Composite membrane with grafted polyhexamethylene biguanide

Abstract

This disclosure relates to a composite membrane comprising a porous support structure, a polyethyleneimine (PEI) layer coated on the support structure, and polyhexamethylene biguanide (PHMB) grafted onto the coating of the support structure. This disclosure also provides a method for producing the composite membrane. This disclosure further provides a filtration and / or diffusion apparatus comprising the composite membrane.

Description

Technical Field

[0001] This disclosure relates to a composite membrane comprising a porous support structure, a polyethyleneimine (PEI) layer coated on the support structure, and polyhexamethylene biguanide (PHMB) grafted onto the coating of the support structure. This disclosure also provides a method for producing the composite membrane. This disclosure further provides a filtration and / or diffusion apparatus comprising the composite membrane. Background of the Invention

[0003] Membrane fabrication processes are typically based on phase inversion processes. In this process, a polymer phase is induced to separate from the solution or molten state through interaction with a non-solvent or by lowering the temperature, thereby forming a membrane. Because phase inversion processes are kinetically controlled, there are limitations on the pore size achievable in a given polymer system, as well as on the chemical and physical properties of the membrane surface. This affects both the membrane's separation performance (separation via size exclusion) and its adsorption properties (chemical and physical interactions between the medium and the membrane surface).

[0004] Membranes can be modified post-production to adjust their surface properties. Post-functionalization methods allow for the addition of functionality to the membrane surface, and to some extent, to the inner surface of the pores.

[0005] Polyhexamethylene biguanide (PHMB), also known as polyhexamethylene biguanide (CAS number 28757-47-3), is a polymer used as a disinfectant and preservative. In most formulations, PHMB hydrochloride is used, CAS number 32289-58-0.

[0006] PHMB has been shown to be effective against Pseudomonas aeruginosa ( Pseudomonas aeruginosa Staphylococcus aureus Staphylococcus aureus ), Escherichia coli ( Escherichia coli Candida albicans Candida albicans ), Aspergillus brasiliensis ( Aspergillus brasiliensis ), Klebsiella pneumoniae ( Klebsiella pneumoniae It is effective against Enterococci and other bacteria.

[0007] Products containing PHMB are used for intraoperative irrigation, preoperative and postoperative skin and mucous membrane disinfection, postoperative dressings, surgical and non-surgical wound dressings, surgical baths / hydrotherapy, management of chronic wounds such as diabetic foot ulcers and burns, routine antiseptic treatment during small incisions, intubation, emergency care, surface disinfection, and sterilization of linen products.

[0008] PHMB eye drops have been used to treat Acanthamoeba ( Acanthamoeba PHMB is used to treat keratitis affecting the eyes. It is also used as an ingredient in certain contact lens cleaning products, cosmetics, personal deodorants, and some veterinary products.

[0009] US 2019 / 174749 A1 discloses methods and formulations for antimicrobial and antibiofouling coatings, the coating comprising: a hollow circular colloidal structure comprising: an active polymer shell; and an active or inert core; wherein the active polymer shell comprises one or more polymers selected from the group consisting of: polyethyleneimine (PEI), functionalized chitosan (CHI), polyquaternium salts, poly(diallyldimethylammonium chloride) (PDDA), and polyhexamethylene biguanide (PHMB); wherein the active or inert core contains one or more disinfectants, bactericides, fragrances, or inert solvents; and wherein the hollow circular colloidal structure is stable for at least 3 months.

[0010] EP 0 735 852 B1 discloses a liquid dispenser for dispensing sterile liquids and maintaining the sterility of the liquids after multiple doses. The dispenser consists of a container for storing the sterile liquid, a nozzle assembly mounted on the container, and an antimicrobial element coated with an antimicrobial material (e.g., a metallic or non-metallic antibacterial agent, an antiviral agent, or an antifungal agent, or a combination thereof). A method for manufacturing the device and the antimicrobial element is also disclosed.

[0011] US 2010 / 075131A1 discloses polyethyleneimine and polyalkylene biguanide ligand-functionalized substrates, methods for manufacturing ligand-functionalized substrates, and methods for using functionalized substrates. Summary of the Invention

[0012] This disclosure provides a composite membrane comprising a porous polymer support structure, a polyethyleneimine (PEI) layer coated on the support structure, and a polyhexamethylene biguanide (PHMB) coating grafted onto the support structure.

