Double-layer hollow fiber membrane for hemodialysis and its manufacturing method

Abstract

The present invention provides a double-layer hollow fiber membrane for enclosing a hollow space through which blood flows and transporting uremic toxins and waste products from the blood to the outside, and a method for manufacturing the same. The double-layer hollow fiber membrane includes a first layer having first pores and a second layer having second pores. The first pores of the first layer and the second pores of the second layer are connected to each other, and the second pores are open pores connected to the outside. The double-layer hollow fiber membrane can remove uremic toxins with molecular sizes from blood while minimizing the loss of blood components and essential proteins due to the pores increasing in size from the first pores to the second pores.

Description

[Technical Field]

[0001] The present invention relates to a double-layer hollow fiber membrane, and more particularly to a double-layer hollow fiber membrane that can transport uremic toxins and waste products from blood to the outside while minimizing the loss of essential elements and proteins from blood, and a method for manufacturing the same. [Background technology]

[0002] Kidney disease occurs when fluids and waste products that should be excreted from the body accumulate in the blood due to a decline in kidney function, causing an imbalance in the body's electrolytes. Chronic kidney disease occurs when kidney disease persists for more than three months, resulting in proteinuria or hematuria due to kidney damage or decline in function. The number of chronic kidney disease patients is steadily increasing worldwide, and in Korea, the number of patients is also increasing every year due to a rapid aging population and an increase in risk factors such as high blood pressure, diabetes, and metabolic syndrome.

[0003] Renal replacement therapies such as hemodialysis, peritoneal dialysis, and kidney transplants are used to remove waste products from the bodies of patients with chronic kidney disease. According to the results of a 2022 survey, the proportion of patients receiving renal replacement therapy was 79.4% for hemodialysis, 4.1% for peritoneal dialysis, and 16.5% for kidney transplants, and it is known that most patients receive hemodialysis treatment (Non-Patent Document 1).

[0004] Hemodialysis (HD) is a treatment method for removing impurities accumulated in the body by circulating blood outside the body. It uses the principle of diffusion due to the concentration difference between the blood and the dialysate to remove uremic toxins and waste products from the blood through a semipermeable membrane hemodialysis filter, and then returns the purified blood to the body. Hemodialysis involves flowing blood through one side of a semipermeable membrane and dialysate through the other side to remove uremic toxins and excess water. However, conventional hemodialysis primarily removes small molecular weight uremic toxins through diffusion due to concentration differences. However, it does not remove large, middle-molecular weight uremic toxins (molecular weights above 1 kD), which led to the need for a new hemodiafiltration method.

[0005] Hemodiafiltration (HDF) is a treatment that adds filtration to hemodialysis. Similar to hemodialysis, hemodiafiltration utilizes a dialysis membrane. However, it differs in that it enhances the convective movement of fluids to remove medium-sized waste products (e.g., urea). Furthermore, various clinical studies have shown that HDF has a higher patient survival rate than conventional hemodialysis. However, current HDF still has a lower rate of uremic toxins and waste removal than healthy kidneys, and the pressurized filtration method can result in the loss of essential substances. Hollow fiber membranes, on the other hand, are filamentous membranes with hollow cores. Hollow fiber membranes are used in therapeutic blood treatments to remove waste products from blood. Hemodialysis membranes are primarily made of polymers, such as cellulose, cellulose acetate, polyamide, polyolefin, polyacrylonitrile, and polysulfone. Among these, polysulfone-based materials and polyvinylpyrrolidone, which exhibit excellent blood compatibility, are rapidly gaining popularity. However, if a large amount of polyvinylpyrrolidone remains in the hollow fiber membrane, it may be released during hemodialysis, causing other side effects.

[0006] Hollow fiber membranes are manufactured using a variety of methods, including the phase inversion method, thermally induced phase separation method, melt spinning method, dry-wet spinning method, and stretching method, but are mainly manufactured using the phase inversion method. However, in the phase inversion method, the position and size of pores are irregularly determined during the phase transition process, resulting in poor filtration accuracy and volume.

[0007] Therefore, there is a need for the development of a hollow fiber membrane that has excellent water permeability and can remove middle molecular weight uremic toxins that are fatal to long-term dialysis patients. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Korean Patent Registration No. 10-1810470 (December 13, 2017) [Patent Document 2] Korean Patent Publication No. 10-2005-0078748 (August 8, 2005) [Non-patent literature]

[0009] [Non-Patent Document 1] Current Status of Renal Replacement Therapy in Japan in 2023, Korean Society of Nephrology Summary of the Invention [Problem to be solved by the invention]

[0010] In order to solve the above-mentioned problems, the first object of the present invention is to provide a double-layer hollow fiber membrane that encloses a hollow space through which blood flows and has pores whose size is adjusted to effectively discharge uremic toxins from the blood.

[0011] A second object of the present invention is to provide a method for producing the double-layer hollow fiber membrane of the first object by adjusting the content of the water-soluble pore-forming polymer. [Means for solving the problem]

[0012] To achieve the first object, the present invention provides a hollow fiber membrane for enclosing a hollow space through which blood flows and for transporting uremic toxins and waste products from the blood flowing through the hollow space to the outside. The double-layer hollow fiber membrane includes a first layer having first pores and a second layer having second pores connected to the first layer and larger than the first pores. The second pores of the second layer are open pores that are connected to the first pores of the first layer and are also connected to the outside.

[0013] To achieve the second object, the present invention provides a method for producing a double-layer hollow fiber membrane by using a spinning solution containing a water-soluble pore-forming polymer. The water-soluble pore-forming polymer may be a polyvinyl resin, a glycol resin, or a mixture thereof. Specifically, the present invention provides a method for producing a double-layer hollow fiber membrane by supplying a bore solution, a first spinning solution prepared by dissolving a polyvinyl resin and a polysulfone resin in a solvent, and a second spinning solution prepared by dissolving a glycol resin and a polysulfone resin in a solvent, to a triple nozzle. The hollow fiber membrane is then spun into a coagulation bath and wound on a winder. The resulting hollow fiber membrane is then gelled in a water bath, washed in a washing bath containing 80 wt% to 100 wt% water and 0 wt% to 20 wt% glycerol, and dried in the air at room temperature to produce the double-layer hollow fiber membrane of the first object. [Effects of the Invention]

[0014] The double-layer hollow fiber membrane of the present invention can remove uremic toxins and waste products from blood flowing through the hollow. Blood flowing through the hollow comes into contact with the first layer of the hollow fiber membrane, and through this contact, the uremic toxins and waste products from the blood can migrate to first pores in the first layer. The migrated uremic toxins and waste products can migrate to second pores in the second layer of the hollow fiber membrane, which are connected to the first pores. The second layer comes into contact with the dialysate, and through this contact, the uremic toxins and waste products from the blood can diffuse into the dialysate through second pores connected to the first pores.

