CA2180222C

CA2180222C - Polysulfone hollow fiber semipermeable membrane

Info

Publication number: CA2180222C
Application number: CA002180222A
Authority: CA
Inventors: Masaaki Shimagaki; Fumiaki Fukui; Takeshi Sonoda; Koji Sugita
Original assignee: Toray Industries Inc
Current assignee: Toray Industries Inc
Priority date: 1995-06-30
Filing date: 1996-06-28
Publication date: 2006-10-10
Anticipated expiration: 2016-06-28
Also published as: ES2237760T3; US6103117A; CN1158273A; KR100432464B1; CA2180222A1; DE69634352D1; KR970000318A; CN1125669C; US5938929A; EP0750938A1; KR100432463B1; ATE289219T1; EP0750938B1; TW474835B; DE69634352T2

Abstract

Respective hollow fiber membranes suitable for use in removing undesired contaminants from blood, in particular in an artificial kidney, have:
(1) per membrane area of 1.6 m2, in vitro clearances for urea and phosphorus respectively of >= 195, and >= 180, ml/min, a .beta.2-microglobulin clearance >= 44 ml/min and an albumin permeability <= 0.5%;
(2) an albumin permeability <= 1.5% and an overall mass transfer coefficient Ko >= 0.0012 cm/min; and (3) a vitamin B12 dialyzance of >= 135 ml/min and an albumin permeability <= 3%.
The membranes can be prepared by spinning hollow fibers from a spinning solution comprising a polysulfone, a hydrophilic polymer, a solvent and water, the spinning solution having a viscosity x at 30°C of 25-130 poise and a quantity y % of water given by:
-0.01× + 1.45 <= y <= -0.01× + 2.25.
The membranes can be incorporated into a hemodialyzer module by a method in which they are preimpregnated with a wetting agent, thereafter kept separate from one another by spacers and then inserted in the module.

Description

POLYSt,)LFONE HOLLOW FIBER SEMIPEEtMEAHLE MEMHRJ\NE
Thia invention relates to a hollow fiber semipermeable membiane and a dialy~ery especially a hemodialyzer containing a semipermeable membrane arid to methods for manufacturing the membrane and dialyzer.
As a material of the membrane used for dialyzere, there were conventionally used a number of polymerio compounds such as cellulose acetate, polyacrylonitri7.e, poly(methyl methaorylate) and polyamide. On the otheer hand, polysulfone resin was initially used as an engineering plastics material. However, on account of its distinguished fes,tur~s in heat stability, resistance to acids and alkalis, and bio-adaptability, it has become noted as e. semipermeable membrane material. In general, most of such membranes comprised of polymeric materials are deficient in affinity to blood because of their hydrophobic surfaces and are not ds.reatly usable far blood treatment.
Thus, methods were devised to render them suitable for use in a dialyzer, namely by inoo=porati,ng into the membranes a hydrophilic polymer or inorganic salt as a pore form~.ng material and removing it by dissolution to form pores and, at the same time, hydrophilically rtiodifying the polymer surface. Among the commercially available dialyzers currently used (three of which ax°e referred to hereinafter as "Company A's Membrane A", "Company H's Membrane H" and 3Q "Company C's Membrane C") for treatment for blood purification, that is, blood dialysis, blood filtration and dialysis, and blood filtration, those intended to keep the albumin permeability at a low level below 0.5% did not give the effects of C"r~" > 195, ~QhoBP~AT0411 ~ 1g0 and C Ba-rro ~ 94, ml/min, as explained myre fully below, Although those of the cellulose system represented by cellulose triacetate (e. g. Company A's Membrane A), generally exhibit a high ~i so~~~

level of removal of low molecular weight urea, they exhibit poor iii-rnicroglobulin (hereinafter ~i2-MG) clearance. For Company A's Membrane A, par membrane area of 1.6 m2, the in vitro urea clearance is 19S ml/min yr higher, the phosphorus clearance is 130 ml/min, the albumin permeability is O.a% or less, but the 1.3 m~ conversion cleeranc~e, per membrane area of 1, g rn', of iii-MG is only about 23 ml/min. On the other hand, although the polysulfone 6lalyzers (Company H's Membrane B, and Company C's Membrane C) have a high capacity for removing pa-MG, with an in vitro clearance per membrane asea of 1.3 m~ of at least 44 ml/min, and an albumin permeability not more than 0.5%, the in vitro clearance, per membrane area of 1.6m~, for urea is only 192m1/min or less and for phosphorus as low as l~7ml/min. Of the dialyzers intended to keep 'the albumin permeability at a level of less than 1.5%, there is none. which has a Ko (general mass transfer coefficient), when measured in a diffusion test with dextran having a molecular weight of 10,000,~and with measurements taken after 1 hour circulation of bovine serum, which exceeds 0.0012 am/min. As stated above the dialyzers of the cellulose system represented by cellulose triacetate (such as Company A's MembranF A) generally exhibit a high clearance of (relatively low molecular 2S weight) urea and moreover, per membrane area of l.6mZ, the in vitro albumin permeability is 0.5% or less. However, the Ko value, when subjected to the abovementione6 dextran diffusion test, is only about 0.0002cm/min. The polysulfone dialyzers exhibit high efficiency in removal of via-MG, but in the abovementioned dextran diffusion test, the Ko value is about O.OOIOcm/min (Company B's Membrane H) or 0.0005 cm/min (Company C's Membrane C). Referring now more particularly to polysulfone membranes disclosed in the patent literature, many of these disclose dialyzers giving an albumin permeability of lees than 3.0%. However, of these dialyzers, those giving a dia.lyzanc~ of vitamin H1 (Dei) of ~ 135 ml/min or more or a dialyzance of urea ~18~2~~2 ~ Ourva 1 of ~ 191 ml/min or more per 1. :~ma area in a module or a 60% or more clearance of a~-microglobulin in clinical use under th~a blood dialysis made, are. not Itnown.
In 'the field of the hemodialyxers, distinguished capacities for removal of urinal. toxic aubstancess are described in JP-B-54373/1993, JP-A-23813/199a and JP-A-300536/1992.
However, with the nowadays increas5.ng number of long-.term dialysis patients and diversY~Eication of d5.alysis technology, higher performances was required of the hemodialyzers. That is, in on-line filtration and dj.alysis and push~pull filtration and dialysis, a very high water permeability is required, and in ordinary blood dialysis, a high capgcity for removal of substances of a molecular weight o:E 10,000 or higher such as pZ-mi,croglobulin is required along with a high capacity for removal of lower molecular weight substances. Furthermore, hitherto, research was directed towards suppression, as far as practicable, of the permeation of albumin which is a useful protein :in blood. However, it was found that harmful.
substancr3s accumulating in dialysis patients were strongly bonded to albumin, so membranes allowing permeation of a certain ~3mount of albumin were called for, and there are a number of reports of the improvement of symptoms by hemodialyzers using such membranes, Howev~r, hemodialyzers satisfying all of these requirements have not yet been obtained. Far examplev, thg polysulfone membrane disclosed ~.n JP-B-54373/1993 is good as a hemodialyzer but is not satisfactory in that it does not provide the Water permeabil3.ty requ?~red in hemodialysis, hemodiafiltration and hemofiltration and removal of low molecular weight substances in blood dialysis. The polysulfone membrane disclosed in JP-H-300636/1992 provides a satisfactory water permeability 76199-?.5 ~18A~~2 but does not have su~~icient capacity for removing uremic toxins, particularly those having a high molecular weight such as via-microglabulin. Moreover, it involves problems in production. For example, during manufacture of tYae hemodialyzer, when incorporating the obtaine8 hollow fiber membrane into a hemodialyzer, potting is carried out in the presence of a wetting agent (such as glycerine) which is added in order to maintain the. water permeability. However, when using the membrane disclosed in ~7P-8-300636/1992, the hollow fibers stick to cane another so that it is di,t~icult for the potting material such as polyurethane to permeate into the gaps of the hollow fibers, resulting in seal.
leakage. Thus, there is not yet provided a pvlysulfone hollow fiber semipermeable membrane which maintains a high blood filtration flow and low albumin permeability aver many hours in clinical use and which has a high urinal toxin selective permeability.
As explained above, with particular reference to commercially available dialy2ers, ~.t~ has been very difficult to provide a semipermeable membrane having high capacities for both clearance of low molecular weight;
urinal toxins and clearance of medium molecular weigY.it proteins such Ets ~3a-MG, and, to our kr~osvledge, there is no dialyzer currently available which has both o~ these respective capacities realized simultaneously. At least vne aspect of the present invention addresses and solves this problem, Similarly, no currently available membrane is capable of achieving, simultaneously a low albumin permeability, in particular < 3%, and a high mass transfer coefficient, Ko as later defined. At least one aspect of the. invention addressee and solves this problem, In addition, as explained above with particular reference to the patent literature, it has also been ~1~fl22~
particularly difficult to provide hemodialyzers capable of achieving, on the cne hand an albumin p3rmeshility of less than 3% while at the same time achieving a I7B1 of >_ 135 ml/min and a D"=aA of ' 151 ml/min (each per membrane area 5 of 1.3 ma) and a ~ p~-MG reduction ~ GO$. At least one aspect o:E the invention addresses end solves this problem.
Thus, according to a first aspect, the invention provides a hollow flbgr membrane, such as a hemodialyzer, hemodiafilter or hemofilter, having ~(i) an albumin permeability of 0.5% os less;
(ii) per membrane area of 1.~6 mz, an in vitro urea clearances of 195 ml/min or mo=e;
(iii) per membrane area of 1.6 m~, an in vitro phosphorus clearance of 180 ml/min or more;
(iv) per membrane area of 1,8 ma, a pZ-microglobulin alearancr~ of ~4 m1/min or more.
According to a second aspect, the invention provides a polyaulfnne hollow fiber aemipermeable membrane characterized by an albumin permeability of less than 1.5%
and, in a dextran diffusion test using a dextzan having a molecular weight of 10,000 and after 1 hour circulation of bovine serum, an overall mass transfer coefficient Ko of 0.0012 em/min or chore.
Another aspect provides such a membrane according to the above first or second aspects of the invention for use in the treatment of blood for removal therefrom of any undesired component, in particular use as an artificial kidney membrane, while yet another aspect provides the use of such a membrane for in vitro treatment of blood.
