Note: Descriptions are shown in the official language in which they were submitted.
~0'~313;~2
-1. Field of the Invention
The present invention relates to ethylene-vinyl
alcohol copolymer membranes which are of use as selective
separation membranes and are particularly valuable as membranes
for the dialysis of blood in artificial kidneys.
2. Description of the Prior Art
Heretofore cuprammonium cellulose membranes have been
widely employed in the dialysis of blood, but because of their
inadequate permeability,there has been a need for new dialysis
membranes. The desiderata of a membrane for artificial kidney
applications include the following. Such a membrane should have
a controlled permeability to water, a very high permeability to
substances of the so-called intermediate molecular weight, i.e.
in the neighborhood o 300 to 6000, a comparatively low
molecular welght dependence, and a high rejection for proteins
and other biologically essential substances. To develop a
membrane having such desired properties, the membrane character-
istics of various high polymer materials have been investigated.
In this connection, we have found that ethylene-vinyl
alcohol copolymers have excellent biological compatibilities,
satisfactory antihaemolytic and antithrombogenic properties and
such other properties as durability, chemical stability, heat-
sealability, etc., thus making these materials suitable membrane
materials for the dialysis of blood.
Hirofugi et al (see Japanese Patent Application Laid
Open No. 113859/1974) have already succeeded in the production -~
of a permeable film from an ethylene-vinyl alcohol copolymer,
but because they dissolved the ethylene-vinyl alcohol copolymer
in a solvent mixture consisting of water and alcohol (e.g.
water-methanol, water-isopropyl alcohol, etc.) and wetcast the
solution, the resultant film showed white turbidity and lacked
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uniformity in structure, there being a thick skin or surface
layer and a multiplicity of pores as large as 2 microns and
upwards in the inner layers. This meant that, while the film
had a high permeability to water, it was not sufficiently
permeable to substances of intermediate molecular weight (e.g.
vitamin B12). Such characteristics, of course, do not make the
film suitable for use as a membrane for blood dialysis applica-
tions and even when it is to be employed for other separation
functions, the range of usage is considerably limited. This is
why, until now, ethylene-vinyl alcohol copolymer membranes have
found only limited application.
There is therefore a need to overcome the afore-
mentioned lack of homogeneity of prior art ethylene-vinyl
alcohol copolymer membranes, and to eliminate the large pores
therein, so that a membrane suitable for the dialysis of blood
can be produced and the inherent biological compatibilities
and structural and chemical characteristics of this category of
:.
copolymer materials suitably employed. So long as one depends
upon the production methods heretofore attempted, however, it
is considered impossible to obtain a membrane having a properly
controlled permeability to water, a high permeability to
substances of intermediate molecular weight and a high rejection
rate for proteins and other essential blood constituents.
Summary of the Invention
It is therefore an object of the present invention to
provide an ethylene-vinyl alcohol copolymer membrane which is
of value as a selective separation membrane, and to provide a
method for producing said membrane.
According to one aspect of the invention there is
provided a separation membrane formed from an ethylenè.vinyl
alcohol copolymer wherein said membrane-has a micropore structure
which is substantially uniform throughout its longitudinal and
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transverse sectional areas and wherein its constituent particles
have an average diameter in the range of 100 to 10,000 Angstrom
units as electron-microscopically determined ~or a dry membrane
and are bonded to each other to form a membrane that is substan-
tially free from pores in excess of 2 microns in diameter.
According to another aspect of the invention there is
provided a method for producing a separation membrane comprises
dissolving an ethylene-vinyl alcohol copolymer with an ethylene
content of 10 to 90 mole percent and a degree of saponification
of not less than 80 mole percent in a solvent selected from
the group consisting of dimethylacetamide, methylpyrrolidone
and dimethylsulfoxide to a polymer concentration (C) in the
range of 10 to 35 percent by weight and introducing the resulting
solution into a coagulation bath to coagulate said solution into
a shaped article wherein said coagulation bath contains water
and from 0 to 50% of a solvent selected from the group consisting
of dimethylacetamide, methylpyrrolidone and dimethylsulfoxide at
a coagulation bath temperature (TC) within the range defined ;~
by the following relation: when 10 _ C < 25, 0 c T ~ C-10 (1)
when 25 ~ C ~ 35, C-25 ~ T < C-8 (2).
