CA1294745C

CA1294745C - Asymmetrical microporous hollow fiber for hemodialysis and a process for manufacturing such fibers

Info

Publication number: CA1294745C
Application number: CA000486874A
Authority: CA
Inventors: Klaus Heilmann
Original assignee: Fresenius SE and Co KGaA
Current assignee: Fresenius SE and Co KGaA
Priority date: 1984-07-17
Filing date: 1985-07-16
Publication date: 1992-01-28
Anticipated expiration: 2009-01-28
Also published as: YU46155B; DE3426331A1; ATE107189T1; DE3587850D1; BR8503391A; JP2916446B2; EP0168783B1; JPH07278948A; YU116885A; ES8605686A1; ES545300A0; JP2782583B2; JPH10121324A; JPS6193801A; JPH0554373B2; EP0168783A1

Abstract

Abstract An asymmetric microporous hollow fiber for hemodialysis is made up of 90 to 99% by weight of a first hydrophobic polymer and 10 to 1% by weight of a second hydrophilic polymer. The fiber has a water adsorbing capacity of 3 to 10% and is produced by extruding a solution containing 12 to 20% by weight of the first polymer and 2 to 10% by weight of the second polymer, the rest be-ing a solvent to give a continuous hollow structure with a wall, causing a precipitation liquor to act on said structure in an outward direction through the wall thereof with the full precipitation thereof and the concurrent dissol-ution and washing out of a part of said first polymer from said extruded structure and then washing out the dissolved out part of the pore-forming substance and the other organic components. Thereafter the fiber so produced is fixed in a washing bath.

Description

7 ~5 BACKGROUND OF THE IN~ENTION
The presPnt invention relates to asymmetrical microporous fibers, particularly for the treatment of blood, and made up of a first polymer which is hydrophobic and a second polymer which is hydrophilic. Furthe:rmore the invention relates to a process for the manufacture of such fibers, in which the polymeric components are dissolved in a polar and aprotic solvent, the solution so produced is lextruded through a spinnerette to form a hollow fiber structure into whose lumen a precipitant is introduced and the resulting hollow fiber is placed in a bath to free it oE compon~ents that are able to be washed out.
DISCUSSION OF THE PRIOR ART
The U.S. Patent 3,615,024 refers to asymmetrical hollow fibers that are manufactured exclusively from a hydrophobic polymer. As a consequence of this, such hollow fibers are no longer water-wettable and for this reason they either may not be allowed to become completely desiccated or they have to be kept filled with a hydrophilic liquid such as glycerol. Otherwise, every time the fibsrs are dried there is a further decrease in the ultrafiltration rate, because their minute pores become increasingly filled with air and are then no longer able to be wetted with water. The outcome of this is that the separation boundary is shifted after each drying out and does not in fact remain constant.
Furthermore the fibers described in this said U.S.
patent made of hydrophobic polymers are not sufEiciently stable and have a relatively poor yield point so that fibers manufactured in keeping with the patent are hard to process.
Another point is that such a fiber will shrink after drying and does not possess a fine-pored structure but rather a coarse-pored finger structure with extensive vacuoles therein mitigating against stability, as has already been inferred in the description so far.

P ,~

It is for this reason that the fibers covered in this U.S. patent are not suitable for purposes of hemodialysis, because their particular structure and their hydrophobic S properties make them hard to process after they have been extruded, and make a specialized treatment necessary before hemodialysis.
The U.S. Patent 3,691,068 gives an account of a membrane that, although it may be used for dialysis, is basically merely a further development: of the membrane as noted in the first said U.S. Patent 3,615,024.
The fiber produced in keeping with this last~named patent undergoes a drying process to remove residual water therein, stemming from the process of manufacture, more or less completely. The outcome of this is that - as we have seen - the small pores become filled with air and for this reason are not able to play any part when the filer is used with water. It is only the large pores that are available for the water that is to be ultrafiltered, with the consequence that the rate of ultrafiltration as a whole is cut down and the solute separation properties of the membrance are altered. The above remarks also apply insofar as it is a question of the mechanical properties of such a membrane and the processing thereof.
Another U.S. Patent, No. 4,051,300, describes a ~5 synthetic hollow fiber that may be used for industrial purposes (such as reverse osmosis and the like~, but not however for hemodialysis. This fiber is manufactured from a hydrophobic polymer with a certain addition of a hydrophilic polymeric pore-forming substance. In view of its purpose of use such a filter has a bursting pressure of 2000 psi (42.2 kg/su. cm) as dependent on the manner of production and the fiber structure.
It is for this reason that although this fiber may successfully be used for reverse osmosis, it is not suitable for hemodialysis, in which the working conditions are quite different. In the case of hemodialysis the important criterion is essentially that the membrance produced have a high sieving coefficient and furthermore a high diffusity. These para-`` ` ~z~ s 01 ~ 3 -02 meters are however not satisfactory in the case of the membrane 03 of the U.S. patent 4,051,300 so that the membrane may not in fact 04 be employed for hemodialysis.
;05 The German Offenlegungsschrift specification 2,917,357 ~06 published November 8, 1979, assigned to Asahi Kasei Kogyo K.K.
07 relates to a semipermeable membrane that may be made of a 08 polysulfone or other material. The fiber has not only an inner 09 skin but furthermore an outer one so tha-t the hydraulic permeability is markedly diminishe~. Owing to the hydrophobic 11 structure, such a membrane is furthermore open to the objections 12 noted earlier herein.
13 Lastly the German Offenlegungsschrift specification 14 3,149,976 published June 30, 1983, assigned to Hoechst AG is with respect to a macroporous hydrophilic membrane of a synthetic 16 polymer as for example a polysulfone with a certain content of 17 polyvinylpyrrolidone (PVP). In this respect the PVP level has to 18 be at least 15~ by weight of the casting solution and the 19 membrane was to have a water uptake capacity of at leas-t 11% by weight of the final membrane.
21 Due to this large residual amount of extractables, this 22 fiber was only suitable for industrial and not for medical 23 purposes, as may furthermore be seen from its structure and 24 its high water absorbing capacity.
As already explained, state of the art hollow fibers 26 are normally utilized for the industrial removal from water, as 27 for example for reverse osmosis or ultrafiltration, or for 28 separating gases.

