Process for crosslinking a polymer

Abstract

The invention relates to a process for crosslinking a polymer, comprising at least the following steps: a) providing a polymer; b) providing a crosslinking agent; c) carrying out one or more crosslinking steps in the presence of said polymer and said crosslinking agent; d) obtaining a crosslinked polymer; characterized in that the crosslinking step or each of the crosslinking steps is carried out at constant temperature or at a temperature that varies linearly or in a stepwise manner, said constant or variable temperature being less than or equal to 15°C, and in that said crosslinking step c) has a duration of between 3 and 72 hours.

Description

METHOD FOR CROSS-CUTTING A POLYMER

[0001] The invention relates to the field of polymer-based formulations used as biomaterials, and more particularly in the medical and aesthetic fields. In all these applications, the formulations must exhibit optimized rheological properties, and good injectability and in vivo performance must be guaranteed. There is a need for products with optimal characteristics and significant advantages in an aesthetic application with good damping capacity provided by an optimized Tan D (Tn Ô) and good hold in the injection zone provided by a very wide plastic range. It has been surprisingly shown that such properties can be obtained by implementing the crosslinking process under specific temperature and time conditions. These properties, as illustrated in Figure 1, can be obtained by optimizing the damping factor or tangent of the phase angle (Tan D (Tn 5)) while maintaining a satisfactory stiffness (elastic modulus G') and increasing the plastic domain.

[0002] The plastic domain is characterized by the evolution of the elastic modulus G' and the viscous modulus G" as a function of the deformation applied to the product.

[0003] When the deformation applied to the gel is within the plastic range, the product is deformed without breaking. When the yield stress is exceeded (intersection G' / G"), the product flows and its damping and filling properties are no longer optimal.

[0004] Figure 1 describes the succession of domains observed during the oscillatory deformation scan.

[0005] It is generally observed that the more rigid a product is (higher G'), the smaller its plastic deformation range becomes. Indeed, a rigid product will generally be more brittle and less able to deform.

[0006] Surprisingly, the process of the invention makes it possible to obtain a cross-linked product that is more rigid but also able to accept very large deformations with the characterization of a very large plastic domain.

[0007] The resulting product then shows optimal characteristics in an aesthetic application where its good damping capacity provided by the Tan D (Tn d) and its good hold in the injection zone provided by a highly optimized plastic domain allow it to present significant advantages.

[0008] The invention relates to a process for preparing a formulation based on crosslinked polymers, for example a formulation based on crosslinked hyaluronic acid, and more particularly a crosslinking process enabling the obtaining of particular properties and in particular an optimized Tan D (Tn 6) and an expanded plastic t range.

[0009] In the context of this application, the creation of covalent bonds between polymer monomers is referred to as "crosslinking".

[0010] When crosslinking is carried out using a crosslinking agent, the crosslinking rate (X) can be theoretically calculated using the following formula: Thus, for example, if a medium contains 100 disaccharide units, and that medium also contains 10 molecules of crosslinking agent, then the degree of crosslinking (X) will be: X = 10 / 100 = 0.1. This degree of crosslinking is therefore not influenced by the degree of polymerization, the molecular weight of the polymer chosen, or the proportion of crosslinking agent that actually reacts with at least one functional group of the polymer. It is a theoretical determination that takes into account only the quantities of crosslinking agent and repeating units present.

[0011] Crosslinking can also be assessed, a posteriori (after crosslinking), by means of the degree of modification (Mod). Unlike the crosslinking rate X, the Mod therefore takes into account the proportion of crosslinking agent that actually reacts with at least one functional group of the polymer.

[0012] The degree of modification can be expressed as follows:

[0013] The repeating unit (or monomer) is, when the polymer is hyaluronic acid, a disaccharide motif.

[0014] The determination of the values ​​in the numerator and denominator depends on the polymer and crosslinking agent chosen, and is well known to those skilled in the art. For example, in the specific case of a formulation based on hyaluronic acid crosslinked with BDDE, the method described in the publication L Nord, A. Emilson, C. Stu tesson, AH Kenne, Degree of Modification of Hyaluronic Acid Dermal Flowers, 18th Congress of the EADV, Berlin, 2009 can be used.

[0015] In the specific case of a formulation based on hyaluronic acid crosslinked with BDDE, the degree of modification can be expressed as follows:

[0016] For example, a hyaluronic acid-based formulation crosslinked with BDDE having a Mod of 1% means that it has one BDDE molecule (monolinked or doubly linked) for every 100 ΔSaccharidal motifs.

[0017] Traditionally, the crosslinking step is carried out at a temperature much higher than ambient temperature, for a fairly short period of time.

[0018] Thus, for example, in application W02009071697 on behalf of the applicant, in example 1, the curing conditions are as follows: 50°C for two hours and twenty minutes (2h20). These curing conditions are quite standard and are almost always applied.

[0019]

[0020] It is only very recently that it has been proposed to use crosslinking temperatures lower than those classically used.

[0021] In application CN 108774330 filed on behalf of BLOOMAGE FREDA BIOPHARM CO LTD, it is proposed, in the context of preparing a formulation intended for application to the skin, to implement crosslinking at varying temperatures. More specifically, for example, in Example 2, a crosslinking process is proposed with temperatures successively ranging from 1 to 4°C, then to 50°C, and this operation is repeated several times. The conclusions in Table 1 indicate that, with regard to the high-temperature step, a temperature between 50°C and 80°C is ideal. It should be noted that the disclosed formulations are biphasic formulations for external use (no injection, simple application to the skin), and that no comments are made concerning the rheology of the formulations or the quantification of the crosslinking performed. Finally, in this request, it is not highlighted that crosslinking takes place between 1 and 4°C.

[0022] In application CN 107936272 on behalf of BLOOMAGE FREDA BIOPHARM CO LTD proposes a crosslinking process that also involves alternating low (0-10°C) and high (30-60°C) temperatures. It should be noted that no comments are made regarding the rheology of the formulations.

[0023] In application CN 108774330 on behalf of BLOOMAGE FREDA BIOPHARM CO LTD, A crosslinking process is proposed which also involves alternating low (1 - 4°C) and high (50 - 80°C) temperatures.

[0024] In application W017016917 filed on behalf of GALDERMA SA, a crosslinking process is disclosed that was carried out at a high concentration of hydroxide ions (1.5-8%), a high concentration of hyaluronic acid (over 10%), and under specific temperature conditions. and very specific times. For example, the process in example 3 corresponds to the following conditions: 29°C, 16 hours.

[0025] In patent application CN 103146003 filed on behalf of SHANGHAI QISHENG BIOLOG PREPARATION CO LTD, a crosslinking process is disclosed that also includes alternating low and high temperatures; for example, in embodiment 1, crosslinking begins at 4°C and is completed at 40°C. It should be noted that no comments are made regarding the rheology of the formulations or the effect of the low temperature on the crosslinking reaction.

[0026] In US patent application 2010 / 0261893 filed on behalf of Tor-Chern Chen, examples of crosslinking at temperatures between 10 and 30°C are reported, specifically to reduce the percentage of crosslinking agent with a free end after reaction. When process temperatures are below 20°C, reaction times are always greater than 10 days and can reach 28 days. Furthermore, no studies are conducted regarding rheological properties; the sole objective is to reduce the crosslinking agent content in the finished product.

[0027] Application KR1018666678 on behalf of Seoul University provides an example of the implementation of a crosslinking process at less than 20 e This is illustrated with reaction times that are greater than 14 days.

[0028] In summary, in the aforementioned requests, the crosslinking is performed either Completely or partially, at temperatures above 30°C with reaction times of less than one day, or when crosslinking temperatures are below 20°C, reaction times are extremely long. Furthermore, the rheological properties described do not correspond to those sought and obtained under the conditions according to the invention.

[0029] As stated above, it has been highlighted by the applicant, that polymer-based formulations exhibiting particularly interesting rheological properties, with good damping capacity provided by an optimized Tan D (Tn d) and good stability in the injection zone provided by a very wide plastic range could be obtained by means of crosslinking carried out exclusively at low temperature (less than or equal to 15°C) in times compatible with industrial production, for example between 3 and 72 hours.

