PROCESS FOR PREPARING A CROSSLINKED COPOLYMER AND ITS USE AS A POROUS MATERIAL

Abstract

The present invention relates to a method for manufacturing a crosslinked copolymer from at least one CO2-charged polyamine and at least one polyelectrophilic monomer. The present invention also relates to a porous material consisting of the crosslinked copolymer obtainable or obtainable by the claimed method, and its use in various applications, and in particular as a tissue adhesive foam. Abstract figure: Figure 2

Description

Title of the invention: PROCESS FOR PREPARING A CROSSLINKED COPOLYMER AND ITS USE AS A POROUS MATERIAL TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a method for manufacturing a crosslinked copolymer as well as a porous material consisting of the crosslinked copolymer obtained by the method of the invention and its uses. STATE OF THE ART

[0002] Biocompatible adhesives can be used in a variety of applications, ranging from surgery to food packaging to medical devices such as wound dressings.

[0003] Surgical operations involve the use of invasive techniques such as sutures, clips, staples to close tissues and contain any bleeding resulting from the operation. These invasive techniques can cause tissue damage, infection, scarring and / or additional bleeding.

[0004] To avoid such complications, it is increasingly common to use tissue adhesives to close tissues after surgery. These tissue adhesives have the advantage of being easy to apply, more flexible, inexpensive and less likely to cause damage than the aforementioned techniques.

[0005] Currently, tissue adhesives validated by European and American regulatory bodies are classified into two categories:

[0006] - adhesives obtained by a so-called “top-down” approach, from biomacro molecules derived from biological extracts (animal, plant, microbial). These macromolecules, such as collagen, albumin, and fibrin, can be postfunctionalized and co-formulated. Fibrin-based tissue adhesives are widely used, particularly to control post-surgical bleeding (Beudert et al. ACS Biomater. Sci. Eng. 2022, 8, 2220-2231). These adhesives are biocompatible, biodegradable, and do not cause tissue necrosis or inflammation. However, since fibrin is an animal protein, there is a significant risk of viral transmission with these adhesives. In addition, they can degrade too quickly and have poor adhesion capabilities, limiting their use in the human body. This top-down approach is also limited by the high cost of the raw material.

[0007] - adhesives obtained by a so-called “bottom-up” approach, from monomers from fossil resources and impacting inputs, which are polymerized and then eventually tually post-functionalized by traditional chemical routes, leading to a product with low biocompatibility (Pascual, G. et al. PLOS ONE 11, e0157920 (2016)). Tissue adhesives based on polyurethane, particularly thermoplastic polyurethane (TPU), have been developed with improved adhesion to muscle tissue and skin (Mouren, A. and Avérous, L. Chem. Soc. Rev. 2023, 52, 277). These adhesives can notably be in the form of foam. However, it is necessary to couple the TPU with other elements (xylose, rosin, hydroxyapatite nanocrystals) to obtain the desired adhesive performance (Bhagat et al. Biomacromolecules, 2017, 18, 3009-3039). These synthetic materials are petroleum-based, poorly biodegradable and poorly biocompatible. In addition, they present risks of tissue inflammation.

[0008] Other types of bottom-up adhesives are cyanoacrylate-based and provide strong and long-lasting adhesion. In addition, they have inherent bactericidal properties. However, because cyanoacrylate degradation products are toxic, these adhesives are limited to topical application (Bhagat et al. Biomacromolecules, 2017, 18, 3009-3039). These adhesives also have the disadvantages of being non-biosourced and non-biodegradable.

[0009] Recently, adhesive hydrogels based on supramolecular interactions have been described (Zhao et al. Chem. Rev. 2022, 122, 5604-5640). Such dynamic interactions make it possible to adapt to the complexity and diversity of biological tissues. These hydrogels are particularly interesting due to their ability to adhere in a humid environment and their "bottom-up" approach using bio-sourced molecules. These materials also have the ability to encapsulate and deliver therapeutic substances. A progressive release of these substances makes it possible to reduce the quantity of active molecules administered during treatment and allows continuous care, greatly improving the effectiveness of treatments compared to conventional methods. However, their use is still limited by the biocompatibility of these new biopolymers, as well as their biodegradability.For example, catechol-based adhesive hydrogels generate rH2O2, a by-product that is lethal to cells. They may also include metal ions as a complexing agent, which can induce high toxicity. A simple-to-produce supramolecular hydrogel would address most of the above-mentioned issues.

