Hollow fiber membrane and hollow fiber membrane filter with improved separation efficiency

Abstract

The present invention relates to a hollow fiber membrane comprising at least one polysulfone-based material and at least one polyvinylpyrrolidone-based polymer, characterized in that the porosity of the hollow fiber membrane is from 77.5% to 82% and the sieving coefficient for dextran with a molecular weight of 10,000 g / mol is from 0.42 to 0.75 and the albumin sieving coefficient of the hollow fiber membrane is less than 0.01.

Description

[0001] This application is a divisional application of Chinese patent application filed on December 8, 2017, with application number 201780075669.9 and entitled "Hollow Fiber Membrane with Improved Separation Efficiency and Manufacture of Hollow Fiber Membrane with Improved Separation Efficiency".

[0002] The subject of this invention

[0003] This invention relates to hollow fiber membranes comprising polysulfone and polyvinylpyrrolidone membrane materials, which have improved separation performance, particularly improved ability to separate substances in the medium molecular weight range and improved selectivity for separating substances in the high and medium molecular weight range.

[0004] The present invention further relates to a method for manufacturing a hollow fiber membrane having polysulfone and polyvinylpyrrolidone membrane materials.

[0005] The present invention also relates to a hollow fiber membrane filter comprising a hollow fiber membrane having uniform permeability.

[0006] In particular, the present invention relates to a method for sterilizing hollow fiber membranes of polysulfone and polyvinylpyrrolidone membrane materials. Background of the Invention

[0007] Hollow fiber membranes are widely used in liquid filtration. In particular, they are used in medical applications to purify water and blood during dialysis treatment in patients with kidney disease. The corresponding hollow fiber membranes form hollow fiber membrane bundles within the filter assembly. This type of filter assembly for blood purification is mass-produced.

[0008] Hollow fiber membranes used for blood purification are typically composed of polysulfone (PSU) and polyvinylpyrrolidone (PVP) because these materials have proven to be preferably blood-compatible, and therefore preferred for use in blood therapy, particularly hemodialysis, from a medical perspective. The basic principles of producing hollow fiber membranes and their manufacture are described below in the prior art:

[0009] Marcel Mudd; Principles of Membrane Technology; Kluwer Academic Publisher, 1996; Chapter 3, Preparation of Synthetic Membranes

[0010] EP 0 168 783

[0011] WO 2007 / 128440.

[0012] According to the methods described in the prior art, a spinning solution is prepared comprising a polysulfone-based hydrophobic material and a vinylpyrrolidone-based hydrophilic polymer (particularly polyvinylpyrrolidone), one or more solvents, and any additives that may be required. Polar aprotic solvents can be used, particularly dimethylacetamide, N-methylpyrrolidone, dimethylformamide, or dimethyl sulfoxide. The spinning solution may also contain small amounts of additives, such as polar protic solvents, such as a low percentage of water.

[0013] The spinning material is extruded through a circular spinneret. The spinneret thus has an inner bore through which a precipitant is guided and co-extruded with the spinning material. The spinning material is extruded into hollow fibers through an annular gap surrounding the inner bore, and the precipitant is introduced into the inner cavity of the hollow fibers. The spun fibers are then introduced into a precipitation bath containing another precipitant, causing the membrane structure to form a hollow fiber membrane through phase inversion and precipitation. Water or a mixture of protons and aprotic solvents (particularly water and dimethylacetamide, N-methylpyrrolidone, dimethylformamide, or dimethyl sulfoxide) is used as the precipitant. The resulting hollow fiber membrane is then passed through a rinsing bath and dried and wound onto a coiler. The hollow fiber membrane can be removed from the coiler as a bundle of hollow fibers. To construct a hollow fiber membrane filter, this bundle of hollow fiber membranes is placed in a housing, preferably a cylindrical housing. The ends of the hollow fiber membrane bundle are embedded in a casting compound, exposing the open ends of the hollow fibers. The casting compound forms a sealed area between the interior of the hollow fiber membrane, the housing, and the region surrounding the hollow fiber membrane. This creates a first chamber in the finished hollow fiber membrane filter, comprising inlet and outlet regions at the ends of the hollow fiber membrane bundles and the interior of the hollow fiber membrane. Consequently, a second chamber is formed in the region within the space between the hollow fiber membranes and between the housing wall and the hollow fiber membrane. Fluid ports on the housing of the hollow fiber membrane filter allow liquids and fluids to be introduced into and out of the first and / or second chambers of the hollow fiber membrane filter.

[0014] Therefore, at least one fluid port forms the inlet of the first chamber of the hollow fiber membrane filter. At least one fluid port forms the inlet of the second chamber of the hollow fiber membrane filter. Additional inlets to the first or second chamber may be provided as needed, depending on the intended application of the hollow fiber membrane filter to be produced. Hollow fiber membrane filters for extracorporeal therapy of blood typically have a first fluid port and a second fluid port for the first chamber of the filter assembly, and a first fluid port and a second fluid port for the second chamber of the filter assembly. Thus, fluid (particularly liquid or gas) can be supplied to or discharged from the chamber of the hollow fiber membrane filter via the first port, or supplied to or discharged from the chamber of the hollow fiber membrane filter via the second port, depending on the flow direction.

[0015] For hollow fiber membrane filters used for medical purposes, especially those used to treat the blood of patients with kidney disease, one or more rinsing and sterilization steps are usually performed during the hollow fiber membrane and filter manufacturing process to purify and sterilize the medical hollow fiber membrane.

[0016] The corresponding method is known in the prior art, in which the hollow fiber membrane in the hollow fiber membrane filter undergoes rinsing and sterilization steps. Specifically, the known sterilization procedure for hollow fiber membranes and hollow fiber membrane filters is the heating sterilization of hollow fiber membrane filters using air, water, or steam. Heating sterilization should be understood as sterilization at a temperature above 100°C using a fluid (e.g., air, water, steam, or mixtures thereof). Heating sterilization, primarily using pure steam, is also called steam sterilization. Such a method for sterilizing dialyzers is described in DE3936785C1. According to the method described in DE3936785C1, the dialyzer undergoes a rinsing process followed by a sterilization process. During sterilization, the dialyzer is rinsed with water or steam heated to above 121°C.

[0017] Other methods known in the art for sterilizing filter assemblies include vacuum steam sterilization, sterilization using sterilizing gases (such as ethylene oxide), and irradiation with ionizing or free radical-forming radiation (such as electron radiation or gamma radiation).

[0018] It has been shown that the thermal cycling during vacuum steam sterilization adversely affects the stability of the hollow fiber membranes to be sterilized. In vacuum steam sterilization, the autoclave evacuation and evacuation procedures are performed alternately. For each evacuation step, the temperature of the autoclave and the hollow fiber membrane filter inevitably drops to a level significantly lower than during the evaporation step. Therefore, the hollow fiber membrane filter undergoes constantly changing material expansion. Consequently, adverse material stresses may occur during vacuum steam sterilization. This places correspondingly complex requirements on material selection, as well as the fabrication and design of the hollow fiber membrane filter.

[0019] Sterilization using ionizing radiation (such as gamma radiation or electron radiation) is combined with high equipment costs and results in long additional treatment times.

[0020] Due to the toxicity of ethylene oxide, sterilization with ethylene oxide also requires substantial system costs. Furthermore, a long period is needed after sterilization to completely eliminate the ethylene oxide.

[0021] Compared to other cited sterilization methods, heat sterilization using water and / or steam rinsing and sterilization steps, as implemented according to DE3936785C1, has proven technically superior in terms of equipment and procedures. In particular, this water / steam heat sterilization has demonstrated superior blood compatibility of the sterilized hollow fiber membrane compared to irradiation or gas sterilization methods.

[0022] However, it has also been shown that the steam sterilization method cited in DE3936785C1 adversely affects the removal rate of hollow fiber membranes for polysulfone membranes containing polyvinylpyrrolidone. It is assumed that the rinsing process during sterilization loosens the PVP present on the hollow fiber membrane. The capillary forces of the membrane pores attract and constrict the flowing PVP into the pores of the hollow fiber membrane, or block the pore cross-section. This results in a smaller pore cross-section for filtration. Therefore, the deposition of PVP in the pores reduces the permeability of the hollow fiber membrane.

[0023] Properly adjusting the production process of hollow fiber membranes attempts to offset the reduced permeability caused by the sterilization procedure. This also leads to an unfavorable widening of the pore size distribution of the hollow fiber membrane. Therefore, the pore size distribution of the hollow fiber membrane directly affects its selectivity.

