Hollow fiber membrane with high biocompatibility and low albumin loss

Abstract

The invention relates to a hollow fiber membrane comprising a membrane material comprising a hydrophobic and a hydrophilic polymer, wherein the hydrophobic polymer comprises a polysulfone and the hydrophilic polymer comprises a polyvinylpyrrolidone in a proportion of 1-9 wt.%, wherein the content of polyvinylpyrrolidone in the near-surface layer of the inner lumen of the membrane is 35 wt.% or more according to the XPS measurement method, and the albumin sieving coefficient, measured according to the method specified in the description, is less than 0.01. The invention further relates to a hollow fiber dialyzer comprising such a membrane.

Description

Technical FieldThe invention encompasses hollow fiber membranes comprising a membrane material comprising a hydrophobic and a hydrophilic polymer and having improved hemocompatibility properties and at the same time only low albumin loss. The invention further relates to a hollow fiber membrane dialyzer comprising such a membrane.BACKGROUND OF THE INVENTIONHollow-fibre membranes are widely used in the purification of liquids. In particular, hollow-fiber membranes are used in medical technology for blood purification in dialysis of kidney-diseased patients. Hollow-fibre membranes are installed in the form of hollow-fibre membrane bundles in filter modules which are used in extracorporeal blood treatment. The production of such filter modules for blood cleaning, so-called dialyzers, takes place on a mass production scale.The hollow-fibre membranes used for blood purification frequently consist of a hydrophobic and a hydrophilic polymer, in particular of polysulfone and polyvinylpyrrolidone, since these materials have proven to be fundamentally haemocompatible and are therefore to be preferred from a medical point of view in blood treatment, in particular in hemodialysis. This is evident in that a very high proportion of the dialyzers commercially available and sold comprises these material groups. Further hydrophobic polymers suitable in principle are polyamide, polyacrylonitrile and regenerated cellulose and derivatives of cellulose, in particular cellulose acetate. Another hydrophilic polymer suitable in principle is polyethylene glycol.The basic principles of hollow fiber membrane manufacture, manufacture and properties thereof are described in the prior art.• Marcel Mulder; Principles of Membrane Technology; Kluwer Academic Publisher 1996; Chapter III, Preparation of synthetic membranes• EP 0 168 783To assess the biocompatibility of commercially available dialyzers, it is proposed according to a method Vienken et al. (A. Erlenötter, P. Endres, B. Nederlof, C. Hornig, J. Vienken; Artificial Organs; 32 (12), 962 (2008)) to allow test blood to circulate through a dialyzer for a predetermined period of time and to detect the side reactions which occur on the basis of a selection of what are known as hemocompatibility markers. The following were used as haemocompatibility markers by this method: the complement factor 5a (C5a) or sC5b-9, the thrombin-antithrombin III complex (TAT), the thrombocyte count ("platelet count"=PLT), the platelet factor 4 ("platelet factor 4"=PF4) and the release of elastase from polymorphonuclear granulocytes (PMN elastase).To assess the biocompatibility of a dialyzer, it is proposed according to this method to evaluate the individual hemocompatibility markers according to a "scoring" system. It is furthermore proposed to calculate a total hemocompatibility score ("Total Hemocompatibility Score"=THS) for a dialyzer from the scoring of the individual hemocompatibility markers and thus to make different dialyzers comparable with regard to their biocompatibility.As a result of this method, it became clear that both the membrane material and the different sterilization methods with which commercially available dialyzers are sterilized can obviously have an influence on the biocompatibility of the hollow fiber membranes. In particular, a difference in the biocompatibility of the dialyzers under investigation was found due to the different membrane materials polysulfone, polyethersulfone / polyarylates, regenerated cellulose, esterified cellulose and the different sterilization methods such as steam sterilization, radiation sterilization (γ-rays or electron beams) and vacuum-steam sterilization.Hollow fiber membranes and dialyzers are used as disposable medical articles in therapeutic blood treatment and are accordingly commercially available as mass-produced articles for the care of patients. The production method of the hollow fiber membranes and dialyzers is therefore often carried out according to economic interests and aspects of productivity. This means that the production of hollow-fiber membranes and dialyzers is oriented in such a way that the required performance properties are achieved, but in addition the production is oriented according to the most cost-effective scales possible. The studies by Vienken et al. make it clear that the production processes of hollow-fiber membranes and dialyzers established in the prior art often do not run optimally with regard to an advantageous biocompatibility that is to be sought.The prior art describes production methods of hollow fiber membranes with the aim of providing hollow fiber membranes which, with a predetermined separation performance, enable high biocompatibility with simultaneous cost-effective production. In particular, in this regard, production methods of hollow fiber membranes are described in which the hollow fiber membranes are modified with a fat-soluble vitamin, e.g. a vitamin E. It is described that such modifications can be effected, for example, by adding vitamin E to the coagulant used in the production process. In this way, a coating of the inner surface of the hollow fiber membranes produced with vitamin E and thus an improved biocompatibility is to be achieved. It is thereby assumed that the vitamin E-modified hollow fiber membranes, when they come into contact with treatment blood, have an antioxidant effect on blood cells or reduce the effect of the immunologically relevant "chemical burst" and generally correct the prooxidative blood status of patients with chronic kidney failure. An example of such an antioxidative action of a modified hollow fibre membrane is described in EP2737916A. It is remarkable here that a comparatively high level of vitamin E is present, which achieves the desired success with respect to the antioxidative action, but results in a comparatively low hydrophilicity of the surface.On the other hand, hydrophobization of the inner surface of polysulfone hollow fiber membranes is discussed in connection with better blood wettability and biocompatibility. In this connection, EP 0 568 045 describes a production of a hollow fiber membrane based on polysulfone.A particular hollow fiber membrane and a production method associated therewith is described in detail in DE102017201630A1. In this case, the production method and in particular the spinning process is modified in such a way that a small amount of about 1 g to about 3 g per kg of precipitant is added to the precipitant which is located in the interior of the membrane which is formed, resulting in a membrane whose region close to the surface of the lumen surface has a higher content of hydrophilic polymer. At the same time, a fat-soluble antioxidant was added to the spin dope, resulting in a more hydrophilic membrane than the prior art for DE102017201630A1 with less elution of hydrophilic polymer. With the aid of the technology disclosed in the specification, it was possible to achieve good hydrophilicity, which can be demonstrated by determining the occupancy of the selective inner surface of the membrane with the aid of X-ray photoelectron spectroscopy. It was possible to detect occupancy values of up to 30% (example 6 of DE102017201630A) on the inner surface. It has proven disadvantageous that a comparatively high loss of albumin has been established in the membranes produced according to DE102017201630A1 which can be contraindicated for particularly sensitive patients. Thus, the albumin sieving coefficient according to Table 2 of the DE102017201630A1 of Example 2 is 0.2% after 5 minutes and 0.05% after 30 minutes. This leads to comparatively high albumin losses during a therapy session. It has proven problematic here that a further higher albumin loss should be avoided, especially in patients with an already low albumin status, which can be established during the progress of the kidney disease. Moreover, it has been found that such dialyzers may in some cases not be sufficiently suitable for supplying patients who have become newly subject to hemodialysis. In addition, it has been found that a further improvement in hemocompatibility, in particular in anti-coagulation properties, is desirable.Object of the InventionIn view of the problems prevalent in the prior art, it has been found that there continues to be a need to provide hollow fiber membranes with improved biocompatibility. In particular, there is a continuing need to find membranes which can ensure excellent biocompatibility and a high therapeutic success, in particular for particularly sensitive patients. A partial object is to provide a hollow fiber membrane or dialyzer which, due to its hemocompatibility, is particularly suitable for patients who become newly hemodialysis-dependent. particularly a further partial object is to be able to provide sterile hollow fiber membranes or dialyzers for patients with critical nutritional or poor albumin status. In particular, however, the provided membrane or the provided dialyzer should be achieved cost-effectively and with a saving in material and plant outlay. A further partial object is to provide a dialyzer with a further improvement in hemocompatibility, in particular in anti-coagulation properties.SUMMARY OF THE INVENTIONA first aspect of the invention relates to a hollow fiber membrane comprising a membrane material comprising a hydrophobic and a hydrophilic polymer, wherein the hydrophobic polymer comprises a polysulfone and the hydrophilic polymer comprises a polyvinylpyrrolidone in a proportion of 1-9% by weight, in particular between 2 and 6% by weight, more particularly between 3 and 5% by weight, characterized in that the content of polyvinylpyrrolidone in the near-surface layer of the inner lumen of the membrane according to measurement method XPS is 35-65% by weight, in particular 40 to 60% by weight, more particularly 44-60% by weight, and in that the albumin sieving coefficient, measured according to the method specified in the description, is less than 0.01%, in particular less than 0.005%, in each case measured according to 30 min according to DIN EN ISO 8637:2014.Such hollow fiber membranes according to the invention are particularly suitable for extracorporeal blood treatment in which patient blood comes into contact with the membrane material