Hollow-fiber membrane with a high degree of biocompatibility and low albumin loss

Abstract

The invention relates to a hollow-fiber membrane, having a membrane material which comprises a hydrophobic polymer and a hydrophilic polymer. 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 layer which is near the surface of the inner lumen of the membrane equals 35 wt.% or more according to the XPS measuring method, and the albumin filter coefficient equals less than 0.01, measured according to the method specified in the description. The invention additionally relates to a hollow-fiber dialyzer comprising such a membrane.

Description

[0001] Hollow fiber membrane with high biocompatibility and low albumin loss

[0002] Technical area

[0003] The invention encompasses hollow fiber membranes comprising a membrane material comprising a hydrophobic and a hydrophilic polymer, offering improved hemocompatibility properties while simultaneously reducing albumin loss. Furthermore, the invention relates to a hollow fiber membrane dialyzer comprising such a membrane.

[0004] Background of the invention

[0005] Hollow-fiber membranes are widely used in the purification of fluids. In particular, hollow-fiber membranes are used in medical technology for blood purification in dialysis for patients with kidney disease. Hollow-fiber membranes are installed in the form of hollow-fiber membrane bundles in filter modules used in extracorporeal blood treatment. Such filter modules for blood purification, called dialyzers, are manufactured on a mass production scale.

[0006] The hollow-fiber membranes used for blood purification often consist of a hydrophobic and a hydrophilic polymer, particularly polysulfone and polyvinylpyrrolidone, as these materials have proven to be inherently hemocompatible and are therefore medically preferable in blood treatment, especially hemodialysis. This is reflected in the fact that a very high proportion of commercially offered and sold dialyzers comprise these material groups. Other hydrophobic polymers that are generally suitable are polyamide, polyacrylonitrile, and regenerated cellulose and cellulose derivatives, particularly cellulose acetate. Another hydrophilic polymer that is generally suitable is polyethylene glycol.

[0007] The basic principles of hollow fiber membrane production, their manufacturing and their properties are described in the state of the art:

[0008] • Marcel Mulder; Principles of Membrane Technology; Kluwer Academic Publisher 1996; Kapitel III, Preparation of synthetic membranes

[0009] • EP 0 168 783

[0010] To assess the biocompatibility of commercially available dialyzers, a method proposed by Vienken et al. (A. Erlenkötter, P. Endres, B. Nederlof, C. Hornig, J. Vienken; Artificial Organs; 32 (12), 962, (2008)) involves recirculating test blood through a dialyzer for a predetermined period of time and recording the adverse reactions that occur using a selection of so-called hemocompatibility markers. The hemocompatibility markers used in this method were complement factor 5a (C5a) or sC5b-9, the thrombin-antithrombin III complex (TAT), the platelet count (PLT), platelet factor 4 (PF4), and the release of elastase from polymorphonuclear granulocytes (PMN elastase). To assess the biocompatibility of a dialyzer, this method proposes evaluating the individual hemocompatibility markers using a scoring system.It is further proposed to calculate a total hemocompatibility score (THS) for a dialyzer from the scoring of the individual hemocompatibility markers, thus making different dialyzers comparable in terms of their biocompatibility.

[0011] The results of this method clearly showed that both the membrane material and the different sterilization methods used to sterilize commercially available dialyzers can clearly influence the biocompatibility of hollow fiber membranes. In particular, differences in the biocompatibility of the dialyzers examined were observed due to the different membrane materials (polysulfone, polyethersulfone / polyarylate, regenerated cellulose, esterified cellulose), and the different sterilization methods, such as steam sterilization, radiation sterilization (y-rays or electron beams), and vacuum steam sterilization.

[0012] Hollow-fiber membranes and dialyzers are used as disposable medical devices in therapeutic blood treatment and are therefore commercially available as mass-produced items for patient care. The manufacturing method for hollow-fiber membranes and dialyzers is therefore often driven by economic interests and productivity aspects. This means that while the production of hollow-fiber membranes and dialyzers is designed to achieve the required performance characteristics, production is also geared to the most cost-effective standards possible. The studies by Vienken et al. clearly show that the state-of-the-art manufacturing processes for hollow-fiber membranes and dialyzers are often suboptimal with regard to the desired advantageous biocompatibility.

[0013] The prior art describes methods for producing hollow fiber membranes with the aim of providing hollow fiber membranes that enable high biocompatibility for a given separation performance and, at the same time, cost-effective production. In particular, manufacturing processes for hollow fiber membranes are described in which the hollow fiber membranes are modified with a fat-soluble vitamin, e.g., vitamin E. It is described that such modifications can be carried out, for example, by adding vitamin E to the coagulant used in the manufacturing process. In this way, the inner surface of the manufactured hollow fiber membranes is coated with vitamin E, thus improving biocompatibility. It is assumed that the hollow fiber membranes modified with vitamin E have an antioxidant effect on blood cells when they come into contact with treatment blood.reduce the effect of the immunologically relevant "chemical brush" and generally correct the pro-oxidative blood status of patients with chronic renal failure. An example of such an antioxidant effect of a modified hollow fiber membrane is described in EP2737916A. It is striking that a comparatively high coating of vitamin E occurs, which achieves the desired antioxidant effect, but results in a comparatively low hydrophilicity of the surface.

[0014] On the other hand, the hydrophilization of the inner surface of polysulfone hollow fiber membranes is being discussed in connection with improved blood wettability and biocompatibility. In this context, EP 0 568 045 describes the production of a hollow fiber membrane based on polysulfone.

[0015] A special hollow-fiber membrane and a corresponding manufacturing method are described in detail in DE102017201630A1. The manufacturing method, and in particular the spinning process, is modified in such a way that a small amount of approximately 1 g to approximately 3 g of hydrophilic polymer per kg of precipitant is added to the precipitant located inside the developing membrane, resulting in a membrane whose near-surface region of the lumen surface has a higher content of hydrophilic polymer. At the same time, a fat-soluble antioxidant was added to the spinning dope, resulting in a more hydrophilic membrane with lower elution of hydrophilic polymer compared to the prior art in DE102017201630A1.Using the technology disclosed in the document, good hydrophilicity was achieved, which can be demonstrated by determining the coverage of the selective inner surface of the membrane using X-ray photoelectron spectroscopy. Coverage values ​​of up to 30% (Example 6 of DE102017201630A1) were detected on the inner surface. A disadvantage has been found in the membranes produced according to DE102017201630A1, which resulted in a comparatively high albumin loss, which may be contraindicated for particularly sensitive patients. According to Table 2 of DE102017201630A1, the albumin sieving coefficient of the example is 20.2% after 5 minutes and 0.05% after 30 minutes. This leads to comparatively high albumin losses during a therapy session.A problem here has been identified: especially in patients with an already low albumin status, which can occur as kidney disease progresses, further albumin loss should be avoided. Furthermore, it has been shown that such dialyzers may not be adequately suited to treat patients who have recently become hemodialysis dependent. Furthermore, it has been shown that further improvement in hemocompatibility, particularly in anticoagulation properties, is desirable.

[0016] Object of the invention

[0017] With regard to the problems prevailing in the prior art, it has become apparent that there is still a need to provide hollow-fiber membranes with improved biocompatibility. In particular, there is still a need to find membranes that can ensure excellent biocompatibility and high therapeutic success, especially for particularly sensitive patients. One sub-task is to provide a hollow-fiber membrane or dialyzer that, due to its hemocompatibility, is particularly suitable for patients who are newly requiring hemodialysis, especially for those with a critical nutritional status or poor albumin status. Another sub-task is to be able to provide sterile hollow-fiber membranes or dialyzers for patients with critical nutritional status or poor albumin status.In particular, the membrane or dialyzer provided should be cost-effective and save on material and equipment costs. A further sub-objective is to provide a dialyzer with further improved hemocompatibility, particularly its anticoagulation properties. Summary of the invention.