[0024] The method in DE3936785C1 further demonstrates that, due to the presence of PVP within the hollow fiber membrane filter, the hollow fiber membrane can adhere together in the dialyzer during a previous water / steam sterilization process. This is not detrimental to the desired sterility. However, it can be observed that the sterilization process on such aggregated hollow fiber membranes produces non-uniform performance characteristics within the hollow fiber membrane filter. In particular, it was found that areas within the hollow fiber membrane filter where hollow fiber membranes aggregated during sterilization exhibited reduced permeability compared to areas where no aggregation of hollow fiber membranes was observed.

[0025] With this in mind, there is reason to further develop the rinsing and sterilization processes for steam sterilization methods used in hollow fiber membrane filters, so as to prevent the aggregation of hollow fiber membranes within the hollow fiber membrane assembly and, additionally, prevent the pores from shrinking or becoming blocked by moved and deposited PVP, while maintaining the high sterility and blood compatibility of the hollow fiber membrane and the hollow fiber membrane filter.

[0026] In this regard, the fundamental characteristic performance of hollow fiber membranes is clearance. Clearance is a measure of the separation capability of a hollow fiber membrane and represents the effort required to remove harmful metabolites during blood purification by treating the hollow fiber membrane. Methods for determining the clearance of hollow fiber membranes are known in the prior art. Reference is made to the standard DIN / EN / ISO 8637:2014. The clearance of hollow fiber membranes is thus determined according to this standard by constructing test filters with membranes suitable for the corresponding environment.

[0027] In the development of hollow fiber membranes for extracorporeal blood therapy, the aim is to develop hollow fiber membranes with the highest possible separation capacity in order to provide an effective type of therapy for extracorporeal blood therapy.

[0028] The ability to separate substances is particularly affected by the membrane's porosity and average pore size. Porosity represents the ratio of pore volumes in the membrane. When a membrane exhibits a higher pore volume than a control membrane, higher material transfer is observed on the membrane walls, which depends on the average pore size.

[0029] Especially for chronic extracorporeal therapy using blood, high separation capacity of plasma proteins in the mid-molecular range is desired. However, simultaneously, high retention of plasma proteins in the high molecular weight range (e.g., albumin) is necessary. Furthermore, high blood compatibility of hollow fiber membranes is also sought in extracorporeal blood therapy.

[0030] The purpose of this invention

[0031] Previous methods in the production of steam-sterilized polysulfone and polyvinylpyrrolidone-based hollow fiber membranes have been shown to have limited separation capacity and selectivity due to the sterilization process, particularly for plasma proteins in the medium molecular weight range at predetermined albumin retention levels.

[0032] Therefore, in a first aspect of the invention, the objective is to provide a hollow fiber membrane having high separation capacity (scavenging rate) in the medium molecular weight range and high retention in the high molecular weight range, thereby exhibiting high blood compatibility, as provided by sterilization by heating with water or steam.

[0033] In a second aspect of the invention, a further objective is to provide a hollow fiber membrane filter that exhibits uniform performance relative to the hollow fiber membrane within the hollow fiber membrane filter.

[0034] In a third aspect of the invention, the objective is to provide an improved method for producing hollow fiber membranes, the method comprising a water- or steam-based rinsing and / or sterilization step without reducing the separation capacity of the hollow fiber membrane during the rinsing and / or sterilization step.

[0035] In a fourth aspect of the invention, the objective is still to provide a water- or steam-based rinsing and / or sterilization method for hollow fiber membrane filters that does not adversely affect the performance of the hollow fiber membrane. Summary of the Invention

[0036] In a first aspect of the invention, it was surprisingly found that hollow fiber membranes with a porosity of 77.5% to 82% and a sieve factor of 0.42 to 0.75 for dextran with a molecular weight of 10,000 g / mol, comprising at least one polysulfone-based material and at least one polyvinylpyrrolidone-based polymer, solved the aforementioned task. Hollow fiber membranes with a nominal pore size distribution radius maximum in the range of 22-26 Å, particularly in the range of 23-26 Å, illustrate preferred embodiments of the invention according to the first aspect.

[0037] In a second aspect of the invention, a hollow fiber membrane filter is shown that solves the aforementioned problem. The hollow fiber membrane filter comprises a cylindrical housing and a plurality of hollow fiber membranes, at least one first fluid port for supplying fluid, particularly liquid or gas, into the interior of the fibers, and at least one first fluid port for discharging the fluid, particularly liquid or gas, from the interior of the fibers. The hollow fiber membranes are disposed inside the housing and sealed at their ends with a casting compound, thereby forming a first chamber surrounding the interior space of the hollow fiber membranes and a second chamber surrounding the space between the hollow fiber membranes.

[0038] Its features are,

[0039] The hollow fiber membrane exhibits uniform separation capability across the cross-section of the hollow fiber membrane filter, as measured by the ultrafiltration coefficients of the hollow fiber membrane in different regions of the hollow fiber membrane filter, which differ from each other by no more than 20%.

[0040] In a third aspect of the invention, it can be seen that the above-mentioned objective is achieved by a novel method for manufacturing hollow fiber membranes from a plurality of polysulfone and PVP-based hollow fiber membranes, comprising the following method steps:

[0041] - Providing spinning solutions containing polysulfone-based materials, particularly polysulfone, vinylpyrrolidone-based polymers, particularly polyvinylpyrrolidone, and aprotic solvents, particularly dimethylacetamide.

[0042] - Provides a coagulant liquid containing water and aprotic solvents, particularly dimethylacetamide.

[0043] - The spinning solution and the coagulant liquid are co-extruded into hollow strands through a concentric annular spinneret, thereby filling the cavity of the strands with the coagulant liquid.

[0044] - Guide the strands through the sedimentation gap.

[0045] - The strands are introduced into a sedimentation bath consisting primarily of water to obtain a hollow fiber membrane.

[0046] - The hollow fiber membrane is guided through at least one rinsing bath and the resulting hollow fiber membrane is dried.

[0047] - Arrange the obtained hollow fiber membranes into hollow fiber membrane bundles.

[0048] - Treat the hollow fiber membrane bundles with water vapor.

[0049] The water vapor treatment is characterized by comprising at least one step, wherein the water vapor is introduced into the interior of the fiber and, under applied pressure, permeates through the membrane wall to reach the exterior of the fiber.

[0050] The spinning solution contains 14% to 18% polysulfone and 3% to 6% polyvinylpyrrolidone, and the coagulant liquid contains 25% to 40% DMAC and 60% to 75% water.

[0051] The temperature of the spinneret is controlled between 70°C and 85°C.

[0052] The temperature of the precipitation bath is controlled between 70°C and 90°C, especially between 75°C and 90°C.

[0053] The hollow fiber membrane is washed at a temperature of 75°C to 90°C.

[0054] The hollow fiber membrane is dried at a temperature of 100°C to 150°C.

[0055] In a fourth aspect of the invention, a method for purifying a hollow fiber membrane filter is shown that solves the aforementioned task, wherein the hollow fiber membrane is sealed at its end within the housing of the hollow fiber membrane filter, forming a first chamber surrounding the interior of the hollow fiber membrane and a second chamber surrounding the space between the hollow fiber membranes, wherein the hollow fiber membrane filter includes at least two fluid ports connected to the first chamber and at least two fluid ports connected to the second chamber, and wherein the fluid ports are configured to connect to a sterilization device, the method comprising at least the following steps:

[0056] - The hollow fiber membrane filter is flushed with a fluid, particularly water, thereby directing the flushing fluid through the first and second chambers of the hollow fiber membrane filter by selecting the fluid port.

[0057] - The hollow fiber membrane filter is sterilized using a sterilizing fluid, particularly heated water or steam, wherein the sterilizing fluid is guided through the first and second chambers of the hollow fiber membrane filter by selecting the fluid port.

[0058] - By selecting the fluid port, fluid, particularly water or water vapor, is supplied to the first or second chamber of the hollow fiber membrane filter, and

[0059] The fluid, particularly water or water vapor, is allowed to pass across the membrane wall into the corresponding second or first chamber of the hollow fiber membrane filter.

[0060] The supply of fluid to the first or second chamber of the hollow fiber membrane filter, and the transmembrane passage of the fluid through the second or first chamber of the hollow fiber membrane assembly, occur between the rinsing and sterilization processes.

[0061] The method therefore involves heat sterilization, particularly steam sterilization using water vapor.

[0062] The rinsing procedure is performed at a temperature of 50°C to 120°C.

[0063] The heat sterilization is carried out at a temperature of 105°C to 140°C, preferably 121°C to 140°C.