[0010] Many other biocompatible adhesives have been tested in recent years (based on polysaccharides, PEG, peptides, etc.) without, however, providing satisfactory performance in terms of strength and speed of adhesion, degradability, stability and ease of implementation. Adhesion in a humid environment in particular represents a real challenge.

[0011] Transdermal patches (TDDS) or "patches" adhere and deliver the substance therapeutic through a layer of pressure-sensitive adhesives (PSAs). Among commercial PSAs, those based on poly(isobutylene) (PIB) (Estraderm®) are suitable for the delivery of low-polar therapeutic molecules. PIBs have low adhesiveness and also a low free volume, limiting the diffusion of target molecules (Benedek et al. Marcel Dekker, 1997). These polymers are also petroleum-based.

[0012] Silicone-based APS (Neupro®), in particular a mixture of poly(dimethylsiloxane) and silicate resin, are biocompatible, easy to produce and have high diffusivity. However, the majority of therapeutic molecules are insoluble in this type of APS (Pfister et al. Pharm. Technol. 1992, 16, 42-58). Silicones are petroleum-based and therefore find limited use in the context of sustainable development.

[0013] Another type of commercial APS used in TDDS is made of poly(acrylate) (BuTrans®). This family of APS is biocompatible, has good adhesion and diffusion properties and a wide range of compatibility with excipients or therapeutic molecules. However, the release of the monomers used as well as the detachment of the TDDS can lead to skin irritation (Lobo et al. Therapeutic Delivery, 2016, 7(1), 33-48).

[0014] A bio-sourced APS, capable of adhering to the skin and delivering therapeutic substances, without tissue irritation, is therefore sought in the context of TDDS.

[0015] Flexible multi-layer packaging materials represent 10% of plastic packaging. Their properties allow a 10% lower carbon footprint compared to food packaging products (Bauer et al. Foods. 2021, 10, 2702-2719). Multi-layer packaging materials are mainly produced by co-extrusion, lamination or coating.

[0016] The different layers are linked either by binder layers, generally poly(ethylene) polymers or copolymers grafted with maleic anhydrides, acid, ester or alcohol functions (Maes et al. Polymer Reviews, 2018, 58(2), 209-246), or by adhesives such as ethylene vinyl acetate, poly(urethane), acrylates or poly(vinyl alcohols) (Aznar et al. Journal of Materials Chemistry, 2011, 21(12), 4358-4370). The difficulty of separating the different layers and the thermal incompatibility of the polymers used make flexible multilayer packaging materials considered non-recyclable.

[0017] A solution to increase recyclability and maintain the barrier and mechanical properties of the material would be to integrate a reversible and bio-sourced glue between the different layers, simplifying their separation, and therefore their recycling (Anukiruthika et al. Comprehensive Reviews in Food Science and Food Safety. 2020, 19(3), 1156-1186).

[0018] A need therefore remains for the provision of a biocompatible material, preferably biosourced, having adhesive properties, which can thus be useful in various applications, in particular as a tissue adhesive for surgery, as a pressure-sensitive adhesive or as a glue for recyclable food packaging, which makes it possible to overcome the aforementioned drawbacks and which is obtained by a process which is easy to implement. Summary of the invention

[0019] The invention relates to a method for manufacturing a crosslinked copolymer comprising the following steps:

[0020] a) Supply:

[0021] - of a polyelectrophilic monomer, and

[0022] - of a polyamine loaded with CO2 obtained by reaction between a gaseous mixture comprising CO2 and a polyamine of formula (I):

[0023] [Chem.l] R2 N - '« '[' R3 R (I)

[0024] in which

[0025] R1, R2, R3 and R4 are independently hydrogen or C1-C6 alkyl,

[0026] R is a hydrogen atom or a carboxylic acid function,

[0027] m is 1, 2, 3, 4, 5, 6, 7 or 8, and

[0028] n is 0, 1, 2, 3, 4 or 5,

[0029] b) Reaction between the CO2-charged polyamine and the polyelectrophilic monomer provided in step a), preferably at a temperature below 70°C, preferably in an aqueous medium, leading to the formation of the crosslinked copolymer.

[0030] The present invention also relates to a porous material consisting of a crosslinked copolymer obtained or capable of being obtained by the process according to the invention.

[0031] The present invention also relates to the use of such a porous material as a tissue adhesive.

