WO2025101552A1 - Dialyseurs utilisant des membranes à fibres creuses de petit diamètre - Google Patents

Dialyseurs utilisant des membranes à fibres creuses de petit diamètre Download PDF

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Publication number
WO2025101552A1
WO2025101552A1 PCT/US2024/054640 US2024054640W WO2025101552A1 WO 2025101552 A1 WO2025101552 A1 WO 2025101552A1 US 2024054640 W US2024054640 W US 2024054640W WO 2025101552 A1 WO2025101552 A1 WO 2025101552A1
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Prior art keywords
dialyzer
membrane
hollow fiber
fiber membrane
blood
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English (en)
Inventor
Rajesh SAHADEVAN
Jiunn TEO
Brodie SCHWINN
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Fresenius Medical Care Holdings Inc
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Fresenius Medical Care Holdings Inc
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Publication of WO2025101552A1 publication Critical patent/WO2025101552A1/fr
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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1621—Constructional aspects thereof
    • A61M1/1623—Disposition or location of membranes relative to fluids
    • A61M1/1627—Dialyser of the inside perfusion type, i.e. blood flow inside hollow membrane fibres or tubes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/08—Hollow fibre membranes
    • B01D69/081—Hollow fibre membranes characterised by the fibre diameter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
    • B01D71/68—Polysulfones; Polyethersulfones
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2313/00—Details relating to membrane modules or apparatus
    • B01D2313/20—Specific housing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2325/00—Details relating to properties of membranes
    • B01D2325/20—Specific permeability or cut-off range
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/24—Dialysis ; Membrane extraction
    • B01D61/243—Dialysis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/44—Polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds, not provided for in a single one of groups B01D71/26-B01D71/42
    • B01D71/441—Polyvinylpyrrolidone

Definitions

  • Hollow fiber membranes are formed into bundles within filter modules and used for the extracorporeal treatment of blood. Filter modules of this type for hemopurification, so-called hemodialyzers, are produced on a mass scale.
  • Conventional hollow fiber membranes for use in hemopurification generally have an inner diameter (ID) between 180 microns (i.e., micrometers or ⁇ m) and 250 microns and wall thicknesses between 30 microns and 50 microns to maintain structural integrity of the membrane and allow intralumenal blood passage without undesired shearing, fouling, and associated hemocompatability issues.
  • ID inner diameter
  • WO2018/167280 describes a hollow fiber membrane dialyzer having undulating fibers with a wall thickness of 20 ⁇ m to 30 ⁇ m, ID of 160 um to 230 um, and a reduced fiber wavelength of 1 mm to 4 mm to improve thermal stability during manufacturing.
  • WO2012/51595 describes cytopheretic cartridges incorporating hollow fiber membrane bundles for therapeutic sequestration of activated leukocytes from blood.
  • the fibers have a theoretical ID of 50 ⁇ m to 240 ⁇ m with a wall thickness of about 40 ⁇ m.
  • Blood passes through filter modules preferably on the outside of the hollow fiber membranes at a low flow rate to reduce shear forces and promote sequestration onto the membrane.
  • WO2008/046779 describes a hollow fiber membrane for use in hemodialysis having a theoretical ID of 50 ⁇ m to 2000 ⁇ m and wall thickness of 10 ⁇ m to 200 ⁇ m.
  • the membrane has four to five distinct layers, including a selective layer with the lowest pore size on its outer surface, and a supportive layer in the middle of the membrane wall that is denser and has a lower pore size than the two adjacent layers.
  • a feature of the present invention is to provide a hollow fiber membrane that has a narrow inner diameter (ID) for the lumenal compartment.
  • ID narrow inner diameter
  • a further feature of the present invention is to provide a hollow fiber membrane that has a narrow inner diameter for the lumenal compartment in combination with a narrow wall thickness.
  • An additional feature of the present invention is to provide hollow fibers which can at least partially remove larger uremic solutes from a patient's fluids, such as blood.
  • a further feature of the present invention is to provide a hollow fiber membrane with a high surface area relative to the weight of the fiber.
  • the present invention relates to a Attorney Docket No: 3192-111-01 PCT porous hollow fiber membrane.
  • the porous hollow fiber membrane includes a lumenal compartment, an inner surface adjacent to the lumenal compartment, and an outer surface.
  • the porous hollow fiber membrane has a wall that is defined from the inner surface to the outer surface and has a wall thickness of from about 10 ⁇ m (micrometers) to about 30 ⁇ m.
  • the lumenal compartment has an inner diameter (ID) of from about 90 ⁇ m to about 160 ⁇ m.
  • An active surface or selective surface is further present at the inner surface of the porous hollow fiber membrane and a non-active region or support region is further present and adjacent to the active surface.
  • the membrane wall may have a generally asymmetric architecture when its porous structure is viewed microscopically or otherwise analyzed for density.
  • the porous hollow fiber membrane has a porosity such that the porosity of the membrane generally increases from the active surface (inner surface) across the wall thickness and to the outer surface.
  • the present invention also relates to porous hollow fiber membranes where the porous hollow fiber membrane includes a lumenal compartment, an inner surface adjacent to the lumenal compartment, and an outer surface.
  • the porous hollow fiber membrane has a wall that is defined from the inner surface to the outer surface and has a wall thickness of from about 10 ⁇ m (micrometers) to about 30 ⁇ m.
  • the lumenal compartment has an inner diameter (ID) of from about 90 ⁇ m to about 160 ⁇ m.
  • An active surface or selective surface is further present at the inner surface, or the outer surface, or both the inner surface and the outer surface of the porous hollow fiber membrane, and a non-active region or support region is further present and adjacent to the active surface(s).
  • the porous hollow fiber membrane has a mass density through the wall thickness, such that the mass density from the inner surface to the outer surface is a gradient of increasing or decreasing mass density.
  • the present invention also relates to a porous hollow fiber membrane having a lumenal compartment and prepared from a solution comprising at least one membrane forming polymer and at least one solvent.
  • the solution can include at least one hydrophobic polymer such as Attorney Docket No: 3192-111-01 PCT polysulfone (PSF), polyethersulfone (PES), polyarylsulfone (PAS), and/or polyarylethersulfone (PAES), at least one hydrophilic polymer, and at least one solvent.
  • the solution can alternatively include one or more polymethyl methacrylate polymers (PMMA), cellulose triacetate (CTA), polyvinylidene fluoride (PVDF), and/or polyacrylonitrile (PAN), or any copolymer thereof, and at least one solvent, and may exclude a hydrophilic polymer.
  • PMMA polymethyl methacrylate polymers
  • CTA cellulose triacetate
  • PVDF polyvinylidene fluoride
  • PAN polyacrylonitrile
  • the porous hollow fiber membrane has a wall thickness of from about 10 ⁇ m to about 30 ⁇ m.
  • the lumenal compartment has an inner diameter (ID) of from about 90 ⁇ m to about 160 ⁇ m.
  • ID inner diameter
  • the porous hollow fiber membrane has a mass density throughout the wall thickness, such that the mass density from the inner surface to the outer surface is a gradient of increasing or decreasing mass density.
  • the present invention further relates to a porous hollow fiber membrane for use in extracorporeal blood therapy.
  • the porous hollow fiber membrane includes a lumenal compartment, an inner surface adjacent to the lumenal compartment, and an outer surface.
  • the porous hollow fiber membrane has a wall that is defined from the inner surface to the outer surface and has a wall thickness of from about 20 ⁇ m to about 26 ⁇ m.
  • the lumenal compartment has an inner diameter (ID) of from about 110 ⁇ m to about 140 ⁇ m.
  • ID inner diameter
  • An active surface is further present at the inner surface of the porous hollow fiber membrane and a non-active region or support region is further present and adjacent to the active surface.
  • the present invention further relates to a process for dialysis, blood oxygenation, or blood separation comprising contacting blood with the porous membrane of the present invention.
  • dialysis can refer to any of the primary and secondary types of dialysis, which can include, e.g., hemodialysis, hemofiltration and/or hemodiafiltration.
  • dialysis can refer to any of the primary and secondary types of dialysis, which can include, e.g., hemodialysis, hemofiltration and/or hemodiafiltration.
  • FIG.6B is a graph that plots B12 Clearance versus Membrane Area for three hollow fiber membranes of the present invention and conventional fiber membrane (F160NRe).
  • FIG. 7 is a table that sets forth hollow fiber membrane samples with Raw Aqueous KUF, Lab. Aqueous KUF, B2M Clearance, and Albumin Sieving coefficient data.
  • FIG.8A is graph that plots Albumin Sieving coefficient numbers versus Raw Aqueous KUF for two hollow fiber membranes of the present invention and a conventional fiber membrane (F160NRe).
  • FIG.8B is a graph that plots Albumin Sieving coefficient versus Membrane Area for three hollow fiber membranes of the present invention and a conventional fiber membrane (F160NRe).
  • FIGS.11A-D is a collection of four graphs that plot Time versus a) platelet reduction (FIG.11A), b) TAT (FIG.11B), c) PF-4 (FIG.11C), and d) sC5b-9 (FIG.11D) for a hollow fiber membrane of the present invention and a conventional fiber membrane.
  • Attorney Docket No: 3192-111-01 PCT [0039]
  • FIG.12 is a collection of four graphs that plot plasma free hemoglobin versus time in one graph and provides bar graphs providing normalized HI, modified index of hemolysis, or hemolysis index for a hollow fiber membrane of the present invention and a conventional fiber membrane (F160NRe).
  • the hollow fiber membrane has a lumenal compartment and an inner surface adjacent to the lumenal compartment.
  • the hollow fiber membrane also has an outer surface.
  • the hollow fiber membrane has a unique combination of physical parameters with respect to an inner diameter of the lumen and wall thickness. More specifically, the inner diameter and the wall thickness are narrow or thin (and thus the overall diameter or outer diameter of the membrane is narrow as well).
  • the inventive hollow fiber membrane may be referred to herein as “Skinny Fibers” for this reason.
  • the hollow fiber membrane is essentially a hollow circular or cylindrical object.
  • the outer diameter is a measurement of the distance of a straight line from one point on the outer wall of the object or membrane, through its center, to an opposite point on the outer wall of the membrane (perpendicular to the cylindrical axis of the lumen).
  • the outer diameter is the longest dimension or longest chord that exists for this measurement.
  • the outer diameter can be an average outer diameter based on taking multiple measurements of the outer diameter at multiple locations of the membrane. For instance, the average outer diameter can be based on 5 measured outer diameters at five different locations of the membrane.
  • the wall thickness of the hollow fiber membrane can be from about 10 ⁇ m to about 30 ⁇ m.
  • the wall thickness can be from 10 ⁇ m to 30 ⁇ m, or from 10 ⁇ m to 25 ⁇ m, or from 20 ⁇ m to 26 ⁇ m, or from 10 ⁇ m to 20 ⁇ m, or from 10 ⁇ m to 15 ⁇ m, or from 15 ⁇ m to 30 ⁇ m, or from 20 ⁇ m to 30 ⁇ m, or from 25 ⁇ m to 30 ⁇ m, or any range based upon any two values described herein.
  • Prior efforts with hollow fiber membrane production have suggested a lower limit to ID and/or wall thickness because of concerns, in part, with fiber collapse and/or manufacturing challenges when handling thin fibers.
  • the hollow fiber membrane and dialyzer of the present invention has a surprisingly high urea and/or sodium mass transfer coefficient per m 2 of membrane surface area (KoA) when compared to conventional high flux dialyzers.