[0013] This disclosure also provides a method for producing the composite membrane and an apparatus comprising the composite membrane.

[0014] The composite membrane of this disclosure exhibits improved endotoxin retention when used for liquid filtration, even when the liquid contains relatively high concentrations of salt and / or sugar (as in dialysates, particularly PD solutions). In prior art membranes, when filtering liquids containing relatively high concentrations of salt and / or sugar, while bacterial retention remains largely unaffected, endotoxin retention rapidly decreases. In contrast, the composite membrane of this disclosure retains its endotoxin retention capacity. This is presumably due to the steric hindrance effect of the covalently bonded PEI and PHMB moieties, which allows their functional groups to interact with micellar endotoxin aggregates. Detailed Implementation

[0015] The composite membrane disclosed herein comprises i) a porous polymer support structure, ii) a polyethyleneimine (PEI) layer coated on the support structure i), and iii) a polyhexamethylene biguanide (PHMB) grafted onto the coating ii) of the support structure.

[0016] The porous polymer support structure i) can have any suitable geometry as required for the intended use; for example, it can take the form of a flat sheet, hollow fiber, or be molded to form a chamber or other desired geometry. In one embodiment of the invention, the porous polymer support structure is a hollow fiber membrane. In another embodiment of the invention, the porous polymer support structure is a flat sheet membrane.

[0017] The porous structure and pore size of the porous polymer support structure can also vary within a wide range. In one embodiment, the support structure has a layered configuration. In another embodiment, the support structure forms a three-dimensional network with a sponge-like structure. In yet another embodiment, the support structure forms a three-dimensional network with a finger-like structure containing macroscopic voids. The pore structure of the support structure can be uniform or asymmetrical.

[0018] In some embodiments, the porous polymer support structure i) is a microporous support structure, i.e., it has an average flow pore diameter greater than 0.1 µm, as determined by capillary flow pore size determination. In one embodiment, the average flow pore diameter is in the range of 0.1 µm to 0.7 µm, for example, 0.2 µm to 0.4 µm. In another embodiment, the average flow pore diameter is greater than 0.3 µm, for example, in the range of 0.3 to 0.7 µm. In yet another embodiment, the average flow pore diameter is greater than 1 µm, for example, in the range of 1 to 10 µm, or in the range of 1 to 5 µm.

[0019] Capillary flow aperture determination is a liquid extrusion technique in which the flow rate through a wet and dry film is measured under a gas pressure differential. Prior to measurement, the film is immersed in a low surface tension liquid (e.g., commercially available under the name Porofil). ® In perfluoroethers, to ensure that all pores, including the pinholes, are filled with wetting fluid. By measuring the pressure required to expel the fluid from the pores, the corresponding diameter can be calculated using the Laplace equation. This method allows determination of the pore size distribution of those pores that play a role in mass transfer. Dead-end pores and isolated pores are ignored. Hollow fiber membranes are measured from the inside out.

[0020] Laplace equation: Dp = 4 cos / ΔP Dp = Hole diameter [m] = Surface tension [N / m]; for Porofil ® It is 0.016 [N / m] ΔP = Pressure [Pa] Cos = Contact angle; cos when fully wetted = 1 In some embodiments, the porous polymer support structure i) is a nanoporous support structure, i.e., having a pore size in the nanometer range, for example, 1 to 20 nm. Such nanoporous support structures are suitable for ultrafiltration or dialysis of liquids.

[0021] The porous polymer support structure i) is composed of a synthetic polymer. Examples of suitable synthetic polymers include polysulfone (PSU); polyethersulfone (PES); polyacrylonitrile (PAN); and copolymers and blends of the individual polymers described above. In one embodiment, the porous polymer support structure comprises a blend of polyethersulfone and polyvinylpyrrolidone. In another embodiment, the porous polymer support structure comprises a copolymer of acrylonitrile and sodium methacrylate.

[0022] A polyethyleneimine (PEI) layer ii) is coated on the support structure, i.e., the surface of the support structure has a coating containing polyethyleneimine ii). In one embodiment, the weight of the PEI layer is 3 to 7 wt%, for example 4 to 6 wt%, of the total weight of the composite film.

[0023] In one embodiment, the PEI has a weight-average molecular weight M in the range of 10 kDa to 1000 kDa, for example, in the range of 25 kDa to 750 kDa. w .