In keeping with the present invention however, a hollow 31 fiber is to be created that may be used for hemodialysis, in 32 which there are special requirements to be met.
33 The properties of such membranes in the form of hollow 34 fibers are dependent on the type of process and the polymers used ~35 therein. Nevertheless it is extremely hard to make a fully `` ` 1~4~45 01 - 3a -03 appropriate choice of the starting products and the right conduc-t 04 of the method of manufacture to be certain of producing a certain 05 type o~ fiber, that is to say one with predetermined membrane 06 properties. These desirable properties include: -07 (a) A high hydraulic permeability with respect to the solvent 08 to be ultrafiltered. The fluid to be ultrafiltered, more 09 particularly water, is in t:his respect to be able to permeate the membrane as efficiently as possible, that is ~11 to say with a high rate for a given surface area and for 12 a given time at a low pressure. The permeabllity rate 13 is in this connection dependent on the number and size 14 of the pores and their length and on the degree to ,p . .

` ~9~L7~5 which wetting by the liquid takes place. It will be seen that in this respect a membrane with the largest possible member of pores S of uniform size and with the lowest possible thickness is to be made available.
(b) A further point is that the membra~e is to have a sharp separation characteristic, i.e. its pore size distribution is to be as uniform as possible in order to give a separation limit with respect to molecules of a certain s;ize, that is to say of a certain molecular weight. In hemodialysis it is more specially desirable that the membrane have properties akin to those of the human kidney. That is to say so as to hold back molecules with a molecular weight of 45,000 and thereover.
(c) Furthermore the membrane is to have a satisfactory degree of mechanical strength to resist the pressures involved and must have an excellent stability.
As a rule this mechanical strength is inversely proportional to the hydraulic permeability or in other words the better the hydraulic permeability the poorer the mechanical strength of a membrane. To this end the asymmetrical membranes noted initially may incorporate a supporting membrane in addition to the separating or barrier layer, such supporting membrane on the one hand backing up the separating membrane of limited mechanical strength and on the other hand being generally without any effect on the hydraulic properties because of its having a substantially larger pore size.
However the supporting member of such an asymmetrical capillary membrane fre~uently has such large pores that there are severe limits to any possible reduction of the thickness of the barrier layer, i.e. the separating properties, and more specially the hydraulic permeability, have so far left something to be desired.
(d) A further property of considerable weight in connection with membranes to be utilized for hemodialysis is the "biocompatibility"
factor, a term used in connection with dialysis to connote a freedom from any response of the body's immune system akin to the response to surfaces such as those on connectors, material of the housing, casting compositions and dialysis membranes.

4~745 - 4a -This response may express itself in an initial drop in the leukocyte count (leukopenia) and of the oxygen partial pressure (P02) followed by a slow recovery of these values and an activation of the complement system.
Such reactions have been described in connection with the use of Il FR D77~ 4/k page 5 3L2~ 4S
regenerated cellulose as a dialysis membrane. The intensity of this react-ion is dependent on the size of the uctive surface.
Therefore one purpose or object of the invention is to make ~3uch a fur-ther development of the hollow fiber of the sort described initially, that it has an excellent wettability while concurrently exhibiting a very low level of ex-tractables .
As part of a further objective of the invention such a hollow fiber is at the same time to have a very good hydraulic permeability and an excellent mechanical strength.
A still further aim of the invention is to create such a hollow fiber that hss an excellent biocompatibility.
In keeping with these and further object~ that will become apparent from the ensuin~ account of the invention hereinafter, an asymmetric micro- porous hollow fiber for the treatment of blood, composed of a hydrophobic first polymer and a hydrophilic second polymer, is so made that it comprises 90% to 99~ by wei~ht of the first polymer and 10~ to 1% by wei~ht of the second polymer with a water absorption capacity of 3 to 10% by weight and is able to be produced by a process in which an extruded solution of 1~% to 20~ by weight of the first polymer and 2% to 11)% by weight of the second polymer, the rest being solvent, with a solution viscosity of 5D0 to 3, 000 cps, is pre^
cipitated from the inside to the outside. After such precipitation a part of the second polymer is dissolved out and a certain part of the solvent are washed out.
The hollow fiber in keeping with the present invention may be looked upon as a step forward in the art inasfar as it has a very high level of hyd-raulic permeability. In fact, the hydraulic permeability of the fiber produced in conformity with the invention is increased so as to be hi gher than the permeability of a comparable hollow fiber membrane of regenerated cellulose by a factor of at least lD
The hollow fiber membrane produced i~n the method of the present invent-ion furthermore has an excellent biological compàtibility. It l~auses practically no leukopenia. ln addition. the hi~hly satisfactory biocompatibility makes it possible for the amount of heparin administered to be lowered.
Lastly no apoxia occurs, that is to say there is no decrease in the oxy-gen partial pressure to values within the deficit ran~e. Accordin~ly the hollow fiber membrane produced in the invention is very much more biocom-lZ~474'~