  • KoA sodium mass transfer coefficient per m 2 of membrane surface area
  • An advantage of the disclosed hollow fiber membrane is that the weight of fiber needed to achieve one m 2 of membrane surface area in a bundle is significantly lower than that required for hollow fiber membranes of conventional dimensions.
  • the porous hollow fiber membrane can be characterized by a fiber weight.
  • Conventional hollow fiber membranes for uses such as blood dialysis may have fiber weights of 16 grams or more per m 2 of membrane surface area.
  • the membrane of the present invention can have a weight of fiber per m 2 membrane area of less than 16 g, less than 15 g, less than 14 g, less than 13 g, less than 12 g, less than 11 g, less than 10 g, or from 10 to 15.9 g, or from 10 to 15.5 g, or from 10 to 14.5 g, or from 10 g to 15 g, or from 11 g to 13 g per m 2 of membrane.
  • the porous hollow fiber membrane can be characterized by a non-active region and one or more active surfaces. As an option, the non-active region of the membrane can be considered a support layer or support region.
  • the active surface can be considered a Attorney Docket No: 3192-111-01 PCT treated surface or a selective surface or selective layer.
  • the active surface of the membrane can be located at only the inner surface of the membrane or only at the outer surface of the membrane, or at both the inner surface and outer surface of the membrane.
  • an active surface or “selective surface” or “selective layer” generally refers to the surface that comes into direct contact with the precipitation fluid during the membrane fabrication step.
  • the active surface can comprise the surface region of the membrane.
  • the non-active region is defined as the region of the membrane that does not come in direct contact with the precipitation fluid during the membrane fabrication step.
  • the non-active region(s) can be exposed to the precipitation fluid at some stage of the fabrication wherein the make-up of the precipitation fluid may change (e.g., higher content of water).
  • the non-active region of the membrane can be the non-active surface or the core of the membrane (i.e., within the wall) or both.
  • the term “core” or “core region” can refer to an inner geometrical center of the membrane body.
  • the active surface or selective surface can be characterized as the surface with the smallest pores (e.g., smallest average pore size) and/or as a surface that is capable of discriminating larger particles and proteins preferably retained in blood (e.g., molecules of molecular weight of 60 kDa or higher, or 65 kDa or higher, or 66 kDa or higher, or 67 kDa or higher) from smaller components including water (e.g., molecules of molecular weight of below 60 kDa, or below 65 kDa, or below 66 kDa, or below 67 kDa) preferably to be removed from blood.
  • smallest pores e.g., smallest average pore size
  • a surface that is capable of discriminating larger particles and proteins preferably retained in blood e.g., molecules of molecular weight of 60 kDa or higher, or 65 kDa or higher, or 66 kDa or higher, or 67 kDa or higher
  • water e.
  • the active surface or selective surface can be characterized as the surface that is directly exposed to blood.
  • the active surface can be characterized by a lower porosity or a lower pore density compared to the non-active region or support region.
  • the porosity and/or pore density (e.g., Attorney Docket No: 3192-111-01 PCT the number of pores per area) at the active surface can be at least 10% lower, at least 20% lower, at least 30% lower, at least 40% lower, or at least 50% lower in porosity (e.g., average porosity) and/or pore density than the highest porosity found elsewhere in the membrane (i.e., the non-active region).
  • One problem that can be encountered with thin-walled hollow fiber membranes is poor structural integrity, leading to collapsed fibers, flats, agglutinations, or similar issues. Utilizing the disclosed methods, however, the inventors have been able to overcome this limitation.
  • the disclosed hollow fiber membrane may not require a distinct denser region in the membrane wall to provide structural integrity, despite the fibers’ narrow or thin ID and wall thickness.
  • the disclosed hollow fiber membrane can be manufactured at relatively low cost using the methods disclosed while retaining the benefits outlined herein.
  • the degree of porosity (e.g., pore density) of the membrane can increase from the active surface or selective surface across the wall thickness and to the surface opposite of the active surface (i.e., a) the surface opposite being the outer surface when the active surface is located at the inner surface of the membrane or b) the surface opposite of the active surface can be the inner surface when the active surface is located at the outer surface).
  • This increase in porosity can be a gradient of increasing porosity (e.g., increasing pore density). This gradient can be linear or non-linear (e.g., exponential and sigmoidal). This feature of “increasing porosity” as described herein and in general, porosity, can be shown, and is preferably shown, using the procedure identified as Measurement Method 2 in the Example section herein. [0060] If the active surface, as an option, is present both at the inner surface and outer surface, then this increase in porosity excludes one of the inner surface or outer surface and the region adjacent to this surface.
  • a Attorney Docket No: 3192-111-01 PCT measurement of porosity starting from immediately adjacent to the inner surface and extending toward the outer surface may show an increasing porosity progressing toward the outer surface until the region adjacent the outer surface is reached or the outer surface itself is reached (i.e., disregarding the thin region of the membrane comprising the outer surface itself).
  • the active surface can be characterized by a higher mass density compared to the non-active region or support region.
  • the mass density at the active surface can be at least 10% higher, at least 20% higher, at least 30% higher, at least 40% higher, at least 50% higher, or greater than 50% higher in mass density (e.g., average mass density) than the lowest mass density found elsewhere in the membrane (i.e., the non-active region).
  • the mass density of the membrane can decrease from the active surface or selective surface across the wall thickness and to the surface opposite of the active surface (i.e., a) the surface opposite being the outer surface when the active surface is located at the inner surface of the membrane or b) the surface opposite of the active surface can be the inner surface when the active surface is located at the outer surface). This decrease in mass density can be a gradient of decreasing mass density.
  • This gradient can be linear or non-linear (e.g., exponential and sigmoidal).
  • the gradient for either the porosity and/or mass density described herein can be based on three measurements at three different locations through the wall thickness along the same chord (e.g., at the exposed active surface, at a depth of 1/3 of the wall thickness, and at a depth of 2/3 of the wall thickness as measured from the exposed active surface).
  • the gradient can alternatively be based on at least four measurements at four (or more) different locations through the wall thickness along the same chord (e.g., at the exposed active surface, at a depth of 1 ⁇ 4 of the wall thickness, at a depth of 1 ⁇ 2 of the wall thickness, and at a depth of 3 ⁇ 4 of the wall thickness, as measured from the exposed active surface).
  • the porosity at a depth of 1/3 from the inner surface and from the outer surface is always higher than the porosity right at the inner surface and right at the outer surface, and the porosity at a depth of 2/3 from the inner surface is about the same as the porosity at a depth of 1/3 from the inner surface.
  • the porosity at a depth of 1 ⁇ 2 or about 1 ⁇ 2 would be the region where the porosity would be the highest in this specific embodiment with two active surfaces.
  • the membrane may be generally more symmetrical in its architecture.
  • the membrane porosity can be described as generally trending from dense on its inner surface to increasing porosity (lower mass density) proceeding across the wall of the membrane towards the center of the wall and then generally trending to more dense (less porous) proceeding from the center of the wall to the outer surface.
  • This architecture is associated with precipitation occurring significantly from both the inner surface and outer surface of the forming membrane, as described herein.
  • the membrane architecture can alternatively be characterized by a term dP/dW, Attorney Docket No: 3192-111-01 PCT where P is the porosity and W is the wall thickness.
  • dP/dW describes the rate of porosity change with respect to location.
  • the absolute value of dP/dW may be used and/or dP/dW may be calculated over only a specific portion of the membrane wall, such as from one surface to a point nearest the midpoint of the membrane, or from one surface to a point 1/3 (or a point 1 ⁇ 4) of the way towards the opposite surface, particularly in the case where both the inner surface and outer surface are selective surfaces.
  • dP/dW as measured from the inner surface to an area generally near the midpoint of the membrane wall (i.e., where the porosity may start to decrease again) would be expected to have a positive rate/slope
  • dP/dW as measured from the area near the midpoint to the outer surface would have a negative rate/slope.
  • the inflection point or region near the midpoint of the membrane wall where porosity changes from progressively increasing to progressively decreasing may be at a measured midpoint half way across the membrane wall or may be slightly shifted to one surface or the other depending on precipitation conditions reflective of the specific environment each surface experiences during membrane formation.
  • the disclosed thin-walled hollow fiber membrane or a portion reflecting about 1 ⁇ 4, 1 ⁇ 2, or 1/3 of the width of the membrane wall has a dP/dW that is significantly higher than conventional membranes, reflecting a membrane with a rapid or sharp porosity gradient relative to the thickness of the membrane.
  • dP/dW may have a generally positive rate/slope from the active surface and toward the other surface.
  • the porosity of a membrane may also be described as the pore volume ratio of a membrane material. With hollow fiber membranes, only the ratio of pore volume on the membrane wall is hereby considered.
  • the central wall region (that is, the wall region that is located in the middle of the outer surface and inner surface, such as a region from a depth of 1/3 to 2/3 from the inner surface or outer surface) has a mass density that is always lower than the exposed active surface and/or always lower than the mass density at a depth that is 1 ⁇ 4 from the exposed active surface.
  • an advantage or attractive feature of the present invention is the ability to avoid a denser region or less porous region in the central wall region (e.g., the area that is 1 ⁇ 2 between the outer surface and inner surface and approximately the area within 10% or within 20% of that 1 ⁇ 2 point) and yet achieve a thin wall and narrow inner diameter without the membrane collapsing or flattening. Thus, physical or structural stability of the membrane is achieved with this unique design of the present invention.
  • the active surface or selective surface can have a surface thickness (or depth from the exposed surface) of about 2 ⁇ m or less or about 1 ⁇ m or less, such as 1 ⁇ m or less or 0.9 ⁇ m or less, or 0.8 ⁇ m or less, or 0.7 ⁇ m or less, or 0.6 ⁇ m or less, or 0.5 ⁇ m or less, or 0.4 ⁇ m or less, or 0.3 ⁇ m or less, or 0.3 ⁇ m or less, or 0.2 ⁇ m or less, 0.1 ⁇ m or less or from 0.01 ⁇ m to 1 ⁇ m or from 0.05 ⁇ m to 1 ⁇ m, or from 0.1 ⁇ m to 1 ⁇ m, or from 0.15 ⁇ m to 1 ⁇ m, or from 0.2 ⁇ m to 1 ⁇ m, or from 0.25 ⁇ m to 1 ⁇ m
  • the wall of the membrane can be characterized as optionally having a spongy morphology.
  • the wall of the membrane can be characterized as optionally having a macrovoid morphology.
  • the hollow fiber membrane can have no or substantially no macrovoids or dendritic cavities. Dendritic cavities are understood as macrovoids having finger-like elongations. Macrovoids are described in the cited literature (“Mulder”). Examples of the formation of dendritic cavities can additionally be found in WO2004/056460 A1 Fig.1, WO2013/034611 A1 Fig. 1, 2 and 3 or WO2015/056460 A1 Fig. 5. Membranes without dendritic cavities or macrovoids can exhibit higher mechanical stability.
  • the active surface of the membrane can have a composition which contains a higher volumetric concentration of an additive that was present in either the spin mass or the bore fluid (precipitation fluid) or both as compared to the non-active region or support region.