[0024] In one embodiment, the PEI layer ii) has been crosslinked by reacting with a bifunctional crosslinking agent having terminal epoxy groups (e.g., diglycidyl ether, such as polyethylene glycol diglycidyl ether (PEG-DGE) or butanediol diglycidyl ether (BDO-DGE)). Crosslinking of the PEI improves the stability of the PEI layer and inhibits the leaching of PEI from layer ii). When the porous polymer support structure i) is composed of a negatively charged polymer (e.g., a copolymer of acrylonitrile and sodium methacrylate sulfonate), crosslinking is not required.

[0025] Polyhexamethylene biguanide (PHMB) iii) is grafted onto the coating ii) of the supporting structure, i.e., the PEI coating has the PHMB portion of the PEI covalently bonded to it by a bifunctional epoxy spacer analogue (e.g., diglycidyl ether, such as poly(ethylene glycol) diglycidyl ether (PEG-DGE), poly(propylene glycol) diglycidyl ether (PPG-DGE), or 1,4-butanediol diglycidyl ether (BDO-DGE)).

[0026] In one embodiment, PHMB has a weight-average molecular weight M in the range of 3 kDa to 5 kDa. w .

[0027] In one embodiment, the weight of PHMB grafted onto the coating is 8 to 15 wt% of the total weight of the composite film, for example, 10 to 12 wt%.

[0028] In one embodiment, the bifunctional epoxy spacer analog has a number-average molecular weight M in the range of 200 Da to 2,500 Da. n .

[0029] This disclosure also provides a method for producing composite membranes.

[0030] Methods for producing composite films include: a) Provide a porous polymer support structure, b) React the porous polymer support structure with an aqueous coating solution containing PEI and optionally a bifunctional crosslinking agent with terminal epoxy groups to obtain a porous polymer support structure coated with PEI. c) React the porous polymer support structure coated with PEI obtained in step b) with an aqueous solution containing PHMB and a bifunctional crosslinking agent with terminal epoxy groups to obtain a composite membrane.

[0031] In step a) of the method for producing the composite membrane, a porous polymer support structure is provided. Various types of porous polymer support structures can be used. Suitable examples include flat sheet membranes, folded membranes, tubular membranes, and hollow fiber membranes.

[0032] In one embodiment, the porous polymer support structure is a hollow fiber membrane. In some embodiments, the hollow fiber membrane has an inner diameter of 50 to 2,000 µm, preferably 50 to 1,000 µm, more preferably 100 to 500 µm. The wall thickness is typically 3% to 30% of the outer diameter, i.e., typically 5 to 200 µm, preferably 10 to 80 µm, more preferably 20 to 70 µm.

[0033] In another embodiment, the porous polymer support structure is a sheet membrane. In one embodiment, the thickness of the sheet membrane ranges from 100 to 500 µm. For most applications, a thickness of 150 to 250 µm may be advantageous. Several sheet membranes can be stacked to form an assembly.

[0034] In step b) of the method, the porous polymer support structure is reacted with an aqueous coating solution containing PEI and optionally a bifunctional crosslinking agent with terminal epoxy groups to obtain a porous polymer support structure coated with PEI.

[0035] In some embodiments of this process, coating is performed using an aqueous solution containing 0.5 to 4.0 wt%, for example, 2.0 to 3.0 wt% of PEI. In some embodiments of this process, the aqueous solution contains 0.05 to 2.0 wt%, for example, 0.1 to 0.5 wt% of a bifunctional crosslinking agent with terminal epoxy groups. In some embodiments, the weight ratio of PEI to crosslinking agent is in the range of 15:1 to 25:1.

[0036] In one exemplary process, a porous polymer support structure is coupled with a polymer containing 2 wt% weight-average molecular weight M. w The PEI is 25 kDa and the number-average molecular weight M is 0.1 wt%. n The reaction was carried out in an aqueous solution of 500 Da PEG-DGE.

[0037] The porous polymer support structure is contacted with the aqueous coating solution for 5 to 60 seconds, for example, 10 to 30 seconds, such as by immersing the porous polymer support structure in the aqueous coating solution. The coated porous polymer support structure is then dried. In some embodiments of this process, the coated porous polymer support structure is dried at a temperature of 50°C to 90°C for 15 to 120 minutes, for example, 30 to 120 minutes. In one exemplary process, the coated porous polymer support structure is dried at 80°C for 2 hours. In another exemplary process, the coated porous polymer support structure is dried at 80°C for 15 minutes.

