Hollow fiber membrane with improved biocompatibility and reduced elution of hydrophilic polymers

Abstract

To provide a hollow fiber membrane with improved biocompatibility.SOLUTION: The present invention relates to a water insoluble antioxidant-containing hydrophobic and hydrophilic polymer-based hollow fiber membrane, in particular, relates to a hollow fiber membrane for blood extracorporeal treatment. The hollow fiber membrane has improved biocompatibility with respect to treated blood, and in particular, has improved complement activation and lower platelet loss improved for the treated blood. Simultaneously, hydrophilic polymer elution from a lumen of the hollow fiber membrane is reduced.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a method for manufacturing hollow fiber membranes, as well as a membrane material comprising a hydrophobic polymer and a hydrophilic polymer, and a type of processed hollow fiber membrane having improved biocompatibility properties, particularly properties improved with respect to C5a activation and "platelet loss".

Background Art

[0002] Hollow fiber membranes are widely used in liquid filtration. In particular, hollow fiber membranes are used for medical purposes to purify blood during dialysis treatment of patients with kidney diseases. Hollow fiber membranes are formed in a hollow fiber membrane bundle within a filter module used for extracorporeal treatment of blood. This type of filter module for blood purification, so-called a dialyzer, is mass-produced.

[0003] Hollow fiber membranes used for blood purification are often composed of hydrophobic polymers and hydrophilic polymers, particularly polysulfone and polyvinyl-pyrrolidone, because these materials have been demonstrated to be particularly blood-compatible and are thus suitable from a medical perspective for the treatment of blood, particularly hemodialysis. By "polysulfone" as understood in the context of the present application is meant a polymer having a sulfone group in the polymer main chain or side chain. Typical representatives of polysulfone are polysulfone based on bisphenol A (PSU), polyethersulfone (PES), polyphenylsulfone, and copolymers containing sulfone groups. Still another representative example of a polysulfone polymer is known in the prior art and is suitable for producing the blood treatment membranes defined by the present invention. By "polyvinylpyrrolidone" is meant a polymer produced using vinylpyrrolidone monomer or its derivatives. Still other suitable hydrophobic polymers are polyamide, polyacrylonitrile, and regenerated cellulose and cellulose derivatives. Polyethylene glycol is still another suitable hydrophilic polymer.

[0004] The basic principles for generating hollow fiber membranes, as well as the products thereof, are described in the following prior art. • Marcel Mulder, "Principles of Membrane Technology," Kluwer Academic Publisher, 1996, Chapter III, Preparation of synthetic membranes. EP 0 168 783

[0005] These methods described in the prior art for producing hollow fiber membranes prepare a spinning solution comprising a polysulfone-based hydrophobic polymer and a vinylpyrrolidone-based hydrophilic polymer, particularly polyvinylpyrrolidone, and one or more solvents and any additives that may be required. Polar aproton solvents, particularly dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), dimethylformamide (DMF), or dimethyl sulfoxide (DMSO), are commonly used as solvents. The term solvent thereby refers to the solubility of the solvent for the polymers used, particularly polysulfone and polyvinylpyrrolidone. The spinning solution may also contain small amounts of additives, such as polar proton solvents like water, at low percentages. Mixtures of solvents are also known in the prior art.

[0006] The spindle is spun through the circular concentric annular gap of the spinneret. The spinneret further has a bore through which a coagulant is guided. The coagulant is usually composed of a mixture of an aproton polar solvent, such as DMAc, and a proton liquid, such as water. The spindle and coagulant are processed by passing the coagulant through the annular gap and bore of the spinneret into the strand, whose lumen contains the coagulant. The strand is then guided through a void, usually through which the spindle of the strand begins to solidify and form a two-phase system of gel and sol phases. Next, the strand is introduced into a precipitation bath containing a precipitant. When the strand is introduced into the precipitation bath, a hollow fibrous membrane structure is formed. Water or a mixture of proton and aproton solvents, in particular water and dimethylacetamide, N-methylpyrrolidone, dimethylformamide, or dimethyl sulfoxide, usually serve as precipitants. The resulting hollow fiber membrane is then passed through a rinsing bath, dried, and wound onto a winding machine. The hollow fiber membrane can be removed from the winding machine in the form of a hollow fiber bundle. To constitute a hollow fiber membrane filter, such a hollow fiber membrane bundle is placed in a housing, preferably a cylindrical housing. The ends of the hollow fiber membrane bundle are embedded in a cast compound, and the open ends of the hollow fibers are exposed. The cast compound forms a sealed region between the interior of the hollow fiber membrane, the housing, and the area surrounding the hollow fiber membrane. This forms the inlet and outlet regions of the ends of the hollow fiber membrane bundle, as well as a first chamber in the finished hollow fiber membrane filter surrounding the interior of the hollow fiber membrane. A second chamber is correspondingly formed from the areas between the hollow fiber membranes and in the space between the housing wall and the hollow fiber membranes. Fluid ports on the housing of the hollow fiber membrane filter allow liquids and fluids to be guided into and out of the first and / or second chambers of the hollow fiber membrane filter.

[0007] Each manufacturing step is crucial for producing hollow fiber membranes with predetermined performance and separation characteristics. The separation function and selectivity of hollow fiber membranes in extracorporeal hematologic filtration applications are substantially critical for each therapeutic use. Therefore, it is important for the manufacturing process to adapt the manufacturing steps to achieve the desired performance characteristics for the hollow fiber membrane required by each therapeutic procedure. However, the manufacturing process also influences the biocompatibility of the hollow fiber membrane. Biocompatibility, by definition, refers to the physiological tolerance of the dialyzer when processing a patient's blood extracorporeally. In particular, the biocompatibility of a hollow fiber membrane or its corresponding hollow fiber membrane filter (hereinafter also referred to as a dialyzer) is understood to mean that it does not induce any adverse reactions, or merely induces minimal adverse reactions, upon contact with blood during extracorporeal hematologic filtration. Such reactions can be caused by interactions between the hollow fiber membrane surface and blood components. These are interactions with blood, particularly at the cellular level, but also with proteins in the plasma.

[0008] A method for evaluating the biocompatibility of commercially available dialyzers, proposed by Vienken et al. (A. Erlenkotter, P. Endres, B. Nederlof, C. Hornig, J. Vienken, "Artificial Organs," 32(12), 962, (2008)), involves recirculating test serum through the dialyzer for a predetermined period and identifying the resulting adverse reactions using so-called blood compatibility markers. This method uses complement factor 5a (C5a), thrombin / antithrombin III complex (TAT), thrombus count ("platelet count" - PLT), platelet factor 4 = PF4, and elastase release from polymorphonuclear granulocytes (PMN elastase) as blood compatibility markers.

[0009] To evaluate the biocompatibility of dialyzers, this method proposes rating individual blood compatibility markers according to a "scoring" system. Furthermore, it is proposed to calculate an "overall blood compatibility score" (THS) for the dialyzer from the scores of the individual blood compatibility markers, thereby making it possible to compare different dialyzers in terms of their biocompatibility.

[0010] This method revealed that both the membrane material and the different sterilization methods used to sterilize commercially available dialyzers can clearly affect the biocompatibility of hollow fiber membranes. In particular, differences in biocompatibility between the dialyzers examined were determined based on different polysulfone, polyethersulfone / polyarylate, regenerated cellulose, and esterified cellulose membrane materials, and different sterilization methods such as steam sterilization, radiation sterilization (gamma rays or electron beam), and vacuum steam sterilization.

[0011] Hollow fiber membranes and dialyzers are used as disposable medical products in therapeutic hematological procedures and are commercially available in large quantities as mass-produced patient care items. The methods for manufacturing hollow fiber membranes and dialyzers, therefore, often reflect economic concerns and productivity considerations. This means that while the manufacture of hollow fiber membranes and dialyzers is directed towards achieving required performance characteristics, it is also directed towards the most cost-effective benchmark. Studies by Vienken et al. have shown that established conventional methods for manufacturing hollow fiber membranes and dialyzers are often not optimal in pursuing favorable biocompatibility.

[0012] The prior art describes a method for producing hollow fiber membranes that possess high biocompatibility with predetermined separation functions while simultaneously being economically feasible. In particular, a method for producing hollow fiber membranes in which the hollow fiber membranes are modified with a fat-soluble vitamin, such as vitamin E, is described. Such modification can be carried out, for example, by adding vitamin E to the coagulant used in the production method. By doing so, the inner surface of the resulting hollow fiber membrane is coated with vitamin E, i.e., improved biocompatibility is achieved. It is hypothesized that the vitamin E-modified hollow fiber membrane will have an antioxidant effect on blood cells when in contact with treated blood, or reduce the effect of immune-related "chemical bursts," and will generally correct the prooxidative blood status of patients with chronic renal failure.

[0013] EP 0 850 678 B1 describes a method for producing polysulfone and polyvinylpyrrolidone-based hollow fiber membranes in which a surfactant and vitamin E are added to the coagulant. The method aims to precipitate vitamin E on the inner surface of the hollow fiber membrane during production. The hydrophobic effect of vitamin E enhances the blood compatibility of the inner surface of the hollow fiber membrane, and therefore achieves an antioxidant effect on blood cells.

[0014] On the other hand, the hydrophilicity of the inner surface of polysulfone hollow fiber membranes has been discussed in relation to improved blood wetting and better biocompatibility. In this regard, EP 0 568 045 describes the production of polysulfone-based hollow fiber membranes. The hollow fiber membranes are produced using a coagulant containing 0.5 to 4% polyvinylpyrrolidone. The addition of polyvinylpyrrolidone to the coagulant thereby achieves an increase in the proportion of polyvinylpyrrolidone on the inner surface of the resulting hollow fiber membrane.

[0015] A common drawback is that high molecular weight polyvinylpyrrolidone, if present, is not fully metabolized by the human organism, and the kidneys can only partially excrete it from the body. As a result, accumulation of high molecular weight polyvinylpyrrolidone is observed in the bodies of long-term dialysis patients. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] EP 0 168 783 [Patent Document 2] EP 0 850 678 B1 [Patent Document 3] EP 0 568 045 [Patent Document 4] DE 102016224627.5 [Non-patent literature]

[0017] [Non-Patent Document 1] "Principles of Membrane Technology" by Marcel Mulder, Kluwer Academic Publisher, 1996, Chapter III, Preparation of synthetic membranes. [Non-Patent Document 2] A. Erlenkotter, P. Endres, B. Nederlof, C. Hornig, J. Vienken, "Artificial Organs", 32(12), 962, (2008) [Non-Patent Document 3] BASF AG brochure, "Volker Buhler-Kollidon® Polyvinylpyrrolidone Excipient for the Pharmaceutical Industry," 9th edition (March 2008), page 37. [Non-Patent Document 4] Erlenkotter et al., "Score Model for the Evaluation of Dialysis Membrane Hemocompatibility," Artificial Organs 32(12):962-998, 2008. [Overview of the Initiative] [Problems that the invention aims to solve]

[0018] Given the problems prevalent in conventional technologies, there is a need to provide hollow fiber membranes with improved biocompatibility. In particular, there is a need to find manufacturing methods that ensure outstanding biocompatibility of sterile hollow fiber membranes or dialyzers. However, these manufacturing methods should be economically achieved, thereby saving on material and system costs.

