polymer membrane

Abstract

Polymer Membrane: The membrane may comprise a polymer membrane made from a polymer selected from aromatic sulfone polymers, polyamides, cellulose, cellulose acetate, polymethyl methacrylate, polyvinyl alcohol, and polyacrylnitril, the polymer membrane having a major surface, and a stilbenoid, isoflavone, or flavone coated on the major surface of the polymer membrane.

Description

[Technical Field]

[0001] The present disclosure relates to microporous membranes. Additionally, the present disclosure relates to processes for producing such membranes. The present disclosure further relates to the use of such membranes for the filtration and purification of liquid media. [Background technology]

[0002] Polymer membranes are used for microfiltration in a wide variety of industrial, pharmaceutical, or medical applications. Membrane separation processes are becoming increasingly important in these applications, due to their advantage of not thermally stressing or even damaging the substances being separated. Ultrafiltration membranes can be used to remove or separate macromolecules. Many other membrane separation process applications are known in the beverage industry, biotechnology, water treatment, and sewage technology. These membranes are generally classified according to their retention capacity, i.e., the capacity to retain particles or molecules of a particular size, or their effective pore size, i.e., the size of the pores that determine their separation behavior. Ultrafiltration membranes thus cover the separation behavior-determining pore size range of approximately 0.01 μm to about 0.1 μm, and can therefore retain particles or molecules in a size range greater than 20,000 Daltons, or greater than about 200,000 Daltons. Better polymer membranes are needed. Summary of the Invention

[0003] Thus, in one aspect, the present disclosure provides a membrane comprising: a polymeric membrane having a major surface made from a polymer selected from an aromatic sulfone polymer, a polyamide, cellulose, cellulose acetate, polymethyl methacrylate, polyvinyl alcohol, and polyacrylnitril; and a stilbenoid, an isoflavone, or a flavone coated on the major surface of the polymeric membrane.

[0004] In another aspect, the present disclosure provides a method that includes forming a polymer membrane from an aromatic sulfone polymer and coating the hollow fiber membrane with a stilbenoid, isoflavone, or flavone.

[0005] In another aspect, the present disclosure provides the use of a polymeric membrane of the present disclosure for the filtration of a liquid. DETAILED DESCRIPTION OF THE INVENTION

[0006] Before any embodiment of the present disclosure is described in detail, it is understood that the invention is not limited in its application to the details of use, construction, and arrangement of components set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways that will become apparent to those skilled in the art upon reading this disclosure. Also, it is understood that the terminology and terminology used herein is for descriptive purposes and should not be regarded as limiting. The use of "including," "comprising," or "having," and variations thereof, herein is meant to encompass the items listed thereafter and equivalents thereof, as well as additional items. It is understood that other embodiments may be utilized and structural or logical changes may be made without departing from the scope of the present disclosure.