[0064] The fluid is supplied to the first or second chamber of the hollow fiber membrane filter, and the transmembrane passage of the fluid through the corresponding second or first chamber of the hollow fiber membrane assembly is carried out at a temperature of 70°C to 98°C.

[0065] Further purging operations are performed using compressed gas, especially sterile compressed air. Attached Figure Description

[0066] Figure 1 The test apparatus used for zeta potential measurement is shown.

[0067] Figure 2 This is a schematic diagram of the cross-sectional area of ​​a hollow fiber membrane filter.

[0068] Figure 3 The first step of a purification process, including rinsing and sterilization steps, is schematically depicted for use in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention.

[0069] Figure 4 The second step of the rinsing and sterilization process used in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention, is schematically depicted.

[0070] Figure 5 The third step in the rinsing and sterilization process used in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention, is illustrated schematically.

[0071] Figure 6The fourth step in the rinsing and sterilization process used in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention, is illustrated schematically.

[0072] Figure 7 A sieve coefficient curve was plotted, from which a measure of the pore size distribution of the membrane of the present invention can be derived.

[0073] Figure 8 The nominal pore size distribution of the membrane of Example 2 and the control membrane of Example 3 is depicted. Detailed Implementation Plan

[0074] Surprisingly, in a first aspect of the invention, it is shown that when the hollow fiber membrane comprises at least one polysulfone-based material and at least one vinylpyrrolidone-based polymer, a hollow fiber membrane with improved separation capability in the medium molecular weight range can be provided, and the hollow fiber membrane has a porosity of 77.5%-82% and a sieve factor of 0.42-0.75 for a molecular weight of 10000 g / mol dextran.

[0075] The hollow fiber membranes according to a first aspect of the invention are characterized by high permeability in the medium molecular weight range. In particular, these hollow fiber membranes are shown to be blood-compatible because they can be produced from polysulfone and polyvinylpyrrolidone-based polymers and can be purified after rinsing and sterilized during sterilization.

[0076] According to a first aspect of the invention, the hollow fiber membrane is made of polysulfone. It is understood that the present invention definition of a polysulfone polymer is a polymer exhibiting sulfone groups in its main chain or side chains. The term polysulfone (PSU) should be understood in the context of this application as a general term for all polymers containing sulfone groups. Typical representatives of polysulfone materials are polysulfone (PSU), polyethersulfone (PES), polyphenylene sulfone, and copolymers containing sulfone groups. Although not listed herein, further representatives of polysulfone polymers are known in the prior art and are suitable for the production of blood therapy membranes as defined in this invention. Polysulfone materials have proven superior to other materials in the manufacture of blood therapy membranes because they are steam sterilizable and exhibit good blood compatibility properties.

[0077]

[0078] Polysulfone (PSU)

[0079]

[0080] Polyethersulfone (PES)

[0081] It should be understood that vinylpyrrolidone polymers are polymers produced using vinylpyrrolidone monomers or their derivatives. In particular, in the context of this invention, polyvinylpyrrolidone (PVP) is ideally suited for the production of the hollow fiber membranes of this invention. PVP is a water-soluble polymer that is used as an auxiliary agent in the production of polysulfone hollow fiber membranes. Furthermore, PVP improves the blood compatibility of polysulfone hollow fiber membranes because it hydrophilizes the hydrophobic polysulfone material, thereby improving its wettability to blood.

[0082]

[0083] Polyvinylpyrrolidone (PVP)

[0084] Blood compatibility refers to the tolerance of the material to human blood, particularly blood in contact with the polysulfone material, where the material has not experienced any negative reactions that could be harmful to the patient's health during blood therapy. These could refer, for example, to coagulation phenomena or a tendency to destroy blood cells (cytotoxicity). The use of PSU / PVP polymers has been shown to be superior in terms of blood compatibility compared to other blood contact materials in hollow fiber membranes.

[0085] In particular, polysulfone and polyvinylpyrrolidone (PVP)-based hollow fiber membrane materials are characterized by their zeta potential values. Zeta potential is a measure of the charge that can be found on the surface of a matrix. Specifically, in blood therapy membranes, this surface charge is associated with harmful reactions. Polysulfone and PPVP membranes exhibit different zeta potential values ​​depending on the method used to produce the hollow fiber membrane.

[0086] The porosity of a membrane represents the pore volume ratio of the membrane material. Because it is a hollow fiber membrane, only the pore volume ratio on the membrane wall is considered. The internal cavity of the hollow fiber membrane is not considered when calculating porosity. Porosity represents a measure of the permeability of the hollow fiber membrane to a fluid, and therefore is also a measure of the membrane's ability to separate molecules of a specific size. In particular, in conjunction with the sieving coefficient of molecules of a specific molecular weight, porosity is considered a measure of the membrane's ability to separate said molecules. In this case, it has been found that hollow fiber membranes having a sieving coefficient of 0.42 to 0.75 for dextran molecules with a molecular weight of 10000 g / mol, and a porosity of 77.5% to 82% for plasma proteins in the average molecular weight range, are characterized by high permeability or clearance rates in the average molecular weight range, and high separation selectivity for high molecular weight plasma proteins, particularly albumin. Preferably, the hollow fiber membrane is characterized by the absence of substantially large pores or dendritic cavities. Dendritic cavities are understood to be large pores with finger-like elongations. Large pores are described in the cited literature (“Mulder”). Examples of dendritic cavity formation can also be found in WO2004 / 056460A1. Figure 1WO2013 / 034611A1 Figure 1 , Figure 2 and Figure 3 Or WO2015 / 056460A1 Figure 5 The membranes found to be free of dendritic cavities or large pores exhibit higher mechanical stability. Further preferred are membranes characterized by a wall thickness of 35 μm or less and substantially free of large pores or dendritic cavities. Ensuring good mechanical stability is particularly important at such small wall thicknesses.

[0087] The sieving factor indicates the proportion of a substance under consideration that can permeate through the membrane wall during filtration. Particularly relevant to hollow fiber membranes with low sieving factors for high molecular weight molecules are those that are largely blocked by the membrane wall during filtration, with only a small percentage able to permeate through the pores of the hollow fiber membrane. Efforts are made in the production of hollow fiber membranes for blood therapy to produce a porous structure that allows for high retention of high molecular weight plasma proteins (e.g., albumin), characterized by a correspondingly low sieving factor of 0.01 for albumin, preferably 0.005, and particularly preferably 0.001. On the other hand, a high sieving factor for low molecular weight molecules means that virtually all of these molecules can permeate through the porous structure of the hollow fiber membrane wall.

[0088] The pore size distribution of the membrane according to the invention is thus constructed to produce a sieving factor of 0.42 to 0.75 as described for dextran with a molecular weight of 10000 g / mol, and the sieving factor of albumin is set to a value less than 0.1 as described.

[0089] In another embodiment of the first aspect of the invention, the hollow fiber membrane of the invention is characterized by a zeta potential value of -3 mV to -10 mV. Particularly noticeable is that harmful reactions of blood cells occur only to a lesser extent within this value range.

[0090] In a further embodiment of the first aspect of the invention, it can be seen that when the porosity of the hollow fiber membrane is 78% to 81%, and particularly 79% to 80.5%, the selectivity of the hollow fiber membrane can be improved.

[0091] In a further embodiment of the first aspect of the invention, it can be seen that when the hollow fiber membrane has a sieve factor of 0.45 to 0.75 for dextran molecules with a molecular weight of 10,000 g / mol (preferably 0.55 to 0.7, particularly 0.6 to 0.7), the selectivity of the hollow fiber membrane can be further improved.

[0092] In a further embodiment of the first aspect of the present invention, it can be seen that when the albumin sieving coefficient of the hollow fiber membrane is less than 0.005, especially less than 0.001, the selectivity of the hollow fiber membrane can be improved.

[0093] In a further embodiment of the first aspect of the invention, it can be seen that the blood compatibility of the hollow fiber membrane can be improved by a hollow fiber membrane having a zeta potential of -4mV to -8mV, particularly -6mV to -8mV.

[0094] In a further embodiment of the first aspect of the present invention, it can be seen that when the PVP content of the hollow fiber membrane is 2.5% to 5%, the blood compatibility of the hollow fiber membrane can be improved.