Brief Description of the Drawin~ -
Figs. 1 to 5 are electronmicrographs showing cross-
sectional views of ethylene-vinyl alcohol copolymer membranes
according to preferred embodiments of the present invention;
Figs. 6 to 7 are electronmicrographs showing the
cross-sectional views of prior art ethylene-vinyl alcohol
copolymer membranes;
Fig. 8 is a cross-sectional view showing the apparatus
for measuring the permeability to water of membrane samples;
and
Fig. 9 is a cross-sectional view showing the apparatus
for measuring the permeability to vitamin B12 or uric acid of
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,~(, .
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membrane samples.
Detailed Description of the Preferred Embodiments
The ethylene-vinyl al.cohol copolymers employable
according to the present invention may be, for example, random,
block o,r graft copolymers. It should, however, be understood
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10';~38~2
that if the ethylene content of such a copolymer be less than
lO mole percent, the resultant memhrane will have only reduced
wet mechanical properties and may suffer a large dissolution
loss. Should the ethylene content be over 90 mole percent,
the membrane will have only reduced biological compatibilities
and poor permeability characteristics. Thus, it is preferable
that the copolymer have an ethylene content in the range of 10
to 90 mole percent and, for better results, in the range of 15
to 60 mole percent. Such an ethylene-vinyl alcohol copolymer
is characterized in that, unlike polyvinyl alcohols, it hardly
loses any amount of its constituents by dissolution, and is
suitable for use as a membrane for the dialysis of blood. As
regards the degree of saponification, to ensure adequate wet
mechanical properties, the ethylene-vinyl alcohol copolymer
should preferably have a degree of saponification of not less
than 80 mole percent, and more preferably not less than 95
mole percent. Normally, a substantially completely saponified
copolymer, i.e. a copolymer having a degree of saponification
in excess of 99 mole percent, is employed. The ethylene-vinyl
alcohol copolymer may contain copolymerizable comonomers such
as methacrylic acid, vinyl chloride, methyl methacrylate,
acrylonitrile, vinyl pyrrolidone, etc. in the range not
exceeding 15 mole percent.
Also falling within the scope of the present invention
are ethylene-vinyl alcohol copolymers obtainable by a cross-
linking procedure either before or after casting, or otherwise
forming into a shaped article. The ethylene-vinyl alcohol
copolymer can be cross-linked by treatment with, for example,
an inorganic cross-linking agent such as a boron compound or an
organic cross-linking agent such as a diisocyanate or dialdehyde.
Alterna,tively, the functional hydroxyl groups of the vinyl
~38Z2
alcohol units may be acetalized by an aldehyde within limits
not exceeding 30 mole percent, suitable aldehydes being
formaldehyde, acetaldehyde, butyraldehyde, benzaldehyde or the
like. The ethylene-vinyl alcohol copolymer employable in the
present invention preferably has a viscosity of l.0 to 50
centipoises as determined by a B-type viscosimeter for a
dimethylsulfoxide solution at a concentration of 3 weight percent
at 30C. If the copolymer has a lower viscosity, that is to say
a lower degree of polymerization, it does not provide a membrane
possessing particularly good mechanical properties. Should the
viscosity be higher than the above upper limit, the copolymer
may not be easy to cast or to form by another method.
Suitable solvents for dissolving the ethylene-vinyl
alcohol copolymer include monohydric alcohols such as methanol,
ethanol, etc.; polyhydric alcohols such as ethylene glycol,
propylene glycol, glycerin, etc.; phenol, m-cresol, methyl-
pyrrolidone, formic acid, etc. and mixtures of the aforesaid
solvents~with water. However, to obtain a blood-dialysis
membrane having a good balance between water-permeability and
solute-permeability characteristics, it is preferable to employ
dimethylsulfoxide, dimethylacetamide or a mixture o~ these
substances as the solvent. Dimethylsulfoxide, in particular, is
desirable because ethylene-vinyl alcohol copolymers are highly
soluble in this solvent. The solvent, particularly dimethyl-
sulfoxide, may include other solvents such as water, methanol,
isopropyl alcohol, dimethylformamide, etc.; other liquids which
are highly miscible with the particular solvent; and/or
inorganic salts, provided that they have precipitation points
below 60C (the temperature at which the ethylene-vinyl alcohol
copolymer completely diæsolved in the solvent starts being
precip~tated as the solution is gradually cooled).