[0019] Accordingly, in a first aspect of the present invention, the task is to provide a method for producing a hollow fiber membrane that enables the production of a hollow fiber membrane having improved biocompatibility with treated blood, and in particular, a hollow fiber membrane having only lower complement activation and lower platelet loss with respect to treated blood. The task in the first aspect of the present invention further comprises providing an economical method for producing such a hollow fiber membrane that can be provided with low system and material expenditures.

[0020] In yet another aspect of the present invention, the task is to provide a hollow fiber membrane exhibiting high biocompatibility with blood treatment. In particular, a second aspect of the present invention addresses the task of providing a hollow fiber membrane characterized by low complement activation and a weak tendency toward platelet loss with respect to treated blood. Furthermore, this task is comprised of enabling the provision of such a hollow fiber membrane at an economically low manufacturing cost. [Means for solving the problem]

[0021] The basic task is solved by the method of the present invention for producing a hollow fiber membrane in which a water-insoluble antioxidant, particularly a fat-soluble vitamin, and more specifically α-tocopherol or tocotrienol, is provided in the spindle, and a hydrophilic polymer is provided in the coagulant.

[0022] A first aspect of this application relates to a method for producing a hollow fiber membrane, comprising the steps of: preparing a spindle containing a hydrophobic and hydrophilic polymer, an aproton polar solvent, and a water-insoluble antioxidant; preparing a coagulant containing at least one aproton polar solvent and / or at least one non-solvent, particularly water; and transporting the spindle through an annular gap of a spinneret having at least one concentric annular gap for transporting the spindle and one central hole for co-transporting the coagulant to form a hollow strand. The process includes the steps of: passing a coagulant through the central hole of a spinneret and transporting it into the lumen of the strand; guiding the formed strand through a void; and introducing the strand into a precipitation bath containing a precipitant, particularly an aqueous precipitant, to form a hollow fiber membrane, thereby the spinning mass containing 0.001 to 0.05% by mass of at least one water-insoluble antioxidant, particularly a fat-soluble vitamin, and more particularly α-tocopherol or tocotrienol, and the coagulant further containing at least one hydrophilic polymer.

[0023] In yet another embodiment of the first aspect, the method is characterized in that the hydrophobic polymer contains a polysulfone.

[0024] In yet another embodiment of the first aspect, the method is characterized in that the hydrophobic polymer in the spindle contains polyvinylpyrrolidone.

[0025] In yet another embodiment of the first aspect, the method is characterized in that the hydrophobic polymer in the coagulant contains polyvinylpyrrolidone.

[0026] In yet another embodiment of the first aspect, the method is characterized in that the coagulant contains 0.5 to 4 g of polyvinylpyrrolidone per 1 kg of coagulant.

[0027] In yet another embodiment of the first aspect, the method is characterized in that the spindle contains 2 to 7% by mass, particularly 3 to 5% by mass, of polyvinylpyrrolidone relative to its total mass.

[0028] In yet another embodiment of the first aspect, the method is characterized in that the coagulant contains 25 to 60% by mass of a polar aproton solvent, particularly DMAc, and 40 to 75% by mass of a polar proton non-solvent, particularly water.

[0029] In yet another embodiment of the first aspect, the method is characterized in that the hydrophilic polymer contained in the coagulant, particularly polyvinylpyrrolidone, has a molecular weight distribution in the range of 200,000 to 2,000,000 g / mol, and in particular a mass-average molecular weight of 900,000 g / mol.

[0030] In yet another embodiment of the first aspect, the method is characterized in that the annular spinneret is temperature-controlled to a temperature of 30 to 85°C, particularly 65 to 85°C.

[0031] In yet another embodiment of the first aspect, the method is characterized in that the sedimentation bath is temperature-controlled to a temperature of 50 to 85°C.

[0032] In yet another embodiment of the first aspect, the method is characterized in that the strand pulling speed is in the range of 100 to 1500 mm / s.

[0033] In yet another embodiment of the first aspect, the method is characterized in that the strand is passed through a spinneret post-settling gap of 50 to 1500 mm before being introduced into the sedimentation bath.

[0034] In yet another embodiment of the first aspect, the process is characterized in that the hydrophilic polymer of the spindle contains polyvinylpyrrolidone (PVP), the hydrophilic polymer in the coagulant contains polyvinylpyrrolidone (PVP), and the mass-average molecular weight (Mw) of the PVP in the coagulant is higher than that of the PVP in the spindle.

[0035] In yet another embodiment of the first aspect, the process is characterized in that the mass-average molecular weight (Mw) of PVP in the spindle is lower than 1,000,000 g / mol, and the mass-average molecular weight (Mw) of PVP in the coagulant is higher than 1,000,000 g / mol.

[0036] The mass-average molecular weight of PVP, which is mentioned several times in this application, is determined by a conventional method of light scattering (generally within the framework of GPC-LS measurement). For this application, please refer to page 37 of the BASF AG brochure "Volker Buhler-Kollidon® Polyvinylpyrrolidone Excipients for the Pharmaceutical Industry," 9th edition (March 2008), and the references cited therein.

[0037] A second aspect of this application relates to providing a hollow fiber membrane characterized by a membrane material containing hydrophobic and hydrophilic polymers, particularly polysulfone and polyvinylpyrrolidone, and a water-insoluble antioxidant, particularly a fat-soluble vitamin, and more particularly 0.005 to 0.25% by mass of α-tocopherol or tocotrienol.

[0038] In yet another embodiment of the second aspect, the hydrophobic polymer includes a polysulfone.

[0039] In yet another embodiment of the second aspect, the hollow fiber membrane shows that in an elution test, the elution of hydrophilic polymers, particularly polyvinylpyrrolidone, is 4000 per individual fiber after a 30-day storage period at 80°C and <5% relative humidity. * 10 -7 Less than mg, and especially 5000 per individual fiber after 60 days at 80°C and <5% relative humidity. * 10 -7 It is characterized by being less than mg.

[0040] In yet another embodiment according to the second aspect, the hydrophilic polymer comprises polyvinylpyrrolidone.

[0041] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that at least one of its surfaces, particularly the surface on the lumen, is additionally coated with polyvinylpyrrolidone.

[0042] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized by having a zeta potential of -1 to less than -7 mV, particularly -1 to -4 mV, on the lumen-facing surface.

[0043] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that the concentration of polyvinylpyrrolidone in the layer near the surface of at least one hydrophilic surface is 22% or more, particularly 24 to 34%, and more particularly 26 to 34%, after XPS measurement.

[0044] In yet another embodiment of the second aspect, the hollow fiber membrane has a CNO determined by TOF-SIMS on the surface of its inner lumen. - and SO2 - The peak height ratio is characterized by being 4.5 or greater, particularly 5.5 or greater, and even more particularly 6.0 or greater.

[0045] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized by having a polyvinylpyrrolidone content of 3 to 5% by mass.

[0046] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that the mass-average molecular weight (Mw) of the PVP on its lumen surface is higher than that of the PVP by volume of the membrane.

[0047] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that the mass-average molecular weight (Mw) of PVP on the surface of its lumen is higher than 1,000,000 g / mol, preferably higher than 2,000,000 g / mol, more preferably higher than 1,000,000 g / mol up to 3,000,000 g / mol, and more preferably higher than 2,000,000 g / mol up to 3,000,000 g / mol, and the mass-average molecular weight (Mw) of PVP by volume of the membrane is lower than 1,000,000 g / mol, preferably between 500,000 g / mol and less than 1,000,000 g / mol.

[0048] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that the ratio of the mass-average molecular weight of PVP in the coagulant to the mass-average molecular weight of PVP in the spinning mass is at least 1.2, preferably at least 2, more preferably 1.2 to 3, and more preferably 2 to 3.

[0049] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that the ratio of the sieving coefficient measured at 5 minutes to the sieving coefficient measured at 30 minutes according to the measurement method described herein is less than 7, and in particular less than 5.

[0050] In yet another embodiment of the second aspect, the hollow fiber membrane is characterized in that the ratio of the sieving coefficient measured at 5 minutes to the sieving coefficient measured at 10 minutes according to the measurement method described herein is less than 3, and in particular less than 2.

[0051] The lower limit for the sieve coefficient ratios mentioned above is 1 for each of them.

[0052] In yet another embodiment of the second aspect, when water wets at least one hydrophilic surface of the hollow fiber membrane, the hollow fiber membrane forms a contact angle smaller than 57°, particularly smaller than 55°, and more particularly smaller than 47°. The lower limit for the contact angle is generally smaller than 30°, preferably smaller than 25°, and more preferably smaller than 20°. The contact angle is determined according to the method of "Determination of Contact Angle θ" described in this application. The hydrophilic surface is understood to be the surface of the hollow fiber membrane that has high hydrophilicity or forms a small contact angle with water, respectively. Preferably, the hydrophilic surface is formed inside the lumen of the hollow fiber membrane.

[0053] The third aspect of this application relates to the use of a coagulant containing 0.5 to 4 g of a hydrophilic polymer, particularly polyvinylpyrrolidone, per 1 kg of the coagulant in a method for manufacturing a hollow fiber membrane having a membrane material containing hydrophobic and hydrophilic polymers, particularly polysulfone and polyvinylpyrrolidone, and at least one water-insoluble antioxidant, particularly a fat-soluble vitamin, and more particularly α-tocopherol or tocotrienol, for the hydrophilization and biocompatibilization of the generated hollow fiber membrane.

[0054] In the fourth aspect, this application relates to a hollow fiber membrane filter including a plurality of hollow fiber membranes according to an embodiment of the second aspect of the present invention or hollow fiber membranes generated according to the method of an embodiment of the first aspect of this application.

[0055] In the fifth aspect, this application relates to a hemodialysis dialyzer including a plurality of hollow fiber membranes manufactured according to the second, sixth, seventh, eighth, or ninth aspect of the present invention or by the treatment of the first aspect of the present invention.

[0056] In the sixth aspect, this application is about less than 4000 * 10 -7 mg per single fiber after a storage period of 30 days at 80 °C and <5% relative humidity, and particularly less than 5000 * 10 -7This relates to a hollow fiber membrane containing a membrane material comprising a hydrophobic polymer and a hydrophilic polymer, characterized in that only less than a mg of hydrophilic polymer, particularly polyvinylpyrrolidone, is eluted, and the hollow fiber membrane has a zeta potential of -1 to less than -7 mV, particularly -1 to -5 mV, and more particularly -1 to -4 mV on the lumen-facing surface.

[0057] In the seventh aspect, the present application relates to the elution of hydrophilic polymers, particularly polyvinylpyrrolidone, to 4000 per single fiber after a storage period of 30 days at 80°C and <5% relative humidity. * 10 -7 Less than mg, and especially 5000 per single fiber after 60 days at 80°C and <5% relative humidity. * 10 -7 The present invention relates to a hollow fiber membrane comprising a membrane material containing a hydrophobic polymer and a hydrophilic polymer, characterized in that the amount is less than mg, and the inner lumen surface has a contact angle with water less than 57°, particularly less than 55°, and even more particularly less than 47°, as measured according to the "determination of contact angle θ" method, and the lower limit of the contact angle is generally less than 30°, preferably less than 25°, and more preferably less than 20°.

[0058] In the eighth aspect, the present application relates to the elution of hydrophilic polymers, particularly polyvinylpyrrolidone, to 4000 per single fiber after a 30-day storage period at 80°C and <5% relative humidity. * 10 -7 Less than mg, and especially 5000 per single fiber after 60 days at 80°C and <5% relative humidity. * 10 -7 This relates to a hollow fiber membrane containing a membrane material comprising a hydrophobic polymer and a hydrophilic polymer, characterized in that the amount is less than mg, and the ratio of the sieving coefficient measured at 5 minutes to the sieving coefficient measured at 30 minutes according to the measurement method described herein is less than 7, and in particular less than 5.