[0038] Optionally, the PEI-coated porous polymer support structure is rinsed with water to remove the leachable PEI, followed by drying. In one exemplary process, the coated porous polymer support structure is immersed in water for 15 minutes and then dried at 80°C for 15 minutes.

[0039] In step c) of the method, the porous polymer support structure coated with PEI obtained in step b) is reacted with an aqueous solution containing PHMB and a bifunctional crosslinking agent having terminal epoxy groups to obtain the composite membrane of the present disclosure.

[0040] In some embodiments of the method, the aqueous solution contains 1 to 10 wt%, for example, 3 to 10 wt% PHMB. In one embodiment, the PHMB has a weight-average molecular weight M in the range of 3 kDa to 5 kDa. w In some embodiments of the method, the aqueous solution contains 1 to 10 wt%, for example 2 to 5 wt%, of a bifunctional crosslinking agent having terminal epoxy groups. In some embodiments of the method, the pH of the aqueous solution is in the range of 8 to 12, for example 9 to 10.

[0041] At a temperature of 20 to 50°C, for example 35 to 40°C, the porous polymer support structure coated with PEI is contacted with an aqueous solution for a period of 1 minute to 24 hours, for example 1 hour to 24 hours, for example 4 to 8 hours, for example by immersing the porous polymer support structure coated with PEI in an aqueous solution, or by pouring an aqueous solution onto the porous polymer support structure coated with PEI.

[0042] The coated porous polymer support structure is then dried. In one exemplary process, the coated membrane is dried at a temperature of 50°C to 90°C for 15 to 120 minutes. In one exemplary process, the coated membrane is dried at 80°C for 30 minutes. In another exemplary process, the coated membrane is dried at 80°C for 15 minutes.

[0043] In a further exemplary process, the coated film is then immersed in water for 15 minutes and then dried at 80°C for 15 minutes.

[0044] In one exemplary process, a porous polymer support structure coated with PEI is combined with a polymer containing 10 wt% weight-average molecular weight M. w The reaction was carried out with an aqueous solution of PHMB with a strength of 3.2 kDa and 2.3 wt% BDO-DGE.

[0045] The composite membrane of this disclosure has been found to exhibit enhanced retention of endotoxins (such as LPS). The composite membrane also exhibits high mechanical stability and has not shown any degradation in filtration performance.

[0046] This disclosure also provides uses for the composite membrane. In one embodiment, the composite membrane of this disclosure is used for liquid filtration. In one embodiment, the filtration is normal flow filtration (NFF). In another embodiment of the invention, the filtration is tangential flow filtration (TFF).

[0047] In one embodiment, the composite membrane of this disclosure is used to filter liquids that may contain endotoxins, preventing endotoxins from entering the filtrate. In one embodiment, the composite membrane is used for filtering dialysate, blocking particles, bacteria, and endotoxins. In a further embodiment, the composite membrane is used for filtering peritoneal dialysis solutions. Removing endotoxins through filtration is particularly challenging because these solutions contain large amounts of sugars (such as glucose or dextrose). In another embodiment, the composite membrane is used to filter solutions to be infused into a patient.

[0048] This disclosure also provides a filtration and / or diffusion device incorporating the membrane of the present invention. The membrane present in the device may be in the form of a sheet or multiple sheets, such as a planar membrane stack. Alternatively, the membrane used in the device may be in the form of hollow fibers or multiple hollow fibers, such as a hollow fiber membrane bundle. Suitable sheets and fibers, their respective properties, and preparation methods have been described above.

[0049] In one embodiment of the device, the interface between the two fluid chambers of the membrane forming apparatus.

[0050] An exemplary device includes two chambers separated by a composite membrane, the first chamber having a fluid inlet and the second chamber having a filtrate outlet. The composite membrane can be a single composite membrane of the sheet membrane type as defined above, or a stack of membranes of the sheet membrane type as defined above.

[0051] Another exemplary device includes a plurality of hollow fiber membranes housed within a housing and configured such that fluid within the external space of the hollow fibers (i.e., the capillary outer chamber) is isolated from fluid passing through the hollow fibers and their respective orifices. Furthermore, the device includes two manifold end chambers within the housing at opposite ends of the device. Each of the two orifices of the hollow fiber lumen is connected to a different end chamber. The end chambers and the capillary outer chamber are separated by a composite membrane of hollow fibers.