Membranes and hollow fiber membrane artificial kidneys comprising such membran~s provid~d by the-above aspect of the presr~nt invention are obtainable, for example, by a method described as follows. This method uses a stock 2~~,~~~~
salution obtainable by adding, to a solution having 7 main hydrophobic polymer and a main hydrophilic polymer admixed and dissolved in a solvent, an additive serving as a non-solvent oz swelling agent for the main hydrophob~.c polymer.
A preferred specific method of preparing the stock solution for use fn a method of the present invention will now be described in more detail.
The stock solution basically comprises a ~ component system of ( 1 ) polysulfone resin, ( ?. ) hydrophilic pol~~rner, (3) solvent and (4) additive.
The polysulfone resin referred to here may comprise repeating units of the formula tl)i a ' " \ - ~ ~ '~,' ".. ~ ' l ~y ~e ~ ,~~
2 0 1 -- ---- In ( 1 ) c7 U'~ ~, and it may include, either on thecae or other residue's, a functional group. Wloreover, any or ~a~.l of the phenylene Z5 groups may be replaced by alkylene groups.
The hydrophilic polymer (2) is a polymer having a compatibility with the polysulfone resin as well as <<
hydrophilic property. Polyvinyl pyrrolidona .is most 30 desirabl~a, but other polyrne~rs ~rhiah may be present additionally or alternatively to the polyvinyl pyrrolldone include a modified polyvinylpyrrolidone, for example, polyvinyl pyrrolidone copolymer, polyethylene glycol.) and polyvinyl acetate). It should be chosen as appropriate 35 for compatibility with the main polysulfone~polymer.
The solvent (3) should dissolve both the polysul.fone ~18~2 resin (l.) and hydrophilic polymer (~). As such svlvE.nts, a variety of solvents may be used, including dimsthyl sulfoxide, dirnethyl acetamide, dimethyl formamide, N-methyl-2-pyrrolicJone and dioxane, but dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide and N-methyl-2-pyrrolidone are particularly preferable.
For the additive (4), any material can,be used Ego long as it has a nompati.bility with the solvent (3) and sE~rves as a good solvent for the hydrophilic polymer (2) anEt a non-solvent or swelling agent for the polysulfone ressin (1)~, and, in particular such a material may be water., methanol, ethanol, isopropanol, hexanol or 1,4-butanediol.
However, considering the cost of product5.an, water 1~; mast preferable. The additive (4) should be chvaen with t:he coagulation of the polysulfone resin (1) taken into consideration.
Howsoever and which of these components are combined is optional, and it will be a matter of ease for thvsae skilled in the art to select a particular combinetiori giving the desired coagulation property, Furthermore, either or both of the solvent (3) and additive (4) respectively may be a mixture of two gar more compounds.
In the case of a stock solution containing a polysulfone resin, hydrophilic polymer and solvent such as that for use in a method embodying the present invention, the additive (4) is to be carefully chosen for the poly-sulfonic resin (1). In particular, it should be free Pram mutual interaction with the polysulfone resin (1.), auch that the polysulfone resin (1) maintains a homonenous system on account of the additive (4) to such a concentration at which it coagulates as a matter of course and has no phase separation produced in a system ttav~.ng no hydrophilic polymer (2) admixe4. Here, i~ the temperature is raised, the molecular motion increases to weaken t:he 218~22~

bond part icularly between the hydraph~l.lic polymer (2) and the additive (4), then the hydrogen band is broken, and so the apparent concentration of the addit_l.ve (4) which is not bonded to the polysulfone resin (1) increases over that at the initial temperature T, resulting in mutual interaction between -the palysulfone resin (1.) and the additive (9.) with consequent coagulation and phase separation of the polysulfone resin (1). When the quantity of the additive (4) in this system fe increased, the stock solution system at the.t~amperature T has the additive (4) added in an amount in excess of the amount held by the hydrophilic polymer (2) at the temperature T, and so the membrane forming ;stock solution undergoes a phase separation.
However, when the temperature is lowered, molecular motion of the h~~drophilic polymer (2) is reduced to increase the amount of bonding of the additive (4) and thus decrease the apparent concentration of the additive (4), and so the system becomes homogeneous again. If the temperature is raised again, the system becomes inhomogeneous, but with the hydrophilic polymer (2) added, the amount of the additive (4) bonding with the hydrophilic polymer (2) increase to give a homogen~ous system, A pxeferred range of concentrations of the polysulfone resin (1) which can allow formation of a membrane having the characteristics desired for a hollow fiber membrane dialyzer of the present invention is 13-20% by weight of the solution. Tv obtain a high water permeability and a large fractional molecular weight, the polymer concentration should be somewhat reduced, and it is more preferably 13-18% by weight. If it is less than 13% by weight, a sufficient viscosity of the membrane forming stock is difficult to obtain, making it difficult to form a membrane. If it exceeds 20% by weight, hardly any penetrating pores are formed.
The hydrophilic polymer (2) or, more specifically, 7r,~.~9-z~

polyvinylpyrrolidons is commercially available in molecular weights of 360,000, 160,000, 40,000 and 10,000, and such a polymer is conveniently used, although a polymer of any other molecular weight can of course be used. The hydrophilic polymer (2) suitable for the hollow fiber membrane dialyze.r is preferably added, particularly i.n the case of polyvinylpyrrolidone, in an am~aunt of 1-20$ try weight o.r, more preferably, 3-IQ~C by weight, but the amount added is governed by the molecular weight of the 10~ polyvinylpyrrolidone, When the amount added is too small, hardly any phase separation occurs, ahd when the polymer concentration is high and the polymer molecular weight is too large, washing after formation of the membrane beeomes .difficult. Thus, one of th~ methods for.obtaining a satisfactory membrane is to use polymers of different molecular weight and have them mixed to assume the rcales~
desired of them, In order to prepare the solution, the polymers (1) and (2) may be admixed, the mixture di,~tsolved in the solvent (3), then the additive (4) added. In the case of wager in particular, it is highly coagulatS.ve for the polysulfone polymer of the formula (1), so it should be strictly .
controlled, preferably to an amount of 1.8 p~xcent by weight ox' less or, more preferably, 1.05-1.70 by wef.ght.
In the case of polyacrylonitrile, it is especially preferable to add this in an amount of ?°6~ by weight. When a less coagulative additive (4) i9 used, the amount added increases as a matter of course. Adjustment.of the added amount of such a coagulative additive has a relationship .
with the equilibrium moisture content of the hydrophobic polymer. As the concentration of the additive (4) increases, the phase separation concentration of the membrane forming stock solution decreases. The phae~:
separation temperature should be determined in consideration of the pore radius of the desired membrane, Typically the membrane is formed by a wet or dry/wet '76199-?.5 la sp5.nning process, preferably a dry/wet spinning process in which the solution passes through a dry zone containing a gas, typically air, at a predetermined xelative humidity and thereafter through a coagulating bath containing a coagulat.f.ng agent. In such a process, in the dry zone a preferred relative humidity is b0-9a%, a preferred temperature is 25-55°C, more preferably 3a-50'C and a preferred residence time is 0.1-1, sec, while in the coagulating bath a preferred temperature is 25-55°C, more prwferably 30-50°C. The form of the hollow fiber membrane used in the dialyaer of the invention may be provided by allowing an infusing solution to flew inside the stock solution when it is discharged from the annular spinning orifice and ruri through a drying zone to a coagulation bath. Hore, the humidity of the dry zone is very important. 8y supplying moisture through the outer surface of the membrane while running it through the wet section, this enables acceleration of the phase e3eparation at about the outer surface and enlargement of the pore diameter, thus providing the effect of reducing the permeation and diffusion resistance at the tim~ of dialysis. If the relative humidity is too high, coa,gul~ati~on of the stack solution on the outez~ surface prevails to redur~e the pore diameter, resulting in an increase in the permeation and diffusion resistance at the time of dialysis. Such relative humidity is governed greatly by the composition of the stuck solution, so it 1.s difficult to define simply the optimum point, but a relative humidity of 60°9a% is preferably used. For ease of processing, the infusing solution preferably compxises basically the solvent (3) used in the stock solution. The compositir5n of the infusing solution directly affects the permeation and diffusion capacities of the activated layet, so it must be precisely determined. In the foregoing range of stuck solution compositions, the composition of the infusing solution is greatly affected by the composition of th~
stock solution, so it is difficult to dafin2 simply the 2~8a~2~
m optimum point. Here, when dimethylacetamide, is used, for example, an aqueous solution of 50-75% by weight is preferably used.
It is very difficult to define the optimum membrane forming stock solution, but through combination of the properties of the four components within the above range of compositions, a particular stock solution can be choqen for providing a desired polysulfone hollow fiber semipermeable membrane of the invention.
Particular reference has been made earlier to problems arising from the methods of preparing hemodialyzers disclosed, for example, .7p-B-54373/1993, JP-A-23813/1994 and JP-A-300636/1992, especially the difficulty in achieving an albumin permeability of < 3% while at the same time achieving, S DB~ of at least 135 ml/min and a Dur,,A of at least 191 ml/min, each per membrane :area of 1.3 mz and %
pZ-MC3 reduction > 60%, all measured under cariditions as later described.
,According to at least a third aspe<st of the invention, membranes providing such a simultaneous combination of characteristics can be obtained.
Thus, the invention grovides, according to yet another aspect, a polysulfone hollow fiber membrane having an albumin permeability S 3% and a Dal (per membrane are: of 1.3 ma) of ~ 135, preferably ~ 140 ml/min, and preferably also a D"r" (per membrane are of 1.3 mZ) >_ 191, more preferably '~ 193 ml/min, and also preferably a %pa-MG
reduction >_ 60%, more preferably > TO%.
In particular, by using hollow fibers obtainable by spinning a particular spinning solution (which may be as described above in relation to aspects Uf the invention earlier described) and infusing solution under particular conditions of the drying zone (details of which are described later), a membrane having characteristics particularly desirable far hemodialysis can be obtained, and, moreover, a hemodialysis module containing such membranes can be provided without deterioration of the membrane, thereby maintaining arch desired characteristics.
t:'or such a purpose, the module is fabricated with a sufficient amount of a wetting agent imparted to the hollow fibers, and after the wetting agent has been removed, the hollow fibers can be filled with water to give a desired product. Here, if the bundle of hollow fibers is provided with the wetting agent imparted to the hollow ,fibers, the hollow fibers stick to one another to make it difficult to form a sealing plate by the potting material, according to one aspects of the invention, so in a mole preferable method, spacers are inserted to prevent adhesion.