of the inner lumen of the hollow fiber membranes. In particular, these membranes according to the invention are particularly suitable for the construction of hollow fiber membrane filters for intermittent or continuous extracorporeal blood purification, since they are predominantly used in therapies for kidney-damaged patients. Membranes according to the invention are preferably suitable for the treatment of particularly sensitive patients whose immune system reacts, to a very particular extent, negatively to contact with membrane material. Anaphylactic reactions are mentioned here, for example, which can even lead to forced termination of a treatment. Very particular mention should also be made of patients with a impaired nutritional state, which is shown by a reduced albumin content in the blood of the patient. The albumin content of the blood of dialysis patients, which is frequently reduced in any case, can be further reduced in special cases. It is suspected that in particular the innate immune system of these patients can react or overreact particularly sensitively. Therefore, treatment of these patients with membranes having a sieving coefficient greater than 0.01% measured after 30 min is often contraindicated. The embodiment according to the invention is therefore characterized in that the albumin sieving coefficient is less than 0.01%, more preferably less than 0.005% or more preferably less than 0.001%, which leads to a particularly low albumin loss. It has proven to be particularly advantageous that in particular the surface of the inner lumen is configured to be particularly hemocompatible, so that the blood reactions are reduced in such a way that, for example, the activation of the proteomic intate complement system is particularly low. This is also particularly important because, due to the low albumin sieving coefficient, the separation of the complement fragments is also reduced compared to membranes with higher albumin loss compared to membranes with particularly high albumin loss. Thus, the special hemocompatibility design of the surface of the inner lumen is of particular importance, which is ensured by the design of the lumen surface according to the invention.The hollow fiber membrane of the invention has at least one hydrophobic and one hydrophilic polymer, in particular the hollow fiber membrane of the invention has polysulfone as the hydrophobic polymer. For the purposes of the present application, "polysulfone" is understood to mean a polymer which has a sulfone group in the main or secondary chain of the polymer. Typical representatives of polysulfones are polysulfone based on the diol bisphenol-A (PSU), polyethersulfone based on the diol bisphenol-S (PES), polyphenylsulfone and copolymers containing sulfone groups. Further representatives of polysulfone polymers are known in the prior art and are suitable for the production of blood treatment membranes in the sense of the present application. If polymers which have neither bisphenol A nor bisphenol S are preferred, the diol component used is in particular the natural-substance-based diol isosorbide. These polysulfone polymers have been found to be superior to other polymers in the preparation of blood treatment membranes because they are steam-sterilized and have good properties in hemocompatibility. The weight proportion of the hydrophobic polymer in the hollow fiber membrane is 91 to 99%, especially 94 to 98%, more especially 97 to 95%.Furthermore, the hollow fiber membrane according to the invention comprises a hydrophilic polymer, in particular a polyvinylpyrrolidone. By "polyvinylpyrrolidone" is meant a polymer prepared using the monomer vinylpyrrolidone or derivatives thereof. In particular, "homo- or copolymeric polyvinylpyrrolidone" (also referred to as PVP) is suitable for the production of hollow-fiber membranes according to the invention in the sense of the present invention on account of the particular haemocompatibility. Polyvinylpyrrolidone is a water soluble hydrophilic polymer used in the production of polysulfone-based hollow fiber membranes. In addition, polyvinylpyrrolidone brings about an improvement in hemocompatibility of hollow fiber membranes comprising hydrophobic polymers because hydrophobic hollow fiber membranes are hydrophilized and thereby become more wettable to blood. The weight proportion of the hydrophilic polymer in the hollow fiber membrane is 1-9% by weight, in particular 2-6% by weight, more in particular 3-5% by weight. Polyvinylpyrrolidone is also to be understood explicitly when copolymers using the monomer vinylpyrrolidone are to be understood. An example of a monomer used for the copolymer insulation is vinyl acetate. Such a possible polymer is known, for example, from Fa. BASF, under the designation VA64 or similar. These hydrophilic polymers have proved to be particularly hemocompatible. In the context of the present application, "hemocompatibility" is understood to mean compatibility with human blood; in particular, this is understood to mean that blood in contact with the materials of the hollow fiber membrane enters into only slight or no negative reactions which may be harmful to the patient in the context of blood treatment therapy. By way of example, this can be understood to mean activation processes of the complement system, blood coagulation system, contact phase system and corpuscular constituents of the blood. The use of polysulfone / polyvinylpyrrolidone based polymers has been found to be superior to other blood contact materials in hollow fiber membranes in blood compatibility.The hollow fiber membrane according to the invention has a concentration of polyvinylpyrrolidone in a near-surface layer of the hollow fiber membrane on the lumen-side surface, which is 35% by weight or more, in particular 35 to 65% by weight, more particularly 40 to 60% by weight, more particularly 44 to 60% by weight, after XPS measurement. The analysis is carried out according to the "measurement method for determining the polyvinylpyrrolidone in a near-surface layer (XPS)" described in the present application. The analysis detects layers close to the surface to a depth of approximately 10 nm. Such membranes thus have a particularly high concentration of PVP on the lumen side with PVP. This leads to good hydrophilicity and thus high hemocompatibility.DE102017201630A1 has shown that a very rational manufacturing method for the production of hemocompatible membranes is to add an amount of the hydrophilic polymer to the precipitant. However, it has been found that the concentrations of polyvinylpyrrolidone in the near-surface layer according to this disclosure are limited to values of 34% or less. Surprisingly, however, it has been found that the concentration of PVP in the near-surface blood contact layer in the inner lumen of the membrane can be increased considerably further if the spinning conditions are selected such that the albumin loss is limited to less than 0.01%, in particular less than 0.005%, more in particular less than 0.001%. It can thus be ensured that excellent hemocompatibility is ensured with simultaneously particularly high albumin loss limitation, which is of particular importance for the particularly sensitive patients. At the same time, the efficient production of the membrane is also ensured. Furthermore, it has surprisingly been found that the elution of hydrophilic polymer, in particular polyvinylpyrrolidone, is further reduced compared to a situation in which the albumin loss would be higher than 0.01%. This also applies if no stabilizing substance such as a fat-soluble antioxidant is added to the spinning dope. Low elution of the water-soluble polymer has proven to be a health advantage for the patient, since eluable hydrophilic polymer can pass into the patient's organism via the extracorporeal blood circulation.The inventors assume that, due to the precipitation conditions, which are set particularly precisely for the low albumin loss, during membrane recovery and / or due to the precise control of the sterilization process of a hollow fiber dialyzer with membrane according to the invention, a substantially greater entanglement of the water-soluble polymer with the hydrophobic polymer takes place. As a result, the reduced elution of hydrophilic polymer, in particular of polyvinylpyrrolidone, ensures that constantly better hydrophilicity of the hollow fiber membrane and thus further improved haemocompatibility is ensured over the period of the extracorporeal blood treatment. The further improved hydrophilicity results in better wettability of the hollow fiber membrane with blood and the formation of an aqueous swelling layer of the hydrophilic polymer. By means of this swelling layer, the electron-negative functional groups of the membrane base material are shielded particularly well from blood contact. This is accompanied by an improved blood compatibility, which can be recognized at a lower complement activation (for example on the basis of the complement fragments C3a, C5a or sC5b-9). The hydrophilicity also causes a reduced platelet loss, since platelets adhere less to hydrophilic surfaces and thus the start of the blood coagulation cascade is prevented. Overall, inflammatory reactions are thus also reduced, which is particularly advantageous for the sensitive patients.In one embodiment, the hollow fiber membrane is characterized in that the ultrafiltration coefficient, measured in human blood according to DIN, is less than 30 ml / (hr*mmHg*m 2), in particular less than 20 ml / (hr*mmHg*m 2). It has been found that sensitive patients and patients who become newly subject to hemodialysis are in part critically responsive to high convective exchange levels, as are preferred in dialysis membranes of the prior art. The limitation of the so-called "blood UF" can effectively oppose these convective effects, so that a slow, but particularly gentle, blood cleaning can be ensured.In a further embodiment, the hollow fiber membrane is characterized in that the ultrafiltration coefficient, measured in water, is less than 150 ml / (hr*mmHg*m 2), in particular less than 100 ml / (hr*mmHg*m 2). In hemodialysis, it can be observed at the beginning of the treatment that a slow build-up of a protein layer, the so-called secondary membrane build-up, takes place. This secondary membrane construction is particularly small in the membrane according to the invention, so that a lower aqueous ultrafiltration coefficient can be set. This has the result that no otherwise occurring excess albumin loss is observable, particularly at the beginning of the treatment.In a particular embodiment, the hollow fiber membrane is characterized in that the ultrafiltration coefficient, measured in water, is less than 150 ml / (hr*mmHg*m 2), in particular less than 100 ml / (hr*mmHg*m 2) and the ultrafiltration coefficient, measured in human blood according to DIN, is less than 30 ml / (hr*mmHg*m 2), in particular less than 20 ml / (hr*mmHg*m 2). Such a membrane