[0018] The object is achieved by a hollow fiber membrane of claims 1-12 and a hollow fiber dialyzer according to claim 13.

[0019] The first aspect of the invention relates to a hollow fiber membrane, having a membrane material which comprises 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.%, in particular between 2 and 6 wt.%, more particularly between 3 and 5 wt.%, characterized in that the content of polyvinylpyrrolidone in the near-surface layer of the inner lumen of the membrane according to the XPS measurement method is 35-65 wt.%, in particular 40 to 60 wt.%, more particularly 44-60 wt.% and 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 after 30 min. according to DIN EN ISO 8637:2014.

[0020] 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, as they are predominantly used in the treatment of patients with kidney damage. Membranes according to the invention are particularly suitable for the treatment of particularly sensitive patients whose immune systems react particularly negatively to contact with membrane material. Examples include anaphylactic reactions, which can even lead to the forced discontinuation of treatment. Patients with a deteriorated nutritional status, as evidenced by a reduced albumin content in the patient's blood, are also particularly suitable.The already frequently reduced albumin content of the blood of dialysis patients can be further reduced in special cases. It is suspected that the innate immune system of these patients may react particularly sensitively or overreact. Therefore, treatment of these patients with membranes having a sieving coefficient greater than 0.01%, measured after 30 minutes, 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 particularly advantageous that the surface of the inner lumen is designed to be particularly hemocompatible, so that blood reactions are reduced to such an extent that, for example, the activation of the proteomic innate complement system is particularly low. This is also particularly important because, due to the low albumin sieving coefficient, the separation of complement fragments is also reduced compared to membranes with higher albumin loss. Thus, the special hemocompatibility design of the surface of the inner lumen is of particular importance, which is ensured by the inventive design of the lumen surface.

[0021] The hollow-fiber membrane according to the invention comprises at least one hydrophobic and one hydrophilic polymer; in particular, the hollow-fiber membrane according to the invention comprises polysulfone as the hydrophobic polymer. For the purposes of the present application, "polysulfone" is understood to mean a polymer that has a sulfone group in the main or side chain of the polymer. Typical examples 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. Other examples of polysulfone polymers are known in the art and, for the purposes of the present application, are suitable for the production of blood treatment membranes. If polymers that contain neither bisphenol-A nor bisphenol-S are preferred, the naturally occurring diol isosorbide is particularly suitable as the diol component.These polysulfone polymers have proven superior to other polymers in the manufacture of blood treatment membranes because they are steam sterilizable and exhibit good hemocompatibility properties. The weight fraction of the hydrophobic polymer in the hollow fiber membrane is 91 to 99%, particularly 94 to 98%, and even more particularly 97 to 95%.

[0022] Furthermore, the hollow fiber membrane according to the invention comprises a hydrophilic polymer, in particular a polyvinylpyrrolidone. “Polyvinylpyrrolidone” is understood to mean a polymer produced using the monomer vinylpyrrolidone or derivatives thereof. “Homo- or copolymeric polyvinylpyrrolidone” (also referred to as PVP) is particularly suitable for the production of hollow fiber membranes according to the invention due to its particular hemocompatibility. Polyvinylpyrrolidone is a water-soluble, hydrophilic polymer used in the production of hollow fiber membranes based on polysulfone. In addition, polyvinylpyrrolidone improves the hemocompatibility of hollow fiber membranes comprising hydrophobic polymers, since hydrophobic hollow fiber membranes are hydrophilized and thus more easily wetted by blood. The weight fraction of the hydrophilic polymer in the hollow fiber membrane is 1-9 wt. %, in particular 2-6 wt.-%, more particularly 3-5 wt.%. Polyvinylpyrrolidone is also explicitly understood to mean copolymers using the monomer vinylpyrrolidone. An example of a monomer used for copolymerization is vinyl acetate. One such possible polymer is marketed, for example, by BASF under the name VA64 or similar. These hydrophilic polymers have proven to be particularly hemocompatible. For the purposes of the present application, "hemocompatibility" is understood to mean compatibility with human blood; in particular, it is understood that blood in contact with the materials of the hollow fiber membrane experiences only minor or no adverse reactions that could be harmful to the patient in the context of blood treatment therapy.Examples include activation processes of the complement system, blood coagulation system, contact phase system, and corpuscular components of the blood. The use of polysulfone / polyvinylpyrrolidone-based polymers in hollow fiber membranes has proven superior to other blood contact materials in terms of their blood compatibility.

[0023] 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 according to XPS measurement is 35 wt.% or more, in particular 35 to 65 wt.%, more particularly 40 to 60 wt.%, more particularly 44 to 60 wt.%. The analysis is carried out according to the "Measurement Method for Determining Polyvinylpyrrolidone in a Near-Surface Layer (XPS)" as described in the present application. The analysis detects near-surface layers down 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 efficient manufacturing method for the production of hemocompatible membranes consists in adding an amount of the hydrophilic polymer to the precipitant.However, it has been shown 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 shown that the concentration of PVP in the near-surface blood contact layer in the inner lumen of the membrane can be significantly increased if the spinning conditions are selected such that albumin loss is limited to less than 0.01%, in particular less than 0.005%, and even more particularly less than 0.001%. This ensures excellent hemocompatibility while simultaneously limiting albumin loss, which is of particular importance for particularly sensitive patients. At the same time, the efficient production of the membrane is ensured.

[0024] Furthermore, it has surprisingly been found that the elution of hydrophilic polymer, especially polyvinylpyrrolidone, is further reduced compared to a situation where albumin loss would be higher than 0.01%. This also applies when no stabilizing substance, such as a fat-soluble antioxidant, is added to the spinning mass. Low elution of the water-soluble polymer proves to be beneficial for the patient, as elutable hydrophilic polymer can enter the patient's body via the extracorporeal bloodstream.

[0025] The inventors suspect that the precipitation conditions during membrane formation, which are particularly precisely adjusted to minimize albumin loss, and / or the precise control of the sterilization process of a hollow-fiber dialyzer with a membrane according to the invention, result in a significantly stronger entanglement of the water-soluble polymer with the hydrophobic polymer. The reduced elution of hydrophilic polymer, particularly polyvinylpyrrolidone, ensures that a consistently improved hydrophilicity of the hollow-fiber membrane and thus further improved hemocompatibility is guaranteed over the period of 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. This swelling layer shields the electronegative functional groups of the membrane base material particularly well from blood contact.This is accompanied by improved blood compatibility, which can be recognized by reduced complement activation (e.g., by the complement fragments C3a, C5a, or sC5b-9). Hydrophilicity also causes reduced platelet loess, as platelets adhere less to hydrophilic surfaces, thus preventing the initiation of the blood coagulation cascade. This also reduces overall inflammatory reactions, which is particularly beneficial for sensitive patients.

[0026] 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 ), especially less than 20 ml / (hr*mmHg*m 2). It has been shown that sensitive patients and patients newly requiring hemodialysis sometimes react critically to high convective exchange rates, such as those favored by state-of-the-art dialysis membranes. Limiting the so-called "blood UF" can effectively counteract these convective effects, ensuring slow but particularly gentle blood purification.

[0027] 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 ), especially less than 100 ml / (hr*mmHg*m 2). During hemodialysis, a slow buildup of a protein layer, known as secondary membrane buildup, can be observed at the beginning of treatment. This secondary membrane buildup is particularly low with the membrane according to the invention, allowing a lower aqueous ultrafiltration coefficient to be set. This means that, especially at the beginning of treatment, no excessive albumin loss, which would otherwise occur, is observed.