That is, according to one aspect of. the'invention, a polysulfone hollow fiber type hemodialyzer is manufactured and obtained by a method character~.zed by preparing a bundle of hollow fibers with a sufficient amount of a wetting agent imparted to the hollow fibers,. forming them into at least one sealing plate, preferably a pair of sealing plates, one at each respective opposite axial end region of the hollow tubular fibers, th~:n rinsing the wetting agent with water and steriliz~.nc), which hemodialyzer is thereby capable of exhibiting albumin permeability of 3.0~ or less and a vitamin Blx dialyzance, per membrane area of l.3ma, of 135 ml/min or higher.
Furthermore, according to this manufacturing method, by employing preferable conditions described herein, it is possible to obtain a hemodialyzer which is characterized by an albumin permeability of 0.1~% to x.4% and a vitamin Hla dialyzanoe of 137 ml/min or higher. Moreover, through combination of more preferable conditions, it is possible to obtain a hemAdialyzer which is characaerized by an albumin permeability of 0.3% to 2»0'k and a vitamin H~a dialyzance of 140 ml/min or higher, Also, by employing snore and more preferable manufacturing conditions in the manufacturing method of the present invention, it i5 possible to obtain a hemodialyzer r~xhibiting a urea dialyzance of 191 ml/rnin or higher, 192 ml/min or higher, and even 193 ml/min or higher.
Furthermore, according to the method off' the present invention, again by employing more and more preFerable conditions, a hemodia~.yzer having a hollow fiber membrane exhibiting a water permeability as high as 500m1/hr ' mmHg m~ or higher, 600, ml,/hr ' mmHg ' ma or ewc~n 700m1/hx ' mmHg m~ or higher is obtainable. Indeed, a hollowr fiber membrane obtained by a method of the prse~nt invention and giving the best clinical evaluation ~xhibited a water permeability higher than 800m1/hr ' mmHg ' ma.' The % removal of p~-microglobulin and the dialyzance of vitamin Hl~ in cl.fnical evaluation are positively correlated, and the vitamin Bra dialyzanr~e may be regarde8 as the best index of the membrane capacity.
Preferred conditions and process steps,in methods embodying the invention area now d~scribed.
The concentration of the polysulforre resin in th.e spinning solution in the manufacturing method according to the invention is preferably 14~a2% by weight and more preferably 17-19% by weight.
The concentration of th~ hydrophilic polymer is preferably 512% by weight and more greierably 7~10% by weight.
'761q9-..2c 2~~o2~z For obtaining a hollow fiber membrane of good charaCte:rietics particularly as a hemodialyzer by spinning St a high speed (which is desirable for reasons of economy), the viscosity of the spinning solution is an important factor. 'foo low a viscos~.ty is not preferrs:d in that end breakage or variation of hallow fiber diameter occurs while control of the albumin permeability becomes difficult, on the other hand, too high a v_i.ecosity i.g not preferred in that variation of the thicicness of the hollow fiber membrane is enlarged while its capacity to cleax urinal toxic substances is reduced.
In 'the spinning aviation according to the manufacturing method of the invention. wspecially if dimethylacetamide is used as a solvent, the viscosity at 30°C .is preferably within the range of ;?5130 poise (about 35-170 poise at 20°C) or, more preferably, AO-110 poise.
Control of the viscosity may be oracle through adjustment o~ the concentration and/or~rnolecular weight of the polysulfane resin and/or concentration and/or molecular weight v:E the hydrophilic polymer in them spinning solution.
The most preferable method is to change the molecular weight of the hydrophilic polymer.
For example, a desired Viscosity may be provided by mixing polyvinylpyrrolidone (K-30) of a weight average , molecular weight of about 40,000 and polyvinylpyrrolidone (K-90) of a weight average molecular weight of about 1,100,000 and changing the mixing ratio.
In a preferred specifio example, where dimethylr~cetamide is used as a solvent, AMOCO
Corporataons's Polysulfon P-3500 used in a concentration of 18% by weight, and polyv3.nylpyrrolidone used in a concentration of 9% by weight, the mixing-ratio of K-30 and K-90 is within the range of about 910-5/4 or, more preferably, about 8/1-5.5/3.5.
In the spinning solution used in a method according to the present invention, it is preferable to add a small 5 amount of water as an agent to regulate the pore diameter in the hollow fiber membrane.
Thus, according to a particular method aspect of the invention there is provided a method of manufacturing a 10 polysulfone hollow fiber membrane, which method comprises spinning hollow fibers from a spinning solution comprising a polysulfone, a hydrophilic polymer, a solvent for each of the polysulfone and hydrophilic polymer and water, which spinning solution has a viscosity x (poise) at 30°C.w~ithin 15 the range of 25-130 poise and s quantity y (wt%) of water present in the spinning solution within the range satisfying the formula: .
-O.Olx + 1.45 _< y <_ -0.01x + 2.25.
When such a method is employed and more particularly, when the most preferred solvent, dimethylacetamide is used, a hollow fiber membrane of good characteristics is obtainable. When the water quantity y (wt %) contained in the solution is within the range satisfying the formula:
-O.olx + 1.65 ~ y S -O.Olx + 2.05, it is more~preferable. In the above formulae, x represents the viscosity (poise) at 30°C of the sp~.nning solution, and x is within the range of 25-130 poise or preferably 40-110 poise.
When the amount of water added is smaller, clouding of the spinning solution due to long storage may be checked (here, it seems that the clouding occurs as the polysulfone oligomer crystallises, and this is not desirable in that if the clouding proceeds, end breakage tends.to occur in spinning), but the pore diameter is reduced to reduce the capacity of the membrane for clearing substances of a molecular weight of 10,17QCJ ar higher gush as p~-micro<~lobulin, and this is not desirable. Conversely, when the amount of water added is greater, this is not desirable in that the spinning solution tends to losE:
stability and causa cla~ud.ing, and furthermore the albumin permeability becomes too high, Moreover, in a preferred manufacturing method oi: the invention, an infusing solution is aactruded from the center of the spinneret to control the inner surface of the hollow fiber by its coagulation and thus provide a membrane having good characteristics as a hemodialyxer. The infusing solution is generally used for the purpose of gradually coagulating the spinning solution from the inner suri:ace of the hollow fiber to form an asymmetric structure, preferably having an overall porosity of at least 78~ and preferably having a fine active layer of the separation membrane, which preferably has an average pore radius S 10 nm, more preferably ~ 8 nm, especially 5 7 nm. Hence the infusion fluid is preferably low in its ability to cause coagulation, and an organic solvent such as,alcohol is usable independently or in a mixture with water.
Acoording to the present invention, a mixture of the solvent used for the spinning solution and water is preferable for ease of recovery and for obtaining high performance, and a mixed sole~nt of dimethylacetamide, which is the most preferable solvent, and water is more preferable.
When a mixture solvent of dimethylacetamide and water is used, the quantity of water ~ (weight %) contained in the infusing solution is defined by the viscosity of the spinning solution in order to obtain a membrane having goad characteristics as a hemodialyzer of the invention, and it is preferably in the range satisfying the formula 0.14x + 25.5 < z ~ 0.14x ~r 37.5 ~isoz2~
and it is mare prel;erable that the watex quantity z (weight%) contained in the infusing solution is in the range satisfying the formula 0.14x * 21.5 s z ~ 4.14x + 3r~.5 where x is the viscosity (poisel of the spinning solution at 30°C ~3nd x is within the range of ~5°'130 poise or more preferably 40-1.10 poise, A ma_mbrane having good characteristics as a hollow fiber membrane far hemodialysis is obtainable by having both.wat3r quantity y (weight ~%) in spinning solution and water quantity z (weight %) in infusing Solution satisfy the foregoing formulae respectively, If the water content is less, coagulation of the spinning solution or that from the inner: surface Is slow, tending to cause end breakage in the drying zone and higher permeation of proteins including albumin. Likewise, an excessive water quantity is not preferable in that the ?0 capacity of the membran~ to remove substances of greater molecular weight such as fix-microglobulin is reduced. On the other hand, its capacity to remove low molecular substances 1s also reduced as the water content is increased further.

The hollow fiber membrane of the pa:esent invention may be spun by the wet spinning method according to which the spinning solution and infusing solution provided as stated above are directly leg from the annular nozzle spinneret to 30 the coagulation bath or by the dry/wet fapinning method according to which the hollow fiber from the spinneret is once exposed to a gaseous phase then led to the coagulation bath. Here, in ordex to obtain good peri:ormance, the dry/wet ;pinning method having the fiber run in the gaseous 35 phase (drying zone) preferably for 0.1-1.0 second or, more preferably, 0.2-0.8 second is desirable.
7~ 199--25 .

As the condition of the drying zone, a relative humidity of 40~ oz more is preferred, and a good performance is provided through contact with a moist air flow of a relative humidity of more preferably at least 6Q~, even more preferably 70$ or higher, most preferably 80% yr higher, say up to 90%.
Next, the spinning solution, now 3~n the form of hollow fiber spun out of the spinneret is led to the coagulation bath. Iii the coagulation bath, 5.t camingles with the solvent, but as it cornea into contact with the coagulating solution which is a non-solvent having a property to coagulate the polysulfone resin, it forms a membrane of a structure in the form of a coazse porous sponge as a supporting layer from the side of the outer surface.
For the coagulation bath, a non-sv7.vent or a mixture of two or mare non-solvents may be used, but from the poS.nt of view of recovery of the solvent, a mixtur~ of the solvent of the spinning solution and wager is preferably used.
The hollow fiber coming out of the coagulation bath is rinsed with water for removal of a substantial part of the solvent component, and it is immersed in a solution of a wetting agent, cut to a predeterm~.ned length and assembled to provide a predetermined number of fibers. Then, the solution of the wetting agent, which has substituted the infusing solution insides the hallow fiber at the time of ,30 immersion, is removed to form ~ bundle of hollow fibers.
For the wetting agent, these may be used an alcohol such as glycerine, ethylene glycol, polypropylene glycol or polyethylene glycol which prevents drying of the bundle of hollow fibers even when it is allowed to stand in air or an aqueous solution of an inorganic salt; however, glycerine is particularly preferable.
'76799-25 It is especially preferred to use .3n aqueous solution of glycerin~, preferably containing a0% or more by weight, mare pr~ferably 60-~75~% by weight, still mare praferat~ly 65-72% by weight o~° glycerine in order to prevent deterioration of the permeability of thn membrane through drying.
