Process for the preparation of membranes with reduced elution rate

Abstract

A method for producing a membrane, the method comprising the steps of: producing a first membrane in a spinning step by extruding a spinning solution, wherein the solution comprises a solvent and a polymer composition dissolved or dispersed in the solvent, irradiating the first membrane in an irradiation step with electron radiation, resulting in the membrane, wherein the polymer composition comprises a hydrophilic polymer, and wherein the irradiation step is carried out with a dose of greater than or equal to 100 kGy.

Description

Technical field of the invention

[0001] The present invention relates to a process for producing membranes, preferably dialysis membranes, wherein the membrane has a reduced elution rate both primarily during the production process and also during use. Background of the invention

[0002] Dialysis membranes often contain hydrophilic additives, such as polyvinylpyrrolidone (PVP). PVP is known to leach due to wall shear stresses during post-membrane manufacturing processes, such as washing and membrane integrity testing, and during dialysis therapy. In addition, residues of organic solvents (e.g., N-methylpyrrolidone (NMP), dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO)), which are required for the spinning process, are eluted.

[0003] It has been shown that 10% of the PVP is eluted from FDX-15GW filters (polyester-polymer alloy-PVP, Nikkiso) after 4 hours of filtration and shear stress, while about 20% of the PVP is eluted from the dialyzer after 24 hours (see M. Matsuda, M. Sato, H. Sakata, T. Ogawa, KI Yamamoto, T. Yakushiji, M. Fukuda, T. Miyasaka, K. Sakai, Effects of fluid flow on elution of hydrophilic modifier from dialysis membrane surfaces, J. Artif. Organs 11 (2008) p. 148-155).

[0004] Furthermore, it is known that FX-140 filters (PSU-PVP fibers, Fresenius) contain 1 mg m -2 Elute PVP after 4 hours of filtration (see [K. Namekawa, M. Matsuda, M. Fukuda, A. Kaneko, K. Sakai, Poly (N-vinyl-2pyrrolidone) elution from polysulfone dialysis membranes by varying solvent and wall shear stress, J. Artif. Organs 15 (2012), p. 185-192).

[0005] In addition, the state of the art shows that 10 to 30 mg m -2PVP is eluted from APS-15SA dialyzers (PSu-PVP, Asahi Kasei Medical Co.) and RENAK dialyzers (PSu-PVP, Kawasumi Laboratories) when the filters are rinsed with physiological saline (see M. Miyata, S. Konishi, Y. Shimamoto, A. Kamada, K. Umimoto, Influence of sterilization and storage period on elution of polyvinylpyrrolidone from wet-type polysulfone membrane dialyzers, Am. Soc. Artif. Intern. Organs J. 61 (2015), pp. 468-473). Furthermore, the same document shows that 0.5-2 mg m -2 PVP eluted from the APS-15SA and RENAK dialyzers after 4 hours of filtration.

[0006] Elution of process or product molecules from membrane matrices has the disadvantage of leading to changes in the structural properties and selectivity of the fibers, as well as a reduction in fouling resistance and blood compatibility. Furthermore, leaching of process or product molecules from the hollow fibers into the bloodstream of a patient with kidney disease could, over time, lead to accumulation in the internal organs, trigger allergies, and cause anaphylactic shock. For example, PVP can activate the C3a protein component, which is responsible for immune reactions (see Metabolism of the plasma expanders dextran and polyvinyl pyrrolidone, Nutrition Reviews, 1953, 11, pp. 281-284; AC Yamashita, K. Sakurai, Dialysis Membranes - Physicochemical Structures and Features in Updates in Hemodialysis, InTech 2015, pp. 163-187).

[0007] To prevent the leakage of molecules from membranes and thus solve the problems mentioned above, the state of the art proposes grafting or coating membranes with hydrophilic additives. One approach is the so-called SlipSkin™ technology. This is a random copolymer consisting of a 50:50 ratio of hydrophilic N-vinylpyrrolidone (NVP) and hydrophobic N-butyl methacrylate (BMA) (see [see text]. Fig. ).