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In dissolving the ethylene-vinyl alcohol copolymer in
the aforementioned solvent, the concentration of the copolymer
should preferably be within the range of 5 to 50 weigh~ percent
and more preferably within the range of 10 to 35 weight percent.
The temperature of the polymer solution should preferably be
within the range of 0 to 120C, more preferably 5 to 60C. The
polymer could be degraded at temperatures higher than 120C,
while it wouLd be too viscous to be easily shaped into an
article at temperatures below 0C.
The coagulating agent to be employed in the coagulation
bath should preferably be an aqueous medium. The aqueous medium
may be water alone or a mixture of water with not more than 50
weight percent of a water-miscible organic solvent, normally
the same solvent as that used in the preparation of the copolymer
solution or casting dope, or a system comprising such a medium
plus an inorganic salt, such as sodium sulfate, dissolved therein.
To obtain a suitable membrane having good permeability
characteristics according to the present invention, it is of
vital importance to select suitable coagulation conditions. If
the coagulation is accomplished under conditions as mild as
practicable, the resultant membrane is such that it is trans-
parent in the wet condition, being substantially free from
large pores exceeding 2 microns in diameter and, instead, having
micropores substantially uniformly distributed throughout its
longitudinal and transverse sectional areas. The term 'mild
conditions' as used herein means that the solution coagulates in
a time of not less than 3 seconds, preferably of 5 seconds or
more, as determined by the method hereinafter described. Thus,
the coagulation time of the solution is determined by casting
a solution of ethylene-vinyl alcohol copolymer onto a glass
plate to obtain a film having a thlckness of 100 microns (as
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measured in pure water) and measuring the time required for the
solution to completely coagulate (i.e. the time at which the
film can be stripped off the glass plate, without leaving a
residue of uncoagulated polymer solution on the glass plate).
Therefore, in forming the copolymer solution into a shaped
article, the solvent, the concentration and temperature of the
polymer solution, and the composition and temperature of the
coagulation bath should be selected according to the ethylene
content and degree of saponification of the ethylene-vinyl
alcohol copolymer employed so as to meet the above coagulation
time requirement. Since the coagulation time varies with film
thickness, trials can be performed under conditions leading to
the attainment of a film having a thickness of 100 microns to
find a coagulation time satisfying the above time requirement
and these conditions are used for the actual production of
separation membranes having various thicknesses. The actual
- production of a membrane does not necessarily require a glass
plate or any other support means but, even in such other cases,
the coagulating conditions selected by the above procedure can
be employed. The coagulation time thus selected is character-
istically much longer than the time heretofore known in
association with the prior art wet-casting process (in which the
solvent is water-alcohol). With a water-alcohol system, the
coagulation time as determined by the above procedure is some-
where between 1 and 2 seconds and slower coagulation cannot be
accomplished even by varying various other conditions. Of
course, even when dimethylsulfoxide is employed as the solvent,
unless the above conditions are satisfied, rapid coagulation
takes place, failing to provide a practically useful membrane
having a satisfactory balance between permeability to water and
permeability to solutes. The factor to be particularly
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considered in achieving such mild coagulation is the coagulation
temperature. When an ethylene-vinyl alcohol copolymer with an
ethylene content of 15 to 60 mole percent and a degree of
saponification of not less than 95 mole percent (preferably 99
mole percent or higher) is dissolved in a solvent based on
dimethylsulfoxide to a polymer concentration of 10 to 35 weight
percent and the resultant solution is extruded or otherwise
contacted with a coagulation bath comprising water as a
principal component, the preferred coagulation temperature is
expressed by the following relations. Assuming that the con-
centration of the copolymer is C and the coagulation temperature
is TC,
When 10 ~ C < 25, 0 - T ~ C - 10 --- (1)
When 35 ~ C ~ 25, C-25 - T - C-8 --- (2)
Thus, under conditions conductive to the above
coagulation time, the coagulation temperature indicated is
.. . .. .
selected.