[0032] Finally, the present invention relates to an article comprising such a porous material. Other aspects of the invention are as described below. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0033] The term “biocompatible” designates a material which does not produce undesirable effects when it is in contact with a living system, in particular with a human being.

[0034] The term "foam" refers to any material in which gas in the form of gas bubbles is dispersed forming pores. The average pore diameter is generally greater than 10 μm, typically determined by X-ray tomography on a GE Phoenix vltomelx s240 tomography device with a Varian Paxscan detector.

[0035] The term "carbamate function" is understood in the present description as the carbamate anion of formula - O or O . It is understood that the carbamate anion XS J. A N' 'O 'N' "O" H j represented in its charged form in the present description, is associated with a positively charged counterion, for example a metallic counterion, preferably chosen from lithium (Li+), sodium (Na+), magnesium (Mg2+), calcium (Ca2+) and potassium (K+) ions, or an ammonium ion as defined below, although this counterion is not systematically represented.

[0036] The terms “ammonium bicarbonate function” designate a functional group of formula v H .. HC(X, .HC0 “ or .HCO;.

[0037] The term "copolymer" designates a polymer comprising at least two different repeating units. A repeating unit corresponds to a group of atoms repeated several times in the polymer in order to form a polymer chain.

[0038] The term "alternating copolymer" refers to a copolymer whose different repeating units systematically alternate with each other so that one repeating unit is never linked to another identical repeating unit. For example, an alternating copolymer comprising repeating units A and B will have the following structure: AB AB AB AB AB AB AB AB AB.

[0039] The terms “alternating crosslinked copolymer” designate an alternating copolymer as defined above comprising crosslinking points between the chains of the copolymer so as to form a three-dimensional network. These crosslinking points may be covalent and optionally non-covalent bonds, for example hydrogen bonds, ji-ji interactions, Vander Vaals bonds, dipole-dipole interactions or ionic interactions.

[0040] The term “diamino acid” designates an amino acid comprising two amine functions and at least one carboxylic acid function.

[0041] In the present description, the “carboxylic acid” functions are equivalently represented in their neutral form -COOH, in their charged form -COO or in their charged form in the presence of a metal counterion -C00M, M being an alkali metal preferably chosen from lithium (Li), sodium (Na), magnesium (Mg), calcium (Ca) and potassium (K).

[0042] An “ammonium function” corresponds to an amine function, primary, secondary, or tertiary, positively charged. The ammonium function can for example be of formula

[0043] -NH2+-, -NH3+, -NHRa+-, -NH2Ra+, -N(Ra)2+- or -NH(Ra)2+, Ra being a group C1-C6 alkyl. Process for manufacturing a crosslinked copolymer

[0044] The inventors have developed a process for obtaining a porous polymeric material meeting the needs expressed in terms of biocompatibility, biodegradability and adhesiveness. The process uses biosourced materials and is carried out under very mild solvent and temperature conditions. Indeed, the polyelectrophilic monomer and the polyamine of formula (I) are mainly biosourced.

[0045] The process for manufacturing a crosslinked copolymer thus comprises the reaction between a polyamine charged with CO2 and a polyelectrophilic monomer, preferably at a temperature below 70°C, preferably in an aqueous medium, leading to the formation of the crosslinked copolymer.

[0046] The reagents and the method are as described below. CO2-charged polyamine

[0047] The CO2-charged polyamine useful in the context of the process of the invention is obtained by reaction between a gaseous mixture comprising CO2 and a polyamine of formula (I):

[0048] [Chem.2] R2 ,-Nk . N 1 n ï R3 R (I) in which R1, R2, R3 and R4 are independently hydrogen or C1-C6 alkyl, R is hydrogen or a carboxylic acid function, m is 1, 2, 3, 4, 5, 6, 7 or 8, and n is 0, 1, 2, 3, 4 or 5. This reaction involves at least one amine function of the polyamine of formula (I) reacting with a CO2 molecule and transforming into an ammonium bicarbonate function or a carbamate function. In preferred embodiments, each of the amine functions of the polyamine of formula (I) transforms into an ammonium bicarbonate function or a carbamate function during the reaction, it being understood that only the primary and secondary amine functions can transform into a carbamate function.