is particularly advantageous since a low loss of albumin is ensured over the entire treatment time of 4 to 8 hours.According to a further development of the invention, the hollow fiber membrane is characterized in that the internal diameter of the hollow fiber is less than 230 μm, in particular less than 200 μm, and is furthermore less than 180 μm. The internal diameter of a membrane is limited in the prior art in that during the treatment of the patient a more or less strong secondary membrane build-up takes place, wherein the deposited proteins, in particular albumin, at least partially denature and thereby trigger a platelet activation and an activation of the proteomic coagulation cascade. This leads to a comparatively high loading of platelets on the membrane, which is why the selection of the inner diameter is greatly limited with regard to small values. Commercially available membranes often have a diameter of 200 μm. The high hydrophilicity and the formation of the aqueous gel layer greatly reduce the protein occupancy and denaturation, resulting in significantly less platelet occupancy. This in turn enables smaller inner diameters of the membrane. A value of 165 μm has proven to be the lower limit on account of the ease of manufacture. Particularly preferred membranes thus have an internal diameter between 165 μm and 185 μm.A further embodiment of the hollow fiber membrane is characterized in that the wall thickness of the hollow fiber is less than 45 μm, in particular less than 40 μm, more in particular 35 μm or less. The suitable choice of wall thickness is therefore particularly important for membranes with low albumin loss to have a comparatively high diffusive and at the same time comparatively low convective proportion of the total mass transfer. Thus, the suitable choice of wall thickness is of particular importance. A particular embodiment has a membrane inner diameter between 165 and 180 μm and at the same time a wall thickness of less than 38, in particular less than 30 μm, which brings about a particularly good separation property.According to a further development of the invention, the hollow fiber membrane is characterized in that the content of PVP in the near-surface layer of the outer surface of the membrane is at least 23% by weight, in particular at least 24%, more particularly between 24 and 30%, measured by the XPS method. Such a membrane has particularly good wettability with the aqueous dialysate, which is guided along the outer side of the membrane in countercurrent to the blood to be purified. During the preparation of the dialyzer for the treatment, the so-called priming, this leads to good air extraction and during the treatment to a reliable guarantee of mass transfer. Limiting the PVP content at the outer surface to high concentrations additionally supports the membrane property of low elution of PVP.In one embodiment, the hollow fiber membrane is characterized in that the largest diameters of the pores in the interior of the membrane are less than 1 μm, in particular less than 0.5 μm. Dialysis membranes often have so-called "macrovoids", which are characterized by cavities with a maximum diameter of more than 1 μm or more than 0.5 μm. The measurement is carried out by recording scanning electron microscopic images of a cryobreak of the membrane. The respective diameter of the largest cavities is used as a measure. 10 images are taken and from these 10 images the largest diameter is used as a measure of the largest diameter of the pores. Such membranes with a large pore diameter have a lower mechanical stability, which is particularly valid when wall thicknesses of the membrane that are less than 40 μm are used.Within the scope of the studies on this invention, embodiments of hollow-fiber membranes have been studied, which are characterized in that the hollow fiber has a content of fat-soluble antioxidant, in particular tocopherol, of 0.005-0.5% by weight. As a result, the elution of hydrophilic polymer after aging can be further reduced. Particular preference is given to hollow-fiber membranes which are characterized in that the elution of the hydrophilic polymer, in particular of polyvinylpyrrolidone, after a storage period of 30 days at 80° C. and a relative air humidity of <5%, is less than 4000*10 -7 mg / per individual fiber, in particular after 60 days at 80° C. and a relative air humidity of <5% is less than 5000*10 -7 mg / individual fiber.In one embodiment, the hollow fiber membrane is characterized in that the selective layer of the membrane is at the lumen surface. Compared with membranes whose selective layer is on the outer surface of the membrane, the advantage of being simple to produce results, since the precipitant can be easily adjusted and then can be guided into the interior of the lumen of the hollow fiber being formed.In contrast, the precise setting of the selectivity of the outer surface is more difficult, since in addition to a medium which has to be guided into the lumen which is formed, a further precipitation medium has to be guided around the outer surface, which requires a higher outlay on apparatus.According to a further development of the invention, the hollow fiber membrane is characterized in that the proportion of uncrosslinked PVPs is less than 1 or less than 0.5, or preferably less than 0.3%, or more preferably less than 0.01%, measured by the method specified in the description. Often, dialyzers employing the membranes of the present invention are sterilized by exposure to high energy radiation. In this case, the irradiation is often carried out with electrons or gamma rays. These methods have the particular feature that, in particular, the hydrophilic polymer is significantly changed. Depending on the production conditions, bonds of the polymer can be broken, resulting in increased elution of the fragments of the polymer, or that--especially during gamma sterilization--crosslinking of the hydrophilic polymer begins, which limits the elution of the hydrophilic polymer, but precisely through the crosslinking reaction reduces the hydrophilicity of the polymer, which is disadvantageous. According to the invention, the hollow fiber is characterized by a particularly low proportion of crosslinked polymer. This is ensured, as described in the experimental part, by carrying out sterilization with hot steam. This results in a hollow fiber in which the proportion of the crosslinked hydrophilic polymer is preferably particularly low; particularly preferably, the value is below the detection limit of the method for determining the proportion of crosslinking.In a further embodiment, the hollow fiber membrane is characterized in that the hollow fiber is 3-dimensionally oriented. This leads to high separation rates, in particular for low molecular weight ureatoxins, and to significant advantages in production, since the waste during production can be reduced by this formation. A 3-dimensionally induced hollow fiber is understood to mean a hollow fiber having at least one first lock in the form of a first wave, which is characterized by a first oscillation plane and a first wavelength, and at least one second lock in the form of a second wave, which is characterized by a second oscillation plane and a second wavelength, wherein the oscillation planes enclose an angle different from 0°, in particular an angle of 50° to 120°, with one another, and wherein the first wavelength is smaller than the second wavelength.In a particular embodiment, the hollow fiber membrane is characterized in that the hollow fiber membrane has a zeta potential on the lumen-side surface of 0 mV to less than -4 mV, in particular less than -3 mV. Thus, a uniformly high hydrophilicity of the lumen surface is ensured, which ensures reliable compliance with the advantages of high hemocompatibility. In addition, in a particular embodiment, it can be ensured even further that lumen diameters of the membrane can be set between 165 and 190 μm, in particular between 165 and 170 μm.A second aspect of the invention relates to a hollow-fiber dialyzer for removing uremic toxins from blood, comprising a cylindrical container and a bundle of hollow fibers, wherein the hollow fibers are fixed at the ends of the housing with the aid of a potting material in such a way that two fluid spaces are formed which are fluidically separated via the membrane wall in such a way that mass transfer can take place only via this membrane, wherein the housing is designed in such a way that two fluid feeds or discharges are connected to the lumen of the membranes of the bundle and that two further fluid feeds or discharges are in fluidic connection with the fluid space bounded by the housing and surrounding the hollow fibers, characterized in that the bundle of hollow fibers comprises at least one plurality of hollow-fiber membranes according to one of claims 1 to.Furthermore, the second aspect of the invention relates to a hollow-fiber dialyzer, which is characterized in that the bult to be purified is guided in the lumen space of the hollow fiber and the dialysate is guided past the outer surface of the hollow fiber in the outer space of the dialyzer.Description of the Invention on the Basis of Measurement Methods, Figures and ExamplesMeasurement Method 1: Determination of Albumin Sieving CoefficientThe albumin sieving coefficient of a hollow fiber membrane is carried out on a filter as in Measurement Method 3. For the measurement, a human plasma according to the standard DIN EN ISO 8637:2014 is used to determine the sieving coefficient. Thus, the "plasma sieving coefficient" of the albumin is determined. The analytical instrument found is the Cobas Integra 400 model plus the Fa. Roche Diagnostics GmbH, Mannheim Use. The measurement is carried out with the aid of the test ALBT2 in the application for urine. A plasma flow rate of 446.6 ml / min and a dialysate flow rate (deionized water) of 89.9 ml / min are established.Measurement Method 2: Determination of zeta potentialFor the determination of the zeta potential of the hollow fiber membranes investigated, a hollow fiber membrane filter (dialyzer) with 10752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm is used. The length of the hollow fiber membranes relevant for the measurement of the zeta potential is 279 mm. The hollow fiber membranes are cast at the ends in the hollow fiber membrane filter to form a first space comprising the interior of the hollow fiber membranes and a second space comprising the space between the hollow fiber membranes. Polyurethane from Fa. The following were used: Elastogran (polyol C6947 and isocyanate 136-20). The casting height at each bundle end is 22 mm. An apparatus according to FIG. 1 is used for the measurement. The hollow fiber membrane filter (1) has fluid accesses (2, 2a, 3, 3a) to the respective first and second spaces of the hollow fiber membrane filter (1). The fluid accesses to the first space of the hollow fiber membrane filter (1) are each provided with an Ag / AgCl electrode (4, 4a) and an access for the pressure measurement (5, 5a) according to FIG. 4a. The fluid inlets (3, 3a) to the second space of the hollow fiber membrane filter (1) are tightly closed, so that the second space of the hollow fiber membrane filter is unfilled. The voltage difference ΔE z( mV) is thus recorded between the two electrodes with the aid of a voltage measuring device (6), and the pressure drop ΔP (N / m 2) is recorded between the accesses for the pressure measurement (5, 5a) with the aid of a pressure measuring device (7). The test liquid consists of a 1 mmolarene solution of KCI in water with a pH of 7.4 and is placed in a reservoir (8) placed approximately 1000 mm above the filter. The pH is adjusted according to the following procedure: 50 mg of K 2 CO 3 are added to 100 liters of the KCl solution. When the container is open, the mixture is stirred until a pH of 7.4 is established. The container is then sealed. The measurement is carried out at a temperature of 23° C.