[0007] The present disclosure provides a membrane comprising a polymeric membrane having a major surface and a wall having a wall thickness. In some embodiments, the polymeric membrane may be a hollow membrane, which may have a continuous hollow lumen extending from one end of the fiber to the other, an outward-facing outer surface forming the exterior of the fiber, an inner surface facing the hollow lumen that defines the boundary of the continuous hollow lumen, and an intermediate wall having a wall thickness. In some embodiments of the hollow membrane, the major surface may be the inner surface. In some embodiments of the hollow membrane, the major surface may be the inner surface. The polymeric membrane may include a stilbenoid, isoflavone, or flavone coated on the major surface of the polymeric membrane. In some cases, the stilbenoid, isoflavone, or flavone may form a layer or at least partially cover the major surface. In some embodiments, the stilbenoid, isoflavone, or flavone may cover more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the major surface of the polymeric membrane. In some embodiments, the stilbenoid, isoflavone, or flavone may cover 100% of the major surface of the polymeric membrane. In some embodiments, the wall may comprise a plurality of pores, and the stilbenoid, isoflavone, or flavone may be coated on the surface of at least some of the plurality of pores. In some embodiments, the stilbenoid, isoflavone, or flavone may cover more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the surface of at least some of the plurality of pores. In some embodiments, the stilbenoid, isoflavone, or flavone may cover 100% of the surface of at least some of the plurality of pores. In some embodiments, the stilbenoid, isoflavone, or flavone may be coated on more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the surface of the plurality of pores. In some embodiments, the stilbenoid, isoflavone, or flavone may cover all of the surface of the plurality of pores.In some embodiments, the stilbenoid, isoflavone, or flavone may be coated on or cover at least a portion of the exterior surface. In some embodiments, the stilbenoid, isoflavone, or flavone may cover more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the exterior surface. In some embodiments, the stilbenoid, isoflavone, or flavone may cover 100% of the exterior surface. In some embodiments, the polymer film may be a flat sheet film having two major surfaces, a first major surface and a second major surface opposite the first major surface. In some of these embodiments, the stilbenoid, isoflavone, or flavone may at least partially cover both the first major surface and the second major surface. In some of these embodiments, the stilbenoids, isoflavones, or flavones may cover more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of both the first major surface and the second major surface.

[0008] The wall thickness (in hollow fiber membrane embodiments, the wall thickness can be measured between the outer and inner surfaces of the hollow fiber membrane) can range from 20 μm to 500 μm, 140 μm to 400 μm, 150 μm to 380 μm, or 160 μm to 380 μm. In some embodiments, to achieve desirable flow, particularly favorable pressure drop, through the lumen of a hollow fiber membrane according to the present disclosure, the inner diameter of the hollow fiber membranes described herein is preferably in the range of 100 μm to 2000 μm, 700 μm to 2000 μm, 800 μm to 1800 μm, or 900 μm to 1600 μm. The wall thickness and diameter (in hollow fiber membrane embodiments, the inner or lumen diameter, and the outer diameter) of the membranes described herein are also determined by conventional inspection methods, such as scanning electron micrographs or transmission electron micrographs (SEM or TEM, respectively), at a magnification of, for example, 400:1.

[0009] Polymeric membranes according to the present disclosure can be prepared by the method disclosed in International Publication No. WO 2019 / 229667(A1) (Malek et al.), which is incorporated herein by reference in its entirety. In some embodiments, the polymeric membrane can be prepared from a homogeneous spinning solution of polymeric components and a solvent system. In this regard, the polymeric components include a polymer selected from aromatic sulfone polymers, polyamides, cellulose, cellulose acetate, polymethyl methacrylate, polyvinyl alcohol, and polyacrylonitrile. The polymeric components may further include at least one hydrophilic polymer. Flat-sheet membranes and methods for their preparation are described, for example, in EP 0361085(B1).

[0010] According to the present disclosure, the concentration of the sulfone polymer in the spinning solution is preferably in the range of 17% to 27% by weight. A concentration below 17% by weight may result in disadvantages, particularly with regard to the mechanical stability of the resulting hollow fiber membrane. On the other hand, a membrane obtained from a spinning solution containing more than 27% by weight of sulfone polymer may exhibit an excessively dense structure and insufficient permeability. The spinning solution preferably contains 20% to 25% by weight of the hydrophobic aromatic sulfone polymer. The sulfone polymer may also contain additives, such as antioxidants, nucleating agents, and UV absorbers, to selectively modify the properties of the membrane.

[0011] Advantageous hydrophobic aromatic sulfone polymers constituting the membrane or used in the method according to the invention are polysulfones, polyethersulfones, polyphenylenesulfones, or polyarylethersulfones. Preferably, the hydrophobic aromatic sulfone polymer is a polysulfone or polyethersulfone having repeating molecular units as shown in formulas (I) and (II) below. [ka]

[0012] A long-chain polymer having repeating polymer units which are compatible with the hydrophobic aromatic sulfone polymer on the one hand and which are themselves hydrophilic is advantageously used as the at least one hydrophilic polymer. W Preferably, a hydrophilic polymer having the formula: is used. The hydrophilic polymer is preferably polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyglycol monoester, polysorbate such as polyoxyethylene sorbitan monooleate, carboxymethyl-cellulose, or a modified or copolymerized version of these polymers. Polyvinylpyrrolidone and polyethylene glycol are particularly preferred.