[0008] By blending the main membrane polymer, polyethersulfone (PES), with small amounts of SlipSkin™, hollow fibers with increased blood compatibility and reduced additive leaching were developed (see ter Beek, O., et al., New membranes based on polyethersulfone - SlipSkin™ polymer blends with low fouling and high blood compatibility, Separation and Purification Technology 225 (2019) 60-73). Avoiding additive leaching was achieved through interactions between the hydrophobic block BMA and PES. The hydrophilic additive (as part of the SlipSkin™ copolymer) was therefore anchored in the membrane matrix. Fig. shows the reduced elution of the SlipSkin™ additive after 24 hours of water filtration of PES-SlipSkin™ hollow fibers.

[0009] Irradiation of the membrane with high doses (> 100 kGy) causes membrane damage as long as no active binding partner is available. For this reason, the current technique involves wetting the membrane with a modification solution during irradiation processes to provide such binding partners. However, this has the disadvantage of making the process more complex and expensive.

[0010] In addition, uncrosslinked binding partners can also elute from the membrane. Summary of the present application

[0011] The disadvantage of the proposed method is that it requires more effort to provide the components required for the SlipSkin™ technology.

[0012] It is therefore an object of the present invention to provide a method that allows the elution of membrane or process components, such as hydrophilic polymers, preferably PVP, or DMAc, from membranes to be prevented without changing the membrane material.

[0013] It has now surprisingly been found that this object is achieved by the method of the present invention, which is a method for producing a membrane, the method comprising the steps: - producing a first membrane in a spinning step by extruding a spinning solution, the solution comprising a solvent and a polymer composition dissolved or dispersed in the solvent, - irradiating the first membrane in an irradiation step with electron radiation, resulting in the membrane, wherein the polymer composition comprises a hydrophilic polymer.

[0014] Without wishing to be bound to any particular theory, it is assumed that irradiation with electron beams leads to the formation of radicals along the polymer backbones. Radical recombination could lead to covalent cross-linking of the polymers and thus anchoring them in the membrane matrix, ultimately leading to reduced elution behavior. This is surprising because cross-linking has previously been considered negative due to its effects on the structural properties and filtration performance of the membrane.

[0015] This results in product improvements in the membrane, such as reduced contamination and significantly improved blood compatibility and patient safety. The latter is primarily due to reduced leaching and dissolution of PVP during therapy. This prevents PVP from accumulating in organs and causing various dysfunctions such as allergies or anaphylactic shock.

[0016] At the same time, the method ensures that all substances introduced into the process can be returned to the cycle in the most economical and environmentally friendly way possible, as the irradiation only takes place after the washing process. Short description of the figures Fig. shows the chemical structures of SlipSkin™ copolymer with N-vinylpyrrolidone (NVP) and N-butyl methacrylate (BMA). Fig.shows TR-FTIR spectra demonstrating the effect of long-term filtration on the presence of the hydrophilic additives PES-SS (a.1) and PES-PVP (b.1). The carbonyl group is represented by the red box. The black lines represent the membranes, and the dashed black lines represent the filtration after 24 hours. The spectra of PES powder (gray lines) and PVP powder (gray dotted lines) are also shown for reference. The data are taken from "Hollow fiber membranes for long-term hemodialysis based on polyethersulfone-SlipSkin™ polymer blends," O. ter Beek, D. Pavlenko, D. Stamatialis, Journal of Membrane Science 604 (2020) 118068. Fig. shows the chemical structural formula of N,N-dimethylacetamide. Definitions

[0017] The term "elution" as used herein refers to the process of removing or dissolving a substance from the membrane using a solvent. This can occur, for example, during membrane washing processes during manufacturing or during the membrane's intended use.

[0018] The term "membrane" as used herein refers to a material, preferably a film, containing pores of a specific size. Preferably, the membrane has pores in the micrometer range. More preferably, the membrane has an average pore size in the range of 0.001 to 10 µm.

[0019] The term "sterile" as used herein refers to the condition of an article that has a significantly reduced number of bacteria and / or viruses on its surface in order to reduce the risk of infection. In particular, the term "sterile" refers to an article or substance that has a microbial load of less than 10 -6The microbial load can be measured, for example, according to ISO 11737-1:2018.