Imparting the wetting agent may pry=_vent deterioration of the membrane performance while fabri~:ating it into a hemodialyzer. However, conversely, in :Forming a seal.fng plate by means of a potting material sur~h as a polyurethane, a problem arises in that adhesion of tha hollow fibers to one another tends to orQUr and this renders it very difficult for the potting material to permeate into the gaps of the hollow fibers, resulting in seal leakage precluding separation of blood and dialyaate by the scaling plate. In order to resolve such a problem, a method which may be employed is that of storing the bundle of hollow fibers in an atmosphere of low humidity for a ZO long period of time after it has been inserted into a casing of the hemodialyzer (for example, storing in a room of a relative humidity of 40% for about 3 days) or that of loosening the ends of the fiber bundle by apply5.ng an air flow of a very low humidity to end part:, then a strong air flow in a vertical direction to both end faces, of the hollow fiber bundle: (for example, applying air at a temperature of 40-60°C and a relative humidity of 10% or less to both end parts of the casing fo:c about 2 hours, then blowing sir strongly in a vertical direction upon the end parts to loosen the ho:llow~fibers at the end parts) before formation of the sealing plate. However, the more preferable method i.s to introduce spacers for preventing adhesion of the. hollow fibers to one another during the process before preparation of tha hollow fiber bundle after the wetting agent has been added.
When used as a hemadialyaer, this method of CA 02180222 1996-07-31, ~iou~~~
za introducing the spacers has also anothe.c effect of a7.lowing the dialyxate to flow to the central part of the holJ.ow fiber bundle to enhance 'the dialytic performance.
Introduction of the spacers may be implemented by imyarting spacer yarns of polyester, poiyamide, polyacrylonitrile, cellulose acetate, silk or cotton along, or helically winding them around, one ar two hollow fibers.
To completely prevent the seal leakage by such a method, it may be necessary to use a thick spacer yarn of diameter of about one half or more i;about 120 microne~ or more)' of the outer diameter of hollow f:i.ber, leading to a greater diameter of the case of the hemodialyzer, and this is not so preferable. A mare preferable method is to introduce spacers in two steps, as described below. That is, in the first step, unit hollow fiber elements area produced by the method of either impart:lng or helical.ly winding spacer yarns of polyester or, the like along or around one or two hollow fibers and, in the second step, bundles of hollow l:ibers are provided by helically winding the spacer yarns as spacers around an aggregate of four or more said unit hollow fiber elements, and five or more said hollow fiber bundles are assembled into s bundle of a specified number of hollow fibers for a hemodialyzer. In this oaso, the unit hollow fiber elements are preferably provided by the helical winding method.
For the spacer yarns introduced in the first and second steps, .relatively bulky and stretchable crimped fibers, finished yarns and spun yarns are preferably used.
In addition, their thickness is preferably finer than that of the polysulfone hollow fiber, more preferably about 1/20 of the outer diameter of hollow fiber, and a fineness of 1/2 to 1/lf3 of the outer diameter of hollow fiber is pref~rable.
Such introduction of Spacers facilitates formation of the sealing plate under conditions where the wetting agent is imparted in a concentration (quantity) sufficient to prevent deterioration of the performance of the membrane by drying, and by this procedure, hemadialyzers having a high water permeability and a high capacity for removal of-.
urinal toxic substances and having an albumin permeability controlled to 3% or less, are obtainable in a high yield.
Fabrication (modulation) of the bundles of hollow fibers thus obtained into hemodialyzers is practicable by any conventional method.
That is, for example, fiber bundles are insertecl in a case of, say, polystyrene resin, and using s potting material such as a polyurethaner a sealing plate through which the hollow fibers pass is formed at each end of: the case using a centrifugal farce, then a :Leak test is performed before the bundles are farmed into the hamodialyzer.
Next, the very small amount of solvent and wetting agent which may remain in the hollow fiber membrane i.s removed by washing with water, then sterilization is carrie4 out while water fills th4 membrane to provideA a desired hemodialyzer product, Washing may be carried out using water at about room temperature, up to, say, 90°C, but is preferably Carried out at a temperature of at least 40°C. In particular, it takes a period of about 2 hours at 55°C Or 15 minutes at 80°C, &o washing with warm water at 55°C or higher is especiahly preferable. zt is also possible to employ repeated washing, for example, washing for a short time, then warming at 50°C or higher, and again washing for a short time.
In 'the oase of a blend membrane additionally containing a water-soluble hydrophilic polymer, there is a danger of dissolution of the hydraphilir. polymer when used for medical purposes.
Rare, it is possible to cross-link the hydrophilic polymer and thus make it insoluble by radiation and/or S heat. Specifically, a heat' treatment (about 120°C) may be given, or gamma-rays or electron beams may be irradiated under wet conditions. The expoaurc dose is adequately 15-35KGy under a submerged condition. When a dose exceeding 20KGy is irradiated, it is possible to carry out a sterilizing treatment simultaneously. Radiation of gamma-rays or electron beams praduces covalent bonds with the-polymer materi.;~ls, and the di9solution of the hydrophilic polymer 1g checked. In the case of the heat treatment, the hydrophilic polymer itself gels f.nto a higher molecule and insoluble form. fo:c sterilization, any conventional method is applicable, that is, sterilization with hot water of a3t 90"C or higher or sterilization by radiation using gamma-rays or electron beams under t?oe water filled conditf,on. Sterilization by radiation using , gamma-rays or electron beams is a preferable method ~.n that it renders the hydrophilic polymer in the membrane insoluble through cross-linking. When using polyvinylpyrrolidone which is the moat preferable hydrophilic polymer present in a membrane according 1:o the invention, radiation of gamma-rays in a dosage within the range of about 20KGy-35KGy causes insolubility throuSth cross-linking of the polyviny.lpyrro~.3~done along faith sterilization as required far medical equipment, and hence this is the most practical method of sterilization.
Radiation sterilization gives rise to lnsolubil~.ty thzough cross-linking of polyvi.nylpyrrolidone simultaneously and thus checks the dissolution of the polymer and enhances the safety of the product. In addition, by this method, it is possible to allow much more pvlyvinylpyrrolidone to be present in the hollow fibers of the product to provide a membrane having good affinity.saith 2~$~~~
z~
water and thus exhibit the high performance attainable by membranes embodying the present invention. Far insolubility through cross-linking c~f polyvinylpyrrolidvne, it is of course possible to separately apply radiation S before sterilization, but it ~.s prefe:rable for obtaining a membrane of high performance to simultaneously implement the cross-linking and sterilization by radiation.
Preferred embodiments of the invention will now be described in more detail with reference to the following Examples in which parts are by weight unless otherwi:~e stated.
Evaluation of the performance of membranes accos;9ing to the invention was made by the following methods.
(1) Water permeability.
Using 30 hollow fibers of a length of about l5cm obtained by cutting the case of a completed hemodialyzer product .
i.e. subsequent to its radiation by gamma-rays, a'smc~ll glass tube module is prepared by repottang respnctivEs opposite ends of the fibers, and the differential pressure between the inside and outside of the membrane, that is, intermembrane differential pressure, is measured by 2S permeation of water. at a pressure c~f about 100mmFig and expressed in ml/hr ~ mmHg ~ m.Z. The water permeation performanoe was calculated by the following~formula.
UFR( ml/hr/m~/mmHg ) - Sew/ ( p x T x A ) wheze Ow is the amount of the filtrate (m1), T the efflux time (hr), F the pressure (mmHg), and A the area of the membrane (m') (in terms of the area of the inner surface of the hollow yarn).
(2) Determination of diffusion by dextran.
eaefcally, this measurement is made similarly to that of the dialytio capacity. It is generally as follows.
Firstly, s hollow fiber membrane dialyaer has a blood side thereof perfused with 500m1 of warmed bovine serum at 37°C
at 200m1/min for 50 minutes but without any flow of the dialysate, then the dialysate is removed and filtration, controlled by the flow rate of the perfusate, occurs at a rate of :20m1/min for 10 minutes tithe foregoing process being regarded as 1-hour circulation of bovine serum).
After storing for J.2 hours in a refrigerator, the dia.lyaer is washed by priming with 21 of physiological salt solution before it is used for testing, t7extrans of respective varying molecular weights (FULKA's product, weight-average molecular weights of 400, 1000, 2000, 2!)000, 50000 and 200000) are each dissolved in water for ultrafiltrati.on at respective concentrations each of O.Smg/ml sa as to provide a solution contain~:ng 3 mg/ml of dextran with a distribution therein of molecular weights. This solution is warmed up to 37"C, and fed to the blood side (ins~.de of the hollow fibers) by a blood pump at a flow rate of 200m1/min, while the dialyzate side has ultrafi:Ltrate~d water kept at 37°C and fed at 500m1/min in countercuzrent flow to that of the blood. Here, the filtering pressure should be adjusted to zero. Accordingly, the diffusing capacity of the membrane is determined under conditions under which no ulttafiltration is caused. Feeding is continued for 20 m:f.nutes until an ec~uil5.brium state j.s established, then samples are taken at the inlet and outlet o~ the blood side and the dialyzing side. Sample solutions are subjected to analysis by a GFC column (T0s0 GPRL:9000) at a column temperature of 40°C, and tha transfer phase at lml/min of pure water for liquid chromatography and sample drive of 50u1. The general mass transfer coefficient is then obtained by d~atermining the change of concentration at the inlet and outlet of the blood side. Thereafter, the Ko value at a point corresponding to a dextran molecular weight of 10,000 is obtained. Here, calibration must be made with dextran of a definite molecular-weight distribution used before the sample is applied to th~a GPC
column. The general mass transfer coefficient is 761 99--2.5 calculated using the following formula.
Clearance, Ct I; rnl /min ) = C ( C8i-CHo ) /C131 ~ Qa ( 2 ) 5 where CHi: module inlet side concentrata.on; GBOa module outlet side concentration; and t~8: module supply liquid (perfusate) flow rate (ml/min).
General mass transfer coefficient FCo(cm/min) - gs/~A X 104 x (1-Oa/S~D) x ln(1-~(C~/Qp)l/L1-(GL/Og)l~ (3) where A - area (m~); and Qp - dialysate flow rate (ml/min).
(3) Measurement of albumin permeability.
Bovine blood (heparin treated blood), of hematoorit value 30% and total protein 5.5g/dl, is fed to the inside of the hollow fiber at 20Um1/min. Controlling the butlet pressure, the filtration ie adjusted to a rate of 20m1/min, and the filtrate i;~ returned to 'the blood tank. One hour after start of refluxing, the blood and filtrate at l:he inlet and outlet of the hollow fiber side are sampled.