  • the active surface of the membrane can contain a concentration of the additive which is at least about 5 vol% higher, or at least about 10 vol.% higher, or at least about 20 vol% higher, or at least about 30 vol% higher, or at least about 40 vol% higher, or at least about 50 vol% higher, or at least about 60 vol% higher, or at least about 70 vol% higher, or at least about 80 vol% higher, or at least about 90 vol% higher, or from about 10 vol% higher to all the additive content, or from 15 vol% to about 99 vol% higher, or from about 20 vol% to about 80 vol% higher, or other higher concentrations, or any range based upon any Attorney Docket No: 3192-111-01 PCT two values described herein, compared to the composition of the non-active region of the membrane or non-active surface, or both.
  • a concentration of the additive which is at least about 5 vol% higher, or at least about 10 vol.% higher, or at least about 20 vol% higher, or at least about 30 vol% higher, or at least about 40 vol% higher,
  • At least about 10 wt.%, or at least about 20 wt%, or at least about 30 wt%, or at least about 40 wt%, or at least about 50 wt%, or at least about 60 wt%, or at least about 70 wt%, or at least about 80 wt%, or at least about 90 wt%, or from about 10 wt% to about 99 wt%, or from 15 wt% to about 90 wt%, or from about 20 wt% to about 80 wt%, or from about 30 wt% to about 70 wt%, or from about 50 wt% to 99 wt%, or from about 75 wt% to 99 wt%, or from about 85 wt% to 99 wt%, or from about 95 wt% to 99 wt% or other percentage amounts, or any range based upon any two values described herein, of all the additive in the membrane can
  • the additive or an additional additive can be or include a water- insoluble antioxidant, such as a fat-soluble vitamin (e.g., Vitamin E).
  • a fat-soluble vitamin e.g., Vitamin E
  • This type of additive can be present in the spin mass and/or the precipitating fluid (bore fluid). Amounts can be, for instance, at least about 0.001 wt% based on the weight of the spin mass or precipitating fluid (e.g., from about 0.001 wt% to 0.05 wt%).
  • the active surface can have a higher gravimetric density compared to the density of the non-active region or a non-active surface, or both, such as at least about 5% higher, or at least about 10% higher, or at least about 20% higher, or at least about 25% higher, from 5% to 50% higher or other values.
  • an example of such an additive is at least one hydrophilic polymer, such as polyvinylpyrrolidone (PVP).
  • the PVP can be one type of PVP or more than one type of PVP, such as two different types of PVPs or three different types of PVPs.
  • the PVP can be a PVP having a K1 to K90 value.
  • the PVP can be a K30, or can be K90, or can be a K45-55 or any two or all three of these.
  • the K value is a term understood in the art.
  • the additive can be present in the membrane in an amount of at least about 0.1 wt.%, or at least about 0.25 wt%, or at least about 0.5 wt%, or at least about 0.75 wt%, or at least about 1 wt%, or at least about 1.25 wt%, or at least about 1.50 wt%, or at least about 2 wt%, or at least about 2.5 wt%, or at least about 3 wt% or 4 wt% or 5 wt% or 6 wt% or 7 wt% or 8 wt% or 9 wt%, or from about 0.1 wt% to about 10 wt%, or from 0.25 wt% to about 10 wt%, or from about 0.5 wt% to about 8 wt%, or from about 0.75 wt% to about 7 wt%, or from about 1 wt% to about 6 wt%, or
  • the precipitation fluid itself is not formulated to be formable into a self-supporting membrane structure, whereas the polymer dope solution or spin mass is membrane-formable, i.e., the polymer dope solution is formable into polymeric matrix defining a self-supporting membrane structure.
  • the spin mass or polymer dope solution can comprise a mixture of at least one polymer (e.g., at least one membrane-forming polymer) and at least one organic solvent that can dissolve the polymer.
  • the mixture of polymer and organic solvent as a preferred option, can be a homogenous mixture.
  • the membrane-forming polymer in an option, is a hydrophobic polymer.
  • the membrane-forming polymer can be, as an option, at least one of polysulfone (PSF), polyethersulfone (PES), polyarylsulfone (PAS), polyarylethersulfone (PAES), polyvinylidene Attorney Docket No: 3192-111-01 PCT fluoride (PVDF), polyacrylonitrile (PAN), or any copolymer thereof.
  • the membrane-forming polymer such as when commercially obtained, may be pre-combined with smaller amounts of other co-additives which can be tolerated in the membrane compositions of the present invention.
  • the membrane-forming polymer can be one or more polymethyl methacrylate polymers (PMMA), cellulose triacetate, or polyacrylonitrile.
  • the organic solvent used to dissolve the membrane-forming polymer can be, as an option, at least one of dimethylacetamide (DMAC), dimethylformamide (DMF), tetrahydrofuran (THF), N-methylpyrrolidone (NMP), N-ethyl-2-pyrrolidone (NEP), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), N-ethylpyrrolidone (NEP), N-octylpyrrolidone, dimethylformamide (DMF), or butyrolactone.
  • DMAC dimethylacetamide
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • NMP N-methylpyrrolidone
  • NEP N-ethyl-2-pyrrolidone
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • NEP N-ethylpyrrolidone
  • the organic solvent can dissolve the membrane-forming polymer(s), e.g., by a wet phase inversion process.
  • the polymer dope solution can further comprise at least one hydrophilic polymer, such as polyvinylpyrrolidone (PVP) (e.g., as described herein) or polyethylene glycol (PEG), or other hydrophilic polymers. If included, the amount of any hydrophilic polymer included in the polymer dope solution can be limited to amounts that do not cause a leaching problem (e.g., an amount below 10 wt% or below 5 wt% or below 1 wt% based on the total weight of the polymer dope solution).
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • the polymer dope solution can have limited or no water content. Premature coagulation of the polymer dope solution is undesirable to an extent that it would interfere with the ability of the polymer dope solution to extrude or cast or otherwise shape the polymer dope solution into a desired form of the membrane for contact with the precipitation fluid and/or to interact in the desired manner with the precipitation fluid.
  • Water content of the polymer dope solution can be, as an option, less than about 7 wt% water, e.g., 0-6.9 wt% water, or 0-6 wt% Attorney Docket No: 3192-111-01 PCT water, or 0-5 wt% water, or 0-4 wt% water, or 0-3 wt% water, or 0-2 wt% water, or 0-1 wt% water, or other amounts, based on total weight of the polymer dope solution.
  • the polymer dope solution can have a composition, as an option, of from about 12 wt% to about 30 wt% membrane-forming polymer, from about 88 wt% to about 63 wt% organic solvent (e.g., polar aprotic solvent), and less than or about 7 wt% water, based on total weight of the polymer dope solution.
  • the polymer dope solution can have a composition of from about 13 wt% to about 19 wt% polymer, from about 87 wt% to about 75 wt% polar aprotic solvent, and less than about 6 wt% water, based on total weight of the polymer dope solution.
  • compositions of the polymer dope solution which include these components may be used.
  • the resulting combination of components in the polymer dope solution can be mixed, filtered, and spun into hollow fibers with contact made with the precipitation fluid and further processed to form a porous hollow fiber membrane.
  • One or both of the surfaces of the hollow fiber membrane i.e., the outer surface and/or the inner surface
  • a surface roughness as measured by atomic force microscope, for example.
  • the surface roughness of the active surface can be lower than the surface roughness of the other surface.
  • the surface roughness of the active surface can be 10 nm or lower, such as 9 nm or lower, or 7 nm or lower, or 5 nm or lower, or from 1 nm to 10 nm or from 1 nm to 7 nm, or from 1 nm to 5 nm, or from 1 nm to 3 nm.
  • the ratio between the surface roughness of the other surface (non-active surface) and the active surface can be at least 20, such as from 20 to 40 or from 21 to 40, or from 25 to 40, or from 30 to 40.
  • the active surface may be the inner surface and the other surface may be the outer surface.
  • Atomic Force Microscope can be used to measure the surface roughness of the Attorney Docket No: 3192-111-01 PCT active surface of fiber membranes (AFM, Bruker Dimension Icon).
  • AFM Bruker Dimension Icon
  • the fiber membranes were glued on to a glass substrate and cut open using a razor blade in axial direction in case if the inner surface is the active surface.
  • the membrane surfaces were imaged at a scan size of 1 ⁇ m x 1 ⁇ m in tapping mode and surface roughness parameter Ra and Rq were then calculated.
  • the surface roughness parameters of the non-active surface of the fiber membranes were evaluated using a profilometer (LEXTTM OLS51003D Laser Scanning Microscope).
  • the hollow fiber membrane can be characterized by a contact angle by using water, when wetting the at least one surface of the hollow fiber membrane (e.g., the active surface or the inner surface).
  • the active surface of the membrane can have a contact angle of less than 57°, in particular less than 55°, more particularly less than 47°, the lower limit for the contact angle typically being less than 30°, preferably less than 25°, more preferably less than 20°.
  • the contact angle is determined according to the method "Determining Contact Angle ⁇ " as described in the present application.
  • the hydrophilic surface is to be understood as that surface of the hollow fiber membrane having higher hydrophilicity or, respectively, forming the smaller contact angle with the water relative to the other surface of the membrane.
  • the hydrophilic surface is formed in the lumen of the hollow fiber membrane.
  • the membranes of the present invention can decrease membrane resistance by at least 20%, at least 30%, at least 40%, or at least 50%, compared to commercially available membranes, such as, but not limited to, Optiflux 160 (Fresenius Medical Care, Waltham, MA), e.g., Optiflux 160NRe.
  • the hollow fiber membrane of the present invention may reduce membrane resistance by 50% or more and overall transport resistance by up to 30%.
  • the membrane resistance (membrane thickness) is based or derived from the thickness of the membrane and therefore reducing the wall thickness in the fiber, as in the present invention, reduces the resistance by the Attorney Docket No: 3192-111-01 PCT same percentage.
  • the membranes of the present invention when operating in a high flux hemodialysis dialyzer housing may be associated with an internal blood compartment filter pressure drop ( ⁇ P) that is at least two times greater than commercially available membranes (e.g., at least three times greater or at least four times greater or at least five time greater), when measured at a blood flow rate of 300 ml/min (e.g., Optiflux 160).
  • ⁇ P internal blood compartment filter pressure drop
  • the transmembrane pressure drop from one end of the dialyzer to the other end of the dialyzer is about 50 mm Hg to about 1000 mmHg at a blood flow rate of 100 to 600 mL/min.
  • the hollow fiber membrane of the present invention can be optionally characterized by its ultrafiltration coefficient (K UF ) or hydraulic permeability (K UF per unit area).
  • K UF is defined as the number of milliliters of fluid per hour that will be transferred across the membrane per mm Hg pressure gradient across the membrane.
  • Hollow fiber membranes produced according to the invention can have a hydraulic permeability, for example, of from at least 50 ml/hr ⁇ mm Hg ⁇ m 2 or higher, such as from about 50 to about 750 ml/hr ⁇ mm Hg ⁇ m 2 , from about 75 to about 500 ml/hr ⁇ mm Hg ⁇ m 2, from about 100 to about 500 ml/hr ⁇ mm Hg ⁇ m 2 , from about 100 to about 400 ml/hr ⁇ mm Hg ⁇ m 2 , or from about 150 to about 250 ml/hr ⁇ mm Hg ⁇ m 2 , or other values.