[0020] The term "sterilization" as used herein refers to a process for destroying all forms of living microorganisms on a substance. Since there is always a certain probability that at least one microorganism will survive such a process, the goal of sterilization is to reduce the number of microorganisms or other potential pathogens originally present. In general, sterilization is considered achieved when the microbial load of the substance or object to be sterilized is below 10 -6The bioburden can be measured, for example, according to ISO 11737-1:2018. Sterilization can be carried out using various methods. In one sterilization process, the object is heated to at least 105 °C to obtain a sterile object. The object should not be deformed by the increased temperature. The heating step is preferably carried out in an autoclave. In another sterilization process, the object is brought into contact with toxic gases such as a mixture of ethylene oxide and carbon dioxide. Finally, sterilization can be achieved by indirectly applying energy to or onto the object, e.g. using ultrasonic waves, ultraviolet light, or high-energy particles (such as electrons, gamma rays, or X-rays), whereby a dose of 45 KGy is not exceeded. Detailed description of the invention

[0021] The present invention relates to a process for producing a membrane, the process comprising the steps of: - producing a first membrane in a spinning step by extruding a spinning solution, the solution comprising a solvent and a polymer composition dissolved or dispersed in the solvent, - Irradiating the first membrane in an irradiation step with electron radiation, whereby the membrane is formed, wherein the polymer composition comprises a hydrophilic polymer, and wherein the irradiation step is carried out with a dose of greater than or equal to 100 kGy.

[0022] It was found that a membrane prepared in this way elutes less PVP and / or DMAc and thus offers the advantages described above.

[0023] The irradiation step is preferably carried out with a dose of 100 to 250 kGy. Below this dose, insufficient or incomplete radicalization of the substrates present may occur. Above this dose, complete or partial damage to the membrane structure may occur. The high radiation dose can lead to decreased mechanical stability. The surface becomes rougher, resulting in a decrease in blood compatibility.

[0024] Preferably, the first membrane is wet in the irradiation step. Wet means that the membrane is wetted, preferably soaked, with a liquid. The liquid can be any liquid that is compatible with the membrane. For example, the liquid can be a precipitating liquid or a washing liquid as described below. Preferably, the liquid contains a non-solvent for the polymer composition. Preferably, the non-solvent is selected from a group consisting of water, glycerol, alcohols, preferably ethanol and / or isopropanol, and mixtures thereof. More preferably, the liquid comprises water. Most preferably, the liquid consists of water.

[0025] In order to return costly process molecules such as DMAc to the cycle, it is better to irradiate the membrane after the washing process in order to wash as much DMAc as possible out of the membrane before it becomes covalently anchored in the membrane.

[0026] The membrane is preferably a membrane for pharmaceutical and / or medical applications. The membrane is particularly preferably a dialysis membrane. The membrane can be a flat fiber membrane or a hollow fiber membrane. The membrane is preferably a hollow fiber membrane.

[0027] The hydrophilic polymer preferably comprises, and preferably consists of, a polymer selected from a group consisting of polyvinylpyrrolidone [PVP], a short-chain glycol having 2 to 10 carbon atoms, triethylene glycol, propylene glycol, polyethylene glycol [PEG] / polyethylene oxide [PEO], and mixtures thereof. More preferably, the hydrophilic polymer comprises PVP. Most preferably, the hydrophilic polymer consists of PVP.

[0028] The solvent in the spinning step of the process of the present invention preferably comprises a component selected from a group consisting of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), and an acetamide, preferably N,N-dimethylacetamide (DMAc). Preferably, the solvent consists of this component.

[0029] In a preferred embodiment of the present invention, the solvent comprises an acetamide, preferably N,N-dimethylacetamide. Even more preferably, the solvent consists of an acetamide, preferably N,N-dimethylacetamide.