+ / - 2° C.For the measurement of the zeta potential, the test liquid is flowed into the first space of the hollow fiber membrane filter comprising the inner space of the hollow fiber membranes through a first fluid inlet (2) and is discharged again from the dialyzer through a second fluid inlet (2a) on the hollow fiber membrane filter which is connected to the inner space of the hollow fiber membranes. In this arrangement, the hollow fiber membrane filter is first rinsed with the test liquid for 10 min until a stable value has been established, and rinsing is optionally carried out for a further 5 min. The pressure difference and the voltage difference are read simultaneously at the pressure measuring device or the multimeter and the zeta potential is calculated therefrom. To increase the measurement accuracy, it is provided that after the measurement value is recorded, the two 4-way valves are switched over in such a way that a reverse flow of the test liquid through the inner space of the hollow-fiber membranes results. The measurement value for the zeta potential is then formed from the mean value of the measurements in both flow directions.The zeta potential is calculated according to the following equation:where ξ = zeta potential (mV)η =Solution viscosity (0.001 Ns / m 2)Λ o= Solution Conductivity (A / (V*m))ε o= Permittivity of vacuum (8.85*10 -12 A*s / (V*m)ε r= Relative Permittivity of Solution (80)E Z= Flow Potential (mV)Δ P= Pressure difference (N / m 2)Measurement Method 3: Determination of Clearance for Sodium and Vitamin B12The clearance of a hollow fiber membrane is determined using a hollow fiber membrane filter constructed according to measurement method 2 in accordance with DIN EN ISO 8637:2014. According to 5.6.1.2 of the standard, aqueous solutions of sodium in a concentration of 5 g / l NaCl and 0.05 g / l vitamin B12 are used as test solutions for the blood region (blood region corresponds to the first space of the hollow fiber membrane filter, comprising the interior of the hollow fiber membranes), distilled water is used for the dialysis liquid region (dialysis liquid region corresponds to the second space of the hollow fiber membrane filter, comprising the fiber interspace), the measurement is likewise carried out against dialysis liquid on the dialysate side. The sodium concentration is determined by conductivity measurements. The concentration of vitamin B12 is determined photometrically. For the clearance experiments, a hollow fiber membrane filter of identical construction is used, which is also used for the measurement according to measurement method 2. In the first space of the hollow fiber membrane filter, which comprises the interior of the hollow fiber membranes, a flow rate of 300 ml / min is established for the hollow fiber membrane filters produced in the context of this application, and in the second space of the hollow fiber membrane filter, a flow rate of 500 ml / min is established.Measurement Method 4: Determination of PVP Content of Hollow Fiber MembraneThe determination of the PVP content of the hollow fiber membrane is carried out with the aid of IR spectroscopy. For this purpose, the sample is first taken from a previously sterilized hollow fiber filter and then dried in a drying cabinet at 105° C. for 2 hours. Then 1 g of the fibre is dissolved in dichloromethane. In addition, calibration standards are established using dried PVP, which is also dissolved in dichloromethane. A concentration range of about 1% to 10% PVP in the hollow fiber is covered. The solutions are each placed in a liquid cuvette with a layer thickness of 0.2 mm. The absorption band of the carbonyl function is used for the evaluation.Measurement Method 5: Determination of Ultrafiltration CoefficientFor the determination of the local ultrafiltration coefficient according to DIN ISO 8637:2014, section 5.6.3, a hollow fiber membrane filter according to the working examples is used. Human blood (blood ultrafiltration coefficient) or, deviating from the standard DIN ISO 8637:2014, water is used as test liquid (aqueous ultrafiltration coefficient). When adjusting the flows of the respective test liquid, care is taken to establish the same maximum transmembrane pressures (TMP) of 600 mmHg. The respective ultrafiltration coefficient is given in the unit of measurement ml / (h*mmHg*m 2). In this case, the area of the filter is calculated from the inner surface of the lumens of the hollow fibers available for the free exchange, so that a normalization is available for different filter sizes.Measurement Method 6: Determination of elution of polyvinylpyrrolidoneHollow fiber membrane filters are tested for eluable portions of polyvinylpyrrolidone. For this purpose, the hollow fiber membrane filters are rinsed with an extractant at a specified temperature for a specified period of time. The extract is then tested for the content of polyvinylpyrrolidone. For this purpose, hollow fiber membrane filters are constructed according to the following instructions:A hollow fiber membrane filter (dialyzer) having 10752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm is used. The inner diameter of the filter housing is 34 mm. The length of the hollow fiber membranes relevant for the measurement of elution is 258 mm. The hollow fiber membranes are potted at the ends in the hollow fiber membrane filter to form a first space comprising the interior of the hollow fiber membranes ("blood space") and a second space ("dialysate space") comprising the space between the hollow fiber membranes. Polyurethane from Fa. The following were used: Elastogran (polyol C6947 and isocyanate 136 20). The casting height at each bundle end is 22 mm. Water serves as the extractant. 1000 ml of deionized water tempered to 37° C. are rinsed through the first space of the hollow fiber membrane filters comprising the interior of the hollow fiber membranes via two ports of the hollow fiber membrane filter. The further two connections of the hollow fiber membrane filter are closed. The flushing operation is carried out in the recirculation mode. For this purpose, a water bath heated to 37° C. is provided. A pump is used to feed temperature-controlled water from the water bath to the hollow fiber membrane filter via a first connection. The first space of the hollow fiber membrane filter is flushed through, the water is removed from the hollow fiber membrane filter via a second connection and returned to the water bath. The flushing in the recirculation mode is carried out for 5 h at a delivery rate of 200 ml / min.The polyvinylpyrrolidone which can be eluted by this method is concentrated in the water bath. The concentration of polyvinylpyrrolidone in the water bath can be determined photometrically. For photometric determination, the orange-brown colour reaction of polyvinylpyrrolidone with iodine / iodine potassium in a weakly acidic solution is used (spectrophotometric determination according to Muller or Musnich).For the procedure, 5.0 ml of citric acid solution and 2.0 ml of Kl 3- solution are added to 10 ml of the extract, mixed and reacted with one another at room temperature for 10 minutes. The absorbance of the sample solution is then determined at 470 nm. The content is determined from the measured extinction with the aid of a calibration determined beforehand. A PVP of the type K81-86 is used for the calibration.In addition, the PVP elution is determined after accelerated aging. For this purpose, a dialyzer is stored in a drying cabinet at 80° C. and a relative air humidity of <5% for a time of 30, 60 and 120 days. After this storage, the PVP elution is determined. The extracted amount of PVP is based on the individual fiber; the amount is given as a value in each case in 10 -7 mg per individual fiber, determined by the above method.Measurement Method 7: Determination of platelet loss and complement activation (Comparison Method)For determination of platelet loss ("patelet loss") and complement activation, 450 ml of human whole blood is taken from healthy donors without taking drugs, which could influence blood coagulation or platelet properties, using a 17G (1.5 mm) needle. 750 IU is placed in the blood bag. Heparin diluted in 50 ml physiological saline solution, so that a heparin concentration of 1.5 IU per ml of the mixture of blood and saline solution is produced. Within 30 min after blood dispensing, the method for determining platelet loss is started.For the hollow fiber membranes to be tested, an apparatus (10) is constructed according to the schematic illustration according to FIG. 2 in order to determine the platelet loss. The apparatus comprises a dialyzer (12), produced as described above, with the hollow fiber membranes to be tested accommodated therein. The apparatus further comprises a tubing system (13), a tube pump (14), a point for taking blood samples (15), a reservoir for blood (16), a pressure sensor (17) at the blood inlet (18) of the dialyzer (12) and a pressure sensor (19) at the blood outlet (20) of the dialyzer (12). For the determination, 200 ml of heparinized blood as described above was used. The blood was conveyed through the tube system (13) (material: PVC, manufacturer Fresenius Medical Care, Germany) through the dialyzer (12) with the aid of the tube pump (14) (manufacturer: Fresenius Medical Care, Germany) through the apparatus (10). A new tube system was used for each measurement. The entire apparatus (10) was rinsed with a 0.9% (w / v) salt solution for 30 min before the measurement. To fill the apparatus with blood, the flushing solution is displaced at a low pump speed with blood which is introduced into the apparatus and discharged until the apparatus has been filled with pure blood. The filling amount with blood was 200 ml. The displaced solution was discarded.To avoid ultrafiltration during the experiment, the dialysate side was filled beforehand with a 0.9% strength salt solution via inlets ( 21, 22) on the dialyzer and then sealed. The platelet loss