[0095] In a further embodiment of the first aspect of the invention, it can be seen that the maximum nominal pore size distribution of the membrane of the present invention is in the range of 22-26 Å (Å = angstrom = 100 ppm). In particular, the maximum nominal pore size distribution within this molecular weight range allows for the desired high separation of medium-molecular-weight plasma proteins. Therefore, the pore size distribution indicates the probability of a specific pore size appearing in a given pore of all hollow fiber membranes. Thus, the maximum nominal pore size distribution predicts the specific pore size that appears most frequently in all pores. It is further demonstrated in this case that by adjusting the nominal pore size distribution during hollow fiber membrane production such that the maximum nominal pore size distribution is in the range of 22-26 Å, preferably in the range of 23 to 26 Å, and the albumin sieving coefficient is in the range of less than 0.01, membranes with improved selectivity can be produced.

[0096] In a second aspect, the present invention relates to hollow fiber membrane filters. The hollow fiber membrane filter comprises a cylindrical housing containing a plurality of hollow fiber membranes. Specifically, the hollow fiber membranes can be manufactured according to embodiments of the first aspect of the invention. The hollow fiber membranes are sealed at the ends of the hollow fiber membrane filter with a casting compound, such that a first chamber surrounds the internal space of the hollow fiber membrane, and a second chamber surrounds the space between the hollow fiber membranes. The hollow fiber membrane filter further comprises a first fluid port for supplying fluid, particularly liquid or gas, to the interior of the hollow fiber membrane and a second fluid port for discharging liquid or gas from the interior of the hollow fiber membrane. The hollow fiber membrane filter is characterized by the hollow fiber membrane having uniformly distributed permeability (particularly a uniform ultrafiltration coefficient) in different regions (particularly in the cross-section of the hollow fiber membrane filter). The uniformity of the permeability of the hollow fiber membrane in different regions of the hollow fiber membrane filter is estimated by the hollow fiber membrane having ultrafiltration coefficients in different regions that differ from each other by no more than 20%.

[0097] The uniform ultrafiltration coefficient of the hollow fiber membrane in a hollow fiber membrane filter is attributed to the process steps employed in the production process that utilize the transmembrane passage of a fluid, particularly water vapor or water. As defined in this invention, water vapor refers to the name of water in a gaseous state. Within the meaning of this application, water vapor also refers to a gaseous form of water accompanied by so-called visible vapor; that is, mist-like water droplets distributed throughout the air. Therefore, the term "water vapor" as used in this application also includes other sub-names of water vapor, such as superheated steam, wet steam, saturated steam, superheated steam, and supercritical steam.

[0098] Transmembrane passage of fluid can allow the fluid to pass through the membrane wall from the first chamber containing the interior of the hollow fiber membrane into the second chamber containing the space between the hollow fiber membranes. In another embodiment, transmembrane passage can pass through the membrane wall from the second chamber containing the space between the hollow fiber membranes into the first chamber containing the interior of the hollow fiber membrane. It is believed that transmembrane passage can affect the purging of PVP pores, thereby eliminating any shrinkage or blockage of the hollow fiber membrane pores caused by deposited PVP that may occur during production. It is further believed that the passage of transmembrane water and / or water vapor also eliminates the aggregation of hollow fiber membranes. As fluid (especially water vapor or water) passes through the transmembrane from the interior to the exterior of the hollow fiber membrane, the flowing fluid dissolves this aggregation from the fiber interior. Therefore, overall deagglomeration of the hollow fiber membrane is observed within the hollow fiber membrane bundle. Fluid flowing into the hollow fiber membrane from the exterior and entering the membrane interior through the membrane wall also causes deagglomeration of the hollow fiber membranes that are adhered together. It is further observed that the ultrafiltration coefficient based on the hollow fiber membrane filter as a whole increases.

[0099] In the sense of the second aspect of the invention, a hollow fiber membrane filter may comprise 50 to 20,000 hollow fiber membranes arranged in a housing of the hollow fiber membrane filter at a packing density of 50% to 70%. Packing density therefore refers to the space filled by the hollow fiber membranes within the bundle of hollow fiber membranes placed in the housing. The packing density of the hollow fiber membranes is the sum of the cross-sectional areas of the individual hollow fiber membranes divided by the total cross-sectional area defining the cross-sectional areas of all hollow fiber membranes in an arrangement. This is typically the cross-section of the housing. For hollow fiber membranes and a housing geometry with a circular cross-section, the packing density is calculated according to the following formula:

[0100]

[0101] d （纤维） It is the average outer diameter of the unloaded hollow fiber membrane.

[0102] d （过滤器） It is the inner diameter of the shell.

[0103] n: The number of hollow fiber membranes in the shell

[0104] The term "unloaded hollow fiber membrane" refers to individual hollow fiber membranes that are not under load. Hollow fiber membranes can deform within their shells under compression; that is, they exhibit deformed cross-sections under load. However, the diameter of the unloaded hollow fiber membrane is always used to calculate the packing density.

[0105] Therefore, during the manufacture of hollow fiber membrane filters, depolymerization of the hollow fiber membrane filter through the transmembrane via fluid is more effective in the case of a tightly packed hollow fiber membrane filter, i.e., a hollow fiber membrane filter with a high packing density, than in the case of a hollow fiber membrane filter with a low packing density. In particular, hollow fiber membrane depolymerization in hollow fiber membrane filters with a packing density of 50-70%, preferably 55-65%, more preferably 55-65%, is considered particularly effective.

[0106] In particular, the transmembrane passage of a fluid (especially water vapor or water) can be achieved within the scope of the heat sterilization procedure, or even be part of the heat sterilization step. In the latter case, water vapor at a working temperature of 121 to 140°C is provided, so that sterilization also occurs as the water vapor passes through the membrane.

[0107] In a third aspect, the present invention relates to a method for manufacturing hollow fiber membrane bundles for use in a hollow fiber membrane filter comprising a plurality of hollow fiber membranes. Specifically, the hollow fiber membrane filter can be a hollow fiber membrane filter according to an embodiment of the second aspect of the invention; further specifically, the hollow fiber membrane can be manufactured according to an embodiment of the first aspect of the invention. The production process includes a spinning method for polysulfone and polyvinylpyrrolidone-based hollow fiber membranes; the spinning method is particularly a dry-wet spinning method. The production process includes the following method steps:

[0108] Provides spinning solutions comprising polysulfone-based materials (especially polysulfone), vinylpyrrolidone-based polymers (especially polyvinylpyrrolidone), and aprotic solvents (especially dimethylacetamide).

[0109] Provides coagulant liquids containing water and aprotic solvents (especially dimethylacetamide).

[0110] The spinning solution and coagulant liquid are co-extruded through a concentric annular spinneret to form a hollow strand, the cavity of which is filled with coagulant liquid.

[0111] Guide the stock line through the sedimentation gap.

[0112] The wire was introduced into a sedimentation bath consisting primarily of water to obtain a hollow fiber membrane.

[0113] The hollow fiber membrane is guided through at least one rinsing bath and the resulting hollow fiber membrane is dried.

[0114] The resulting hollow fiber membranes are arranged into hollow fiber membrane bundles.

[0115] Hollow fiber membrane bundles were treated with water vapor.

[0116] A further feature of the method is a water vapor treatment, which includes at least one step in which water vapor is introduced into the fiber and permeates through the membrane wall to the outside of the fiber under applied pressure.

[0117] After the hollow fiber membrane is arranged into a hollow fiber membrane bundle and before the hollow fiber membrane bundle is treated with water vapor, according to known prior art methods, the hollow fiber membrane bundle can be placed in the housing of the hollow fiber membrane filter and the ends of the hollow fiber membrane bundle are cast with curable resin.

[0118] The hollow fiber membrane bundle cast into the housing can be further processed into a hollow fiber membrane filter, forming two fluid flow chambers, whereby the first chamber surrounds the interior of the hollow fiber membrane and the second chamber surrounds the space between the fibers, and wherein the hollow fiber membrane filter has at least one port for fluid to enter the first chamber of the hollow fiber membrane filter and at least one port for fluid to enter the second chamber of the hollow fiber membrane filter. Then, a steam treatment step of the hollow fiber membrane bundle can be achieved within the hollow fiber membrane filter by introducing water vapor through the first fluid port into the first chamber of the hollow fiber membrane filter surrounding the interior of the hollow fiber membrane, pressing it through the membrane wall into the second chamber of the hollow fiber membrane filter surrounding the space between the hollow fiber membranes, and guiding it out of the second chamber via the second port on the hollow fiber membrane filter.

[0119] The steam treatment step can be performed during rinsing or during heat sterilization; in particular, when the hollow fiber membrane is incorporated into the hollow fiber membrane filter as a hollow fiber membrane bundle, the steam treatment step itself constitutes the rinsing step.