02 patible than hollow Eibers as currently offered commercially for 03 hemodialysis and has an ameliorated hydraulic behavior.
04 An embodiment of the invention is an asymmetric 05 microporous wettable hollow fiber, consisting essentially of an 0~ inner barrier layer and an outer, open foam-like layer, the 07 fiber comprising a hydrophobic first organic polymer in an 08 amount e~ual to 90 to 99% by weight and 10 to 1~ by weight of 09 polyvinyl pyrrolidone which is produced by the ~ollowing steps:
wet spinning a solution made up of a solvent, of 12 to 20% by 11 weight of the first polymer and of 2 to 10% by weight of the 12 polyvinyl pyrrolidone, the solution having a viscosity of 500 to 13 3,000 cps, through the ring duct of a spinnerette having an 14 external ring duct and an internal hollow core, simultaneously passing through the hollow internal core a precipitant solution 16 comprising an aprotic solvent in conjunction with at least 25%
17 by weight of a non-solvent, to produce a hollow prefiber, 18 casting the prefiber into an aqueous washing bath, the 19 spinnerette and the upper surface of the washing bath being separated by an air gap, the air gap being so provided that ~ull 21 precipitation of components of the prefiber and passage of the 22 precipitant solution through the outer surface of the prefiber 23 will have occurred before the prefiber enters the washing bath 24 thereby, dissolving out and washing away a substantial portion of the polyvinyl pyrrolidone and of the the solvent, to form the 26 desired ~iber, the fibre having a high clearance rate according 27 to DIN 58352, of 200-~90 ml/min for urea and 200~250 ml/min for 28 creatinine and phosphate, at a blood flow rate of 300 ml/min, 29 for about 10,000 fibres having a total area of 1.25 m2 of active surface.
31 Another embodiment of the invention is an.asymmetric 32 microporous wettable hollow fiber, consisting essentially of an 33 inner barrier layer and an outer, open foam-like layer, the 3~ fiber comprising a hydrophobic first organic polymer in an amount equal to 90 to 99% by weight and 10 to 1% by weight of 36 polyvinyl pyrrolidone, the fibre having the following 37 characteristics: a high rate of water permeability of about .

~.;; ;~ .

~.~94745 - 6a -2 30-600 ml/h per sq. meter per mmHg, a high clearance according 3 to DIN 58352, of 200-290 ml/min for urea, 200-250 ml/min for 4 Vitamin Bl2 and 50-120 ml/min for insulin, at a blood flow rate of 300 ml/min, for about lO,000 fibres having 1.25 m2 of 6 active surface, and high sieving coefficients of l.0 for 7 Vitamin Bl2, about 0.99 for insulin, 0. 5-0. 6 for myoglobin and 8 under 0.005 for human albumin. Active surface means the 9 surface area of all fibres is a filtering unit. Clearance means the ratio of cleared volume/uncleared volume.
11 The method of the invention may be based on the use 12 of synthetic polymers that are readily soluble in polar, 13 aprotic solvents and may be precipitated therefrom with the 14 formation of membranes. When such precipitation takes place it leads to the production of an asymmetric, anisotropic 16 membrane, which on the one side has a skin-like microporous 17 barrier layer, and on the opposite side has a supporting 18 membrane, that is used to improve the me~hanical properties of 19 this barrier layer, without thereby having any influence on the hydraulic permeability however.
21 Polymers that may be used as the membrane forming 22 first polymer include:
23 Polysulfones, such as polyethersulfones and more 24 specifically polymeric aromatic polysulfones, that are constituted by recurrent units of the formulas I and II:

29 ~o ~ C--<~ 0~ S2 ~1 (l) \ I J
31 CH3 n 36 to ~ S2 ~3~ (ll) n ~%~47 ~5 1 - 6b -3 It will be clear from the formula I that here the 4 polysulfone contains alkyl groups, more specifically methyl groups in the chain, whereas the polyethersulfone of formula 6 II only has aryl groups, that are joined together by ether and 7 by sulfone bonds. ~
8 Such polysulfones ~ polyethersulfones, that come 9 within the definition polyarylsulfones, are well known and are marketed under the trade mark UDEL by Union Carbide 11 corporation. They may be used separately or as blends.

.....

lZ947 ~5 Furthermore polycarbonates may be used, composed of linear polyesters of carboxylic acids and as marketed for example under the name of Lexanm by General Electric Company.
Further materials that may be utilized are polyamides, that i8 to say polyhexamethyleneadipamides, as marketed for example by Dupont Inc under the name of Nomex~.
Other polymers comin~ into question for use in the invention include for example PVC, polymers of modified acrylic acid3 und halogenated polymer~, polyethers, polyl;rethanes and copolymer~ thereof.
However the use of polyarylsulfones and more particularly of polysulfones i~ preferred. I
The hydrophilic second polymer may for example ~e a long-chained poly- I
mer, that contains recurrent inherently hydrophilic polymeric units.
Such hydrophilic second poly~er~ may be polyvinylpyrrolidone (PVP), that has been used for a large number of medical purposes, as for example as a plasms expander. PVP consists of recurrent units of the general ~ormula lII