is carried out at 37° C., for example in an incubator (Fa. Memmert, Germany) over a period of 180 min, wherein at the beginning of the measurement, after 30, 60, 120 and 180 min, samples are taken at the point for taking blood samples (15). The pressure at the blood inlet (18) and at the blood outlet (19) is measured to ensure a consistent course of conditions during the performance of the determination. When significant pressure changes occur, the measurement must be discarded. The blood was pumped through the apparatus at a volume rate of 200 ml / min.Hemocompatibility was determined by the parameters complement activation (sC5b-9) and by platelet loss. Platelet loss was determined in triplicate using an automatic hematology analyzer (K4500 Sysmex, Norderstedt, Germany).Complement activation was determined in duplicate using an ELISA test kit "MicroVue™ Complement SC5b-9 Plus EIA from Fa. Quidel Corporation, Athens, USA. The measurement parameter used was the factor sC5b-9, which can be dialyzed as a particularly high molecular weight protein only to a small extent during the test.The evaluation of the parameters complement activation and platelet loss is carried out as described in the publication "Score Model for the Evaluation of Dialysis Membrane Biocompatibility", Erlenkotter et al., Artificial Organs 32(12):962-998, 2008 according to the formulae (1, complement activation) and (2, platelet loss). For the determination of the platelet loss, the measurement period is in each case the first 60 min of the overall test. Therefore, for formula 1, the following conditions apply: with I PLT= mean platelet loss (%), t1=0 min, t2=60 min, Δc PLT= platelet concentration, T II= 60 min.In the measurements, a further filter according to Comparative Example 2 was determined in each case with the second half of the blood donor and the measurement results were determined relative (in %) to this comparative filter. Thus, the natural severe variations in blood response of different donors could be computationally compensated. Further, Examples and Comparative Examples described below were prepared using the same batches of raw materials.Measurement Method 8: Determination of Polyvinylpyrrolidone in a Near-Surface Layer (XPS)The content of the polyvinylpyrrolidone in the near-surface layer was determined by photoelectron spectroscopy (XPS or ESCA). With the aid of this method, the proportion of polyvinylpyrrolidone in a layer of about 5-10 nm can be determined. This layer, which is tested with the aid of the XPS method, is referred to below as "layer close to the surface". It is determined by the measurement conditions.A hollow fiber membrane is separated with the aid of a scalpel or other sharp knife, so that the inner surface and thus the selective layer or the respective outer surface of the hollow fiber membrane is exposed. This sample is fixed on a sample plate and placed in the sample chamber. The measurement conditions are set as follows:Apparatus: Thermo VG Scientific, Type K-Alphaexcitation radiation: monochromatic x-ray radiation, Al Kα, 75 W- Diameter of sample spot: 200 μm- Fitting energy: 30 eVAngle between source and analyzer: 54°Spectral resolution for an Ag3d signal: 0.48 eV:- Applied vacuum: 10 -8 mbarThe charge was compensated by means of a Food Gun.The content of PVP in the layer close to the surface was determined with the aid of the values found in mass % of nitrogen (N) and sulfur (S) by the following equation:This equation is valid for the use of polysulfone based on bisphenol A; for polyethersulfone, the following equation is to be applied:For other polysulfones, the molecular weight of the monomer unit assigned to sulfur must be determined; in the case of copolymers, the proportion of the sulfur-containing monomer in the copolymer must be taken into account.A determination is made on 3 hollow fiber membranes each and the mean of these measurements is calculated.Embodiment 1: Production of a hollow fiber membrane and a filter according to the inventionA spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Fa. Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland) and 79.7 parts by weight of DMAc are processed with stirring, heating to 60° C. and degassing to give a homogeneous spinning dope. Subsequently, the spinning dope is treated with α-tocopherol (Fa. Sigma Aldrich) is added, so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt %. For the preparation of the coagulant, 39% by weight of DMAc and 61% by weight of water are mixed and polyvinylpyrrolidone (K81 / 86 from Ashland) is added, so that the fraction of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular gap nozzle with the centrally guided coagulant to form a spun filament having a lumen diameter of 185 μm and a wall thickness of 35 μm. The coagulant is carried inside the hollow strand. The temperature of the annular gap nozzle is 71° C. The spun yarn is passed through a precipitation chamber, the atmosphere of which has a relative humidity of 100%. The height of the precipitation gap is 200 mm, and a passage time through the precipitation gap of 0.4 sec is set. The spun filament is then introduced into a precipitation bath consisting of water, which is tempered to 80° C. and precipitated to form a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths which are tempered to a temperature of 75° C. to 90° C. The hollow fiber membrane then passes through a drying process between 100° C. and 150° C. The hollow fiber membrane obtained is subsequently taken up by a coiler and brought together to form a bundle of threads. Hollow fiber membrane bundles are produced from the chopped bundle of filaments.The hollow fiber membrane bundle is further processed into a hollow fiber membrane filter as follows. The hollow fiber membrane bundle is equipped with 10752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm and prepared as above. The bundle is inserted into a polypropylene housing. The free length of the hollow fiber membranes relevant for mass transfer is 279 mm. The hollow fiber membranes are cast at the ends in the hollow fiber membrane filter to form a first space comprising the interior of the hollow fiber membranes and a second space comprising the space between the hollow fiber membranes. Polyurethane from Fa. The following were used: Elastogran (polyol C6947 and isocyanate 136-20). The casting height at each bundle end is 22 mm. The inner diameter of the housing at the smallest location in the middle of the housing is 34 mm. The obtained hollow fiber membrane filter is purified and sterilized according to a steam sterilization method as described in Patent Application The obtained hollow fiber membrane filter is purified and sterilized according to the following description.FIG. 3 shows a schematic illustration of a first step of a cleaning process of a hollow fiber membrane filter, comprising rinsing and sterilization steps as used in the production of hollow fiber membranes according to the invention or of hollow fiber membrane filters according to the first or second aspect of the invention. Figure 3 shows a fluid access 118 to a first space 119 of a hollow fibre membrane filter 113 comprising the interior space of the hollow fibre membranes which is in fluid communication with a port 101 via a conduit 109 with a valve 105. Another fluid port 117 is in fluid communication with port 102 via line 110, valve 106, and provides access to a second space 120 of hollow fiber membrane filter 113 which includes a space between the hollow fiber membranes. A further fluid access 114 is in fluid communication via line 111 with valve 107 and the connection 103 and forms an access to the one second space 120 of the hollow fiber membrane filter. Fluid port 115 is in fluid communication with a valve 108 and port 104 via conduit 112. Furthermore, the connector 101 and 103 are in fluid communication via the connector 101 a.In the first step shown, the flushing process is conveyed via connection 104 a flushing liquid through line 112 to the hollow fiber membrane filter 113. The rinsing liquid is temperature-controlled sterile water, with temperatures of 50 to 98° C. being maintained. Valve 108 is switched to flow. The rinsing liquid flows via the second fluid access 115 into the first space 119 of the hollow fiber membrane filter and leaves this first space via the first fluid access 118. With the aid of the arrangement, all the hollow-fibre membranes of a hollow-fibre membrane bundle are flushed through on their inner side.The flushing liquid furthermore passes through a bubble detector 114, which does not take on any function in this flushing operation, and line 109 and is directed via connection 101 and connecting piece 101 ato line 111. Via the fluid access 114, the rinsing liquid enters the second space 120 of the filter module 113 and flushes through the second space which is formed in the intermediate space between the hollow fiber membranes. Via fluid access 117 and line 110, the flushing liquid returns, which is either discarded or is available again for a flushing process by processing.FIG. 4 shows a schematic illustration of the second step of a rinsing and sterilization process as it is used in the production of hollow-fiber membranes according to the invention or of hollow-fiber membrane filters according to the invention according to the first or second aspect of the invention. With reference to FIG. 4, a compressed air flushing is explained. Ports 201, 202 are supplied by a source of pressurized air supplying sterile air. The compressed air is conveyed via the lines 209 and 201 via the opened valves 205 and 206 and by pump means, not shown, to the hollow fiber membrane module 213. From the previous flushing step according to the flushing process according to FIG. 3, the first space 219 and the second space 220 are initially still filled with water. The valves 207 and 208 are open and are prepared for draining rinsing liquid. The compressed air is conveyed through the filter module at a pressure of 1.5 to 2 bar. The compressed air conveys residual water via the fluid inlets 218, 217 in each case from the first and the second space of the hollow fiber membrane filter further via the fluid inlets 215 and 214 into the returning part of the flow path switching. Residual water and compressed air are discharged via the lines 212, 211. The rinsing operation is carried out for 2 to 5 minutes. Since the same pressure prevails in both spaces 219 and 220, the membrane wall is not flushed away. As a result, the pores of the membrane wall remain water-filled from the flushing process.FIG. 5 shows a schematic representation of a third step of a rinsing and sterilization process as it is used in the production of hollow fiber membranes according to the invention or of hollow fiber membrane filters according to the invention according to the first or second aspect of the invention. FIG. 5 shows the connections 302 and 304, wherein a blocking valve position of the valves 306 and 308 is