[0028] 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 ), especially 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 ), especially less than 20 ml / (hr*mmHg*m 2). Such a membrane is particularly advantageous because it ensures low albumin loss over the entire treatment time of 4 to 8 hours. According to a development of the invention, the hollow fiber membrane is characterized in that the inner diameter of the hollow fiber is less than 230 pm, in particular less than 200 pm, and furthermore less than 180 pm. The inner diameter of a membrane is limited in the prior art by the fact that during the treatment of the patient a more or less strong secondary membrane buildup takes place, whereby the deposited proteins, in particular albumin, are at least partially denatured and thereby trigger platelet activation and activation of the proteomic coagulation cascade. This leads to a comparatively strong coating of the membrane with platelets, which is why the choice of the inner diameter is very limited with regard to small values.Commercially available membranes often have a diameter of 200 pm. Due to their high hydrophilicity and the formation of the aqueous gel layer, protein deposition and denaturation are greatly reduced, resulting in significantly lower platelet deposition. This, in turn, allows for smaller membrane inner diameters. A value of 165 pm has been established as the lower limit due to ease of manufacture. Particularly preferred membranes therefore have an inner diameter between 165 pm and 185 pm.

[0029] A further embodiment of the hollow fiber membrane is characterized in that the wall thickness of the hollow fiber is less than 45 pm, in particular less than 40 pm, more particularly 35 pm or less. The appropriate choice of wall thickness is particularly important because membranes with low albumin loss have a comparatively high diffusive and, at the same time, a comparatively low convective component of the overall mass transfer. Thus, the appropriate choice of wall thickness is particularly important. A particular embodiment has a membrane inner diameter between 165 and 180 pm and, at the same time, a wall thickness of less than 38, in particular less than 30 pm, which results in particularly good separation properties.

[0030] According to a further development of the invention, the hollow-fiber membrane is characterized in that the PVP content in the near-surface layer of the outer surface of the membrane is at least 23 wt.%, in particular at least 24%, further in particular between 24 and 30%, measured according to the XPS method. Such a membrane exhibits particularly good wettability with the aqueous dialysate, which is passed along the outer surface of the membrane in countercurrent to the blood to be purified. This leads to good ventability during the preparation of the dialyzer for treatment, the so-called "priming", and to a reliable guarantee of mass transfer during treatment. Limiting the PVP content on the outer surface to high concentrations additionally supports the membrane property of low PVP elution.

[0031] In one embodiment, the hollow fiber membrane is characterized in that the largest diameters of the pores inside the membrane are less than 1 pm, in particular less than 0.5 pm. Dialysis membranes often have so-called “macrovoids,” which are characterized by cavities with a maximum diameter of more than 1 pm or more than 0.5 pm. The measurement is performed by taking scanning electron microscopic images of a cryo-fracture of the membrane. The respective diameter of the largest cavities is used as a measure. Ten images are taken, and from these 10 images, the largest diameter is used as a measure for the largest diameter of the pores. Such membranes with large pore diameters have lower mechanical stability, which is particularly true when membrane wall thicknesses of less than 40 pm are used.

[0032] As part of the investigations for this invention, embodiments of hollow-fiber membranes were investigated which are characterized in that the hollow fiber has a content of fat-soluble antioxidant, in particular tocopherol, of 0.005-0.5 wt.%. This allows the elution of hydrophilic polymer after aging to be further reduced. Particularly preferred are hollow-fiber membranes which are characterized in that the elution of the hydrophilic polymer, in particular polyvinylpyrrolidone, after a storage period of 30 days at 80°C and a relative humidity of <5%, is less than 4000*10' 7 mg / per single fiber, especially after 60 days at 80°C and a relative humidity of < 5% less than 5000*10' 7 mg / single fiber.

[0033] In one embodiment, the hollow fiber membrane is characterized in that the selective layer of the membrane is located at the lumen surface. Compared to membranes with a selective layer located on the outer surface of the membrane, this membrane has the advantage of being easy to manufacture, since the precipitant can be easily adjusted and then introduced into the lumen of the hollow fiber being formed. In contrast, precisely adjusting the selectivity of the outer surface is more difficult, since in addition to a medium that must be introduced into the lumen being formed, another precipitating medium must be introduced around the outer surface, which requires more equipment.

[0034] According to a further development of the invention, the hollow-fiber membrane is characterized in that the proportion of non-crosslinked PVP is less than 1% or less than 0.5%, or preferably less than 0.3%, or more preferably less than 0.01%, measured according to the method specified in the description. Dialyzers in which the membranes according to the invention are used are frequently sterilized by exposing them to high-energy radiation. Irradiation is frequently carried out with electrons or gamma rays. These methods have the special feature that, in particular, the hydrophilic polymer is significantly altered.Depending on the production conditions, polymer bonds may be broken, resulting in increased elution of polymer fragments, or - particularly during gamma sterilization - crosslinking of the hydrophilic polymer may occur. While this limits the elution of the hydrophilic polymer, the crosslinking reaction also 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 section, by sterilization with hot steam. This results in a hollow fiber in which the proportion of crosslinked hydrophilic polymer is preferably particularly low; more preferably, the value is below the detection limit of the method for determining the crosslinking proportion.

[0035] In a particular embodiment, the hollow fiber is crimped, preferably using regular undulations with a wavelength of less than or equal to 30 mm.

[0036] In a further embodiment, the hollow fiber membrane is characterized in that the hollow fiber is 3-dimensionally undulated. This leads to high separation rates, particularly for low-molecular-weight ureatoxins, and to significant advantages in manufacturing, since this feature can reduce waste during production. A 3-dimensionally undulated hollow fiber is understood to be a hollow fiber having at least one first curl in the form of a first wave, which is characterized by a first plane of oscillation and a first wavelength, and at least one second curl in the form of a second wave, which is characterized by a second plane of oscillation and a second wavelength, wherein the planes of oscillation enclose an angle with one another that is different from 0°, in particular an angle of 50° to 120°, and wherein the first wavelength is smaller than the second wavelength.

[0037] In a particular embodiment, the hollow fiber membrane is characterized in that the hollow fiber membrane has a zeta potential of 0 mV to less than -4 mV, in particular less than -3 mV, on the lumen-side surface. This ensures a consistently high hydrophilicity of the lumen surface, which reliably ensures the benefits of high hemocompatibility. Furthermore, in a particular embodiment, this further ensures that the lumen diameter of the membrane can be adjusted between 165 and 190 pm, in particular between 165 and 170 pm.

[0038] The 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 both ends to the ends of the housing by means of a potting material in such a way that two fluid spaces are formed which are fluidically separated by the membrane wall in such a way that mass exchange can only take place via this membrane, wherein the housing is designed in such a way that two fluid inlets and outlets are connected to the lumen of the membranes of the bundle and that two further fluid inlets and outlets are in fluidic connection with the fluid space delimited by the housing and surrounding the hollow fibers, characterized in that the bundle of hollow fibers comprises at least a plurality of hollow fiber membranes according to one of claims 1 to 12.

[0039] Furthermore, the second aspect of the invention relates to a hollow fiber dialyzer, which is characterized in that the lump to be cleaned is guided in the lumen 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 based on measurement methods, figures, and examples

[0040] Name of the figures:

[0041] Fig.1 : Apparatus for determining the zeta potential

[0042] Fig. 2: Apparatus for determining platelet loss and complement activation

[0043] Fig. 3 to 6: Apparatus for carrying out the rinsing and sterilization process

[0044] Measurement method 1: Determination of the albumin sieving coefficient

[0045] The albumin sieving coefficient of a hollow fiber membrane is determined on a filter as described in Method 3. Human plasma is used for the measurement in accordance with the DIN EN ISO 8637:2014 standard for determining the sieving coefficient. The plasma sieving coefficient of albumin is thus determined. The analyzer used is a Cobas Integra 400 plus model from Roche Diagnostics GmbH, Mannheim. The measurement is performed using the ALBT2 test in the urine application. A plasma flow of 446.6 ml / min and a dialysate flow (deionized water) of 89.9 ml / min are set.

