Note: Descriptions are shown in the official language in which they were submitted.
12371Z6~
Hollow fiber membrane for dialysis
The present invention relates to a novel hollow fiber
membrane. More particularly, it relates to a hollow
fiber membrane made of a cellulose ester which is suit-
able for artificial kidneys.
It is known that cellulose esters can be processed to
form hollow fiber membranes which may be used for various
processes. For example, these membranes may be used for
separation processes involving energy savings, such as
processes for desalinating sea water or salt water, and
ultrafiltration of aqueous solutions containing various
solutes.
It is also known that cellulose esters are suitable
for the preparation of hollow fiber membranes useful for
artificial kidneys because they have good biocompatibility
and are easily produced, and hence, extensive studies
have been carried out in this regard. Generally, in
order to be suitable for artificial kidneys, the material
used for the hollow fibers should satisfy the following
six conditions:
(1) it should have good dialysis performance, i.e. a
suitable ultrafiltration rate (hereinafter referred to
as 'IUFRn) and also excellent permeability by solutes such
as urea, creatinine, etc.;
(2~ the hollow fiber membrane made therefrom should not
1237260
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permit leakage of blood;
(3) it should have good compatibility with blood, i.e.
it should have low thrombogenicity and hemolysis;
(4) after the hemodialysis, no blood should remain in
the module (i.e. the hollow fiber membrane assembly of
the separation apparatus);
(5) an acceptably small amount of material should be
dissolved out of the hollow fiber membrane; and
(6) during storage or during hemodialysis, no change
of the dialysis performance, particularly UFR, should
be observed.
A hollow fiber membrane which satisfies all of the
above conditions has not previously been produced. It
is known that when the thickness of the hollow fiber
membrane is reduced, the product shows better perme-
ability by solutes such as urea, uric acid, creatinine,
etc. and higher dialysis efficiency, so dialysis modules
incorporating such membranes can be made smaller and the
amount of blood which has to be circulated outside the
patient's body is advantageously reduced. However, when
the membrane thickness is reduced, the hollow fiber
membrane disadvantageously exhibits poor maintenance of
dialysis performance, i.e. the sixth requirement of those
given above, namely a change of dialysis performance,
particularly lowering of UFR, during storage or during
hemodialysis. A conventional hollow fiber membrane made
of cellulose ester should therefore have a thickness of
not less than about 20 ~ in order to prevent this dis-
advantage, but such a membrane still has some problems
with respect to dialysis performance, that is, it is
difficult to provide improved UFR and a high permeability
for urea.
The present inventors have carried out extensive
research for improved hollow fiber membranes having no
change of dialysis performance during storage or during
hemodialysis while maintaining the advantages of thin
membranes.
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According to one aspect of the invention there
is provided a hollow fiber membrane suitable for di-
alysis comprising cellulose ester and having a membrane
thickness of less than 20 ~, and a yield strength Sb
(g/filament) after being heat-treated at 80C for
20 hours which satisfies the following formula (I):
0.90 ~ Sb/Sa ~ 1.10 (I) wherein Sa is the yield
strength (g/filament) of the hollow fiber membrane
measured before the heat treatment.
Suitable cellulose esters used for the preparation
of the dialysis membrane of the present invention include
cellulose diacetate, cellulose triacetate, cellulose
propionate, cellulose butyrate, cellulose acetate pro-
pionate and the like, which may be used alone or in
combination of two or more thereof.
The hollow fiber membrane of the present invention
should essentially satisfy the condition that it has a
membrane thickness of less than 20 ~, and the condition
of the above formula (I). Although it is known that when
the membrane has a reduced thickness, it shows better
permeability by solutes such as urea or creatinine,
hollow fiber membranes having a membrane thickness of
about 20 ~ or more are normally employed to provide
acceptable storage stability and stability during
the dialysis procedure. In contrast, the hollow fiber
membrane of the present ~nvention can be made thin while
maintaining a strong membrane structure. When the ratio
of Sb/Sa is less than 0.9, the hollow fiber membrane
shows an undesirable lowering of yield strength during
storage over a long period of time, and hence, when it
is used for hemodialysis, it has unstable strength and
leakage of blood may be induced, which is a fatal draw-
back for artificial kidneys. On the other hand, when the
ratio of Sb/Sa is over 1.1, the hollow fiber membrane
tends to become dense in structure when exposed to high
temperatures during storage or transportation, and hence,
~237260
the dialysis performance is decreased and the original
hemodialysis capacity can not be obtained, which can have
a severe effect on patients. The yield strength of the
hollow fiber membrane is measured by a universal tensile
tester, that is, by subjecting a fixed length of the
hollow fiber (50 mm) to stretching at a tensile rate of
10 mm/minute to obtain a stress-strain curve, followed
by calculating the yield strength from the yield point
obtained from the curve.