[0052] Example

[0053] Example 1: Membrane Preparation

[0054] A microporous flat sheet membrane (Pall Supor Mach VC-200) with a pore size of 0.2 µm was used with a membrane containing 2 wt% weight-average molecular weight M w The PEI is 25 kDa and the number-average molecular weight M is 0.1 wt%. n The reaction was performed with an aqueous solution of 500 Da PEG-DGE. Circular membrane samples with a diameter of 60 mm were used.

[0055] Immerse the membrane in the aqueous coating solution for 10 seconds. Dry the coated membrane at 80°C for 2 hours.

[0056] Circular membrane samples with a diameter of 50 mm were punched out from the dried membrane. To remove leachable PEI, the membrane samples were rinsed with water at a flow rate of 400 ml / min for 30 min. The samples were then dried overnight at ambient temperature.

[0057] The experiment was performed 60 times. The weight of the film before coating and after drying was measured, and the mass increase was determined. The average mass increase for a sample with a diameter of 50 mm was (5.2 ± 0.5) mg.

[0058] The PEI-coated membrane sample was mixed with a sample containing 10 wt% weight-average molecular weight M w The reaction was carried out using an aqueous solution of 3.2 kDa PHMB hydrochloride, 2.3 wt% BDO-DGE, and 0.15 wt% NaOH. The pH of the solution was 10.

[0059] The PEI-coated membrane sample was immersed in an aqueous solution and reacted at 40°C for 20 hours. The membrane was then dried at 80°C for 30 minutes.

[0060] To remove leached PHMB, the membrane sample was rinsed with water at a flow rate of 400 ml / min for 30 min. The sample was first dried overnight at ambient temperature, and then dried in an oven at 60°C for 15 min.

[0061] The experiment was performed 60 times. The weight of the coated film was measured before and after the reaction with PHMB, and the mass increase was determined. The average mass increase of the sample was (14.2 ± 1.8) mg.

[0062] Example 2

[0063] ET interception

[0064] To test the endotoxin (ET) rejection rate of the membrane, a test solution (challenge solution) was pumped through the membrane. The filtrate was collected and its LPS content was analyzed. The logarithmic rejection value (LRV) was calculated based on the difference between the ET concentration in the challenge solution and the concentration in the filtrate.

[0065] The composite membrane was stamped with a surface area of ​​0.8 cm². 2 Circular membrane samples were prepared. Under aseptic conditions, the samples were placed in the filter holder with the upstream side of the membrane facing upwards.

[0066] A stock solution was prepared from lyophilized endotoxin using LAL reagent water (LRW) and then vortexed at 2700 rpm for 30 min. The test solution was placed in an Erlenmeyer flask. A challenge solution was prepared by adding a prescribed volume of ET stock solution to the test solution. Due to the aggregation behavior of LPS, the exact ET concentration cannot be predicted, as the size and number of aggregates contained in that volume can vary considerably. Therefore, a sample of the challenge solution was always taken to determine its exact LPS concentration.

[0067] The challenge solution was stirred with a magnetic stirrer for 15 minutes to ensure uniform LPS distribution, and then pumped through a filter holder with a test membrane. The first two ml of filtrate was discarded. Two ml of filtrate was then collected in a sample container. A predetermined sampling time period exists depending on the set flow rate.

[0068] The sample container was weighed before and after the experiment to determine the exact flow rate from the filtrate weight and sampling duration. The sample was then diluted 10-fold increments with the matrix solution (LPS-free) used in the experiment to obtain an ET concentration of approximately 1 EU / mL for subsequent Limulus Amebocyte Lysate (LAL) assays.

[0069] Limulus amebocyte lysate (LAL) assay was performed to quantify the endotoxin content in samples. In LAL, endotoxins from Gram-negative bacteria catalyze the activation of proenzymes contained in horseshoe crab hemocytes. The active enzyme reacts with an added synthetic peptide coupled to p-nitroaniline dye. Yellow p-nitroaniline is released from the colorless substrate and can be spectrophotometrically measured at 405 nm. The increase in color intensity is proportional to the endotoxin concentration. The limit of detection for this assay is 0.005 EU / mL, and the upper limit of the detection range is 5 EU / mL. The LRV of the test membrane can be determined by comparing the initial concentration of the challenge solution in the filtration experiment with the concentration of ET after filtration: LRV = log 10 (C 挑战溶液 / C 滤液 ).