[0013] In the context of the present disclosure, the at least one hydrophilic polymer may further comprise a mixture of different hydrophilic polymers. The hydrophilic polymer may be, for example, a mixture of chemically different hydrophilic polymers or hydrophilic polymers with different molecular weights, for example, a mixture of polymers with molecular weights differing by five or more times. Preferably, the at least one hydrophilic polymer comprises a mixture of polyvinylpyrrolidone or polyethylene glycol and a hydrophilically modified aromatic sulfone polymer. The hydrophilically modified aromatic sulfone polymer is also preferably a sulfonated aromatic sulfone polymer, particularly a sulfonated modification of the hydrophobic aromatic sulfone polymer used in the membranes and methods according to the present disclosure. A mixture of polyethersulfone, sulfonated polyethersulfone, and polyvinylpyrrolidone may be particularly advantageously used. The presence of the hydrophilically modified aromatic sulfone polymer results in hollow fiber membranes with particularly stable hydrophilic properties in applications.

[0014] The polymer membrane made of aromatic sulfone polymer can then be coated on its main surface with stilbenoids, isoflavones, or flavones. The stilbenoids, isoflavones, or flavones can be dissolved in a solvent to form a coating solution. The solvent can be selected from the group consisting of ethanol and isopropanol. In some embodiments, the coating solution can be prepared by dissolving the stilbenoids, isoflavones, or flavones in a solvent at less than 1 wt%, less than 0.9 wt%, less than 0.8 wt%, less than 0.7%, less than 0.6%, or less than 0.5 wt% at room temperature. In some embodiments, the coating solution can be prepared by dissolving the stilbenoids, isoflavones, or flavones in a solvent at 0.8 wt%, 0.7 wt%, 0.6 wt%, 0.5 wt%, or 0.4 wt%. The polymer membrane can be immersed in the coating solution. After immersing the polymer membrane in the coating solution and incubating for a certain period of time, for example, 10 minutes, the coating solution can be drained from the polymer membrane. The polymer membrane is immersed in the coating solution and incubated for a certain period of time, e.g., 10 minutes, after which the coating solution is drained from the polymer membrane. To dry the polymer membrane, the polymer membrane can be connected to a nitrogen source and a gentle gas flow applied through the membrane to evaporate the solvent, leaving the stilbenoid, isoflavone, or flavone coated on the major surface of the polymer membrane.

[0015] In hollow fiber membrane embodiments, the coating solution can be flowed into the lumen of the hollow fiber membrane. Due to the very good wetting properties of the solvent on the aromatic sulfone polymer fibers, the coating solution can cover the membrane wall and also penetrate into the extracapillary volume. After the lumen is completely filled with the coating solution and incubated for a certain time, for example, 10 minutes, the coating solution can be drained from the hollow fiber membrane. After this step, capillary forces allow the hollow fiber membrane to remain completely immersed in the coating solution.

[0016] (Isoflavones) used in this application can include those disclosed in U.S. Pat. No. 8,883,010 (B2) (Chandrasekaran et al.), such as flavones, isoflavones, or combinations thereof. Exemplary (iso)flavones may be isolated naturally occurring isoflavones, synthetic isoflavones, or combinations thereof. In exemplary embodiments, the flavone or isoflavone may be a polyphenol, i.e., a hydroxy(iso)flavone having at least one hydroxyl group (i.e., a hydroxyflavone or hydroxyisoflavone), such as a molecule having at least two phenolic groups. While not fully understood, it is believed that the phenolic group in the hydroxy(iso)flavone contributes to the antioxidant properties of the hydroxy(iso)flavone molecule and aids in the retention of the molecule within the matrix.