According to the preferred contemplated mode of use,
the ethylene-vinyl alcohol copolymer membrane is formed in the
shape of flat sheet, tubing or hollow fiber, with or without
the aid of a supporting device. The coagulation may be achieved
by means of a plurality of baths, but in such a setup, at
least the first of the coagulation series of baths must
satisfy the aforementioned requirement.
The structure of the membrane thus produced can be
examined with a scanning electron microscope. In this method,
~; the dry membrane is frozen with liquid nitrogen and broken so
that it exposes a fracture cross section. This sectional area ~ -
is coated with gold to a thickness of 100 Angstrom units and
examined under an electron microscope. Using an accelerating
voltage~iof 20 KV, the secondary electron image can be observed
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-, ,, . . ': ' . ' ' ' . :.
1(~738'Z2
and photographed.
A membrane subjected to the above electron-microscopic
examination was prepared by dissolving a completely saponified
ethylene-vinyl alcohol copolymer with an ethylene content of 33
mole percent in dimethylsulfoxide to a concentration of 20
percent and coagulating the solution in water at 5C to a thick-
ness of 50 microns. The electronmicrographs of the resulting
membrane are shown in Figs. 1 to 5. The electronmicrographs
of Figs. 1 and 2 were taken at magnifications of 2400 times and
8000 times, respectively, using an electron-microscope (JSM-2;
manufactured by Nihon Denshi Kabushiki Kaisha). Figs. 3 to 5
are the electronmicrographs of the same membrane taken at
magnifications of 12,000, 12,000 and 24,000 times, respectively,
using an electron microscope (HFS-2; manufactured by Hitachi
Seisakusho, K. K.). It will be seen from Fig. 1 that, at a
magnification of 2,400 times, the membrane is substantially
homogeneous throughout its cross-section, indicatlng that, at
magnifications of this order, no porous structure is
ascertainable.
When the membrane of the present invention is examined
at higher magnifications, it is found, as from Fig. 2, that the
membrane consists of small particles bonded together, suggesting
that tiny gaps between the particles contribute to the excellent
permeability of the membrane. This structure is more clearly
apparent from Figs. 3 to 5. Fig. 3 shows the structure near the
surface of the membrane; Fig. 4 shows the inner zone of the
same membrane; and Fig. 5 is a electronmicrograph of the membrane
taken at a greater magnification of the same inner zone.
These electronmicrographs show that the membrane
according to this embodiment of the present invention has the
following structure. Its constituent particles have an average
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diameter substantially in the range of 100 to 10,000 Angstrom
units, normally within the range of 500 to 5,000 Angstrom units,
and are bonded to each other to form a self-supported membran-
eous structure. The term 'average particle diameter' as used
throughout this specification, including the claims, means the
average of particle sizes throughout the membrane as found by
electron micrographic observation.
As will be seen from these electronmicrographs, any
two adjacent particles in many cases do not contact each other
at a point but have a plane of contact in common, thus being
bonded to each other to form a membrane whilst retaining their
independent particulate identities. Where the shape Gf a
particle has been distorted by its bonding to the ad~oining
particle, the particle diameter is calculated assuming the
intact shape of the particle that could be visualized if it were
not bonded to the ad~acent particle but independently present.
The membrane shown in the electronmicrographs has an average
particle diameter of about 2,000 Angstrom units.
Thus, while, as aforesaid, the constituent particles
of the membrane have an average particle diameter in the range
of 100 to 10,000 Angstrom units, the individual particles also
respectively have a diameter substantially wihtin the range of
100 to 10,000 Angstrom units. It holds true, roughly speaking,
that these particles are distributed substantially evenly in ; ~-
the direction of the thickness of the membrane, although there
is a tendency for the surface layers of the membrane to comprise
comparatively large particles while the inner or core layers of
the membrane comprise relatively small particles. Although
some of the individual particles are too small to be discrete
enough on electronmicrographs, such particles are not numerous
and are,,disregarded in the computation of an average particle
diameter.