[0070] Filtration of PD solution

[0071] Using a PD solution containing 4.25 wt% glucose (Dianeal) ® The membrane was tested using a challenge solution prepared by Baxter Healthcare, which contained 600 EU / ml of endotoxin. E. Coli O55:B5 CSE). In each experiment, at ambient temperature, the total was 120,000 EU / cm. 2 Endotoxins were filtered through the membrane sample.

[0072] A volume of 160 ml is contained within a surface area of ​​0.8 cm². 2 The membrane sample was filtered using a filter holder. The flow rate was 2 ml / min, and the filtration time was 80 min. The total filtration efficiency was 96,000 EU (120,000 EU / cm³). 2 Endotoxins were filtered through each membrane sample. Fluid samples were collected from the challenge solution, the filtrate after initial filtration (FS), the filtrate pool (FP), and the filtrate after final filtration (FE). LRV was determined as described above.

[0073] Table 1 shows the results of the uncoated film (A) used as the starting material in Example 1, the PEI coated film (B) obtained in Example 1, and the composite film (C) obtained in Example 1.

[0074] Table 1

Claims

1. A composite membrane comprising i) Porous polymer support structure, ii) A polyethyleneimine (PEI) layer coated on the support structure i), and iii) Polyhexamethylene biguanide (PHMB) grafted onto the coating ii) of the supporting structure.

2. The composite membrane according to claim 1, wherein the porous polymer support structure i) is a flat sheet membrane.

3. The composite membrane according to claim 1, wherein the porous polymer support structure i) is a hollow fiber membrane.

4. The composite membrane according to any one of claims 1 to 3, wherein the porous polymer support structure i) comprises at least one synthetic polymer selected from polysulfone (PSU), polyethersulfone (PES), polyacrylonitrile (PAN), and copolymers and blends of these individual polymers.

5. The composite membrane according to any one of claims 1 to 4, wherein the polyethyleneimine (PEI) layer ii) has been crosslinked by reacting with a bifunctional crosslinking agent having terminal epoxy groups.

6. The composite membrane according to any one of claims 1 to 5, wherein the weight of the polyethyleneimine (PEI) layer (ii) is 3 wt% to 7 wt% based on the total weight of the composite membrane.

7. The composite membrane according to any one of claims 1 to 6, wherein the weight of PHMB grafted onto coating ii) is 8 to 15 wt% based on the total weight of the composite membrane.

8. The composite membrane according to any one of claims 1 to 7, wherein the PHMB portion is covalently bonded to the PEI layer via diglycidyl ether (ii).

9. A method for preparing a composite membrane according to any one of claims 1 to 8, the method comprising: a) Provide a porous polymer support structure, b) React the porous polymer support structure with an aqueous coating solution containing PEI and optionally a bifunctional crosslinking agent with terminal epoxy groups to obtain a porous polymer support structure coated with PEI. c) React the porous polymer support structure coated with PEI obtained in step b) with an aqueous solution containing PHMB and a bifunctional crosslinking agent with terminal epoxy groups to obtain a composite membrane.

10. The method of claim 9, wherein the aqueous coating solution used in step b) comprises 0.5 to 4.0 wt% PEI based on the total weight of the aqueous coating solution.

11. The method according to claim 9 or 10, wherein the aqueous coating solution used in step b) comprises 0.05 to 2.0 wt% of a bifunctional crosslinking agent having terminal epoxy groups, based on the total weight of the aqueous coating solution.

12. The method according to any one of claims 9 to 11, wherein the aqueous solution containing PHMB and a bifunctional crosslinking agent having terminal epoxy groups used in step c) contains 1 to 10 wt% PHMB based on the total weight of the aqueous solution.

13. The method according to any one of claims 9 to 12, wherein, based on the total weight of the aqueous solution, the aqueous solution containing PHMB and a bifunctional crosslinker having terminal epoxy groups used in step c) contains 1 to 10 wt% of the bifunctional crosslinker having terminal epoxy groups.

14. A filtration and / or diffusion device comprising a composite membrane according to any one of claims 1 to 8.

15. The filtration and / or diffusion device according to claim 14, wherein the composite membrane is in the form of a planar sheet or a stack of planar sheets.

16. Use of the composite membrane according to any one of claims 1 to 8 in dialysis fluid filtration.

17. The use according to claim 16, wherein the dialysate is a solution for peritoneal dialysis.

18. Use of the composite membrane according to any one of claims 1 to 8 in filtering solutions to be infused into a patient.

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