[0015] The second pores are connected to the first pores, allowing uremic toxins and waste products in the blood that have passed through the first pores to diffuse into the dialysate without hindrance. Furthermore, the second pores have a larger pore size than the first pores, which increases the contact area between the uremic toxins and waste products in the blood that have passed through the first pores and the dialysate, thereby serving as a faster diffusion path.

[0016] In addition, the first pores of the double-layer hollow fiber membrane of the present invention include first pores suitable for removing uremic toxins of medium molecular size, and essential proteins and albumin larger than the uremic toxins can be maintained at a safe level without being filtered out, and the membrane can be used as a separation membrane for hemodialysis, hemofiltration, or hemodiafiltration. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is an enlarged image of a triple nozzle used in the method for producing a double-layer hollow fiber membrane of the present invention. [Figure 2] 1 is a conceptual diagram showing a process of forming open pores through a triple nozzle in the method for producing a double-layer hollow fiber membrane of the present invention. [Figure 3] 1 is a graph showing the average values ​​of the outer diameter, inner diameter, membrane thickness, and porosity of the double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 4] 1 is a diagram showing the process of forming a mini-module containing a double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 5]FIG. 1 is a SEM photograph of a cross section of a double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 6] FIG. 2 is a SEM photograph showing the first and second pores of the open pore structure of the double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 7] 1 is a flow chart for measuring the porosity of a double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 8] 1 is a schematic diagram of a filtration device for confirming the pure water permeability of a double-layer hollow fiber membrane prepared by the method of the present invention using a mini-module including the hollow fiber membrane. [Figure 9] 1 is a graph showing the water permeability of a double-layer hollow fiber membrane manufactured by the manufacturing method of the present invention. [Figure 10] 1 is a schematic diagram of a filtration device for determining the serum albumin loss rate of a double-layer hollow fiber membrane prepared by the method of the present invention using a mini-module containing the hollow fiber membrane. [Figure 11] 1 is a graph showing the serum albumin loss rate of a double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 12] 1 is a schematic diagram of a filtration device for confirming the molecular weight cutoff of a double-layer hollow fiber membrane prepared by the method of the present invention using a mini-module containing the hollow fiber membrane. FIG. [Figure 13] 1 is a graph showing the pore size, standard deviation of pore size, and molecular weight cutoff of a double-layer hollow fiber membrane produced by the production method of the present invention. [Figure 14] 1 is a schematic diagram of a filtration device for confirming the hemodialysis performance of a double-layer hollow fiber membrane manufactured by the manufacturing method of the present invention using a mini-module containing the hollow fiber membrane. [Figure 15] 1 is a graph showing the serum albumin loss rate and urea and creatinine removal rates of a double-layer hollow fiber membrane produced by the production method of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0018] Hereinafter, the present invention will be described in detail with reference to the embodiments and drawings so that those skilled in the art can easily carry out the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Therefore, the embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below, but may be embodied in other forms.

[0019] Throughout the present specification, when a part "comprises" a certain element, this means that it can further include other elements, but not excluding other elements, unless otherwise specified.

[0020] Throughout the present specification, the term "step of" or "step of" does not mean "step for".

[0021] Throughout the present specification, the term "membrane" refers to another general thin interface that regulates the permeation of chemical species in contact with it, said membrane containing pores with finite dimensions as defined in the following description.

[0022] Example The present invention provides a double-layer hollow fiber membrane for enclosing a hollow space through which blood flows and transporting uremic toxins and waste products from the blood to the outside. The double-layer hollow fiber membrane includes a first layer having first pores and a second layer having second pores connected to the first layer and larger than the first pores. The second layer having the second pores can come into contact with the dialysate.

[0023] In the double-layer hollow fiber membrane, the first pores of the first layer and the second pores of the second layer may be connected to each other so that uremic toxins and waste products in the blood flowing through the hollow fiber can pass through. The second pores of the second layer may have an open pore structure connected to the outside so that the uremic toxins and waste products in the blood can diffuse into the dialysate. In the double-layer hollow fiber membrane, the pore size of the first pores may be smaller than those of blood components such as red blood cells, platelets, and white blood cells, and essential proteins such as albumin, but larger than those of medium-sized uremic toxins and waste products. The pore size of the first pores is specifically 5 nm to 12 nm, preferably 8 nm to 11 nm. In the double-layer hollow fiber membrane, the pore size of the second pores may be larger than the first pore size, specifically 0.1 μm to 1.5 μm, preferably 0.3 μm to 1.0 μm.

[0024] In the double-layer hollow fiber membrane, the first pores in the first layer and the second pores in the second layer may be formed with pores of different sizes by using different water-soluble pore-forming polymers. Furthermore, the pore size, uniformity, and degree of open pore formation can be controlled by varying the composition of the water-soluble pore-forming polymers. The pore-forming agent may be a polyvinyl-based resin or a glycol-based resin. Specifically, the first pores in the first layer may be formed by a polyvinyl-based resin, and the second pores in the second layer may be formed by a glycol-based resin. The polyvinyl-based resin forming the first pores in the first layer may be induced to diffuse toward the second layer due to the influence of the glycol-based resin forming the second pores in the second layer, and this diffusion may affect the formation of the second pores with an open pore shape. The glycol-based resin forming the second pores in the second layer may affect the size of the first pores due to its relatively high content and low molecular weight. Furthermore, the polyvinyl resin of the first layer and the glycol resin of the second layer can affect the size and uniformity of the first pores and the second pores by adjusting their contents.

[0025] The water-soluble pore-forming polymer polyvinyl resin is one or more resins selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinylacetate (PVAc), polyvinylalcohol (PVA), and polyethylene-co-vinylacetate (PEVA), specifically PVP. The water-soluble pore-forming polymer glycol resin is one or more resins selected from the group consisting of ethylene glycol (EG), diethylene glycol (DEG), triethylene glycol (TEG), propylene glycol (PG), and polyethylene glycol (PEG), specifically PEG.