(111) ' CH- CH n wherein n is a whole number of 90 to 4400.
PVP is produced by the polymerisation of N-vinyl-2-pyrrolidone, the degree of polymerisation being dependent on the selection of polymerisation method. For example PVP products may be produced with a mean molecular weight of 10,000 to 45tJ,00U and may also be used for the purposes of the pr~
sent invention. Such polysulfones are marketed by GAF Corporation under the trade connotations K-15 to K-90 and by Bayer AG under the trade name of Xollidon .
Another hydrophilic second polymer that may be used may be in the form of polyethyleneglycol and polyglycol monoesters and the copolymers of poly-ethyleneglycols with polypropyleneglycol, as for example the polymers that are marketed by BASF AG under the trade desi~nations of Pluronic~ F 68, F 88, F
108 and F 127.
Still further materials that may be used are polysorbates, as for example ~ Tr~de M~rk ..~

lZ~7'~5 polyoxyethylenesorbitane monooleate, monolaurate or monopalmitate.
Such polysorbates are for example marketed under the name TweenTM, the preferred forms thereof being the hydrophilic Tween products as for example Tween 20, 40 and the like.
Finally water soluble cellulose derivatives may be employed such as carboxymethylcellulose, cellulose acetate and the like in addition to starch and its derivatives.
The preferred material is PVP.
The polar, aprotic solvents wiLl generally be solvents in which the first polymers are readily soluble, that is to say with a solubility such that one may produce a solution with a concentration of at least roughly 20% by weight of the synthetic polymer. Aprotic solvents belonging to this class are for example dimethylformamide (DMF), dimethylsulfoxide (DMS0), dimethylacetamide (DMA), N-methylpyrroli~one and mixtures thereo~.
Such aprotic solvents may be mixed with wate~ in any quantity and consequently may be washed out of the fibers after precipitation.
~0 In ~ddition to the pure polar, aprotic solvents it is furthermore ; possible to use mixtures thereof or mixtures of them with water, care being taken to observe the upper solubility limit of at least of about 20% by weight for the fiber forming polymer. As regards the conditions of precipitation, some advantage is to be ~ainad by ; 25 adding a small amount of water.
The first polymer is dissolved in the aprotic solvent at a rate of about 12 to 20 and more speciallv 14 to 18 or more limitedly about 16% by weight of the casting solution at room temperature, in which respect certain limitations with respect to viscosity, now to be explained, are observed in connection with the hydrophilic polymer. It has been seen from experience that in the case o~ a fiber forming polymer content in the solvent of under about 12% by weight, the hollow fibers formed are no longer strong - Trade Mark ~4~
_ 9 _ enough so that in other words considerable trouble is experienced when they are further processed or used. On the other hand when S the level of the fiber forming polymer in the solution is in excess of 20% by weight, the fibers are overly dense and this makes for less satisfactory hydraulic properties.
In order to ameliorate the formation of pores or to make it possible at all, such a solution having the fiber forming polymer 10 in the above noted constituents will have a certain level of a hydropholic, second polymer, which reduces the desired pores when the predominantly hydrophobic fiber forming polymer is precipitated or coagulated. It is best, as notecl earlier, for the second polymer to be used in an amount of about 2 to 10 and more specially lS 2.5 to 8%, by weight of the casting solution such level being compatible with the said viscosity limits for the composition of the solution. It is preferred for a certain amount of this water soluble polymer to be retained in the precipitated hollow fiber so that the same is more readily wetted. Consequently the finished ; 20 hollow fiber may contain an amount of the second polymer that is equal to up to about 10% by weight and more specially 5 to 8% by weight of the polymeric membrane.
In keeping with the invention the solution containing the fiber forming polymer and the second polymer is to possess a viscosity of about 500 to 3,000 and more specially 1,500 to ~,500 cps (Centipoise) at 20C, i.e. at room temperature. These viscosity values have been measured with a regular rotary viscosity measuring instrument such as a ~aake instrument. ~he degree of viscosity, that is to say more specially the internal friction of the solution, is one of the more important parameters to be observed in running the process of the present invention. ~n the one hand the viscosity is to preserve or maintain the structure of the extruded hollow fiber configuration until precipitation takes place, and on the other hand it is not to obstruct the precipitation, that is to say the coagulation of the hollow fiber , , -7~5 - 9a -after access of the precipitating solution to the extruded viscous solution, in which respect use is best made of DMS0, DMA or a mixture thereof as a solvent. In this respect the experience ma~e has been that by keeping to the viscosity range as noted above, one may be certain of producing hollow fiber membranes that have excellent hydraulic and mechanical properties.
The finished, clear solution, that is completely freed of undissolved particles by filtering it, is then supplied to the extrusion or wet-spinning as described in what follows.
Normally a wet-spinning spinnerette is used that is generally on the lines of that disclosed in the U.S. Patent 3,691,068. This spinnerette or nozzle has a ring duct with a diameter equaling the outer diameter of the hollow fiber. A spinnerette core projects coaxially into this duct and runs therethrough. In this respect the outer diameter of this core is generally equal to the bore diameter of the hollow fiber, that is to say the lumen diameter thereof. The precipitating liquor, which is to be described in what follows, is pumped through this hollow core so that it emerges from the tip of it and makes contact with the hollow fiber configuration that is made up of the extruded 12~L745 02 liquid. Further details of the system may be seen from the 03 specification of the said U.S. ~atent 3,691,068 inasfaras the 04 production of the hollow fiber is concerned.
05 The precipitating liquor is in the form of one of 06 the above noted aprotic solvents in conjunction with a 07 certain amount of non-solvent, more specially water, that on 08 the one hand initiates the precipitation of the fiber 09 building first polymer and on the other hand however dissolves the second polymer. A useful effect is produced if 11 the aprotic solvent or mixture is the same as the solvent 12 used in the solution containing the fiber forming polymer.
13 In connection with the make-up of the precipitating liquor 14 made of an organic, aprotic solvent or mixture of solvents and non-solvent, one has to take into account the fact that 16 with an increment in the level of non-solvent the 17 precipitating properties of the precipitating liquor become 18 more pronounced so that the size of the pores formed in the 19 membrane will become increasingly smaller and this offers a way of controlling the pore characteristics of the separating 21 membrane by the selection of a given precipitating liquor.
22 On the other hand the precipitating liquor is still to have a 23 certain level of non-solvent, equal to at least about 25% by 24 weight, in order to make possible precipitation to the desired degree. In this respect a general point to be borne 26 in mind is that the precipitating liquor will mix with the 27 solvent of the solution containing the polymers so that the 28 greater the distance from the inner face of the hollow fiber, 29 the lower the water content in the aprotic solvent. Since the fiber itself however is to be fully precipitating before 31 the washing liquor gets to it, the above limits will apply 32 for the minimum water content in the precipi~ating liquor.
33 If the content of the non-solvent is low, as for 34 example at the level of about 25% by weight, a membrane with coarse pores will be produced that lends itself to use as a 36 plasma filter for example one that only retains relatively 37 large fractions in the blood such as erythrocytes.