[0059] In the ninth aspect, the present application relates to the elution of hydrophilic polymers, particularly polyvinylpyrrolidone, to 4000 per single fiber after a storage period of 30 days at 80°C and <5% relative humidity.* 10 -7 Less than mg, and especially 5000 per single fiber after 60 days at 80°C and <5% relative humidity. * 10 -7 This relates to a hollow fiber membrane containing a membrane material comprising a hydrophobic polymer and a hydrophilic polymer, characterized in that the amount is less than mg, and the ratio of the sieving coefficient measured at 5 minutes to the sieving coefficient measured at 30 minutes according to the measurement method described herein is less than 3, and in particular less than 2.

[0060] The lower limit for the sieve coefficient ratios mentioned above is 1 for each of them.

[0061] In a tenth aspect, the present invention relates to a hollow fiber membrane comprising a membrane material containing a hydrophobic polymer and a hydrophilic polymer, characterized in that the platelet loss measured by the “Platelet Loss (Absolute Method)” method is less than 50%, preferably less than 30%, and particularly preferably less than 20%. Using the hollow fiber membrane according to the present invention, it is possible to achieve platelet loss of zero or slightly above zero, for example, in the range of 10% or less, for example, 5%, 3%, or 1%. [Brief explanation of the drawing]

[0062] [Figure 1] A schematic diagram of the dialysis machine testing apparatus is shown. [Figure 2] This shows the test setup for measuring the zeta potential of a hollow fiber membrane. [Figure 2a] This shows the test setup for measuring the zeta potential of a hollow fiber membrane. [Figure 3] The TOF-SIMS spectrum (anion) of Example 2 is shown. [Figure 3b] The TOF-SIMS spectrum of Comparative Example 2 is shown. [Modes for carrying out the invention]

[0063] A first aspect of the present invention relates to a method for producing a hollow fiber membrane, comprising the steps of: preparing at least one spindle containing hydrophobic and hydrophilic polymers, particularly polysulfone and polyvinylpyrrolidone, at least one aproton polar solvent, and one water-insoluble antioxidant; preparing at least one coagulant containing at least one aproton polar solvent and at least one non-solvent, particularly water; transporting the spindle, particularly through at least one annular gap of a spinneret, to form a hollow strand; transporting the coagulant, particularly through the central hole of the spinneret, into the lumen of the strand; and introducing the strand into a sedimentation bath, wherein the spindle contains 0.001 to 0.05% by mass of a water-insoluble antioxidant, particularly a fat-soluble vitamin, and more particularly α-tocopherol or tocotrienol, and the coagulant further comprises at least one hydrophilic polymer.

[0064] In one embodiment of the method of the present invention, the coagulant contains a hydrophilic polymer, particularly polyvinylpyrrolidone, in an amount of 0.5 to 4 g / kg, especially up to 1 g / kg, especially up to 1.5 g / kg, especially up to 2 g / kg, especially up to 2.5 g / kg, especially up to 3 g / kg, and even more especially less than 4 g / kg.

[0065] The method of the present invention has the advantage that a hydrophilic polymer, particularly polyvinylpyrrolidone, dissolved in a coagulant, can be deposited on the inner surface of the hollow fiber membrane during its production. In particular, it has been shown that the deposition of a hydrophilic polymer on the inner surface of the hollow fiber membrane results in high hydrophilicity, and therefore high blood compatibility of the hollow fiber membrane. A high proportion of hydrophilic polymer, particularly polyvinylpyrrolidone, deposited on the inner surface of the hollow fiber membrane results in a decrease in complement activation, measured as C5a, and a reduction in "platelet loss," compared to a comparative hollow fiber membrane without polyvinylpyrrolidone deposited on its inner surface.

[0066] The method according to the present invention has another advantage in that a hydrophilic polymer, particularly polyvinylpyrrolidone, deposited on the surface of a hollow fiber membrane can be fixed to the surface within the hollow fiber membrane in a ratio of water-insoluble antioxidants, particularly fat-soluble vitamins, and especially α-tocopherol or tocotrienol.

[0067] In the context of this invention, the term "fixation" means that, in contact with a liquid, hydrophilic polymers, particularly polyvinylpyrrolidone, on the surface of the hollow fiber membrane can be eluted only to a certain extent. In particular, providing only 0.001% by mass of a water-insoluble antioxidant, especially a fat-soluble vitamin, to the spindle is sufficient to produce a fixation effect on water-soluble polymers, particularly polyvinylpyrrolidone, precipitated from the coagulant onto the surface of the hollow fiber membrane. For a significant improvement in blood compatibility to be determined, a percentage of fat-soluble vitamins in the spindle smaller than 0.001% by mass results in an excessively weak fixation effect on water-soluble polymers, particularly polyvinylpyrrolidone, from the coagulant. Even if the percentage of water-insoluble antioxidants, particularly fat-soluble vitamins, in the spindle exceeds 0.05%, there is no further discernible enhancement in the fixation of water-soluble polymers, particularly polyvinylpyrrolidone, from the coagulant. Furthermore, higher percentages of water-insoluble antioxidants, particularly fat-soluble vitamins, in the spindle may reduce the hydrophilic properties of the hollow fiber membrane surface, which are caused by the deposition of water-soluble polymers, especially polyvinylpyrrolidone. Moreover, this reduction in hydrophilic properties adversely affects blood compatibility, particularly with respect to platelet loss.

[0068] Hollow fiber membranes produced according to the method of the first aspect of the present invention are characterized in particular by improved blood compatibility. In particular, with respect to complement activation, measured as C5a, it has been found to be significantly reduced compared to a comparative hollow fiber membrane composed of polysulfone and polyvinylpyrrolidone materials. Complement activation is therefore considered a blood compatibility marker used to evaluate the biocompatibility of hollow fiber membranes. In particular, a reduction of at least 50% in C5a activation values ​​was observed compared to a standard hollow fiber membrane composed of polysulfone and polyvinylpyrrolidone. That is, the complement activation of hollow fiber membranes produced according to the present invention is only 50% of that of commercially available comparative hollow fiber membranes. In an alternative embodiment of the production method of the present invention according to the first aspect of the present invention, it is possible to produce hollow fiber membranes that induce only C5 complement activation of up to 40%, preferably up to 30%, preferably up to 20%, preferably up to 10%, and more preferably up to 8%, of the complement activation that can be determined in the case of a comparative hollow fiber membrane. In particular, the method of the present invention makes it possible to adjust the complement activation characteristics of the hollow fiber membrane by adding 0.001 to 0.05% by mass volume of a water-insoluble antioxidant, especially a fat-soluble vitamin, and more particularly α-tocopherol or tocotrienol, to the spindle, and by adding a water-soluble polymer, especially polyvinylpyrrolidone, to the coagulant at a ratio of 0.5 g to 4 g per kg of coagulant. In this case, the use of the method of the present invention is naturally not solely focused on optimally reducing complement activation, but also on controlling other blood compatibility markers, especially the "platelet loss" value, and performance parameters of the hollow fiber membrane to take the most favorable values ​​possible.

[0069] As defined by this invention, the term "comparative hollow fiber membrane" means a hollow fiber membrane produced under the same spinning conditions and having the same ratio of hydrophobic polymers and hydrophilic polymers, particularly polysulfone and polyvinylpyrrolidone, but which does not contain any water-insoluble antioxidants within the hollow fiber membrane, particularly any fat-soluble vitamins, or further does not contain any coating of water-soluble polymers, particularly polyvinylpyrrolidone, on at least one surface of the hollow fiber membrane. In this example, this type of hollow fiber membrane is provided by a commercially available "Fresenius FX60" dialyzer.

[0070] As defined in this invention, the term “coagulant” means an agent that causes a phase reversal within a strand when the strand jointly determines the pore structure of a hollow fiber membrane through the precipitation void. The coagulant comprises at least one polar aproton solvent and one non-solvent, as well as a water-soluble polymer according to this invention, in particular polyvinylpyrrolidone.

[0071] The coagulant contains, preferably, 25 to 60% by mass, particularly 35 to 55% by mass, of a polar aproton solvent, particularly dimethylacetamide, and 40 to 75% by mass, particularly 45 to 65% by mass, of a polar proton non-solvent, particularly water, relative to the total mass of the coagulant. Furthermore, the coagulant contains 0.5 g to 4 g per kg of coagulant, particularly more than 1 g, particularly more than 1.5 g, particularly more than 2 g, particularly more than 2.5 g, particularly less than 4 g per kg of coagulant, and particularly less than 3 g, of a water-soluble polymer, particularly polyvinylpyrrolidone.

[0072] In the context of this application, the terms “solvent” and “non-solvent” refer to the solubility of the film-forming hydrophobic polymer, which is the main component of the hollow fiber membrane produced by the method of the present invention. Therefore, since the film-forming polymer can be dissolved in polar aproton solutions such as DMAc (dimethylacetamide), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), and NMP (N-methylpyrrolidone), these solutions are applicable solvents. In contrast, polar proton solutions such as water, ethanol, or acetic acid cannot dissolve the film-forming polymer and are therefore applicable non-solvents in the context of this application, as they can be used for precipitation of the spindle during the production of the hollow fiber membrane.

[0073] In one embodiment, the method of the present invention is characterized by a hydrophilic polymer having a molecular weight distribution in the range of 200,000 g / mol to 2,000,000 g / mol contained in the coagulant, particularly a mass-average molecular weight of 900,000 g / mol, especially polyvinylpyrrolidone.

[0074] The molecular weight of the hydrophilic polymer used affects the deposition of the hydrophilic polymer, particularly polyvinylpyrrolidone, from the coagulant by the production method of the present invention onto at least one surface of the hollow fiber membrane, especially the inner surface. Low molecular weight hydrophilic polymers, particularly polyvinylpyrrolidone, are less likely to be fixed to the respective surfaces of the strand or hollow fiber membrane. In contrast, high molecular weight hydrophilic polymers, particularly polyvinylpyrrolidone, exhibit stronger adsorption properties and are therefore more reliably fixed to the inner surface of the strand or hollow fiber membrane. Thus, it has been shown to be advantageous to use hydrophilic polymers, particularly polyvinylpyrrolidone, having a molecular weight distribution in the range of 200,000 g / mol to 2,000,000 g / mol. In the typically Gaussian molecular weight distribution of hydrophilic polymers, particularly polyvinylpyrrolidone, the proportion of low molecular weight polymers is at a lower concentration than that of polymers in the intermediate molecular weight range. Commercially available polyvinylpyrrolidones designated as K80 to K90 are included here as examples of suitable hydrophilic polymers.

[0075] The hydrophilic polymer, particularly polyvinylpyrrolidone, having a mass-average molecular weight of 700,000 g / mol to 1,200,000 g / mol, particularly 900,000 g / mol, and / or a molecular weight distribution in the range of 200,000 g / mol to 2,000,000 g / mol, is particularly applicable to the deposition of a hydrophilic polymer, especially polyvinylpyrrolidone, on the inner surface of a strand or hollow fiber membrane by the manufacturing method of the present invention.