[0030] N,N-Dimethylacetamide is typically used in the medical device industry to manufacture porous hollow-fiber membranes used in dialyzers for chronic and acute renal replacement therapy. It serves as a solvent for the spinning solution, which can consist of polysulfone (PSU) and poly-N-vinylpyrrolidone (PVP). However, it has now been discovered that N,N-dimethylacetamide can harm the unborn child. From a toxicological perspective, exposure to N,N-dimethylacetamide should not exceed 60 mg per patient over 24 hours.

[0031] It is therefore a further object of the present invention to further reduce the elution of N,N-dimethylacetamide from a membrane. It has now been surprisingly discovered that the process of the present invention reduces the elution of N,N-dimethylacetamide, when used as a solvent, by the irradiation step. Without wishing to be bound to any particular theory, it is assumed that a portion of the N,N-dimethylacetamide is radically fixed to the polymer backbone of the membrane by the irradiation.

[0032] The advantage of the present invention is that membranes can be produced that comply with toxicological regulations and / or require fewer washing steps in the manufacturing process. Furthermore, the treatment of the wash water containing N,N-dimethylacetamide is facilitated.

[0033] The spinning step of the process according to the present invention is carried out according to a phase inversion process, in which the polymer composition is dissolved in the solvent in a dissolving step to form the spinning solution. The spinning solution is preferably degassed in a degassing step and filtered in a filtration step prior to spinning.

[0034] After dissolution, the spinning solution is extruded in an extrusion step. The temperature of the spinning solution is preferably adjusted as it passes through the spinneret or slot die. Preferably, the temperature of the spinneret or slot die can be controlled and monitored. The spinning solution is extruded through the spinneret (for hollow fibers) or the slot die (for flat fibers).

[0035] Furthermore, the spinning step of the manufacturing process of the present invention comprises a precipitation step. In one embodiment, after passing through the spinning shaft, the extruded spinning solution enters a precipitation bath. The precipitation bath contains a non-solvent for the polymer composition. Optionally, the precipitation bath can also contain the solvent in a concentration of up to 55 wt.%. If the solvent is N,N-dimethylacetamide, it is preferably present in a range of up to 20 vol.%. In a process according to a preferred embodiment of the present invention for producing a hollow fiber membrane, the spinning solution is preferably extruded through an outer annular gap of a nozzle with two concentric openings. Simultaneously, a precipitation liquid containing a non-solvent for the polymer composition is extruded through an inner opening of the spinneret.At the outlet of the spinneret, the precipitation liquid comes into contact with the spinning solution, initiating the precipitation of the polymer composition.

[0036] During the precipitation step, the solvent in the spinning solution is exchanged with the non-solvent in the precipitation liquid and / or the precipitation bath. This exchange changes the polymer composition of the spinning solution from a dissolved form to an undissolved, solid form. During the precipitation step, the pore structure and pore size distribution are determined by the kinetics of the exchange between solvent and non-solvent. The process takes place at a specific temperature, which influences the viscosity of the polymer solution.

[0037] During the production of membranes according to the invention, the temperature of the spinneret, and thus of the spinning solution and the precipitating liquid, as well as the temperature of the spinning shaft, are preferably carefully controlled. In principle, the membranes according to the invention can be produced in a temperature range between 30 and 70 °C.

[0038] As already mentioned, temperature influences the viscosity of the spinning solution and thus determines the kinetics of the pore formation process through the exchange of solvent with non-solvent. The viscosity of a spinning solution for producing membranes according to the present invention should generally be in the range of 3000 to 7400 mPa s at 22°C, preferably 4900 to 7400 mPa s (22°C), and particularly preferably 4400 to 6900 mPa s (22°C). To obtain foam- or sponge-like structures, the viscosity can be increased, for example, to values ​​up to 15000 mPa s.

[0039] The non-solvent of the precipitating liquid or the precipitating bath is preferably selected from a group consisting of water, glycerol, alcohols, preferably ethanol and / or isopropanol, and mixtures thereof. The precipitating liquid or the precipitating bath preferably contains non-solvents and solvents. The solvent content is preferably between 5 and 75 wt.%, based on the total mass of the precipitating liquid or the precipitating bath, and preferably between 10 and 70 wt.%.

[0040] In a further preferred embodiment of the invention, the method further comprises the step: - Washing the membrane in one washing step with a washing liquid.