[0049] Thus, the CO2-charged polyamine provided in step a) is typically of the following formula (II):

[0050] [Chem.3] R'? s A .Xk Y -rô-fy R (II)

[0051] in which

[0052] X represents an NR2a group or an ammonium group NHR2a+,

[0053] Y represents an NR3a group or an ammonium group NHR3a+,

[0054] R1 and R4 are independently a hydrogen atom or a C1-C6 alkyl,

[0055] R2a and R3a are independently a hydrogen atom, a C1-C6 alkyl or a carboxylic acid function,

[0056] R is a hydrogen atom or a carboxylic acid function,

[0057] m is 1, 2, 3, 4, 5, 6, 7 or 8, and

[0058] n is 0, 1, 2, 3, 4 or 5.

[0059] It is understood that the CO2-charged polyamine of formula (II) may carry one or more positive charge(s) via the presence of one or more ammonium functions and / or one or more negative charges via the presence of one or more carbamate functions. Although not systematically represented, each of these charged functions is associated with a counterion so that the CO2-charged polyamines are electrically neutral. Thus, an ammonium function is in particular associated with a bicarbonate anion of formula HCO3 or with a carbamate function, for example carried by another CO2-charged polyamine molecule. In the same way, a carbamate function present on the molecule is associated with a metal cation or with an ammonium function, for example carried by another CO2-charged polyamine molecule.

[0060] In certain preferred embodiments, m is 1 or 2, especially 1.

[0061] When R1 and / or R4 is a C1-C6 alkyl, it is preferably a methyl, an ethyl or a propyl, in particular a methyl.

[0062] The polyamine of formula (I) is preferably chosen from the following polyamines:

[0063] [Chem. 4] CO:;M CO2M COaM CO2M A A. A NHï A ' 2 H2N NH2 Pib Pic Pld p-je H X . H P2b P2c P2d P2e P3a P3b P2f P2g

[0064]

[0065]

[0066] M being an alkali metal preferably chosen from lithium (Li), sodium (Na), magnesium (Mg), calcium (Ca) and potassium (K). In certain preferred embodiments, the polyamine of formula (I) is a diamino acid, for example selected from the compounds Pib, Pic, Pld and Pie represented above. In certain particularly preferred embodiments, the CO2-charged polyamine of formula (II) corresponds to one of the following formulas: [Chem. 5] O . O' CUOW CGOM (D3) and A^A COOM (D4),

[0067] in which M is as defined above, n is as defined above, x is equal to 2 or 3, y is equal to x-2, it being understood that each polyamine is associated with an adequate counterion if necessary to be electrically neutral. More preferably, the polyamine of formula (I) is a lysine (Pie compound). The lysine used is in particular derived from biological fermentation, therefore entirely biosourced. The reaction between a gas mixture comprising CO2 and lysine then leads to a lysine loaded with CO2 corresponding to one or more of the following formulas:

[0068] [Chem.6] A O M ° V'" "x . :> H ° (L1X O O" OA Q TO .-V TO O TO. M 'VN "OMA AHA û (L3) and O Q 6 Ai H ,Ô.....À , •. „.,x M' ' y - A Oh (L4), in which A is an NH2 or NH3+ group, M is an alkali metal preferably chosen from lithium (Li), sodium (Na), magnesium (Mg), calcium (Ca) and potassium (K),

[0069] it being understood that each polyamine is associated with an adequate counterion if necessary to be electrically neutral.

[0070] The different forms of the CO2-charged polyamine of formula (II) are generally found as a mixture in the reaction medium resulting from step a) and can exchange with each other (the CO2-charged polyamines of formula (II) can pass from one form to the other). For example, when the polyamine of formula (I) is lysine, the reaction medium resulting from step a) comprises as a mixture the different forms L1 to L4 as described above.

[0071] The CO2-charged polyamine useful in the context of the process of the invention can be obtained by reaction between a gaseous mixture comprising CO2 and a polyamine of formula (I) according to the following steps:

[0072] i) dissolving a polyamine of formula (I) in a suitable solvent leading to the production of a solution of polyamine of formula (I),

[0073] ii) bubbling a gas mixture comprising CO2 into the polyamine solution of formula (I),

[0074] iii) recovery of the corresponding CO2-loaded polyamine.

[0075] Step iii) includes for example the precipitation of the CO2-loaded polyamine, its filtration and its possible washing. Alternatively, the CO2-loaded polyamine can be recovered in the form of a solution of said polyamine in the solvent of step i).

[0076] The gas mixture comprising CO2 may consist of CO2.