[0030] For example, with regard to hyaluronic acid-based formulations, it has been shown that using a low crosslinking temperature allows for: to obtain polymers exhibiting a lower degree of modification (Mod) than that obtained at higher temperatures, including: o the elastic modulus G' is optimized and is always less than 1000 Pa; o the viscous modulus G" is optimized (values ​​of G" much higher than those of formulations according to the prior art); o en; the reduction of polymer degradation during crosslinking; the optimization of the value of Tan D (Tn d) (being the ratio of the viscous modulus G" divided by the elastic modulus G') in order to obtain an improved formulation that better accepts the stresses related to the deformation of the product to have a target value within the range of 0.25 to 1 ( 0.25£ Tan D (Tn d))£ 1) good injectability characteristics; reduced energy consumption (compared to a high temperature, or compared to variable temperatures); a reliable, reproducible process requiring little human intervention; a simplified process; a very efficient crosslinking and allowing minimal modification of the polymer which can ensure better biocompatibility (good rheological properties obtained, with a fairly low Mod).

[0031] Even more surprisingly, it was shown that when a formulation based on several polymers (these polymers being, for example, hyaluronic acids) cross-linked at low temperature prior to their interpenetration by mixing, was prepared according to the process of the Invention, then the formulations obtained using the process according to the Invention had even improved properties.

[0032] For example, as will be demonstrated in the examples, the crosslinking process according to the invention makes it possible to obtain particularly interesting Tan D 1Hz values ​​(target values ​​> 0.25). It has been observed that for Tan D values ​​> 0.25, the resulting material exhibits a decrease in its brittleness and an increase in its deformation capacity; this appears ideal for a medical filling application where damping of deformation is important. In the specific case of aesthetics, this characteristic is a significant advantage because it allows for natural correction after injection. The aim of this process is therefore to optimize the damping factor while maintaining a satisfactory G' stiffness equivalent to the state of the art.

[0033] Finally, it was highlighted that the effectiveness of the crosslinking was very good, as very good rheological properties are obtained with a relatively low Mod (%); which ensures improved biocompatibility.

[0034] The invention relates to a method for crosslinking a polymer, comprising at least the following steps: a) we have a polymer; b) a crosslinking agent is available; c) one or more crosslinking steps are carried out in the presence of said polymer and said crosslinking agent; d) a cross-linked polymer is obtained; characterized in that the crosslinking step or each of the crosslinking steps is carried out at a constant temperature or at a variable temperature in a linear or stepped manner, said constant or variable temperature being less than or equal to 15°C (temperature (£ 15°C).

[0035] The polymer crosslinking process according to the invention is also characterized in that the crosslinked polymer obtained in step d) exhibits a G' ≤ 1000 Pa.

[0036] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinked polymer obtained in step d) exhibits a G' £800 Pa.

[0037] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the crosslinked polymer obtained in step d) exhibits a G' ≤ 600 Pa.

[0038] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinked polymer obtained in step d) exhibits a G' ≤ 500 Pa.

[0039] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the crosslinked polymer obtained in step d) has a G' < 300 Pa.

[0040] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinked polymer obtained in step d) exhibits a G' ≤ 200 Pa.

[0041] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinked polymer obtained in step d) exhibits a G' ≤ 100 Pa.

[0042] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the crosslinked polymer obtained in step d) exhibits a G' ≤ 50 Pa.

[0043] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinked polymer obtained in step d) has a G' having a value in the range of 50 and 610 Pa (50 ≤ G' ≤ 610).

[0044] The polymer crosslinking process according to the invention is also characterized in that the crosslinked polymer obtained in step d) has a Tan D (Tn d) whose value is between 0.25 and 1 (0.25 Tan D (Tn d))5 1).

[0045] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the crosslinked polymer obtained in step d) has a Tan D (Tn d) whose value is between 0.50 and 1 (0.505 Tan D (Tn 6)) 5 1).

[0046] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the crosslinked polymer obtained in step d) has a Tan D (Tn 6) whose value is between 0.75 and 1 (0.755 Tan D (Tn d))5 1)

[0047] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinked polymer obtained in step d) has a tan having a value in the range of 0.3 and 0.6 (0.3 5 Tan D (Tn d) 5 0.6).

[0048] The invention also relates to the polymer obtained by the process according to the invention.

[0049] In one embodiment, the polymer according to the Invention has a G' 5 1000 Pa tan D (Tn d) whose value is between 0.25 and 1 (0.255 Tan D (Tn d))5 1).

[0050] In one embodiment, the polymer according to (Invention has a G' 5,800 Pa.

[0051] In one embodiment, the polymer according to the invention has a G' 5,600 Pa.

[0052] In one embodiment, the polymer according to the invention has a G' 5,500 Pa.

[0053] In one embodiment, the polymer according to the Invention has a G' 5,300 Pa.

[0054] In one embodiment, the polymer according to the invention has a G' 5200 Pa.

[0055] In one embodiment, the polymer according to the invention has a G' 5 100 Pa.

[0056] In one embodiment, the polymer according to the invention has a G' 5 50 Pa.

[0057] In one embodiment, the polymer according to the invention has a G' having a value within the interval 50 and 610 Pa (50 5 G' 5 610).

[0058] In one embodiment, the polymer according to the invention has a tan D (Tn d) whose value is between 0.50 and 1 (0.505 tan D (Tn d))5 1).

[0059] In one embodiment, the polymer according to the Invention has a Tan D (Tn 6) whose value is between 0.75 and 1 (0.755 Tan D (Tn d))5 1)

[0060] In one embodiment, the polymer according to the invention has a Tan D (Tn d) whose value is between 0.3 and 0.6 (0.3 ≤ Tan D (Tn d) ≤ 0.6).

[0061] In one embodiment, the polymer according to the invention is characterized in that it is chosen from the group of polysaccharides.

[0062] In one embodiment, the polymer according to the Invention is characterized in that it consists of a mixture of polymers.

[0063] In one embodiment, the polymer according to the invention is a mixture of hyaluronic acids, or of hyaluronic acid salts.

[0064] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinking step or each of the crosslinking steps is carried out at a constant temperature.

[0065] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at least one crosslinking step is carried out at variable temperature.

[0066] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at least one crosslinking step is carried out at variable temperature in a linear manner.

[0067] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that at least one crosslinking step is carried out at variable temperature in stages.

[0068] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said constant or variable temperature is less than or equal to 15°C (temperature ≤ 15°C).

[0069] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at least 90% of the crosslinking is carried out at a constant or variable temperature less than or equal to 15°C (temperature ≤ 15°C).

[0070] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at least 80% of the crosslinking is carried out at a constant or variable temperature less than or equal to 15°C (temperature ≤ 15°C).

[0071] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that at least 70% of the crosslinking is carried out at a constant or variable temperature less than or equal to 15°C (temperature ≤ 15°C).

[0072] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinking step at constant or variable temperature Less than or equal to 15°C (temperature ≤ 15°C) represents at least 90% of the time of exposure of the reactants.

[0073] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the crosslinking step at constant or variable temperature Less than or equal to 15°C (temperature ≤ 15°C) represents at least 80% of the time of exposure of the reactants.

[0074] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the crosslinking step at constant or variable temperature Less than or equal to 15°C (temperature ≤ 15°C) represents at least 70% of the time of exposure of the reactants.

[0075] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said constant or variable temperature is less than or equal to 12°C (temperature ≤ 12°C).

[0076] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said constant or variable temperature is less than or equal to 10°C (temperature ≤ 10°C).

[0077] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said constant or variable temperature is Less than or equal to 9°C (temperature ≤ 9°C).

[0078] The solidification temperature of a reaction medium is the temperature at which the medium becomes solid. For an aqueous medium, this temperature will be 0°C, or slightly lower depending on the salt concentration of the medium.

[0079] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said constant or variable temperature is between the solidification temperature and 15°C.

[0080] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said constant or variable temperature is between the solidification temperature and 10°C.

[0081] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said constant or variable temperature is between the solidification temperature and 9°C.

[0082] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that before step c), a step of dissolving said polymer is carried out.

[0083] The polymer is dissolved by adding water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS, or by adding a sodium hydroxide or acid solution to obtain the pH compatible with carrying out the crosslinking reaction.

[0084] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that at the latest during step c), a step is carried out to adjust the pH to a crosslinking pH.

[0085] The pH adjustment is carried out by adding a preferably mineral acid solution, for example hydrochloric acid, or a preferably mineral base, for example sodium hydroxide or potassium hydroxide, the acid and base solutions being added in an amount that allows the target crosslinking pH to be reached.

[0086] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at the latest during step c), a step is carried out to adjust the pH to a crosslinking pH suitable for said crosslinking agent.