[0120] Manufacturing hollow fiber membrane filters according to the above method enables the production of hollow fiber membrane filters in which the hollow fiber membrane pores are free from PVP clogging or shrinkage, and in which the individual hollow fiber membranes do not aggregate. This results in increased clearance of the hollow fiber membranes in the hollow fiber membrane filters produced according to the method of the present invention, because a larger membrane surface is effectively provided for transmembrane exchange of material through the individual fibers and pores that are removed by the deposited PVP.

[0121] The manufacturing method further ensures excellent biocompatibility of the hollow fiber membrane when a steam treatment step is performed during heat sterilization. In this case, damaged cell debris and endotoxins that occur under sterilization conditions are washed away from the membrane surface. Therefore, in a preferred embodiment, the hollow fiber membrane bundles are further processed into filters prior to the steam treatment step, and the hollow fiber membrane filters are steam treated during the sterilization process.

[0122] In a further embodiment of the third aspect of the invention, the spinning solution is used for the spinning process on a hollow fiber membrane, comprising 14-18% of a polysulfone-based polymer (preferably polysulfone) and 3-6% of a vinylpyrrolidone-based polymer (preferably polyvinylpyrrolidone). A polar aprotic solvent, preferably dimethylacetamide (DMAC), constitutes another percentage of the spinning solution.

[0123] In a further embodiment of the third aspect of the invention, the method of the invention for producing hollow fiber membrane bundles is characterized in that the coagulant liquid comprises 25% to 40% of a polar aprotic solvent, particularly dimethylacetamide, particularly 25% to 40% of DMAC and 60% to 75% of water.

[0124] In a further embodiment of the third aspect of the invention, the method of the invention for producing hollow fiber membrane bundles is characterized by controlling the precipitation bath temperature at 75°C to 85°C during the spinning process. This precipitation bath temperature contributes to high ultrafiltration coefficients and high sieving coefficients for molecules in the medium molecular weight range.

[0125] In a further embodiment of the third aspect of the invention, the method of the invention for producing hollow fiber membrane bundles is characterized in that the hollow fiber membrane is washed at a temperature of 75°C to 90°C. During the washing process, a washing liquid (preferably water) is introduced into the hollow fiber membrane filter, and the filters in the first and second chambers are rinsed with water. This process blows residual particles and elutable components from the hollow fiber membrane and filter housing out of the hollow fiber membrane filter.

[0126] In a further embodiment of the third aspect of the invention, the method of the invention for producing hollow fiber membrane bundles is characterized by drying the hollow fiber membrane at a temperature of 100°C to 150°C.

[0127] In a further embodiment of the third aspect of the invention, the method of the invention is characterized in that the water vapor treatment of the hollow fiber membrane bundle is carried out at a temperature above 60°C to 140°C.

[0128] In a fourth aspect, the present invention relates to a sterilization procedure for sterilizing a hollow fiber membrane filter. According to this, a hollow fiber membrane filter comprising a plurality of hollow fiber membranes is sterilized, the hollow fiber membranes being sealed at the ends of a housing of the hollow fiber membrane filter, thereby forming a first chamber surrounding the interior of the hollow fiber membranes and a second chamber surrounding the space between the hollow fiber membranes. The hollow fiber membrane filter further comprises at least two fluid ports connected to the first chamber and at least two fluid ports connected to the second chamber, whereby the fluid ports are configured to connect to a sterilization device, and wherein the method comprises at least the following steps:

[0129] The hollow fiber membrane filter is flushed with a fluid (especially water), thereby directing the flushing fluid through the first and second chambers of the hollow fiber membrane filter by selecting fluid ports.

[0130] The hollow fiber membrane filter is sterilized with a sterilizing fluid (especially water or steam), thereby guiding the sterilizing fluid through the first and second chambers of the hollow fiber membrane filter via selected fluid ports.

[0131] Fluid (especially water or water vapor) is supplied to the first or second chamber of the hollow fiber membrane filter by selecting a fluid port, and

[0132] Fluid (especially water or water vapor) passes across the membrane wall into the corresponding second or first chamber of the hollow fiber membrane filter.

[0133] One embodiment of the method according to the fourth aspect of the invention provides a rinsing step for the hollow fiber membrane incorporated in a hollow fiber membrane filter, which sterilizes the water or steam using sterile water or steam, respectively. In this case, sterilization means that the rinsing step is performed under heat and pressure conditions. The sterilization conditions for the heat sterilization of the hollow fiber membrane filter exist at temperatures above 105°C to 150°C (preferably 121°C to 140°C) and absolute pressures of 1.1 bar to 10 bar (preferably 2 bar to 4 bar).

[0134] In a further embodiment of the fourth aspect of the invention, the method comprises the steps of introducing a fluid (particularly water or water vapor) into a first chamber of a filter assembly, conveying it through the membrane wall to a second chamber via the resulting pressure difference, and discharging it therefrom. Alternatively, the fluid (particularly water or water vapor) may also be guided into the second chamber of the hollow fiber membrane filter via a selected fluid port, and enter the first chamber from the second chamber of the hollow fiber membrane filter via the resulting pressure difference through the membrane wall. Thus, the fluid port of the hollow fiber membrane filter is connected to a sterilization device capable of conveying sterilizing fluid (particularly heated water and / or water vapor) to the hollow fiber membrane filter. Preferably, the fluid (particularly water or water vapor) is conveyed into the first chamber through a first fluid port, and, if appropriate, the other fluid port leading to the first chamber of the hollow fiber membrane filter is blocked. However, the fluid (particularly water or water vapor) may also be conveyed into the hollow fiber membrane filter simultaneously through both fluid ports. In both cases, the accumulation of pressure from the conveyed fluid (particularly water or water vapor) causes the fluid (particularly water or water vapor) to flow through the membrane wall and into the second chamber. In the second chamber, the fluid that has already flowed through (especially water or water vapor) can be discharged through another fluid port.

[0135] In a further embodiment of the fourth aspect of the invention, it is recognized that transmembrane flow of fluids (particularly water or water vapor) occurs preferentially prior to the sterilization process.

[0136] In a further embodiment of the fourth aspect of the invention, sterilization of the hollow fiber membrane filter is performed by supplying sterilizing liquid through two fluid ports, which are provided for supplying fluid to the first and second chambers of the hollow fiber membrane filter. Fluid is discharged from the first and second chambers of the hollow fiber membrane filter via two corresponding additional fluid ports for discharging fluid, thereby purging the two chambers and the filter with the sterilizing liquid. Sterile water at a temperature controlled between 105°C and 140°C is preferably used as the sterilizing liquid.

[0137] A further embodiment of the fourth aspect of the invention can provide a rinsing operation using a fluid (particularly sterile water). Alternatively, an aqueous mixture can be used as the rinsing liquid. Preferably, rinsing occurs at an elevated temperature. Thus, the rinsing liquid is preferably at a temperature of 50°C to 120°C. In particular, the rinsing operation can better remove particles and further elutable substances at elevated temperatures. If the membrane material also contains hydrophilic components, excessively high temperatures during the rinsing operation are undesirable, as they can cause excessive membrane material adhesion. Preferred rinsing temperatures are 60°C to 98°C, and particularly preferred are 70°C to 98°C.

[0138] Steam sterilization is performed at a temperature of 124°C ± 5°C. The technical system cannot always precisely maintain the pre-selected temperature. Therefore, it has proven technically advantageous to select a temperature between 105°C and 140°C. This allows for setting pressures up to 4 bar. At a sterilization temperature of 124°C, the desired sterility can be achieved within 12 minutes. Alternatively, sterilization can also be performed at lower temperatures for longer durations, such as maintaining the temperature at 121°C for 15 minutes.

[0139] Transmembrane passage of fluids (e.g., water or water vapor) preferably occurs at elevated temperatures. Therefore, sterile forms of water vapor are preferred. Specifically, transmembrane water vapor passage at temperatures between 50°C and 98°C can also elute particles and elutable substances from the membrane walls and inner pore surfaces rather than directly on the membrane surface.

[0140] A purging step, using compressed air or an alternative compressed gas between the first rinsing step and the entire sterilization and rinsing process, has proven advantageous. In this process, sterile compressed air is used to vent the two chambers of the filter assembly without creating a pressure gradient across the membrane material between the first and second chambers. Liquid from the preceding rinsing process is thus retained in the pores. This intermediate step facilitates the subsequent transmembrane purging procedure. Therefore, this further embodiment of the fourth aspect of the invention is characterized by utilizing compressed gas (especially sterile compressed air) for the further purging operation.

