Indian Patents
Title of Invention

HYDROPHILIC MICROPOROUS MEMBRANE
Abstract A hydrophilic microporous membrane comprising a thermoplastic resin, which is subjected to a hydrophilizing treatment by a graft polymerization reaction of a hydrophilic vinyl monomer containing a hydroxyl group with a cross- linking agent in a graft ratio of 6 to 30%, wherein the cross-linking agent is used at a proportion to the hydrophilic vinyl polymer of 0 to 10 mol%, wherein the hydrophilic microporous membrane has a maximum pore size of 10 to 100 nm, and has a coarse structure layer and a fine structure layer, which are formed in one piece, wherein the above-described coarse structure layer has a higher open pore ratio and exists on at least one side of the membrane surface and has a thickness of 2 m or more, and the above- described fine structure layer has a lower open pore ratio and has a thickness of 50% or more of the whole membrane thickness.
Full Text DESCRIPTION
HYDROPHILIC MICROPOROUS MEMBRANE
TECHNICAL FIELD
The present invention relates to a
hydrophilic microporous membrane suitable for removing
microparticles such as viruses.
BACKGROUND ART
Recently in the refining process of a plasma
derivative or a biopharmaceutical, there is a need for
technology for removing pathogenic agents such as a
virus and a pathogenic protein in order to enhance
safety. Among the methods for removing pathogenic
agents such as a virus is a membrane filtration method.
Since the separation operation is conducted, in this
membrane filtration method, according to the size of
the particles based on the sieve principle, the method
is efficacious for all the pathogenic agents
irrespective of the type of pathogenic organism as well
as the chemical or thermal characteristics of the
pathogenic organism. Therefore, industrial utilization
of the removal of pathogenic agents using the membrane
filtration method has been prevailing in recent years.
Since infection with an infectious virus
among pathogenic agents may cause serious diseases,
removal of contaminating viruses is highly reguired.
Types of viruses include smallest viruses, such as
parvovirus, with a diameter of about 18 to 24 run,
medium-sized viruses, such as Japanese encephalitis
virus, with a diameter of about 40 to 45 nm and
relatively large viruses, such as HIV, with a diameter
of about 80 to 100 nm, etc. In order to remove these
virus groups physically by the membrane filtration
method, a microporous membrane having a pore size of
about 10 to 100 nm is required, and particularly the
needs for removing small viruses such as parvovirus are
increasing in recent years.
In the meantime, when the membrane filtration
method is applied in the refining process of a plasma
derivative or a biopharmaceutical, it is desirable not
only to enhance the virus removal ability but to allow
rapid permeation of a large quantity of physiologically
active substances in order to improve productivity.
However,.when a subject to be removed is a
small virus like parvovirus, since its size is
extremely small, as small as 18 to 24 nm, it was
difficult to satisfy both of the virus removal
performance and the amount and rate of permeation of
physiologically active substances by conventional
technology.
That is, conventional microporous membranes
have drawbacks that they can allow permeation of high-
molecular-weight physiologically active substances,
such as human immunoglobulin and Factor VIII, at a
sufficient permeation rate while they cannot remove
small viruses such as parvovirus; or they can remove
small viruses such as parvovirus while they cannot
allow permeation of high-molecular-weight
physiologically active substances, such as human
immunoglobulin and Factor VIII, at a substantial
permeation rate.
International Publication WO91/16968 pamphlet
discloses a process comprising immersing a membrane
with a solution containing a polymerization initiator
and a hydrophilic monomer, allowing polymerization
within micropores, thereby adhering a hydrophilic resin
to the surface of the micropores. This method,
however, has a defect that the hydrophilic resin merely
adheres to the surface of the micropores, and
therefore, part of the adhering hydrophilic resin may
be dissolved out upon washing out low-molecular weight
substances generated in the reaction and hydrophilicity
of the membrane may be easily lost. In addition, if a
cross-linking agent is used in a large amount and
copolymerization is performed in order to prevent
dissolution-out, high permeability will not be attained
for protein solutions.
JP-A-07-265674 describes a polyvinylidene
fluoride film having low adsorptivity for goat
immunoglobulin which can effectively remove small
particles from a solution. It is described that this
film is useful for removing viruses from the solution.
According to the Examples thereof, however, this
hydrophilic film shows a low adsorptivity for goat
immunoglobulin, and does not have sufficient
permeability for physiologically active substances such
as globulin comparable to the present invention.
JP-A-62-179540 describes a hydrophilic hollow
fiber porous membrane comprising a hydrophilic hollow
fiber porous membrane composed of polyolefin and side
chains containing a neutral hydroxyl group grafted to
the membrane. The Examples thereof, however, only
describe a hydrophilic microporous membrane having an
average pore size of 0.1 to 0.16 jj.m and does not
describe a small pore sized microporous membrane having
a maximum pore size of 10 to 100 pm.