[0076] In yet another form, the process according to the present invention is characterized in that the hydrophilic polymer in the spindle contains polyvinylpyrrolidone (PVP), the hydrophilic polymer in the coagulant contains polyvinylpyrrolidone (PVP), and the mass-average molecular weight (Mw) of the PVP in the coagulant is higher than that of the PVP in the spindle. The use of such a PVP type has been shown to be very advantageous because it results in very high lumen surface coverage by the PVP, so that the PVP introduced into the coagulant has the highest possible mass-average molecular weight. However, a drawback is that the viscosity of the solution increases by increasing the molecular weight of the polymer to the same concentration as this molecular weight. By using such a suitable PVP type having a molecular weight optimally adjusted according to the present invention, it is possible to increase the viscosity of the spindle in an optimally low range, particularly below 15,000 mPas, and especially below 5,000 mPas, as measured at 40°C in stage r.3 using a German Haake VT550 viscometer. Using a Haake rotating body "MV1 (MV-DIN)" (shear rate 38.7 / s) at 30 rpm, the high mass-average molecular weight in the coagulant improves lumen coverage of the membrane. This results in optimal blood compatibility values ​​and low elution values ​​after degradation testing. From a processing standpoint, it is necessary to maintain a minimum spindle viscosity of at least 800 mPas, as measured according to the method described above.

[0077] In the other processing performed, the mass-average molecular weight (Mw) of PVP in the spindle is lower than 1,000,000 g / mol, for example, 995,000 g / mol or 900,000 g / mol, preferably between 500,000 g / mol and less than 1,000,000 g / mol, and the mass-average molecular weight (Mw) of PVP in the coagulant is not higher than 1,000,000 g / mol, for example, 1,005,000 g / mol or 1,100,000 g / mol, particularly not higher than 2,000,000 g / mol, preferably higher than 1,000,000 and up to 3,000,000 g / mol, more preferably higher than 2,000,000 g / mol and up to 3,000,000 g / mol. The ratio of the mass-average molecular weight of PVP in the coagulant to the mass-average molecular weight of PVP in the spindle is preferably at least 1.2, preferably at least 2, more preferably 1.2 to 3, and more preferably 2 to 3. This ratio can be achieved, for example, by using Ashland's PVP K81 / 86 as the PVP for addition to the spindle and PVP K90 or particularly preferably K120 as the PVP for addition to the coagulant. Such a processing method results in a particularly good and easily implementable process using the optimal spindle viscosity, thus resulting in an optimal asymmetric membrane structure with a good sieve curve, and at the same time resulting in a particularly blood-compatible membrane with low elution values ​​and good blood compatibility for PVP after degradation.

[0078] The term "molecular weight distribution" is well known and defined in polymer physics. Within the scope of this application, the molecular weight distribution of a polymer sample refers to the probability density distribution at which polymer molecules of a particular molecular weight will be present in the polymer sample. The molecular weight distribution of polyvinylpyrrolidone or polyethylene glycol can be determined using known measurement methods, such as gel permeation chromatography (GPC) combined with a suitable light scattering detector, for example, a multi-angle laser scattering (MALLS) detector.

[0079] The term "mass-average molecular weight (Mw)" indicates the mass content of the most frequently present molecular weight in a polymer sample. Given the known molecular weight distribution, the mass-average molecular weight reflects a characteristic average value for the polymer sample, in this case polyvinylpyrrolidone or polyethylene glycol, and those skilled in the art can infer the size of the polymer molecules present in the sample from this value.

[0080] In one embodiment of the manufacturing method of the present invention, the temperature of the annular spinneret is controlled to 30°C to 85°C, particularly 65°C to 85°C.

[0081] By controlling the temperature of the annular spindle, the spindle mass and coagulant within the strand are brought to the same or substantially the same temperature as they are transported. Adjusting the temperature of the extruded spindle mass and coagulant can influence the coagulation process as the strand passes through the sedimentation gaps. However, in particular, the temperature of the annular spindle is pre-set to further enhance the porosity structure desirable for the hollow fiber membrane morphology.

[0082] In the manufacturing method of the present invention, the strand withdrawal rate is between 100 mm / s and 1500 mm / s. At a predetermined sedimentation void height, the strand withdrawal rate is one of the determinants of the strand processing time.

[0083] In this case, the term "sedimentation gap" refers to the distance between the spinneret and the liquid level in the precipitation bath.

[0084] The term "processing time" refers to the length of time required for the spindle to pass through the sedimentation pores from the spinneret to the liquid level in the sedimentation bath. Processing time can be used to particularly influence the outer pore structure.

[0085] In a second aspect, the present invention relates to an improved biocompatible hollow fiber membrane having a membrane material containing hydrophobic and hydrophilic polymers, particularly polysulfone and polyvinylpyrrolidone, and further containing a water-insoluble antioxidant, particularly a fat-soluble vitamin, in a ratio of 0.005 to 0.25% by mass relative to the total mass of the membrane material. The fat-soluble vitamin is preferably α-tocopherol or tocotrienol. Pentaerythritol tetrakis (3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate) (Irganox 1010, manufactured by BASF) is yet another example of a water-insoluble antioxidant.

[0086] Such hollow fiber membranes are therefore particularly suitable for extracorporeal procedures in which the patient's blood comes into contact with the membrane material of the hollow fiber membrane. Since these hollow fiber membranes are primarily used to treat patients with renal impairment, the hollow fiber membranes of the present invention are particularly suitable for constituting hollow fiber membrane filters for extracorporeal blood procedures. Since elutable hydrophilic polymers can enter the patient's body through extracorporeal blood circulation, it can be seen that low elution of hydrophilic polymers, particularly polyvinylpyrrolidone, is advantageous to the patient's health.

[0087] Furthermore, the low elution of hydrophilic polymers, particularly polyvinylpyrrolidone, ensures stable and good hydrophilicity of the hollow fiber membrane throughout the in vitro blood treatment period. This improved hydrophilicity induces good blood wetting of the hollow fiber membrane, and therefore improved blood compatibility that can be recognized by low complement activation (C5a). Moreover, this hydrophilicity reduces the adhesion of stent bulbs to the hydrophilic surface, thereby inhibiting the initiation of the coagulation cascade and thus promoting a reduction in "platelet loss."

[0088] The term "water-insoluble antioxidant" refers to a substance that has an antioxidant effect and is water-soluble only at a temperature of 25°C with a water content of less than 2 mg / l. As defined in this application, the term "fat-soluble vitamin" refers to a vitamin that accumulates in the adipose tissue of the human body. This term is well known in relation to human physiology and thus indicates a specific classification of vitamins. In relation to this application, the term "fat-soluble" relates to the fact that a vitamin is a nonpolar substance that is either weakly soluble in water or insoluble. Regarding fat-soluble vitamins, the vitamin E substance group is the most familiar segment of such so-called fat-soluble vitamins. Vitamin E is therefore a general term for fat-soluble substances with antioxidant properties. Alpha-tocopherol and tocotrienol are among the most common representative examples of vitamin E.

[0089] The hollow fiber membrane according to the present invention comprises at least one hydrophobic polymer and one hydrophilic polymer, and in particular the hollow fiber membrane according to the present invention contains polysulfone as the hydrophobic polymer. Within the scope of the meaning of this application, “polysulfone” shall be understood as a polymer having sulfone groups in the main chain or side chains of the polymer. In the context of this application, the term polysulfone shall be understood as a general term for all polymers containing sulfone groups. Typical representative examples of polysulfones are bisphenol A (PSU), polyethersulfone (PES), polyphenylsulfone, and polysulfones based on copolymers containing sulfone groups. Yet another representative example of polysulfone polymers is known in the prior art and is suitable for the manufacture of blood treatment membranes as defined in this application. Polysulfones are steam sterilizable and exhibit good properties with respect to blood compatibility, and have been shown to be superior to other polymers in the manufacture of blood treatment membranes. The mass percentage of the hydrophobic polymer in the hollow fiber membrane is 94 to 97.5%.

[0090] The hollow membrane of the present invention further comprises a hydrophilic polymer, particularly polyvinylpyrrolidone. “Polyvinylpyrrolidone” is understood to be a polymer produced using vinylpyrrolidone monomer or its derivatives. In particular, “polyvinylpyrrolidone” (also called PVP) is suitable for the production of the hollow fiber membrane of the present invention within the scope of the present invention. Polyvinylpyrrolidone is a water-soluble hydrophilic polymer used in the production of polysulfone-based hollow fiber membranes. Furthermore, polyvinylpyrrolidone improves the blood compatibility of the hollow fiber membrane containing the hydrophobic polymer by making the hydrophilic hollow fiber membrane more blood-friendly, thereby increasing its wetting properties for blood. The mass percentage of the hydrophilic polymer in the hollow fiber membrane is 3 to 5%.

[0091] Where applicable in this application, “blood compatibility” is understood to mean compatibility with human blood, in particular, that blood in contact with the material of the hollow fiber membrane does not undergo any adverse reactions that may be harmful to the patient’s health during blood procedures. Such reactions may refer to activation treatments of the complement system, blood coagulation system, contact phase system, and blood cell elements. The use of polysulfone / polyvinylpyrrolidone polymers has been shown to be superior to other blood-contacting materials in hollow fiber membranes in terms of blood compatibility.

[0092] In an alternative embodiment according to a second aspect of the present invention, the hollow fiber membrane of the present invention is further characterized by being at least partially coated on at least one surface with a hydrophilic polymer, in particular polyvinylpyrrolidone.

[0093] Coating with a hydrophilic polymer, particularly polyvinylpyrrolidone, induces further hydrophilization of the hollow fiber membrane on at least one coated surface of the hollow fiber membrane. A hollow fiber membrane according to a second aspect of the present invention has been shown to retain the hydrophilic polymer to incoming aqueous liquids, such as blood or water, due to its low content of water-insoluble antioxidants, particularly fat-soluble vitamins, especially α-tocopherol or tocotrienol. Furthermore, it has been recognized that the majority of the hydrophilic polymer, particularly polyvinylpyrrolidone, applied to at least one surface of the hollow fiber membrane during the coating process can be immobilized by water-insoluble antioxidants, particularly fat-soluble vitamins, contained within the hollow fiber membrane. Dissolution tests have revealed less dissolution of the hydrophilic polymer, particularly polyvinylpyrrolidone, compared to a moderately coated hollow fiber membrane without any water-insoluble antioxidants. In particular, polyvinylpyrrolidone can be used to coat the hollow fiber membrane in such a way that only a sufficient amount of polyvinylpyrrolidone can precipitate on at least one surface of the hollow fiber membrane to make the chemically hydrophobic polymer membrane surface hydrophilic.

[0094] Coating of at least one surface of a hollow fiber membrane with a hydrophilic polymer, particularly polyvinylpyrrolidone, can be achieved using a coating solution containing the hydrophilic polymer applied to the surface of the hollow fiber membrane. It has been shown to be advantageous to apply a hollow fiber membrane coating composed of a hydrophilic polymer, particularly polyvinylpyrrolidone, during the spinning process when producing a hollow fiber membrane composed of hydrophobic and hydrophilic polymers. The hydrophilic polymer, particularly polyvinylpyrrolidone, is thereby added to a coagulant and conveyed through a concentric annular spinneret together with a spindle containing hydrophobic and hydrophilic polymers, particularly polysulfone and polyvinylpyrrolidone, and at least one water-insoluble antioxidant, particularly a lipid-soluble vitamin. The strand is then internally moistened with the hydrophilic polymer, particularly polyvinylpyrrolidone, dissolved in the coagulant. A membrane structure is formed in contact with the coagulant, and the strand is further introduced into a sedimentation bath, thereby fixing the hydrophilic polymer, particularly polyvinylpyrrolidone, from the coagulant onto the membrane surface.