[0077] The CO2-loaded polyamine can be in the form of a powder or a solution. Polyelectrophilic monomer

[0078] The polyelectrophilic monomer is for example chosen from ethylene diacrylate glycol, poly(ethylene glycol) diacrylate having a number-average molar mass Mn ranging from 250 to 6000 g / mol, poly(ethylene glycol) dimethacrylate having a number-average molar mass Mn ranging from 250 to 6000 g / mol ethylene glycol dimethacrylate, ethoxylated glycerol triacrylate, poly(ethoxylated glycerol triacrylate), ethoxylated glycerol trime-thacrylate, poly(ethoxylated glycerol trimethacrylate), poly(propoxylated glycerol triacrylate), poly(propoxylated glycerol trimethacrylate), isopropoxylated glycerol triacrylate, isopropoxylated glycerol trimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, vanillin diacrylate and vanillin dimethacrylate.

[0079] The polyelectrophilic monomer is preferably bio-sourced. For example, glycerol is obtained from triglycerides, animal fats or vegetable oils. Ethylene glycol can be produced by pyrolysis and then hydrogenation of sugars. Acrylic acid can be obtained from glycerol, malonyl-Coa or [3-Alanine.

[0080] The reaction between the CO2-charged polyamine (polynucleophilic species) and the polyelectrophilic monomer leads to the formation of a crosslinked copolymer. This reaction is a copolymerization.

[0081] Advantageously, the reaction between the CO2-charged polyamine and the polyelectrophilic monomer is carried out in water.

[0082] The reaction is preferably carried out at a temperature below 70°C, for example from 25°C to 40°C.

[0083] Preferably, the polyamine is a polynucleophilic species and the monomer with which it reacts during step b) is a polyelectrophilic monomer.

[0084] In a particular embodiment, the CO2-charged polyamine is a CO2-charged lysine and the polyelectrophilic monomer is ethylene glycol diacrylate.

[0085] Advantageously, at least a portion of the ammonium bicarbonate and carbamate functions of the polyamine loaded with CO2, during step b) of the process according to the invention, are converted into gaseous CO2 and into free amine by contact with the polyelectrophilic monomer. The gradual release of gaseous CO2 allows the continuous diffusion of the pore-forming agent. The release of the amine linked to the gradual release of gaseous CO2 allows controlled polymerization leading to the production of an alternating crosslinked copolymer.

[0086] However, the ammonium carbamate functions of the CO2-charged polyamine, which are more thermally stable than the bicarbonate functions, can remain present on the crosslinked copolymer, giving it unprecedented physical properties in terms of adhesiveness, hydrophilicity and polarity.

[0087] The process according to the invention makes it possible to manufacture crosslinked copolymers, in particular porous materials made of such crosslinked polymers, without ca talysers and without injection of gas or exogenous pore-forming agents during the polymerization process.

[0088] The copolymer obtained, due to its crosslinked appearance, has a homogeneous three-dimensional porous structure with open pores. Porous materials

[0089] The invention relates to a porous material consisting of a crosslinked copolymer capable of being obtained or obtained according to the process of the invention.

[0090] Due to the choice of its components, the porous material of the invention is biocompatible and / or biosourced.

[0091] The porous material of the invention typically has:

[0092] - an adhesion force on a surface ranging from 0.5 N to 10 N according to the method of tensile adhesion measurement. The measurement is carried out with a MARS 60 rheometer, with a Peltier furnace and parallel plane geometries of 8 mm diameter. A displacement speed of 6 mm / min and temperatures between 250C and 40°C are used;

[0093] - an HLB value ranging from 10 to 18 according to the Davies and Griffin method;

[0094] - an apparent density (pa) ranging from 400 to 900 kg / m3, typically calculated from the equation below where m; is the initial mass of the crosslinked copolymer, r is its radius and h is its height (when the copolymer is in a cylindrical shape). The dimensions of the copolymer are typically measured using a digital caliper,

[0095] [Math.l] Pq = ----7--T JH' * î * M

[0096] - a volume swelling index (Q) ranging from 50% to 600%. The index of Volumetric swelling is typically measured by cutting the crosslinked copolymer into three pieces at its core. The dimensions of these pieces are typically measured using a digital caliper, and then the pieces are placed in enough CH2Cl2 to be completely submerged. The medium is then stirred for 24 hours. The swelling index is calculated from the equation below, where Vf is the volume of the copolymer after 24 hours in CH2Cl2 and V; is the initial volume of the crosslinked copolymer;