[0026] The double layer hollow fiber membrane has a water permeability of 120LMHbar. -1 ~330LMHbar -1 and preferably 150LMHbar -1 ~300LMHbar -1 The permeability of the hollow fiber membrane is 120LMHbar. -1 If it is smaller, the filtering effect of uremic toxins and waste products in the blood will decrease, and the pressure will exceed 330LMHbar. -1 If it is larger, essential elements and proteins in the blood may be lost.

[0027] The double-layer hollow fiber membrane can be used as a separation membrane for hemodialysis, hemofiltration, or hemodiafiltration to filter uremic toxins and waste products from blood. The uremic toxins or waste products to be filtered may be one or more uremic toxins or waste products selected from the group consisting of urea, uric acid, beta-2 microglobulin, lambda free light chain, kappa free light chain, creatinine, hippuric acid, indoxyl sulfate, p-cresol, oxalates, guanidines, phenol, and homocysteine. The double-layer hollow fiber membrane is used for the purpose of removing uremic toxins or waste products from blood and improving one or more kidney diseases selected from the group consisting of diabetic nephropathy, chronic renal failure, acute renal failure, subacute renal failure, glomerulonephritis, malignant nephropathy, vascular microvascular disease, transplant rejection, glomerular disease, renal hypertrophy, renal proliferation, proteinuria, contrast-induced nephropathy, toxin-induced kidney damage, oxygen free-radical-mediated nephropathy, and nephritis.

[0028] The present invention also provides a method for manufacturing a double-layer hollow fiber membrane using a spinning solution containing a water-soluble pore-former polymer. Specifically, the present invention provides a method for manufacturing a double-layer hollow fiber membrane using a first spinning solution containing a first water-soluble pore-former polymer and a polysulfone-based resin, and a second spinning solution containing a second water-soluble pore-former polymer and a polysulfone-based resin. The first spinning solution can be prepared by dissolving the first water-soluble pore-former polymer and the polysulfone-based resin in a solvent, and the second spinning solution can be prepared by dissolving the second water-soluble pore-former polymer and the polysulfone-based resin in a solvent. The first and second spinning solutions can be supplied to a triple nozzle together with a bore solution, spun, and then wound up on a winder to form a double-layer hollow fiber membrane. The formed double-layer hollow fiber membrane is gelled in a water tank, washed in a washing tank containing 80 wt% to 100 wt% water and 0 wt% to 20 wt% glycerol, and then dried in the air at room temperature to produce a double-layer hollow fiber membrane.

[0029] In the manufacturing method, the temperature of the triple nozzle may be 40°C to 55°C. In the manufacturing method, a bore solution may be supplied to a first nozzle, which is the most central part of the triple nozzle, a first spinning solution may be supplied to a second nozzle provided on the outer peripheral surface of the first nozzle, and a second spinning solution may be supplied to a third nozzle provided on the outer peripheral surface of the second nozzle. The flow rate of the bore solution supplied to the first nozzle may be 0.1 ml / min to 1.5 ml / min, specifically 0.3 ml / min to 1.0 ml / min. The flow rates of the first and second spinning solutions supplied to the second and third nozzles may be 0.1 ml / min to 1.0 ml / min, specifically 0.1 ml / min to 0.5 ml / min.

[0030] In the manufacturing method, the bore solution acts as an internal coagulant and contributes to the formation of a double-layer hollow fiber membrane. The bore solution may be a solution containing one or more selected from the group consisting of water, glycerol, N-methyl-2-pyrrolidone, glycol-based resin, alcohol solvent, and ketone solvent, specifically, a solution containing one or more selected from the group consisting of water, glycerol, dimethoxyethanol, N-methyl-2-pyrrolidone, methanol, ethanol, isopropanol, acetone, and dimethylacetamide, preferably glycerol dissolved in a solvent, more preferably glycerol dissolved in N-methyl-2-pyrrolidone.

[0031] The solvent may be an aprotic polar solvent, and the aprotic polar solvent is one or more solvents selected from the group consisting of acetone, acetonitrile, dimethyl acetamide (DMAc), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), methyl ethyl ketone, methyl n-propyl ketone, N-methyl-2-pyrrolidone, propylene carbonate, nitromethane, sulforane, and hexamethylphosphoramide (HMP), and is preferably N-methyl-2-pyrrolidone.

[0032] The first spinning solution may contain a polyvinyl resin, a polysulfone resin, and N-methyl-2-pyrrolidone. Specifically, the first spinning solution may contain 1 wt% to 20 wt% of a polyvinyl resin, 10 wt% to 20 wt% of a polysulfone resin, and 65 wt% to 85 wt% of N-methyl-2-pyrrolidone. The polyvinyl resin is a water-soluble resin and can form uniform water channels in the support layer, thereby affecting the size of the water channels formed in the first and second layers of the double-layer hollow fiber membrane to be manufactured. When the polyvinyl resin is contained in an amount less than 1 wt%, the solvent dissociates from the first spinning solution, reducing the solidification rate. This reduced solidification rate increases the size of the formed pores, allowing blood components and essential proteins to diffuse into the dialysis solution. Furthermore, if the polyvinyl resin content exceeds 20 wt%, the pore size becomes excessively large, allowing blood components and essential proteins such as albumin to diffuse into the dialysis fluid. Therefore, the polyvinyl resin content is preferably 1 wt% to 20 wt%.

[0033] The second spinning solution may contain a glycol-based resin, a polysulfone-based resin, and N-methyl-2-pyrrolidone. Specifically, the second spinning solution may contain 5 wt% to 30 wt% of a glycol-based resin, 10 wt% to 20 wt% of a polysulfone-based resin, and 50 wt% to 80 wt% of N-methyl-2-pyrrolidone. The glycol-based resin is a water-soluble resin and can form uniform water channels in the support layer, thereby affecting the formation and size of the water channels in the double-layer hollow fiber membrane. If the glycol-based resin is contained in an amount less than 5 wt%, the pore size will not increase and the water permeability will decrease. If the glycol-based resin is contained in an amount greater than 20 wt%, the pore size will become excessively large, allowing blood components and essential proteins to diffuse into the dialysis fluid. Therefore, the glycol-based resin is preferably contained in an amount of 5 wt% to 20 wt%. In the above manufacturing method, the polysulfone-based resin contained in the first and second spinning solutions has excellent chemical resistance and mechanical properties, is highly biocompatible, and can be used as a membrane material with low cost. If the polysulfone-based resin is contained in an amount less than 10 wt%, the mechanical properties decrease, while if it exceeds 20 wt%, the hollow fiber membrane becomes thick and the effectiveness of removing uremic toxins and waste products from the blood decreases. Therefore, the polysulfone-based resin is preferably contained in an amount of 10 wt% to 20 wt%. Specifically, the polysulfone-based resin is one or more resins selected from the group consisting of polyethersulfone (PES), polysulfone (PSU), and polyphenylenesulfone (PPSU). Preferably, PES is highly hydrophilic, causes little membrane fouling by organic substances, and is bisphenol-A-free.