[0141] This invention is based on the description of the measurement method, accompanying drawings, and embodiments.

[0142] Measurement Method 1: Determining Porosity

[0143] Hollow fiber membrane bundles, pre-dried in a drying oven at 105°C for 2 hours and composed of identical hollow fiber membranes, were weighed. The average fiber length, average inner diameter, average outer diameter, and fiber number were determined. The average dimensions of at least 10 different fibers in the hollow fiber membrane bundle were determined. Dimension determination occurred at a constant temperature of 20°C. The volume of permeate through the membrane wall of the hollow fiber membrane bundle was calculated from the dimensions, assuming the geometry of the hollow fiber membrane corresponds to a hollow cylinder. Based on the determined volume and measured weight, the average density of the inner membrane structure of the hollow fiber membrane could be calculated. The porosity, expressed as a percentage, was obtained by the ratio between the density determined under fully dense polysulfone material and the theoretical hollow fiber membrane density, conforming to the following formula:

[0144]

[0145] Measurement Method 2: Determining the ζ-potential

[0146] To determine the zeta potential of the hollow fiber membranes under evaluation, a hollow fiber membrane filter (dialyzer) with 10,752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm was used. The length of the hollow fiber membrane associated with the zeta potential measurement was 279 mm. The hollow fiber membranes were sealed at the ends of the hollow fiber membrane filter, creating a first chamber surrounding the interior of the hollow fiber membranes and a second chamber surrounding the space between the hollow fiber membranes. Polyurethane (polyol C6947 and isocyanate 136-20) from Elastogran was used as the casting material. The casting height at each bundle end was 22 mm. Figure 1 The device is used for measurement. The hollow fiber membrane filter (1) includes fluid ports (2, 2a, 3, 3a) leading to the corresponding first and second chambers of the hollow fiber membrane filter (1). The fluid ports leading to the first chamber of the hollow fiber membrane filter (1) are each provided with ports for Ag / AgCl electrodes (4, 4a) and pressure gauges (5, 5a). The fluid ports (3, 3a) leading to the second chamber of the hollow fiber membrane filter (1) are tightly sealed so that the second chamber of the hollow fiber membrane filter is not filled. Therefore, the potential difference ΔEz (mV) is recorded by the voltmeter (6) between the two electrodes, and the pressure ΔP (N / m) between the passages of the pressure gauges (5, 5a) is recorded by the voltmeter (6) between the two electrodes. 2 The decrease in pH was recorded by pressure gauge (7). The test solution consisted of a 1-molar KCl aqueous solution with a pH of 7.4, and was provided in a reservoir (8) located approximately 1000 mm above the filter. The pH was set according to the following rule: 50 mg K2CO3 was added to 100 L of KCl solution. The mixture was stirred in an open container until the pH reached 7.4. The container was then tightly sealed. Measurements were performed at a temperature of 23 °C ± 2 °C.

[0147] To measure the zeta potential, the test liquid is poured through the first fluid port (2) into the first chamber of the hollow fiber membrane filter, which surrounds the internal space of the hollow fiber membrane, and then output from the dialyzer through the second fluid port (2a) on the hollow fiber membrane filter, which is connected to the internal space of the hollow fiber membrane. In this configuration, the hollow fiber membrane filter is first flushed with the test liquid for 10 minutes until a stable value is reached, and flushed for another 5 minutes if necessary. The pressure difference and potential difference are read simultaneously from a pressure gauge and a multimeter, respectively, and the zeta potential is calculated from them. To improve measurement accuracy, two four-way valves are switched after the measurement value is acquired to generate reverse flow of the test liquid through the internal space of the hollow fiber membrane. The measured value of the zeta potential is then formed by averaging the measured values ​​in the two flow directions.

[0148] The zeta potential is derived from the following equation:

[0149] ζ=

[0150] Where ζ = ζ potential (mV)

[0151] η = solution viscosity (0.001 Ns / m) 2 )

[0152] Λ o =Solution conductivity (A / (V)) m))

[0153] ε o =Vacuum permittivity (8.85) 10 -12 A s / (V m)

[0154] ε r =Relative solution permittivity

[0155] E Z =flow potential (mV)

[0156] Δ P =Pressure difference (N / m) 2 )

[0157] Measurement Method 3: Determining the dextran sieve coefficient

[0158] The dextran sieving factor of the hollow fiber membrane was measured on a fully constructed hollow fiber membrane filter according to DIN EN ISO 8637:2014. Accordingly, a filter with 10,752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm was used. The effective length of the hollow fiber membrane was 235 mm. The effective length of the hollow fiber membrane should be understood as the length of the hollow fiber membrane without casting compounds, which can be used to determine permeability performance, such as sieving factor, clearance rate, and ultrafiltration coefficient. The inner diameter of the hollow fiber membrane filter was 34 mm at the center. Otherwise, the hollow fiber membrane filter exhibited the same structure as described in "Measurement Method 2". Unlike the standard, an aqueous dextran solution containing dissolved dextran or a mixture of several dextrans within this molecular weight range with a broad molecular weight distribution of 1,000 to 100,000 Da was used as the test liquid to produce an indicated molecular weight distribution. The dextran solution was passed through the fluid port into the first chamber of the hollow fiber membrane filter, which surrounds the hollow fiber membrane, at a flow rate of 446.6 ml / min. A pure water flow of 89.9 ml / min was introduced into the second chamber of the hollow fiber membrane filter via the fluid port. After 12 minutes, the dextran concentration was determined by gel permeation chromatography and sieving coefficient curves over the entire molecular weight range thus defined, based on the corresponding molecular weights at the first and second fluid ports of the first chamber of the hollow fiber membrane filter across the entire molecular weight range.

[0159] Measurement Method 4: Determining the albumin screening coefficient

[0160] As in Measurement Method 3, the albumin sieving factor was determined on the hollow fiber membrane using a filter. In the measurement, the sieving factor was determined using human plasma according to DIN EN ISO 8637:2014. This determined the “plasma sieving factor” for albumin. A Cobas Integra 400 plus analyzer from Roche Diagnostics GmbH (Mannheim) was used as the analytical device. Measurements were performed using the ALBT2 test in urine. A plasma flow rate of 446.6 ml / min and a dialysate flow rate of 89.9 ml / min (deionized water) were established.

[0161] Measurement Method 5: Determining the clearance rates of sodium, phosphate, and vitamin B12

[0162] The clearance rate of the hollow fiber membrane was determined based on a hollow fiber membrane filter constructed according to Measurement Method 2 of DIN EN ISO 8637:2014. According to 5.6.1.2 of the standard, a sodium aqueous solution with a concentration of 5 g / L NaCl and 0.05 g / L Vitamin B12 were used as the test solution for the blood zone (the blood zone corresponds to the first chamber of the hollow fiber membrane filter surrounding the interior of the hollow fiber membrane); therefore, distilled water was used for the dialysis fluid zone (the dialysis fluid zone corresponds to the second chamber of the hollow fiber membrane filter surrounding the fiber voids). Phosphate was used in the dialysis fluid at a concentration of 3 mmol / L, and the dialysis fluid on the dialysate side was measured again. For phosphate, the following dialysis fluid was prepared: 34.63 L water, 102.9 g NaHCO3, 210.68 g NaCl, 2.61 g KCl, and 5.15 g CaCl2. 2H₂O, 3.56g of MgCl₂ 6H₂O, 6.31 g of CH₃COOH, and 38.5 g of glucose monohydrate were used. Phosphate was determined photometrically after reaction with ammonium molybdate in sulfuric acid solution, using a Cobas integra 400 plus apparatus from Roche Diagnostics GmbH (Mannheim, Germany) and a (Roche) PHOS2 test. Sodium concentration was determined by measuring conductivity. Vitamin B12 concentration was determined photometrically. Scavenging rate was tested using a hollow fiber membrane filter of the same structure, also according to measurement method 2. A flow rate of 300 ml / min was set in the first chamber of the hollow fiber membrane filter, which surrounds the hollow fiber membrane produced within the scope of this application, and a flow rate of 500 ml / min was set in the second chamber of the hollow fiber membrane filter.