[0087] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at the latest during step c), a step is carried out to adjust the pH to a crosslinking pH greater than 10.

[0088] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that at the latest during step c), a pH adjustment step is carried out to a crosslinking pH less than 3.

[0089] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at the latest during step c), a pH adjustment step is carried out to a crosslinking pH greater than 10, said crosslinking agent being BDDE.

[0090] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that at the latest during step c), a pH adjustment step is carried out to a crosslinking pH Less than 3, said crosslinking agent being BDDE.

[0091] In one embodiment, the polymer crosslinking process according to the invention is characterized in that at the latest during step c), a step is carried out to adjust the pH to a crosslinking pH, said crosslinking pH being greater than 10.

[0092] Crosslinking begins when the following 3 conditions are met: presence of the polymer, presence of the crosslinking agent, reaction medium at an appropriate pH.

[0093] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that the initiation of crosslinking is caused by the addition of said crosslinking agent.

[0094] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the initiation of crosslinking is caused by the addition of said polymer.

[0095] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the initiation of crosslinking is caused by the application of a crosslinking pH.

[0096] In one embodiment, the polymer crosslinking process according to the invention is characterized in that after step c), a step is carried out to adjust the pH to a pH between 6 and 8.

[0097] In one embodiment, the polymer crosslinking process according to the invention is characterized in that after step c), a step is carried out to adjust the pH to a pH between 6 and 8.

[0098] Depending on the pH of the reaction medium at the end of the crosslinking reaction, the pH is adjusted by adding a solution of preferably mineral acid, for example hydrochloric acid or of preferably mineral base, for example sodium hydroxide or potassium hydroxide, the acid and base solutions being added in a quantity that allows a pH between 6 and 8 to be reached.

