in particular their esters, such as in particular provitamin B5 also known as panthenol, tocopherol (vitamin E) and its esters (such as tocopherol acetate), ascorbic acid and its derivatives (vitamin C);

[0188] - enzymes, such as coenzyme Q10, ubiquinone;

[0189] - resorcinol derivatives such as phenyl ethyl resorcinol, 4-n-butylresorcinol and 4-(tetrahydro-2H-pyran-4-yl)benzene-1,3-diol;

[0190] - Urea, hydroxyureas, glycerol, polyglycerols, glycerol glucoside, diglycerol glucoside, polyglyceryl glucoside, xylityl glucoside, glycerol, collagen, glycerin

[0191] - alpha-hydroxy acids such as lactic acid or glycolic acid and their derivatives,

[0192] - hydroxycinnamate derivatives such as ferulic acid;

[0193] - allantoin; Tl

[0194] - guaiazulene and its derivatives;

[0195] - bisabolol;

[0196] - sunscreens and sun filters, in particular triazine derivatives, cinnamic derivatives, benzophenone derivatives such as benzophenone-4, aminobenzoic acid (PABA), 4-Bis(polyethoxy)-para-aminobenzoic acid polyethoxyethyl ester (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

[0197] - their mixtures.

[0198] The active pharmaceutical ingredient can be an active molecule.

[0199] In the context of the invention, small molecules or "small molecules" correspond to pharmaceutical active ingredients obtained from chemical synthesis and whose molecular weight is usually less than about 1500-2000 g / mol.

[0200] Preferably the active pharmaceutical ingredient is a small molecule, with a molecular weight of less than about 1500-2000 g / mol.

[0201] SMALL MOLECULES

[0202] 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).

[0203] Other medications used to treat cardiovascular diseases include non-selective beta-blockers (alprenolol, propranolol, timolol, 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).

[0204] We will also mention for treatments with sex hormones, progestins alone, estrogens alone and progestins combined with estrogens (Group G).Among the anti-infectives for systemic use, we will mention 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, quinoxalins, glycopeptide antibacterials, polymyxins, nitrofurans, and the pleuromutilins.Among systemic anti-infectives, we should also mention the group of systemic antifungals such as amphotericin B, hachemycin, miconazole, ketoconazole, and clotrimazole. Also among systemic anti-infectives are the group of drugs against mycobacteria such as aminosalicylic acid, cycloserine, rifampicin, rifamycin, rifabutin, rifapentine, capreomycin, isoniazid, protionamide, tiocarlide, ethionamide, pyrazinamide, ethambutol, terizidone, morinamide, bedaquiline, delamanid, amithiozone, clofazimine, dapsone, and 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).Among anti-inflammatory drugs, we can mention the group of non-steroidal anti-inflammatory drugs (NSAIDs) such as phenylbutazone, diclofenac, ketorolac, piroxicam, meloxicam, ibuprofen, ketoprofen, oxaprozin, mefenamic acid, rofecoxib, etoricoxib, niflumic acid, and nabumetone. We can also mention the group of steroidal anti-inflammatory drugs (SADs) such as fludrocortisone, triamcinolone, betamethasone, dexamethasone, methylprednisolone, prednisone, hydrocortisone, rimexolone, and cortivazol.

[0205] Other analgesics include natural opium alkaloids, phenylpiperidine derivatives, diphenylpropylamine derivatives, benzomorphane derivatives, oripavine derivatives, morphinane derivatives, acetylsalicylic acid and its derivatives, pyrazolones, and anilides. Antiepileptics include barbiturates and their derivatives, hydantoin and its derivatives, oxazolidine derivatives, succinimide, benzodiazepines, and carboxamide.

[0206] Among the anti-parkinsonian drugs, we will mention anticholinergic agents (biperiden, tropatepine, benzotropine) and dopaminergic agents (levodopa, amantadine, bromocriptine, ropinirole, rotigotine, selegiline, tolcapone, budipine).

[0207] Finally, we should 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.

[0208] Other antihistamines for systemic use include aminoalkyl ethers, substituted alkylamines, substituted ethylenediamines, phenothiazine derivatives, piperazine derivatives, and other compounds such as cyproheptadine, triprolidine, loratadine, acrivastine, and mizolastine.

[0209] Among the active pharmaceutical ingredients used in ophthalmology, we should also mention anti-infectives such as antibiotics, sulfonamides, antivirals, and fluoroquinolones. We should also mention anti-inflammatories such as corticosteroids alone and non-steroidal anti-inflammatory drugs (NSAIDs). Among the antiglaucoma and miotic agents, we should also mention sympathomimetic antiglaucoma agents, parasympathomimetics, carbonic anhydrase inhibitors, beta-blockers, and prostaglandin analogs. 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 treating ocular vascular disorders, we should mention antineovascular agents.