dispensed with differently from in DE102016224627A1 so that the outflow of flushing fluids is not blocked. Water vapor is conveyed via connection 301 into the sterilization system and conveyed via line 309 to filter module 313. The water vapor propagates in the first space 319 of the hollow fiber membrane filter, and a discharge via the fluid access 315 is possible, since connection 304 is not blocked.This rinsing process may be complete after a few minutes. Specifically, the rinsing operation is performed for 2 to 5 minutes. Temperatures of 50° C. to 98° C. are maintained, in particular also in order to thermally condition the filter module for the subsequent sterilization process.FIG. 6 shows a schematic illustration of a fourth step of a rinsing and sterilization process, as is used in the production of hollow-fiber membranes according to the invention, or of hollow-fiber membrane filters according to the invention, according to the first or second aspect of the invention. According to the fourth step, a sterilizing fluid such as water vapor is conveyed into the hollow fiber membrane filter at a temperature of 124° C. and a pressure of about 2 bar. Connections 401, 402, 403, 404 can be flowed through by the open valves 405 to 408. The clean steam is conveyed into the hollow fiber membrane filter via the lines 409 and 410 and flows through the first space 419 and the second space 420 of the filter module 413. The pure steam is returned via the lines 412 and 411 and the fluid inlets 415 and 414 and is either discarded or reused by treatment. The sterilization process can be carried out for 5 to 30 minutes, depending on the sterilization temperature chosen. At the preferred temperature of 124° C., sterilization after about 12 minutes is considered complete.For the further quality test, a bubble point test known from the prior art follows. In this test, one side of a membrane is pressurized with a gas at a higher pressure than the opposite side of the membrane which is impinged by a liquid. For this purpose, the second space 120, 220, 320, 420 of the hollow fiber membrane filters shown in FIGS. 3 to 6 is flushed with sterile compressed air, wherein the first space remains liquid-filled from the flushing process. A higher pressure is applied by the sterilization system in the second space than in the first space 119, 219, 319, 419. Since the pores from the preceding flushing step are water-filled, a transfer of the compressed gas from the first space into the second space will only begin when the applied pressure overcomes the surface tension of the water in the pores. The amounts of gas passing into the first space can be analyzed in the bubble detectors 114, 214, 314, 414 shown and the results evaluated accordingly. By means of the quantity of the detected gas bubbles correlating to an applied pressure in the second space of the filter modules 120 to 420, conclusions can be drawn about the quality of the membrane material and a decision can be made as to whether the filter module is compliant with the specification.It is subsequently provided that the first space is likewise flushed with sterile compressed air. A further rinsing step with pure steam ensures that remaining water is removed from previous rinsing processes. A drying process at 115° C. of about 16 minutes then takes place, during which the filter module is flushed with sterile compressed air until the desired degree of drying is reached. The hollow fiber membrane filter is then free from condensate water at room temperature.The hollow fiber filter according to Example 1 was measured for platelet loss and complement activation by Measurement Method 6 as compared with Comparative Example 2. There was a decrease in platelet loss of 71.0% and a reduction in complement activation of 60.6%. It was found, in particular with respect to the loss of platelets, that only comparatively very little loss of platelets occurred in the filter itself. A portion of the platelet loss was also associated with the leads. Membranes and hollow fiber filters according to the invention thus have a particularly high hemocompatibility with very low albumin loss.Example 2: Preparation of a hollow fiber membrane and a filter of the present inventionA spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Fa. Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland) and 79.7 parts by weight of DMAc are processed with stirring, heating to 60° C. and degassing to give a homogeneous spinning dope. Subsequently, the spinning dope is treated with α-tocopherol (Fa. Sigma Aldrich) is added, so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt %. For the preparation of the coagulant, 41 wt.% of DMAc and 59 wt.% of water are mixed and polyvinylpyrrolidone (K81 / 86 from Ashland) is added, so that the fraction of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular gap nozzle with the centrally guided coagulant to form a spun filament having a lumen diameter of 185 μm and a wall thickness of 35 μm. The coagulant is carried inside the hollow strand. The temperature of the annular gap nozzle is 71° C. The spun yarn is passed through a precipitation chamber, the atmosphere of which has a relative humidity of 100%. The height of the precipitation gap is 200 mm, and a passage time through the precipitation gap of 0.4 sec is set. The spun filament is then introduced into a precipitation bath consisting of water, which is tempered to 80° C. and precipitated to form a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths which are tempered to a temperature of 75° C. to 90° C. The hollow fiber membrane then passes through a drying process between 100° C. and 150° C. The hollow fiber membrane obtained is subsequently taken up by a coiler and brought together to form a bundle of threads. Hollow fiber membrane bundles are produced from the chopped bundle of filaments.The hollow fiber membrane bundle is further processed into hollow fiber membrane filters as in Example 1. The resulting hollow fiber membrane filter is sterilized by a steam sterilization method as described in Example 1.Example 3: Production of a hollow fiber membrane and a filter according to the inventionA spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Fa. Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland) and 79.7 parts by weight of DMAc are processed with stirring, heating to 60° C. and degassing to give a homogeneous spinning dope. Subsequently, the spinning dope is treated with α-tocopherol (Fa. Sigma Aldrich) is added, so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt %. For the preparation of the coagulant, 43% by weight of DMAc and 57% by weight of water are mixed and polyvinylpyrrolidone (K81 / 86 from Ashland) is added, so that the fraction of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular gap nozzle with the centrally guided coagulant to form a spun filament having a lumen diameter of 185 μm and a wall thickness of 35 μm. The coagulant is carried inside the hollow strand. The temperature of the annular gap nozzle is 71° C. The spun yarn is passed through a precipitation chamber, the atmosphere of which has a relative humidity of 100%. The height of the precipitation gap is 200 mm, and a passage time through the precipitation gap of 0.4 sec is set. The spun filament is then introduced into a precipitation bath consisting of water, which is tempered to 80° C. and precipitated to form a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths which are tempered to a temperature of 75° C. to 90° C. The hollow fiber membrane then passes through a drying process between 100° C. and 150° C. The hollow fiber membrane obtained is subsequently taken up by a coiler and brought together to form a bundle of threads. Hollow fiber membrane bundles are produced from the chopped bundle of filaments.The hollow fiber membrane bundle is further processed into hollow fiber membrane filters as in Example 1. The resulting hollow fiber membrane filter is sterilized by a steam sterilization method as described in Example 1.Comparative Example 1: Production of a hollow fiber membrane and a filterA spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Fa. Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland) and 79.7 parts by weight of DMAc are processed with stirring, heating to 60° C. and degassing to give a homogeneous spinning dope. Subsequently, the spinning dope is treated with α-tocopherol (Fa. Sigma Aldrich) is added, so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt %. For the preparation of the coagulant, 35 wt % of DMAc and 65 wt % of water are mixed and polyvinylpyrrolidone (K81 / 86 from Ashland) is added, so that the fraction of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular gap nozzle with the centrally guided coagulant to form a spun filament having a lumen diameter of 185 μm and a wall thickness of 35 μm. The coagulant is carried inside the hollow strand. The temperature of the annular gap nozzle is 71° C. The spun yarn is passed through a precipitation chamber, the atmosphere of which has a relative humidity of 100%. The height of the precipitation gap is 200 mm, and a passage time through the precipitation gap of 0.4 sec is set. The spun filament is then introduced into a precipitation bath consisting of water, which is tempered to 80° C. and precipitated to form a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths which are tempered to a temperature of 75° C. to 90° C. The hollow fiber membrane then passes through a drying process between 100° C. and 150° C. The hollow fiber membrane obtained is subsequently taken up by a coiler and brought together to form a bundle of threads. Hollow fiber membrane bundles are produced from the chopped bundle of filaments.The hollow fiber membrane bundle is further processed into a hollow fiber membrane filter as in Example 1 and purified, sterilized and dried as follows.FIG. 3 shows a schematic illustration of a first step of a cleaning process of a hollow fiber membrane filter, comprising rinsing and sterilization steps as used in the production of hollow fiber membranes according to the invention or of hollow fiber membrane filters according to the first or second aspect of the invention. Figure 3 shows a fluid access 118 to a first space 119 of a hollow fibre membrane filter 113 comprising the interior space of the hollow fibre membranes which is in fluid communication with a port 101 via a conduit 109 with a valve 105. Another fluid port 117 is in fluid communication with port 102 via line 110, valve 106, and provides access to a second space 120 of hollow fiber membrane filter 113 which includes a space between the hollow fiber membranes. A further fluid access 114 is in fluid communication via line 111 with valve 107 and the connection 103 and forms an access to the one second space 120 of the hollow fiber membrane filter. Fluid port 115 is in fluid communication with a valve 108 and port 104 via conduit 112. Furthermore, the connector 101 and 103 are in fluid communication via