[0017] In one embodiment, the (iso)flavone may include at least one of a hydroxyflavone and a hydroxyisoflavone. The hydroxyflavone or hydroxyisoflavone may be a mono-, di-, tri-, or tetra-hydroxyisoflavone (i.e., one, two, three, or four of the hydrogen atoms in the flavone or isoflavone molecule are replaced with hydroxyl groups), such as trihydroxyisoflavone. The hydroxyflavone or hydroxyisoflavone may further include one or more additional substituents, such as an alkoxy and / or glucose moiety. In one embodiment, the phytochemical includes a hydroxyisoflavone, such as a mono-, di-, or trihydroxyisoflavone.

[0018] In one embodiment, hydroxyisoflavones are substituted derivatives of isoflavones that are linked to the isoflavone molecule by replacing one, two, three, or four hydrogen atoms with hydroxyl groups. In some embodiments, the isoflavone structure may be further substituted with one or more alkoxy groups, such as methoxy or ethoxy groups.

[0019] Exemplary hydroxyisoflavones can be selected from the following: Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one, also known as 4',5,7-trihydroxyisoflavone), has the following structure: [ka] Daidzein (7-hydroxy-3-(4-hydroxyphenyl)chromen-4-one (IUPAC), or 4',7-dihydroxyisoflavone), has the following structure: [ka] • Glycitein (7-hydroxy-3-(4-hydroxyphenyl)-6-methoxy-4-chromenone (IUPAC), or 4',7-dihydroxy-6-methoxyisoflavone). • Prunetin (5-hydroxy-3-(4-hydroxyphenyl)-7-methoxychromen-4-one, or 4',5-dihydroxy-7-methoxyisoflavone). • Biochanin A (5,7-dihydroxy-3-(4-methoxyphenyl)chromen-4-one, or 5,7-dihydroxy-4'-methoxyisoflavone). • Orobol (3-(3,4-dihydroxyphenyl)-5,7-dihydroxychromen-4-one, or 3',4',5,7-tetrahydroxyisoflavone). ●Santal (7-methoxy-5,3',4'-trihydroxyisoflavone). • Pratensein (5,7-dihydroxy-3-(3-hydroxy-4-methoxyphenyl)chromen-4-one, or 4'-methoxy-3',5,7-trihydroxyisoflavone). • Formononetin (7-hydroxy-3-(4-methoxyphenyl)chromen-4-one, or 7-hydroxy-4'-methoxyisoflavone). - and glucosides, β-glycosides, and alkoxy-substituted derivatives thereof, and combinations thereof.

[0020] In some embodiments, the isoflavones may comprise at least one of the group consisting of genistein and daidzein, hi some embodiments, the isoflavones may comprise a mixture of two or more isoflavones.

[0021] In some embodiments, the isoflavone may include genistein. Genistein is a particularly interesting hydroxyisoflavone. It has a molecular weight of 270 g / mol, melts at 306°C, and can reduce oxidative stress and the concentration of pro-inflammatory cytokines without being toxic or activating platelet adhesion processes.

[0022] Stilbenoids as used herein include aglycones such as piceatannol, pinosylvin, pterostilbene, resveratrol, gnetol, oxyresveratrol, and glycosides such as astringin and piceid. Stilbenoids are hydroxylated derivatives of stilbene. They have a C6-C2-C6 structure. In biochemical terms, they belong to the phenylpropanoid family.

[0023] Polymer films prepared according to the methods of the present disclosure can provide a homogenous / uniform distribution of stilbenoids, isoflavones, or flavones on a major surface of the polymer film (in some embodiments, the entire major surface) even at lower loading levels (up to 10% by weight). Thus, polymer films of the present disclosure can provide a high surface concentration and bulk density of stilbenoids, isoflavones, or flavones on a major surface of the polymer film even at lower loading concentrations compared to polymer films prepared with a mixture of polymer and flavone.