  • a hydraulic permeability for example, of from at least 50 ml/hr ⁇ mm Hg ⁇ m 2 or higher, such as from about 50 to about 750 ml/hr ⁇ mm Hg ⁇ m 2 , from about 75 to about 500 ml/hr ⁇ mm Hg ⁇ m 2, from about 100 to about 500 ml/hr ⁇ mm Hg ⁇ m 2 , from about 100 to about
  • the hydraulic permeability can be at least 150 ml/hr ⁇ mm Hg ⁇ m 2 , or at least 170 ml/hr ⁇ mm Hg ⁇ m 2 , or at least 200 ml/hr ⁇ mm Hg ⁇ m 2 , such as from 150 ml/hr ⁇ mm Hg ⁇ m 2 to 300 ml/hr ⁇ mm Hg ⁇ m 2 .
  • Attorney Docket No: 3192-111-01 PCT [0099] Hollow fiber membranes with a thin wall and low ID have a high surface area relative to the amount of polymer used to form each fiber, potentially reducing material requirements (e.g., spin mass) and/or production costs while achieving comparable or superior performance to dialyzers incorporating conventional fibers.
  • the membranes of the present invention can reduce spin mass consumption by at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, or at least about 50 wt% compared to commercially available membranes, such as, but not limited to, Optiflux F160NRe.
  • the savings in spin mass and/or improved efficiency may be characterized by calculating the weight of a hollow fiber membrane bundle (in grams) required to yield one square meter of membrane surface area (in m 2 ). In this respect, a lower value is preferable.
  • the inventive membrane has a fiber weight per m 2 surface area that is less than about 16 grams, less than about 15 grams, or less than about 14 grams, or less than about 13 grams, or less than about 12 grams, or less than about 11 grams, or less than about 10 grams.
  • the savings in spin mass and/or improved efficiency of the inventive membrane may be characterized in terms of the weight of a hollow fiber membrane bundle (in grams) required to achieve a particular target performance metric, such as clearance of specific analytes from blood, or an ultrafiltration target.
  • sodium clearance targets of 280 ml/min may be used as a reference point for conventional hemodialyzers, at a blood flow rate (Qb) of 300 ml/min and dialysate flow rate (Qd) of 500 ml/min.
  • a method of forming a hollow fiber membrane according to an example of the present application includes steps 101A, 101B, 102, 103, and 104.
  • steps 101A and 101B polymer dope solution and precipitation fluid are provided, which are used in the production of the porous hollow fiber membrane.
  • the contacting of the polymer dope solution with precipitation fluid in step 102 is followed by rinsing of the membrane in step 103 and drying the rinsed membrane in step 104.
  • an additive may be included with the precipitation fluid in step 101B.
  • the additive may be hydrophilic, have low water solubility, and be soluble in a water-polar aprotic solvent mixture, as described herein.
  • the precipitation fluid can exclude an additive.
  • the membrane may be primed (e.g., in saline or other acceptable fluid) for a standard or prolonged period to rehydrate the membrane and any associated additive, such as for example, to a predetermined moisture content, or for a predetermined time.
  • a standard priming with saline or other fluid may generally last 10 minutes or about 10 minutes.
  • the hollow fiber can be produced in a method of the present invention, as an option, which comprises extruding or wet spinning the polymer dope solution through an outer ring duct of a spinneret comprising an outer ring duct and an internal hollow core and simultaneously passing the precipitation fluid through the internal hollow core, wherein the precipitation fluid acts directly on the polymer dope solution after issuing from the spinneret.
  • the spun fiber can be cast into an aqueous washing bath with an air gap Attorney Docket No: 3192-111-01 PCT provided between the base of the spinneret and the aqueous washing bath.
  • Precipitation of dope solution can initiate as the precipitation fluid comes into contact with the precipitation fluid.
  • the precipitation process can continue into the aqueous washing bath.
  • the precipitation process can generally be terminated before the hollow fiber gets as far as the surface of the bath that also dissolves out the organic liquid contained in the hollow fiber and finally fixes the fiber structure.
  • the first step can be for the inner face of the fiber-like structure to be coagulated so that a dense discriminating layer in the form of a barrier for molecules that are larger than about 60,000 Daltons can be formed.
  • the hollow fiber optionally can be texturized in order to improve the exchange properties thereof.
  • the fiber so produced can be handled in a conventional manner, for example, by winding onto a bobbin, cutting to a desired length, bundling and/or using in manufacture of dialyzers from the cut fibers.
  • a method according to an example of the present application for producing a hollow fiber membrane is shown, indicated by the identifier 400, includes steps 401, 402, and 403.
  • step 401 polymer dope solution can be extruded through the spinneret outer ring duct.
  • precipitation fluid passes through Attorney Docket No: 3192-111-01 PCT the spinneret internal hollow core.
  • the precipitation fluid directly contacts the inner surface of the polymer dope solution discharged from the spinneret.
  • the hollow fiber is rinsed and dried.
  • the spin masses of the present invention preferably contain low amounts of water.
  • the spin masses can contain 4 wt% water or less (based on the weight of the spin mass), such as 0.001 wt% to 4 wt%, 0.01 wt% to 4 wt%, 0.1 wt% to 4 wt%, 0.5 wt% to 3.5 wt%, 0.75 wt% to 3 wt%, 0.9 wt% to 1.7 wt%, and the like.
  • the spin masses once formed and prior to being used are preferably clear and not cloudy.
  • the spin mass solution is transparent and not opaque.
  • the spin mass solution is preferably as clear as water (though a different color than water).
  • the spin mass can have a viscosity, for example, of from about 500 to 10,000 cps or higher and more specifically 1,000 to 2,500 cps (centipoise) at about 25oC (1 atm) or at about room temperature. These viscosity values can be measured with a standard rotary viscosity measuring instrument, such as a Haake instrument.
  • the casting solution can be freed of undissolved particles, if present, by filtering it, and can then be supplied to an extrusion or wet- spinning spinneret.
  • a wet-spinning spinneret which can be used for spinning hollow fibers of the present invention can be types, for example, shown in U.S. Pat. Nos.3,691,068; 4,906,375; and 4,051,300, all of which are incorporated in their entireties by reference herein.
  • the spinneret or nozzle for example, can have a ring duct with a diameter equaling or approximating the desired outer diameter of the hollow fiber.
  • the outer diameter orifice can be, as an option, from about 0.2 mm to about 0.5 mm and the inner diameter can be from about 0.1 mm to about 0.4 mm, or other suitable sizes.
  • An advantage of the disclosed hollow fiber membrane is that it is possible to prepare the disclosed thin walled, low ID fibers using spinnerets commonly employed for manufacturing conventionally-sized hollow fiber membranes, such as Attorney Docket No: 3192-111-01 PCT spinnerets used to manufacture the Optiflux 160 (Fresenius Medical Care, Waltham, MA).
  • a spinneret hollow core can typically extrude solution coaxially into and through this duct through which the precipitating fluid is fed simultaneously with polymer dope solution being fed between the outer surface of the hollow core and inner bore of the ring duct.
  • the precipitating fluid can be pumped through this hollow core so that the precipitating solution emerges from the core tip and makes contact with the hollow fiber configuration that is made up of the extruded polymer dope solution.
  • a hollow fiber or capillary membrane can be formed by the precipitating fluid acting in an outward direction on the polymer solution after issuing from the wet-spinning spinneret.
  • the amount or ratio of the precipitating fluid supplied to the polymer dope solution in the spinneret can be dependent, for example, on the dimensions of the wet-spinning spinneret, that is to say, the dimensions of the finished hollow fiber. In this respect, it can be desirable, as an option, that the dimensions of the fiber upon precipitation are not changed from those of the hollow fiber configuration before precipitation but after extrusion.
  • the amount of first composition of the active surface can be controlled by controlling the ratio of the precipitating fluid to the polymer dope solution.
  • the ratios of the volumes used of precipitating fluid to polymer dope solution can be in a range, as an option, of from about 1:0.5 to about 1:4, or other values, given an equal flow rate of the precipitating fluid and of the polymer dope solution, to the area ratios of the hollow fiber, i.e., the ring-area formed by the polymeric substance and the area of the fiber lumen.
  • the precipitating fluid can be supplied to the extruded configuration directly upstream from the spinneret such that the inner or lumen diameter of the extruded and not yet precipitated configuration generally corresponds to the dimensions of the ring spinneret, from which the material is extruded.
  • the amount or ratio of the precipitating solution supplied to the casting solution in the spinneret can be dependent, for example, on the dimensions of the wet-spinning spinneret, and accordingly, the dimensions of the finished hollow fiber.
  • the dimensions of the fiber are not changed to be different from those of the hollow fiber configuration before precipitation but after extrusion.
  • the ratios of the volumes used of precipitating solution to polymer solution can be in a range, for example, of from about 1:0.5 to about 1:5, with such volumetric ratios being equal, for an equal exit speed of the precipitating solution and of the casting solution, to the area ratios of the hollow fiber, i.e., the ring-area formed by the polymeric substance and the area of the fiber lumen.
  • the precipitating solution can be supplied to the extruded configuration directly upstream from the spinneret such that the inner or lumen diameter of the extruded and not yet precipitated configuration generally corresponds to the dimensions of the ring spinneret, from which the material is extruded.
  • a portion of the hydrophilic polymer e.g., PVP
  • the hydrophilic polymer if used (in addition to the membrane forming polymer) can dissolve or wash out of the spinning composition during the rinsing step, whereas a portion can be retained in the coagulated fiber.
  • From about 5% to about 95% by weight of the second polymer e.g., the hydrophilic polymer(s)
  • the hydrophilic polymer(s) can be dissolved out of the spinning composition so that from about 95% (or more) to about 5% by weight of the hydrophilic polymer used can be left therein.
  • a majority of the hydrophilic polymer e.g., PVP, can remain in the fiber.
  • the hydrophilic polymer can remain in the fiber. Pore formation can be caused by movement of the PVP toward the inner lumen of the fiber without necessarily being dissolved out.
  • the temperature of the annular spinneret By controlling the temperature of the annular spinneret, the spin mass and coagulant within the strand are brought to the same temperature or virtually the same temperature when being conveyed. By regulating the temperature of the extruded spin mass and the extruded coagulant, the coagulation process can be influenced while the strand passes through Attorney Docket No: 3192-111-01 PCT the precipitation gap.
  • the temperature of the annular spinneret is to be preset so as to also have a desired pore structure to the hollow fiber membrane form.
  • the annular spinneret is temperature-controlled to a temperature of 30 °C to 85°C, for example from about 30 °C to 45°C, or from about 45 °C to 65°C, or from about 65 °C to 85°C.
  • the annular spinneret is temperature-controlled to a temperature of about 40 °C to 45 °C.
  • the inventive method for producing a hollow fiber membrane bundle is characterized by the precipitating bath being temperature-controlled to 75°C to 85°C in the spinning process.
  • This precipitating bath temperature contributes to a high ultrafiltration coefficient and a high sieving coefficient for molecules in the mid-molecular weight range.
  • other factors influencing fiber ID, wall thickness, porosity and separation performance are the air gap height, dope fluid flow rate (Qd), bore fluid flow rate (Qb), dope velocity at the spinneret (Vd), bore fluid velocity at the spinneret (Vb), fiber take up velocity (Vt) and draw ratio DR (Vt/Vd).
  • the “air gap” or “precipitation gap” height is the distance between the spinneret and the liquid level of the precipitating bath. This gap is controlling for the precipitation time at a given speed of downward motion, that is to say, a given speed of extrusion. This distance can be dependent on solution viscosity, the weight and the precipitation rate of the fiber.