[0097] [Math.2] the A Q = 100

[0098] - an average pore diameter ranging from 50 qm to 1 mm. The average pore diameter is typically determined by X-ray tomography on a tomographic device GE Phoenix vltomelx s with a Varian Paxscan detector. Acquisition is performed with a polychromatic source operating at 280 keV and with a voxel size of 10 qm3. Image processing is performed using Fiji software; and / or

[0099] - a mass degradation temperature at 10% mass (Tdi0%) ranging from 150°C to 400°C. The mass degradation temperature at 10% by mass is typically measured by thermogravimetric analysis (TGA) on a Mettler Toledo 2 TGA device, with a heating ramp of 10°C / min, from 25°C to 600°C under nitrogen flow.

[0100] The material of the invention can be depolymerized and is therefore useful as a recyclable material. Use of porous materials

[0101] The porous material of the invention, that is to say the crosslinked copolymer capable of being obtained or obtained according to the method of the invention, is in the form of a foam. It is in particular a biocompatible adhesive foam. Biocompatible adhesive foams are particularly useful for reconstructive surgery, for example post-ablation and / or pre-implant reconstructive surgery.

[0102] The porous material of the invention can also be used for the manufacture of orthoses, prostheses and medical devices. In particular, the porous material of the invention can be used for the manufacture of tissue adhesives, pressure-sensitive adhesives (PSAs) for example integrated into transdermal patches (TDDS) or patches.

[0103] The porous material of the invention can also be used as pharmaceutical and cosmetic excipients.

[0104] The porous material of the invention can further be used in fields other than the medical field, for example it can be useful for preparing food packaging, tissue glues and glues for multi-layer materials.

[0105] The invention also relates to any article comprising a porous material according to the invention, in particular chosen from a porous hydrogel, a colloidal polymer, a multi-layer food packaging and a transdermal patch. FIGURES

[0106] The invention will be described below with reference to the appended figures, given solely as non-limiting examples. Figures 1 to 3 illustrate certain aspects of the invention.

[0107] Figures 4 to 6 show a porous material according to the invention.

[0108] [Fig.lA] schematically represents the four stages of the synthesis of a lysine powder loaded with CO2, namely the dissolution of the lysine leading to the production of a lysine solution, the bubbling of CO2 into said lysine solution, the precipitation of the lysine loaded with CO2 and the filtration of the lysine loaded with CO2. [Fig.lB] schematically represents the two stages of the synthesis of a lysine solution loaded with CO2, namely the dissolution of the lysine leading to obtaining a lysine solution and the bubbling of CO2 into said lysine solution, leading to the lysine solution loaded with CO2.

[0109] [Fig.2] schematically represents the polymerization between a polyamine charged with CO2, here lysine charged with CO2, which is a dinucleophilic species, and ethylene glycol diacrylate, which is a dielectrophile monomer, leading to the production of an alternating copolymer forming a porous material according to the invention.

[0110] [Fig.3] is a photograph showing the porogenic effect of CO2 during the formation of the alternating copolymer, i.e. the porous material according to the invention during the polymerization between carbonated lysine and ethylene glycol diacrylate.

[0111] [Fig.4] is a photograph showing a macroscopic view of the porous material according to the invention obtained from lysine loaded with CO2 and ethylene glycol diacrylate.

[0112] [Fig.5] is a photograph showing a microscopic view (1 mm) of the porous material according to the invention obtained from lysine loaded with CO2 and ethylene glycol diacrylate. EXAMPLES

[0113] Example 1: synthesis of a crosslinked copolymer according to the invention

[0114] First step: synthesis of a lysine powder loaded with CO2

[0115] This synthesis is inspired by the synthesis described by J. Bru, (Bru, Jean. L-Lysine Carbamate. DE2951132A1, July 10, 1980)) and is based on the carba-matation (I) and / or carbonation (II) reactions of lysine below.

[0116] The synthesis of CO2-loaded lysine powder comprises four steps, namely the dissolution of lysine leading to obtaining a lysine solution (1)), bubbling CO2 into said lysine solution, precipitation of CO2-loaded lysine (2)) and filtration of CO2-loaded lysine according to the reaction scheme below and [Fig.lA]:

[0117] [Chem.7]

[0118] [Chem. 8] O

[0119] in which X is a carbamate function, a bicarbonate ion (HCO3) or a carboxylate ion, Y is a primary, secondary or tertiary ammonium or possibly a metal ion (Li+, Na+, K+, Mg2+, Ca2+).