[0041] Preferably, the irradiation step is performed after the washing step. This ensures that the washed-out, costly DMAc can be recovered in maximum quantity and reintroduced into the process cycle. Preferably, the membrane is dried in a drying step after the washing step.

[0042] The washing liquid preferably contains a non-solvent such as the precipitation liquid and / or the precipitation bath. The non-solvent is preferably selected from a group consisting of water, glycerol, alcohols, preferably ethanol and / or isopropanol, and mixtures thereof. The washing liquid particularly preferably contains water; the washing liquid preferably consists of water.

[0043] Preferably, the process of the present application does not comprise a further step in which the chemical composition or the surface of the membrane is modified.

[0044] In a further preferred embodiment of the invention, the method according to the present invention further comprises the step: - Sterilizing the membrane in one sterilization step.

[0045] Preferably, the membrane in such a process is a dialysis membrane, since a sterile membrane is necessary for this application. The process according to claim 4, wherein the irradiation step is carried out before or during the sterilization step, preferably carried out before the sterilization step. Sterilization can typically be achieved using various process steps, essentially either increasing the temperature or irradiating the membrane. If irradiation is used in the sterilization process, the irradiation dose is typically no more than 45 kGy. However, this dose is not sufficient to achieve the effect of the invention. In this respect, either the dose of irradiation is increased in the sterilization step or additional irradiation is carried out during the sterilization step by increasing the temperature. Typically, the sterilization step takes place after the washing step and drying step.The membrane is preferably drawn into the dialyzer and sterilized.

[0046] In an alternative preferred embodiment of the present invention, the method does not include a sterilization step. This embodiment is used when the membrane does not require sterilization. This is particularly the case when there is no pharmaceutical or medical application, especially if it is not a dialysis membrane. This embodiment is preferably used for the production of water purification membranes.

[0047] Preferably, the first membrane comprises a hydrophobic polymer. Also preferably, the polymer composition comprises a hydrophobic polymer.

[0048] The hydrophobic polymer preferably comprises a polymer selected from a group consisting of a polyamide [PA], a polyacrylonitrile [PAN], a polymethyl methacrylate [PMMA], a polyacrylic acid [PAA], a polycarbonate [PC], a polyurethane [PUR], a polysulfone [PSU], a sulfonated polysulfone [SPSU], a polyethersulfone [PES], a sulfonated polyethersulfone [SPES], a polyphenylsulfone [PPSU], a sulfonated polyphenylsulfone [SPPSU], and mixtures thereof. More preferably, the hydrophobic polymer comprises a polymer selected from a group consisting of a polysulfone [PSU], a sulfonated polysulfone [SPSU], a polyethersulfone [PES], a sulfonated polyethersulfone [SPES], a polyphenylsulfone [PPSU], a sulfonated polyphenylsulfone [SPPSU], and mixtures thereof. Even more preferably, the hydrophobic polymer comprises polysulfone [PSU].Particularly preferably, the hydrophobic polymer consists of one of the polymers described. Most preferably, the hydrophobic polymer consists of polysulfone [PSU].

[0049] Preferably, the first membrane of the process according to the present invention comprises polysulfone and PVP. More preferably, the first membrane of the process according to the present invention consists of polysulfone and PVP. Experimental part

[0050] Examples showing the effect of the present invention are discussed below. Measurement methodsa) Determination of PVP extractExtraction

[0051] For the extraction, 1.2 ± 0.1 g of fibers were weighed. The fiber sample was then mixed with 200 ml of deionized water and stirred. The deionized water had a temperature of 37 °C. The extraction was carried out under the following conditions and in an airtight container: - Temperature: 37 °C - Stirrer speed: 8 - Extraction time: 120 min

[0052] The aqueous extract is separated and the PVP content is measured as described below. Iodine method

[0053] Diluted aqueous PVP solutions develop a reddish-brown color when KJ3 solution is added. Two reagent solutions are required for extract analysis: a) Preparation of citric acid solution with a concentration of 0.2 mol / l or 38.4 g / l. b) Potassium iodide solution: 0.81 g sublimed iodine and 1.44 g potassium iodide are dissolved in 1 l of deionized water

[0054] The following mixture is pipetted together in the given order: - 5 ml sample (aqueous extract) - 2.5 ml citric acid solution - after one minute reaction time, 1 ml of potassium iodide solution.