[0046] Measurement method 2: Determination of the zeta potential

[0047] To determine the zeta potential of the hollow fiber membranes under investigation, a hollow fiber membrane filter (dialyzer) with 10,752 hollow fiber membranes with an inner diameter of 185 pm and a wall thickness of 35 pm was used. The length of the hollow fiber membranes relevant for measuring the zeta potential was 279 mm. The hollow fiber membranes were potted at the ends in the hollow fiber membrane filter in such a way that a first space is created that encompasses the interior of the hollow fiber membranes and a second space is created that encompasses the space between the hollow fiber membranes. Polyurethane from Elastogran (Polyol C6947 and Isocyanate 136-20) was used as the potting material. The potting height at each bundle end was 22 mm. An apparatus as shown in Fig. 1 was used for the measurement. The hollow fiber membrane filter (1) has fluid accesses (2, 2a, 3, 3a) to the first and second chambers of the hollow fiber membrane filter (1).The fluid inlets to the first chamber of the hollow-fiber membrane filter (1) are each provided with an Ag / AgCl electrode (4, 4a) and an inlet for pressure measurement (5, 5a) as shown in Fig. 4a. The fluid inlets (3, 3a) to the second chamber of the hollow-fiber membrane filter (1) are tightly sealed, leaving the second chamber empty. The potential difference AE is thus measured between the two electrodes. Z (mV) is recorded using a voltage measuring device (6), between the pressure measurement accesses (5, 5a) the pressure drop AP (N / m 2) is recorded using a pressure gauge (7). The test liquid consists of a 1 mmol solution of KCl in water with a pH of 7.4 and is placed in a reservoir (8) that is placed approximately 1000 mm above the filter. The pH is adjusted according to the following procedure: 50 mg of K2CO3 are added to 100 liters of the KCl solution. With the container open, stir until a pH of 7.4 is reached. The container is then tightly closed. The measurement is carried out at a temperature of 23°C + / - 2°C.

[0048] To measure the zeta potential, the test fluid flows through a first fluid inlet (2) into the first chamber of the hollow fiber membrane filter, which encompasses the inner chamber of the hollow fiber membranes, and is then discharged from the dialyzer through a second fluid inlet (2a) on the hollow fiber membrane filter, which is connected to the inner chamber of the hollow fiber membranes. In this arrangement, the hollow fiber membrane filter is first rinsed with the test fluid for 10 minutes until a stable value is established; if necessary, the rinse is continued for a further 5 minutes. The pressure difference and the voltage difference are read simultaneously on the pressure measuring device or multimeter, and the zeta potential is calculated from this. To increase measurement accuracy, the two 4-way valves are switched after the measured value has been recorded so that the test fluid flows in reverse through the inner chamber of the hollow fiber membranes.The measured value for the zeta potential is then calculated from the average of the measurements in both flow directions.

[0049] The zeta potential is calculated using the following equation: with , - Zeta potential (mV) q = solution viscosity (0.001 Ns / m 2 )

[0050] Ao = conductivity of the solution (A / (V*m))

[0051] £o = permittivity of the vacuum (8.85 * 10' 12 A * s / (V * m)

[0052] £ r — relative permittivity of the solution ( 80 )

[0053] E z = streaming potential (mV)

[0054] AP = pressure difference ( N / m 2 )

[0055] Measurement method 3: Determination of clearance for sodium and vitamin B12

[0056] The 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. Aqueous solutions of sodium at a concentration of 5 g / l NaCl and 0.05 g / l vitamin B12 are used as test solutions for the blood zone (the blood zone corresponds to the first chamber of the hollow fiber membrane filter, encompassing the interior of the hollow fiber membranes) in accordance with 5.6.1.2 of the standard. Distilled water is used for the dialysis fluid zone (the dialysis fluid zone corresponds to the second chamber of the hollow fiber membrane filter, encompassing the interfiber space). The measurement is also performed against dialysis fluid on the dialysate side. The sodium concentration is determined by conductivity measurements. The vitamin B12 concentration is determined photometrically.For the clearance tests, a hollow-fiber membrane filter of the same design is used, which is also used for the measurement according to Measurement Method 2. In the first chamber of the hollow-fiber membrane filter, which contains the interior of the hollow-fiber membranes, a flow rate of 300 ml / min is set for the hollow-fiber membrane filters produced within the scope of this application; in the second chamber of the hollow-fiber membrane filter, a flow rate of 500 ml / min is set. Measurement Method 4: Determination of the PVP content of the hollow-fiber membrane.

[0057] The PVP content of the hollow fiber membrane is determined using IR spectroscopy. For this purpose, the sample is first taken from a previously sterilized hollow fiber filter and then dried for 2 hours in a drying oven at 105°C. Then, 1 g of the fiber is dissolved in dichloromethane. Calibration standards are also prepared using dried PVP, which is also dissolved in dichloromethane. This covers a concentration range of approximately 1% to 10% PVP in the hollow fiber. The solutions are each transferred into a liquid cuvette with a path length of 0.2 mm. The absorption band of the carbonyl function is used for evaluation.

[0058] Measurement method 5: Determination of the ultrafiltration coefficient

[0059] To determine the local ultrafiltration coefficient according to DIN ISO 8637:2014, Section 5.6.3, a hollow fiber membrane filter is used as shown in the examples. Human blood (blood ultrafiltration coefficient) or, deviating from the DIN ISO 8637:2014 standard, water is used as the test fluid (aqueous ultrafiltration coefficient). When setting the flow rates of the respective test fluids, care is taken to ensure that the same maximum transmembrane pressures (TMP) of 600 mmHg are set. The respective ultrafiltration coefficient is expressed in the unit ml / (h*mmHg*m 2 ). The filter area is calculated from the inner surface of the hollow fiber lumen available for free exchange, so that a standardization for different filter sizes is available.

[0060] Measurement method 6: Determination of the elution of polyvinylpyrrolidone

[0061] Hollow fiber membrane filters are tested for elutable polyvinylpyrrolidone fractions. 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 polyvinylpyrrolidone content. For this purpose, hollow fiber membrane filters are constructed according to the following procedure: A hollow fiber membrane filter (dialyzer) is used with 10,752 hollow fiber membranes with an inner diameter of 185 pm and a wall thickness of 35 pm. The inner diameter of the filter housing is 34 mm. The length of the hollow fiber membranes relevant for measuring elution is 258 mm. The hollow fiber membranes are sealed at the ends of the hollow fiber membrane filter in such a way that a first chamber is created that encompasses the interior of the hollow fiber membranes (“blood chamber”) and a second chamber (“dialysate chamber”) is created that encompasses the space between the hollow fiber membranes.Polyurethane from Elastogran (Polyol C6947 and Isocyanate 13620) is used as the potting material. The potting height at each bundle end is 22 mm. Water serves as the extraction agent. 1000 ml of deionized water heated to 37°C is flushed through the first chamber of the hollow-fiber membrane filters, which contains the interior of the hollow-fiber membranes, via two connections on the hollow-fiber membrane filter. The other two connections on the hollow-fiber membrane filter are closed. The flushing process is carried out in recirculation mode. For this purpose, a water bath heated to 37°C is provided. A pump supplies tempered water from the water bath to the hollow-fiber membrane filter via a first connection. The first chamber of the hollow-fiber membrane filter is flushed, the water is drained from the hollow-fiber membrane filter via a second connection and returned to the water bath.Flushing in recirculation mode is carried out for 5 h at a flow rate of 200 ml / min.

[0062] The polyvinylpyrrolidone eluted by this method concentrates in the water bath. The concentration of polyvinylpyrrolidone in the water bath can be determined photometrically. The orange-brown color reaction of polyvinylpyrrolidone with iodine / potassium iodide in a weakly acidic solution is used for photometric determination (spectrophotometric determination according to Müller or Breinlich).