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As these particles are bonded together to form a
membrane, a multiplicity of tiny gaps are created between the
particles. The gaps vary in size and shape but the variations
are by far smaller than those of the hitherto-known ethylene-
vinyl alcohol copolymer membranes and it is apparently for this
reason that the membrane according to the present invention
displays permeability charac~eristics distinct from those of
the prior art membranes.
Furthermore, the membrane according to the present
invention is substantially skinless; that is to say, it has no
dense and thick surface layer. While, as will be seen from
Fig. 3, there is occasionally a very thin skin (on one side
only, having a thickness of about 1 percent based on the overall
thickness of the membrane), the membrane may be said to be
substantially skinless because the presence of a skin layer of
this order does not interfere with the permeability of the
membrane to any significant extent.
Structural views of the inner layers of prior art
ethylene-vinyl alcohol copolymers are æhown in Figs. 6 and 7.
Figs. 6 and 7 are electronmicrographs taken at the magnification
of 2,400 times and 8,000 times, respectively, using an electron
microscope, JSM-2 of Nihon Denshi Kabushiki Kaisha. This prior-
art membrane was prepared by dissolving an ethylene-vinyl
alcohol copolymer similar to the above in a solvent mixture
(7:3) of methanol and water and forming the resultant solution
into a membraneous article. The concentration of the solution,
and the composition and temperature of the coagulation bath
employed were the same as those employed for the production of
the membrane shown in Figs. 1 to 5 involving the use of
dimethylsulfoxide as the solvent. As will be seen from Fig. 6,
the pri4r-art membrane reveals a porous structure even at a
1~738Z2
magnification of 2,400 times, having many large pores (diameter
more than 2 microns). This structure is more apparent at a
magnification of 8,000 times. Thus, comparison of the membrane
according to the present invention with the prior art membrane
at once shows a marked difference in micro-structure. Whereas
the prior art membrane contains a large number of pores larger
than 2 microns in diameter, the membrane according to the
present invention is substantially devoid of pores exceeding
the above pore size limit.
The prior art ethylene-vinyl alcohol copolymerm~mbrane is
produced by a forming process involving the employment of a
solvent mixture of water and an organic solvent such as methanol,
isopropyl alcohol or the like, but because of the inadequate
solubility of the copolymer in such a solvent mixture, the
coagulation time is of necessity short irrespective of what
conditions are employed. Thus, it is impossible to effect
a slow coagulation such as that feasible in accordance with
the present invention. It follows, then, that the prior art
.: .
membrane contains many pores larger than 2 microns in diameter
and, although it is not evident in the electronmicrographs,
there is a thick skin on the surface (a dense skin layer as
thick as about 3 percent or more based on the overalll thickness
of the membrane). Therefore, the prior art membrane is inhomo-
geneous, shows a white turbidity and fails to exhibit the ~ -
desired permeability characteristics.
Because it is formed by using the aforementioned
particular solvent under the conditions defined hereinbefore,
the membrane according to the present invention is substantially
free from pores larger than 2 microns in diameter, It is a
membrane having a substantially homogeneous micro-structure
which is usually transparent in the wet condition and displays
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lQ738'~Z
the characteristics desired in a separation membrane and,
particularly, in a membrane for the dialysis of blood. Thus,
the membrane according to the present invention usually has a
permeability to water of 10 to 200 x 10 16 cm2, a permeability
to vitamin B~2 of not less than 0.8 x 10 7 cm2 per second and,
in addition, has the mechanical strength required of a membrane
for the dialysis of blood. Usually, there is a good balance
between permeability to water and permeability to vitamin B12
The membrane formed as above can be rinsed with water
at a low temperature not exceeding 50C, if required. The
membrane may be maintained in wet condition without being dried
and, if required, may be sterilized before use. However, the
storing of the membrane in water before and after use is a dis-
advantageous factor in transportation and in assembling membranes
into a module. It is therefore desirable to produce a dry film
retaining the advantageous properties mentioned above. For
this purpose, the wet membrane just after formation can be
dipped into a water-miscible organic non-solvent in order to
replace the aqueous solvent present on the surface aDd/or inside
the membrane with the non-solvent and, thereafter, the membrane
can be dried at atmospheric or reduced pressure and at a
temperature below the glass transition point of the ethylene-
vinyl alcohol copolymer, preferably in the neighborhood of room
temperature. By the above procedure may be obtained a dry
permeable membrane retaining the desired permeability
characteristics. Suitable organic solvents for this purpose,
include lower aliphatic alcohols or ketones of 1 to 5 carbon
atoms, such as methanol, ethanol, amyl alcohol, acetone, methyl
ethyl ketone, diethyl ketone and so forth. Acetone is par-
ticularly desirable.