[0210] 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.

[0211] The ingredient may also be intended for local administration, particularly topical application.

[0212] The composition may be non-crosslinked or crosslinked. The composition advantageously comprises a product of the crosslinking of polyester, glycerol, and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid and cyclic carboxylic polyanhydride A.

[0213] The composition is advantageously obtained by crosslinking: o 100 parts by weight of at least one polyester of glycerol and an aliphatic diacid or carboxylic diester monomer, as described above; o 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, as described above; o in the presence of 5 to 300 parts by weight of at least one leachable ingredient, as described above.

[0214] Advantageously, the product of the crosslinking of glycerol polyester and a diacid or carboxylic diester aliphatic monomer and cyclic carboxylic polyanhydride A comprises only ester functions.

[0215] 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.

[0216] One 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.

[0217] 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.

[0218] 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.

[0219] 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).

[0220] crosslinking process

[0221] The invention also relates to a method for preparing a composition according to the invention, at least partially crosslinked, comprising the following steps: c) 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; d) Crosslinking the mixture from step a).

[0222] Preferably, step a) of mixing is carried out in the absence of solvent, diluent or other additive.

[0223] Step a) advantageously includes mixing:

[0224] - 100 parts by weight of at least one polyester of glycerol and one aliphatic diacid or carboxylic diester monomer, as defined previously with

[0225] - from 5 to 100, in particular from 10 to 60, parts by weight of at least one cyclic carboxylic polyanhydride A as defined above and

[0226] - from 5 to 300 parts by weight of at least one leachable ingredient as defined above. Advantageously, step a) comprises the following steps: a1) Mix the polyester of glycerol and an aliphatic diacid or carboxylic diester monomer and the cyclic carboxylic polyanhydride A; a2) add the leachable ingredient to the mixture obtained from step a1); a3) mix the mixture obtained from step a2).

[0227] Step a1) advantageously comprises the following steps: a11) heating the polyester of glycerol and a diacid or carboxylic diester aliphatic monomer to a temperature T a allowing the fusion of polyester and glycerol, advantageously at a temperature T a ranging from 20°C to 100°C, more advantageously ranging from 30°C to 80°C; a12) add the cyclic carboxylic polyanhydride A to the molten glycerol polyester obtained following step a11); a13) homogenize, preferably by manual or mechanical stirring, the mixture obtained following step a12).

[0228] During step a12), the cyclic carboxylic polyanhydride A can be introduced in solid form.

[0229] Step a2) consists, after homogenization obtained at the end of step a13), of incorporating the leachable ingredient at a temperature T a ranging from 20 to 120°C, more advantageously ranging from 30 to 110°C.

[0230] The purpose of step a3) is to homogenize, preferably by manual or mechanical stirring, the mixture obtained following step a2).

[0231] Advantageously, step a) also includes a step a4) of cooling, to room temperature, the mixture obtained following step a3). At the end of step a), the uncrosslinked composition is obtained.

[0232] Advantageously, step b), also called the crosslinking step, comprises the following steps: b1) Pressurizing the mixture obtained from step a) in a mold at a target temperature T c ranging from 100°C to 200°C; then b2) maintenance at temperature T c and under pressure for a heating time under pressure tch sufficient to obtain the crosslinking of the polyester; then b3) cooling to room temperature and recovery of the crosslinked composition.

[0233] Advantageously, in steps b1) and b2), a platen press will be used, the plates of which have been preheated to temperature T c .

[0234] The temperature T c advantageously varies from 110°C to 175°C, preferably from 120°C to 160°C. 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.

[0235] 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 Lh varies from 12 hours to 120 hours.

[0236] 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 enabling the release of a releaseable ingredient.

[0237] 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.

[0238] The vehicle may be of natural origin, may be biodegradable and / or biocompatible.

[0239] Adjusting the degree of crosslinking of the vehicle allows control of the release time of the ingredient.

[0240] METHODS Measurement of the size distribution of the ingredient:

[0241] The volumetric particle size distribution can be measured by laser granulometry using 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 Mastersizer 3000's measuring cell. The measurement is carried out in accordance with ISO 13320-1 and, by determining the laser diffraction angles of the ingredient particles, allows for the determination of, among other things, the D10 and D50 diameters—that is, the diameters below which 10% and 50% of the total particle population, respectively, are present.

[0242] Shore A hardness measurement:

[0243] Shore A hardness measurements were performed using a portable Shore durometer according to ASTM D2240:2021 at room temperature (23°C±2°C).