  • the air gap can be set at a distance, for example, from 0.0 meters to about 1.0 meters.
  • the air gap may be expressed in millimeters and is from about 10 mm to about 100 mm, or from about 15 mm to about 50 mm, or from about 20 mm to about 40 mm.
  • the air gap can be from about 22 mm to about 29 mm.
  • processing time identifies the length of time it takes the spin mass to pass through the air gap from the spinneret to the liquid level of the precipitating bath. The processing time can in particular be used to influence the outer pore structure but also fiber diameter and wall thickness.
  • the pumping rate of the precipitative fiber, Vd can be lower than the draw rate from the spinneret Vt, creating a “draw ratio” (DR) which also reduces the diameter of the fiber and may decrease wall thickness.
  • the draw ratio is greater than 2.2, greater than about 2.5, or greater than about 2.8, or greater than about 3.0, or greater than about 3.3, or greater than about 3.5, or greater than Attorney Docket No: 3192-111-01 PCT about 4.0.
  • the DR can be from 2.25 to 5 or from 2.5 to 5, or from 2.75 to 5, or from 3 to 5, or from 3.25 to 5, or from 3.5 to 5, or from 3.75 to 5, or from 4 to 5, or from 4.5 to 5, or from 2.5 to 4.75, or from 2.5 to 4.5 or any range based upon any two values described herein.
  • a draw ratio greater than 3.5 may provide a combination of a thin-walled, low ID hollow fiber membrane with excellent hydraulic permeability, clearance, and/or related performance benefits which nevertheless retains excellent structural integrity.
  • the coagulated fiber can be rinsed in a bath that normally contains water and in which the hollow fiber is kept, such as for about 3 minutes to 10 minutes or more, for washing out the dissolved organic constituents and for fixing the microporous structure of the fiber.
  • the fiber can be passed through a hot drying zone.
  • the hollow fiber produced can have a thin radially inner barrier layer on the inside surface which is adjacent an outer open-pore support region.
  • the inner face fiber manufactured can contain a dense barrier layer which has a pore diameter, for example, of from about 0.0005 ⁇ m to about 0.1 ⁇ m, or other values.
  • the hollow fiber dialyzer can further be sterilized using electron beam (e-beam) sterilization, gamma ray irradiation, steam sterilization (including inline steam), or other methods known in the art.
  • the hollow fiber membranes of the present invention can be used, as an option, for dialysis membranes, ultrafiltration membranes, and microfiltration membranes.
  • the dialysis membranes can be, for example, hemodialysis membranes or hemofilters. Semi-permeable membrane filtration is often used in the purification of proteins, microfiltration and ultrafiltration being the most commonly practiced techniques.
  • Microfiltration can be defined as a low-pressure membrane filtration process which removes suspended solids and colloids generally larger than Attorney Docket No: 3192-111-01 PCT 0.1 ⁇ m in diameter. Such processes can be used to separate particles or microbes that can be seen with the aid of a microscope such as cells, macrophage, and cellular debris. Ultrafiltration membranes are characterized by pore sizes which enable them to retain macromolecules having a molecular weight ranging from about 500 Daltons to about 1,000,000 Daltons. Ultrafiltration is a low-pressure membrane filtration process which separates solutes in a range of from about 0.01 ⁇ m to 0.1 ⁇ m. Ultrafiltration can be used for concentrating proteins, and removing bacteria and viruses from a solution.
  • Ultrafiltration also can be used for purification treatments, such as water purification.
  • Dialysis membranes can be ultrafiltration membranes which comprise biocompatible materials, such as the hollow fiber membranes of the present invention.
  • a further goal of the present invention is to prepare hollow fiber membranes with high surface area relative to the volume of each fiber, requiring less spin mass to achieve a total target surface area when such fibers are bundled together, for example, for dialysis applications.
  • a given number of the described “Skinny Fibers” i.e., the hollow fiber membranes of the present invention
  • utilizing the hollow fiber membranes of the present invention may reduce the material costs of production for each dialyzer by at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or more than about 60%, without a reduction in therapeutic benefit compared to a conventional dialyzer.
  • the membranes of the present invention can reduce the housing size that houses a bundle of membranes by at least 30%, at least 35%, at least 40%, Attorney Docket No: 3192-111-01 PCT at least 45%, or at least 50%, while still achieving comparable performance of a dialyzer having a larger housing.
  • the inventive hollow fiber membranes are not limited to any one housing type.
  • Suitable housings may be formed from various polymers (synthetic resins or plastics) including polycarbonate, polypropylene, polyethylene, and any other suitable housing material or combination thereof.
  • the membranes of the present invention can achieve improved sieving/clearance performance. Clearance data can be measured on hollow fibers of the present invention, for example, according to DIN 58,352.
  • the hollow fiber membranes of the present invention can have an albumin sieving coefficient of less than about 20%, from about 0.001% to about 1%, from about 0.01% to about 0.75%, from about 0.1% to about 0.5%, from about 0.05% to about 10%, or more than 0.5%.
  • the maximum blood flow for a patient can be from about 450 ml/min to about 500 ml/min.
  • polyaryletherpolymer fiber e.g., a sulfone polymer fiber like a polysulfone fiber
  • a polyaryletherpolymer fiber e.g., a sulfone polymer fiber like a polysulfone fiber
  • the hollow fiber membranes of the present invention such as a polysulfone-based Attorney Docket No: 3192-111-01 PCT fiber fabricated into a dialyzer, for example, of about 1.4 m 2 area, can have a middle molecule (lysozyme) clearance rate of from about 1 ml/min of lysozyme to about 300 ml/min of lysozyme, from about 10 ml/min of lysozyme to about 300 ml/min of lysozyme, from about 50 ml/min of lysozyme to about 250 ml/min of lysozyme, or from about 75 ml/min of lysozyme to about 150 ml/min of lysozyme.
  • the hollow fiber membranes of the present invention such as a polyarylether polymer fiber (e.g., a sulfone polymer fiber like a polysulfone fiber) fabricated into a dialyzer, for example, of about 1.4 m 2 area, can have a creatinine clearance rate of from about 1 ml/min of creatinine to about 300 ml/min of creatinine, from about 10 ml/min creatinine to about 300 ml/min of creatinine, from about 50 ml/min of creatinine to about 290 ml/min of creatinine, or from about 75 ml/min of creatinine to about 150 ml/min of creatinine.
  • a polyarylether polymer fiber e.g., a sulfone polymer fiber like
  • the hollow fiber membranes of the present invention such as a polyarylether polymer fiber (e.g., a sulfone polymer fiber like a polysulfone fiber) fabricated into a dialyzer, for example, of about 1.4 m 2 area, can have a beta-2-microglobulin clearance rate of from about 1 ml/min of beta-2-microglobulin to about 300 ml/min of beta-2-microglobulin, from about 10 ml/min of beta-2-microglobulin to about 300 ml/min of beta-2-microglobulin, from about 20 ml/min of beta-2-microglobulin to about 200 ml/min of beta-2-microglobulin, or from about 30 ml/min of beta-2-microglobulin to about 150 ml/min of beta-2-microglobulin.
  • a polyarylether polymer fiber e.g., a sulfone polymer fiber like a polysulfone fiber
  • Sodium clearance can be ascertained with aqueous solutions for hollow fibers having 1.25 square meters of active surface area according to DIN 58,352 at a blood flow rate of about 280 mL/min. The clearance is equal to or lower than the blood flow or inlet flow.
  • sodium clearance may approach the theoretical maximum clearance value of 300 ml/min with some dialyzer sizes (total Attorney Docket No: 3192-111-01 PCT membrane areas).
  • the sodium clearance of hollow fibers of the present invention can be, for example, from about 200 to about 300, or from about 250 to about 275, or from about 260 to about 280, or from about 265 to about 275, or other values.
  • the hollow fibers of the present invention such as the polyarylether polymer fiber (e.g., a sulfone polymer fiber like a polysulfone fiber) can have a sodium clearance rate of from about 1 ml/min of sodium to about 300 ml/min of sodium, from about 10 ml/min of sodium to about 300 ml/min of sodium, from about 50 ml/min of sodium to about 290 ml/min of sodium, or from about 75 ml/min of sodium to about 295 ml/min of sodium.
  • Membranes made from fibers of the present invention can have an excellent separation boundary.
  • the sieving coefficients for example, can be measured as 1.0 for Vitamin B12, about 0.99 for inulin, from about 0.9 to about 1.0 for myoglobin, and under 0.01 for human albumin, or other values.
  • each of the hollow fibers for example, can be from about 110 ⁇ m to about 220 ⁇ m or from about 100 ⁇ m to about 190 ⁇ m.
  • the hollow fibers produced with the present invention can approximate, at least in part, natural kidney function with respect to separating properties (e.g., sieving coefficient).
  • One advantage of the inventive dialyzer is that it is able to achieve excellent middle molecule clearance without a significant increase in albumin loss, when compared to conventional high flux dialyzers. Other approaches to improve middle molecule clearance rely on increased membrane porosity that necessarily also causes additional albumin loss.
  • inventive dialyzer and membrane achieve improved clearance through a novel thin- walled membrane structure associated with a high end-to-end pressure drop and transmembrane pressure gradient, and very high surface area to volume ratio, avoiding the Attorney Docket No: 3192-111-01 PCT disadvantages of highly porous membrane structure.
  • inventive dialyzer and membrane do not require complex modifications to production methods used in conventional high flux dialyzers, and thus also save costs and production time.
  • the technical advantages of the inventive hollow fiber membrane may relate primarily to their unique physical dimensions (ID and wall thickness, for instance), allowing a very large total membrane surface area to be packed into a conventionally-sized or even relatively small dialyzer housing.
  • Dialyzer housing volume may be calculated as total (empty) internal volume of the housing of the dialyzer compartment.
  • the A/HV is greater than about 60 cm -1 , or greater than about 65 cm -1 , or greater than about 70 cm -1 , or greater than about 75 cm -1 .
  • A/HV is between about 55 cm -1 and about 100 cm -1 , or between about 60 cm -1 and about 90 cm -1 , or between about 65 cm -1 and about 80 cm -1 , or from 60 cm -1 to 140 cm -1 .
  • the membrane of the present invention can include a combination of different fibers.
  • This combination can be utilized in a dialyzer housing as described herein.
  • the combination can be where a) a portion of the fibers that comprise the membrane are described above (e.g., fibers having a unique combination of physical parameters with respect to an inner diameter of the lumen and to wall thickness, for instance where the inner diameter and the wall thickness are narrow or thin.
  • the inner diameter can be from about 90 ⁇ m to about 160 ⁇ m and/or the wall thickness can be from about 10 ⁇ m to about 30 ⁇ m), and b) a portion of the fibers are outside of one or both the ID and wall thickness.
  • the b) portion can include conventional fibers (e.g., an inner diameter (ID) between 180 microns and 250 microns and wall thicknesses between 30 microns and 50 microns).
  • the b) portion can comprise, as an example, from 0.1% to 99% of the number of fibers that form the membrane.
  • the a) portion can Attorney Docket No: 3192-111-01 PCT comprise, as an example, from about 0.1% to 99% of the number of fibers that form the membrane.
  • at least a majority by number (e.g., 50.1% to 99.99%) of the fibers that form the membrane are fibers of the present invention, namely a) fibers with a small ID and wall thickness.