, A dry membrane retaining the above-mentioned
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10'73~;3Z'~
permeability characteristics may also be obtained in such a
manner that, instead of replacing the water with an organic
solvent, the membrane may be freshly formed and treated in the
wet condition with a polyhydric aliphatic alcohol having 2 to
4 carbon atoms or an adduct of 1 to 20 moles of ethylene oxide
to such a polyhydric alcohol in an aqueous, alcoholic or
other solution and at a temperature of not more than 50C and,
thereafter, the membrane can be dried at a temperature not in
excess of 50C. In such cases, the resultant membrane contains
about 20 to 120 percent of the polyhydric alcohol or polyhydric
alcohol-ethylene oxide reactant based on the ethylene-vinyl
alcohol copolymer which, however, may subsequently be easily -
removed by rinsing prior to dialysis after being built into a
modular unit. Suitable polyhydric alcohols having 2 to 4
carbon atoms include ethylene glycol, diethylene glycol,
propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin and
so forth, glycerin being particularly preferred. It is also -
possible to incorporate such a polyhydric aliphatic alcohol
into the wet-coagulation bath so that the membrane will contain
said alcohol as the membrane is formed.
The separation membrane according to the present
invention is normally put to use as a flat sheet or tube with
a thickness in the range of 10 to 100 microns. It may also
be formed and used in the shape of a hollow fiber, which may
measure about 50 to 1,500 microns in outer diameter and about
10 to 300 microns in wall thickness.
While the ethylene-vinyl alcohol copolymer membrane
according to the present invention has properties which, as
mentioned hereinbefore, are particularly beneficial for use as
an artificial kidney membrane for the dialysis of blood, it is
also us~ful as a filtration and separation medium for bacteria,
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proteins, viruses and colloidal substances and may also be
used for other dialytic or ultrafiltration purposes.
The following Examples are intended to further
illustrate the present invention without limiting its scope
described hereinbefore and set out in the appended claims.
Example 1
An eth~lene-vinyl alcohol copolymer having an ethylene
content of 33 mole ~ and a degree of saponification of not less
than 99 mole % was dissolved in dimethylsulfoxide to prepare
a solution of 24~ concentration at a temperature of 40C.
This solution was formed into a membrane in a coagulation
bath comprising water, the membrane being 50 microns thick.
The membrane thus freshly formed and in wet condition was
tested for permeability to uric acid, vitamin sl2 and water.
The results are set forth in Table 1. The properties of the
cuprophane membrane currently available on the market for
artificial kindney use are also shown in Table 1. It will
be obvious from these data that the membrane according to the
present invention is considerably superior to the conventional
membrane for the purposes of blood dialysis.
The permeability behaviors of these membranes against
water, uric acid and vitamin B12 were determined by the follow-
ing procedures.
(i) The permeability to water of each membrane was determined
by the apparatus illustrated in Fig. 8 at 37C and 100 - 300
mm Hg and the permeability coefficient k was calculated by means
of equation (3).
k = VL~/tA ~P(cm ) --- (3)
where V: volume of permeated water (cm3)
L: thickness of the membrane (cm)
~: viscosity of water (~/cm.sec)
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~ t: permeation time (sec.)