[0163] Measurement Method 6: Determining the Local Ultrafiltration Coefficient

[0164] As described in "Measurement Method 3", a hollow fiber membrane filter with 10,752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm was used to determine the local ultrafiltration coefficient. The effective length of the hollow fiber membrane was 235 mm. The effective length of the hollow fiber membrane should be understood as the length of the hollow fiber membrane without casting compounds, which can be used to determine permeability properties such as sieving coefficient, clearance rate, and ultrafiltration coefficient. The inner diameter of the hollow fiber membrane filter was 34 mm at the center. The blood-side inlet cap of the filter was removed from the hollow fiber membrane assembly and replaced with the inlet of a device comprising a circular portion that directs the test liquid flow only to a hollow fiber bundle with a diameter of 1 cm. Unlike the DIN ISO 8637:2014 standard, water was therefore used as the test liquid, and thus the "water-containing ultrafiltration coefficient" known to those skilled in the art was determined. The device was designed such that the end of the device penetrates approximately 3 mm into the upper end of the hollow fiber membrane bundle, resulting in a seal between the device and the hollow fiber membrane bundle. This ensures that only a localized circular surface area with a diameter of 1 cm is measured. To measure a larger area, use improved equipment or reposition the equipment to the desired location. Figure 2 A schematic diagram of the cross-sectional area of ​​the hollow fiber membrane filter can be seen in the image. When setting the flow rate of the test liquid, be sure to set the same transmembrane pressure (TMP) as in the measurement of the aqueous ultrafiltration coefficient based on DIN ISO 8637:2014. The maximum TMP setting is 600 mmHg.

[0165] Measurement Method 7: Determining the PVP Content of Hollow Fiber Membranes

[0166] The PVP content of the hollow fiber membrane was determined by IR spectroscopy. In this process, the sample was first dried in a drying oven at 105°C for 2 hours. Then, 1 g of fiber was dissolved in dichloromethane. A calibration standard using dried PVP was also prepared, similarly dissolved in dichloromethane. This covered a concentration range of approximately 1% to 10% PVP in the hollow fiber. The solutions were each placed in a small fluid container to achieve a layer thickness of 0.2 mm. The absorption bands of the carbonyl functional groups were used for evaluation.

[0167] Measurement Method 8: Depicting the nominal aperture distribution and nominal average aperture

[0168] From such Figure 7The sieving coefficient curve depicted in the figure begins to derive a measure of the pore size distribution of the membrane of the present invention. For this purpose, as described in measurement method 3, sieving coefficient curves are obtained for dextran samples or mixtures of multiple dextran samples with a wide molecular weight distribution. For each molecular weight, the sieving coefficient curve provides the probability of passage of the corresponding dextran molecule through the membrane wall. Given a specific temperature and a specific solvent, molecular weight is related to a specific molecular size, which can be defined by the Stokes radius. The relationship between the Stokes radius and molecular weight yields the J. Bandrup, EH Immergut equation (“Polymer Handbook” (1989) VII pp. 112-113, John Wiley):

[0169]

[0170] Where M represents the molecular weight of the dextran. The molecular weight is converted into a value based on, for example, computer software (such as the "Excel" program). Figure 7 The Stokes radius for each data point on the sieving coefficient curve. A similar description to the sieving coefficient curve depicts the probability of a dextran molecule passing through at a specific Stokes radius; that is, a specific molecular size can pass through the membrane wall. Simultaneously, this description provides information about the pore size distribution structure, indicating how probable membrane pores of a specific size are to allow dextran molecules of a predetermined molecular size to pass through; i.e., the Stokes radius.

[0171] Furthermore, an Excel software program is used to perform a transformation to establish a first derivative at each point on the curve. The resulting curve progression indicator curve depicts a measure of the nominal pore size distribution of the membrane being evaluated. For the membrane according to the invention and the control membrane, the corresponding curve progression is as follows: Figure 8 As shown, the maximum value of the distribution curve depicts the nominal average pore size of the membrane.

[0172] Example 1: Method for purifying hollow fiber membrane filters

[0173] Figure 3 The first step of a purification process, including rinsing and sterilization steps, is schematically depicted for use in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention. Figure 3A fluid port 118 is shown for the first chamber 119 of a hollow fiber membrane filter 113, which surrounds the interior of the hollow fiber membrane. This chamber is fluidly connected to connector 101 via a line 109 having a valve 105. Another fluid port 117 is fluidly connected to connector 102 via line 110 and valve 106, forming the inlet to the second chamber 120 of the hollow fiber membrane filter 113, which surrounds the space between the hollow fiber membranes. Another fluid port 114 is fluidly connected to valve 107 and connector 103 via line 111, forming the inlet to the second chamber 120 of the hollow fiber membrane filter. A fluid port 115 is fluidly connected to valve 108 and connector 104 via line 112. Connectors 101 and 103 are further fluidly connected via connector 101a.

[0174] In one embodiment of the flushing procedure, as depicted, in a first step, flushing fluid is delivered to the hollow fiber membrane filter 113 via connection 104 through line 112. Preferably, the flushing fluid is temperature-controlled sterile water, thereby maintaining a temperature of 50 to 98°C. Valve 108 is then switched to flow through. The flushing fluid flows into the first chamber 119 of the hollow fiber membrane filter via a second fluid port 115 and exits the first chamber via a first fluid port 118. This arrangement allows for flushing of the interior of all hollow fiber membranes within the hollow fiber membrane bundle.

[0175] The flushing fluid is further guided through bubble detector 114 (which is inactive in this flushing operation) and line 109, and through connector 101 and connector 101a to line 111. The flushing fluid enters the second chamber 120 of the hollow fiber membrane filter 113 via fluid port 114 and purges the second chamber formed in the space between the hollow fiber membranes. The return flow of the purge fluid occurs via fluid port 117 and line 110, and it is then discarded or treated so that it can be reused for further flushing operations.

[0176] Figure 4 The second step of the rinsing and sterilization process used in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention, is schematically depicted. Figure 4 This is used to illustrate compressed air purging. A compressed air source supplying sterile air is provided with connections 201 and 202. Compressed air is delivered via open valves 205 and 206 through lines 209 and 210, and via a pumping device (not shown) to the hollow fiber membrane module 213. The first chamber 219 and the second chamber 220 initially still use air from the preceding... Figure 3The flushing operation involves water filling during the flushing step. Valves 207 and 208 are opened and prepared for discharging the flushing liquid. Compressed air is supplied through the filter assembly at a pressure of 1.5 to 2 bar. The compressed air further discharges residual water from the first and second chambers of the hollow fiber membrane filter through corresponding fluid ports 215 and 214 to the return section of the flow path loop via corresponding fluid ports 218 and 217. The residual water and compressed air are discharged via lines 212 and 211. The flushing process lasts 2 to 5 minutes. Since equal pressure exists in chambers 219 and 220, there is no rinsing through the membrane wall. Therefore, the pores of the membrane wall remain filled with water from the flushing procedure.

[0177] Figure 5 The third step in the rinsing and sterilization process used in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention, is illustrated schematically. Figure 5 Connections 302 and 304 are depicted, which prevent the discharge of flushing fluid via valves 306 and 308 in the closed valve position. Water vapor is delivered to the sterilization system via connection 301 and to the filter assembly 313 via line 309. The water vapor is dispersed in the first chamber 319 of the hollow fiber membrane filter; due to the blockage of connection 304, it is impossible to discharge via fluid port 315. The dispersion of water vapor in line 312 can only be achieved by compressing pressurized pure steam or by diffusion.

[0178] Because the pressure in the first chamber is higher than the pressure in the second chamber, pure vapor transmembrane passage occurs. According to... Figure 3 The first step of the rinsing and sterilization operation involves evacuating residual water from the pores during rinsing and conveying it through the second chamber 320 in line 311. Line 310 is not used for fluid delivery because connector 302 is closed. Adjacent hollow fiber membranes are largely separated from each other through a transmembrane rinsing procedure. Water vapor is thus delivered into the filter assembly at a pressure of 1.3 to 2 bar. Thorough rinsing of the pores also prevents adhesion of the hollow fibers. This rinsing process can be terminated after several minutes. Specifically, the rinsing procedure lasts 2 to 5 minutes. The temperature is maintained between 50°C and 98°C, particularly for heat conditioning of the filter assembly for subsequent sterilization procedures.

[0179] Figure 6The diagram schematically depicts the fourth step in the rinsing and sterilization process used in the production of hollow fiber membranes according to the invention, specifically hollow fiber membrane filters according to the first, second, and third aspects of the invention. According to the fourth step, a sterilizing fluid (e.g., steam) is supplied to the hollow fiber membrane filter at a temperature of 124°C and a pressure of 2 bar. This flow is thus achieved by opening valves 405 to 408 via connectors 401, 402, 403, and 404. Pure steam is supplied to the hollow fiber membrane filter via lines 409 and 410, and the first chamber 419 and the second chamber 420 of the filter assembly 413 are purged. The pure steam is returned via lines 412 and 411 and fluid ports 415 and 414, and is discarded or disposed of for reuse. Depending on the selected sterilization temperature, the sterilization process can last from 5 to 30 minutes. At the preferred temperature of 124°C, sterilization is considered complete after 12 minutes. Further rinsing steps can be performed to bring the hollow fiber membrane filter to a purified and sterile form for use.