  • the present invention further relates to a process of using the porous hollow fiber membrane for at least one of membrane filtering or solute and/or solvent exchange which can comprise contacting aqueous-based fluid or contacting blood with the porous hollow fiber membrane described herein.
  • a process for dialysis, blood oxygenation, or blood separation filtering of the present invention can comprise contacting blood with a porous hollow fiber membrane as described herein.
  • the present invention will be further clarified by the following examples, which are intended to be only exemplary of the present invention. Unless indicated otherwise, all amounts, percentages, ratios and the like used herein are by weight. [00139] EXAMPLES [00140] Measurement method 1: Determining Porosity (density-based method).
  • a hollow fiber membrane bundle having previously been dried for 2 hours at 105°C in a drying cabinet and consisting of identical hollow fiber membranes is weighed.
  • the mean length of the fibers, the average inner diameter and average outer diameter and the number of fibers is determined.
  • the mean dimensions are determined for at least 10 different fibers of the hollow fiber membrane bundle. The determining of the dimensions occurs at a constant temperature of 20°C.
  • a volume osmosed through the membrane walls of the hollow fiber membranes of the hollow fiber membrane bundle is calculated from the dimensions by assuming that the geometry of the hollow fiber membranes corresponds to a hollow cylinder. From the volume as ascertained and the measured weight, the average density of the membrane structure within the hollow fiber membranes can be calculated.
  • Porosity measured fiber density *100 compact polysulfone density
  • Measurement method 2 Determining Porosity (image analysis method).
  • Membrane porosity may also be determined using image analysis of cross sections of hollow fiber membranes. The hollow fiber membrane is cut in sections in an axial direction. One option is used to measure porosity, as follows. [00144] The inner surface is observed by scanning electron microscope (SEM) operating at an applied voltage of 15.0 kV at 50,000x.
  • SEM scanning electron microscope
  • the process is performed using fields chosen randomly at the active surface, at approximately 1/3 of the way across the wall of the membrane measuring from the active surface, and at approximately 2/3 of the way across the wall of the membrane measuring from the active surface (in triplicate for each region).
  • fields were chosen at the active surface, at approximately 1/4 of the way across the wall of the membrane measuring from the active surface, at approximately 1/2 of the way across the wall of the membrane measuring from the active surface, and at approximately 3 ⁇ 4 of the way across the wall of the membrane measuring from the active surface (in triplicate for Attorney Docket No: 3192-111-01 PCT each region).
  • a region that represents only 1 ⁇ 4 of the thickness, 1 ⁇ 2 of the thickness, or 3 ⁇ 4 of the thickness may be chosen to measure porosity, with fields chosen only within that corresponding portion of the membrane wall.
  • fields may be chosen only within the first 1 ⁇ 4 of the thickness of the membrane, starting from the active surface, to determine the porosity or a change in porosity (dP/dW) only within that first region of the membrane wall nearest the active surface.
  • fields may be chosen only within a defined distance starting from the active surface, such as within the first 2 ⁇ m, the first 3 ⁇ m, the first 4 ⁇ m, the first 5 ⁇ m, the first 6 ⁇ m, the first 7 ⁇ m, the first 8 ⁇ m, the first 9 ⁇ m, the first 10 ⁇ m. Porosity in all such cases may be reported as percent (%) porosity per unit length ( ⁇ m).
  • Measurement method 3 Determining contact angle ⁇ .
  • the contact angle of a hollow fiber membrane is determined by the capillary method, wherein the hollow fiber membrane serves as the capillary. The hollow fiber membrane is fixed in a measuring stand.
  • Deionized water stained with 0.25 mg/ml methylene blue, is filled into the trough disposed at the base of the measuring stand.
  • the hollow fiber membrane previously given a new cut edge transverse to the longitudinal extension by a straight razor, is immersed in the solution and the capillary height (h) determined after a 20-minute waiting period by ascertaining the height of the stained solution in the hollow fiber membrane above the liquid level of the test liquid in the trough.
  • a new hollow fiber membrane is used after each measurement.
  • the internal radius r of each hollow fiber membrane is determined at the cut edge by light microscopy.
  • the Young-Laplace equation for capillary pressure can be used to calculate the contact angle: [00149]
  • Measurement method 4 Determination of polyvinylpyrrolidone and nitrogen in a near-surface layer (XPS).
  • Analysis of at least some of the characteristics mentioned herein can be achieved using Raman spectroscopy, IR Spectroscopy, photoelectron spectroscopy (XPS or ESCA), energy dispersive X-ray spectroscopy (EDS or EDX), or other suitable analytical technique for this evaluation. In general, unless stated otherwise, all measurements are based on conditions of 25 deg C and 1 atm. The content of polyvinylpyrrolidone in a layer near the surface may be, for example, determined using photoelectron spectroscopy (XPS or ESCA).
  • This method can be used to determine the proportion of polyvinylpyrrolidone in a layer of approximately 5-10 nm thick.
  • This layer which is sampled using the XPS method, is referred to in the following as the “near-surface layer” and is defined by the measuring conditions.
  • An X-ray photoelectron spectrometer (XPS, Kratos, Manchester, UK) may be used to quantify the elemental composition (specifically of fluorine) in the top 10 nm of the inner lumen of the inventive membranes and conventional Optiflux membranes. Under ultra-low vacuum, an X-ray is used to excite the surface of the material causing ejection of electrons with specific binding energies characteristic of particular atoms.
  • XPS analysis identifies the chemical elements present on the top 3-30 atomic layers Attorney Docket No: 3192-111-01 PCT (10-100 ⁇ ) of samples.
  • a hollow fiber membrane is split using a scalpel or other sharp blade so that the inner surface and thus the selective layer of the hollow fiber membrane is exposed. This sample is fixed on a sample plate and put into the sample chamber.
  • the measuring conditions are defined as follows: - apparatus: Thermo VG Scientific, K-Alpha model - excitation radiation: monochromatic X-ray, AI K ⁇ , 75 W - sample spot diameter: 200 ⁇ m - pass energy: 30 eV - angle between source and analyzer: 54° - spectral resolution for an Ag3d signal: 0.48 eV - applied vacuum: 10 -8 mbar - charge compensation provided by flood gun.
  • test and control dialyzers were first primed by filling the dialysate side of the dialyzer with saline through the dialysate port, then capped and then filling the blood side of the dialyzers with saline. Saline was allowed to recirculate for 10 min and then flushed through each dialyzer. After both the skinny and control dialyzers were completely primed, the donor blood was introduced into the system. Simulations were performed using a blood flow rate of 100 mL/min for 60 min and dialysate flow rate of zero. Hemoconcentration was maintained throughout the experiment. During the experiment, samples were withdrawn for complete blood counts (CBC) and platelet activation at 0, 5, 15, 30, 45 and 60 minutes during the simulation.
  • CBC complete blood counts
  • the platelet activation samples were prepared for plasma by centrifugation and analyzed using platelet factor-4 (PF-4) ELISA kits (DPF40). Platelet count reduction was analyzed with whole blood from CBC using the ADVIA 120 hematology system. All values were normalized to the hematocrit measured in whole blood at each individual time points by calculating the platelet value at that time point multiplied by the initial hematocrit divided by hematocrit at that point. [00160] Measurement Method 6 – Measuring Hemolysis. [00161] The normalized index of hemolysis (NIH) characterizes the concentration of free hemoglobin in plasma (per 100 L of pumped blood) taking into account the hematocrit, the blood flow rate, and the circulation time.
  • NIH normalized index of hemolysis
  • blood was circulated through the individual dialyzers at a flow rate of 600 mL/min by placing the venous port of the dialyzer submerged in to the blood approximately half way.
  • approximately 1.7 mL of blood samples is collected in to a 5 mL centrifuge tube at 5, 30, 60, 120, 180 and 240 minute time points for each system being tested.
  • These blood aliquots samples collected at different time points were centrifuged at 4000x rpm for 15 minutes then immediately pipette off the plasma in to a clean centrifuge tube.
  • the free hemoglobin (fHb) content of the isolated plasma at different time points were then evaluated using the CRIPPS method.
  • the partial absorbance of oxyhemoglobin at 576.5 nm is calculated relative to the linear baseline between 560.0 and 592.0 nm.
  • NIH normalized index of hemolysis
  • MIH modified index of hemolysis
  • HI hemolysis index
  • the MIH uses these parameters and includes a correction to the total hemoglobin concentration measured in the blood.
  • V volume recirculated (mL)
  • %HCT Averaged % Hematocrit (HCT)
  • Qb Blood flow rate (mL/min)
  • ⁇ T Sampling time interval (min).
  • the MIH equation used is provided below. The MIH equation produces a very small number so the final values are raised to the 10 6 to reduce the decimal places.
  • Conventional hollow fiber membranes (ID ⁇ 185 ⁇ m, wall thickness ⁇ 35 ⁇ m) were prepared using wet spinning annular spinnerets having an outer diameter D1 of 0.4 mm and inner diameter D2 of 0.2 mm.
  • Spinning dope solution was prepared by dissolving 16 wt% polysulfone P3500 (PS, from Solvay) and 4 wt% polyvinylpyrrolidone K90 (PVP) in Dimethylacetamide (DMAC) under agitation. Spinning dope was processed into a homogeneous mixture and extruded through the outer ring of the spinneret along with a centrally controlled precipitant (bore fluid) that was fed into the interior of the hollow strand.
  • the bore fluid was a DMAC solution containing 45.5 wt% water.
  • the spinneret annular gap width was 50 ⁇ m with an inner diameter Attorney Docket No: 3192-111-01 PCT of 200 ⁇ m.
  • the temperature of the spinneret and precipitation bath, draw ratio, and other parameters are shown in Table 1 below.
  • the extruded strand was guided through a precipitant chamber into a water precipitation bath heated to approximately 63° C, where it precipitated into a hollow fiber membrane.
  • the air gap was 30 mm.
  • the hollow fiber membrane was subsequently guided through rinsing baths kept at a temperature of 75° C to 90° C.
  • the ends of the hollow fiber membranes were potted in the housing of the hollow fiber membrane dialyzer as generally known in the art, so that a first chamber (blood side) was formed within the collective lumenal space of the hollow fibers and a second chamber (dialysate side) was formed between the outer surface of the hollow fibers and the inner wall of the housing.
  • the dialyzer was sterilized using electron beam (e-beam) radiation.
  • the total membrane area (A) of the hollow fiber bundle in the dialyzer housing was 1.4 m 2 at a pack factor (PF) of 44%.
  • the active surface was at the inner surface of the porous hollow fiber membrane and a non-active region or support region was further present and adjacent to the active surface.
  • the Attorney Docket No: 3192-111-01 PCT membrane wall had a generally asymmetric architecture, and the porous hollow fiber membrane had a porosity such that the porosity of the membrane increased from the active surface (inner surface) across the wall thickness and to the outer surface.
  • the porous hollow fiber membrane had a mass density through the wall thickness, such that the mass density from the inner surface to the outer surface was essentially a gradient of decreasing mass density.
  • dP/dW within the first 1 ⁇ 4 of the thickness of the membrane, closest to the active surface was determined for the membranes of Example 1 (4.5 %/ ⁇ m), Example 5 (8.1 %/ ⁇ m), and Example 6 (10.2 %/ ⁇ m).
  • Example 1 4.5 %/ ⁇ m
  • Example 5 8.1 %/ ⁇ m
  • Example 6 10.2 %/ ⁇ m
  • A Total membrane surface area
  • Housing volume was calculated as total internal volume of the housing within the dialyzer compartment.