[0120] Synthesis of CO^-loaded lysine in solid form

[0121] 10g of lysine.HCl were solubilized in 10 mL of H2O and 6.17 g of KOH. Then, 50 mL of methanol was added to the previously obtained lysine solution. Then, CO2 was bubbled into the solution using a strainer at a flow rate of 0.100 mVmin.

[0122] After 10 min, a precipitate formed and bubbling was maintained for at least 1 h.

[0123] The precipitate was then filtered and washed with a few milliliters of cold methanol, then the solid was dried under vacuum in order to evaporate the residual methanol.

[0124] A fine beige-colored powder was obtained.

[0125] The analysis of this fine powder was carried out by 13Cq NMR spectroscopy; this analysis confirmed the presence of CO2 in the medium in the form of hydrogen carbonate or ammonium carbamate for a loading rate (number of CO2 molecules captured per amine function) aN = 0.8. The loading rate is calculated according to the following equation:

[0126] aN =nC02 / (nAmine*NNHx)

[0127] in which nCO2 is the number of moles of CO2;

[0128] nAmine is the number of moles of amine and

[0129] NNHx is the number of NHx patterns.

[0130] The CO2-loaded lysine powder obtained according to the reaction presented above comprises, preferably consists of, a mixture of lysine having ammonium carbamate functions and ammonium bicarbonate functions. Synthesis of CO2-charged lysine in solution

[0131] In an alternative, the synthesis of the CO2-loaded lysine solution comprises two steps, namely the dissolution of the lysine leading to the production of a lysine solution and the bubbling of CO2 into said lysine solution, as illustrated in [Fig.lB]

[0132] 10g of lysine.HCl were solubilized in 10 mL of H2O and 6.17 g of KOH. Then, CO2 was bubbled into the solution using a strainer at a flow rate of 0.100 m3 / min. The reaction was monitored by pH measurement. When the pH was stable, bubbling was stopped and the CO2-charged lysine solution was obtained.

[0133] The analysis of this solution was carried out by 13C NMR spectroscopy; this analysis confirmed the presence of CO2 in the medium in the form of hydrogen carbonate or ammonium carbamate for a loading rate (number of CO2 molecules captured per amine function) aN = 0.8. The loading rate is calculated according to the following equation:

[0134] aN =nC02 / (nAmine*NNHx)

[0135] in which nCO2 is the number of moles of CO2;

[0136] nAmine is the number of moles of amine and

[0137] NNHx is the number of NHx motifs.

[0138] The CO2-charged lysine solution obtained according to the reaction presented above comprises a mixture of CO2-charged lysines randomly exhibiting ammonium carbamate functions and / or ammonium bicarbonate functions. Second step: Manufacture of the porous materials

[0139] The manufacture of the porous material is based on the polymerization reaction of glycol diacrylate with lysine (Lys) loaded with CO2 according to the reaction scheme below.

[0140] [Chem.9] O; <9 ■■ § WK! 4 -•'T'--. .x'x ----------------------l>ySx'x vO.. .Zx. -•■'A ■ ' '' OK * '' ol " H2O f" X MU Ô 25-73*0 I £ 7'® î ,xCO-< • ' l J .yCOj

[0141] K-Lysine solutions with a concentration defined between [0.5-2] mol / L as well as lysine solutions with a loading rate defined between aN =0 and aN =0.8 and a concentration between [1-5] mol / L were prepared.

[0142] An example of formulation comprises a quantity of K-Lysine of concentration 2 mol / L, equal to 2.2 mmol (1.1 mL), 2.2 mmol (0.4 mL) of K-Lysine loaded with CO2 of concentration 5 mol / L comprising an initial loading rate at aN = 0.4 as well as 5 g of poly(ethylene glycol) diacryalte (575 g / mol).

[0143] The resulting formulation was then vortexed for 10 seconds and a polyelectrophilic / polyamine emulsion was then produced. The emulsion was brought to 37°C in an oven without stirring. Gelling of the medium can be observed in 10 min, then a porous hydrogel / foam is produced and crosslinked in 3 to 4 hours.