[0055] For the blank value, deionized water is used instead of the sample. The measurement is performed after a reaction time of 10 minutes. For serial measurements, the reaction time may be 10 to 12 minutes.

[0056] The determination of the PVP content according to the iodine method is carried out spectrophotometrically at a wavelength of λ = 422.0 nm. The extinction coefficient ε(λ) at the wavelength λ is 0.02314 cm 2 mg -1 .

[0057] The concentration of PVP is calculated according to equation (I): c(PVP)=E(422 nm)ε(PVP,422 nm) where c(PVP) Concentration PVP in [mg / l] E(422 nm) measured absorbance ε(PVP; 422 nm) Extinction coefficient for PVP at 422.0 nm UV method

[0058] The aqueous extract of the fiber sample is measured spectrophotometrically without any analytical preparation of the sample. The measurement is carried out at a wavelength of λ = 220.0 nm. The extinction coefficient ε(λ) at wavelength λ is 0.01418 cm 2 mg -1 The concentration of the components DMAc, PVP, DMA (dimethylamine) and acetic acid is the sum of the concentration at the wavelength 220nm (see equation (II)): cTotal=ETotal(220 nm)εTotal(220 nm) where c Gesamt Total concentration in [mg / l] E Gesamt (220 nm) measured absorbance at 220 nm ε Gesamt (220 nm) Total extinction coefficient at 220 nm Evaluation

[0059] From the concentration in the extract (determined by the iodine or UV method), the volume of the extract solution and the fiber mass, the extractable PVP content is calculated according to equation (III): m(PVP)=mPVPmF=c(PVP∗VE)mF where m(PVP) extractable PVP content based on fiber mass [mg / g] c(PVP) Concentration of PVP in the extract [mg / l] V E Volume of extract solution [I] m PVP Mass of PVP in extract [mg] m F Fiber mass [g] b) Determination of N,N-dimethylacetamide (DMAc) extract

[0060] The concentrations of the components DMAc, DMA (dimethylamine), and acetic acid are calculated as sum parameters in the form of DMAc concentration. PVP also shows absorption at a wavelength of 220 nm. The extinction coefficient ε(λ) for PVP at this wavelength λ is 0.00612 cm 2 mg -1 . Therefore, the PVP content in the fiber extract must be determined using the iodine method and included in the calculation of the DMAc content according to equation (IV). c(DMAc) =ETotal(220 nm)−E(PVP,220 nm)ε(DMAc,220 nm)= ETotal(220 nm)−c(PVP,iodine)∗ε(PVP,220 nm)ε(DMAc,220 nm) where c(PVP, iodine) PVP concentration calculated according to the iodine method [mg / l] ε(PVP, 220 nm) Extinction coefficient for PVP at 220 nm E Gesamt (220 nm) measured absorbance at 220 nm ε(DMAc; 220 nm) Extinction coefficient for DMAc at 220 nm

[0061] From the concentration in the extract, the volume of the extract solution and the fiber mass, the extractable DMAc content is calculated according to equation (V): m(DMAc)=mDMAcmF=c(DMAc)∗VEmF where m(DMAc) extractable DMAc content based on fiber mass [mg / g] c(DMAc) Concentration of DMAc in the extract [mg / l] V E Volume of extract solution [l] m DMAc Mass of DMAc in extract [mg] m F Fiber mass [g] Examplesa) Membrane

[0062] A xevonta® dialyzer fiber from B. Braun SE was used as the membrane. b) Dry vs. wet irradiation PVP elution (IE1; CE1-3)

[0063] In the following examples, the influence of irradiation of the membranes in the dry and wet state was investigated. Three comparative examples and one example according to the invention were made, in which the membrane from step a) CE1 were irradiated unwashed but dried with 200 kGy; CE2 were washed but dried and irradiated with 200 kGy; CE3 were washed, dried, but not irradiated; IE1 washed but wet irradiated with 200 kGy. Irradiation