[0063] For the procedure, 10 ml of the extract are mixed with 5.0 ml of citric acid solution and 2.0 ml of Kl3 solution, mixed, and reacted for 10 minutes at room temperature. The absorbance of the sample solution is then determined at 470 nm. The content is determined from the measured absorbance using a previously determined calibration. A PVP of type K81-86 is used for 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 humidity of < 5% for a period of 30, 60, and 120 days. After this storage, the PVP elution is determined. The extracted amount of PVP is related to the individual fiber; the value is the amount in 10'. 7 mg per single fiber, determined according to the above method.

[0064] Measurement method 7: Determination of platelet loess and complement activation (comparison method)

[0065] To determine platelet loss and complement activation, 450 ml of human whole blood is drawn from healthy donors without medications that could affect blood coagulation or platelet properties using a 17G (1.5 mm) needle. The blood bag is filled with 750 IU of heparin diluted in 50 ml of normal saline to achieve a heparin concentration of 1.5 IU per ml of the blood-saline mixture. The method for determining platelet loss is started within 30 minutes of blood donation.

[0066] For the hollow fiber membranes to be tested, an apparatus (10) is set up according to the schematic representation in Figure 2 to determine platelet loss. The apparatus comprises a dialyzer (12), manufactured as described above, with the hollow fiber membranes to be tested accommodated therein. The apparatus further comprises a tubing system (13), a peristaltic pump (14), a blood sample collection point (15), a blood reservoir (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). 200 ml of the heparinized blood, as described above, were used to carry out the determination. The blood was pumped through the tubing system (13) (material: PVC, manufacturer: Fresenius Medical Care, Germany) through the dialyzer (12) with the aid of the peristaltic pump (14) (manufacturer: Fresenius Medical Care, Germany) through the apparatus (10).A new tubing system was used for each measurement. The entire apparatus (10) was rinsed with a 0.9% (w / v) saline solution for 30 minutes prior to measurement. To fill the apparatus with blood, the flushing solution was displaced and drained away with blood introduced into the apparatus at low pump speed until the apparatus was filled with pure blood. The blood volume was 200 ml. The displaced solution was discarded.

[0067] To avoid ultrafiltration during the experiment, the dialysate side was pre-filled with a 0.9% saline solution via inlets (21, 22) on the dialyzer and then sealed. The platelet loss is carried out at 37°C, e.g., in an incubator (Memmert, Germany), over a period of 180 min, with samples being taken at the blood sampling site (15) at the start of the measurement and after 30, 60, 120, and 180 min. The pressure at the blood inlet (18) and the blood outlet (19) is measured to ensure constant conditions during the determination. If significant pressure changes occur, the measurement must be discarded. The blood was pumped through the apparatus at a volume rate of 200 ml / min.

[0068] Hemocompatibility was determined using complement activation (sC5b-9) and platelet loss. Platelet loss was determined in triplicate using an automated hematology analyzer (K4500 Sysmex, Norderstedt, Germany).

[0069] Complement activation was determined in duplicate using an ELISA test kit "MicroVue™ Complement SC5b-9 Plus EIA" from Quidel Corporation, Athens, USA. The measurement parameter was sC5b-9, which, as a particularly high-molecular-weight protein, can only be dialysed to a small extent during the test.

[0070] The evaluation of complement activation and platelet loss parameters is performed as described in the publication "Score Model for the Evaluation of Dialysis Membrane Hemocompatibility," Erlenkötter et al., Artificial Organs 32(12):962-998, 2008, using formulas (1, complement activation) and (2, platelet loss). For the determination of platelet loss, the measurement period is the first 60 minutes of the entire experiment. Therefore, the following conditions apply to formula 1:

[0071] Formula (1) with IPLT = mean platelet loss (%), t1= 0 min, t2 = 60 min, A c P T = platelet concentration, Tn = 60 min.

[0072] During the measurements, a further filter according to Comparative Example 2 was used with the second half of the blood donation, and the measurement results were determined relative (in %) to this comparison filter. This allowed the naturally strong fluctuations in blood reaction among different donors to be mathematically compensated. Furthermore, the examples and comparative examples described below were produced using the same batches of raw materials.

[0073] Measurement method 8: Determination of polyvinylpyrrolidone in a near-surface layer (XPS)

[0074] The polyvinylpyrrolidone content in the near-surface layer was determined using photoelectron spectroscopy (XPS or ESCA). This method allows the polyvinylpyrrolidone content to be determined in a layer of approximately 5-10 nm. This layer, sampled using the XPS method, is referred to below as the "near-surface layer." It is determined by the measurement conditions.

[0075] A hollow fiber membrane is cut open using a scalpel or other sharp knife, exposing the inner surface and thus the selective layer or the respective outer surface of the hollow fiber membrane. This sample is fixed on a sample plate and placed in the sample chamber. The measurement conditions are set as follows:

[0076] - Apparatus: Thermo VG Scientific, type K-Alpha

[0077] - Excitation radiation: monochromatic X-rays, AI Ka, 75 W

[0078] - Diameter of the sample spot: 200pm

[0079] - Pass energy: 30 eV

[0080] - Angle between source and analyzer: 54°

[0081] - Spectral resolution for an Ag3d signal: 0.48 eV:

[0082] - Applied vacuum: 10' 8 mbar - The charge was compensated with the help of a flood gun.

[0083] The PVP content in the near-surface layer was determined using the values ​​found in mass % of nitrogen (N) and sulfur (S) using the following equation:

[0084] PVP content [in mass %] = 100 * (N*111 ) / (N*111 + S*442)

[0085] This equation is valid for the use of polysulfone based on bisphenol A; for polyethersulfone the following equation applies:

[0086] PVP content [in mass %] = 100 * (N*111 ) / (N*111 + S*232)

[0087] For other polysulfones, the molecular weight of the monomer unit attributable to sulfur must be determined; for copolymers, the proportion of the sulfur-containing monomer in the copolymer must be taken into account.

[0088] A determination is carried out on 3 hollow fiber membranes and the mean value of these measurements is calculated.

[0089] Embodiment 1: Production of a hollow fiber membrane and a filter according to the invention

[0090] A spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland), and 79.7 parts by weight of DMAc is stirred, heated to 60°C, and degassed to form a homogeneous spinning dope. α-Tocopherol (from Sigma Aldrich) is then added to the spinning dope so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt.%. To prepare the coagulant, 39 wt.% DMAc and 61 wt.% water are mixed, and polyvinylpyrrolidone (K81 / 86 from Ashland) is added so that the proportion of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular die with the centrally guided coagulant into a spinning thread with a lumen diameter of 185 pm and a wall thickness of 35 pm. The coagulant is guided inside the hollow spinning thread.The temperature of the annular gap nozzle is 71°C. The spun yarn is passed through a precipitation chamber with an atmosphere having a relative humidity of 100%. The height of the precipitation gap is 200 mm, and the passage time through the precipitation gap is set at 0.4 seconds. The spun yarn is then introduced into a precipitation bath consisting of water heated to 80°C, where it is precipitated into a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths heated to a temperature of 75°C to 90°C. The hollow fiber membrane then undergoes a drying process between 100°C and 150°C. The fiber is given a first curl of 7 mm and a second curl of 30 mm, with the respective oscillation planes being at an angle of 90° to each other, as described in DE102016002440A1. The resulting hollow fiber membrane is then taken up by a reel and assembled into a sheet of threads.Hollow fiber membrane bundles are produced from the reeled thread sheet.