Analyzing the blood side by HCG method and filtrate side by CHB method kits, the albumin permeability (~S) is calculated from the concentrations.
Albumin permeability ( % ) ~ 2,~_C_~,~ x 100 ( 4 ) (C8i t CBo) where Cf: albumin content in filtrate; CHi: albumin content at module inlet: and CSo: albumin content at the module outlet.
(4) Determination of in vitro ~a-MG removal capacity.
Basically, this determination is made similarly to that of the dialytic capacity. In a minimodule of a membrane area of 25cma. human p~--MG is dissolved in a concentration of a ~~
5mg/ml in 30m1 of irref il.ter~ecl tacav~iat~ s~~rnat0., and ttxe solution is perfused to the inside of t:Ya~= holl.0~~~ fabers at a rate of lm~./min, while t:r~ ther t~F.t~.si~~es of c.3a~~ ts~~liaw f.Gbet°s, 140m1 of phasptuate buffex~ec:~ sc~l:i.oy4y (P~.~;~) kept, ~~~:. ~"7°t::' is perfused at a rate of 2Qm1/mi.n i.at a closed system. After 4-hours perfusion, the sod utl.ons:;, of i:~er.f~us;iot~ can the inside and outside of tYte ha7l.ow 9~i~ve;r~,,; are c;c:~:l'lec:~ted. Then, the clearance is c:alc:t_nlat:.ecl~ ar~td i~.~» ~ra:ltae p~:r° membrane area of 1,.8m~ is obtained.
(5) Determinatian of tim cl.eGrzab~c~~~;~ ~u~f urea anti phasphorus.
Preparing 501 of a pY~ydial~.5gica~. :~a~.t. sa:Lutian Containing each of 1000ppm. Y,,f ar~~~ an~:I X70 ~:'p~w~ ~;~:: p~°tc~sphori.c acid as blood ( i . a . perf usate ) s~:~ i n..tfi.icr:rr aaEC~. 10f~ "d of physi ologic,al salt solutian as dialysi..s solution, lwhe cYonce:ntrations at the blood side inlet and ~m.rt:~.er G~f_ t:he ~i.i..aly<.Pr are measured with the blood f low set. a t 2(~Orn.°~ i mini" c:i.;i.a'~ ~x~:~t; a f law at: 500m1 /min, and the standard c~.earartces cart the Llr'ari and dialyzate sides are calculated, and their oean r~a~.ues a:re a.ase~~.

(6) Determinatian caf p;~ros~.t:y.
A sample is .observed taxing a sE:anni-nc~ a Leatron microscope to canfi.rm t~-~.at: substan~:i~~~l. rn~:~n:;r°av~:,ritis ~ re:Ya"rring to a strr.tature in which mac~ravuids aiaen disc.~aa°~ticzta~:;~a..rsly;i in ~uhe inner :Layer part and the parosi.ty :is c~~lculated from the fiber weight ~
in a dry daondition, hollow fi.ber~ anembraa:re size' (inner diameter :ID and me,mbr.,.~tte t:l°a.ic~'k~tes:~.'. ~7"L') r polymezT
s~>ec:ifi<~
gravity d and hollow ~~~iber LeragPNtv 2 as k~callraws:

2~~~~~~!
., .~
c ~. .. e,; ~ ~.~
Porosity ( '" ~ - ~c 100 r~ ~~~~ ~ x ~a ~ ~~~ :p ( 7 ~ C9bservation of mE~m~~x'arm strrrr:tuxve .
Freeze, drya.ng the k~o~lr~w fiber mern~st:wrre~, the structures of lt:i C.'rOSS_.S~c.:tlcJn ariP:~ LC'~r'~F_°'.T" slll~;cA~;'.'t' <)r:'E.A
t)r.7sE'C'11E?d ~'l',~ c1 sa;annirrg E.~lectrorx mi~:~~r4~sco~e, '~~raE~ ,~~r~:.,r.agP pore radius of the active layer is calculated ~:;Prrc~rrgtr measuremerrt of a freeze dried sample (3, 5 cam ler~gthrr 0. "~g.r key the N2 adsor,ntion 1~ rnet;had (BFT met:hoti) , ( ~c ) ( s ) p~-microglabu l irr remova:l .
Blood dialysa.s is ray r~.E~d ~arW.. arpor~ s:~.x patients of a weight of 50kg-60kg acrd ,:~ y3,~ -xru.L:c~~gLol~w.:kl i.r~ l..eve ~. of 25-3 5mgl l, hap~arirr baitzg ~rddad t:.~ rya L~.~.c>r:>~:~ ~~~.;Gr~..rre~ ~:~ialysi.s ~~;~
an anti-coagulant, wit~r a ~alc~~d flow aye 2C~l.~lrr~~.lmirr, dialyzate flow at 500mllmin, and water removal in 4 h<>r.~.rs at. °t...5-3.51., and the j3~,-microglobul:i.n c:,r)nr;,:~r~t::.ra~;ic:~rr~ b~~fs~ar:e ;:~rrd after irhe dialysis ax°e rneasuretl arid t:4al.~~,alat;ea:~ ~~y i::ht~ l.t~te~ i.mmu:no-aggluti:natian 20 method, with compensatiory made for the ~ar.otei:n concentration, and the mean value is ~rsed, TheX '.. globulin removal is r_alculated fror~r ~~32-MG1- ~ ~VR'~-MG2 ~- f d:'tp1 i s;:"tY~~ 1 ~ x l.nQ
~~~.._p.qG 1 where:
~tpl is t3-~e total laro ~ei.n eaorrcentx at.7 on before dialysis;
Ctp~ is the total ~>r~>1::E~i.rr c:°c)rkcerrtz at,:~.on ~~ftex dia7.ysis;
CR2-MG1 is the total ~i~-r4G corrcerr~,xat:.icrrr before dialysis; and 3~ C(32-MG1 is the total ~3,~-MG conc.entratiosr after dialysis.

( 9 ~ Viscosity of :spi.nan:irng solit::i ~a~r°c Me;~suremEnt is made ~.~s~_~~.~g a_~~_~-~,pe ~is~:-osa.met.er (TOKTMEKKU
Corp. , W'-811 digital. visCOSimeter) anc:~ the spinning solution sarrGpled i.n an amount o:F ~OOn~L car:. ~nr.~r:er with ~~are t;~ken so that ttue measurement w~auld rx~at: L.~e .~ffe~~ted kay the inner diameter of the vessel.
1U ~ Dialy2ances ~:"f ~~re~~ arrc~ vit;«~n:irr E~ 2 A perfusate for dialysis is abtairred b~ dissolving each of 1~ 60c~ of urea anc~ 1.2g of arit,arn~.~~ E ,~ :l r, 5G7 l:r.ters ~~f water, 7. ,_ concentrati<ans of pcx fcrsat~a 4~t 4:.iv~S peria~a-te irrle~t and outlet and concentrations of f.~.~al~zate atthe d:~aly~ate .inlet and c>ut.let of the ,;:~ial.yaF~r aa;e ~nHSa:~erecl w~t.h the perfusate flow set at 2nOmllmin, dial~z,at~: ~':low~ art }~Clini.fmir~, and filtration speed at lOml/min, then the blood based and dialyzate-based dia.ly~ar~ces are c:al~~~~lui:.ed,, a~rzc:~ ~t~~e:~x m~~f~an values expressed in ml/min are empl.oye~3.
Example 1 20 1$ parts of ~ po:ly~~ul~~or~e ~ ~N~~)~':C ~ s ~de1--E3500 ~ arrd 9 parts of polyvinylpyrrol ..done ( ~A~~" K3C~ ) were added to 71. 95 parts of da.metYa~ylac.ev~ami.de fi~r~~~ 1 . ~~5 ~.~arv,s of water, and the mixture wa:: heated at '~0~"C ~.or: 1.~" h~.~urs to dissolve the components into a spinning solut:i;~~n> Thas solution was extruded from «n ar~rnu:lr~x° s~~ir:anirog c~r:a.fi;:::~~ of ~~ut.eu diameter 0.3mm and ir~nez di.ameoe.r 0.2n~m ~.oge~t°~~er with a solution consisting of t5 parts e~f cdimettryla~Yetamide and 35 parts of watar as ;~ Coz°a ;~c~la~::Lcar~~ w:J tl:~i.zr ~a ~ha~~t:.~,e caf t.lua s~~ironinc~

28a solution. The core/sheath passed from the orifice into a dry zone which is 300 mm in length and which contains air at a relative humidity of 88o and a temperature of 30°C, at a speed of 40 m/min. The core/sheath then entered a coagulating bath of a 20~ aqueous dimethylacetamide solution at a temperature of 40°C, in which a hollow fiber membrane was formed. This hollow fiber membrane was inserted in a case to form a module with a membrane area of 1.6m2 with potting. After 'irradiation of_ the module with gamma-rays with the membrane in a wet condition,. clearances of urea and of_ phosphorus and albumin permeability were determined. The in vitro urea clearance was found to be 19Gm1/min, phosphorus clearance was 181m1/min, and albumin permeability was O.:L2o.
Further, the- 1.8m2 conversion clearance, i.e. clearance per area of J..8 m2, of J32-MG was 44m1/min.
Example 2 18 Parts o.f a polysulfone (A110C0's Udel-P3500) and *Trade-mark ' ~ 76199-25 parts of polyvinylpyrrolidone (BASF~'K30) were added to' 71.70 parts of dimethylacetamide and 1.30 parts of w2~ter, and the mixture was heated at 90°C for 12 hours to dissolve the components into a membrane stock solution. This solution was extruded from an annular spinning orifice of outer diameter 0.3mm and inner diameter 0.2mm together with a solution consisting of 65 parts of dimethylacetamida and 35 parts of water as a core solution to form a hollow fiber membrane under the same conditions as in Example 1, except that the relative humidity of the air in the dry zone was 73% and the dry zone length was 350 mm. This hollow fiber membrane was inserted in a case to form a module with a membrane area of 1.6m= through potting. After gamma-ray irradiation with the membrane in a wet state, clearances of urea and of phosphorus and albumin permeability were determined. The in vitro urea clearance was 196m1/min, phosphorus clearance was 188m1/min, and albumin permeability was 0.17%. The l.8ma conversion clearance of ~a-MG was 53m1/min.