[0064] For the irradiation step, 96 fibers, each 33 cm long, were individually fixed parallel to each other at the top and bottom ends of a mobile carrier and then guided beneath the irradiation source at a transport speed of 1.9 m / min. The radiation window was 10 cm long. At a voltage of 160 kV and a current of 15 mA, this resulted in a total dose of 200 kGy. The fiber was irradiated under the electron beam irradiation source for 3.2 s. Wash

[0065] The fibers were washed in a cascade-like setup consisting of four 5-liter wash tanks, each equipped with a magnetic stirrer to ensure continuous circulation. The composition of the wash solutions and the residence times of the fibers in each wash tank were implemented as follows: 1. 0.1 M Urea wash solution, 7.5 min 2. 1 M sodium chloride wash solution, 7.5 min 3. Ultrapure water, 5 min 4. Ultrapure water, 5 min Drying

[0066] The final drying was carried out at 21 °C using room air for 24 h. Results

[0067] The PVP content in the extract was determined for all experiments. The values ​​can be found in Table 1. Table 1: PVP in the extract of examples CE1-3 and IE1 Example PVP in extract [mg / g] CE1 4,16 CE2 2,45 CE3 1,56 IE1 0,22

[0068] Based on comparative example CE1, which exhibits the highest PVP content in the extract, it can be assumed, especially in comparison to the untreated membrane (CE3), that irradiation of the dry membrane without binding partner affects the membrane itself, releasing PVP. Both the unwashed (CE1) and the washed (CE2) membranes, which were irradiated dry, exhibit higher PVP content in the extract than the untreated, dry membrane (CE3). However, a comparison of the PVP extracts from examples CE1 and CE2 also shows that the PVP content in the extract can be reduced by a washing step.

[0069] In the inventive example IE1, the membrane is wet irradiated. This results in a significant reduction (by 91% compared to CE2) in the PVP content in the extract. Without wishing to be bound by such a theory, it is assumed that the PVP is cross-linked in this process, while at the same time, no deterioration of the membrane occurs. c) Dry vs. wet irradiation N,N-dimethylacetamide elution (IE1; CE1-3)

[0070] In the following examples, the influence of irradiation of the membranes in the dry and wet state was investigated. Four comparative examples and two examples according to the invention were prepared, in which the membranes from step a): CE1 were irradiated unwashed but dried with 200 kGy; CE2 were washed but dried and irradiated with 200 kGy; CE3 were washed, dried, but not irradiated; IE1 washed but wet irradiated with 200 kGy;

[0071] For all experiments, the proportion of N,N-dimethylacetamide in the extract was determined. The values ​​can be found in Table 2. Table 2: N,N-Dimethylacetamide in the extract of examples CE1-3 and IE1 Example N,N-Dimethylacetamide extract [mg / g] CE1 0,11 CE2 0,01 CE3 0,03 IE1 0,09

[0072] Comparative example CE3 exhibits the highest N,N-dimethylacetamide content in the extract after a washing step. All other examples with a washing step (CE2, IE1) show lower N,N-dimethylacetamide content in the extract. Irradiation is carried out simultaneously in all of these examples (CE2 and IE1 with 200 kGy). It can therefore be shown that irradiation according to the invention ensures that less N,N-dimethylacetamide is present in the extract. Without wishing to be bound by such a theory, it is assumed that the irradiation also crosslinks parts of the N,N-dimethylacetamide with the polymer backbone.