[0099] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that after step c), a step is carried out to adjust the pH to a pH between 6 and 8 by adding at least one acid, namely hydrochloric acid (HCl). [000100] In one embodiment, the polymer crosslinking process according to the invention is characterized in that before step d), a purification step is carried out. [000101] In one embodiment, the polymer crosslinking process according to the invention is characterized in that before step d), a purification step by dialysis is carried out. [000102] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that before step d), a purification step is carried out by dialysis using a dialysis solution or solvent chosen from the group consisting of phosphate buffers for example PBS and water. [000103] In one embodiment, the polymer crosslinking process according to the invention is characterized in that before step d), a step of removing said crosslinking agent is carried out. [000104] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that before step c), a cooling step is carried out at the crosslinking temperature. [000105] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said polymer of step a) is a mixture of polymers. [000106] In the context of this application, all the polymers mentioned may be brought together in the form of a mixture during step a), whether they are polymers of the same type (for example, a mixture of hyaluronic acid having different molecular weights) or of different types (for example, a mixture of hyaluronic acid and chitosan). During the crosslinking step, crosslinking between the different polymers may occur. [000107] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said polymer of step a) is a mixture of hyaluronic acids, or salts of hyaluronic acids. [000108] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said polymer of step a) is a mixture of 2 hyaluronic acids or hyaluronic acid salts. [000109] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said polymer of step a) is a mixture of 3 hyaluronic acids or hyaluronic acid salts. [000110] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said polymer of step a) is a mixture of 4 hyaluronic acids or hyaluronic acid salts. [000111] In one embodiment, the polymer crosslinking process according to the invention is characterized in that the bringing together of said polymer and at least one crosslinking agent takes place in a solvent. [000112] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said at least one crosslinking agent is selected from the group consisting of ethylene glycol diglycidyl ether, butane glycol diglycidyl ether (BDDE), polyglycerol polyglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, a bis- or polyepoxy such as 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane, a dialkyl sulfone, divinyl sulfone, formaldehyde, epchlorohydrin or glutaraldehyde, carbodiimides such as, for example, 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), trimetaphosphates, such as for example sodium trimetaphosphate, calcium trimetaphosphate, or barium trimetaphosphate. [000113] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said at least one crosslinking agent is selected from the group consisting of ethylene glycol diglycidyl ether, butane glycol diglycidyl ether (BDDE), polyglycerol polyglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, a bis- or polyepoxy such as 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane, trimetaphosphates, such as sodium trimetaphosphate, calcium trimetaphosphate, or barium trimetaphosphate. [000114] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said at least one crosslinking agent is selected from the group consisting of ethyleneglycoldlglycidyl ether, butanediololdlglycidyl ether (BDDE), polyglycerolpolyglycldyl ether, polyethyleneglycoldlglycidyl ether, polypropyleneglycoldlglycidyl ether, a bis- or polyepoxy such as 1,2,3,4-dlepoxybutane or 1,2,7,8-dlepoxyoctane. [000115] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said at least one crosslinking agent is chosen from the group consisting of trimetaphosphates, such as sodium trimetaphosphate, calcium trimetaphosphate, or barium trimetaphosphate. [000116] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said at least one crosslinking agent is chosen from the group consisting of epoxides, for example 1,4-butanediol diglycidyl ether (BDDE), epihalohydrins, dlvinylsulfone (DVS). [000117] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said at least one crosslinking agent is dlvinylsulfone (DVS). [000118] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said at least one crosslinking agent is 1,4-butanedlol diglycidyl ether (BDDE). [000119] In the context of this application, the BDDE is particularly preferred. [000120] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said at least one crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE), and said step c) is carried out at a pH greater than 10. [000121] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said crosslinking step c) has a duration of between 3 and 72 hours. [000122] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said crosslinking step c) has a duration of between 3 and 60 hours. [000123] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said crosslinking step c) has a duration of between 3 and 50 hours. [000124] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said crosslinking step c) has a duration of between 5 and 50 hours. [000125] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said crosslinking step c) has a duration of between 10 and 50 hours. [000126] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said crosslinking step c) has a duration of between 15 and 48 hours. [000127] In one embodiment, the polymer crosslinking process according to the invention is characterized in that said crosslinking step c) has a duration of between 20 and 30 hours. [000128] In one embodiment, the polymer crosslinking process according to the Invention is characterized in that said crosslinking step c) has a duration of between 21 and 28 hours. [000129] When several successive crosslinkings are carried out, the durations mentioned are the total durations (sum of the durations of the successive crosslinkings). [000130] In one embodiment, during step c), the implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent takes place in a reaction medium in which said polymer is hydrated and / or swollen. [000131] In one embodiment, during step c), the implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent takes place in a medium in which said polymer is hydrated and / or swollen by the addition of water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS. In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the polymer concentration is between 0.05 and 30% by mass, relative to the total mass of the crosslinking reaction medium. [000132] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the polymer concentration is between 1 and 30% by mass, relative to the total mass of the reaction medium. [000133] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the polymer concentration is between 5 and 25% by mass, relative to the total mass of the reaction medium. [000134] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the polymer concentration is between 10 and 15% by mass, relative to the total mass of the reaction medium. [000135] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of hyaluronic acid, or one of its biologically acceptable salts, alone or in mixture, and said crosslinking agent, the concentration of hyaluronic acid is between 0.05 and 30% by mass, relative to the total mass of the reaction medium. [000136] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of hyaluronic acid, or one of its biologically acceptable salts, alone or in mixture, and said crosslinking agent in a crosslinking reaction medium, the concentration of hyaluronic acid is between 1 and 30% by mass, relative to the total mass of the reaction medium. [000137] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of hyaluronic acid, or one of its biologically acceptable salts, alone or in mixture, and said crosslinking agent, the polymer concentration is between 5 and 25% by mass, relative to the total mass of the reaction medium. [000138] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of hyaluronic acid, or one of its biologically acceptable salts, alone or in mixture, and said crosslinking agent, the concentration of hyaluronic acid is between 10 and 15% by mass, relative to the total mass of the reaction medium. [000139] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the crosslinking reaction medium comprises sodium hydroxide (NaOH). [000140] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the concentration of sodium hydroxide is between 0.5 and 1.5% by mass, relative to the total mass of the reaction medium. [000141] In one embodiment, during step c), implementation of the crosslinking step(s) in the presence of said polymer and said crosslinking agent, the concentration of sodium hydroxide is between 0.8 and 1% by mass, relative to the total mass of the reaction medium. [000142] The Invention also relates to a method for preparing a formulation comprising at least one crosslinked polymer obtained according to the method of the Invention. [000143] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one hydration and / or swelling step. [000144] In one embodiment, the hydration and / or swelling step in a liquid is carried out by adding water or an aqueous saline solution, for example a phosphate buffer solution, for example PBS. [000145] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one hydration and / or swelling step in an aqueous solution to obtain a polysaccharide concentration of between 2 mg / g and 50 mg / g, relative to the total mass of said formulation. [000146] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one hydration and / or swelling step in an aqueous solution to obtain a polysaccharide concentration of between 4 mg / g and 40 mg / g, relative to the total mass of said formulation. [000147] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one hydration and / or swelling step in an aqueous solution to obtain a polysaccharide concentration of between 5 mg / g and 30 mg / g, relative to the total mass of said formulation. [000148] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one hydration and / or swelling step in an aqueous solution to obtain a polysaccharide concentration of between 10 mg / g and 30 mg / g, relative to the total mass of said formulation. [000149] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one hydration and / or swelling step in an aqueous solution to obtain a polysaccharide concentration of approximately 20 mg / g, relative to the total mass of said formulation. [000150] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention includes a homogeneous mixing step of Y identical or different crosslinked polymers, crosslinked prior to their interpenetration by mixing, Y being between 2 and 5, characterized in that at least one of the Y polymers is crosslinked according to the crosslinking process according to the invention. [000151] In one embodiment, Y = 2 and 1 polymer is crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000152] In one embodiment, Y = 2 and 2 polymers are crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000153] In one embodiment, Y = 3 and 1 polymer is crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000154] In one embodiment, Y = 3 and 2 polymers are crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000155] In one embodiment, Y = 3 and 3 polymers are crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000156] In one embodiment, Y = 2, the 2 polymers are hyaluronic acids, or hyaluronic acid salts, having different molecular masses. [000157] In one embodiment, the Y polymers are mixed before swelling of each of said Y polymers. [000158] In one embodiment, the Y polymers are mixed after swelling of each of said Y polymers. [000159] In one embodiment, the Y polymers are mixed before swelling. In one embodiment, the Y polymers are mixed after swelling. [000160] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one terminal sterilization step. [000161] In one embodiment, the process for preparing the formulation comprising at least one crosslinked polymer according to the invention further comprises a terminal sterilization step. [000162] In one embodiment, said terminal sterilization step is carried out by heat, by moist heat, by gamma radiation, by an accelerated electron beam. [000163] In one embodiment, said terminal sterilization step is carried out by steam autoclaving. [000164] In one embodiment, steam autoclaving is carried out at a FO ≥ 4 minutes. [000165] In one embodiment, steam autoclaving is carried out at FO ≥ 10 minutes. [000166] In one embodiment, steam autoclaving is carried out at FO ≥ 15 minutes. [000167] In one embodiment, steam autoclaving is carried out at FO ≥ 20 minutes. [000168] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one active ingredient. [000169] In one embodiment, at least one active ingredient is added in powder form. [000170] In one embodiment, at least one active ingredient is added in the form of a solution or suspension. [000171] In one embodiment, at least one active ingredient is added in the form of a solution or suspension, in a solvent or solution chosen from the group consisting of water, aqueous saline solutions for example a phosphate buffer solution, for example PBS. [000172] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one active ingredient selected from the group consisting of local anesthetics, vitamin C derivatives, anti-inflammatories, polyols, and mixtures thereof. [000173] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic. [000174] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic to obtain a local anesthetic concentration of between 0.1 and 5%, relative to the total mass of said formulation. [000175] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic to obtain a local anesthetic concentration of between 0.1 and 4%, relative to the total mass of said formulation. [000176] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic to obtain a local anesthetic concentration of between 0.1 and 2%, relative to the total mass of said formulation. [000177] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further includes at least one step of adding at least one local anesthetic to obtain a local anesthetic concentration of between 0.1 and 1%, relative to the total mass of said