[0024] The polymer membranes of the present disclosure, which use stilbenoids or flavones, such as genistein, as an active coating, can reduce dialysis-induced oxidative stress (DIOS) and membrane-induced inflammation (MII) by reducing reactive oxygen levels and the levels of several cytokines. Cytokines are a family of proteins involved in numerous immunological functions, including the production and regulation of other cytokines. They play an important role in regulating hematopoiesis and mediate the differentiation and proliferation of various cell types. For example, endotoxins (such as bacterial components) from dialysate have been shown to induce the secretion of IL-1β from neutrophils, which causes fever and hypotension during hemodialysis. IL-1β and TNF-α are known for their autocrine (i.e., inducing / regulating their own secretion) and paracrine signaling (inducing / regulating the secretion of other cytokines) functions. Clinically, it has been demonstrated that serum concentrations of IL-1β and TNF-α increase several-fold during hemodialysis, depending on the membrane selected. Although polymer membrane surfaces may also induce cytokine secretion through direct contact of PBMCs with membrane- and dialysate-derived endotoxins, complement-mediated cytokine secretion is generally accepted as a common mechanism by which hemodialysis membranes induce inflammation. In hemodialysis, an alternative pathway of complement activation leads to the formation of complement fragments, such as C3b, which coat the membrane surface by adsorbing to it. C3b molecules, along with other soluble complement fragments, such as C3a and C5a, subsequently stimulate PBMCs to induce enhanced secretion of pro-inflammatory cytokines. DIOS is initiated when excessive production of oxygen radicals overwhelms the body's natural antioxidant defense mechanisms. MII triggers an undesirable immune response induced by high concentrations of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6, and tumor necrosis factor-R (TNF-R), in the blood.The bioincompatibility of polymeric membranes has been implicated as a major source of excess reactive oxygen species (ROS) during hemodialysis that contribute to DIOS.

[0025] Patients undergoing maintenance hemodialysis are exposed to increased oxidative stress, which promotes arteriosclerosis, the main cause of excess mortality in this patient population. Excess oxygen attacks low-density lipoproteins, which leads to the formation of plaque in the arteries and heart attacks. Dialysis membranes can generate free oxidative radicals when in contact with the patient's blood, which further exacerbates oxidative stress. The flavone-coated polymer membranes of the present disclosure can reduce the oxidative stress caused by dialysis membranes, which can be measured by different parameters in the blood, such as peroxide production and oxidative burst.

[0026] The antioxidant properties of polymeric films coated with stilbenoids or flavones can be understood by considering the mechanism of oxygen radical formation. Upon cell activation, membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) and the cytoplasmic components of the enzyme assemble within the membrane to form the active enzyme. NADPH oxidase converts O2 into the superoxide anion (O2 ·- ), which then rapidly dismutates to hydrogen peroxide (HO). This series of events is called the electron transport chain. HO can then be converted by the enzyme myeloperoxidase to highly reactive compounds such as hypochlorous acid (HOCl). Therefore, functionally intact NADPH oxidase may be important for neutrophils to undergo the oxidative burst. In this case, genistein successfully inhibited the expression of NADPH, the first step in the electron transport chain that forms superoxide anion and subsequently dismutates it to HO.

[0027] The polymeric membranes of the present disclosure have been found to reduce serum levels of certain cytokines and promote a reduction in reactive oxygen species (ROS), which are known to play important roles in mutagenesis, carcinogenesis, and particularly tumor promotion. Genistein can inhibit both the priming events necessary for high levels of ROS production. In some embodiments, the polymeric membranes of the present disclosure can reduce the oxidative burst (i.e., ROS production) by more than 50%, more than 60%, or more than 70% compared to membranes without the flavone coating, as measured by the methods described in the Examples. In some embodiments, the polymeric membranes of the present disclosure can reduce HO by more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, or more than 50% compared to membranes without the flavone coating, as measured by the methods described in the Examples.