[0073] In connection with the results from experiment b), it can be said that with wet irradiation both PVP and N,N-dimethylacetamide elution of a membrane is reduced without affecting the polymer of the membrane. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited non-patent literature

[0000] M. Matsuda, M. Sato, H. Sakata, T. Ogawa, KI Yamamoto, T. Yakushiji, M. Fukuda, T. Miyasaka, K. Sakai, Effects of fluid flow on elution of hydrophilic modifier from dialysis membrane surfaces, J. Artif. Organs 11 (2008) p. 148-155

[0003] K. Namekawa, M. Matsuda, M. Fukuda, A. Kaneko, K. Sakai, Poly (N-vinyl-2pyrrolidone) elution from polysulfone dialysis membranes by varying solvent and wall shear stress, J. Artif. Organs 15 (2012), p. 185-192

[0004] M. Miyata, S. Konishi, Y. Shimamoto, A. Kamada, K. Umimoto, Influence of sterilization and storage period on elution of polyvinylpyrrolidone from wet- type polysulfone membrane dialyzers, Am. Soc. Artif. Intern. Organs J. 61 (2015), p. 468-473

[0005] Metabolism of the plasma expanders dextran and polyvinyl pyrrolidone, Nutrition Reviews, 1953, 11, p. 281- 284

[0006] A.C. Yamashita, K. Sakurai Dialysis Membranes-Physicochemical Structures and Features in Updates in Hemodialysis, InTech 2015, p.163 - 187

[0006] ter Beek, O., et al., New membranes based on polyethersulfone - SlipSkin™ polymer blends with low fouling and high blood compatibility, Separation and Purification Technology 225 (2019) 60-73

[0008]

Claims

[1] A method for producing a membrane, the method comprising the steps of: - producing a first membrane in a spinning step by extruding a spinning solution, the solution comprising a solvent and a polymer composition dissolved or dispersed in the solvent, - irradiating the first membrane in an irradiation step with electron radiation, resulting in the membrane, wherein the polymer composition comprises a hydrophilic polymer, and wherein the irradiation step is carried out with a dose of greater than or equal to 100 kGy. [2] The method according to claim 1, wherein the hydrophilic polymer comprises, preferably consists of, a polymer selected from a group consisting of polyvinylpyrrolidone [PVP], a short-chain glycol having 2 to 10 C atoms, triethylene glycol, propylene glycol, polyethylene glycol [PEG] / polyethylene oxide [PEO] and mixtures thereof. [3] The method according to claim 1 or 2, wherein the first membrane is wet in the irradiation step, preferably wetted with a liquid, more preferably soaked with a liquid. [4] The method according to claim 3, wherein the liquid is a non-solvent for the polymer composition. [5] The method according to claim 4, wherein the non-solvent is selected from a group consisting of water, glycerin, alcohols, preferably ethanol and / or isopropanol, and mixtures thereof, preferably the liquid comprises water, most preferably the liquid consists of water. [6] The method according to any one of the preceding claims, wherein the irradiation step is carried out with a dose of 100 to 250 kGy. [7] The method according to any one of the preceding claims, wherein the membrane is a membrane for pharmaceutical and / or medical application, preferably a dialysis membrane. [8] The process according to any one of the preceding claims, wherein the solvent comprises a component selected from a group consisting of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) and an acetamide, preferably N,N-dimethylacetamide, preferably consisting of this component. [9] The method according to any one of the preceding claims, wherein the method further comprises the step of: - Washing the dialysis membrane in a washing step with a second solvent. [10] The method according to claim 9, wherein the irradiation step is performed after the washing step. [11] The method according to any one of the preceding claims, wherein the method further comprises the step of: - Sterilizing the membrane in one sterilization step. [12] The method according to claim 11, wherein the irradiation step is carried out before or during the sterilization step, preferably before the sterilization step. [13] The method according to any one of the preceding claims, wherein the first membrane comprises a hydrophobic polymer. [14] The method according to any one of the preceding claims, wherein the polymer composition comprises a hydrophobic polymer. [15] The method according to any one of claims 13 or 14, wherein the hydrophobic polymer comprises, preferably consists of, a polymer selected from a group consisting of a polyamide [PA], a polyacrylonitrile [PAN], a polymethyl methacrylate [PMMA], a polyacrylic acid [PAA], a polycarbonate [PC], a polyurethane [PUR], a polysulfone [PSU], a sulfonated polysulfone [SPSU], a polyethersulfone [PES], a sulfonated polyethersulfone [SPES], a polyphenylsulfone [PPSU], a sulfonated polyphenylsulfone [SPPSU], and mixtures thereof.

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