[0095] In yet another embodiment according to a second aspect of the present invention, the hollow fiber membrane of the present invention is characterized by a hollow fiber membrane having a zeta potential of -1mV to -7mV, particularly -1mV to -5.5mV, and particularly -1mV to -4mV on at least one hydrophilic surface, particularly the lumen-side surface.

[0096] A hollow fiber membrane in which at least one hollow fiber membrane surface is coated with a hydrophilic polymer, particularly polyvinylpyrrolidone, using the method described above, has a more neutral zeta potential than a comparative membrane composed of the same membrane material but not additionally coated with a hydrophilic polymer.

[0097] The hollow fiber membrane of the present invention has a minimum contact angle with water when wetted. When the surface of the hollow fiber membrane of the present invention is wetted with water, the contact angle measured by a method of measuring the capillary expansion of water is less than 57°, particularly less than 55°, and more preferably less than 47°. Preferably, the inner lumen surface exhibits such a small contact angle.

[0098] The contact angle that water takes with respect to the membrane surface is a measure of the membrane surface's hydrophilicity. As described above, coating with hydrophilic polymers, particularly polyvinylpyrrolidone, hydrophilizes the membrane surface without substantially increasing the total hydrophilic polymer content of the hollow fiber membrane. Therefore, coating constitutes an overall economical and procedurally advantageous method for hydrophilizing the hollow fiber membrane on at least one membrane surface, particularly the blood surface. In particular, this polyvinylpyrrolidone coating has minimal PVP thickness and therefore hardly alters the total PVP content of the hollow fiber membrane. A small contact angle indicates high internal membrane hydrophilicity. In contrast, commercially available hollow fiber membranes, such as the Fresenius FX60 dialyzer, have been found to have a contact angle of 64°. The FX60 hollow fiber membrane, containing polysulfone and polyvinylpyrrolidone, therefore does not contain additional polyvinylpyrrolidone applied by membrane surface coating. Furthermore, these hollow fiber membranes have no α-tocopherol content in the membrane material. In contrast, the hollow fiber membrane of the present invention, having a polyvinylpyrrolidone concentration of 1500 ppm and an α-tocopherol content of 0.05% by mass in the coagulant, showed a contact angle of 52°. Furthermore, a decrease in the contact angle was found to correlate with a decrease in complement activation, measured as C5a. Moreover, a decrease in the contact angle was found to correlate with a reduction in "platelet loss."

[0099] The hollow fiber membrane according to the present invention is characterized by a hollow fiber membrane that does not contain water-insoluble antioxidants, particularly lipid-soluble vitamins, in the membrane material and exhibits lower complement activation, particularly down to 50%, than a comparative membrane that does not contain a coating of a hydrophilic polymer, particularly PVP, on at least one surface of the hollow fiber membrane.

[0100] It has been shown that complement activation can be adjusted by applying a hydrophilic polymer, particularly polyvinylpyrrolidone, to the surface of the hollow fiber membrane through a coagulant during the manufacturing of the hollow fiber membrane. Coagulant concentrations of hydrophilic polymer, particularly PVP, are particularly preferred at 0.5 g to 4 g, particularly up to 3 g, particularly up to 2 g, and particularly up to 1.5 g per kg of coagulant.

[0101] The hollow fiber membrane of the present invention further exhibits a lower, particularly 60%, "platelet loss" than a comparative hollow fiber membrane composed of polysulfone and polyvinylpyrrolidone, which does not contain a water-insoluble antioxidant in the membrane material and does not contain a polyvinylpyrrolidone coating on at least one hollow fiber membrane surface.

[0102] It has been shown that the decrease in platelet count can be controlled by the amount of hydrophilic polymer, particularly polyvinylpyrrolidone, applied, and the amount of water-insoluble polymer, particularly lipid-soluble vitamins, present in the hollow fiber membrane. In particular, the interaction between the hydrophilic polymer, especially polyvinylpyrrolidone, and the water-insoluble polymer, especially lipid-soluble vitamins, and even more specifically α-tocopherol or tocotrienol, results in lower platelet loss than in the case of the corresponding comparative hollow fiber membrane.

[0103] In yet another embodiment of the present invention, a hollow fiber membrane exhibits a polyvinylpyrrolidone concentration in the near-surface layer of the hollow fiber membrane on the lumen-side surface, which is 22% or more, particularly 24 to 34%, and even more particularly 26 to 34%, according to XPS measurement. The analysis is carried out according to the "Method for Determining Polyvinylpyrrolidone in the Near-Surface Layer (XPS)" described in this application. The analysis covers the near-surface layer down to a depth of about 10 nm. Such a membrane has a particularly good PVP coating on the lumen side, thereby resulting in good hydrophilicity, and therefore high biocompatibility.

[0104] On at least one surface, particularly the hydrophilic surface, and more particularly the lumen-side surface, the hollow fiber membrane of the present invention has a surface layer of 4.5 or greater, particularly 5.5 or greater, and more particularly 6.0 or greater, on which the "CNO in the surface layer using TOF-SIMS" described in this application is formed. - and SO2 - The peak height ratio of surface CNO4 is 4.5 or greater, as determined by "Determination of the peak height ratio of surface CNO4". - and SO2 -The peak height ratio is shown. The TOF-SIMS measurement method is an analytical method with particularly high surface sensitivity, meaning that only the outermost single layer of the surface is analyzed. Therefore, the surface coverage of the lumen of a hydrophilic polymer film can be determined particularly well and reliably. A high degree of coverage should be targeted as it enhances hydrophilicity and biocompatibility.

[0105] Due to the high concentration of hydrophilic polymers, particularly polyvinylpyrrolidone, on the surface in contact with the treated blood, the hydrophobic polymers, particularly polysulfone, are obscured and therefore no longer in contact with blood cells or plasma proteins. Coating at least one surface of the hollow fiber membrane with blood has the advantage of allowing effective coating with a small amount of hydrophilic polymer, particularly polyvinylpyrrolidone, which can be fixed onto the surface of the hollow fiber membrane by a water-insoluble antioxidant in the spindle. This, therefore, ensures that a hollow fiber membrane with improved biocompatibility can be economically produced, as only small amounts of water-soluble antioxidants, particularly fat-soluble vitamins, and small amounts of hydrophilic polymers, particularly polyvinylpyrrolidone, may be used, especially for the biocompatibility effect.

[0106] The hollow fiber membrane of the present invention further exhibits a polyvinylpyrrolidone elution rate of 4000 per individual fiber after being stored for 30 days at 80°C and <5% relative humidity, as determined in the elution test method according to the "Measurement Method for Determining Polyvinylpyrrolidone Elution". * 10 -7 Less than mg, and 5000 per individual fiber after 60 days under the same storage conditions. * 10 -7 This indicates less than mg. Preferably, polyvinylpyrrolidone elution is 2000 per individual fiber after storage at 80°C and <5% relative humidity for 30 days. * 10 -7 Less than mg, and 3000 per individual fiber after 60 days under the same storage conditions. * 10 -7 It shows less dissolution than mg.

[0107] In this context, "polyvinylpyrrolidone elution" is understood as the flow of a contact fluid that elutes polyvinylpyrrolidone from a hollow fiber membrane. For example, due to its hydrophilicity to aqueous solutions, such as blood, polyvinylpyrrolidone may dissolve and be washed away from the membrane material or from the surface of the hollow fiber membrane. In one elution test method, an extractant, particularly water, flows in contact with the hollow fiber membrane on the surface of a hollow fiber membrane coated with polyvinylpyrrolidone. The amount of polyvinylpyrrolidone eluted from the hollow fiber membrane can be determined from the concentration of polyvinylpyrrolidone in the extractant.

[0108] As described above, the elution of polyvinylpyrrolidone from the hollow fiber membrane of the present invention is less than the elution measured on a hollow fiber membrane having a membrane material composed of polysulfone and polyvinylpyrrolidone, but without additional fat-soluble vitamins and additional polyvinylpyrrolidone coating. Thus, the polyvinylpyrrolidone coating can increase the hydrophilicity of the surface of the hollow fiber membrane, especially the inner surface of the hollow fiber membrane, and at the same time, it has the advantage of reducing elution compared to the comparative hollow fiber membrane. In particular, this provides a medical advantage as only a small amount of polyvinylpyrrolidone elutes from the hollow fiber membrane and does not enter the human body during extracorporeal blood treatment. The infiltration of polyvinylpyrrolidone into the human body should be considered dangerous, especially because the human body becomes unable to metabolize polyvinylpyrrolidone of a predetermined molecular weight, and the kidneys can only partially excrete it.

[0109] In yet another embodiment of the hollow fiber membrane of the present invention, the total amount of hydrophilic polymer, particularly polyvinylpyrrolidone, present in the hollow fiber membrane is 3 to 5% by mass, particularly more than 3% by mass, particularly more than 3.5% by mass, particularly less than 5% by mass, and even more particularly less than 4.5% by mass. Such a composition allows for the adjustment of a balanced mechanical stability profile, appropriate porosity, and good hydrophilicity.

[0110] The hollow fiber membrane according to the present invention has a PVP mass-average molecular weight (Mw) on the lumen surface that is higher than that of PVP in the membrane volume. A low PVP molecular weight in the membrane volume has been shown to be desirable as such a composition allows for a high PVP content in the membrane volume and therefore has particularly high hydrophilicity. At the same time, a particularly high polyvinylpyrrolidone molecular weight on the lumen surface of the membrane has been shown to result in high coverage and therefore particularly optimized surface hydrophilicity. Such membranes have particularly high biocompatibility and exhibit low PVP elution after degradation.

[0111] In another embodiment of the hollow fiber membrane, the membrane has a lumen-surface mass-average PVP molecular weight (Mw) higher than 1,000,000 g / mol, for example, 1.005,000 g / mol or 1,100,000 g / mol, particularly higher than 2,000,000 g / mol, preferably higher than 1,000,000 g / mol and up to 3,000,000 g / mol, and more preferably higher than 2,000,000 g / mol and up to 3,000,000 g / mol. In the volume of the membrane, it has been shown that a mass-average PVP molecular weight lower than 1,000,000 g / mol, for example, 995,000 g / mol or 900,000 g / mol, preferably between 500,000 g / mol and less than 1,000,000 g / mol, is advantageous. The ratio of the mass-average molecular weight of PVP in the coagulant to the mass-average molecular weight of PVP in the spindle is preferably at least 1.2, preferably at least 2, more preferably 1.2 to 3, and more preferably 2 to 3, because such a composition allows for a high PVP content in volume and therefore has particularly high hydrophilicity. At the same time, it has been shown that a particularly high mass-average PVP molecular weight on the surface of the lumen of the membrane results in a high occupancy and therefore particularly optimized surface hydrophilicity. Such membranes have particularly high biocompatibility and exhibit low PVP elution after degradation.

[0112] Another hollow fiber membrane according to the present invention has a ratio of less than 7, and in particular less than 5, of the sieving coefficient measured at 5 minutes to the sieving coefficient for albumin measured at 30 minutes according to the measurement method “determination of plasma albumin sieving coefficient” described herein.

[0113] Another hollow fiber membrane according to the present invention has a ratio of less than 3, and in particular less than 2, of the sieving coefficient for albumin measured at 5 minutes to the sieving coefficient measured at 10 minutes according to the measurement method "determination of plasma albumin sieving coefficient" described herein.