[0091] The hollow-fiber membrane bundle is further processed into a hollow-fiber membrane filter as follows. The hollow-fiber membrane bundle is equipped with 10,752 hollow-fiber membranes, each with an inner diameter of 185 μm and a wall thickness of 35 μm, and manufactured 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 potted at the ends in the hollow-fiber membrane filter in such a way that a first space is created that contains the interior of the hollow-fiber membranes and a second space is created that contains the space between the hollow-fiber membranes. Polyurethane from Elastogran (polyol C6947 and isocyanate 136-20) is used as the potting material. The potting height at each bundle end is 22 mm. The inner diameter of the housing at its smallest point in the center of the housing is 34 mm.The hollow fiber membrane filter obtained is cleaned and sterilized according to the following description.

[0092] Fig. 3 shows a schematic representation of a first step of a cleaning process for 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 and second aspects of the invention. Fig. 3 shows a fluid access 118 to a first space 119 of a hollow fiber membrane filter 113, which comprises the inner space of the hollow fiber membranes and is in fluid communication via a line 109 with a valve 105 and a connection 101. A further fluid access 117 is in fluid communication via line 110 and valve 106 with connection 102 and forms access to a second space 120 of the hollow fiber membrane filter 113, which comprises a space between the hollow fiber membranes.Another fluid inlet 114 is fluidly connected via line 111 to valve 107 and port 103, forming access to the second chamber 120 of the hollow fiber membrane filter. Fluid inlet 115 is fluidly connected via line 112 to a valve 108 and port 104. Furthermore, ports 101 and 103 are fluidly connected via connector 101a.

[0093] In the first step of the rinsing process shown, a rinsing fluid is pumped through line 112 to the hollow fiber membrane filter 113 via connection 104. The rinsing fluid is temperature-controlled sterile water, with temperatures of 50 to 98°C being maintained. Valve 108 is switched to flow. The rinsing fluid flows into the first chamber 119 of the hollow fiber membrane filter via the second fluid inlet 115 and leaves this first chamber via the first fluid inlet 118. With the aid of this arrangement, all hollow fiber membranes of a hollow fiber membrane bundle are rinsed on their inner surfaces.

[0094] The rinsing fluid then passes through a bubble detector 114, which performs no function in this rinsing process, and line 109, and is directed to line 111 via port 101 and connector 101a. The rinsing fluid enters the second chamber 120 of the filter module 113 via fluid inlet 114 and flushes through the second chamber formed in the space between the hollow fiber membranes. The rinsing fluid is returned via fluid inlet 117 and line 110, where it is either discarded or reprocessed to make it available for another rinsing process.

[0095] Fig. 4 shows a schematic representation of the second step of a rinsing and sterilization process as 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. A compressed air rinse is explained with reference to Fig. 4. Connections 201, 202 are supplied by a compressed air source which supplies sterile air. The compressed air is conveyed to the hollow fiber membrane module 213 via the lines 209 and 201, via the open valves 205 and 206 and by pump means not shown. From the previous rinsing step according to the rinsing process according to Fig. 3, the first chamber 219 and the second chamber 220 are initially still filled with water. The valves 207 and 208 are open and prepared for the discharge of 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 from the first and second chambers of the hollow-fiber membrane filter via fluid inlets 218 and 217, respectively, and then via fluid inlets 215 and 214 into the return section of the flow path circuit. Residual water and compressed air are discharged via lines 212 and 211. The flushing process lasts for 2 to 5 minutes. Since the same pressure prevails in both chambers 219 and 220, the membrane wall is not flushed. As a result, the pores of the membrane wall remain filled with water from the flushing process.

[0096] Fig. 5 shows a schematic representation of a third step of a rinsing and sterilization process, as 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, the connections 302 and 304 are shown, whereby, unlike in DE102016224627A1, a blocking valve position of the valves 306 and 308 is omitted, so that the outflow of rinsing fluids is not blocked. Water vapor is conveyed into the sterilization system via connection 301 and conveyed via line 309 to the filter module 313. The water vapor spreads in the first chamber 319 of the hollow fiber membrane filter; discharge via fluid inlet 315 is possible because connection 304 is not blocked.

[0097] This rinsing process can be completed after a few minutes. Typically, the rinsing process lasts 2 to 5 minutes. Temperatures of 50°C to 98°C are maintained, particularly to thermally condition the filter module for the subsequent sterilization process.

[0098] Fig. 6 shows a schematic representation of a fourth step of a rinsing and sterilization process as 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 steam at a temperature of 124°C and a pressure of approximately 2 bar is conveyed into the hollow fiber membrane filter. Connections 401, 402, 403, 404 can be flowed through via the open valves 405 to 408. The pure steam is conveyed into the hollow fiber membrane filter via lines 409 and 410 and flushes the first space 419 and the second space 420 of the filter module 413. The pure steam returns via lines 412 and 411 and the fluid inlets 415 and 414 and is either discarded or reused by processing.The sterilization process can take between 5 and 30 minutes, depending on the selected sterilization temperature. At the preferred temperature of 124°C, sterilization is considered complete after approximately 12 minutes.

[0099] Further quality control is carried out using a “bubble point” test known from the prior art. In this test, one side of a membrane is subjected to a gas at a higher pressure than the opposite side of the membrane, which is subjected to a liquid flow. For this purpose, the second chamber 120, 220, 320, 420 of the hollow fiber membrane filters shown in Figures 3 to 6 is rinsed with sterile compressed air, while the first chamber remains filled with liquid from the rinsing process. The sterilization system applies a higher pressure to the second chamber than to the first chamber 119, 219, 319, 419. Since the pores are filled with water from the previous rinsing step, the pressurized gas will only begin to pass from the first chamber to the second chamber when the applied pressure overcomes the surface tension of the water in the pores.The gas quantities passing into the first chamber can be analyzed in the bubble detectors 114, 214, 314, and 414 shown, and the results evaluated accordingly. The quantity of detected gas bubbles, correlated with the applied pressure in the second chamber of the filter modules 120 to 420, can be used to draw conclusions about the quality of the membrane material and determine whether the filter module complies with the specifications.

[0100] The first chamber is then also to be rinsed with sterile compressed air. A further rinsing step with pure steam ensures that any remaining water from previous rinsing processes is removed. This is followed by a drying process at 115°C for approximately 16 minutes, during which the filter module is rinsed with sterile compressed air until the desired degree of dryness is achieved. The hollow fiber membrane filter is then free of condensate water at room temperature. The hollow fiber filter according to Example 1 was measured in comparison to Comparative Example 2 with regard to platelet loss and complement activation using measurement method 6. The result was a reduction in platelet loss of 71.0% and a reduction in complement activation of 60.6%. In particular, with regard to platelet loss, it was found that comparatively very little platelet loss occurred in the filter itself. Part of the platelet loss was also attributable to the supply lines.Membranes and hollow fiber filters according to the invention thus exhibit particularly high hemocompatibility with very low albumin loss.

[0101] Example 2: Production of a hollow fiber membrane and a filter according to the invention

[0102] A spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland), and 79.7 parts by weight of DMAc is stirred, heated to 60°C, and degassed to form a homogeneous spinning dope. α-Tocopherol (from Sigma Aldrich) is then added to the spinning dope so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt.%. To prepare the coagulant, 41 wt.% DMAc and 59 wt.% water are mixed, and polyvinylpyrrolidone (K81 / 86 from Ashland) is added so that the proportion of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular die with the centrally guided coagulant into a filament with a lumen diameter of 185 pm and a wall thickness of 35 pm. The coagulant is guided inside the hollow filament. The temperature of the annular die is 71°C.The spun yarn is passed through a precipitation chamber with an atmosphere having a relative humidity of 100%. The height of the precipitation gap is 200 mm, and the passage time through the precipitation gap is set at 0.4 seconds. The spun yarn is then introduced into a precipitation bath consisting of water heated to 80°C, where it is precipitated into a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths heated to a temperature of 75°C to 90°C. The hollow fiber membrane then undergoes a drying process between 100°C and 150°C. The fiber is given a first curl of 7 mm and a second curl of 30 mm, with the respective vibration planes being at an angle of 90° to each other, as described in DE102016002440A1. The resulting hollow fiber membrane is then taken up by a reel and gathered into a sheet of yarn. Hollow fiber membrane bundles are produced from the reeled thread sheet.