formulation. [000178] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one local anesthetic to obtain a local anesthetic concentration of between 0.1 and 0.5%, relative to the total mass of said formulation. [000179] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic to obtain a local anesthetic concentration of approximately 0.3%, relative to the total mass of said formulation. [000180] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic selected from the group consisting of Ildocaine, mepivacaine, and mixtures thereof. [000181] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely Ildocaine. [000182] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely Ildocaine, to obtain an Ildocaine concentration of between 0.1 and 5%, relative to the total mass of said formulation. [000183] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely Ildocaine, to obtain an Ildocaine concentration of between 0.1 and 4%, relative to the total mass of said formulation. [000184] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely Ildocaine, to obtain an Ildocaine concentration of between 0.1 and 2%, relative to the total mass of said formulation. [000185] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further includes at least one step of adding at least one local anesthetic, namely lidocaine, to obtain a lidocaine concentration between 0.1 and 1%, relative to the total mass of said formulation. [000186] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one local anesthetic, namely Ildocaine, to obtain an Ildocaine concentration of between 0.1 and 0.5%, relative to the total mass of said formulation. [000187] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely Ildocaine, to obtain a local anesthetic concentration of approximately 0.3%, relative to the total mass of said formulation. [000188] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely meplvacaine. [000189] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely meplvacaine, to obtain a meplvacaine concentration between 0.1 and 5%, relative to the total mass of said formulation. [000190] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one local anesthetic, namely meplvacaine, to obtain a meplvacaine concentration between 0.1 and 4%, relative to the total mass of said formulation. [000191] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely meplvacaine, to obtain a concentration of meplvacaine between 0.1 and 2%, relative to the total mass of said formulation. [000192] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely meplvacaine, to obtain a concentration of meplvacaine between 0.1 and 1%, relative to the total mass of said formulation. [000193] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one local anesthetic, namely mepivacaine, to obtain a concentration of mepivacaine between 0.1 and 0.5%, relative to the total mass of said formulation. [000194] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one local anesthetic, namely meplvacaine, to obtain a local anesthetic concentration of approximately 0.3%, relative to the total mass of said formulation. [000195] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one vitamin C derivative. [000196] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one vitamin C derivative selected from the group consisting of ascorbyl phosphates (such as magnesium ascorbyl phosphate, sodium ascorbyl phosphate), ascorbyl glycosides (such as ascorbic acid-2-glucoside), and mixtures thereof. [000197] In one embodiment, said at least one vitamin C derivative is magnesium ascorbyl phosphate. [000198] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the invention further comprises at least one step of adding at least one anti-inflammatory. [000199] In one embodiment, the process for preparing a formulation comprising at least one cross-linked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one anti-inflammatory chosen from the group consisting of steroidal and non-steroidal anti-inflammatories. [000200] In one embodiment, said at least one anti-inflammatory drug is chosen from the group consisting of steroidal anti-inflammatory drugs (such as, for example, dexamethasone, prednisolone, corticosterone, budesonide, sulfasalazine, mesalamine, cetirizine, diphenhydramine, antipyrine, methyl salicylate, loratadline, thymol, carvacrol, bilisabolol, allantoin, eucalyptol, phenazone (antipyrine), propyphenazone) and non-steroidal anti-inflammatory drugs (such as, for example, buprofen, naproxen, fenoprofen, ketoprofen, flurblprofen, oxaproxen, indomethacin, sulindac, etodolac, the ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lomoxlcam, isoxicam, acid mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxlb, rofecoxlb, valdecoxlb, parecoxlb, lumlracoxlb, etorlcoxlb, flrocoxlb, or sucrose octasulfate and / or its salts). [000201] In one embodiment, said at least one anti-inflammatory is chosen from the group consisting of sucrose octasulfate and its salts. [000202] In one embodiment, said at least one anti-inflammatory is chosen from the group consisting of sucrose octasulfate and its sodium and potassium salts. [000203] In one embodiment, said water-soluble salt of sucrose octasulfate is chosen from the group consisting of alkali metal salts, alkaline earth metal salts, silver salts, ammonium salts, amino acid salts. [000204] In one embodiment, said water-soluble salt of sucrose octasulfate is chosen from the group consisting of alkali metal salts or alkaline earth metal salts. [000205] In one embodiment, said water-soluble salt of sucrose octasulfate is the sodium salt of sucrose octasulfate or the potassium salt of sucrose octasulfate. [000206] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol. [000207] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol selected from the group consisting of mannitol, sorbitol, glycerol, maltitol, lactitol and erythritol. [000208] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol selected from the group consisting of mannitol, sorbitol and glycerol. [000209] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol to obtain a polyol concentration of between 0.1 mg / ml and 50 mg / ml, relative to the total mass of said formulation. [000210] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol to obtain a polyol concentration of between 5 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000211] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol to obtain a polyol concentration of between 10 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000212] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol to obtain a polyol concentration of between 20 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000213] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one step of adding at least one polyol to obtain a polyol concentration of between 30 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000214] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol, namely mannitol. [000215] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding mannitol to obtain a mannitol concentration of between 5 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000216] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding mannitol to obtain a mannitol concentration of between 10 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000217] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding mannitol to obtain a mannitol concentration of between 20 mg / ml and 40 mg / ml, relative to the total mass of said formulation. In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one step of adding mannitol to obtain a mannitol concentration of between 30 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000218] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding at least one polyol, namely sorbitol. [000219] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one step of adding sorbitol to obtain a concentration of sorbitol between 5 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000220] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one step of adding sorbitol to obtain a concentration of sorbitol between 10 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000221] In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the Invention further comprises at least one step of adding sorbitol to obtain a concentration of sorbitol between 20 mg / ml and 40 mg / ml, relative to the total mass of said formulation. In one embodiment, the process for preparing a formulation comprising at least one crosslinked polymer obtained according to the process of the invention further comprises at least one step of adding sorbitol to obtain a concentration of sorbitol between 30 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000222] The invention also relates to a formulation comprising at least one cross-linked polymer obtained according to the process of the invention. [000223] In one embodiment, the formulation is characterized in that the polymer concentration is between 2 mg / g and 50 mg / g, relative to the total mass of said formulation. [000224] In one embodiment, the formulation is characterized in that the polymer concentration is between 4 mg / g and 40 mg / g, relative to the total mass of said formulation. [000225] In one embodiment, the formulation is characterized in that the polymer concentration is between 5 , mg / g and 30 mg / g, relative to the total mass of said formulation. [000226] In one embodiment, the formulation is characterized in that the polymer concentration is between 10 mg / g and 30 mg / g, relative to the total mass of said formulation. [000227] In one embodiment, the formulation is characterized in that the polymer concentration is approximately 20 mg / g, relative to the total mass of said formulation. [000228] In one embodiment, the formulation is characterized in that it is injectable. [000229] In one embodiment, the formulation is characterized in that it is sterile. [000230] In one embodiment, the formulation is characterized in that it is monophasic. [000231] In one embodiment, the formulation is characterized in that it is injectable and sterile. [000232] In one embodiment, the formulation is characterized in that it is injectable, sterile and monophasic. [000233] In one embodiment, said formulation comprising at least one polymer crosslinked according to the process of the Invention comprises a homogeneous mixture of Y identical or different crosslinked polymers, crosslinked prior to their interpenetration by mixing, Y being between 2 and 5, characterized in that at least one of the Y polymers is crosslinked according to the process of preparing a crosslinked polymer according to the invention. [000234] In one embodiment, Y = 2 and 1 polymer is crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000235] In one embodiment, Y = 2 and 2 polymers are crosslinked according to the process for preparing a crosslinked polymer according to the invention. [000236] In one embodiment, Y = 3 and 1 polymer is crosslinked according to the process for preparing a crosslinked polymer according to the invention. [000237] In one embodiment, Y = 3 and 2 polymers are crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000238] In one embodiment, Y = 3 and 3 polymers are crosslinked according to the process for preparing a crosslinked polymer according to the Invention. [000239] In one embodiment, Y = 2, the 2 polymers are hyaluronic acids, or hyaluronic acid salts, having different molecular masses. [000240] In one embodiment, said formulation further comprises at least one active ingredient selected from the group consisting of local anesthetics, vitamin C derivatives, anti-inflammatories, polyols, and mixtures thereof. [000241] In one embodiment, said formulation further comprises at least one local anesthetic. [000242] In one embodiment, the mass percentage of said at least one local anesthetic is between 0.1 and 5%, relative to the total mass of said formulation. [000243] In one embodiment, the mass percentage of said at least one local anesthetic is between 0.1 and 4%, relative to the total mass of said formulation. [000244] In one embodiment, the mass percentage of said at least one local anesthetic is between 0.1 and 2%, relative to the total mass of said formulation. [000245] In one embodiment, the mass percentage of said at least one local anesthetic is between 0.1 and 1%, relative to the total mass of said formulation. [000246] In one embodiment, the mass percentage of said at least one local anesthetic is between 0.1 and 0.5%, relative to the total mass of said formulation. [000247] In one embodiment, the mass percentage of said at least one local anesthetic is approximately 0.3%, relative to the total mass of said formulation. [000248] In one embodiment, said formulation further comprises at least one active ingredient. [000249] In one embodiment, said formulation further comprises at least one local anesthetic selected from the group consisting of lidocaine, meplvacaine, and mixtures thereof. [000250] In one embodiment, said local anesthetic is lidocaine. [000251] In one embodiment, said local anesthetic is lidocaine, the mass percentage of lidocaine being between 0.1 and 5%, relative to the total mass of said formulation. [000252] In one embodiment, said local anesthetic is lidocaine, the mass percentage of lidocaine being between 0.1 and 4%, relative to the total mass of said formulation. [000253] In one embodiment, said local anesthetic is lidocaine, the mass percentage of lidocaine being between 0.1 and 2%, relative to the total mass of said formulation. [000254] In one embodiment, said local anesthetic is lidocaine, the mass percentage of lidocaine being between 0.1 and 1%, relative to the total mass of said formulation. [000255] In one embodiment, said local anesthetic is Ildocaine, the mass percentage of Ildocaine being between 0.1 and 0.5%, relative to the total mass of said formulation. [000256] In one embodiment, said local anesthetic is mepivacaine. [000257] In one embodiment, said local anesthetic is mepivacaine, the mass percentage of mepivacaine being between 0.1 and 5%, relative to the total mass of said formulation. [000258] In one embodiment, said local anesthetic is mepivacaine, the mass percentage of mepivacaine being between 0.1 and 4%, relative to the total mass of said formulation. [000259] In one embodiment, said local anesthetic is mepivacaine, the mass percentage of mepivacaine being between 0.1 and 2%, relative to the total mass of said formulation. [000260] In one embodiment, said local anesthetic is mepivacaine, the mass percentage of mepivacaine being between 0.1 and 1%, relative to the total mass of said formulation. [000261] In