[0114] The membrane to be used for dialysis is typically adjusted by optimizing the manufacturing parameters for a therapeutically desirable sieving coefficient measured after 30 minutes according to the method described herein. After this time, equilibrium of the sieving coefficient is largely established, and thereafter this equilibrium remains constant over a dialysis period of 4 hours or longer. However, at the start of the test being performed and at the start of dialysis, the membrane is coated with blood components, particularly proteins, thereby causing an initial decrease in the sieving coefficient. A greater membrane coverage results in a more pronounced decrease in the sieving coefficient, requiring the membrane to be opened more widely. This results in a larger albumin decrease within the first few minutes of dialysis. The membrane according to the present invention exhibits only a lower sieving coefficient decrease at the start of the test or dialysis, and therefore results in only a therapeutically desirable lower albumin decrease.

[0115] Another hollow fiber membrane according to the present invention comprises a membrane material containing a hydrophobic polymer and a hydrophilic polymer and is characterized by a platelet loss of less than 50%, preferably less than 30%, and particularly preferably less than 20%, as measured according to “Determination of Platelet Loss”. Platelet loss is caused by the adsorption of the membrane to the lumen surface, resulting in deterioration of the patient’s blood and simultaneously a reduction in the available cross-section of the lumen, which may sometimes result in a significant pressure drop on the blood side during dialysis. When platelet loss occurs, individual fibers may become completely clogged, reducing the performance of the filter. In treatment, this effect must be counteracted by adding heparin, and when using the filter according to the present invention, due to the low platelet loss, at least some patients may only need to add a small amount of heparin.

[0116] Description of the present invention based on examples The present invention will be described below based on measurement methods and exemplary embodiments, which are not limited to any particular method.

[0117] Measurement method for determining polyvinylpyrrolidone elution The hollow fiber membrane is analyzed for the amount of polyvinylpyrrolidone that can be leached. In this process, the hollow fiber membrane filter is washed with an extractant at a fixed temperature for a fixed period of time. This extract is then examined for polyvinylpyrrolidone content. For this purpose, the hollow fiber membrane filter is structured according to the following specifications.

[0118] A hollow fiber membrane filter (dialyzer) is used, having 10,752 hollow fiber membranes with an inner diameter of 185 μm and a wall thickness of 35 μm. The inner diameter of the filter housing is 34 mm. The hollow fiber membrane length significant for measuring elution is 258 mm. The hollow fiber membranes are sealed at their ends within the hollow fiber membrane filter to create a first chamber ("blood chamber") surrounding the interior of the hollow fiber membranes and a second chamber ("dialysis fluid chamber") surrounding the space between the hollow fiber membranes. Polyurethane (polyol C6947 and isocyanate 136-20) manufactured by Elastogran is used as the casting compound. The casting height at each bundle end is 22 mm. Water acts as an extractant, and 1000 ml of deionized water at a controlled temperature of 37°C is flowed through the first chamber of the hollow fiber membrane filter surrounding the interior of the hollow fiber membranes and through two hollow fiber membrane filter ports. Two further ports of the hollow fiber membrane filter are closed. The cleaning process ensures the recirculation mode. For this purpose, a water bath maintained at a temperature of 37°C is provided. A pump supplies temperature-controlled water from the water bath to the hollow fiber membrane filter through the first port. The first chamber of the hollow fiber membrane filter is cleaned, and the water is discharged from the hollow fiber membrane filter through the second port and returned to the water bath. This recirculation mode cleaning is performed using a flow rate of 200 ml / min.

[0119] Polyvinylpyrrolidone that can be eluted according to this method is concentrated in a water bath. The concentration of polyvinylpyrrolidone in the water bath can be determined by photometric method. For photometric determination (spectroscopy by Muller or Breinlich), the orange-brown reaction between polyvinylpyrrolidone in a weak acid solution and iodine / potassium iodide is used.

[0120] This method includes adding 10 ml of extractant to 5.0 ml of citric acid solution and 2.0 ml of Kl3 solution, mixing, and allowing it to stand at room temperature for 10 minutes to allow further reaction. Next, the absorbance of the sample solution is determined at 470 nm. A predetermined calibration is used to determine the content from the measured absorbance. PVP K81-86 is used for this calibration.

[0121] PVP elution is determined in addition to accelerated degradation. Here, each dialyzer is stored in a dry cabinet at 80°C and <5% relative humidity for periods of 30, 60, and 120 days, in each case. PVP elution is determined after this storage period. The amount of PVP extracted is correlated to individual fibers, and each value is 10 times the amount per individual fiber determined by the method described above. -7 It is expressed as a quantity in mg.

[0122] Measurement methods (comparison methods) for determining "platelet loss" and complement activation. To determine platelet loss and complement activation, whole human blood is collected using a 17G (1.5 mm) needle from healthy donors who are not taking any medications that may affect blood coagulation or platelet characteristics. 750 IU of heparin, diluted in 50 ml of saline solution to achieve a heparin concentration of 1.5 IU / ml in the blood / saline mixture, is added to the blood collection bag. The method for determining platelet loss is initiated within 30 minutes of donation.

[0123] As shown in the schematic diagram in Figure 1, the platelet loss measurement apparatus (1) for testing hollow fiber membranes is configured. The apparatus includes a dialyzer (2) containing the hollow fiber membrane to be manufactured and analyzed as described above. Furthermore, the apparatus includes a hose system (3), a hose pump (4), a blood sample collection point (5), a blood reservoir (6), a pressure sensor (7) at the blood inlet (8) of the dialyzer (2), and a pressure sensor (9) at the blood outlet (10) of the dialyzer (2). For this determination, 200 ml of heparinized blood, as described above, is used first. The blood is transported by the hose system (3) (material: PVC, manufacturer: Fresenius Medical Care, Germany) through the dialyzer (2) of the apparatus (1) using the hose pump (4) (manufacturer: Fresenius Medical Care, Germany). A new hose system is used for each measurement. Before measurement, the entire apparatus (1) is washed for 30 minutes with a 0.9% (w / v) saline solution. To fill the device with blood, the rinse solution is drained and replaced with blood introduced into the device at a low pumping speed until only pure blood fills the device. The blood filling capacity is 200 ml. The replaced solution is discarded.

[0124] To prevent ultrafiltration during analysis, the dialysate side is first filled with 0.9% saline solution through ports (11, 12) on the dialyzer and then sealed. Next, platelet loss is determined, for example, in an incubator (Memmert, Germany) at 37°C for 180 minutes, so that a sample is taken at the blood sample collection point (5) at the start of the measurement, and then again at 30, 60, 120, and 180 minutes. To ensure that conditions remain constant during the measurement, the pressure at the blood inlet (8) and blood outlet (9) is measured. If there is a significant pressure change, the reading must be excluded. Blood is pumped through the device at a volumetric rate of 200 ml / min.

[0125] Blood compatibility is determined using complement activation (C5a) parameters and platelet loss. Platelet loss is determined by a three-step determination using an automated hematology analyzer (K4500 Sysmex, Germany, Norderstedt).

[0126] Complement activation is determined by a two-step determination using the ELISA test kit (EIA-3327) manufactured by DRG Instruments, Marburg, Germany. The C5a factor, resulting from the activation of the proteolytic C5a factor, functions as a measurement parameter. In addition to the C5a factor, another fragment called the C5b factor is produced. The evaluation of the complement activation parameter and the platelet loss parameter is carried out according to formulas (1, complement activation) and (2, platelet loss), as described in the published paper "Score Model for the Evaluation of Dialysis Membrane Hemocompatibility" by Erlenkotter et al., Artificial Organs 32(12):962-998, 2008. 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 2.

number

[0127] During the measurement, another filter (FX60 from Fresenius Medical Care, Germany) is also measured using the remaining half of each donated blood sample as a baseline, and the measurement result is determined by comparison with this baseline filter (in units of percentage). This makes it possible to mathematically compensate for the wide range of inherent variations in blood responses from different donors. Example and comparative examples were generated using the same raw material batch.

[0128] Measurement method (absolute method) for determining platelet loss The measurements are performed in the same manner as the comparison method for determining platelet loss, but the results obtained are used absolutely and are not compared with the FX60 filter. Furthermore, different test filter structures are used, and the membranes used have an inner diameter of 210 μm and a wall thickness of 40 μm, are assembled into bundles of 10,752 fibers, and placed in a filter housing having an inner diameter of 38.4 mm. The filters are cast in the same manner as described above so that fibers of the same effective length are available. Blood is then passed through each filter in the same manner as described above, and platelet loss parameters are determined, but not compared with the reference filter.

[0129] Measurement method for determining zeta potential To determine the zeta potential of the hollow fiber membrane to be analyzed, a hollow fiber membrane filter (dialyzer) containing 10,752 hollow fiber membranes with an inner diameter of 185 μm and a wall thickness of 35 μm is used. The inner diameter of the filter housing is 34 mm. The hollow fiber membrane length significant for measuring the zeta potential is 285 mm. The hollow fiber membranes are sealed at their ends within the hollow fiber membrane filter to create 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 C6247 and isocyanate 136-20) from Elastogran is used as the casting compound. The casting height at each bundle end is 22 mm. The apparatus shown in Figure 2 / Figure 2a is used for this measurement. The hollow fiber membrane filter (1) includes fluid ports (2, 2a, 3, 3a) to its first and second chambers. As shown in Figure 2a, each of these fluid ports to the first chamber of the hollow fiber membrane filter (1) is provided with ports for an Ag / AgCl electrode (4, 4a) and a pressure gauge (5, 5a). The fluid port (3, 3a) to the second chamber of the hollow fiber membrane filter (1) is sealed so that the second chamber of the hollow fiber membrane filter remains unfilled. Potential difference ΔE between the two electrodes z(mV) is therefore recorded by the voltmeter (6) and the pressure drop ΔP (N / m) between the communication passages relative to the pressure gauge (5, 5a). 2 The pressure is recorded by a pressure gauge (7). The test solution consists of a 1 mole KCl aqueous solution with a pH of 7.4 and is supplied into a tank (8) located approximately 1000 mm above the filter. This pH value is set according to the following rules: Add 50 mg of K2CO3 to 100 liters of KCl solution. Stir this mixture in an open container until the pH reaches 7.4. Then tightly seal the container. The measurement is performed at a temperature of 23°C ± 2°C.

[0130] To measure the zeta potential, the test fluid is injected through a first fluid port (2) into a first chamber of a hollow fiber membrane filter surrounding the internal space of the hollow fiber membrane, and then discharged again from the dialyzer through a second fluid port (2a) on the hollow fiber membrane filter connected to the internal space of the hollow fiber membrane. In this configuration, the hollow fiber membrane filter is washed with the test fluid for 10 minutes initially, and then for an additional 5 minutes if necessary, until a stable value is reached. Simultaneously, the pressure difference and potential difference are read from a pressure gauge / multimeter, from which the zeta potential is calculated. To improve measurement accuracy, two four-way valves are switched to allow backflow of the test fluid through the internal space of the hollow fiber membrane after the acquisition of the measurement values. Next, a measurement value for the zeta potential is formed from the average measurement values ​​in both flow directions. The calculation of the zeta potential is derived from the following equation.

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[0131] Measurement method for determining the contact angle θ The contact angle of the hollow fiber membrane is determined by the capillary method, in which the hollow fiber membrane functions as a capillary. The hollow fiber membrane is fixed in a measuring stand. Deionized water colored with 0.25 mg / ml methylene blue is filled into a bucket placed at the base of the measuring stand. The hollow fiber membrane, with a new transverse cut edge pre-cut with a Western-style razor relative to its longitudinal extension, is immersed in this solution, and the capillary height h is determined by checking the height of the colored solution inside the hollow fiber membrane above the liquid level of the test solution in the bucket after a 20-minute waiting period. A new hollow fiber membrane is used after each measurement. At the cut edge, the inner radius r of each hollow fiber membrane is determined by optical microscope.