[0028] It has been found that the polymeric membranes of the present disclosure can effectively retain blood cells, such as white blood cells, red blood cells, and platelets, which are important for blood function. In some embodiments, the polymeric membranes of the present disclosure can retain more than 90%, 95%, 98%, 99%, or 100% of white blood cells or red blood cells, as measured by the methods described in the Examples. In some embodiments, the polymeric membranes of the present disclosure can retain more than 70%, 75%, 80%, 85%, or 90% of platelets, as measured by the methods described in the Examples. In some embodiments, the polymeric membranes of the present disclosure can increase platelet retention by more than 50%, 60%, 70%, 80%, 90%, or 100% compared to membranes without the flavone coating.

[0029] The polymer membranes of the present disclosure can reduce the concentration of thrombin-antithrombin complex (TAT), reducing the impact of dialysis membranes on the coagulation system and cell activation, without being toxic or activating the platelet adhesion process. Thrombin-antithrombin complex (TAT) significantly increases during the coagulation process, which can lead to platelet activation. In some embodiments, the polymer membranes of the present disclosure can reduce plasma TAT levels by more than 10%, 20%, or 30% compared to membranes without flavone coating.

[0030] The polymeric membranes of the present disclosure may be suitable for use in applications in the field of filtration. Due to the unique combination of properties of the polymeric membranes described herein, preferably obtained from the methods described herein, the present disclosure further provides the use of the membranes described herein for the filtration of liquids, for example, microfiltration or ultrafiltration. "Microfiltration" and "ultrafiltration" have their usual meanings in the art. Preferably, the uses described herein involve the clarification and / or purification of liquid media, particularly aqueous liquids. The polymeric membranes of the present disclosure can be used in several extracorporeal blood purification procedures, including dialysis.

[0031] The following examples are intended to illustrate, but not limit, the present disclosure. [Example]

[0032] The objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.

[0033] Materials and Test Methods Genistein was obtained from Herb-key (China Shaanxi NHK Technology), Shaanxi, China. Resveratrol (product number R5010) was obtained from Sigma-Aldrich Company, St. Louis, MO.

[0034] White blood cell counts (WBC), red blood cell counts (RBC), and platelet counts (PC) were determined using an ABX Pentra 60 cell counter (Axon Lab AG, Reichenbach, Germany).

[0035] Total lipid peroxide levels in plasma samples were determined using a chromogenic assay kit (obtained from Immundiagnostik AG, Bensheim Germany) according to the manufacturer's instructions.

[0036] Complement component 5a (C5a) levels in plasma samples were determined using an ELISA assay kit (obtained from DRG Instrument GmbH, Marburg, Germany) according to the manufacturer's instructions.

[0037] Thrombin-antithrombin complex (TAT) levels in plasma samples were determined using an ELISA assay kit (obtained from Siemens Healthcare Diagnostics, Marburg, Germany) according to the manufacturer's instructions.

[0038] The oxidative burst activity of blood samples was determined by flow cytometry using a FACSVERSE flow cytometer (Becton Dickinson GmbH, Heidelberg, Germany). Blood samples were incubated with dihydrorhodamine 123 (DHR123), a non-fluorescent dye (DHR123 is taken up by neutrophils in the sample), for 10 min at 37°C. Next, blood cells were stimulated with and without formyl peptide (N-formyl Nle-Leu-Phe-Nle-Try-Lys) for 15 min at 37°C, and then red blood cells were lysed with BD PHARM LYSE lysis solution (Becton Dickinson GmbH). Upon generation of reactive oxygen species, DHR was oxidized to the fluorescent dye rhodamine. In the assay, oxidative burst activity was proportional to the intracellular fluorescence intensity of rhodamine (relative fluorescence units, RFU) measured by the flow cytometer. For each sample, 5,000 neutrophils were acquired within a gate for forward scatter (FSC) versus side scatter (SSC). FSC and SSC were analyzed on a linear scale, and fluorescence data were analyzed on a biexponential scale. Data acquisition and analysis were performed using FACSUITE software (version 1.05, Becton Dickinson GmbH). A formyl peptide-primed lipopolysaccharide (100 ng / mL, from S. minnesota R 595)-primed blood sample served as a positive control. Oxidative burst activity was expressed as the geometric mean of rhodamine fluorescence intensity (RFU) and calculated from the difference in the geometric mean between samples incubated with and without formyl peptide.