Example 3 18 Parts of a polysulfone (AMOCO'S Udel-P350D) and 12 parts of polyvinylpyrrolidone (BASF K30) were added to .68.55 parts of di.methylaoetamide and 1.45 parts of water, Z5 and the mixture was heated at 9D°C for 12 hours to dissolve the components into a membrane stock solution. This solution was extruded from an annular spinning orifice of outer diameter 0.3mm and inner diameter 0.2mm together with a solution consisting of 65 parts of dimethylacetamide and 32 parts of water as a core solution to form a hollow fiber membrane under the same conditions as in Example l, ~sxcept that the relative humidity of th~a air in the dry zone was 85%'and the dry zone length was 350 mm. This hollow fiber membrane was inserted in a case to give a module with a membrane area of 1.6m2 through potting. After gamma-ray irradiation with the membrane in a wet state, clearances of urea and of phosphorus and albumin permeability were *Trade-mark ~18t122~
determined. The Ln vitro urea clearance was 197m1/min, phosphozus clearance was 185m1/min, and albumin permeability was ass 0.32%. The l.Hma conversion clearance of ~3a-MG was 59m1/min.

Comparative Example 1 18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 parts of pvlyvinylpyrrolidone (BASF K30) were added ro 72.00 parts of dimethylace~tamide and 1..0 part of water, and 10 the mixture was heated at 90~C for 12 hours to dissolve the components and thus glue a membrane stock solution. This solution was extruded from an annular spinning orifice of outer diameter 0.3mm and inner diameter 0.2mm together with a solution consisting of 65 parts of dimethylaoetamide and 15 35 parts of water as a core solution to form a hollow fiber membrane under the same conditions as in Example 1, except that the relative humidity of the air in the dry zone. was 85% and the dry zone length was 350 mm. This hollow fiber membrane was inserted in a case to give a module with a 20 membrane area of l.6mZ through potting. After gamma-ray irradiati,owwith t'he module in a wet state, the clearances of urea and of phosphozus and albumin pHrmaability were determined. The urea clearanc$ was 195m1/min, phosphorus clearance was 181m1/min, and albumin permeability was 25 0. 12%, The 1. Brna ronversion clearance of iii-MG was 42m1/min.
Example 4 18 Parts of a polysulfone (AMOCO's Udel-P3500) and 9 30 parts of polyvinylpyrrolidone (BASF K30) were added to 71.7 parts of dimethylacetamide and 1.3 parts of water, and the mixture was heated at 90°C for 12 hours to dissolve the components into a membrane stock solution. This solution was extruded from an annular orifice provided by respective axial ends of a pair of coaxial tubes of outer diameter 0.3mm and inner 8iameter 0.2mm together with a solution consisting of 70 parts of dimethylaoetamide and 30 parts of ~~~~2~~
water as a core solution to form a hallow fiber membrane under the same conditions as .in Example 1, except that the relative humidity of the air in the dry zone was 85%, the length of the dry zone was 250 mm and the coagulation temperature was 50°C. This hollaw fiber membrane was inserted in a case to form a module with a membrane area of l,bmz through potting. Next, after gam~ria--ray radiation in a wet state, the albumin permeability was determined, end it was 0.75, and in the diffusion test w~.th dextrin, the general mass transfer coefficient Ko af"ter 1 hour circulation of bovine serum was, at the dextrin molecular weight 10,000, 0.0018cm/min»
This hollow fiber membrane was confirmed to be a membrane having a :spongy structure in the internal layer part, a hydrophilic property provided by polyvinylpyrrolidons, a parasity of x"9.5% and an asymmetrical structure with an average pore radius of active layer of 6.'7nm.
Example 5 19 Parts of a polyaulfvne (AMCICa's Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K30) were added to 70.7 parts of dimethylacetamide and 1.3 parts of water, and the mixture was heated at 90°C far 12 hours tn dissolve the components and form a membrane stock solution. This solution was extruded from an annular o~rific~ (provided as in Example 4) of outer diameter O.~mm and inner diameter 0.2mm 'together with a solution consisting of 70 parts of dimethylacetamide and 30 parts of water as a core solution to form a hollow fiber membrane under the same conditions as in Example 1, except that the relative humidity of the air in the dry zone was 85%, the dry zone length was 250 mm and the coagulation temperature was 50°C. This hollow fiber membrane was inserted in a case to give a module with a membrane eras of l.6ma through potting.' Next, after gamma-ray irradiation with the membrane in a wet state, the CA 02180222 ~ ~ ~ ~ ~ 1~

albumin permeability was measured, and was 0,5$%, and in a dextran diffusion test, the general mas~~ transfer coefficient Ko after 1 hour circulation of bovine serum was, for a dextran molecular weight of 10,000, 0,0015cm/min.
mhis hollow fiber membrane was confirmed to be a membrane having a spongy structure in the inner layer part, and to.have a hydrophilic property provided by the polyvinylpyrrolidone, a porosity of ?8.;t% and an asymmetrical structure with an active layer having an average pore radius of 5.2nm.
Example 6 19 Parts of a polysul~ane (AMOCO'S Udel-P3500) and 9 parts of polyvinylpyrrolidone (HASF K601 were added t:0 ?0.0 parts o~ dimethylscetsmida and 2,0 parts of water, and the mixture was heate8 at 90°C for 12 hours to dissolve t:he components into a membrane stock solution. Thfs solution Was extruded from an annular orifice (provided as in Example 4) of outer diameter 0.3mm and inner diameter 0.2mm together with a solution consisting of 63 parts of dimethylacetamide and 37 parts of water as a core soa.ution to form a hollow fiber membrane under the same conditions as in Example 1, eucept that thA dry zone length was 350 mm and the coagulation temperature was 50°C. This hollow fiber membrane was inserted in a aasA to form a modu7.e with a membrane area of 1.6m~ through pottinn. Next, after gamma-ray irradiation with the membrane in a wet atal:e, thA
albumin permeability was measured, and was 1,38%, and in a dextran diffusion test, the general mass transfer coefficient Ko after 1 hour circulation of bovine serum was, for a dextran molecular weight of 10,000, 0.0022cm/min.
This hollow fibex membrane was confirmed to be F~
membrane having a spongy structure in the internal layer part, a hydrophilic property provided by polyvinylpyrrolidone, a porosity o~ 81.2% and an asymmetr:Lcal structure with an active layer having an average pore radius of 5,8nm.
Comparative 5xample 2 13 Parts of a polysulfane (AMOCO'S Udel-P3500) and 9 parts of polyvinylpyrrolidone (BASF K30) were added to 71,95 parts o~ dimethylacetamide and 1.05 parts of water, and the mixture wa=. heated at 90°C for 12 hours to dissolve the components into a membrane stock solution. This solution was extruded from an annular orifice (provided as in Example 4) of voter diameter 0.3mm and inner diameter 0.2mrn together with a solution consisting of 65 parts of dimethylacetamide and 35 parts of water as a core solution to form a hollow f3.ber membrane under the same conditions as in Example 1. This hollow fiber m9mhrane was inserted in a case to form a module with a membrane area of l.6ma through potting. Then, after gamma-ray irradiation with the membrane in a wet state, the albumin permeability was measured and was 0.12%, and in a dextran diffusion test, the general mass transfer coefficient Kc~ was, after 1 hour circulation of bovine serum, LI.UOU9cm/mi.n.
This hollow fiber membrane was aoni~irmsd to be a membrane having a spongy structure 3n the inner layer part, a hydrophilic property provided by the polyvinylpyrrolidone, a porosity of 78.:>.% and an asymmetrical structure with an active layer having an average pore radius of 5.3nm.
Example 7 18 Parts of a polyaul~one (AM~CO's "P-3500"), 6 parts of polyvinylpyrrolidone (B~1SF'g "K30"; molecular weight, about 40,000) and 3 parts of polyvinylpyrrolidone (BASF's "K90": moleoular wen ght, about 1,100,00U)~were added to a mixed solution of 11.95 parts o~ dimethylacetamide and 1.05 parts of water, and the mixture heated at 80°C with stirring for 12 hours to dissolve the components, to prepare a spinning solution. This spinning solution was a homogeneous, slightly opaque but otherwj.se clear solution of a viscosity of 76,9 poise at 30°C.
This spinning solution was extruded from an annular nozzle spinneret at 30°C, while an infusing solution prepared by mixing 60 parts of dimethylF~cetamide and ~40 parts of water was introduced from a central part of the spinneret nozzle. Settf.ng the length o!: the dry zone at r 250mm and allowing moist air of a relative humidity of 88$
to flow tn the section, spinning was carried out at a speed of 40 m/tnin. The hollow thread was then led to a coagulation bath (dimethylacetamide/water (weight ratio) -20/80) at a temperature of 40°C, and the hollow thread coming out of the coagulation bath was washed and then immersed in a 68% by weight aqueous sohrtilon of glycerine.
After removing the excessive glycerine .sticking to the surface, a unit hollow fiber element was provided by helically winding a finished false twist polyester yarn of 50 denier 5 filaments (about 88 microns) around 2 hollow fibers in a Z direction at 0.5 winding per lOmm of hollow fiber. Then, assemt~ling 29 units of such unit hollow fiber ' 25 elements, the same finished polyester yarn was wound around the assembly nearly at the same pitch in an 5 direction.
8y thus providing 2 layers of spacers, sin assembly of unit hollow fiber elements was fabricated. sy assembly then of 221 assemblies of unit hollow fiber elements, a hollow fiber bundle was provided. This hollow fiber bundle was revolved in ~ centrifugal separator to remove the aqueous solution of glycer:~ne replacing the infusing solution and sealed in the hollow threads to give a bundle of hollow Fibers to be inserted in a hemodia7.yzer case. This hollow fiber had an inner diameter of 200 microns and an outer diameter of 280 microns, and the hollow fiber bundle had 10,609 hollow fibers assembled fn it.
7f199-25 This hollow fiber bundle was insert:ed in a hemodialysis case of an inner diameter of 40mm. Then, with a temporary cap fitted to each end of the case, polyurethane was ir~txoduced from the inlet of the dialysis solution and than solidified. Removing the temporary caps and cutting off the polyurethane and the end parts of hollow thread bundle corning out of the Fends of the case, header caps were fjated, and a leak test: was conducted using air at a pressure of 0.$kg/cmZ.
As the result of the leak test using 1000 samples, failures were found in 1.2 samples. Looking into the cause, they were found to be caused by end breakage and thread cut due to Simple failure in work or contact of the hollow fiber bundle with j:he end part or inner wall of the oase when it was inserted in the case, and there was no seal leakage found in the polyuxsthane sealing plate.