Thus, the hollow fiber membrane of the present in-
vention is characterized in that, owing to a desirable
membrane thickness and dynamic properties, the dialysis
performance, particularly UFR, is not lowered during
storage or transportation, or during hemodialysis. For
example, a hollow fiber membrane of the present invention
showed the following UFR reten~ion in a storage test and
in a bovine blood filtration test. That is, a module for
dialysis was prepared from a hollow fiber membrane of the
present invention and was kept at 55C for 15 days, and
then the storage UFR retention (%) was calculated by the
following formula:
Storage UFR retention = UFR value after storage x 100
(%) UFR value before storage
The hollow fiber membrane of the present invention showed
. a storage UFR retention of more than 90 ~.
Besides, a module for dialysis prepared from a hollow
fiber membrane of the present invention was subjected to
a filtration test of bovine blood wherein the hematocrit
value was controlled to 40 % under a transmembrane pressure
of about 300 mmHg, and the change of UFR was measured with
lapse of time, and the UFR retention (%) in the bovine
blood filtration test was calculated by the following
formula:
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UFR retention UFR value 120 minutes after
in bovine _ initiation of filtration test
blood filtration UFR value 15 minutes after x 100
test (%) initiation of filtration test
The hollow fiber membrane of the present invention showed
a UFR retention in the bovine blood filtration test of
more than 90~.
In practice, the hollow fiber membrane of the present
invention has a membrane thickness of not less than 5 ~,
because according to known techniques, a round, uniform
hollow fiber membrane having a thickness of less than 5
cannot be produced by spinning. The cellulose ester
hollow fiber membrane of the present invention generally
has an inner diameter of 100 ~ to 400 ~, preferably 150
to 300 ~. It is advantageous to provide appropriate
crimps in the hollow fiber membrane in order to increase
the dialysis efficiency. This allows the membrane thick-
ness to be reduced while preventing an undesirable biased
flow within the module. Preferably 10 to 35 crimps are
provided per 10 cm length of the hollow fiber membrane and
the crimp amplitude L (unit: micron) (which expresses the
size of the crimp) is preferably in the range of from 65 %
of the outer diameter of the hollow fiber membrane to the
outer diameter of the hollow fiber membrane plus 50 ~.
When the crimp amplitude is within the above range, the
hollow fiber membrane can be used to form a module having
improved dialysis performance while preventing undesirable
biased dialysate flow, and further, the module can be made
compact and the membrane can be made sufficiently thin.
The cellulose ester hollow fiber membrane of the
present invention can be prepared in the following manner.
A spinning solution of a cellulose ester may be
extruded through circular slits around an inner tube of
a spinneret having a double structure comprising an inner
tube and an outer tube while simultaneously extruding
a core solution through the inner tube of the spinneret,
passing the spinning solution extruded from the
, .,
circular slit throuyh a gaseous atmosphere, introducing
the same into an aqueous coagulation bath, washing the
coagulated hollow fibers with hot water, passing them
through a glycerin bath, drying with hot air, reeling
them onto a bobbin, and then heat-treating the reeled
hollow fibers.
In order to obtain the desired hollow fiber membrane~
the spinning should be done under the following conditions,
all of which should be satisfied simultaneously.
The spinning solution should have a cellulose ester
concentration of 27 to 37 % by weight; the coagulation
bath should have a water content of 65 to 90 % by weight,
preferably 70 to 85 % by weight; the washing with hot
water should be done with water having a temperature of
40 to 80C; the glycerin bath should have a glycerin
concentration of 25 to 60 % by weight and the temperature
of the glycerin solution should be 35 to 80C; and the
heat treatment of the reeled fibers should be carried out
under a humidity of lO to 20 g-H2O/kg-dry air and at a
dry-bulb temperature of 60 to 100C.
When the above conditions are satisfied, a desirable
hollow fiber membrane can be produced, but when such a
hollow fiber membrane of rather thin wall thickness is
used for dialysis, e.g. for the dialysis of blood, sub-
stances remaining in the cellulose ester material tend
to leach out and flow to the patient. Accordingly, it
is preferable to reduce the amount of such substances
remaining in the thin hollow fiber membrane as much as
possible. For such a purpose, it is preferable to control
the starting materials very thoroughly ~i.e. by checking
the impurities in the starting materials) and also to
ensure that the washing with hot water takes place thor-
oughly. In particular, with regard to the cellulose ester
used as the starting material, which is a solid material
and is difficult to control as far as impurities are
concerned, it is preferable first to extract it with
1~3726~
fifteen times its volume of a mixed solvent consisting of
acetone and water (55 : 45 by volume) at 20C for 1 hour~
A cellulose ester having an extraction rate of less than
0.5 % by weight is particularly preferred.
The hollow fiber membrane thus obtained has a membrane
thickness of less than 20 and a yield strength Sb
after heat treatment according to formula (I~ as mentioned
hereinbefore and shows a suitable UFR as well as good
maintenance of the dialysis performance during storage and
during the dialysis procedure without undesirable problems
such as leakage of blood, thrombogenicity, hemolysis and
retaining of blood. Thus, the hollow fiber membrane of
the present invention is useful for the dialysis of body
liquids, and particularly for the dialysis of blood.
The present invention is illustrated by the follow-
ing Examples, but should not be construed to be limited
thereto.