one embodiment, said local anesthetic is mepivacaine, the mass percentage of mepivacaine being between 0.1 and 0.5%, relative to the total mass of said formulation. [000262] In one embodiment, said formulation further comprises at least one vitamin C derivative. [000263] In one embodiment, said at least one vitamin C derivative is chosen from the group consisting of ascorbyl phosphates (such as magnesium ascorbyl phosphate, sodium ascorbyl phosphate), ascorbyl glycosides (such as ascorbic acid-2-glucoside), and mixtures thereof. [000264] In one embodiment, said at least one vitamin C derivative is magnesium ascorbyl phosphate. [000265] In one embodiment, said formulation further comprises at least one anti-inflammatory. [000266] In one embodiment, said at least one anti-inflammatory is chosen from the group consisting of steroidal and non-steroidal anti-inflammatory drugs. [000267] In one embodiment, said at least one anti-inflammatory is chosen from the group consisting of steroidal anti-inflammatory drugs (such as, for example, dexamethasone, prednisolone, corticosterone, budesone, sulfasalazine, mesalamin, cetirizine, dlphenhydramine, antipyrine, methyl salicylate, loratadine, thymol, carvacrol, bisabolol, allantoin, eucalyptol, phenazone (antipyrine), propyphenazone) and non-steroidal anti-inflammatory drugs (such as, for example, ilbuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, diclofenac, nabumetone, piroxicam, meloxlcam, tenoxicam, droxicam, lomoxlcam, isoxlcam, mefenamic acid, adde medofenamic acid, flufenamic acid, tolfenamic acid, celecoxil, rofecoxil, valdecoxib, parecoxil, lumiracoxl, etoricoxil, flrocoxl, or sucrose octasulfate and / or its salts). [000268] In one embodiment, said at least one anti-inflammatory is chosen from the group consisting of sucrose octasulfate and its salts. [000269] In one embodiment, said at least one anti-inflammatory is chosen from the group consisting of sucrose octasulfate and its sodium and potassium salts. [000270] In one embodiment, said water-soluble salt of sucrose octasulfate is chosen from the group consisting of alkali metal salts, alkaline earth metal salts, silver salts, ammonium salts, amino acid salts. [000271] In one embodiment, said water-soluble salt of sucrose octasulfate is chosen from the group consisting of alkali metal salts or alkaline earth metal salts. [000272] In one embodiment, said water-soluble salt of sucrose octasulfate is the sodium salt of sucrose octasulfate or the potassium salt of sucrose octasulfate. [000273] In one embodiment, said formulation further comprises at least one polyol. [000274] In one embodiment, said formulation further comprises at least one polyol selected from the group consisting of mannitol, sorbitol, glycerol, maltitol, lactitol and erythritol. [000275] In one embodiment, said formulation further comprises at least one polyol selected from the group consisting of mannitol, sorbitol and glycerol. [000276] In one embodiment, said formulation further comprises at least mannitol. [000277] In one embodiment, the mass percentage of said polyol being between 0.1 mg / ml and 50 mg / ml, relative to the total mass of said formulation. [000278] In one embodiment, the mass percentage of said polyol being between 5 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000279] In one embodiment, the mass percentage of said polyol being between 10 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000280] In one embodiment, the mass percentage of said polyol being between 20 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000281] In one embodiment, the mass percentage of said polyol being between 30 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000282] In one embodiment, said formulation further comprises at least mannitol, the mass percentage of said mannitol being between 0.1 mg / ml and 50 mg / ml, relative to the total mass of said formulation. [000283] In one embodiment, said formulation further comprises at least mannitol, the mass percentage of said mannitol being between 5 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000284] In one embodiment, said formulation further comprises at least mannitol, the mass percentage of said mannitol being between 10 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000285] In one embodiment, said formulation further comprises at least mannitol, the mass percentage of said mannitol being between 20 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000286] In one embodiment, said formulation further comprises at least mannitol, the mass percentage of said mannitol being between 30 mg / ml and 40 mg / ml, relative to the total mass of said formulation. [000287] The formulations obtained by the process which is the subject of the invention have numerous applications. [000288] Medical applications include, for example, injections to replace deficient biological fluids, such as synovial fluid in joints, injections following surgery to prevent peritoneal adhesions, periurethral injections to treat incontinence, and injections following presbyopia surgery. Aesthetic applications include, for example, injections to fill wrinkles, fine lines, and skin imperfections, or to augment volume, such as that of the lips, cheekbones, etc. [000289] The applications targeted are more particularly those commonly used in the context of injectable viscoelastics and polysaccharides used or potentially usable in the following pathologies or treatments: - Aesthetic injections on the face: for filling wrinkles, skin defects or adding volume (cheekbones, chin, lips); - Volumetric injections to the body: breast and buttock augmentation, G-spot augmentation, vaginoplasty, vaginal lip reconstruction, penis enlargement; - in joint surgery and in dental surgery for filling periodontal pockets for example. - treatment of osteoarthritis, Injection into the joint as a replacement or supplement to deficient synovial fluid; - Peri-urethral injection for the treatment of urinary incontinence due to sphincter insufficiency; - Post-surgical injection to prevent peritoneal adhesions in particular; - Injection following presbyopia surgery by sternal laser incisions; - Injection into the vitreous cavity; - Injection during cataract surgery; - Injection for the treatment of cases of vaginal dryness; - Injection into the genitals. [000290] More specifically, in cosmetic surgery, depending on its viscoelastic and residual properties, the formulations obtained by the process that is the subject of the Invention may be used: - for filling fine, medium or deep wrinkles, and to be injected with fine diameter needles (27 Gauge for example); - as a volumizer with injection using larger diameter needles, for example 22 to 26 gauge, and longer (30 to 40 mm for example); in this case, its cohesive nature will ensure that it stays in place at the injection site. [000291] These examples of use are in no way limiting, and the formulations obtained according to the process that is the subject of the Invention are more broadly intended for: - to fill volumes; - to generate spaces within certain tissues, thereby promoting their optimal functioning; - to replace deficient physiological fluids. [000292] The following embodiments are applicable to the polymer crosslinking process according to the invention, to the process of preparing a formulation comprising a polymer obtained by the process according to the invention, to the formulation according to the invention, as well as to the various uses of said formulation. [000293] In one embodiment, said polymer is chosen from the group of polysaccharides. [000294] In one embodiment, said polymer is chosen from the glycosaminoglycan (GAG) group. [000295] In one embodiment, said polymer is chosen from the group of glycosaminoglycans (GAGs), such as chondroitin, keratan, heparin, iTieparosan or hyaluronic acid, and mixtures thereof. [000296] In one embodiment, said polymer is chosen from the group consisting of hyaluronic acid, keratin, heparin, cellulose, cellulose derivatives, alginic acid, xanthan gum, carrageenan, chlorosan, chondroitin, heparosan and their biologically acceptable salts, alone or in mixture. [000297] In one embodiment, said polymer is hyaluronic acid, or one of its biologically acceptable salts, alone or in mixture. [000298] In the context of this application, hyaluronic acid, or one of its biologically acceptable salts, alone or in mixture, are preferred. [000299] In one embodiment, said polymer is chosen from the group consisting of hyaluronic acid, sodium hyaluronate, and mixtures thereof. [000300] In one embodiment, said polymer is hyaluronic acid. [000301] In one embodiment, said polymer is chosen from the group consisting of sodium hyaluronate and potassium hyaluronate. [000302] In one embodiment, said polymer is sodium hyaluronate. [000303] In the context of this application, sodium hyaluronate is the particularly preferred polymer. [000304] In one embodiment, said polymer is hyaluronic acid, or one of its salts, chemically modified by substitution. [000305] In one embodiment, said polymer is a hyaluronic acid, or one of its salts, substituted by a group providing lipophilic or hydrating properties, such as substituted hyaluronic acids as described in patent application FR 2 983 483 in the name of the applicant. [000306] In the context of this application, Mw or "molecular mass" refers to the average molecular mass by weight of the polymers, measured in Daltons. [000307] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 0.01 MDa and 5 MDa. [000308] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 0.01 MDa and 3.5 MDa. [000309] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 0.5 MDa and 3.5 MDa. [000310] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 2.75 MDa and 3.25 MDa. [000311] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 0.75 MDa and 1.25 MDa. [000312] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 2 MDa and 5 MDa. [000313] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 2 MDa and 4 MDa. [000314] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 0.5 MDa and 2 MDa. [000315] In one embodiment, said hyaluronic acid or one of its salts has a molecular mass between 0.5 MDa and 1.5 MDa. [000316] In one embodiment, said at least one reducing agent is selected from the group consisting of ethylene glycol diglycidyl ether, butane diglycidyl ether (BDDE), polyglycerol polyglycidyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, a bis- or polyepoxy such as 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane, a dialkyl sulfone, divinyl sulfone, formaldehyde, epichlorohydrin or glutaraldehyde, carbodiimides such as, for example, 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), trimetaphosphates, such as, for example, sodium trimetaphosphate, calcium trimetaphosphate, or barium trimetaphosphate. [000317] In one embodiment, said at least one resolving agent is chosen from the group consisting of ethyleneglycoldiglycidyl ether, butanedioldiglycidyl ether (BDDE), polyglycerolpolyglycidyl ether, polyethyleneglycoldiglycidyl ether, polypropyleneglycoldiglycidyl ether, a bis- or polyepoxy such as 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane, trimetaphosphates, such as sodium trimetaphosphate, calcium trimetaphosphate, or barium trimetaphosphate. [000318] In one embodiment, said at least one reducing agent is chosen from the group consisting of ethyleneglycoldiglycidyl ether, butanedioldiglycidyl ether (BDDE), polyglycerolpolyglycidyl ether, polyethyleneglycoldiglycidyl ether, polypropyleneglycoldiglycidyl ether, a bis- or polyepoxy such as 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane. [000319] In one embodiment, said at least one reducing agent is chosen from the group consisting of trimetaphosphates, such as sodium trimetaphosphate, calcium trimetaphosphate, or barium trimetaphosphate. [000320] In one embodiment, said at least one crosslinking agent is chosen from the group consisting of epoxides, for example 1,4-butanedlol dlglycldyl ether (BDDE), epihalohydrins, divlnylsulfone (DVS). [000321] In one embodiment, said at least one crosslinking agent is divlnylsulfone (DVS). [000322] In one embodiment, said at least one crosslinking agent is 1,4-butanedlol dlglycldyl ether (BDDE). [000323] In the context of this application, the BDDE is particularly preferred. [000324] In one embodiment, the crosslinking ratio X is between 0.001 and 0.5. [000325] In one embodiment, the crosslinking ratio X is between 0.01 and 0.4. [000326] In one embodiment, the crosslinking ratio X is between 0.03 and 0.23. [000327] In one embodiment, the crosslinking ratio X is between 0.03 and 0.20. [000328] In one embodiment, the crosslinking ratio X is between 0.03 and 0.15. [000329] In one embodiment, the crosslinking ratio X is between 0.03 and 0.10. [000330] In one embodiment, the crosslinking ratio X is between 0.10 and 0.15. [000331] In one embodiment, the crosslinking ratio X is between 0.08 and 0.15. [000332] In one embodiment, the degree of modification of said crosslinked polymer is less than 5%. [000333] In one embodiment, the degree of modification of said crosslinked polymer is less than 4%. [000334] In one embodiment, the degree of modification of said crosslinked polymer is less than 3.5%. [000335] In one embodiment, the degree of modification of said crosslinked polymer is Less than 3%. [000336] In one embodiment, the degree of modification of said crosslinked polymer is less than 2.5%. Example· [000337] In the context of the examples, a number of parameters were measured. Determination of rheological parameters G', G” and Tan D (Tn B): [000338] TA Instruments DHR-2 apparatus. Cone-type geometry with a 2° angle and a diameter of 40mm. Frequency sweep method (logarlthmic sweep), strain of 0.8% (strain within the linear range), frequency range from 0.08 to 5 Hz, readings taken at a frequency of 1Hz. Determining the MoD: [000339] The proton NMR spectra are obtained on a 400 MHz spectrometer. The MoD value is calculated from the integrals of the N-acetyl signal group of hyaluronic acid and a BDDE signal (two -CH2- groups). The ratio of the integrals of these two signals (crosslinking agent / NAc HA) corresponds to the MoD. [000340] The Mod value (%) was determined by the method previously mentioned (hyaluronic acid crosslinked with BDDE), and using the formula also previously mentioned. Measure of injectability: [000341] Use of a tensile bench and a force sensor (N). The tensile bench applies a displacement speed to the syringe stem, the gel is expelled from the needle (27G1 / 2); the force in Newtons is recorded by the sensor during the ejection of the gel at a speed of 13mm / min. Evaluation of resistance to enzymatic degradation (hyaluronldaaes): [000342] A hyaluronidase solution (Sigma Aldrich H3506) (value see table 7 U / g in phosphate buffer) is prepared. This solution (20 mL) is mixed with 1 g of the gel to be tested, and the mixture is then maintained at 37°C for 5 to 10 minutes. [000343] The gel mixed with enzymes is then analyzed by rheology using TA Instrument DHR-2 equipment. Geometry with a 2° angle and a diameter of 40 mm. Frequency oscillation method (logarlthmic sweep), strain of 0.8%, temperature of 37°C, fixed frequency of 1 Hz applied. [000344] The analysis consists of monitoring the loss of G'(Pa) as a function of time. The time at which the initial G' of the formulation is halved corresponds to the half-life of the analyzed product. 