the connector 101 a.In the first step shown, the flushing process is conveyed via connection 104 a flushing liquid through line 112 to the hollow fiber membrane filter 113. The rinsing liquid is temperature-controlled sterile water, with temperatures of 50 to 98° C. being maintained. Valve 108 is switched to flow. The rinsing liquid flows via the second fluid access 115 into the first space 119 of the hollow fiber membrane filter and leaves this first space via the first fluid access 118. With the aid of the arrangement, all the hollow-fibre membranes of a hollow-fibre membrane bundle are flushed through on their inner side.The flushing liquid furthermore passes through a bubble detector 114, which does not take on any function in this flushing operation, and line 109 and is directed via connection 101 and connecting piece 101 ato line 111. Via the fluid access 114, the rinsing liquid enters the second space 120 of the filter module 113 and flushes the second space which is formed in the intermediate space between the hollow fiber membranes. Via fluid access 117 and line 110, the flushing liquid returns, which is either discarded or is available again for a flushing process by processing.FIG. 4 shows a schematic illustration of the second step of a rinsing and sterilization process as it is used in the production of hollow-fiber membranes according to the invention or of hollow-fiber membrane filters according to the invention according to the first or second aspect of the invention. With reference to FIG. 4, a compressed air flushing is explained. Ports 201, 202 are supplied by a source of pressurized air supplying sterile air. The compressed air is conveyed via the lines 209 and 201 via the opened valves 205 and 206 and by pump means, not shown, to the hollow fiber membrane module 213. From the previous flushing step according to the flushing process according to FIG. 3, the first space 219 and the second space 220 are initially still filled with water. The valves 207 and 208 are open and are prepared for draining rinsing liquid. The compressed air is conveyed through the filter module at a pressure of 1.5 to 2 bar. The compressed air conveys residual water via the fluid inlets 218, 217 in each case from the first and the second space of the hollow fiber membrane filter further via the fluid inlets 215 and 214 into the returning part of the flow path switching. Residual water and compressed air are discharged via the lines 212, 211. The rinsing operation is carried out for 2 to 5 minutes. Since the same pressure prevails in both spaces 219 and 220, the membrane wall is not flushed away. As a result, the pores of the membrane wall remain water-filled from the flushing process.FIG. 5 shows a schematic representation of a third step of a rinsing and sterilization process as it is used in the production of hollow fiber membranes according to the invention or of hollow fiber membrane filters according to the invention according to the first or second aspect of the invention. In FIG. 5, connections 302 and 304 are shown, which block the outflow of flushing fluids by a blocking valve position of valves 306 and 308. Water vapor is conveyed via connection 301 into the sterilization system and conveyed via line 309 to filter module 313. The water vapor propagates in the first space 319 of the hollow fiber membrane filter, and it is not possible to conduct it through the fluid access 315 since connection 304 is blocked. Water vapor in line 312 may only be expanded by compression of the pressurized clean vapor or diffusion.Since there is a higher pressure in the first space than in the second space, a transmembrane transition of the pure vapor takes place. Residual water remaining in the pores from the rinsing process after the first step of the rinsing and sterilizing process of FIG. 3 is carried away and conveyed into the conduit 311 via the second space 320. This rinsing process may be complete after a few minutes. Specifically, the rinsing operation is performed for 2 to 5 minutes. Temperatures of 50° C. to 98° C. are maintained, in particular also in order to thermally condition the filter module for the subsequent sterilization process.FIG. 6 shows a schematic illustration of a fourth step of a rinsing and sterilization process, as is used in the production of hollow-fiber membranes according to the invention, or of hollow-fiber membrane filters according to the invention, according to the first or second aspect of the invention. According to the fourth step, a sterilizing fluid such as water vapor is conveyed into the hollow fiber membrane filter at a temperature of 124° C. and a pressure of about 2 bar. Connections 401, 402, 403, 404 can be flowed through by the open valves 405 to 408. The clean steam is conveyed into the hollow fiber membrane filter via the lines 409 and 410 and flows through the first space 419 and the second space 420 of the filter module 413. The pure steam is returned via the lines 412 and 411 and the fluid inlets 415 and 414 and is either discarded or reused by treatment. The sterilization process can be carried out for 5 to 30 minutes, depending on the sterilization temperature chosen. At the preferred temperature of 124° C., sterilization after about 12 minutes is considered complete.For the further quality test, a bubble point test known from the prior art follows. This test represents a pressure holding test in which a gas at a higher pressure is applied to one side of a membrane than the opposite side of the membrane which is acted upon by a liquid. For this purpose, the second space 120, 220, 320, 420 of the hollow fiber membrane filters shown in FIGS. 3 to 6 is flushed with sterile compressed air, wherein the first space remains liquid-filled from the flushing process. A higher pressure is applied by the sterilization system in the second space than in the first space 119, 219, 319, 419. Since the pores from the preceding flushing step are water-filled, a transfer of the compressed gas from the first space into the second space will only begin when the applied pressure overcomes the surface tension of the water in the pores. The amounts of gas passing into the first space can be analyzed in the bubble detectors 114, 214, 314, 414 shown and the results evaluated accordingly. By means of the quantity of the detected gas bubbles correlating to an applied pressure in the second space of the filter modules 120 to 420, conclusions can be drawn about the quality of the membrane material and a decision can be made as to whether the filter module is compliant with the specification.It is subsequently provided that the first space is likewise flushed with sterile compressed air. A further rinsing step with pure steam ensures that remaining water from previous rinsing processes is removed. A drying process at about 115° C. of about 16 minutes then takes place, during which the filter module is flushed with sterile compressed air until the desired degree of drying is reached.Comparative Example 2: Production of a hollow fiber membrane and a filterA spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Fa. Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland) and 79.7 parts by weight of DMAc are processed with stirring, heating to 60° C. and degassing to give a homogeneous spinning dope. Subsequently, the spinning dope is treated with α-tocopherol (Fa. Sigma Aldrich) is added, so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt %. For the preparation of the coagulant, 39 wt.% DMAc and 61 wt.% water are mixed without adding polyvinylpyrrolidone to the coagulant. The spinning dope is processed through an annular gap nozzle with the centrally guided coagulant to form a spun filament having a lumen diameter of 185 μm and a wall thickness of 35 μm. The coagulant is carried inside the hollow strand. The temperature of the annular gap nozzle is 71° C. The spun yarn is passed through a precipitation chamber, the atmosphere of which has a relative humidity of 100%. The height of the precipitation gap is 200 mm, and a passage time through the precipitation gap of 0.4 sec is set. The spun filament is then introduced into a precipitation bath consisting of water, which is tempered to 80° C. and precipitated to form a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths which are tempered to a temperature of 75° C. to 90° C. The hollow fiber membrane then passes through a drying process between 100° C. and 150° C. The hollow fiber membrane obtained is subsequently taken up by a coiler and brought together to form a bundle of threads. Hollow fiber membrane bundles are produced from the chopped bundle of filaments.The hollow fiber membrane bundle is further processed into hollow fiber membrane filters as in Example 1. The resulting hollow fiber membrane filter is sterilized by a steam sterilization method as described in Example 1.Example 4 Preparation of a hollow fiber membrane and a filter according to the inventionThe membrane is prepared in the same manner as in Comparative Example 1, except that a mixture of 24% by weight of DMAC in water is used as precipitant with the addition of the same amount of PVP in the precipitant. The hollow fiber filter is prepared in the same manner as in Comparative Example 1.Tabular Summary of the Measurement ResultsTable 1 Table 1Example 110.724<0.001Example 212.330<0.001Example 313.132<0.002Example 413,320,7<0,001See Bspl.1371500,05See Bspl. 21125<0.001A particularly low albumin sieving coefficient is achieved at a sufficiently high ultrafiltration rate. Table 2 Table 2Example 1262129Example 2263130Example 3263136See Bspl. 1278157See Bspl. 2263135Despite the particularly low albumin sieving coefficient, a sufficiently high clearance of the low- and medium-molecular test substances is achieved for the examples. Table 3 Table 3Example 156,428,1Example 253,326,0Example 344,125,4See Bspl. 128,623,9See Bspl. 223,521,9Despite the use of the same amount of PVP in the precipitant as in, for example, Comparative Example 1, a substantially higher loading with PVP on the lumen side is achieved. A higher loading is also achieved on the outer side, so that, owing to the improved hydrophilicity of the outer side, in each case improved wetting with aqueous dialysate is achieved, which results in improved priming of the dialyzer before use. The increase in hydrophilicity of the lumen side leads to a much improved hemocompatibility, which could be demonstrated by comparison of Example 1 with Comparative Example 1. The zeta potential of the examples is higher than -3 mV in each case, which highlights the particularly hydrophilic character of the lumen surface.References included in the specificationThis list of documents cited by the applicant has been produced in an automated manner and is only included for the better information of the reader. The list is not part of the German patent application or utility model application. The DPMA does not take any adhesion for any faults or omissions.Patent Literature citedEP 0 168 783