[0180] For further quality testing, the following is a "bubble point" test known in the prior art. This test constitutes a pressure holding test, in which one side of the membrane is subjected to a gas at a higher pressure than the opposite side of the membrane with fluid flow. Therefore, Figures 3 to 6 The second chambers 120, 220, 320, and 420 of the hollow fiber membrane filter shown are purged with sterile compressed air, thereby keeping the first chamber filled with liquid from the rinsing process. A sterilization system applies a higher pressure in the second chamber than in the first chambers 119, 219, 319, and 419. Because the pores are filled with water from the previous rinsing step, the compressed gas from the first chamber does not break through the second chamber until the applied pressure overcomes the surface tension of the water in the pores. As shown, the gas volume entering the first chamber can be analyzed in bubble detectors 114, 214, 314, and 414, and the results can be evaluated accordingly. By correlating the detected gas bubble volume with the pressure applied in the second chambers of the filter assemblies 120 to 420, conclusions can be drawn regarding the quality of the membrane material and whether the filter assembly meets specifications.

[0181] The first chamber can then be flushed with sterile compressed air in the same manner. Where appropriate, a further flushing step using pure steam can ensure the removal of any water remaining from the previous flushing process. Afterward, a drying process can be performed, in which the filter assembly is flushed with sterile compressed air until the desired degree of dryness is achieved.

[0182] Example 2: Embodiments of the hollow fiber membrane of the present invention

[0183] A spinning solution consisting of 16 parts by weight of polysulfone (Solvay P3500), 4.4 parts by weight of polyvinylpyrrolidone (Ashland K82-86), and 79.6 parts by weight of DMAC was stirred, heated to 60°C, and degassed to process it into a homogeneous spun material. The spun material was extruded into strands through an annular spinneret, with a centrally controlled precipitant consisting of 35% DMAC and 65% water. The precipitant guided within the hollow strands. The annular spinneret temperature was 70°C. The extruded strands were guided through a settling chamber with an atmospheric relative humidity of 100%. The settling gap height was 200 mm; the settling gap residence time was set to 0.4 seconds. The strands were introduced into a settling bath consisting of water, controlled at 80°C, and precipitated into a hollow fiber membrane. The hollow fiber membrane was then passed through a rinsing bath, with the temperature controlled between 75°C and 90°C. The hollow fiber membrane is then dried between 100°C and 150°C. The resulting hollow fiber membrane is then wound onto a winding machine to form a tow. The hollow fiber membrane tow is made from the wound tow. The porosity of the hollow fiber membrane is then determined.

[0184] The hollow fiber membrane bundles were further processed into hollow fiber membrane filters using the known techniques shown in Measurement Method 3. The resulting hollow fiber membrane filters were then connected in the next step to the sterilization equipment according to Example 1 and to hollow fiber membrane filters sterilized according to the method described in Example 1. For sterilized hollow fiber membrane filters at five different locations on the hollow fiber membrane filters, the sieving factor for dextran with a molecular weight of 10000 g / mol, the zeta potential, the sieving factor for albumin, the PVP content of the fibers, and the local water content ultrafiltration factor were determined. The results are listed in Table 1.

[0185] Example 3: Comparative Example

[0186] The same materials as in Example 2 were used. A spinning solution consisting of 16 parts by weight of polysulfone, 4 parts by weight of polyvinylpyrrolidone, and 80 parts by weight of DMAC was stirred, heated to 50°C, and degassed to process it into a homogeneous spun material. The spun material was extruded into strands through an annular spinneret, with a centrally controlled precipitant consisting of 54% DMAC and 46% water. The precipitant was guided within the hollow strands. The temperature of the annular spinneret was 40°C. The extruded strands were guided through a sedimentation chamber with an atmospheric relative humidity of 30%. The sedimentation gap height was 600 mm, and a sedimentation gap residence time of 1.35 seconds was set. The strands were introduced into a sedimentation bath consisting of water, with the temperature controlled at 68°C, and precipitated into the hollow fiber membrane. The hollow fiber membrane was then passed through a rinsing bath, with the temperature controlled between 75°C and 90°C. Subsequently, the hollow fiber membrane underwent a drying process between 100°C and 150°C. The resulting hollow fiber membrane was then wound onto a winding machine to form a tow. Hollow fiber membrane bundles are made from wound fiber bundles. The porosity of the hollow fiber membranes is then determined.

[0187] Hollow fiber membrane bundles were further processed into hollow fiber membrane filters using known techniques. The resulting hollow fiber membrane filters were sterilized in the next step according to the method described in the prior art (DE3936785C1). For sterilized hollow fiber membrane filters at five different locations on the hollow fiber membrane filters, the sieving factor for dextran with a molecular weight of 10000 g / mol, the zeta potential, the sieving factor for albumin, the PVP content of the fibers, and the local ultrafiltration were determined. The results are listed in Table 1.

[0188] Table 1

[0189]

Claims

1. A hollow fiber membrane for hemodialysis, comprising at least one polysulfone-based material and at least one polyvinylpyrrolidone-based polymer, characterized in that, The hollow fiber membrane has a porosity of 77.5% to 82%, a sieve factor of 0.42 to 0.75 for dextran with a molecular weight of 10,000 g / mol, and an albumin sieve factor of less than 0.

01.

2. The hollow fiber membrane according to claim 1, characterized in that, The zeta potential of the hollow fiber membrane is -3mV to -10mV.

3. The hollow fiber membrane according to claim 1 or 2, characterized in that, The hollow fiber membrane has a porosity of 78% to 81%.

4. The hollow fiber membrane according to claim 3, characterized in that, The hollow fiber membrane has a porosity of 79% to 80.5%.

5. The hollow fiber membrane according to claim 1, characterized in that, The hollow fiber membrane has a sieving coefficient of 0.45 to 0.75 for dextran with a molecular weight of 10,000 g / mol.

6. The hollow fiber membrane according to claim 5, characterized in that, The hollow fiber membrane has a sieving coefficient of 0.55 to 0.7 for dextran with a molecular weight of 10,000 g / mol.

7. The hollow fiber membrane according to claim 5, characterized in that, The hollow fiber membrane has a sieving coefficient of 0.6 to 0.7 for dextran with a molecular weight of 10,000 g / mol.

8. The hollow fiber membrane according to claim 1, characterized in that, The hollow fiber membrane has a sieving coefficient of less than 0.005 for albumin.

9. The hollow fiber membrane according to claim 8, characterized in that, The hollow fiber membrane has a sieving coefficient of less than 0.001 for albumin.

10. The hollow fiber membrane according to claim 1, characterized in that, The zeta potential of the hollow fiber membrane is -4mV to -8mV.

11. The hollow fiber membrane according to claim 10, characterized in that, The zeta potential of the hollow fiber membrane is -6mV to -8mV.

12. The hollow fiber membrane according to claim 1, characterized in that, The hollow fiber membrane has a PVP content of 2.5% to 5% by weight.

13. The hollow fiber membrane according to claim 1, characterized in that, The hollow fiber membrane contains 18% to 27% PVP based on XPS analysis.

14. The hollow fiber membrane according to claim 1, characterized in that, The maximum radius of the nominal aperture distribution is in the range of 22-26 angstroms.

15. The hollow fiber membrane according to claim 14, characterized in that, The maximum radius of the nominal aperture distribution is in the range of 23-26 angstroms.

16. A hollow fiber membrane filter comprising a cylindrical housing and a plurality of hollow fiber membranes according to any one of claims 1 to 15, at least one first fluid port for supplying fluid to the interior of the fibers, and at least one first fluid port for discharging the fluid from the interior of the fibers, the hollow fiber membranes being disposed inside the housing and sealed at their ends with a casting compound, thereby forming a first chamber surrounding the interior space of the hollow fiber membranes and forming a second chamber surrounding the space between the hollow fiber membranes. Its features are, The hollow fiber membrane exhibits uniform separation capability across the cross-section of the hollow fiber membrane filter, as measured by the ultrafiltration coefficients of the hollow fiber membrane in different regions of the hollow fiber membrane filter, which differ from each other by no more than 20%.

17. The hollow fiber membrane filter of claim 16, wherein the fluid is a liquid or a gas.

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