A: area of the membrane (cm2)
~ P: measuring pressure (g/cm .sec2)
(ii) The permeabilities to solutes such as vitamin Bl2 and uric
acid were determined by means of the apparatus illustrated in
Fig. 9 at 37C and the permeability constants P were calculated -
by means of equation (4). The concentrations were measured by
ultraviolet spectrometry. -
- L S l _ C2/Cl 2
P (l ~ ln~ V C (cm /sec.) --- (4)
Vl V2)At ~l ~ 2/Vl . 2/C
Where L: thickness of the membrane (cm) ;
A: area of the membrane (cm2)
Cl: the concentration of the solute in the chamber l aftcr
t seconds
C2: the concentration of the solute in the chamber 2 after
t seconds
Vl: volume of chamber l
V : volume o chamber 2
(At t = 0, 1: the solute side, 2: the pure water side)
.
Table l
. _ . .
Permeabilities
Sample Uric acid ¦ Vitamin Bl2 ~ater
(cm2/sec x 107) ¦ (cm2/sec x 108) (cm2 x 10l6)
~ B
Ethylene-vinyl
alcohol copoly-11.6 35.1 llO
mer membFane _ _
Cuprophane 5.9 8.4 7.5
3Q membrane
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r~
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1073822
Then, the ethylene-vinyl alcohol copolymer membrane was
subjected to an elution test. The results are shown in
Table 2, together with the corresponding data on the
C ~
~u~rop~al~ membrane. The above elution test was performed
in the following manner. The sample membrane was cut to 1.5 cm
square, and 2 grams of the specimens were heated together with
100 ml of distilled water at 70C for predetermined time
periods. Ten ml. of the extract was taken, and following
the addition of 20 ml of a 0.01 N-aqueous solution of potassium
permanganate and 1 ml~of a 3N-aqueous solution of sulfuric acid,
the extract was boiled for 3 minutes and, then, allowed to
cool. Then, 1 ml of an aqueous solution of potassium iodide
(10 wt. %) was added, whereupon iodine was liberated to turn
the solution from violet to reddish yellow. This liberated
iodine was titrated with sodium thiosulfate and the difference
from the blank was taken as the amount of potassium permanganate
consumed. One ml of an aqueous solution of starch (1~) was
added as an indicator. Of course, a fresh extract was used
for each of the elution runs.
Table 2
Consumption of KMnO4, ml
Sample 1st elution 2nd elution 3rd elution
__ (1 hr.) (2 hrs.) (2 hrs.)
_
thylene-vinyl alcohol 1.12 0.32 0.11
copolymer membrane
~ ........................ . .
membrane 15.80 0.87 0.31
It will be seen from Table 2 that, compared with the
cuprophane widely employed nowadays as a dialysis membrane for
artificial kidney use, the ethylene~vinyl.alcohol copolymer
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10738'ZZ
membrane according to the present invention yields only reduced
amounts of extracted substances.
The in vitro blood compatibility of the ethylene-vinyl
alcohol copolymer membrane was evaluated in the following
manner. In the first place, an antihaemolysis test was performed
as follows. The sample membrane was cut into a square 2 cm x
2 cm, which was then laid on the bottom of a glass test tube f
18 mm diameter. In the test tube was put 3 ml of a 10% suspension
of red blood cells and the tube was left standing at 37C
for 49 hours. Thereafter, the suspension was centrifuged
and 0.2 ml of the supernatant was taken and diluted to 10 ml.
Then, the absorbance at 413 nm was measured to determine the
amount of haemoglobin (relative amount) produced by haemolysis.
The result was 0.66 for the present membrane, in constrast
to 0.76 for the control cuprophane.
The anti-coagulation test was performed by a procedure
similar to the :kinetic method of Imai-Nosé. Thus, the ACD blood
; of a dog was put on a wet specimen in a dish and an aqueous
solution of CaC12 was added to the suspension to initiate the
coagulation reaction at 37C. After 5 minutes and 30 seconds,
~;~ the clot of blood accounted for 40 weight % (with the weight of
the glass as 100), in contrast t~o the corresponding value of
~ro ~ ~
42% for the control ~oprGp~hm~ It is thus clear that the
blood compatibility of the ethylene-vinyl alcohol copolymer
membrane according to the present invention relatively superior
to that of the conventional membrane.