`` ~2~74S

02 It is preferred that the casting solution comprises 03 at least 35% by weig~t of the non-solvent. A further point 04 is that the amount of the precipitating liquor supplied to 05 the polymer solution is as well a signiEicant parameter for 06 the conduct of the process in keeping with the present 07 invention. This ratio is more importantly dependent on the 08 dimensions of the wet-spinning spinnerette, that is to say 09 the dimensions of the finished hollow fiber. In this respect it is a useful effect that on precipitation the dimensions of 11 the fiber are not different from those of the hollow fiber 12 configuration before precipitation and after extrusion. For 13 this reason the ratio of the volumes used of precipitating 14 liquor and of polymer solution may be in the range of between 1:0.5 and 1:1.25, such volumes being equal, given an equal 16 exit speed (as is preferred) of the precipitating liquor and 17 of the polymer solution, to the area ratios of the hollow 18 fiber, i.e. the ring-area formed by the polymeric substance 19 on the one hand and the area of the fiber lumen on the other.
It is best for so much precipitating liquor to be 21 supplied to the extruded configuration directly upstream from 22 the spinnerette that the inner or lumen diameter of the so 23 extruded, but so far not pecipitated, configuration generally 24 corresponds in the dimensions of the ring spinnerette, from ~25 which the material is extruded.
26 It is useful that the outer diameter of the hollow 27 fibers is equal to rouqhly 0.1 to 0.3 mm whereas the 28 thickness of the membrane amounts to about 10 to 100 and more ~29 specially 15 tc 50 or more limitedly to 40 microns. As we have seen above, the precipitation method is generally the 31 same as the one disclosed in the German Auslegeschrift 32 specification 2,236,226 published February 14, 1974, assigned 33 to Forschungsinstitut Berghof GmbH, so that reference may be 34 had thereto for further details. Consequently an asymmetrical capillary membrane is formed by the 36 precipitating liquor acting in an outward direction on the 12~74S

01 - lla -02 polymer solution after issuing from the wet-spinning 03 spinnerette. In keeping with the invention, the 04 precipitation is generally terminated before the hollow fiber 05 gets as far as the surface of a rinsing bath that dissolves 06 out the organic liquid contained in the hollow fiber and 07 finally fixes the fiber structure.
08 When precipitation takes place the first step is 09 for the inner face of the fiber-like structure to be coagulated so that a dense microporous layer in the form of a 11 barrier for molecules that are larger than 30,000 to 40,000 12 Daltons is ~ormed.
13 With an increase in the distance from this barrier 14 there is an increasing dilution of the precipitation liquor with the solvent contained within the spinning composition so 16 that the precipitation action becomes less vigorous in an 17 outward direction. The consequence of this is that a 18 coarse-pored, sponge-like structure is formed in an outward 19 direction, that functions as a supporting layer for the inner membrances.
21 When precipitation takes place most of the second 22 polymer is dissolved out of the spinning composition, whereas 23 a minor fraction is retained in the coagulated fiber and may 24 not be extracted therefrom. The dissolving out of li Fl~ ~77'3 4/k 12g~7L~5 pa~e 1;~