[0004] EP 2737916A

[0009] EP 0 568 045

[0010] DE 102017201630A1 [0011, 0018]DE 102017201630A

[0011] DE 102016224627A1

[0065] Cited Non-Patent LiteratureMarcel Mulder; Principles of Membrane Technology; Kluwer Academic Publisher 1996; Chapter III, Preparation of Synthetic Membranes

[0004] A. Erlenkotter, P. Endres, B. Nederlof, C. Hornig, J. Vienken; Artificial Organs; 32 (12), 962 (2008

[0005] DIN EN ISO 8637:2014 [0013, 0035]DIN ISO 8637:2014

[0041] Score Model for the Evaluation of Dialysis Membrane Biocompatibility", Erlenötter et al., Artificial Organs 32(12):962-998, 2008

[0051]

Claims

Hollow fibre membrane comprising a membrane material comprising a hydrophobic and a hydrophilic polymer, wherein the hydrophobic polymer comprises a polysulfone and the hydrophilic polymer comprises a polyvinylpyrrolidone in a proportion of 1-9% by weight, in particular between 2 and 6% by weight, further in particular between 3 and 5% by weight, characterized in that the content of polyvinylpyrrolidone in the near-surface layer of the inner lumen of the membrane according to measurement method XPS is 35% or more, in particular 35-65% by weight, further in particular 40 to 60% by weight, further in particular 44-60% by weight, and in that the albumin sieving coefficient, measured according to the method specified in the description, is less than 0.01%, in particular less than 0.005%, further in particular less than 0.001%.Hollow fibre membrane according to claim 1, characterised in that the ultrafiltration coefficient, measured in blood, is less than 30 ml / (h*mmHg*m 2), in particular less than 20 ml / (h*mmHg*m 2).Hollow fibre membrane according to claim 1, characterised in that the ultrafiltration coefficient, measured in water, is less than 150 ml / (h*mmHg*m 2), in particular less than 100 ml / (h*mmHg*m 2).Hollow fibre membrane according to claim 1, characterised in that the internal diameter of the hollow fibre is less than 230 μm, in particular less than 200 μm, further in particular less than 180 μm, further in particular between 165 and 185 μm.Hollow fibre membrane according to claim 1, characterised in that the wall thickness of the hollow fibre is less than 45 μm, in particular less than 40 μm.Hollow fibre membrane according to claim 1, characterised in that the content of PVP in the near-surface layer of the outer surface of the membrane is at least 23 wt.-%, in particular at least 24 %, more particularly between 24 and 30 %, measured according to the XPS method.Hollow fibre membrane according to claim 1, characterised in that the largest diameters of the pores in the interior of the membrane are less than 1 μm, in particular less than 0.5 μm.Hollow fibre membrane according to claim 1, characterised in that the hollow fibre has a content of fat-soluble antioxidant, in particular tocopherol, of 0.005 - 0.5 wt.%.Hollow fibre membrane according to claim 1, characterised in that the elution of the hydrophilic polymer, in particular of polyvinylpyrrolidone, after a storage period of 30 days at 80°C and a relative air humidity of <5%, is less than 4000*10 -7 mg / per single fibre, in particular after 60 days at 80°C and a relative air humidity of <5% is less than 5000*10 -7 mg / single fibre.Hollow fibre membrane according to claim 1, characterised in that the proportion of non-cross-linked PVP is less than 1 wt.% or less than 0.5 wt.% or less than 0.3 wt.% or less than 0.01 wt.%, measured according to the method indicated in the description.Hollow fibre membrane according to claim 1, characterised in that the hollow fibre is 3-dimensionally oriented.Hollow fiber membrane according to claim 1, characterized in that the hollow fiber membrane has a zeta potential of 0 mV to less than -4 mV on the lumen-side surface.Hollow-fibre dialyzer for removing uremic toxins from blood, comprising a cylindrical container and a bundle of hollow fibres, wherein the hollow fibres are fixed at both ends with the aid of a potting material at the ends of the housing in such a way that two fluid spaces are formed which are fluidically separated via the membrane wall in such a way that mass transfer can take place only via this membrane, wherein the housing is designed in such a way that two fluid feeds or discharges are connected to the lumen of the membranes of the bundle and that two further fluid feeds or discharges are in fluidic connection with the fluid space bounded by the housing and surrounding the hollow fibres, wherein the culture to be purified is guided in the lumen space of the hollow fibre and the dialysate in the outer space of the dialyzer is guided past the outer surface, characterized in that, said bundle of hollow fibers comprises at least a plurality of hollow fiber membranes according to any one of claims 1 to 12.

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