Next, a module found aoceptable in the leak test was washed with pure water running through a reverse osmotic membrane for 30 minutes at 80°C and packed. Then, it was irradiated and sterilized by gamma-rays at a power of 32KGy, and a hemodialyxer of an effective length of 195mm and an effective area of 1.3m2 was provided. This dialyzer was found to be acceptable for all ~.tem:~ of the approval standard for hemodialysis apparatus. The water permeability of the hollow fiber cut out of this module was 815m1/hr ' mmHg ' ma. The albumin permeability of the module waa 1.2%, urea dialyaance was 195m1/min, and vitamin Hla dialyzsnce was 143m1/mln.
In addition, when this module was used for clinical evaluation, it gave a very high $ pa-rnicraglobulin removal at 73% and was found usable without any problem such as residual blood.
Example 8 76:199-25 ~I$02'~
~s 18 pants of a polysulfone (AM0c;0's "P-3500") and. 9 parts of polyvinylpyrrolidone iBASF''s "fC-30") were added to a mixed solution of 71.6 parts of dimethylacetamide and ' 1. 40 parts of water, and the ml.~cture wa;~ heated at 90 ° C
with agitation for 12 hours to ~3issolve the components and form a spinning solution. This spinning solution had a viscosity of 28.4 poise at 30°C (38.8 poise.at ;~0°C).
This spinning solution was extruded from an annular nozzle spinneret at 30°f, while an infu:~ing solution prepared by mixing 65 parts of dimethylagcetamide and 35 parts of water was ~.n,jected from the central part of the spinneret. The solution emitted from the spinneret r~ntered a dry zone set at a length of 350mm, whc;re it was exposed to moist air of a relative humidity of t34$ in this section.
Spinning was carried out at a speed of 40m/min, and a hemodialyzer was fabricated by a method similar to that in Example 7. However, during the course of fabrication, a leak test was conducted with 1000 samples used. Fai7_ures ooourred in 17 samples, but the causes were the same with those in Example 7"
The thus obtained dialyzer of an effective area of l.3mZ was found acceptable for all item: of the approval standard of hemodialyzers. The water permeability o!: the hollow fiber cut out of the dialyzer was lOml/hr ' mmHg ma, and the albumin permeability of the module was 0.4$, and the urea and v:Ltamin Bla dialyzances were respectively 194m1/min and 139m1/min. In the clinical evaluation of this module, it gave a ~ ~~-microglobulin removal of 57%
and was found usab:Le without any problem such as residual blood.
Example 9 18 Parts of a polysulfona (AMOCO's "P-3800") and 9 parts of s polyvinylpyrrolidone (BASF's '~K-30") were added to a mixed solution of '71.8 parts of dimethy:Lacetamide and 1.2 parts of water, and the mixture was heated at 80°C with agitation for 12 hours to dissolve the components and form a spinning solution. This solution had a viscosity c~f 26.8 poise at 30°C, Then, using as an infusing solution, a composition of 60 parts of dimethylacetami6e and 40 parts of water, a hemodialyzer was prepared by a method similar to that in Exa~rnple 7.
The water permeability of the hollow fiber cut out of this dialyzer was 740m1/hr ' rnmHg ° m~, t:he albumin permeability of the module was 0.1%, and the urea and vitamin Hla dialyzances wer~ respectively 192m1/min and ' 136m1/min, per area of 1.3 mz. when th5,s module was used for a clinical test, it gave a $ ~~-micxoglobulin removal of 62~ and was found usable without any problem such as reBidual blood.
Example 10 Assembling 170 and 306 bundles of hollow fibers in the course of process of Example 7, bundles of hollow fibers were prepared, and they were inserted in hemodialysis cases of inner diameter 35.5mm and 46.Smm respectively to produce hemodialyzers by the same method as that in Example 7.
The effective areas were respectively l.Om~ and 1.8m~, and when the vitamin 9i~ dislyaances were measured, they were 127m1/min and 165m1,/min.
Example 1l Using the bundle of hollow fib~rs in the course of process of Example 9 but changing the assembled numb~r of fibers, bundles of hollow fibers were prepared. Then, they were inserted in hemodialysis cases of inner diameters of 35.5mm, 44.Omm and 46.5mm, and hemodialyzers with effective erase of l.Omx, 1.6m~ and 1.8m~ were prepared by the same method as that in Example 9..

Measuring the urea and vitamin J812 d~.alyzanees and albumin permeabilities, the urea dialyzances were 187m1/min, 195m1/min and 197m1/min: vit.3min B~Z dialy~:ances were 122m1/min, 14"7ml/min and 156m1,/min; and albumin permeabilitias were 0.2%, 0.1% and 0.2~%, respectivel~~.
comparative Example 3 1B Parts of a polysulfone (AMOCO'S "P-3500") ancG 9 parts of a polyvinylpyrrolidone (BASF's "K-30") were added to a mixed solution of 44 parts of dimethylacetamide, 28 parts of dimethylsulfoxi.de and 1.0 part of water, a.ncG the mixture was heated~st 80°C with agitation for 15 hours to dissolve the components and form a spinning solution. This spinning solution had a viscosity of 32.9 poise at 3C!°C.
This spinning solution was extruded from an annular c~rif3ce nozzle spinneret at 30°G, while, as an infusing solution, an admixture of 60 parts of dimethylacetamide and 40 parts of water was injected through the central part of the?
spinc~eret. Then, a hemodialyzer was prepared by the same method as that in 8xample 7.
The water permeability of the hollow fiber cut Taut of the dialyzer was 830m1/hr ' mmHg ~ m~, the a:Lbumin permeability of the module waa 0.2% and the vitamin E3la dialyzance was 132m1/min.. In a clinical test to which this module was subjected, the ~a-microglobulin removal rate was as low as 49%.
Comparative Example 4 after washing the coagulated and desolvated hollow thread of Example '7, it was immersted in a 45% by weight aqueous solution of glycerine. After the excessive ' glycerine sticking to the surface was removed, it waa taken on a hexagonal hank, each side of whl.ch had a length of 60cm, and air dried at room temperatrare. Then, by cutting it out;of the hank, a bundle of hollow fibers was prepared.
This hollow fiber bundle was an ass~nbly of 10,608 hollow ~18a222 fibers. The hollow fiber bundle was in:~erted in a hemodialysis case of an inner diametex~c~f 4omm, and dry air was blown vertically to both end faces of the hollow fiber bundle to loosen the end parts. Then, aealing plates were S formed by the same method as that in Example 7.
Introducing pressure airy from the dialy:zate side and filling water to the blood side, a leak test was made according to the bubble point method. 'then, through the gamma-ray sterilization by the same method as that in Example 7, a hemodialyaer was prepazed.
The water permeability of the hollow fiber cut cut of this module was 410m1/hr ' mmHg ' m~, albumin permeability was 0.3%, urea dia~lyzanoe was l~Oml/min, and vitamin dialyzance was 125m1/min. Thes~ values :~f water permeability and urea and vitamin B,z dialyzance were all relatively low. That is, when a low concentration of glycerine is added,. the tube plate may be formed reac'lily without spacers, but deterioration in the permeability of the hollow fiber occurred due to drying. Thus it was difficult to produce a hemodia~,yzer of high performance such as that according to the present invention.

Claims

1. A hollow fiber membrane which comprises a polysulfone resin and a hydrophilic polymer and is characterized by:
(i) an albumin permeability no more than 0.5%;
(ii) per membrane area of 1.6 m2, an in vitro urea clearance of at least 195 ml/min;
(iii) per membrane area of 1.6 m2, an in vitro phosphorus clearance of at least 180 ml/min; and (iv) per membrane area of 1.8 m2, a f3z-microglobulin clearance of at least 44 ml/min.

2. The hollow fiber membrane according to claim 1, wherein the polysulfone resin has a repeating unit of the formula:

3. The hollow fiber membrane according to claim 1 or 2, wherein the hydrophilic polymer is at least one member selected from the group consisting of polyvinyl pyrrolidone, polyvinyl pyrrolidone copolymer, polyethylene glycol and polyvinyl acetate.

4. The hollow fiber membrane according to claim 3, wherein the hydrophilic polymer comprises polyvinyl pyrrolidone.

5. The hollow fiber membrane according to claim 3, wherein the hydrophilic polymer is cross-linked.

6. A module for the treatment of blood for removal therefrom of an undesired material, which module comprises:
a housing and, disposed within the housing, a hollow fiber membrane, wherein the housing has at least a dialysate inlet to allow entry into the housing of a dialysate and wherein the hollow fiber membrane has an internal periphery defining a blood flow conduit and an external periphery for contact thereof with the dialysate in the housing, the hollow fiber membrane being capable of allowing selective passage, across the membrane from the internal to the external periphery thereof, of the undesired material, whereby during passage of the blood through the blood flow conduit, the undesired material in the blood passes across the membrane into the dialysate, the hollow fiber membrane comprising a polysulfone resin and a hydrophilic polymer and being characterized by:
(i) an albumin permeability no more than 0.5%;
(ii) per membrane area of 1.6 m2, an in vitro urea clearance of at least 195 ml/min;
(iii) per membrane area of 1.6 m2, an in vitro phosphorus clearance of at least 180 ml/min; and (iv) per membrane area of 1.8 m2, a .beta.2-microglobulin clearance of at least 44 ml/min.

7. The module according to claim 6, wherein a bundle of the hollow fiber membranes is disposed within the housing, whereby when the housing is filled with the dialysate, the dialysate is disposed between the respective hollow fiber membranes of the bundle thereof and surrounds the respective external peripheries thereof.

8. A method for the treatment of blood to remove therefrom an undesired material, in which blood is separated from a dialysate by a hollow fiber membrane capable of allowing selective passage across the membrane, using a hollow fiber membrane which comprises a polysulfone resin and a hydrophilic polymer and is characterized by:
(i) an albumin permeability no more than 0.5%;
(ii) per membrane area of 1.6 m2, an in vitro urea clearance of at least 195 ml/min;
(iii) per membrane area of 1.6 m2, an in vitro phosphorus clearance of at least 180 ml/min; and (iv) per membrane area of 1.8 m2, a .beta.2-microglobulin clearance of at least 44 ml/min.

9. A hollow fiber semipermeable membrane which comprises a polysulfone resin and a hydrophilic polymer and is characterized by an albumin permeability of less than 1.5% and, in a dextran diffusion test using a dextran having a molecular weight of 10,000 and after 1 hour circulation of bovine serum, an overall mass transfer coefficient Ko of at least 0.0012 cm/min.