[0039] Hemolysis was measured at three wavelengths (OD 380nm , O.D. 415nm , O.D. 450nm) by spectrophotometer (UV1650PC spectrophotometer, Shimadzu Deutschland GmbH, Duisburg, Germany) and background corrected according to Herboe M, Scandinavian Journal of Clinical and Lab Investigation, 1959, 11, pages 66-70. Plasma free hemoglobin [fHb] (g / dL) was calculated using formula A. To reflect hemolysis, fHb at the end of the experiment was set relative to the total hemoglobin at baseline.

[0040] Formula A:

number

[0041] Example 1. Preparation of a dialyzer module containing a membrane coated with genistein A coating solution of genistein (0.4 wt%) in ethanol was prepared and added to a 5 L pressurizable vessel. PUREMA polyethersulfone, hollow fiber, capillary membrane type H (inner diameter 200 micrometers, wall thickness 30 micrometers, active surface area 1.1 m) was used. 2, obtained from 3M Company, St. Paul, MN) was inserted into the dialyzer module. The dialyzer module was in tubular form with open connector elements at each end of the tubing. Two side ports located near the top and bottom of the module were closed with clamps. The dialyzer module was mounted vertically by connecting the bottom connector of the module to the valve port of a pressurizable container using PTFE (polytetrafluoroethylene) tubing. The container was pressurized (0.4 bar), and the valve was opened to allow the coating solution to flow into the membrane lumen. When the lumen was completely filled and the coating solution began to exit the open top connector, the valve was closed. The coating solution was maintained in the dialyzer module for 10 minutes, and then the tubing was removed from the bottom connector to drain the coating solution from the dialyzer module. During the process, the coating solution was observed to penetrate the capillary membrane wall and fill a portion of the extracapillary volume. After draining the coating solution, a nitrogen gas source was attached to the bottom connector, and a gentle stream of nitrogen was passed through the membrane to evaporate any residual ethanol.

[0042] Comparative Example A. Preparation of a Dialyzer Module Containing a Membrane Not Coated with Genistein The same procedure was followed as described in Example 1, except a different coating solution was used: the coating solution was ethanol without any other additives.

[0043] Example 2. Analysis of human blood Dialyzer modules prepared according to Example 1 and Comparative Example A were analyzed using freshly donated human blood samples (pooled from two to three donors). The same pool of heparinized blood (3.5 IU / mL standard heparin, #H3149, Sigma-Aldrich, Steinheim, Germany) was used as the blood source for all experiments. The two side ports of each module were closed with clamps. Each dialyzer module was mounted vertically, and saline solution (1 L, NaCl concentration 0.9%) was recirculated through the module at 250 mL / min for 30 minutes. The saline solution flowed through the module from the lower connector to the upper connector. Next, 1 L of a second NaCl solution (0.9%) was pumped through the module in a single pass (60 mL / min), and the liquid flowed from the lower connector to the upper connector and exited the module through the upper connector. An aliquot (240 mL) from the heparinized blood pool was then recirculated through the module at 250 mL / min for 180 minutes. During the recirculation step, the blood was maintained at 37°C, and blood flow through the module was in the same direction as the preceding saline recirculation step. Blood samples were taken both before (t = 0) and after (t = 180) the recirculation step and subsequently analyzed. The results are reported in Table 1. For WBCs, RBCs, and PCs, counts obtained after the recirculation step (t = 180) were compared with the corresponding baseline counts obtained before the recirculation step (t = 0) and then reported as a percentage of baseline. Blood samples obtained after the recirculation step (t = 180) were used to measure TAT, C5a, total lipid peroxides, and oxidative burst activity.