[0034] In the above-described method, after preparing the first and second spinning solutions, a process of removing impurities by supplying an inert gas may be added, and the inert gas may be one or more inert gases selected from the group consisting of neon, argon, nitrogen, and helium.

[0035] In the above manufacturing method, the types of polyvinyl resin and glycol resin contained in the first spinning solution and the second spinning solution are the same as those described above for the double-layer hollow fiber membrane, and therefore, the above description is incorporated herein by reference.

[0036] In the manufacturing method, an external coagulation liquid may be added to the coagulation tank in which the bore solution, the first spinning solution, and the second spinning solution are spun. The external coagulation liquid may be any liquid that can replace the bore solution, which is the internal coagulant, and is specifically a solvent or a non-solvent, preferably a non-solvent containing a small amount of solvent.

[0037] The non-solvent may be water, a glycol resin, a C1-C4 alcohol, or a mixture thereof, and the solvent may be glycerol, N-methyl-2-pyrrolidone, or a ketone solvent. The temperature of the coagulation bath is a temperature at which the phase transition rate can be accelerated, specifically, 10°C to 30°C, and preferably 10°C to 25°C.

[0038] In the above-described manufacturing method, the air gap between the triple nozzle and the coagulation tank is 15 cm to 180 cm, preferably 25 cm to 100 cm. If the length of the air gap is less than 15 cm, the spinning solution is not sufficiently stretched before coagulation, making it difficult to control the specifications of the hollow fiber membrane (outer diameter, inner diameter, thickness, and pore size). Furthermore, if the length of the air gap is more than 180 cm, the time during which the stretched spinning solution is exposed to an external environment that is difficult to maintain constant increases, which may affect the formation of a hollow fiber membrane with a uniform structure and result in unexpected defects.

[0039] In the above-described manufacturing method, the atmospheric temperature between the triple nozzle and the coagulation bath is 15° C. to 120° C., and preferably 20° C. to 100° C. The atmospheric humidity between the triple nozzle and the external coagulation liquid is 45% to 55%, and preferably 45% to 80%.

[0040] The winder that takes up the hollow fiber membrane formed by the above manufacturing method can take up the hollow fiber membrane at a speed of 7 m / min to 25 m / min, preferably 10 m / min to 20 m / min. If the take-up speed is less than 7 m / min, uneven solution extrusion occurs, destroying the membrane structure. If the take-up speed is more than 25 m / min, the pore size becomes excessively large, causing the leakage of blood albumin, a valuable protein, and the spinning dope being unable to keep up with the take-up speed, which can cause defects and breakage during continuous processing. Therefore, the take-up speed of the winder is 7 m / min to 25 m / min.

[0041] The present invention will be described in detail below through production examples and experimental examples.

[0042] <Production Example 1> Production of first spinning solution <1-1> Preparation of spinning solution No. 1-1 280 g of polyethersulfone (PES) and 100 g of polyvinylpyrrolidone (PVP) were placed in a 2 L round-bottom flask containing N-methyl-2-pyrrolidone (hereinafter referred to as NMP) solvent.

[0043] The mixture was stirred at 200 rpm at 60°C for 1 day and then degassed at room temperature to prepare a 1-1 spinning solution. The 1-1 spinning solution was purged with nitrogen at a pressure of 18 psi to remove impurities.

[0044] <1-2> Preparation of No. 1-2 spinning solution A spinning dope 1-2 was prepared in the same manner as in Preparation Example <1-1>, except that 280 g of PES and 200 g of PVP were added to the NMP solvent.

[0045] <1-3> Preparation of No. 1-3 spinning solution A spinning dope 1-3 was prepared in the same manner as in Preparation Example <1-1>, except that 280 g of PES and 50 g of PVP were added to the NMP solvent.

[0046] <Production Example 2> Production of second spinning solution <2-1> Preparation of spinning solution No. 2-1 280 g of PES and 400 g of polyethylene glycol (PEG) were placed in a 2 L round-bottom flask containing NMP solvent.

[0047] The mixture was stirred at 200 rpm at 60°C for 1 day and then degassed at room temperature to prepare a 2-1 spinning solution. The 2-1 spinning solution was purged with nitrogen at a pressure of 18 psi to remove impurities.

[0048] <2-2> Preparation of spinning solution No. 2-2 A spinning dope 2-2 was prepared in the same manner as in Preparation Example <2-1>, except that 280 g of PES and 560 g of PEG were added to the NMP solvent.

[0049] <2-3> Preparation of the 2-3 spinning solution A spinning dope 2-3 was prepared in the same manner as in Preparation Example <2-1>, except that 280 g of PES and 240 g of PEG were added to the NMP solvent.

[0050] <2-4> Preparation of No. 2-4 spinning solution A spinning dope No. 2-4 was prepared in the same manner as in Preparation Example <2-1>, except that 280 g of PES and 20 g of PEG were added to the NMP solvent.

[0051] <Production Example 3> Production of bore solution NMP solvent was mixed with deionized water (DI water) and 100 g of glycerol, and the mixture was stirred at 180 rpm for 1 hour to prepare a bore solution.

[0052] The prepared bore solution was stored in a brown bottle at 45°C.

[0053] <Production Example 4> Production of double-layer hollow fiber membrane <4-1> First, production of double-layer hollow fiber membrane The 1-1 spinning solution of Preparation Example <1-1>, the 2-1 spinning solution of Preparation Example <2-1>, and the bore solution prepared in Preparation Example 3 were supplied to a triple nozzle to prepare a double-layer hollow fiber membrane.