[0103] The hollow fiber membrane bundle is further processed into hollow fiber membrane filters as described in Example 1. The resulting hollow fiber membrane filter is sterilized using a steam sterilization process as described in Example 1.

[0104] Example 3: Production of a hollow fiber membrane and a filter according to the invention

[0105] A spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland), and 79.7 parts by weight of DMAc is stirred, heated to 60°C, and degassed to form a homogeneous spinning dope. α-Tocopherol (from Sigma Aldrich) is then added to the spinning dope so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt.%. To prepare the coagulant, 43 wt.% DMAc and 57 wt.% water are mixed, and polyvinylpyrrolidone (K81 / 86 from Ashland) is added so that the proportion of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular die with the centrally guided coagulant into a filament with a lumen diameter of 185 pm and a wall thickness of 35 pm. The coagulant is guided inside the hollow filament. The temperature of the annular die is 71°C.The spun yarn is passed through a precipitation chamber with an atmosphere having a relative humidity of 100%. The height of the precipitation gap is 200 mm, and the passage time through the precipitation gap is set at 0.4 seconds. The spun yarn is then introduced into a precipitation bath consisting of water heated to 80°C, where it is precipitated into a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths heated to a temperature of 75°C to 90°C. The hollow fiber membrane then undergoes a drying process between 100°C and 150°C. The fiber is given a first curl of 7 mm and a second curl of 30 mm, with the respective vibration planes being at an angle of 90° to each other, as described in DE102016002440A1. The resulting hollow fiber membrane is then taken up by a reel and gathered into a sheet of yarn. Hollow fiber membrane bundles are produced from the reeled thread sheet.

[0106] The hollow fiber membrane bundle is further processed into hollow fiber membrane filters as described in Example 1. The resulting hollow fiber membrane filter is sterilized using a steam sterilization process as described in Example 1.

[0107] Comparative Example 1 : Production of a hollow fiber membrane and a filter

[0108] A spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland), and 79.7 parts by weight of DMAc is stirred, heated to 60°C, and degassed to form a homogeneous spinning dope. α-Tocopherol (from Sigma Aldrich) is then added to the spinning dope so that the proportion of α-tocopherol in the total mass of the spinning dope is 0.01 wt.%. To prepare the coagulant, 35 wt.% DMAc and 65 wt.% water are mixed, and polyvinylpyrrolidone (K81 / 86 from Ashland) is added so that the proportion of polyvinylpyrrolidone is 1.5 g per kg (1000 ppm) of coagulant. The spinning dope is processed through an annular die with the centrally guided coagulant into a filament with a lumen diameter of 185 pm and a wall thickness of 35 pm. The coagulant is guided inside the hollow filament. The temperature of the annular die is 71°C.The spun yarn is passed through a precipitation chamber with an atmosphere having a relative humidity of 100%. The height of the precipitation gap is 200 mm, and the passage time through the precipitation gap is set at 0.4 seconds. The spun yarn is then introduced into a precipitation bath consisting of water heated to 80°C, where it is precipitated into a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths heated to a temperature of 75°C to 90°C. The hollow fiber membrane then undergoes a drying process between 100°C and 150°C. The fiber is given a curl of 7.5 mm. The resulting hollow fiber membrane is then taken up by a reel and gathered into a yarn sheet. Hollow fiber membrane bundles are produced from the reeled yarn sheet.

[0109] The hollow fiber membrane bundle is further processed into a hollow fiber membrane filter as in Example 1 and cleaned, sterilized, and dried as follows. Fig. 3 shows a schematic representation of a first step in a cleaning process for 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. Fig. 3 shows a fluid access 118 to a first space 119 of a hollow fiber membrane filter 113, which comprises the inner space of the hollow fiber membranes and is in fluid communication with a valve 105 and a connection 101 via a line 109. A further fluid access 117 is in fluid communication with connection 102 via line 110 and valve 106 and forms access to a second space 120 of the hollow fiber membrane filter 113, which comprises a space between the hollow fiber membranes.Another fluid inlet 114 is fluidly connected via line 111 to valve 107 and port 103, forming access to the second chamber 120 of the hollow fiber membrane filter. Fluid inlet 115 is fluidly connected via line 112 to a valve 108 and port 104. Furthermore, ports 101 and 103 are fluidly connected via connector 101a.

[0110] In the first step of the rinsing process shown, a rinsing fluid is pumped through line 112 to the hollow fiber membrane filter 113 via connection 104. The rinsing fluid is temperature-controlled sterile water, with temperatures of 50 to 98°C being maintained. Valve 108 is switched to flow. The rinsing fluid flows into the first chamber 119 of the hollow fiber membrane filter via the second fluid inlet 115 and leaves this first chamber via the first fluid inlet 118. With the aid of this arrangement, all hollow fiber membranes of a hollow fiber membrane bundle are rinsed on their inner surfaces.

[0111] The rinsing liquid then passes through a bubble detector 114, which performs no function in this rinsing process, and line 109 and is directed via connection 101 and connecting piece 101a to line 111. Via fluid inlet 114, the rinsing liquid enters the second chamber 120 of the filter module 113 and flushes through the second chamber formed in the space between the hollow fiber membranes. The rinsing liquid is returned via fluid inlet 117 and line 110 and is either discarded or, after processing, made available again for a rinsing process. Fig. 4 shows a schematic representation of the second step of a rinsing and sterilization process as 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. A compressed air rinse is explained with reference to Fig. 4.Connections 201, 202 are supplied by a compressed air source which supplies sterile air. The compressed air is conveyed via lines 209 and 201, through the open valves 205 and 206, and by pumping means not shown, to the hollow fiber membrane module 213. From the previous rinsing step according to the rinsing process according to Fig. 3, the first chamber 219 and the second chamber 220 are initially still filled with water. The valves 207 and 208 are open and prepared for the drainage of 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 from the first and second chambers of the hollow fiber membrane filter via the fluid inlets 218, 217 and then via the fluid inlets 215 and 214 into the return part of the flow path circuit. Residual water and compressed air are drained off via lines 212, 211. The rinsing process is carried out for 2 to 5 minutes.Since the same pressure prevails in both chambers 219 and 220, the membrane wall is not flushed. As a result, the pores of the membrane wall remain filled with water from the flushing process.

[0112] Fig. 5 shows a schematic representation of a third step of a rinsing and sterilization process, as 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, which block the outflow of rinsing fluids by a blocking valve position of the valves 306 and 308. Water vapor is conveyed into the sterilization system via connection 301 and via line 309 to the filter module 313. The water vapor spreads in the first chamber 319 of the hollow fiber membrane filter; discharge via fluid inlet 315 is not possible because connection 304 is blocked. Water vapor can only spread in line 312 via compression of the pressurized pure steam or by diffusion.

[0113] Since the pressure in the first chamber is higher than in the second chamber, a transmembrane transfer of the pure steam occurs. Residual water remaining in the pores from the rinsing process after the first step of the rinsing and sterilization process shown in Fig. 3 is removed and conveyed via the second chamber 320 into line 311. This rinsing process can be completed after a few minutes. In particular, the rinsing process is carried out for 2 to 5 minutes. Temperatures of 50°C to 98°C are maintained, particularly to thermally condition the filter module for the subsequent sterilization process.