[0132] To calculate the contact angle, the following Young-Laplace equation for capillary pressure can be used.

number

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[0133] Measurement method for determining the polyvinylpyrrolidone content of hollow fiber membranes The PVP content of hollow fiber membranes is determined using IR spectroscopy. In this process, a sample of the hollow fiber membrane is first dried in a drying cabinet at 105°C for 2 hours, and then 1 g of the hollow fiber membrane is dissolved in dichloromethane. Furthermore, a calibration standard is established using dried PVP also dissolved in dichloromethane. This covers a PVP concentration range of approximately 1 to 10% within the hollow fibers. Each solution is injected into a fluid cuvette until a layer thickness of 0.2 mm is achieved. The absorption band of CO carbonyl vibrations is used for this evaluation.

[0134] Measurement method (XPS) for determining polyvinylpyrrolidone in the near-surface layer The polyvinylpyrrolidone content in the layer near the surface is determined using photoelectron spectroscopy (XPS or ESCA). This method can be used to determine the ratio of polyvinylpyrrolidone in a layer of approximately 5–10 nm. Hereafter, this layer sampled using the XPS method will be referred to as the "near-surface layer," and this layer is defined by the measurement conditions.

[0135] The hollow fiber membrane is divided using a scalpel or other sharp blade so that the inner surface of the hollow fiber membrane, and therefore a selective layer, is exposed. This sample is fixed onto a sample plate and placed in a sample chamber. The measurement conditions are defined as follows: - Equipment: Thermo VG Scientific K-Alpha model -Excitation radiation: single wavelength X-ray, AI Kα, 75W -Sample spot diameter: 200 μm - Pass energy: 30 eV - Angle between light source and analyzer: 54° - Spectral resolution for Ag3d signal: 0.48 eV -Applied vacuum: 10 -8 mbar - Charge compensation applied by a flood gun The PVP content in the near-surface layer is determined by the following formula, using values ​​found for the atomic percentages of nitrogen (N) and sulfur (S). PVP content [unit: mass%]=100 * (N * 111) / (N * 111+S * 442) This formula applies to the use of bisphenol A-based polysulfones, while the following formula will be used for polyethersulfones. PVP content [unit: mass%]=100 * (N * 111) / (N * 111+S * 232) For other polysulfones, it is necessary to determine the molecular weight of the monomer units that can be assigned to sulfur, and for copolymers, the ratio of sulfur-containing monomers to the copolymer must be considered. Each decision is made for three hollow fiber membranes, and the average of these measurements is calculated.

[0136] CNO4 in the surface using TOF-SIMS - and SO2 - Measurement method for determining peak height ratio The surface layer composition is determined by secondary ion mass spectrometry. A time-of-flight mass spectrometer is used as the ion detector. The sample is prepared in the same manner as for near-surface determination and introduced into the sample chamber. A TOF-SIMS IV model from ION-TOF GmbH (Münster, Germany) is used for this measurement. The measurement is performed by nanoAnalytices (Münster, Germany). This measurement method determines the relative chemical composition of the sample surface, represented by the first monolayer of the surface or by the first one to three monolayers, respectively. The essential measurement parameters are as follows: -Mass resolution: m / dm>8000 - Mass range <3000 m / z - Distance between sample and light source: 2mm -1st primary ion: Bi+, accelerating voltage 30kV -After acceleration: 30kV -Secondary ion polarity: Negative and positive - Primary ion irradiation rate: 2.65 * 10 per measurement 8 individual ions - Sampling surface size: 10,000 μm 2 (100 × 100 μm) -Applied vacuum: 10 -8 mbar - Pulse width: 10 ns (unbunched), 5 ns (bunched) - Bunch formation: Yes (high resolution measurement) -Charge neutralization: Yes When selecting measurement parameters, CNO - The peak height of the ions was 0.1 counts and 2 counts per channel. * 10 5 Care must be taken to ensure that the count is established during the process. Anion spectroscopy was used for evaluation, and as a result, the molecular weight of CNO42 was determined. - Ions and SO2 with a molecular weight of 64 - The ions were evaluated for each sample. As a result, CNO - This represents the PVP signal, SO2 - This represents the signal for polysulfone. The anion spectrum is plotted, and the respective peak height H, representing the molecular weight of each, is measured. These peak heights H are then set relative to each other, and the determined values ​​represent the measured parameter for the ratio of PVP to polysulfone.

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[0137] Measurement method for determining the sieving coefficient of plasma albumin The albumin sieving coefficient of the hollow fiber membrane is measured on the finished hollow fiber membrane filter according to DIN EN ISO 8637:2014. A filter with 10,752 hollow fiber membranes having an inner diameter of 185 μm and a wall thickness of 35 μm is used. The effective length of the hollow fiber membrane is 235 mm. The effective length of the hollow fiber membrane is the length of the potting-free hollow fiber membrane that can be used to determine permeability such as the sieving coefficient, clearance, and ultrafiltration coefficient. The inner diameter of the hollow fiber membrane filter is 34 mm in the middle. The hollow fiber membrane filter has the same structure as described in "Method for Measuring Zeta Potential". Human plasma is used to determine the sieving coefficient based on DIN EN ISO 8637:2014. That is, the "plasma sieving coefficient" of albumin is determined. The plasma solution passes through the fluid inlet at a flow rate of 500 ml / min and then through the first chamber of the hollow fiber membrane filter surrounding the inside of the hollow fiber membrane. In the second chamber of the hollow fiber membrane filter, a backflow of pure water at 100 ml / min is set through the fluid inlet. After 5, 10, and 30 minutes, the albumin concentrations are determined at the first and second fluid inlets and on the filtration side of the first chamber of the hollow fiber membrane filter, and the sieving coefficient is determined from there according to the standard. A Cobas Integra 400 Plus model from Roche Diagnostics GmbH is used as the analytical instrument. The measurement is performed using the ALBT2 test for urine applications. [Examples]

[0138] Example 1: Production of the hollow fiber membrane of the present invention A spinning solution consisting of 16 parts by mass of polysulfone (P3500, Solvay), 4.3 parts by mass of polyvinylpyrrolidone (K81 / 86, Ashland), and 79.7 parts by mass of DMAc is stirred, heated to 60°C, and degassed to process the solution into a uniform spinning mass. Next, α-tocopherol (Sigma Aldrich) is added to this spinning mass so that the percentage of α-tocopherol relative to the total mass of the spinning mass is 0.01% by mass. To produce a coagulant, 35% by mass of DMAc and 65% by mass of water are mixed, and polyvinylpyrrolidone (K81 / 86, Ashland) is added so that the percentage is 1 g per kg (1000 ppm) of coagulant. The spinning mass is passed through an annular spinning die with the coagulant induced in the center to process it into a strand having a lumen diameter of 185 μm and a wall thickness of 35 μm. A coagulant is passed through the hollow strand. The temperature of the annular spinneret is 70°C. The strand is guided through a sedimentation chamber in an atmosphere with 100% relative humidity. The height of the sedimentation gap is 200 mm, and a residence time of 0.4 seconds is set in the sedimentation gap. The strand is introduced into a sedimentation bath consisting of water temperature-controlled to 80°C and precipitated into a hollow fiber membrane. Next, the hollow fiber membrane is passed through a rinsing bath temperature-controlled to 75°C to 90°C. After that, the hollow fiber membrane is subjected to a drying treatment between 100°C and 150°C. The resulting hollow fiber membrane is then wound onto a winding machine to form a tow. A hollow fiber membrane bundle is produced from the wound tow.

[0139] Furthermore, the hollow fiber membrane bundles are processed into hollow fiber membrane filters using known techniques. The resulting hollow fiber membrane filters are then sterilized according to the steam sterilization method described in patent application DE 102016224627.5. Measurement methods for determining zeta potential, complement activation, and platelet loss are performed on the thus sterilized hollow fiber membrane filters. The individual test results for the hollow fiber membranes manufactured according to Example 1 are shown in Table 1.

[0140] Example 2: Production of the hollow fiber membrane of the present invention To produce the hollow fiber membrane and filter of the present invention, the same basic conditions as in Example 1 are selected, the only difference being that the percentage of polyvinylpyrrolidone in the coagulant is 1.5 g per kg (1500 ppm) of the coagulant. Measurement methods for determining zeta potential, complement activation, and platelet loss are performed on the sterilized hollow fiber membrane filter as described above. Furthermore, as described above in "Measurement Method for Determining Polyvinylpyrrolidone Elution," accelerated degradation is applied to the sterilized hollow fiber membrane filter at 80°C for 30 / 60 days. PVP elution is determined after each degradation. The contact angle is measured, the PVP content within the hollow fiber membrane is measured, the polyvinylpyrrolidone content in the near-surface layer is measured, and further CNO in the surface layer is measured by TOF-SIMS. - and SO2 - To measure the peak height ratio, the hollow fiber membrane filter manufactured according to the above was opened, the hollow fiber membrane was removed, and the individual values ​​were checked. The individual test results for the hollow fiber membrane manufactured according to Example 2 are shown in Table 1. Furthermore, the albumin sieving coefficient was determined after 5 minutes, 10 minutes, and 30 minutes. The data is shown in Table 2. In addition, a membrane with dimensions of 210 μm lumen diameter and 40 μm wall thickness was manufactured according to the above specifications, and platelet loss was determined using this membrane according to the absolute method.

[0141] Example 3: Production of the hollow fiber membrane of the present invention The same basic conditions as in Example 1 were selected to produce the hollow fiber membrane and corresponding filter of the present invention, the only difference being that the percentage of polyvinylpyrrolidone in the coagulant was 2500 ppm by mass. Measurement methods for determining zeta potential, complement activation, and platelet loss were performed on the sterilized hollow fiber membrane filter as described above. The individual test results for the hollow fiber membrane produced according to Example 3 are shown in Table 1.

[0142] Example 4: Production of the hollow fiber membrane of the present invention To produce the hollow fiber membrane and corresponding filter of the present invention, the same basic conditions as in Example 1 are selected, except that the percentage of polyvinylpyrrolidone in the coagulant is 3000 ppm by mass, and the concentration of α-tocopherol (vitamin E) in the spindle is 0.05% (w / w). Measurement methods for determining zeta potential, complement activation, and platelet loss are performed on the sterilized hollow fiber membrane filter as described above. Furthermore, as described above in "Measurement method for determining polyvinylpyrrolidone elution," accelerated degradation is applied to the sterilized hollow fiber membrane filter at 80°C for 30 / 60 days. PVP elution is determined after each degradation. The individual test results for the hollow fiber membrane produced according to Example 4 are shown in Table 1.