[0054] Referring to Figure 1, the triple nozzle is a nozzle consisting of a first nozzle at the center, a second nozzle provided on the outer periphery of the first nozzle, and a third nozzle provided on the outer periphery of the second nozzle. Referring to Figure 2, a first spinning solution, a second spinning solution, and a bore solution were supplied to the triple nozzle to produce a double-layer hollow fiber membrane.

[0055] Specifically, a triple nozzle with a 25 cm air gap and a nozzle temperature of 50°C was prepared (ambient temperature: 20°C-30°C, humidity: 40%-50%). The 1-1 spinning solution, 2-1 spinning solution, and bore solution were allowed to stand at room temperature for 12 hours to remove bubbles. The bore solution was then simultaneously supplied to the first nozzle of the triple nozzle at a flow rate of 0.7 ml / min, the first spinning solution to the second nozzle at a flow rate of 0.333 ml / min (1 rpm), and the second spinning solution to the third nozzle at a flow rate of 0.333 ml / min (1 rpm). The supplied first spinning solution, second spinning solution, and bore solution were simultaneously spun into a coagulation bath containing water at 25°C and wound up at a speed of 13 m / min using a winder to produce hollow fiber membranes. The produced hollow fiber membranes were gelled in a water bath, washed with water, and stored by immersing in glycerol.

[0056] As a result, a double-layer hollow fiber membrane having an outer diameter of 298.1 μm, an inner diameter of 229.8 μm, and a thickness of 33.2 μm was produced.

[0057] <4-2> Manufacture of the second double-layer hollow fiber membrane A double-layer hollow fiber membrane was prepared in the same manner as in Preparation Example <4-1>, except that the 1-1 spinning solution of Preparation Example <1-1>, the 2-2 spinning solution of Preparation Example <2-2>, and the bore solution prepared in Preparation Example <3> were supplied to a triple nozzle.

[0058] As a result, a double-layer hollow fiber membrane having an outer diameter of 284.6 μm, an inner diameter of 221.2 μm, and a thickness of 33.8 μm was produced.

[0059] <4-3> Manufacturing the third double-layer hollow fiber membrane A double-layer hollow fiber membrane was prepared in the same manner as in Preparation Example <4-1>, except that the 1-1 spinning solution in Preparation Example <1-1>, the 2-3 spinning solution in Preparation Example <2-3>, and the bore solution prepared in Preparation Example 3 were supplied to a triple nozzle.

[0060] As a result, a double-layer hollow fiber membrane having an outer diameter of 286.9 μm, an inner diameter of 223.5 μm, and a thickness of 34.5 μm was produced.

[0061] <4-4> Manufacture of the fourth double-layer hollow fiber membrane A double-layer hollow fiber membrane was prepared in the same manner as in Preparation Example <4-1>, except that the 1-2 spinning solution in Preparation Example <1-2>, the 2-1 spinning solution in Preparation Example <2-1>, and the bore solution prepared in Preparation Example <3> were supplied to a triple nozzle.

[0062] As a result, a double-layer hollow fiber membrane having an outer diameter of 288.2 μm, an inner diameter of 214.9 μm, and a thickness of 35.9 μm was produced.

[0063] <4-5> Manufacture of the fifth double-layer hollow fiber membrane A double-layer hollow fiber membrane was prepared in the same manner as in Preparation Example <4-1>, except that the spinning solution 1-3 in Preparation Example <1-3>, the spinning solution 2-1 in Preparation Example <2-1>, and the bore solution prepared in Preparation Example 3 were supplied to a triple nozzle.

[0064] As a result, a double-layer hollow fiber membrane having an outer diameter of 290.0 μm, an inner diameter of 227.5 μm, and a thickness of 32.6 μm was produced.

[0065] <4-6> Manufacture of the sixth double-layer hollow fiber membrane A double-layer hollow fiber membrane was prepared in the same manner as in Preparation Example <4-1>, except that the 1-2 spinning solution in Preparation Example <1-2>, the 2-4 spinning solution in Preparation Example <2-4>, and the bore solution prepared in Preparation Example 3 were supplied to a triple nozzle.

[0066] As a result, a double-layer hollow fiber membrane having an outer diameter of 282.8 μm, an inner diameter of 217.6 μm, and a thickness of 35.7 μm was produced.

[0067] Referring to FIG. 3, it was confirmed that the average outer diameter, average inner diameter, average membrane thickness, and average porosity of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> were within the average ranges for hollow fiber membranes, and that the outer diameter, inner diameter, membrane thickness, and porosity of the hollow fiber membranes were hardly affected by the spinning solution.

[0068] <Production Example 5> Fabrication of a double-layer hollow fiber membrane mini-module Perfluoroalkoxy alkane (PFA) tubing with an inner diameter of 3.98 mm and an outer diameter of 6.4 mm was cut to an effective membrane distance of 9.5 cm, and a module exterior was fabricated that could separate the blood and dialysate sections using a T-type one-touch fitting.

[0069] 18 to 20 pieces of the first to sixth double-layer hollow fiber membranes manufactured in Examples <4-1> to <4-6> were cut to 250 mm so that the packing rate was about 10%. Both ends of the tubing were potted, dried for 12 hours, and then the epoxy injection section was cut off to fabricate a mini-module.

[0070] The number of times of use of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> and the effective surface area of ​​the prepared modules are shown in Table 1 below.

[0071] [Table 1]

number

[0072] Referring to Figure 4, the fabrication of the double-layer hollow fiber membrane mini-module involves the steps of selecting and cutting the hollow fiber membranes (Figure 4(a) to (d)); assembling the tubing profile and the hollow fiber membranes (Figure 4(e)); injecting epoxy into both ends of the assembled tubing profile and then drying it (Figure 4(f) to (g)); and cutting the dried epoxy (Figure 4(h)).

[0073] <Experimental Example 1> Structural analysis of double-layer hollow fiber membrane The first to sixth double-layer hollow fiber membranes prepared in Preparation Examples 4-1 to 4-6 were cut in half under a nitrogen solution and then coated with platinum (Pt) for 3 minutes. The cross sections (×200) and sides (×1,500) of the coated double-layer hollow fiber membranes, the cross sections (×10,000) and surfaces (×500) of the second layers of the double-layer hollow fiber membranes, and the cross sections and surfaces (×10,000 and ×100,000) of the first layers of the double-layer hollow fiber membranes were measured using a scanning electron microscope (SEM).