  • FIG. 9A shows the reported clearance performance of various Fresenius Medical Care dialyzers for sodium, creatinine and Vitamin B12, with their respective membrane surface areas (1.5- 2.5 m 2 ).
  • Example 8 Pressure Drop.
  • the end-to-end pressure drop was measured at different flow rates using the membranes of Example 1 (comparative) and Example 5 (ID ⁇ 125 ⁇ m, thickness ⁇ 25 ⁇ m).
  • FIG.10 shows the pressure drop vs. flow rate for each dialyzer. Both theoretical (dotted lines) and experimentally measured values (solid lines) are shown to demonstrate that the theoretical values are consistent with actual measured values. The data suggests that at a given flow rate, pressure drop across Skinny Fiber dialyzer (ID ⁇ 125 ⁇ m) is approximately 2.5 times higher than across the conventional dialyzer (here, the Optiflux 160). [00187] Example 9. Hemocompatability.
  • the results are shown in FIG.12, including Plasma Free Hemoglobin, fHb (FIG.12A), Hemolysis Index /HI (FIG. 12B), the Modified Index of Hemolysis/MIH (FIG. 12C), and Hemolysis Index (FIG. 12D).
  • Reference results for the comparative F160NRe dialyzer (A 1.5 m 2 ) are also shown.
  • Example 10 Mass Transfer Coefficient.
  • the mass transfer coefficient for sodium was measured as a function of membrane area Na Ko (ml/min.m 2 ) in dialyzers prepared from the hollow fiber membranes of Examples 1-6. Mass transfer is primarily a diffusional process and is primarily impacted by membrane thickness. Because the wall of the inventive membrane is thinner, the mass transfer coefficients for the inventive membranes in Examples 2-6 are about 18-65% higher compared to Example 1. However, this difference and cost benefit of skinny fiber is magnified when the mass transfer coefficient is normalized by the bundle weight (wt) of the fiber as seen in Table 2.
  • the results shown in FIG.13 demonstrate that the inventive dialyzers have higher sodium clearance than comparable dialyzers of the same size (i.e., same membrane surface area) and even have higher sodium clearance than most of the larger dialyzers evaluated.
  • the inventive dialyzers Designs 1, 2, and 3 were evaluated for the ratio of membrane surface area to housing volume. This was calculated in multiple ways to capture different aspects. Results are shown in Table 4 below. As shown, the surface area to housing volume ratio (measured either as ECV or ICV) in the inventive dialyzers is significantly greater than conventional dialyzers using the same housing.
  • the ECV is a reference to the external capillary space volume (external capillary volume), which means the remaining volume/space left after the given housing is loaded with fiber membrane to the desired area.
  • the ratio of surface area to this amount of left over volume/external capillary volume is determined and identified as SA/ECV.
  • the ICV is the internal capillary space volume (internal capillary volume), which means the volume of liquid/blood required to fill all of the fibers in the housing/dialyzer.
  • the ratio of surface area of the membranes to the ICV is identified as SA/ICV.
  • the ECV can be understood to be the dialysate volume required to fill a dialyzer and ICV can be understood to be the blood volume required to fill that same dialyzer.
  • the present invention includes the following aspects/embodiments/features in any order and/or in any combination: [00201]
  • the present invention in part relates to a porous hollow fiber membrane comprising: a. a lumen compartment, b. an inner surface adjacent to the lumen compartment, and an outer surface; c.
  • the present invention also relates to a porous hollow fiber membrane comprising: a. a lumen compartment, b. an inner surface adjacent to the lumen compartment, and an outer surface; c. a wall having a wall thickness of about 10 ⁇ m (micrometers) to about 30 ⁇ m; d. an inner diameter (ID) of about 90 ⁇ m to about 160 ⁇ m; e. a selective surface at the inner surface, the outer surface, or both; and f.
  • porous hollow fiber membrane has a mass density throughout the wall thickness, such that the mass density from the inner surface to the outer surface is a gradient of increasing or decreasing mass density.
  • ID is about 100 ⁇ m to about 140 ⁇ m.
  • wall thickness is about 20 ⁇ m to about 26 ⁇ m.
  • OD outside diameter
  • porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the fiber bundle weight per unit membrane area is less than 13 g.
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the selective surface has a thickness or depth of about 1 ⁇ m Attorney Docket No: 3192-111-01 PCT or less.
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the wall has a spongy or macrovoid morphology.
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the contact angle at the inner surface is 40-90°.
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the PVP content at the inner surface as determined by XPS is greater than at the outer surface or a region between the inner surface and outer surface.
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the surface roughness, R a of the inner surface is less than 10 nm.
  • porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein a ratio between the surface roughness, R a of the non-selective surface to the selective surface is greater than 35.
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the hydraulic permeability is greater than about 150 ml/h.mmHg.m2.
  • porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the hydraulic permeability is greater than about 200 ml/h.mmHg.m2.
  • Attorney Docket No: 3192-111-01 PCT [00219]
  • the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect wherein the ratio of mass transfer coefficient of B2M to the albumin sieving coefficient is in the range of 4,500- 750,000 mL/min/m 2 .
  • the present invention also relates to a porous hollow fiber membrane prepared from a solution comprising: at least one polyarylether polymer, at least one hydrophilic polymer, and at least one solvent, wherein the hollow fibers each have: an inner diameter of about 90 ⁇ m to about 160 ⁇ m, and a wall thickness of about 10 ⁇ m to about 30 ⁇ m; and wherein the porous hollow fiber membrane has a mass density throughout the wall thickness, such that the mass density from the inner surface to the outer surface is a gradient of increasing or decreasing mass density.
  • the present invention also relates to a porous hollow fiber membrane for use in extracorporeal blood therapy, the membrane comprising: a. a lumenal compartment, b.
  • the present invention also relates to a dialysis membrane prepared from a solution Attorney Docket No: 3192-111-01 PCT comprising: 10 to 30 wt. % of at least one polyarylether polymer, 1 to 10 wt.
  • the dialysis membrane has: a molecular weight retention onset (MWRO) of from 4.8 kDa to 5.2 kDa, and a molecular weight cut-off (MWCO) of from 24.5 kDa to 28 kDa, as determined by dextran sieving before blood contact with the dialysis membrane.
  • MWRO molecular weight retention onset
  • MWCO molecular weight cut-off
  • the polymeric membrane formed from the method can have a molecular weight cut-off (MWCO) of from about 24.5 kDa to about 28 kDa such as from about 25 kDa to about 27 kDa.
  • the present invention also relates to a method of making the porous hollow fiber membrane of any preceding or following embodiment/feature/aspect, said method comprising: a) providing a solution comprising at least one polyarylether polymer and at least one hydrophilic polymer, at least one polymer and at least one solvent; b) forming the porous hollow fiber membrane by passing said solution through a spinneret to form the porous hollow fiber membrane; c) passing said porous hollow fiber membrane from step (b) through at least one precipitation bath comprising an aqueous solution; d) passing said porous hollow fiber membrane from step (c) through at least one washing bath; e) passing said porous hollow fiber membrane from step (d) through at least one drying chamber; and f) collecting said porous hollow fiber membrane from step (e).
  • PAES poly(aryl)ethersulfone
  • PSF polysulfone
  • PES polyethersulfone
  • PAES polyarylethersulfone
  • PAES polyvinylidene fluoride
  • PVDF polyacrylonitrile
  • CT cellulose triacetate
  • said at least one polar aprotic solvent is dimethylacetamide (DMAC), N-methyl-2- pyrrolidone (NMP), dimethylsulfoxide (DMSO), diphenylsulfone (DFS), or any combinations thereof.
  • DMAC dimethylacetamide
  • NMP N-methyl-2- pyrrolidone
  • DMSO dimethylsulfoxide
  • DFS diphenylsulfone
  • the present invention also relates to a method to form the porous hollow fiber membrane polymeric fibers of any preceding claims, said method comprising supplying a spin mass to a spinneret simultaneously with a bore fluid and casting polymeric fibers, wherein said spin mass comprises at least one polymer and at least one organic solvent and said bore fluid comprises at least one aqueous solvent and/or at least one organic solvent.
  • the present invention also relates to a method for manufacturing a hollow fiber membrane of any preceding or following embodiment/feature/aspect, said method comprising the method steps: • preparing at least one spin mass comprising a hydrophobic and a hydrophilic polymer, at least one aprotic polar solvent, • preparing at least one precipitation fluid or coagulant comprising at least one aprotic polar solvent and/or at least one non-solvent (e.g., water), • conveying the spin mass through at least one annular gap of a spinneret into a hollow strand, • conveying the precipitation fluid through a central bore of the spinneret into the lumen of the strand, • introducing the strand into a precipitating bath and obtaining the hollow fiber membrane.
  • a method for manufacturing a hollow fiber membrane of any preceding or following embodiment/feature/aspect comprising the method steps: • preparing at least one spin mass comprising a hydrophobic and a hydrophilic polymer, at least one aprotic polar solvent
  • the present invention also relates to a method for manufacturing the hollow fiber membrane of any preceding or following embodiment/feature/aspect, said method comprising: Attorney Docket No: 3192-111-01 PCT • providing a spin mass or spinning solution comprising a polysulfone-based material, in particular polysulfone, a vinylpyrrolidone-based polymer, in particular polyvinylpyrrolidone, an aprotic solvent, in particular dimethylacetamide, • providing a precipitation fluid or coagulant liquid comprising water and an aprotic solvent, in particular dimethylacetamide, • co-extruding the spinning solution and the coagulant liquid through a concentric annular spinneret into a hollow strand, whereby the cavity of the strand is filled with coagulant liquid, • conducting the strand through a precipitation gap, • introducing the strand into a precipitating bath comprised substantially of water so as to obtain the porous hollow fiber membrane, • conducting the hollow fiber membranes through at least one rin
  • the present invention also relates to a dialyzer comprising a cylindrical housing with three compartments, a plurality of porous hollow fiber membranes within said housing, a first compartment defined by the internal wall of the housing having a total housing volume (HV), a Attorney Docket No: 3192-111-01 PCT second compartment within the plurality of porous hollow fiber membranes, the plurality of porous hollow fiber membranes having a total membrane surface area (SA), and third compartment is the volume of the housing not occupied by the plurality of porous hollow fibers (IV, dialysate volume), wherein the porous hollow fiber membranes comprise: a. an outer surface, an inner surface, and a wall having a wall thickness measured from the outer surface to the inner surface; b.
  • a lumen compartment c. the wall thickness of about 10 ⁇ m to about 30 ⁇ m; d. an inner diameter (ID) of about 90 ⁇ m to about 160 ⁇ m; e a selective surface at the inner surface, the outer surface, or both; and f. a support region adjacent to the selective surface, wherein the dialyzer SA/HV ratio is greater than 60 cm -1 .
  • ID inner diameter
  • e selective surface at the inner surface, the outer surface, or both
  • f. a support region adjacent to the selective surface wherein the dialyzer SA/HV ratio is greater than 60 cm -1 .
  • the dialyzer of any preceding or following embodiment/feature/aspect, wherein the urea mass transfer coefficient, Ko is in the range of 900 to 1400 mL/min/m 2 .
  • the dialyzer of any preceding or following embodiment/feature/aspect wherein a ratio between the mass transfer coefficient of B2M to the sieving coefficient for human albumin is in the range of 4,500 to750,000 mL/min/m 2 .