[0244] Measurement of in vitro release:

[0245] Discs of the composition, 10 mm in diameter and 2 mm thick, were prepared and weighed. They were then individually incubated in 200 ml of aqueous PBS buffer at 37.5°C. The amount of ingredient released (caffeine in the examples) 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 ingredient contained in the discs had been released into the liquid phase was determined.

[0246] Measurement of uptake in phosphate saline buffer (PBS):

[0247] Cross-linked polyester discs containing the active ingredient, with a diameter of 10 mm and a thickness of 2 mm, are manufactured and then weighed (initial mass mO). Each disc is then individually incubated in glass flasks containing 200 mL of 0.01 M phosphate-buffered saline (PBS) at a temperature of 37.5 °C. Discs are taken at different times. At each sampling, the disc is first rinsed with ultrapure water, weighed (mass before drying, mAS), and subjected to a freeze-drying process according to the following steps:

[0248] 1. Pre-freeze at -70°C for 1 hour;

[0249] 2. Freeze-drying for 48 hours.

[0250] After drying, the sample is weighed (post-drying mass, mPS).

[0251] The percentage of PBS taken is then calculated using the following formula: 100 Macrostructure analysis: SEC RI

[0252] The SEC (Size Exclusion Chromatography) technique separates macromolecules in solution according to their size using columns filled with a porous gel. Macromolecules are separated according to their hydrodynamic volume, with the largest being eluted first.

[0253] While not an absolute method, SEC allows us to understand the molar mass distribution of a polymer. From commercial standard products, the various number-average molar masses (Mn) and weight-average molar masses (Mw) can be determined, and the polydispersity index (Ip = Mw / Mn), also called "dispersity," can be calculated.

[0254] Size exclusion chromatography analyses were performed using a Viscotek instrument (Malvern Instruments) equipped with four columns, a guard column, and three detectors (differential refractometer, differential viscometer, and light scattering). Samples were dissolved at a concentration of 1 mg / mL in unstabilized THF, then stirred for two hours before injection.

[0255] One mL of a sample solution was filtered through a 0.45 µm PTFE membrane. 100 µL of this solution was eluted in THF at a flow rate of 1 mL min⁻¹ at 35 °C. OmniSEC software was used for data acquisition and analysis.

[0256] The technique used is size exclusion chromatography (SEC) with a column set optimized for the separation of low-mass species.

[0257] The analytical conditions used in the study are described in the following table:

[0258] THF eluent without antioxidant

[0259] Injection volume 100 pL

[0260] Temperature 35 °C

[0261] Waters RI Detector

[0262] Mobile phase flow rate 1 mL / min

[0263] Columns 2 Mixed D + 2 Mixed E

[0264] The calibration used for Moore's calculation is a PS calibration, covering a range from 2,520,000 to 162 g.mol-1.

[0265] The calibration used is a mixed low and medium mass PS calibration from PSS Standards. The mass range extends from 162 to 66,000 g·mol⁻¹. The calibration allows the determination of Mn (g·mol⁻¹), Mw (g·mol⁻¹), and D (Mw / Mn) values ​​in PS equivalent.

[0266] Measurement of caffeine content by liquid chromatography. The analytical technique used is high-performance liquid chromatography (HPLC). A UV detector is used because caffeine contains chromophores. The calibration range 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 HPLC-UV analysis was performed using a Waters C18 Xbridge column (150 mm x 4.6 mm x 5 µm) placed in a column oven at 25°C. The mobile phases used were %A: ammonium bicarbonate (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). Under these conditions, caffeine exhibited a retention time of 7.4 min.

[0267] -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 along 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.

[0268] -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 obtained peak area 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.

[0269] Preparation of the phosphate-buffered saline (PBS) solution for the external calibration curve: 1 PBS pellet in 200 mL of ultrapure water. The calibration curves prepared are as follows: SM: 20 mg of caffeine in 100 mL of PBS, S1: 400 mg of SM in 20,000 mg of PBS, S2: 2,000 mg of SM in 18,000 mg of PBS, S3: 4,000 mg of SM in 16,000 mg of PBS, S4: 8,000 mg of SM in 12,000 mg of PBS, S5: 12,000 mg of SM in 8,000 mg of PBS, S6: 16,000 mg of SM in 4,000 mg of PBS. The analysis, performed by HPLC-UV, uses a Waters C18 Xbridge column (150 mm x 4.6 mm x 3.5 µm) placed in a column oven at 25°C. The mobile phases used are %A: ACN and %B: Water + 0.1% formic acid, with a flow rate of 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 volume of the samples is 10pL and the working wavelength for quantifying caffeine is 283 nm.