Example 1
Cellulose diacetate (extraction rate with acetone,
water = 55/45 by volume: 0.32 % by weight, 33 part~
by weight), N-methyl-2-pyrrolidone (54 parts by weight)
and ethylene glycol (13 parts by weight) were mixed and
dissolved to form a spinning solution. The spinning
solution was spun in a spinning machine provided with
a circularorifice nozzle.
The spinning solution was supplied from the outer tube
and liquid paraffin was extruded as a core solution from
the inner tube. The hollow spinning solution extruded
from the circular orifice was run through air for a length
of 5 cm and then introduced into a coagulation bath
containing 75 parts by weight of water. The coagulated
hollow fibres were thoroughly washed with hot water at
50C, passed through an aqueous solution of glycerin
having a glycerin concentration of 45 % by weight at
40C, passed through a drying zone having a counter flow
of drying air at 60C, and then reeled by a winder onto
:~23726~
a bobbin. The hollow fibers eeled onto the bobbin
were heat-treated within a sealed room at a humidity
of 14 g-H2O/kg-dry air and at a temperature of 70C
for 15 hours.
The cellulose diacetate hollow fibers thus obtained
were round and had an inner diameter of 200~ , a membrane
thickness of 15~ , a crimp number of 17 crimps/10 cm, and
a crimp amplitude of 180~ .
A module for dialysis (1.1 m2) was assembled employ-
ing the hollow fiber membrane thus produced. The module
for dialysis had a UFR of 5.9 ml/hr.mmHg when measured
according to the dialyzer performance evaluation standard
provided by the Nippon Artificial Organs Association. When
this module for dialysis was used for the dialysis of blood
at a blood flow rate of 200 ml/minute, the clearance of
urea was 174 ml/minute.
The yield strength of the hollow fiber membrane for
dialysis was measured before and after the heat treatment
at 80C for 20 hours, and the retention ratio (Sb/Sa)
was calculated therefrom. The retention ratio was found
to be 1.03. When the module for dialysis was kept at
55C for 15 days (said 55C representing the highest
temperature to which the module might be exposed during
transportation), the retention of UFR was an excellent
93 %. In a bovine blood filtration test, the module for
dialysis also showed an excellent 95 ~ retention of UFR.
Reference Example 1
A hollow fiber membrane having an inner diameter of
200 ~ and a membrane thickness of 27 ~ was produced in
the same manner as described in Example 1 except that the
extrusion amount of the starting spinning solution and
the spinning rate were changed~
A module suitable for dialysis (1.1 m20 was assembled
from the resulting hollow fiber membrane. This module
showed a yield strength retention ratio tSb/Sa) (before
and after the heat treatment at 80~C for 20 hours) of 1.01.
~Z37Z6~
g
However, when the dialysis performance of the module
for dialysis was tested in the same manner as described
in Example 1, it showed a UFR of 3.5 ml/hr.mmHg and a
clearance of urea of 1~0, which were insuf f icient for
dialysis.
Reference Example 2
The same spinning colution and core solution as used
in Example 1 were spun through a circular orifice. The
hollow spinning solution extruded from the cyclic orifice
was run in air for a length of 5 cm and then introduced
into a coagulation bath containing 60 parts by weight
of water. The coagulated hollow fibers were thoroughly
washed with water at room temperature, passed through
an aqueous solution of glycerin having a glycerin con-
centration of 45 ~ by weight at 40C, passed through a
drying zone having a counter flow of drying air at 60C,
and then reeled with a winder onto a bobbin.
The cellulose diacetate hollow fibers thus obtained
had an inner diameter of 200 ~, and a membrane thickness
of lS ~.
A module for dialysis (1.1 m2) was assembled from the
resulting hollow fiber membrane. This module for dialysis
showed a yield strength retention ratio (Sb/Sa) ~before
and after the heat treatment at 80C for 20 hours) of 1.15.
However, when the module for dialysis was kept at 55C
for 15 days, it showed a UFR retention of 83 %, which
was insufficient for dialysis. Besides, it also showed
an insufficient 81 % UFR retention in a bovine blood
filtration test.
Example 2
A cellulose diacetate hollow fiber membrane having a
membrane thickness of 15 ~ was produced in the same manner
as described in Example 1 except that the amount of water
in the coagulation bath was 80 parts by weight and the
concentration of glycerin in the glycerin bath was 50
by weight.
.~
12:~726tll
-- 10 --
A module for dialysis (1.1 m2) was assembled from
the resulting hollow fiber membrane. The UFR of the
module for dialysis was measured in the same manner as
described in Example 1. As a result, it had a UFR of
6.1 ml/hr.mmHg and a clearance of urea of 176 ml/minute.
Besides, the yield strength of the hollow fiber membrane
was measured before and after the heat treatment at 80C
for 20 hours and then the retention ratio (Sb/Sa) was
calculated. As a result, the ratio was found to be 1002
Moreover, the UFR retention during storage and that in a
bovine blood filtration test were tested and were found
to be 94 % and 94 %, respectively.