[0143] Example 5: Production of a hollow fiber membrane according to the present invention For the production of the hollow fiber membrane and filter according to the present invention, the same initial conditions as in Example 1 were selected, but the difference was that the ratio of polyvinylpyrrolidone in the coagulant was 1.5 g (1500 ppm) per 1 kg of coagulant, and K90 type PVP was used in the coagulant. Furthermore, K81 / 86 type PVP was used in the spindle. The measurement method for determining the zeta potential was performed on the hollow fiber membrane filter sterilized using the method described above. The contact angle was measured, the polyvinylpyrrolidone content in the near-surface layer was measured, and further, the CNO in the surface layer was measured by TOF-SIMS. - and SO2 - To measure the peak height ratio, the hollow fiber membrane filter manufactured according to the above was opened, the hollow fiber membrane was removed, and the individual values ​​were checked. The results of the individual investigations of the hollow fiber membrane manufactured according to Example 5 are shown in Table 1. The membrane according to this example shows a particularly high PVP ratio on the inner lumen surface compared to Design Example 2. Furthermore, the albumin sieving coefficient was determined after 5 minutes, 10 minutes, and 30 minutes. The data are shown in Table 2.

[0144] Example 6: Hollow fiber membrane production according to the present invention For the production of the hollow fiber membrane and filter according to the present invention, the same initial conditions as in Example 1 were selected, but the difference was that the ratio of polyvinylpyrrolidone in the coagulant was 1.5 g (2000 ppm) per 1 kg of coagulant, and as a result, K90 type PVP was used in the coagulant. Furthermore, K81 / 86 type PVP was used in the spindle. The measurement method for determining the zeta potential was performed on the hollow fiber membrane filter sterilized using the method described above. The contact angle was measured to measure the polyvinylpyrrolidone content in the near-surface layer, and further, the CNO in the surface layer was measured using TOF-SIMS. - and SO2 - To measure the peak height ratio, a properly prepared hollow fiber membrane filter is opened, and the hollow fiber membrane is removed and its respective value is checked. The results of individual investigations of the hollow fiber membranes manufactured according to Example 6 are shown in Table 1. The membranes according to this example have a particularly high PVP ratio on the inner lumen surface.

[0145] Example 7: Production of a hollow fiber membrane according to the present invention For the production of the hollow fiber membrane and filter according to the present invention, the same initial conditions as in Example 1 were selected, but the difference was that the ratio of polyvinylpyrrolidone in the coagulant was 1.5 g (1000 ppm) per 1 kg of coagulant, and as a result, K90 type PVP was used in the coagulant. Furthermore, K81 / 86 type PVP was used in the spindle. The measurement method for determining the zeta potential was performed on the hollow fiber membrane filter sterilized using the method described above. The contact angle was measured to measure the polyvinylpyrrolidone content in the near-surface layer, and further, the CNO in the surface layer was measured using TOF-SIMS. - and SO2 - To measure the peak height ratio, a properly prepared hollow fiber membrane filter is opened, and the hollow fiber membrane is removed and its respective value is checked. The results of the individual investigations of the hollow fiber membranes manufactured according to Example 7 are shown in Table 1.

[0146] Comparative Example 1: Manufacturing of a comparative hollow fiber membrane The same basic conditions as in Example 1 were selected to produce the comparative hollow fiber membrane and the corresponding filter, with the difference being that the percentage of polyvinylpyrrolidone in the coagulant was 1.5 g / kg of coagulant (1500 ppm) by mass, and the percentage of α-tocopherol in the spindle was 0.00%. The measurement methods for determining complement activation and platelet loss were performed on the sterilized hollow fiber membrane filter as described above. Furthermore, as described above in "Measurement Method for Determining Polyvinylpyrrolidone Elution," the sterilized hollow fiber membrane filter was subjected to accelerated degradation at 80°C for 30 / 60 days. PVP elution was determined after each degradation. The individual test results for the hollow fiber membrane produced according to Comparative Example 1 are shown in Table 1.

[0147] Comparative Example 2: Manufacturing of a comparative hollow fiber membrane The same basic conditions as in Example 1 were selected to produce the comparative hollow fiber membrane and the corresponding filter, the only difference being that the percentage of polyvinylpyrrolidone in the coagulant was 0 g / kg of coagulant, and the percentage of tocopherol in the spindle was 0.00%. Measurement methods to determine zeta potential, complement activation, platelet loss, and polyvinylpyrrolidone elution were performed on the sterilized hollow fiber membrane filter as described above. Furthermore, accelerated degradation was applied to the sterilized hollow fiber membrane filter at 80°C for 30 / 60 days, as described above in "Measurement method for determining polyvinylpyrrolidone elution". PVP elution was determined after each degradation.

[0148] The contact angle was measured, the PVP content within the hollow fiber membrane was measured, the polyvinylpyrrolidone content in the near-surface layer was measured, and further, the CNO content in the surface layer was measured by TOF-SIMS. - and SO2 -To measure the peak height ratio, the hollow fiber membrane filter produced according to the above was opened, the hollow fiber membrane was removed, and the individual values ​​were checked. The individual test results for the hollow fiber membrane manufactured according to Comparative Example 2 are shown in Table 1. In addition, the albumin sieving coefficient was determined after 5 minutes, 10 minutes, and 30 minutes. The data are given in Table 2. Furthermore, following the specifications above, a membrane with a lumen diameter of 210 μm and a wall thickness of 40 μm was manufactured, and platelet loss was determined using this membrane according to the absolute method.

[0149] Comparative Example 3: Production of a comparative hollow fiber film The same initial conditions as in Example 1 were selected for the production of the comparative hollow fiber membrane and the corresponding filter, but the difference was that the ratio of polyvinylpyrrolidone in the coagulant was 5 g / kg of coagulant (5000 ppm) parts by mass, and the ratio of α-tocopherol in the spindle was 0.01%. During the spinning process, the fibers were crushed, and therefore, it was not possible to construct a filter suitable for the measurement method. It was also not possible to perform even one fiber measurement (contact angle).

[0150] (Table 1) Table 1: Test results for Examples 1 to 7 and Comparative Examples 1 and 2 TIFF0007855641000006.tif208155

[0151] PVP leaching was determined after degradation at 80°C and <5% relative humidity for 30 / 60 days, respectively. The unit of measurement is 10 per individual fiber. -7 The value is mg. Other measurements were determined using non-degraded samples. Furthermore, the contact angle was determined for a commercially available Fresenius FX60 dialyzer. This value was found to be 64°. Table 1 shows platelet loss by comparative method. PVP content in the near-surface layer Example 2: 24.1% Example 5: 28.7% Example 6: 29.8% Example 7: 27.7% Comparative Example 2: 21.3% Surface CNO via TOF-SIMS- and SO2 - Peak height ratio Example 2: 5.15 Example 5: 6,50 Example 6: 6,20 Example 7: 5,20 Comparative Example 2: 4.04

[0152] The TOF-SIMS spectrum (anion) of Example 2 is shown in Figure 3, and the TOF-SIMS spectrum of Comparative Example 2 is shown in Figure 3b.

[0153] (Table 2) Table 2 Albumin sieving coefficients for Examples 2 and 5 and comparative examples TIFF0007855641000007.tif31170

[0154] There is a clear decrease in the sieving coefficient over time. After 30 minutes, it reaches a nearly constant equilibrium. Since such dialyzers have only a small initial albumin decrease, it is preferable to aim for the smallest possible decrease in the albumin sieving coefficient. Accordingly, the ratios of the sieving coefficients after 5 minutes and 10 minutes, or after 5 minutes and 30 minutes, are also given and shown in Table 3.

[0155] (Table 3) Table 3. Ratio of sieving coefficients for Examples 2 and 5 and Comparative Example 3. TIFF0007855641000008.tif26141

[0156] The comparative example shows a significantly larger decrease in the sieving coefficient at the start of the test. This means that, after a longer test period, the membrane or dialyzer according to the present invention shows only a significantly smaller initial albumin decrease compared to dialyzers with the same equilibrium sieving coefficient. Therefore, the nutritional status of patients treated with the membrane or dialyzer according to the present invention is improved.

[0157] (Table 4) Data from the determination of platelet loss by absolute method TIFF0007855641000009.tif21140

[0158] To determine this data, 68 tests were conducted for Example 2 and 22 tests for Comparative Example 2, and the average value was calculated from each of these measurements. The membrane according to the present invention has been shown to have significantly lower platelet loss as measured according to the “Determination of Platelet Loss” (absolute method) method, and is therefore more blood compatible. [Explanation of symbols]

[0159] 1. Apparatus for determining platelet loss 2 Dialyzer 6. Blood reservoir 7. Pressure Sensor 8. Blood inlet

Claims

1. A hollow fiber membrane having a membrane material containing polysulfone, polyvinylpyrrolidone, and at least one water-insoluble antioxidant, The polyvinylpyrrolidone content in the near-surface layer of the inner lumen of the membrane, as measured by XPS, is 22% by mass or more. The elution of polyvinylpyrrolidone after storage at 80°C and less than 5% relative humidity for 30 days was 4000 * 10 per individual fiber. -7 The hollow fiber membrane, characterized in that it is less than mg.

2. The hollow fiber membrane according to claim 1, characterized in that the hollow fiber membrane contains at least one water-insoluble antioxidant in an amount of 0.005 to 0.25% by mass relative to the total mass of the hollow fiber membrane.

3. The hollow fiber membrane according to claim 1 or 2, characterized in that the zeta potential of the inner lumen-side surface of the hollow fiber membrane is -1 mV or more and less than -7 mV.

4. CNO in the surface layer of the inner lumen of the membrane, as measured by TOF-SIMS. - and SO 2 - A hollow fiber membrane according to any one of claims 1 to 3, characterized in that the peak height ratio with respect to is 4.5 or more.

5. A hollow fiber membrane according to any one of claims 1 to 4, characterized in that the polyvinylpyrrolidone content of the hollow fiber membrane is 3 to 5% (w / w).

6. A hollow fiber membrane according to any one of claims 1 to 5, characterized in that the mass-average molecular weight (Mw) of polyvinylpyrrolidone (PVP) on the inner lumen surface of the membrane is higher than the mass-average molecular weight (Mw) of PVP in the volume of the membrane.

7. The hollow fiber membrane according to claim 6, wherein the mass-average molecular weight (Mw) of PVP on the surface of the inner lumen of the membrane is greater than 1,000,000 g / mol, and the mass-average molecular weight (Mw) of PVP in the volume of the membrane is less than 1,000,000 g / mol.

8. The hollow fiber membrane according to claim 6 or 7, wherein the ratio of the mass-average molecular weight of PVP in the coagulant to the mass-average molecular weight of PVP in the spindle is at least 1.

2.

9. The hollow fiber membrane according to any one of claims 1 to 8, wherein the ratio of the albumin sieving coefficient measured after 5 minutes by the measurement method specified herein to the sieving coefficient measured after 30 minutes is less than 7, and the measurement of the albumin sieving coefficient is performed on the finished hollow fiber membrane filter using human plasma in accordance with DIN EN ISO 8637:2014.

10. The hollow fiber membrane according to any one of claims 1 to 9, wherein the ratio of the albumin sieving coefficient measured after 5 minutes by the measurement method specified herein to the sieving coefficient measured after 10 minutes is less than 3, and the measurement of the albumin sieving coefficient is performed on the finished hollow fiber membrane filter using human plasma in accordance with DIN EN ISO 8637:2014.

11. A hollow fiber membrane according to any one of claims 1 to 10, characterized in that the contact angle with water on the inner lumen surface, as measured by the "contact angle θ measurement" method, is less than 57°.

12. A hollow fiber membrane according to any one of claims 1 to 11, characterized in that the platelet loss measured by the "platelet loss measurement" method is less than 50%.

13. A hollow fiber membrane filter comprising a plurality of hollow fiber membranes according to any one of claims 1 to 12.

14. The hollow fiber membrane filter according to claim 13, wherein the hollow fiber membrane filter is a dialyzer for hemodialysis.

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