[0044] For the module of Example 1, results are reported from a single experiment. For the module of Comparative Example A, results are reported as the average (with standard deviation) from experiments using three separate modules (n=3). A separate aliquot of heparinized blood from the blood pool was used for each module tested.

[0045] [Table 1]

[0046] Example 3 A sheet of 3M MICROPES Type 1F PH polyethersulfone membrane (110 micrometers thick, obtained from 3M Company) was immersed in a solution of resveratrol (0.8 wt%) in ethanol at room temperature for 5 minutes. The membrane was removed from the solution and allowed to dry overnight at room temperature.

[0047] Comparative example B A sheet of 3M MICROPES Type 1F PH polyethersulfone membrane (110 micrometers thick) was immersed in ethanol at room temperature for 5 minutes. The membrane was removed from the solution and allowed to dry at room temperature overnight.

[0048] Example 4 Samples (4.5 cm diameter) were punched out from the membranes prepared according to Example 3 and Comparative Example B. Each sample was placed in a Petri dish containing 10 mL of saline (NaCl concentration 0.9%). The dish was shaken on an orbital shaker at 70 revolutions per minute (rpm) for 40 minutes. The saline was then removed from the dish and replaced with 10 mL of fresh saline, and the dish was shaken for 1 minute. The saline was then removed from the dish and replaced with 8 mL of heparinized human blood (3.5 IU / mL standard heparin, #H3149, Sigma-Aldrich) and shaken (70 rpm) for 3 hours at 37°C. Each blood sample was tested for total lipid peroxides and oxidative burst activity. Results are reported in Table 2 as the average (with standard deviation) from experiments using three separate membrane samples (n=3).

[0049] [Table 2]

[0050] All references and publications cited herein are expressly incorporated by reference in their entirety into this disclosure. Exemplary embodiments of the invention have been discussed, and reference has been made to possible variations within the scope of the invention. For example, features described in the context of one exemplary embodiment may be used in the context of other embodiments of the invention. These and other variations and modifications of the invention will be apparent to those skilled in the art without departing from the scope of the invention, and it should be understood that the invention is not limited to the exemplary embodiments described herein. Accordingly, the present invention is to be limited only by the claims provided below and their equivalents.

Claims

1. A polymer film made from a polymer selected from aromatic sulfone polymers, polyamides, cellulose, cellulose acetate, polymethyl methacrylate, polyvinyl alcohol, and polyacrylonitrile, having a main surface, and A stilbenoid, isoflavone or flavone coated on the main surface of the polymer film, A film comprising.

2. The polymer film according to claim 1, wherein the stilbenoid, isoflavone or flavone covers more than 75% of the main surface of the polymer film.

3. The polymer film according to claim 1 or 2, wherein the aromatic sulfone polymer contains polyethersulfone.

4. The polymer film according to any one of claims 1 to 3, wherein the isoflavone contains hydroxyisoflavone.

5. The polymer film according to any one of claims 1 to 4, wherein the isoflavone is selected from the group consisting of genistein, daidzein, glycitein, prunetin, biocanin A, orobol, santal, pratensein, formononetin, and glucosides, 13-glycosides, and derivatives thereof substituted with alkoxy, and combinations thereof.

6. Forming a polymer film from an aromatic sulfone polymer and Coating the polymer film with a stilbenoid, isoflavone, or flavone, A method comprising.

7. The method according to claim 6, wherein the isoflavone is selected from the group consisting of genistein, daidzein, and combinations thereof.