the second polymer facilitates the forrnation of pores. A useful effect is pro-duced if the greater part ot the ~cond polymer is dissolved out of the spin-ning composition, whereas the rest ^ as noted earlier on - is retained within the coagulated fiber.
Normally one will aim at dissolving out 60 to 95~ by weight of the second polymer from the spinnirlg composieion so that on~y 4() to 5! by weight of the second polymer used will be left therein. lt is more p~rticularly preferred for less than 30% by weight of the originully used second polymer to be left therein so that the finished polymer contains 90 to 99~ and more specially 95 t 9896 by weight of the first polymer, the rest being second polymer.
As we have seen earlier the PVP is dissolved out of the spinning com-position during the precipitation operation and remains in a dissolved condit-ion in the precipitating liquor, something that again is not without an effect on the precipitation conditions, because the solvent properties of the second polymer have an effect on the overall characteristics of the precipitating liquor. Consequently the second polymer as well plays a part, to~ether with the solvent components of the precipitating liquor, in controlling the precip^
itation reaction.
A point to be noted in this connection is that the method is best under-taken without any spinning draft. Draft in this connection means that the exit speed of the fiber-like structure from the ring spinnerette differs from (and is usually greater than) the speed at which the precipitated fiber is drawn off. This is responsible for s~retching of the structure as it issues form the ring spinnerette and causes the precipitation reaction to take place in such a way that the pores formed are stretched in the draft direction and for this reason are permanently deformed. It has been seen in this respect that in the case of a fiber spun with a draft the ultrafiltration rate is very much slower than is the case with a fiber produced without such spinnerette draft. In this respect the invention is preferabl~ so undertaken that the speed of emergence of the spinnin g composition from the spinnerette and the drawing off speed of the fiber produced are generally the same. There is then the beneficial effect that there is no de-lormation of the pores formed in the fiber or to a constriction of the fiber lumen and to a thinning out of the fiber wall.
A further parameter that is si gnificant is the distnnce between the SUI'-face of the rinsing bath and the spinnerette, because such distance is con-11 FR 0779 4/ k ~Z9~ ii page 1~

trolling for the precipitation time at a given speed of downward motion, thatis to ~ay a given speed of extrusion. However the precipitation height is limited, because the weight of the fiber represents a certain limit, which if exceeded will cause the fiber structure, so far not precipitated, to break under its own weight. This distance is dependent on the viscosity, the weight and the precipitation rate of the fiber. It is best for the distance between the spinnerette and` the precipitating bath not he greater than about one meter.
After precipitation the coagulated fiber i~ rin~ed in a bath that normally contains water and in which the hollow fiber is kept for up to about 30 minutes and more specially for about 10 to 20 minutes for washing out the dissolved organic constituents and for fixing the microporous structure of the fiber.
After that the fiber is passed through a hot drying zone.
Then the fiber is preferably texturized in order to improve the exchange properties thereof.
After this there i~ a conventional treatment of the fiber as 90 produced, that is to say winding onto a bobbin, cutting the fibers to a desired length and manufacture of dialyzer~ from the tufts of the cut fiber.
On its inner face the fiber manufactured in l~eeping with the present invention has a microporous barrier layer, that has a pore diameter of 0.1 to 2 microns. Next to this barrier layer on the outside thereof there is a foam-like supporting structurs, that i9 significantly different to the lamellae-like structures of the prior art.
In other respects the dimensions of the fiber as so produced are in line with the values given above.
The semipermeable membrane produced in keeping with the invention has a water permeability of about 30 to 600 ml/ h per sq O meter x mm H g, and more specially about 200 to 400 ml/ h per sq . meter x mm H g .
Furthermore the hollow fiber produced in keeping with the instant in-vention ha~ a water absorption capacity of 3 to 10 and more specia~ly 6 to 8%
by weight. The water absorption capacity was ascertained in the following manner.
Water-vapor saturated air is passed at r~om temperature ~25 ~:) through a dialyzer fitted with hollow fibers as produced in the invention and in a dry condition. In this respect air is introdùced under pressure into a water bath 11 FR 077~ 4/k 31.;2~L7~5i page 1~1 and after saturation with water vapor i9 run into the dialyæer. A~3 soon aq a stendy state has been reached, it is then possible for the water absorption capacity to be measured~
The clearance data were measured on fibers in keeping with the invention for an active surface of 1.25 aq. meter~ in line with DIN 58,:352. ln the case of a blood flow rate of 300 mllminute in each case the clearance for urea is between 200 and 290 or typically 270, for creatinine and phosphate between 200 and 250, typically about 23U, for vitamin B12 between ll0 and 150, typically 140 and for inulin between 50 and 1:~0, typically 90 ml/minute.
Furthermore the membrane of the invention has an excellent separation boundary. The sieving coefficients measured are 1. 0 for vitamin B12, about 0.99 for inulin, 0.5 and 0.6 for myoglobin and under 0.005 for human albumin.
It will be seen from this that the fiber produced in keeping with the invent-ion is more or less exactly in line with a natural kidriey with respect to its separating propertie~ (sieving coeff1cien~).
- Further useful effects, working examples and details of the invention will be gathered from the following account of possible forms thereof using the fi g ures .
LIST OF T~lE DIFFERENT VIEWS OP THE FIGURES.
Figure 1 is a magnified view of part of a qection through the wal~ of a hollow fiber.
Fi gure 2 is a graph to show clearance as function of blood flow rate in a fiber of the inventionO
Figure 3 is an elimination graph for molecule~ of different mole-cular weight as a function of blood flow rate.
Figure d~ is a graph with respect to ultrafiltration to show changes in the filtrate flow rate a~ a function of the transmefnbrane pressure.
Figure 5 is a graph to show changes in filtrate flow rate as a function of the hematocrit value.
Figure 6 is a graph to show changes in filtrate flow rate as a function of the protein content.
Figure 7 is a graph of clearance data for urea, creatinine and phosphateO
Figure 8 is a graph of the sieving coefficient3 for molecules of di~ferent molecular weights.