10. The hollow fiber membrane according to claim 9, wherein the membrane has a hydrophilic property provided by the hydrophilic polymer, a porosity of at least 78% and an asymmetrical structure including an active layer thereof, which active layer has an average pore radius of less than nm.

11. A module for the treatment of blood for removal therefrom of an undesired material, which module comprises:
a housing and, disposed within the housing, a hollow fiber membrane, wherein the housing has at least a dialysate inlet to allow entry into the housing of a dialysate and wherein the hollow fiber membrane has an internal periphery defining a blood flow conduit and an external periphery for contact thereof with the dialysate in the housing, the hollow fiber membrane being capable of allowing selective passage, across the membrane from the internal to the external periphery thereof, of the undesired materials, whereby during passage of the blood through the blood flow conduit, the undesired material in the blood passes across the membrane into the dialysate, the hollow fiber membrane comprising a polysulfone resin and a hydrophilic polymer and being characterized by an albumin permeability of less than 1.5% and, in a dextran diffusion test using a dextran having a molecular weight of 10,000 and after 1 hour circulation of bovine serum, an overall mass transfer coefficient Ko of at least 0.0012 cm/min.

12. The module according to claim 11, wherein a bundle of the hollow fiber membranes is disposed within the housing, whereby when the housing is filled with dialysate, the dialysate is disposed between the respective hollow fiber membranes of the bundle thereof and surrounds the respective external peripheries thereof.

13. A method for the treatment of blood to remove therefrom an undesired material, in which blood is separated from a dialysate by a hollow fiber membrane capable of allowing selective passage across the membrane, wherein the hollow fiber membrane comprises a polysulfone resin and a hydrophilic polymer and is characterized by an albumin permeability of less than 1.5% and, in a dextran diffusion test using a dextran having a molecular weight of 10,000 and after 1 hour circulation of bovine serum, an overall mass transfer coefficient Ko of at least 0.0012 cm/min.

14. A polysulfone hollow fiber membrane containing a hydrophilic polymer in the membrane, characterized by an albumin permeability of no more than 3.0% and a vitamin B12 dialyzance of at least 135 ml/min per membrane area of 1.3 m2, the vitamin B12 dialyzance being measured during dialysis using, as perfusate, an aqueous solution containing urea and vitamin B12 at a perfusate flow rate of 200 ml/min, and using, as a dialysate, water at a dialysate flow rate of 500 ml/min and a filtration speed of 10 ml/min.

15. The polysulfone hollow fiber membrane according to claim 14, having an albumin permeability of 0.1% to 2.4% and a vitamin B12 dialyzance of at least 137 ml/min per membrane area of 1.3 m2.

16. The polysulfone hollow fiber membrane according to claim 15, having an albumin permeability of 0.3% to 2.0% and a vitamin B12 dialyzance of at least 140 ml/min in a module per membrane area of 1.3 m2.

17. The polysulfone hollow fiber membrane according to claim 14, wherein the urea dialyzance per membrane area of 1.3 m2 is at least 191 ml/min, the urea dialyzance being measured during dialysis of blood containing added urea and vitamin B12 at a blood flow rate of 200 ml/min, using water as a dialysate at a dialysate flow rate of 500 ml/min and a filtration speed of 10 ml/min.

18. The polysulfone hollow fiber membrane according to claim 17, wherein the urea dialyzance per membrane area of 1.3 m2 is at least 192 ml/min.

19. The polysulfone hollow fiber membrane according to claim 18, wherein the urea dialyzance in a module of a membrane area of 1.3 m2 is at least 193 ml/min.

20. The polysulfone hollow fiber membrane according to any one of claims 14 to 19, wherein the water permeability of the hollow fiber is at least 500 ml/hr.cndot.mmHg.cndot.m2.

21. The polysulfone hollow fiber membrane according to claim 20, wherein the water permeability of the hollow fiber is at least 600 ml/hr.cndot.mmHg.cndot.m2.

22. The polysulfone hollow fiber membrane according to claim 21, wherein the water permeability of the hollow fiber is at least 700 ml/hr.cndot.mmHg.cndot.m2.

23. The polysulfone hollow fiber membrane according to any one of claims 14 to 22, having a % .beta.2-microglobulin removal, in clinical use for blood dialysis with a module per membrane area of 1.3 m2, of at least 60%.

24. The polysulfone hollow fiber membrane according to claim 21, wherein the % .beta.2-microglobulin removal is at least 70%.

25. The polysulfone hollow fiber membrane according to any one of claims 14 to 24, wherein the hydrophilic polymer is polyvinylpyrrolidone.

26. A module for the treatment of blood for removal therefrom of an undesired material, which module comprises:

a housing and, disposed within the housing, a hollow fiber membrane, wherein the housing has at least a dialysate inlet to allow entry into the housing of a dialysate and wherein the hollow fiber membrane has an internal periphery defining a blood flow conduit and an external periphery for contact thereof with the dialysate in the housing, the hollow fiber membrane being capable of allowing selective passage, across the membrane from the internal to the external periphery thereof, of the undesired material, whereby during passage of the blood through the blood flow conduit, the undesired material in the blood passes across the membrane into the dialysate, the hollow fiber membrane comprising a polysulfone resin and a hydrophilic polymer and being characterized by an albumin permeability of no more than 3.0% and a vitamin B12 dialyzance of at least 135 ml/min per membrane area of 1.3 m2, the vitamin B12 dialyzance being measured during dialysis of blood containing added urea and vitamin B12 at a blood flow rate of 200 ml/min, using water as a dialysate at a dialysate flow rate of 500 ml/min and a filtration speed of 10 ml/min.

27. The module according to claim 26, wherein a bundle of the hollow fiber membranes is disposed within the housing, whereby when the housing is filled with dialysate, the dialysate is disposed between the respective hollow fiber membranes of the bundle thereof and surrounds the respective external peripheries thereof.

28. A method for the treatment of blood to remove therefrom an undesired material, in which blood is separated from a dialysate by a hollow fiber membrane capable of 46a allowing selective passage across the membrane, wherein the hollow fiber membrane comprises a polysulfone resin and a hydrophilic polymer and is characterized by an albumin permeability of no more than 3.0% and a vitamin B12 dialyzance of at least 135 ml/min per membrane area of 1.3 m2, the vitamin B12 dialyzance being measured during dialysis of blood containing added urea and vitamin B12 at a blood flow rate of 200 ml/min, using water as a dialysate at a dialysate flow rate of 500 ml/min and a filtration speed of ml/min.

29. A method of manufacturing a polysulfone hollow fiber membrane, which method comprises spinning hollow fibers from a spinning solution comprising a polysulfone, a hydrophilic polymer, a solvent for each of the polysulfone and hydrophilic polymer and water, which spinning solution has a viscosity x (poise) at 30°C within the range of 25-130 poise and a quantity y (wt%) of water present in the spinning solution within the range satisfying the formula -0.01x + 1.45 <= y <= -0.01x + 2.25.

30. A method of manufacturing a palysulfone hollow fiber membrane hemodialyzer module, which method comprises spinning hollow fibers from a spinning solution comprising a polysulfone, a hydrophilic polymer, a solvent for each of the polysulfone and hydrophilic polymer and water, which spinning solution has a viscosity x (poise) at 30°C within the range of 25-130 poise and a quantity y (wt%) of water present in the spinning solution within the range satisfying the formula -0.01x + 1.45 <= y <= -0.01x + 2.25, and thereafter incorporating the membrane in a module.

31. A method according to claim 30, wherein an infusing solution comprising a compound selected from an organic solvent and a mixture of an organic solvent and water is introduced into the hollow fibers during said spinning thereof to form a core liquid, said spinning of the hollow fibers includes a coagulation step, subsequent to said coagulation, the infusing solution is then washed out and, the hollow fibers are then impregnated with a wetting agent, and which method includes additional steps, carried out while the hallow fibers are impregnated with an aqueous solution of the wetting agent, of forming a bundle of the hollow fibers and inserting the said bundle into a module case for a hemodialyzer to provide an intermediate product by formation of at least one sealing plate, and subsequently washing off the wetting agent with water, and thereafter sterilizing the product.

32. A method according to claim 30, wherein the viscosity x (poise) of the spinning solution at 30°C is within the range of 40-110 poise, and the wager quantity y (wt%) contained in the spinning solution is within the range satisfying the formula -0.01x + 1.65 <= y <= -0.01x + 2.05.

33. A method according t.o claim 31, wherein the quantity z(wt%) of water present in the infusing solution is within the range satisfying the formula -0.14x + 25.5 <= z <= -0.14x + 37.5.

34. A method according to claim 33, wherein the viscosity x (poise) of the spinning solution at 30°C is within the range of 40-110 poise, and the water quantity z (wt%) contained in the infusing solution is within the range satisfying the formula -0.14x + 28,5 <= z <= -0.14x + 34.5.

35. A method according to claim 31, wherein the solvent is dimethylacetamide and the infusing solution is a mixture of dimethylacetamide and water.

36. A method according to claim 30, wherein the hollow fiber is brought into contact with a moist air flow of a relative humidity of at least 70% for 0.1-1.0 second in a dry zone in a dry/wet. spanning method.

37. A method according to claim 36, wherein the contact time of the hollow fiber with the moist air flow is 0.2-0.8 second.

38. A method according to claim 31, wherein the wetting agent is removed with hot water at a temperature of at least 40°C, then the hemodialyzer is filled with water and the hollow fiber membrane is irradiated with gamma rays in a dose of 20KGy to 35KGy.

39. A method according to claim 38, wherein the wetting agent is removed with hot water at a temperature of at least 55°C.

40. A method according to claim 31, wherein during the said step of forming the bundle of hollow fibers while impregnated with the aqueous solution of the wetting agent, spacers are disposed between the fibers to prevent adhesion of the hollow fibers to one another.

41. A method according to claim 31, wherein respective spacer yarns are introduced around respective groups each selected from one and two hollow fibers having impregnated therein an aqueous solution of the wetting agent, to produce respective unit hollow fiber elements, other respective spacer yarns are helically wound around respective groups each of at least four of the unit hollow fiber elements to form respective assemblies of the unit hollow fiber elements, then at least five assemblies of the unit hollow fiber elements are assembled to form a bundle of hollow fiber membranes for insertion into a hemodialysis case.

42. A method according to claim 29, wherein the hydrophilic polymer is polyvinylpyrrolidone.