Claims

Claims

1. A process for manufacturing a crosslinked copolymer comprising the following steps: a) Providing - a polyelectrophilic monomer, and - a CO2-charged polyamine obtained by reaction between a gas mixture comprising CO2 and a polyamine of formula (I): FF (I) N** yl^.^t R3 R in which R1, R2, R3 and R4 are independently a hydrogen atom or a C1-C6 alkyl, R is a hydrogen atom or a carboxylic acid function, m is 1, 2, 3, 4, 5, 6, 7 or 8, and n is 0, 1, 2, 3, 4 or 5, b) Reacting the CO2-charged polyamine and the polyelectrophilic monomer provided in step a), preferably at a temperature below 70°C, preferably in an aqueous medium, leading to the formation of the crosslinked copolymer.

2. A method of manufacturing a crosslinked copolymer according to claim 1 wherein the polyelectrophilic monomer is ethylene glycol diacrylate, poly(ethylene glycol) diacrylate having a number-average molar mass Mn ranging from 250 to 6000 g / mol, poly(ethylene glycol) dimethacrylate having a number-average molar mass Mn ranging from 250 to 6000 g / mol, ethylene glycol dimethacrylate, ethoxylated glycerol triacrylate, poly(ethoxylated glycerol triacrylate), ethoxylated glycerol trime-thacrylate, poly(ethoxylated glycerol trimethacrylate), poly(propoxylated glycerol triacrylate), poly(propoxylated glycerol trimethacrylate), isopropoxylated glycerol triacrylate, isopropoxylated glycerol trimethacrylate, pentaerythritol tetraacrylate, pentaerythritol tetramethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, vanillin diacrylate or vanillin dimethacrylate.

3. A process for manufacturing a crosslinked copolymer according to claim 1 or 2 in which the CO2-charged polyamine is of formula (II): R4VM .XL x (H) Yi-ny R in which X represents an NR2a group or an ammonium group NHR 2 <14- Y represents an NR3a group or an ammonium group NHR 3a+ ? R1 and R4 are independently a hydrogen atom or a C1-C6 alkyl, R2a and R3a are independently a hydrogen atom, a C1-C6 alkyl or a carboxylic acid function, R is a hydrogen atom or a carboxylic acid function, m is 1, 2, 3, 4, 5, 6, 7 or 8, and n is 0, 1, 2, 3, 4 or 5.

4. A method of manufacturing a crosslinked copolymer according to any one of claims 1 to 3, wherein the polyamine of formula (I) is selected from the following polyamines: ÇO2M CO2M COjM co2m Pib pic Md pie H HjN H2N NHj H2N^^ NH2 H,N * P2b P2c P2d P2e HN " N NH-, H2N - HH P3a P3b P2f P2g M being an alkali metal preferably selected from lithium (Li), sodium (Na), magnesium (Mg), calcium (Ca) and potassium (K).

5. A process for manufacturing a crosslinked copolymer according to any one of claims 1 to 4, wherein the CO2-charged polyamine of formula (II) corresponds to one of the following formulas: 9 .. <D1)’ y®fH ^(NHX) v®(D2), (HxN) " i -0 n « r COOM n COOM 'Y O f yY k ,nh - k-Afc.,--'-,. ,.nh (HXNL ' O N y COOM n COOM dans lesquelles n est tel que défini dans la revendication 1, M est un métal alcalin préférablement choisi parmi le lithium (Li), le sodium (Na), magnesium (Mg), calcium (Ca) and potassium (K),x is equal to 2 or 3, y is equal to x-2.

6. A method of manufacturing a crosslinked copolymer according to claim 5, in which the CO2-charged polyamine is a CO2-charged lysine corresponding to one or more of the following formulae: AO (L1), O (L2), o AA © © AM' V" ' 'N' 'O ■ O" NH 1 : : O A. MV ' A Ô O (L3) and A (L4), in ©A Av O' 'NH 0 MA ■ o, -AA © ô MY' ■ NO nho in which A is an NH2 or NH3+ group, M is an alkali metal preferably chosen from lithium (Li), sodium (Na) and potassium (K).

7. 7. Porous material comprising a crosslinked copolymer capable of being obtained or obtained by the process according to any one of claims 1 to 6.

8. 8. Use of a porous material according to claim 7, as tissue adhesive, pressure-sensitive adhesives (PSA) for example integrated into transdermal patches (TDDS) or patches, as pharmaceutical and cosmetic excipients or glues for multi-layer materials.

9. An article comprising a porous material as defined in claim 7.

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