[0114] Fig. 6 shows a schematic representation of a fourth step of a rinsing and sterilization process as 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 steam at a temperature of 124°C and a pressure of approximately 2 bar is conveyed into the hollow fiber membrane filter. Connections 401, 402, 403, 404 can be flowed through via the open valves 405 to 408. The pure steam is conveyed into the hollow fiber membrane filter via lines 409 and 410 and flushes the first space 419 and the second space 420 of the filter module 413. The pure steam returns via lines 412 and 411 and the fluid inlets 415 and 414 and is either discarded or reused by processing.The sterilization process can take between 5 and 30 minutes, depending on the selected sterilization temperature. At the preferred temperature of 124°C, sterilization is considered complete after approximately 12 minutes.

[0115] Further quality control is carried out using a “bubble point” test known from the prior art. This test is a pressure maintenance test in which one side of a membrane is subjected to a gas at a higher pressure than the opposite side of the membrane, which is subjected to a liquid flow. For this purpose, the second chamber 120, 220, 320, 420 of the hollow fiber membrane filters shown in Figs. 3 to 6 is rinsed with sterile compressed air, while the first chamber remains filled with liquid from the rinsing process. The sterilization system applies a higher pressure to the second chamber than to the first chamber 119, 219, 319, 419. Since the pores are filled with water from the previous rinsing step, the pressurized gas will only begin to pass from the first chamber to the second chamber when the applied pressure overcomes the surface tension of the water in the pores.The gas quantities passing into the first chamber can be analyzed in the bubble detectors 114, 214, 314, and 414 shown, and the results evaluated accordingly. The quantity of detected gas bubbles, correlated with the applied pressure in the second chamber of the filter modules 120 to 420, can be used to draw conclusions about the quality of the membrane material and determine whether the filter module complies with the specifications.

[0116] The first chamber is then also flushed with sterile compressed air. A further flushing step with pure steam ensures that any remaining water from previous flushing processes is removed. This is followed by a drying process at approximately 115°C lasting approximately 16 minutes, during which the filter module is flushed with sterile compressed air until the desired degree of dryness is achieved.

[0117] Comparative Example 2: Production of a hollow fiber membrane and a filter

[0118] A spinning solution consisting of 16 parts by weight of polysulfone (P3500 from Solvay), 4.3 parts by weight of polyvinylpyrrolidone (K81 / 86 from Ashland), and 79.7 parts by weight of DMAc is stirred, heated to 60°C, and degassed to form a homogeneous spinning dope. α-Tocopherol (from Sigma Aldrich) is then added to the spinning dope so that the proportion of α-tocopherol in the total spinning dope mass is 0.01 wt.%. To produce 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 die with the coagulant fed centrally into a filament with a lumen diameter of 185 μm and a wall thickness of 35 μm. The coagulant is guided inside the hollow filament. The temperature of the annular gap nozzle is 71 °C.The spun yarn is passed through a precipitation chamber with an atmosphere having a relative humidity of 100%. The height of the precipitation gap is 200 mm, and the passage time through the precipitation gap is set at 0.4 seconds. The spun yarn is then introduced into a precipitation bath consisting of water heated to 80°C, where it is precipitated into a hollow fiber membrane. The hollow fiber membrane is then passed through rinsing baths heated to a temperature of 75°C to 90°C. The hollow fiber membrane then undergoes a drying process between 100°C and 150°C. The fiber is given a first curl of 7 mm and a second curl of 30 mm, with the respective vibration planes being at an angle of 90° to each other, as described in DE102016002440A1. The resulting hollow fiber membrane is then taken up by a reel and gathered into a sheet of yarn. Hollow fiber membrane bundles are produced from the reeled thread sheet.

[0119] The hollow fiber membrane bundle is further processed into hollow fiber membrane filters as described in Example 1. The resulting hollow fiber membrane filter is sterilized using a steam sterilization process as described in Example 1.

[0120] Example 4 Production of a hollow fiber membrane and a filter according to the invention

[0121] The membrane is prepared in the same manner as in Comparative Example 1, except that a mixture of 24 wt.% DMAC in water with the same amount of PVP in the precipitant is used as the precipitant. The hollow fiber filter is prepared in the same manner as in Comparative Example 1.

[0122] Tabular summary of the measurement results

[0123] Table 1

[0124] A particularly low albumin sieving coefficient is achieved with a sufficiently high ultrafiltration rate.

[0125] Table 2

[0126] Despite 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

[0127] Despite using the same amount of PVP in the precipitant as, for example, in Comparative Example 1, a significantly higher coverage of PVP is achieved on the lumen side. A higher coverage is also achieved on the outer side, so that, due to the improved hydrophilicity of the outer side, improved wetting with aqueous dialysate is achieved, resulting in improved priming of the dialyzer before use. The increased hydrophilicity of the lumen side leads to significantly improved hemocompatibility, which was demonstrated by comparing Example 1 with Comparative Example 1. The zeta potential of each of the examples is greater than -3 mV, which underscores the particularly hydrophilic nature of the lumen surface.

Claims

Claims 1. 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.%, in particular between 2 and 6 wt.%, more particularly between 3 and 5 wt.%, characterized in that the content of polyvinylpyrrolidone in the near-surface layer of the inner lumen of the membrane according to the XPS measurement method is 35% or more, in particular 35-65 wt.%, more particularly 40 to 60 wt.%, more particularly 44-60 wt.%, and 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%, more particularly less than 0.001%.

2. Hollow fiber membrane according to claim 1, characterized in that the ultrafiltration coefficient, measured in blood, is less than 30 ml / (h*mmHg*m2 ), especially less than 20 ml / (h*mmHg*m 2 ) is.

3. Hollow fiber membrane according to one of claims 1 or 2, characterized in that the ultrafiltration coefficient, measured in water, is less than 150 ml / (h*mmHg*m 2 ), especially less than 100 ml / (h*mmHg*m 2 ), is.

4. Hollow fiber membrane according to one of claims 1 to 3, characterized in that the inner diameter of the hollow fiber is less than 230 pm, in particular less than 200 pm, more particularly less than 180 pm, more particularly between 165 and 185 pm.

5. Hollow fiber membrane according to one of claims 1 to 4, characterized in that the wall thickness of the hollow fiber is less than 45 pm, in particular less than 40 pm.

6. Hollow fiber membrane according to one of claims 1 to 5, 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%, further in particular between 24 and 30%, measured by the XPS method.

7. Hollow fiber membrane according to one of claims 1 to 6, characterized in that the largest diameters of the pores in the interior of the membrane are less than 1 pm, in particular less than 0.5 pm.

8. Hollow fiber membrane according to one of claims 1 to 7, characterized in that the hollow fiber has a content of fat-soluble antioxidant, in particular tocopherol, of 0.005 - 0.5 wt.%.

9. Hollow fiber membrane according to one of claims 1 to 8, 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 humidity of < 5%, is less than 4000*10' 7 mg / per single fiber, especially after 60 days at 80°C and a relative humidity of < 5% less than 5000*10' 7 mg / single fiber.

10. Hollow fiber membrane according to one of claims 1 to 9, characterized in that the proportion of non-crosslinked 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 specified in the description.

11. Hollow fiber membrane according to one of claims 1 to 10, characterized in that the hollow fiber is 3-dimensionally undulated.

12. Hollow fiber membrane according to one of claims 1 to 11, characterized in that the hollow fiber membrane has a zeta potential of 0 mV to less than -4 mV on the lumen-side surface.

13. 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 both ends to the ends of the housing by means of a potting material in such a way that two fluid spaces are formed which are fluidically separated by the membrane wall in such a way that a mass exchange can only take place via this membrane, wherein the housing is designed in such a way that two fluid inlets and outlets are connected to the lumen of the membranes of the bundle and that two further fluid inlets and outlets are in fluidic connection with the fluid space delimited by the housing, which surrounds the hollow fibers, wherein the bundle to be cleaned is guided in the lumen space of the hollow fiber and the dialysate is guided past the outer surface in the outer space of the dialyzer, characterized in that the bundle of hollow fibers comprises at least a plurality of hollow fiber membranes according to one of claims 1 to 12.

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