[0074] Referring to Figures 5 and 6, the cross section of the hollow fiber membrane manufactured by the hollow fiber membrane manufacturing method of the present invention was measured by SEM, and it was confirmed that a double-layer hollow fiber membrane composed of a first layer including first pores and a second layer including second pores could be manufactured.

[0075] Referring to Figure 6, the cross sections of the first and second layers of the double-layer hollow fiber membrane of the present invention were measured, and it was confirmed that there was a clear difference in pore size between the first and second pores, and that the pores were larger from the first pores toward the second pores.

[0076] It was also confirmed that the first and second pores were connected, and the second pores were open pores that allowed substances to pass through to the outside.It was also confirmed that there was a clear difference in pore size between the membrane surface of the second layer and the membrane surface of the first layer of the double-layer hollow fiber membrane.

[0077] <Experimental Example 2> Porosity test of double-layer hollow fiber membrane The first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> were dried in an oven at 50°C for one day and then cut into 10 cm bundles. The mass of each bundle was measured, and the weighed bundle was then immersed in isopropanol (IPA) for 24 hours.

[0078] After the loading, the bundle was taken out and the IPA on the surface and inside the hollows was removed, and the mass of the hollow fiber membrane bundle in a wet state with the IPA permeating the pores was measured to calculate the porosity.

[0079] The porosity was calculated using Equation 2.

number

[0080] Referring to Figure 7, the porosity of the double-layer hollow fiber membrane was measured by measuring the mass of the dry separation membrane; supporting the dry separation membrane in IPA; and measuring the mass of the supported, wet separation membrane.

[0081] The porosity of the double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> calculated by Equation 2 above is shown in Table 2 below.

[0082] [Table 2]

[0083] <Experimental Example 3> Pure water permeability test (PWP) measurement of double-layer hollow fiber membrane The pure water permeability of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> was confirmed using a filtration device.

[0084] Referring to FIG. 8(a), the filtration device capable of measuring the pure water permeability of the mini-module manufactured in <Preparation Example 5> includes a feed unit, a gear pump, a filtration unit, and a pressure gauge.

[0085] Four liters of ultrapure water (DI-water) was prepared in a feed section, and the feed section and the mini-module were connected so that the water could be circulated to the hollow fiber section of the mini-module.

[0086] Before the measurement, in order to stabilize the hollow fiber membrane of the mini-module, the transmembrane pressure (TMP) was adjusted to 0.9 bar ([(supply pressure (P feed-in ) + concentration pressure (P feed-out )) / 2]), the filtration section was closed and ultrapure water was circulated for 30 minutes to stabilize the hollow fiber membrane.

[0087] After stabilization, the filtration section capable of supplying to the second layer of the mini-module was left open in one direction and connected to a beaker capable of collecting the permeate solution. After this connection, the zero point of the pressure gauge was adjusted and the gear pump was adjusted so that the flow rate of ultrapure water was 50 ml / min to 80 ml / min. After that, the ultrapure water was purified for 40 minutes at transmembrane pressures of 0.3 bar, 0.6 bar, and 0.9 bar, and the amount of ultrapure water filtered was recorded at 1-minute intervals.

[0088] Referring to Figure 8(b), the water permeability can be calculated using the following mathematical formula 3. The water permeability was calculated using the average value measured after 10 minutes in a stabilized state.

number

[0089] The water permeabilities of the double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> calculated using Equation 3 are shown in Table 3 below.

[0090] [Table 3]

[0091] Referring to Figure 9, it was confirmed that the water permeability of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> increased as the contents of the pore-forming agents PVP and PEG contained in the first and second spinning solutions increased. However, it was confirmed that the content of PEG had a greater effect than that of PVP on the change in water permeability (Figure 9(b)). This confirmed that the contents of the pore-forming agents contained in the first and second spinning solutions were proportional to the water permeability, and the increase in water permeability varied depending on the respective pore-forming agents.

[0092] In addition, the water permeability of the first to sixth double-layer hollow fiber membranes manufactured in Manufacturing Examples <4-1> to <4-6> is 150 LMHbar, which can be used as a separation membrane for hemodialysis, hemofiltration, or hemodiafiltration. -1 ~300LMHbar -1 It was confirmed that the results were within the range.

[0093] <Experimental Example 4> Measurement of serum albumin loss rate of double-layer hollow fiber membrane The serum albumin (BSA) loss rate of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> was determined using a filtration device.

[0094] Referring to Figure 10(a), the serum albumin loss rate was determined using the same filtration device as in Experimental Example 3, except that 500 ml of a 1,000 ppm BSA solution was prepared in the feed instead of ultrapure water.

[0095] To stabilize the hollow fiber membrane of the mini-module, the transmembrane pressure (TMP) was adjusted to 0.9 bar ([(supply pressure (P feed-in ) + concentration pressure (P feed-out )) / 2]), the filtration section was closed and ultrapure water was circulated for 60 minutes to stabilize the hollow fiber membrane.

[0096] After stabilization, the filtration section, which could supply the second layer of the mini-module, was left open in one direction and connected to a beaker capable of collecting the permeate solution. After connection, the gear pump was adjusted so that the transmembrane pressure was 0.8 bar and the flow rate of the 1,000 ppm BSA solution was 50 ml / min to 80 ml / min. The solution filtered while the BSA solution was circulating was collected at 10-minute intervals for 30 minutes, with 10 ml to 15 ml collected at each time point in the supply and filtration sections.

[0097] Referring to Figure 10(b), the serum albumin loss rate was calculated using the following mathematical formula 4. The serum albumin loss rate can be calculated by reading the 280 nm wavelength absorbance after measuring the UV-vis spectrum and comparing it with a previously prepared calibration curve.

number

[0098] The serum albumin loss rates of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples <4-1> to <4-6> calculated using Equation 4 are shown in Table 4 below.

[0099] [Table 4]

[0100] 11(a) to (c), it was confirmed that the serum albumin loss rates of the first to sixth double-layer hollow fiber membranes prepared in Preparation Examples 4-1 to 4-6 were affected by the PVP in the first spinning solution and the PEG in the second spinning solution. Furthermore, in the case of the fifth double-layer hollow fiber membrane prepared using the first-third spinning solution, which contains a low PVP content, the solvent dissociated slowly in the first-third spinning solution, slowing the polymer solidification rate. This resulted in an increase in the second pore size of the second layer of the double-layer hollow fiber membrane, resulting in an increase in the serum albumin loss rate.