ExamPle 2
Ethylene-vinyl alcohol copolymers with an ethylene content of
33 mole % and that of 45 mole %, respectively, both having a
30l degree of saponification of not less than 99~, were each dissolved
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1073~Z~
in methanol-water, n-propanol-water or dimethylsulfoxi.de,
and each solution was formed into membranes under various
conditions. These membranes were tested for permeability
characteristics. The results are set forth in Table 3,
~ ' ~ ~
a) a) ':
3 .~ $ Q ~ :~
o ~ ~ o ,,_ ~ __
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-- 19 --
10738ZZ
(Note) 3-1 to 3-8: Temperature of polymer.solution 60C, 3-9 to .
3-10:40C coagulation ~ath: water; the thickness of membranes:
50 microns.
It will be apparent from the above results that when
membranes are formed under conditions such that the coagulation
is completed in times less than the limit of 3 seconds as
defined in this specification, the resultant membranes do not
satisfy the permeability requirements for membranes for the
dialysis of blood. In contrast, when formed under conditions
corresponding to a time of not less than 3 seconds, the membranes
have high permeability to water and to vitamin B12.
It is also obvious from Table 3 that the use of a solvent
mixture of alcohol and water does.not provide a membrane with a
good balance between permeability to water and permeability to
vitamin B12.
Example 3
Ethylene-vinyl alcohol copolymers (degree of saponification:
99 mole % or more) with an ethylene content of 33 mole ~ and that
of 45 mole %, respectively, were each dissolved in dimethyl-
sulfoxide and the resultant solutions were respectively extrudedthrough dies into a coagulation bath (water) to prepare membranes.
The relation of coagulating conditions to permeability ~.
characteristics is shown in Table 4.
- 20 -
10738~Z
_ .
~o
,,
~X ~ ~D O O 1~ 0 a~
_ o~ o er~ o ~ ~
~` , ,~ . -
~o
_Ix
~q ~ ~ u~ In
.~ ~ ~ r~
:~ ~
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~ X
~ ,~ c,
11~ a) Lt~ ul O O N ~ U)~
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E~ I ., ~:: h .
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O ~ 3 ,4 0 ~ W 0 ~ ~DO ~ N
.~1 O ~ ~ 1
~ U -I ~J P. . '
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~0 ~ ~
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o o ~ ~ o N ~ N
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_ _
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. ~ ~
Z' r~ ~.
' ' '
.
,
* "33" and "45" stand ~or the ethylene contents of the ethylene-
vinyl alcohol copolymers employed.
It will be seen from Table 4 that where the coagulation
temperatures are high as in 33-3, 45-2 and 45-4, the
permeabi~ities to water of the membranes tend to be too high.
- 21 -
.. . . . , . . . , . , . ~ .
1073822
Example 4
The membrane of No. 33-2 of Example 3 was further
after-treated to evaluate the possible degradation of the
membrane characteristics. The results are shown in Table 5.
Table 5
Sample ~ondition Permeabilities
No. treatment Uric acid Vitamin B12 Water
~cm /sec x 10 ) (cm /sec x 108) (cm2 x 1016)
~ ~ __
33-2 Membrane 10.5 35 146
just form
ed and we -
33-2-a Acetone 9.5 35 146
replace-
ment, fol
lowed by
drying at
room temp.
33-2-b Dipped in 10.0 35 144
20% a~ue-
ous gly-
cerin,
followed
by drying
tetmpm '
It will be seen from Table 5 that neither acetone
replacement followed by drying at room temperature nor glycerin
treatment followed by drying at room temperature results in
no degradation of permeability performance, thus invariably
giving rise to dry membranes retaining the excellent permeabi-
lity characteristics. This result is additional evidence of -
the usefulness of the ethylene-vinyl alcohol copolymer membrane
according to the present invention for blood dialysis purposes.
-
.,
- 2~ -
.
~ ,:. - , :