[0270] EXAMPLE

[0271] The following example is given for illustrative purposes only, but should 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.

[0272] 1. Materials and methods

[0273] The compositions studied are based on the following compounds:

[0274] [Table 2]

[0275] Percentages are expressed as a percentage of the total mass of the composition.

[0276] Characteristics of the starter products

[0277] [Table 3] [Table 4]

[0278] [Table 5]

[0279] Procedure for the synthesis of glycerol and sebacic acid polyester:

[0280] In a 10L double-walled stainless steel reactor equipped with an instrumented distillation column configured for total reflux and a condenser connected to a distillate recovery vessel, glycerol (2.8 kg, 1 molar equivalent) 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 minutes. After the glycerol has dissolved, sebacic acid (6.15 kg, 1 molar equivalent) is added to the aqueous mixture in the reactor. Finally, the remaining water (0.81 kg) is added. 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 medium temperature of 162 °C, measured using an immersion probe. The stirring speed is increased to 80 rpm when the temperature of the medium exceeds 90°C. The medium is left under reflux at the beginning of the test.When the vapor temperature at the top of the distillation column reaches 98°C, and after a 15-minute equilibration period, the column configuration is switched to total draw-off to selectively recover the water produced during the reaction. Esterification of the medium is carried out over a total duration of 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. A vacuum system is then connected to the distillation condenser, and a pressure below atmospheric pressure is applied to the reactor contents. The pressure is reduced slowly and 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.

[0281] Composition preparation protocol

[0282] Step a)

[0283] The compounds are mixed according to the following successive steps:

[0284] Place a 100mL beaker on a hot plate equipped with a PT100 probe to control the temperature;

[0285] Introduce the poly(glycerol sebacate);

[0286] Heat the polymer to 50°C.

[0287] In a bowl of the planetary mixer, mix the quantity of Bis Anhydride and caffeine then the quantity of preheated PGS.

[0288] Run 3 cycles (350 rpm / 10 s + 1500 rpm / 15 s + 2500 rpm / 2 min + 1500 rpm / 15 s + 350 rpm / 10 s) with the planetary mixer until a homogeneous mixture is obtained.

[0289] Cool to room temperature.

[0290] Step b): crosslinking

[0291] Crosslinked compositions are prepared according to the following successive steps: Place 15g of the mixture of the desired formulation in the middle of a 2mm thick mold, between two sheets of silicone;

[0292] Place under a platen press at 140°C (no humidity control);

[0293] Allow the materials to cross-link during time t C desired hour (24h, 48h or 72h);

[0294] Cool to room temperature;

[0295] Remove from the mold and cut out discs of 10 mm in diameter and 2 mm thick to be used for the release test.

[0296] 2. Results

[0297] The discs were weighed and incubated in 200 ml of aqueous PBS buffer at 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.

[0298] A first release test was conducted for the crosslinked compositions CO, C1, and C2 over 24h, 48h, and 72h. Even in the absence of a crosslinking agent, composition C0 is crosslinked. [Table 6]

[0299] [Table 7] [Table 8]

[0300] A second release test was conducted for the crosslinked CO and C2 compositions over 48 hours. Even in the absence of a crosslinking agent, the CO composition was crosslinked. Under release conditions similar to the previous examples, water absorption (as a percentage by mass) was measured.

[0301] [Table 9] The results, which reflect the water content (taken in PBS), show that composition C2 absorbs twice as much water as composition CO. These results might have suggested that caffeine, being hydrophilic, would be released more rapidly through a more pronounced dissolution process. However, the measured release time shows that caffeine is released more slowly by composition C2 than by composition CO. Discussion

[0302] It is clear that the compositions according to the invention, comprising poly(glycerol sebacate), a bis-anhydride, and caffeine (C1 and C2), exhibit longer total caffeine release times than the composition comprising only poly(glycerol sebacate) and caffeine (CO), regardless of the crosslinking time applied. This characteristic can be used to better respect the window of activity, particularly the therapeutic window, for a given active ingredient, while also ensuring longer treatment duration for the user or patient and thus improving their comfort.