35 Measurement of the plastic domain, rheological measurements in deformation: [000345] TA Instrument DHR-2 apparatus. Geometry with an angle of 2° and a diameter of 40mm. Strain scanning method: logarithmlc sweep, strain from 0.1 to 1000%, frequency of 1Hz. [000346] Observation of the plastic domain ranging from the deformation (in %) for which G' (Pa) drops by 10% compared to the Initial G'; up to the deformation (in %) of the crossing of G' and G". Example 1: Rheological properties of a formulation obtained in accordance with the process of the Invention. [000347] Example 1 illustrates the influence of implementing the process according to the invention on the properties (G', G" and Tan D (Tn 6), Mod) of the resulting formulation. In this example, the properties (G', G", Tan D (Tn d) and Mod) of a formulation obtained according to the process of the invention were compared with those of a formulation obtained using a commonly used crosslinking method (of the type described in application W02009071697). Formulation preparation process [000348] Each of the two formulations being compared is prepared according to the following process: [000349] Injectable grade sodium hyaluronate fibers (1 g; molecular weight: 3 MDa) are weighed into a container. A 1% aqueous solution of sodium hydroxide in water (7.4 g) is added, and the mixture is homogenized for approximately 1 hour with a spatula, at room temperature and 900 mm Hg. [000350] An appropriate amount of BDDE to obtain a crosslinking ratio X of about 0.14 is added to the uncrosslinked sodium hyaluronate gel obtained in the previous step, the whole being homogenized with a spatula for about 30 minutes at room temperature and at 900 mm Hg. [000351] The crosslinking conditions are as follows: - 3hl0 at 50°C for the prior art process (comparative); and - 23 to 26 hours at approximately 9°C for the process according to the invention. [000352] For each of the processes, the final crosslinked gel is then neutralized by adding HCl₂IN and placed in a phosphate buffer bath to stabilize the pH and allow its hydration, or swelling, up to a hyaluronic acid concentration of 30 mg / g. The gel is then dialyzed in a phosphate buffer bath until a hyaluronic acid concentration of 20.9 mg / g is obtained. The pH of the gels after this step corresponds to the pH of the buffer, approximately 7.2. The final gels are then homogenized, and measurements of parameters (G', G", Mod) are performed. [000353] In summary, the two processes compared differ only in the conditions of crosslinking temperature and crosslinking time. [000354] Properties of the formulations obtained (before sterilization) [000355] The results of the determination of the rheological parameters and the Mod are given in Table 1 below: [000356] It is noted that the formulations obtained using the process according to the invention have a G' (401 Pa) much higher than that of the compositions obtained using the prior art process (253 Pa). [000357] Also, the value of G" is more than three times greater in the process according to the present invention compared to the commonly used process. [000358] Finally, and very surprisingly, these improved rheological properties are obtained even though the Mod in % of the formulation prepared using the process according to the Invention is lower. Properties of the formulations obtained (after sterilization) [000359] Both formulations are sterilized by autoclaving (F0=44min), and a second measurement of the same parameters (G', G") is carried out. [000360] The results of the determination of the rheological parameters and the Mod are given in Table 2 below: [000361] It is noted that the G' of the formulation prepared with the process according to the invention (401 Pa / 153 Pa) is more affected by sterilization than the G' of the formulation prepared with the commonly used process (253 Pa / 159 Pa), the G' of the two formulations being similar after sterilization. [000362] It is noted that the G" of the formulation prepared with the process according to the Invention remains much higher than the G" of the formulation prepared with the process commonly used after sterilization. [000363] It follows from the above that the value of Tan D (tan 6) of the formulation prepared with the process according to the invention is doubled during sterilization (0.27 / 0.52), whereas the value of Tan D (tan 6) of the formulation prepared with the commonly used process is relatively little modified (0.13 / 0.17). [000364] In summary, the value of Tan D, already higher for the formulation prepared according to the invention before sterilization, is further increased during the sterilization step. [000365] The process according to the invention thus makes it possible to obtain formulations having very good rheological properties, while maintaining a relatively low Mod (%) (good crosslinking efficiency). In our example, the gel exhibits an equivalent stiffness G' and shows deformation (optimized damping); the gel is characterized as less brittle. Injectability of the formulation prepared according to the process of the invention [000366] The injectability of the formulation prepared according to the process of the invention was measured. [000367] An injection force of less than 35 N at 13 mm / min is observed after sterilization for the gel obtained by the commonly used process and for the process according to the Invention. This makes it possible to meet the applications targeted in this application. [000368] The formulation according to the Invention is therefore a formulation that can be described as injectable. Example 2: Rheological properties of a formulation obtained in accordance with the process which is the subject of the invention. [000369] The processes used in Example 2 are identical to those of Example 1, except that both formulations are based on hyaluronic acid with a weight average molecular mass of 0.9 MDa and have a crosslinking ratio X of approximately 0.09. [000370] The results of the determination of the rheological parameters and the Mod are given in Table 3 below: [000371] It is noted that the formulation obtained by means of the process according to the invention has a G' Lower than that of the formulation obtained according to the prior art process. [000372] The value of G" of the formulation obtained by means of the process which is the subject of the Invention is two times greater than that of the formulation obtained according to the commonly used process. [000373] It follows from the above that the value of Tan D 1Hz is optimized within the framework of the formulation obtained according to the process of the Invention. [000374] Here again, the formulation obtained by the process of the invention exhibits improved rheological properties, while having a relatively low Mod (%). Example 3: Rheological properties of a formulation obtained in accordance with the process which is the subject of the Invention. [000375] The two formulations prepared according to the commonly used processes of Examples 1 and 2 (before sterilization) are mixed in proportions 50 / 50. This results in a formulation comprising two previously cross-linked and mixed / interpenetrated formulations. [000376] The two formulations prepared according to the processes according to the invention of examples 1 and 2 (before sterilization) are also mixed in proportions 50 / 50. This results in a formulation comprising two previously cross-linked and mixed / interpenetrated formulations. [000377] The results of the determination of the rheological parameters and the Mod are given in Table 4 below: [000378] It is noted that the value of G' (358 Pa) of the formulation according to the Interpenetrated Invention is much closer to the high value (example 1; 401 Pa) than the low value (example 2; 198 Pa) of the formulations constituting it. [000379] It is also noted that the value of G" (119 Pa) of the formulation according to the invention is higher than each of the values ​​of the formulation constituting it (example 1, 107 Pa; example 2; 89 Pa). [000380] In summary, the rheological properties of the interpenetrated formulations prepared according to the process of the invention have particularly surprising and unexpected rheological characteristics. [000381] The formulation obtained according to the process according to the Invention was then sterilized (F0 = 14.5 minutes) and tested for its injectable quality. [000382] It has been shown that at a speed of 13 mm / min and at room temperature (Gauge 27 1 / z ), the injectability is less than 35N. The formulation obtained according to the process according to the invention is therefore perfectly injectable. Example 4: Implementation of the Invention on high-mass hyaluronic acids [000383] Injectable grade sodium hyaluronate fibers (lg; molecular weight: 3 MDa) are weighed into a container. A 1% aqueous solution of sodium hydroxide in water (7.4g) is added, and the mixture is homogenized for approximately 1 hour with a spatula, at room temperature and 900 mm Hg. [000384] An appropriate amount of BDDE to obtain a crosslinking ratio X of about 0.14 is added to the uncrosslinked sodium hyaluronate gel obtained in the previous step, the whole being homogenized with a spatula for about 30 minutes at room temperature and at 900 mm Hg. [000385] The crosslinking conditions for the four tests are as follows: 3hl0 at 50°C for the prior art process (comparative), - 24 hours at 9°C, - 24 hours at 2°C, 48 hours at 9°C for the process according to the invention. [000386] For each of the processes, the final crosslinked gel is then neutralized by adding HClIN and placed in a phosphate buffer bath to stabilize the pH and allow its hydration, or swelling, to a hyaluronic acid concentration of approximately 40 mg / g. The gel is then dialyzed in a phosphate buffer bath until a hyaluronic acid concentration of approximately 26 mg / g is obtained. The pH of the gels at the end of this step corresponds to the pH of the buffer, i.e., approximately 7.2. The final gels are then homogenized and sterilized by auto-dashing, and the following measurements are taken: G', G" ; for all reaction times and temperatures. MoD; for reaction times of 24 and 48h and a temperature of 9°C. Half-life time (resistance to hyaluronidase enzymes); for a reaction time of 48h and a temperature of 9°C. [000387] It is noted that the G' of the formulas with a reaction time of 24h are relatively close to the reference formula, while the Tan D (Tn 6) is optimized. [000388] It is observed that the more the reaction time and temperature increase (according to the invention) the closer the Tan D (Tn 6) gets to that of the commonly used process. [000389] Surprisingly, the 48h - 9°C process allows for both optimized G' and Tan D (Tn 6) values ​​and a reduction in MoD (%). The formula then provides optimized properties for a filling application (formula that is both more rigid and has better damping) and with improved block compatibility. [000390] The results in the table above are unexpected, since the MoD of the 48h - 9°C formulation is lower than the reference (commonly used process), the hyaluronic acid then has fewer crosslinking bridges and should exhibit less persistence. [000391] Surprisingly, the opposite is measured, the half-life times are indeed similar but for a higher enzyme concentration for the invention. [000392] In summary, the formula crosslinked for 48h at 9°C presents significant and surprising advantages such as good deformation capacity, retained rigidity as well as optimized block compactness and resistance to enzymatic degradation. Example 5; Implementation of the Invention on medium-mass hyaluronic acids [000393] The processes used in this example are identical to those of example 4, except that both formulations are based on hyaluronic acid with a weight average molecular mass of 0.9 MDa and have a crosslinking ratio X approximately equal to 0.09. [000394] The crosslinking conditions for the four tests are as follows: - 3hl0 at 50°C for the prior art process (comparative), 24 hours at 9°C, 24 hours at 2°C, 48 hours at 9°C for the process according to the invention. [000395] For each of the processes, the final crosslinked gel is then neutralized by the addition of HCl₂IN and placed in a phosphate buffer bath to stabilize the pH and allow its hydration, or swelling, to a hyaluronic acid concentration of approximately 40 mg / g. The gel is then dialyzed in a phosphate buffer bath until a hyaluronic acid concentration of approximately 26 mg / g is obtained. The pH of the gels after this step corresponds to the pH of the buffer, approximately 7.2. The final gels are then homogenized and analyzed in G' / G" for all reaction times. MoD measurements are also presented for reaction times of 24 and 48 hours and a temperature of 9°C. [000396] The formulations are then sterilized in the autoclave, and the measurements in G' / G" for all reaction times are carried out again. [000397] Before sterilization, we observe here again, an optimization of the G" and therefore of the Tan D (Tn d) thanks to the Invention. [000398] The strain sweep shown in Figure 2 (Strain sweep curves) also surprisingly demonstrates a highly optimized plastic domain for the 48h - 9°C formula. We can see from this curve that at equivalent G', the product obtained by the process according to the Invention has the widest plastic range. [000399] The MoD values ​​obtained are relatively low. Surprisingly, it is observed that the G' of the reference and the 48h - 9°C process are identical, while the MoD (%) of the invention is lower. A product with the same stiffness performance is obtained with less transformation of the hyaluronic acid. [000400] The 48h - 9°C formula is again very interesting and allows, for a relatively conserved G', to significantly improve the deformability of the product.