11 FR ~77~ 4I k puL~e 15 '74~j ~" DETAILED ACCOUNT OF WORKIMG EXAMPLES OF THE INVENTION.
The examples explain the invention. In the absence of any statement to the contrary, the percentages are by wei~ht.
Example 1 A wet-spinning polymer solution waa prepared containing 159~ by weight of polysulfone, 9~ by weight of PVP (MW: 40,000), 30% by weight of DMA, 45%
by weight of DMSO and 1~ by weight of water. This solution was freed of undissolved matter.
The solution so prepared was pumped to a wet-spinning spinnerette, that at the same time was supplied with a precipitating liquor in the form of a mixture of 40~ by weight of water and 60% by weight of 1:1 DMA/DMSO at 40 C.
The ring spinnerette had an outer diameter of the orifice of about 0. 3 mm and inner dia~eter of about 0. 2 mm so that it was generally in line with the dimensions of the hollow fiber.
The hollow fiber produced had an inner face with a microporous barrier layer of about 0.1 micron next to an open-pored, sponge structure.
In figure 1 the reader will see magnified sections of the membrane pro-duced, figure la showing the inner face or barrier layer with a magnification Of lO, oOO and figure lb showing the outer face with a magnification of 4, 500 .
This membrsne still contained PVP so that it was readily wetted by water.
Example 2 The membrane as produced in example 1 was tested with respect to per-meability. It was found that the permeability for water is very hi gh and for this membrane there wa~ a value of about 210 rnl/h sq. meter x mm Hg.
For blood the ultrafiltation coefficient was however lower, because as is the c se with all synthetic membranes a so-called secondary membrane i8 formed (though to a lesser degree than in the prior art) degrading the hydraulic properties. This secondary membrane is normally composed of pro-teins and lipoproteins, who~e overall concentration in the blood has an effect on the amount that may be filtered, and obstructs flow through the capillaries.
The ultrafiltration coefficients were measured using the method given in Int. Artif. Organ. 1982~ pages 23 to 26. The results will be seen in figure 4.
The clearance data were ascertained in the lab with aclueous solutions in 11 F~ 77~ 4/k 12~4745 page 16 line with DIN 58,352 (insulin with hu~l~an plasma). This gave the relation to be seen in figure 2 between clearance and blood flow (without filtration amount) .
At a blood flow rate of 30() ml/min the following elimination graph may be plotted, that is increased when there is an additional filtrate flow of 60 rrll/ min (HDF treatment). For comparison th~e net filtration graph has been plotted for Q = 300 ml/ min and QF = 100 ml/ min together with QB = 400 ml/ min and Q
130 mlJ min (fi~ure 2) .
It i~ only in the case of molecules with weights above those o~,insulin that the elimination with HF (hemofiltration) is greater than with HD (hemodia-lysis) using the fiberR produced in the invention.
The filtrate flow rate possible with a constant blood flow rate is given a~
a function of the TMP (transmembrane pressure) in figure 4.
It will be seen from this fi gure 4 that the filtrate flow continues to rise with an incrensing TMP till a maximum level is reached~ The increase in the blood viscosity is then so pronounced that a further increase in the TMP does not lead to any further increase in the filtrate rate.
On departing from the given figure~ (hematocrit 28% and protein 6%~
these levels will be reached even at lower TMP figures (for higher blood figures) or, respectively, at a higher TMP (for smaller blood values). ~he degree to which this is of practical importance will be seen from figures 5 and 6.
In this respect figure 5 shows filtrate rate as a function of hematocrit and figure 6 shows filtrate rate as a function of the protein content for a hollow fiber produced by the process of the invention.
At a blood flow rate of 300 ml/min and a filtrate rate of 150 ml/min there is an increase - as may be seen from the fi gures - in the hematocrit ~alue and the total protein of 2896 and 6% (arterial) respectively to 56% and 12% (venous)respectively .
Example 3 The fiber produced in example 1 has excellent properties when used in vivo.
It will be seen from figure 7 what clearances are possible with the fiber produced in the invention for urea, creatinine and phosphate.
On stepping up the filtrate rate from 0 ml/ min to S0 ml/ min the increase în clearance at Q = 200 ml/min was ::IL2947L~S Page 17 2~ for urea 3~ for creQtinine 4% for phosphate 8~ for i~sulin 40% for beta-microglobulin An incrense in the totnl cIenrnnce by addition~l filtrntion will only serve a useful purpose if the substanceg to be eliminated have hi6~her molcculur wei~hts than the traditionPI "mcdium molecules".
- The stability of clearance was also tested in various research centres. The res~llts are given in the fo] lowing table I
Table I
Example center A Example Center B

t=20 min t=90 rnin. Start Hl) HD end Urea 261 269 148 133 15 Clearance 260 271 163 149 282 2~7 168 127 277 2~6 1~4 133 0 = 266+13 26~+6 165+16 1~43+15 Creatir~ine 222 219 137 1~0 CIearance 225 223 164 155 269 257 150 1 ~1 214 233 137 16fi ~ = 234+18 23~+16 14~tll 199~10 30 Phosphllte 118 132 Clearance 154 150 137 1~3 1~6 1~)~
; 141 11~
35 0 inean value 124 lS0 0 = 141+17 1~ 20 It will be seen from this that clenrance is practicnlly constnnt over the duration of treatment, the differences being within normsl error deviations - Finally in figure 8 the changes in sieve coefficient as a function of molecular weight are to be seen. This will mnlce it clear that ~he fibers pro-duced using the method of the invention have nearly the same properties ns a natural kidney and great1y outdo conventional membranes of the prior art.

.