  • the dialyzer of any preceding or following embodiment/feature/aspect wherein the transmembrane pressure drop from one end of the dialyzer to the other end of the dialyzer is in the range of 100 to 1000 mm Hg when the flow rate varies from 100 to 600 mL/min.
  • the dialyzer of any preceding or following embodiment/feature/aspect wherein the transmembrane pressure drop from one end of the dialyzer to the other end of the dialyzer is in the range of 200 to 300 mm Hg when the flow rate varies from 100 to 600 mL/min.
  • the dialyzer of any preceding or following embodiment/feature/aspect wherein the dialyzer comprises greater than 10,000 hollow fiber membranes.
  • the dialyzer of any preceding or following embodiment/feature/aspect wherein the effective fiber length to the fiber inner diameter (ID) ratio is in the range of 1400 to 3250 or in the range of 1840 to 3250. (The fiber length for instance can be 294000 ⁇ m or within 30%, or within 20%, or within 10%, or within 5%, or within 1% of this length).
  • MWRO molecular weight retention onset
  • the MWRO can be based or determined using a dextran solution in water and following Attorney Docket No: 3192-111-01 PCT DIN EN 1508637:2014.
  • This MWCO can be a value for describing the retention capabilities of the membrane and refers to the molecular mass of a solute where the membrane has a rejection of 90%, corresponding to a sieving coefficient of 0.1.
  • the MWCO can also be described as the molecular mass of the solute, such as for example dextrans or proteins, at which the membrane allows passage of 10% of these molecules.
  • the MWCO can be based or determined using a dextran solution in water and following DIN EN 1508637:2014.
  • a method of hemodialysis comprising passing blood through a first chamber of a dialysis filter comprising the dialysis membrane or dialyzer of any preceding claim, such that the blood contacts a first side of the hollow fiber membrane; and passing a dialysis solution through a second chamber of the dialysis filter such that the dialysis solution contacts a second opposite side of the hollow fiber membrane to remove waste products from the blood, wherein the first chamber is inside the hollow fiber membrane and the second chamber is between the hollow fiber membrane and an inner wall of the dialysis filter.
  • a method of hemodialysis comprising passing blood through a first chamber of a dialysis filter comprising the dialysis membrane or dialyzer of any preceding claim, such that the blood contacts a first side of the hollow fiber membrane; and passing a dialysis solution through a second chamber of the dialysis filter such that the dialysis solution contacts a second opposite side of the hollow fiber membrane to remove waste products from the blood, wherein the second chamber is inside the hollow fiber membrane and the first chamber is between Attorney Docket No: 3192-111-01 PCT the hollow fiber membrane and an inner wall of the dialysis filter.
  • any preceding or following embodiment/feature/aspect wherein the pore size across the wall thickness progressively increases from the selective surface through the support region and to the opposite surface.
  • the membrane is prepared from a solution comprising: at least one polyarylether polymer, at least one hydrophilic polymer, at least one solvent, and wherein the hollow fibers each have an inner diameter of from about 90 ⁇ m to about 140 ⁇ m; and a wall thickness of from about 20 ⁇ m to about 28 ⁇ m.
  • porous hollow fiber membrane or method of any preceding or following embodiment/feature/aspect wherein the membrane is characterized by a rate of change in porosity dP/dW, wherein P is the porosity (in percent) and W is the wall thickness (in ⁇ m).
  • dP/dW as measured within a region that is no less than 1 ⁇ 4 of the thickness of the membrane wall, is at least 5.0 %/ ⁇ m.
  • porous hollow fiber membrane or method of any preceding or following embodiment/feature/aspect wherein dP/dW, as measured within a region that is no less than 1 ⁇ 4 of the thickness of the membrane wall, is at least 8.0 %/ ⁇ m.
  • dP/dW as measured within a region that is no less than 1 ⁇ 4 of the thickness of the membrane wall, is at least 10.0 %/ ⁇ m.
  • porous hollow fiber membrane or method of any preceding or following embodiment/feature/aspect wherein beneath the selective surface, there is a region of thickness, no less than 2 micron in thickness, where a slope of increasing porosity is at least 5.0 %/ ⁇ m (or at least 8.0 %/ ⁇ m, or at least 10.0 %/ ⁇ m).
  • porous hollow fiber membrane or method of any preceding or following embodiment/feature/aspect wherein dP/dW, as measured within a region that is no less than 1 ⁇ 4 of the thickness of the membrane wall, is from 5.0 %/ ⁇ m to 20 %/ ⁇ m, or from 8.0 %/ ⁇ m to 20 %/ ⁇ m, or from 10 %/ ⁇ m to 20 %/ ⁇ m, or from 5.0 %/ ⁇ m to 18 %/ ⁇ m, or from 8.0 %/ ⁇ m to 18 %/ ⁇ m, or from 10 %/ ⁇ m to 18 %/ ⁇ m.
  • porous hollow fiber membrane or method of any preceding or following embodiment/feature/aspect wherein dP/dW, as measured within the first 1 ⁇ 4 of the thickness of the membrane wall closest to the active surface, is from 5.0 %/ ⁇ m to 20 %/ ⁇ m, or from 8.0 %/ ⁇ m to 20 %/ ⁇ m, or from 10 %/ ⁇ m to 20 %/ ⁇ m, or from 5.0 %/ ⁇ m to 18 %/ ⁇ m, or from 8.0 %/ ⁇ m to 18 %/ ⁇ m, or from 10 %/ ⁇ m to 18 %/ ⁇ m.
  • porous hollow fiber membrane or method of any preceding or following embodiment/feature/aspect wherein beneath the selective surface, there is a region of thickness, no less than 2 micron in thickness, where a slope of increasing porosity is from 5.0 %/ ⁇ m to 20 %/ ⁇ m, or from 8.0 %/ ⁇ m to 20 %/ ⁇ m, or from 10 %/ ⁇ m to 20 %/ ⁇ m, or from 5.0 %/ ⁇ m to 18 %/ ⁇ m, or from 8.0 %/ ⁇ m to 18 %/ ⁇ m, or from 10 %/ ⁇ m to 18 %/ ⁇ m.
  • the present invention can include any combination of these various features or embodiments above and/or below as set forth in sentences and/or paragraphs. Any combination of Attorney Docket No: 3192-111-01 PCT disclosed features herein is considered part of the present invention and no limitation is intended with respect to combinable features. [00288] Applicants specifically incorporate the entire contents of all cited references in this disclosure. Further, when an amount, concentration, or other value or parameter is given as either a range, preferred range, or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed.

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  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)

Abstract

La présente invention concerne des dialyseurs qui utilisent des membranes à fibres creuses poreuses ayant une combinaison unique de paramètres physiques par rapport à un diamètre interne de la lumière et à une épaisseur de paroi. Plus spécifiquement, le diamètre interne et l'épaisseur de paroi sont étroits ou minces. Le diamètre interne peut être d'environ 90 µm à environ 160 µm et l'épaisseur de paroi peut être d'environ 10 µm à environ 30 µm. L'invention concerne en outre des procédés d'utilisation des dialyseurs ainsi que d'autres paramètres des membranes à fibres poreuses.
PCT/US2024/054640 2023-11-07 2024-11-06 Dialyseurs utilisant des membranes à fibres creuses de petit diamètre Pending WO2025101552A1 (fr)

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US63/547,602 2023-11-07

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Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3691068A (en) 1971-01-08 1972-09-12 Amicon Corp Dialysis membrane and its use
US4051300A (en) 1973-09-03 1977-09-27 Gulf South Research Institute Hollow synthetic fibers
US4906375A (en) 1984-07-14 1990-03-06 Fresenius, Ag Asymmetrical microporous hollow fiber for hemodialysis
EP0716859A2 (fr) * 1994-12-16 1996-06-19 TOYO BOSEKI KABUSHIKI KAISHA Trading under the name of Toyobo Co., Ltd. Module de purification du sang, membrane de purification de sang et son procédé de fabrication
WO2004056460A1 (fr) 2002-12-20 2004-07-08 Gambro Lundia Ab Membrane a fibres creuses asymetriques permselective permettant de separer des mediateurs toxiques de sang
WO2008046779A1 (fr) 2006-10-18 2008-04-24 Gambro Lundia Ab Membrane à fibres creuses et procédé de fabrication associé
JP2008173163A (ja) * 2007-01-16 2008-07-31 Nikkiso Co Ltd 血液浄化器、及び、その製造方法
EP1518564B1 (fr) * 2003-09-24 2008-08-06 Nipro Corporation Dispositif à fibres creuses pour traitement du sang
JP4843993B2 (ja) * 2005-04-26 2011-12-21 東洋紡績株式会社 血液浄化器
WO2012051595A1 (fr) 2010-10-15 2012-04-19 Cytopherx, Inc. Cartouche de cytophérèse et son utilisation
WO2013034611A1 (fr) 2011-09-08 2013-03-14 Gambro Lundia Ab Fibre creuse
WO2015056460A1 (fr) 2013-10-18 2015-04-23 マッスル株式会社 Robot
WO2018167280A1 (fr) 2017-03-17 2018-09-20 Fresenius Medical Care Deutschland Gmbh Membrane à fibres creuses pourvue de propriétés de diffusion améliorée
EP3388139A1 (fr) * 2017-04-13 2018-10-17 Gambro Lundia AB Dispositif d´hémodialyse optimisé pour la purification du sang

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3691068A (en) 1971-01-08 1972-09-12 Amicon Corp Dialysis membrane and its use
US4051300A (en) 1973-09-03 1977-09-27 Gulf South Research Institute Hollow synthetic fibers
US4906375A (en) 1984-07-14 1990-03-06 Fresenius, Ag Asymmetrical microporous hollow fiber for hemodialysis
EP0716859A2 (fr) * 1994-12-16 1996-06-19 TOYO BOSEKI KABUSHIKI KAISHA Trading under the name of Toyobo Co., Ltd. Module de purification du sang, membrane de purification de sang et son procédé de fabrication
WO2004056460A1 (fr) 2002-12-20 2004-07-08 Gambro Lundia Ab Membrane a fibres creuses asymetriques permselective permettant de separer des mediateurs toxiques de sang
EP1518564B1 (fr) * 2003-09-24 2008-08-06 Nipro Corporation Dispositif à fibres creuses pour traitement du sang
JP4843993B2 (ja) * 2005-04-26 2011-12-21 東洋紡績株式会社 血液浄化器
WO2008046779A1 (fr) 2006-10-18 2008-04-24 Gambro Lundia Ab Membrane à fibres creuses et procédé de fabrication associé
JP2008173163A (ja) * 2007-01-16 2008-07-31 Nikkiso Co Ltd 血液浄化器、及び、その製造方法
WO2012051595A1 (fr) 2010-10-15 2012-04-19 Cytopherx, Inc. Cartouche de cytophérèse et son utilisation
WO2013034611A1 (fr) 2011-09-08 2013-03-14 Gambro Lundia Ab Fibre creuse
WO2015056460A1 (fr) 2013-10-18 2015-04-23 マッスル株式会社 Robot
WO2018167280A1 (fr) 2017-03-17 2018-09-20 Fresenius Medical Care Deutschland Gmbh Membrane à fibres creuses pourvue de propriétés de diffusion améliorée
EP3388139A1 (fr) * 2017-04-13 2018-10-17 Gambro Lundia AB Dispositif d´hémodialyse optimisé pour la purification du sang

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