[0101] Also, referring to FIG. 11(b), it was confirmed that the serum albumin loss rate increased as the amount of PEG contained in the second spinning solution increased.

[0102] Also, referring to FIG. 11(c), it was confirmed that the loss rate varies greatly depending on the PVP contained in the first spinning solution.

[0103] It was also confirmed that the first and third double-layer hollow fiber membranes of Preparation Examples <4-1> and <4-3> had a serum albumin loss rate of 1% or less. The hollow fiber membranes of the other Preparation Examples had a serum albumin loss rate of more than 1%, and were therefore limited in their use.

[0104] <Experimental Example 5> Measurement of molecular weight cut-off (MWCO) of double-layer hollow fiber membrane The molecular weight cut-off (MWCO) of the first and third double-layer hollow fiber membranes prepared in Preparation Examples <4-1> and <4-3>, which have a serum albumin loss rate of 1% or less, was confirmed using a filtration device.

[0105] 12, the molecular weight cut-off (MWCO) was confirmed using the same filtration device as in Experimental Example 3, except that PEG (MW: 400 Da, 2 kDa, 10 kDa, 44 kDa, 70 kDa, 100 kDa) with a concentration of 200 ppm was prepared in the feed instead of ultrapure water. The MWCO was analyzed by measuring total organic carbon (TOC), so TOC calibration solutions with concentrations of 100 ppm, 80 ppm, 40 ppm, 20 ppm, and 10 ppm were prepared.

[0106] To stabilize the hollow fiber membrane of the mini-module, the transmembrane pressure (TMP) was adjusted to 0.9 bar ([(supply pressure (P feed-in ) + concentration pressure (P feed-out )) / 2]), the filtration section was closed and ultrapure water was circulated for 60 minutes to stabilize the hollow fiber membrane.

[0107] After stabilization, the filtration section capable of supplying the second layer of the mini-module was left open in one direction and connected to a beaker capable of collecting the permeate solution. After this connection, 500 ml of PEG (MW: 400 Da, 2 kDa, 10 kDa, 44 kDa, 70 kDa, 100 kDa) with a transmembrane pressure of 0.8 bar and a concentration of 200 ppm was prepared. The gear pump was adjusted to a flow rate of 50 ml / min to 80 ml / min and a TMP of 0.8 bar. After circulating the PEG for 15 minutes, the permeate solution and the feed solution were collected in 10 ml to 15 ml volumes, respectively, to terminate the circulation.

[0108] Before using PEG with different molecular weights, the filtration unit was closed, the supply line was connected in reverse, and the filtration unit was washed with ultrapure water at a flow rate of 80 ml / min to 160 ml / min under a TMP of 0.8 bar.

[0109] The concentration of the collected solution was calculated by TOC, and the calculated transmittance by molecular weight was calculated using the following mathematical formula 5.

number

[0110] The molecular weight cut-off of the first and third double-layer hollow fiber membranes prepared in Preparation Examples <4-1> and <4-3> calculated using Equation 5 is shown in Table 5 below. MWRO (molecular weight retention onset) in Table 5 below refers to the molecular weight of uremic toxins at which the sieving coefficient begins to decrease to 90% or less at the onset of molecular weight retention. MWCO (molecular weight cut-off) is the molecular weight cut-off.

[0111] [Table 5]

[0112] Referring to Figure 13(a), the MWRO and MWCO of the first and third double-layer hollow fiber membranes prepared in Preparation Examples <4-1> and <4-3> were examined. As a result, it was confirmed that the first and third double-layer hollow fiber membranes were able to remove medium- and large-molecular uremic toxins.

[0113] 13(b), it was confirmed that the average pore size of the first and third double-layer hollow fiber membranes prepared in Preparation Examples <4-1> and <4-3> was within the target range of 6 nm to 11 nm, and the standard deviation of the pore sizes was small. Furthermore, it was confirmed that the average pore size of the third double-layer hollow fiber membrane was larger than that of the first double-layer hollow fiber membrane, but the pores were more uniformly formed than in the first double-layer hollow fiber membrane, thereby reducing the albumin loss rate.

[0114] Therefore, it was confirmed that the average pore size, deviation, and pore uniformity of the hollow fiber membrane can be controlled by adjusting the contents of PVP in the first spinning solution and PEG in the second spinning solution, and that a hollow fiber membrane having a large average pore size, small deviation, and uniform pores can have a low serum albumin loss rate and improved removal properties for high molecular weight uremic toxins. Therefore, it was confirmed that the contents of PVP and PEG in the spinning solutions can be adjusted depending on the intended use of the hollow fiber membrane.

[0115] <Experimental Example 5> Measurement of hemodialysis performance of double-layer hollow fiber membrane The hemodialysis performance of the first double-layer hollow fiber membrane in Preparation Example <4-1> was confirmed using a filtration device including two linked pumps.

[0116] 14, artificial blood and dialysate were simultaneously supplied to the blood and dialysate sections of the mini-module fabricated with the first double-layer hollow fiber membrane using two interlocking pumps to confirm the hemodialysis performance by checking the removal rate of uremic toxins. The artificial blood was prepared by mixing 26 g / L BSA, 1 g / L urea, and 0.1 g / L creatinine in phosphate buffer saline (PBS).

[0117] To stabilize the hollow fiber membrane of the mini-module, the transmembrane pressure (TMP) was adjusted to 0.9 bar ([(supply pressure (P feed-in ) + concentration pressure (P feed-out )) / 2]), the filtration section was closed and ultrapure water was circulated for 60 minutes to stabilize the hollow fiber membrane.

[0118] After stabilization, artificial blood and dialysate were prepared in respective beakers, and the flow rate of the linked pump was adjusted so that the transmembrane pressure was 0 bar (TMP=[(P1+P2) / 2-(P3+P4) / 2]=0 bar).

[0119] Before the initial artificial blood flow, 6 ml of the solution was collected and passed through a UV-vis spectrum to measure the concentrations of BSA, urea, and creatinine. Six ml of the solution was collected from the blood and dialysate sections every hour for four hours to measure their concentrations. After the four-hour measurement, all of the solutions in the mini-module and hollow fiber membranes were collected in the blood and dialysate sections, and the final volume change was measured.

[0120] The amount of uremic toxins permeated was calculated using the measured volume according to the following mathematical formula 6:

number

[0121] The uremic toxin and creatinine removal rates of the first double-layer hollow fiber membrane prepared in Preparation Example <4-1> calculated by Equation 6 are shown in Table 6 below.