Claims

1. An asymmetric microporous wettable hollow fiber, consisting essentially of an inner barrier layer and an outer, open foam-like layer, said fiber comprising a hydrophobic first organic polymer in an amount equal to 90 to 99% by weight and 10 to 1% by weight of polyvinyl pyrrolidone which is produced by the following steps:
(a) wet spinning a solution made up of a solvent, of 12 to 20% by weight of the first said polymer and of 2 to 10% by weight of the polyvinyl pyrrolidone, said solution having a viscosity of 500 to 3,000 cps, through the ring duct of a spinnerette having an external ring duct and an internal hollow core, (b) simultaneously passing through said hollow internal core a precipitant solution comprising an aprotic solvent in conjunction with at least 25% by weight of a non-solvent, to produce a hollow prefiber, (c) casting said prefiber into an aqueous washing bath, said spinnerette and the upper surface of said washing bath being separated by an air gap, said air gap being so provided that full precipitation of components of said prefiber and passage of said precipitant solution through the outer surface of said prefiber will have occurred before said prefiber enters said washing bath thereby, (d) dissolving out and washing away a substantial portion of the¦polyvinyl pyrrolidoneland of the said solvent, to form the desired fiber, said fibre having a high clearance rate according to DIN 58352, of 200-290 ml/min for urea and 200-250 ml/min for creatinine and phosphate, at a blood flow rate of 300 ml/min, for about 10,000 fibres having a total area of 1.25m2 of active surface.

2. The hollow fiber as claimed in claim 1 wherein said hydrophobic first polymer is selected from the group consisting of: a polyarylsulfone, a polycarbonate, a polyamid, a polyvinyl chloride, a modified acrylic acid polymer, a polyether, a polyurethane and a copolymer thereof.

3. The hollow fiber as claimed in claim 2 wherein said first hydrophobic polymer is selected from the group consisting of: a polysulfone and a polyethersulfone.

4. The hollow fiber as claimed in claim 1 wherein said polyvinyl pyrrolidone has a mean molecular weight of 10,000 to 450,000.

5. The hollow fiber as claimed in claim 1 containing 95 to 98% by weight of the first said polymer, the rest being said polyvinyl pyrrolidone.

6. The hollow fiber as claimed in claim 1 having a water absorption capacity equal to 3 to 10% of the weight of the hollow fiber.

7. The hollow fiber as claimed in claim 6 wherein said water absorption capacity is equal to 6 to 8% by weight.

8. The method for producing an asymmetric microporous hollow fiber, comprising the steps of preparing a solution for wet spinning, said solution containing 12 to 20% by weight of a first hydrophobic polymer and 2 to 10% by weight of a hydrophilic second polymer, the rest being a solvent, said solution having a viscosity in the range of 500 to 3,000 cps, extruding said solution through a ring-like spinnerette to give a continuous hollow structure with a wall, causing a precipitation liquor to act on said structure in an outward direction through the wall thereof with the concurrent dissolution and washing out of a part of said first polymer from said extruded structure, said liquor furthermore precipitating said structure, and then washing out the said solvent and the dissolved out part of the second polymer forming pores in said wall.

9. The method as claimed in claim 8 wherein said hydrophobic first polymer is selected from the group consisting of: a polyarylsulfone, a polycarbonate, a polyamide, a polyvinyl chloride, a modified acrylic acid polymer, a polyether, a polyurethane and a copolymer thereof.

10. The method as claimed in claim 9 wherein said hydrophobic first polymer is selected from the group consisting of: polysulfone and polyethersulfone.

11. The method as claimed in claim 8 wherein said second water-soluble polymer is selected from the group consisting of: a polyvinylpyrrolidone, a polyethyleneglycol, a polyglycolmonoester, a copolymer of polyethyleneglycol and polypropyleneglycol, a water soluble derivative of cellulose, and a polysorbate.

12. The method as claimed in claim 11 wherein said second polymer has a molecular weight of 10,000 to 450,000.

13. The method as claimed in claim 8 wherein said solvent is selected from the group consisting of:
dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and a mixture thereof.

14. The method as claimed in claim 8 wherein said liquor is made up of on the one hand a mixture of a solvent selected from the group consisting of: dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, and a mixture thereof, and a non-solvent on the other hand.

15. The method as claimed in claim 14 wherein said precipitating liquor comprises at least 35% by weight of said non-solvent, the rest thereof being said solvent, said solvent being aprotic.

16. The method as claimed in claim 8 wherein said liquor and said solution are used in a volumetric ratio of between 1:0.5 and 1:1.25.

17. The method as claimed in claim 8 wherein said extruded structure is moved through such a height as is sufficient completely to precipitate it by the time it reaches a rinsing bath.

18. The method as claimed in claim 8 wherein said hollow structure is taken up in the process of spinning with zero draft.

19. The method as claimed in claim 8 comprising the step of introducing so much of said liquor into said extruded structure directly downstream from said spinnerette that the inner diameter of said hollow fiber is materially equal to the external diameter of a core within said spinnerette.

20. An asymmetric microporous wettable hollow fiber consisting essentially of an inner barrier layer and an outer, open foam-like layer, said fiber comprising a hydrophobic first organic polymer in an amount equal to 90 to 99% by weight and 10 to 1% by weight of polyvinyl pyrrolidone, said fibre having the following characteristics:

21 (a) a high rate of water permeability of about 30-600 ml/h per sq. meter per mmHg, (b) a high clearance rate according to DIN 58352, of 200-290 ml/min for urea, 200-250 ml/min for Vitamin B12 and 50-120 ml/min for insulin, at a blood flow rate of 300 ml/min, for fibres having 1.25 m2 of active surface, and (c) high sieving coefficients of 1.0 for Vitamin B12, about 0.99 for insulin, 0.5-0.6 for myoglobin and under 0.005 for human albumin.

22