Note: Descriptions are shown in the official language in which they were submitted.
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 ,~
74S
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.
29 ACCOUNT OF THE INVENTION
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 -
02
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
-- 4 --
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'~
01 - 6 -
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:
26
27 CH3
28
29 ~o ~ C--<~ 0~ S2 ~1 (l)
\ I J
31 CH3 n
32
33
34
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
01 - 10 -
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.
38
`` ~2~74S
01 - 11 -
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
261 265 140 137
245 252 168 171
282 2~7 168 127
277 2~6 1~4 133
275 268 182 148
0 = 266+13 26~+6 165+16 1~43+15
Creatir~ine 222 219 137 1~0
CIearance 225 223 164 155
231 232 133 145
235 260 142 15G
269 257 150 1 ~1
23Y 242 152 138
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
166 156
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.
.