Claims

DEMANDS 1. A process for crosslinking a polymer, comprising at least the following steps: a) we have a polymer; b) we have a retracting agent; c) one or more crosslinking steps are carried out in the presence of said polymer and said crosslinking agent; d) a cross-linked polymer is obtained; characterized in that the crosslinking step or each of the crosslinking steps is carried out at constant temperature or at variable temperature in a linear or stepwise manner, said constant or variable temperature being less than or equal to 15°C and in that said crosslinking step c) has a duration of between 3 and 72 hours.

2. A polymer crosslinking method according to claim 1, characterized in that the crosslinking step or each of the crosslinking steps is carried out at a constant temperature.

3. A method for crosslinking a polymer according to any one of the preceding claims, characterized in that the crosslinked polymer obtained in step d) has a Tan D (Tn 6) ≥ 0.

25.

4. A method for crosslinking a polymer according to any one of the preceding claims, characterized in that the crosslinked polymer obtained in step d) has a G' ≤ 1000.

5. A method for crosslinking a polymer according to any one of the preceding claims, characterized in that said polymer is selected from the group of polysaccharides.

6. Method for preparing a formulation comprising at least one cross-linked polymer obtained according to the method of claims 1 to 4.

7. The process according to claim 5, said formulation comprising at least one polymer crosslinked according to the process of the invention, comprises a homogeneous mixture of Y identical or different crosslinked polymers, crosslinked prior to their Interpenetration by mixing, Y being between 2 and 5, characterized in that at least one of the Y polymers is crosslinked according to the process for preparing a crosslinked polymer according to the Invention.

8. A process according to claim 5 or 6, characterized in that said polymer is selected from the group of polysaccharides.

9. Formulation comprising at least one crosslinked polymer obtained according to the process of claims 1 to 4.

10. Formulation according to claim 8, characterized in that it further comprises at least one active ingredient selected from the group consisting of local anesthetics, vitamin C derivatives, anti-inflammatories, polyols, and mixtures thereof.

11. Polymer characterized in that it has a G' ≤ 1000 Pa and a tan D (Tn 6) whose value is between 0.25 and 1 (0.25 ≤ Tan D (Tn d)) ≤ 1).

12. Polymer according to claim 11, characterized in that it is selected from the group of polysaccharides.

13. Polymer according to any one of claims 11 or 12 characterized in that it is composed of a mixture of hyaluronic acids, or of salts of hyaluronic acids.