[0122] [Table 6]

[0123] Referring to FIG. 15, it was confirmed that the first double-layer hollow fiber membrane prepared in Preparation Example <4-1> maintained a low serum albumin loss rate while maintaining a high urea and creatinine removal rate.

[0124] In conclusion, the present invention has confirmed that a double-layer hollow fiber membrane comprising a first layer having hollow, first pores and a second layer having second pores can be manufactured by using a first spinning solution containing a polyvinyl-based resin and a polysulfone-based resin and a second spinning solution containing a glycol-based resin and a polysulfone-based resin.

[0125] It was confirmed by SEM that the first and second pores in the double-layer hollow fiber membrane were interconnected pores, with the pore size increasing from the first pore toward the second pore, and that the second pores were open pores that allowed substances to pass through to the outside.

[0126] The present invention also confirmed that a double-layer hollow fiber membrane having a desired pore size and water permeability can be manufactured by adjusting the content (wt%) of the polyvinyl resin contained in the first spinning solution and the content (wt%) of the glycol-based resin contained in the second spinning solution.The present invention also confirmed that the double-layer hollow fiber membrane manufactured using the first spinning solution and the second spinning solution has a low serum albumin loss rate and an excellent urea and creatinine removal rate, and can be used as a separation membrane for hemodialysis, hemofiltration, or hemodiafiltration.

Claims

1. A double-layer hollow fiber membrane that encloses the hollow space through which blood flows and transfers uremic toxins and waste products from the blood to the outside. The double-layer hollow fiber membrane is A double-layer hollow fiber membrane comprising: a first layer having first pores; and a second layer connected to the first layer and having second pores larger in size than the first pores.

2. 2. The double-layer hollow fiber membrane according to claim 1, wherein the first pores of the first layer and the second pores of the second layer are connected to each other.

3. The double-layer hollow fiber membrane according to claim 1 , wherein the second pores of the second layer are open pores connected to the outside.

4. 2. The double-layer hollow fiber membrane according to claim 1, wherein the pore size of the first pores in the first layer is 5 nm to 12 nm, and the pore size of the second pores in the second layer is 0.1 μm to 1.5 μm.

5. 10. The dual-layer hollow fiber membrane of claim 1, wherein the pores of the first layer and the pores of the second layer are formed by different water-soluble pore-former polymers.

6. The water-soluble pore-forming polymer may be one or more polyvinyl resins selected from the group consisting of polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc), polyvinyl alcohol (PVA), and polyethylene-co-vinylacetate (PEVA), and ethylene glycol (EG), diethylene glycol (DEG), triethylene glycol (TEG), propylene glycol (PG), and polyethylene glycol (PEVA). The double-layer hollow fiber membrane according to claim 5, wherein the resin is one or more glycol-based resins selected from the group consisting of glycol, PEG, and PEG.

7. The double layer hollow fiber membrane has a resistance of 150 LMHbar. －１ ~300LMHbar －１ 2. The double-layer hollow fiber membrane of claim 1, having a water permeability of

8. 2. The double-layer hollow fiber membrane according to claim 1, which is used as a separation membrane in hemodialysis, hemofiltration, or hemodiafiltration to filter uremic toxins and waste products from blood.

9. 9. The double-layer hollow fiber membrane of claim 8, wherein the uremic toxins and waste products in the blood are one or more uremic toxins or waste products selected from the group consisting of urea, uric acid, beta-2 microglobulin, lambda-free light chain, kappa-free light chain, creatinine, hippuric acid, indoxyl sulfate, p-cresol, oxalates, guanidine, phenol, and homocysteine.

10. preparing a first spinning solution by dissolving a first water-soluble pore-forming polymer and a polysulfone-based resin in a solvent; preparing a second spinning solution by dissolving a second water-soluble pore-forming polymer and a polysulfone-based resin in a solvent; supplying a bore solution, the first spinning solution, and the second spinning solution to a triple nozzle; The bore solution, the first spinning solution, and the second spinning solution are spun into a coagulation bath and wound up by a winder to form a hollow fiber membrane; gelling the wound hollow fiber membrane in a water bath and washing it in a washing bath containing 80 wt % to 100 wt % water and 0 wt % to 20 wt % glycerol; and A method for producing a double-layer hollow fiber membrane, comprising: drying the washed hollow fiber membrane in air at room temperature.

11. The bore solution is supplied to a first nozzle, which is the most central nozzle of the triple nozzle; The first spinning solution is supplied to a second nozzle provided on an outer circumferential surface of the first nozzle, The method for producing a double-layer hollow fiber membrane according to claim 10, wherein the second spinning solution is supplied to a third nozzle provided on an outer circumferential surface of the second nozzle.

12. 11. The method for producing a double-layer hollow fiber membrane according to claim 10, wherein the flow rate of the bore solution supplied to the nozzle is 0.3 ml / min to 1.0 ml / min, and the flow rates of the first spinning solution and the second spinning solution are 0.1 ml / min to 0.5 ml / min.

13. The method for producing a double-layer hollow fiber membrane according to claim 10, wherein the bore solution comprises at least one selected from the group consisting of water, glycerol, N-methyl-2-pyrrolidone, glycol-based resins, alcohol solvents, and ketone solvents.

14. the first water-soluble pore-forming polymer is one or more polyvinyl resins selected from the group consisting of polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, and polyethylene vinyl acetate copolymer; the second water-soluble pore-forming polymer is one or more glycol-based resins selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, and polyethylene glycol; The method for producing a double-layer hollow fiber membrane according to claim 10, wherein the polysulfone-based resin is one or more resins selected from the group consisting of polyethersulfone, polysulfone, and polyphenylenesulfone.

15. 11. The method for producing a double-layer hollow fiber membrane according to claim 10, wherein the first spinning solution comprises 1 wt % to 20 wt % of a first water-soluble pore-former polymer, 10 wt % to 20 wt % of a polysulfone-based resin, and 65 wt % to 85 wt % of N-methyl-2-pyrrolidone.

16. 11. The method for producing a double-layer hollow fiber membrane according to claim 10, wherein the second spinning solution comprises 5 wt % to 30 wt % of a second water-soluble pore-former polymer, 10 wt % to 20 wt % of a polysulfone-based resin, and 50 wt % to 80 wt % of N-methyl-2-pyrrolidone.

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