Claims

1. DEMANDS 1. Composition based on a glycerol polyester and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid comprising o 100 parts by weight of at least one glycerol polyester and an aliphatic monomer selected from a dicarboxylic acid and a diester of a dicarboxylic acid, o 5 to 100, preferably 10 to 60 parts by weight of cyclic carboxylic polyanhydride A, o 5 to 300 parts by weight 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, The representative -O- ; -S- ; -S(O)- ; -S(O)2- ; -C(O)- ; -NR n R n - with R n and R n'independently chosen from H or an alkyl group in Ci-Ce, 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): in which • Li represents a bond; -O- ; -S- ; -S(O)- ; -S(O)2- ; -NR n R n - with R n and R n'independently chosen from H or an alkyl group in Ci-Ce; -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-; -NR m - with R m chosen from H or a alkyl group in Ci-Ce, ; -P- ; -P(O)- ; -SiR a Rb- with R a and Rb independently representing a -OH, Ci-Ce alkyl or Ci-Ce alkoxy group, said aliphatic chain being substituted or unsubstituted by one or more, in particular one or two, Ci-Ce alkyl, Ci-Ce alkoxy, hydroxyl, nitro, cyano, halogen, or Ci-Ce haloalkyl groups, • 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 Ci-Ce, a hydroxyl group, an alkoxy group in Ci-Ce, 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 an alkyl group in Ci-Ce, a hydroxyl group, an alkoxy group in Ci-Ce, 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: o A CC bond or a C=C bond linking the four carbon atoms of the two carboxylic anhydride functions, o a saturated, instaurated or aromatic carbocycle, optionally bridged, said carbocycle comprising from 4 to 30 carbon atoms, and o a saturated, instaurated or aromatic heterocycle, 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-Ce alkyl group, a hydroxyl, a C1-Ce alkoxy, nitro, cyano, or halogen atom.

4. Composition according to claim 3, characterized in that the cyclic carboxylic polyanhydride A comprises or consists of a compound of formula (la): in which L1 represents a bond, C(O)-, -O-, -S(O)2-, or an aliphatic chain of 1 to 20 carbon atoms, in which one or two methylene units is / are optionally replaced by a heteroarylene, arylene, -C(O)-, -O-, -S-, -S(O)-, -S(O)2- group, said aliphatic chain being substituted or unsubstituted by one or two groups preferably selected from a Ci-Ce alkyl, Ci-Ce alkoxy, or Ci-Ce haloalkyl; n and m independently represent 0 or 1, and X and Y independently represent a Ci-Ce alkyl group, a hydroxyl, or a halogen atom.

5. Composition according to any one of the preceding claims, characterized in that the cyclic carboxylic polyanhydride A comprises or consists of a compound selected from: Benzophenone-3,3',4,4'-tetracarboxylic acid bis-anhydride (BTDA); 4,4'-(4,4'-Isopropylidenediphenoxy)phthalic acid bis-anhydride (BPADA); 4,4'-Diphthalic acid bis-anhydride (BPDA); 4,4'-Oxydiphthalic acid bis-anhydride (ODPA); 4,4'-Hexafluoroisopropyldenediphthalic acid bis-anhydride (6FDA); 4,4'-Isopropyldenediphthalic acid bis-anhydride; 3,3',4,4'-Diphenylsulfonetetracarboxylic acid bis-anhydride (DSDA), preferably 3,3',4,4'-Benzophenone-tetracarboxylic acid bis-anhydride (BTDA); 4,4'-(4,4'-Isopropylidenediphenoxy)phthalic acid bis-anhydride (BPADA); 4,4'-Diphthalic acid bis-anhydride (BPDA); 4,4'-Oxydiphthalic acid bis-anhydride (ODPA), preferably again 3,3',4,4'-Benzophenone-tetracarboxylic acid bis-anhydride (BTDA);4,4'-(4,4'-Isopropylidenediphenoxy)phthalic acid bis-anhydride (BPADA).; 6. 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): in which 'I represents a single or double DC connection, 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-Ce alkyl group, a hydroxyl, a Ci-Ce alkoxy, nitro, cyano, or halogen atom.

7. Composition according to the preceding claim, wherein the polyester of glycerol and an aliphatic diacid or carboxylic diester monomer has a molar mass in number M n 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 C1-C10, preferably in C1-C4, preferably methyl or ethyl.

9. Composition according to any one of the preceding claims, wherein the polyester of glycerol and of a diacid aliphatic monomer or carboxylic diester is Polyglycerol sebacate.

10. 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, varies from 70 to 100, typically from 80 to 100.

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

12. A process for preparing a composition according to any one of the preceding claims, comprising the following steps: a) Mixing 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, as defined in any one of the preceding claims, with 5 to 100, preferably 10 to 60 parts by weight of cyclic polycarboxylic anhydride A, as defined in any one of the preceding claims, and 5 to 300 parts by weight of the leachable ingredient; b) Crosslinking the mixture of step a).

13. 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 chosen 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).

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

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

16. Use of a cyclic carboxylic polyanhydride A, as defined in any one of claims 1 to 6, 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.

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