JP-A-07-505830 describes a process which
comprises irradiating hydrophobic microporous membrane
of polyolefin or partially fluorinated polyolefin, etc.
with ultraviolet ray and polymerizing a bifunctional
monomer which has two reactive groups. According to
the above-described method, however, hydrophilicity is
lost due to cross-linking in hydrophilic diffusive
layer and sufficient filtration rate cannot be attained
for a protein solution.
International Publication WO01/14047 pamphlet
describes a filtration membrane for physiologically
active substances wherein the logarithmic removing
ratio for parvovirus is three or more and the
permeation ratio for bovine immunoglobulin having a
monomer ratio of 80% or more is 70% or more. However,
the main membrane disclosed here comprises hollow
fibers made of cellulose, and since the mechanical
strength when it is wet with water is low, filtration
pressure cannot be made high, and therefore, it is very
difficult to achieve a high permeation rate.
DISCLOSURE OF THE INVENTION
An object of the present invention is to
provide a hydrophilic microporous membrane which has
high removing ability for small viruses such as
parvovirus, and allows permeation of physiologically
active high-molecular-weight substances, such as
globulin and Factor VIII, at a high rate and in large
quantities.
The present inventors have conducted
intensive studies for attaining the above-described
object and consequently have completed the present
invention.
That is, the present invention is as follows:
1. A hydrophilic microporous membrane comprising
a thermoplastic resin, having been subjected to
hydrophilizing treatment and having a maximum pore size
of 10 to 100 nm, wherein when 3 wt% bovine
immunoglobulin having a monomer ratio of 80 wt% or more
is filtered at a constant pressure of 0.3 MPa, an
average permeation rate (Iiter/m2/h) for 5 minutes from
the start of filtration (briefly referred to as
globulin permeation rate A) satisfies the following
formula (1) and an average permeation rate (Iiter/m2/h)
for 5 minutes from the time point of 55 minutes after
the start of filtration (briefly referred to as
globulin permeation rate B) satisfies the following
formula (2):
Globulin permeation rate A > 0.0015 x maximum
pore size (nm)2'75 (1)
Globulin permeation rate B/globulin
permeation rate A > 0.2 (2).
2. The hydrophilic microporous membrane
according to the above 1 having a receding contact
angle of water of 0 to 20 degrees.
3. The hydrophilic microporous membrane
according to the above 1 or 2, wherein a logarithmic
reduction value of porcine parvovirus at the time point
by which 55 liter/m2 has been permeated from the start
of filtration is 3.or more.
4. The hydrophilic microporous membrane
according to any of the above 1 to 3, wherein both of a
logarithmic reduction value of porcine parvovirus at
the time point by which 5 liter/m2 has been permeated
from the start of filtration and a logarithmic
reduction value of porcine parvovirus at the time point
by which further 5 liter/m2 has been permeated after 50
liter/m2 is permeated are 3 or more.
5. The hydrophilic microporous membrane
according to any of the above 1 to 4, wherein an
accumulated permeation volume in three hours after the
start of filtration is 50 liter/m2 or more when 3 wt%
bovine immunoglobulin having a monomer ratio of 80 wt%
or more is filtered at a constant pressure of 0.3 MPa.
6. The hydrophilic microporous membrane
according to any of the above 1 to 5, wherein the
above-described microporous membrane containing a
thermoplastic resin is a microporous membrane having a
coarse structure layer with a higher open pore ratio
and a fine structure layer with a lower open pore
ratio, and the above-described coarse structure layer
exists on at least one side of the membrane surface and
has a thickness of 2 pm or more and the thickness of
the above-described fine structure layer is 50% or more
of the whole membrane thickness, and the above-
described coarse structure layer and the above-
described fine structure layer are formed in one piece.
7. The hydrophilic microporous membrane
according to the above 6, wherein the thickness of the
above-described coarse structure layer is 3 jam or more.
8. The hydrophilic microporous membrane
according to the above 6, wherein the thickness of the
above-described coarse structure layer is 5 pm or more.
9. The hydrophilic microporous membrane
according to any of the above 1 to 8, wherein the
above-described thermoplastic resin is polyvinylidene
fluoride.
10. The hydrophilic microporous membrane
according to any of the above 1 to 9, wherein the
above-described hydrophilizing treatment is a graft
polymerization reaction of a hydrophilic vinyl monomer
having one vinyl group to the surface of the pores of
the hydrophilic microporous membrane.
11. The hydrophilic microporous membrane
according to the above 10, wherein the above-described
hydrophilic vinyl monomer contains a hydroxyl group.
12. The hydrophilic microporous membrane
according to any of the above 1 to 11, wherein an
adsorption amount per 1 g of the membrane is 3 mg or
less when dead-end filtration at a constant pressure of
0.3 MPa is performed using a 0.01 wt% bovine
immunoglobulin solution and a filtrate of 50 liter/m2
from the start of filtration is collected.
13. The hydrophilic microporous membrane
according to any of the above 1 to 12 for use in
removing viruses from a liquid containing a
physiologically active substance.
14. A hydrophilic microporous membrane,
characterized in that both of a logarithmic reduction
value of porcine parvovirus at the time point by which
5 liter/m2 has been permeated from the start of
filtration and a logarithmic reduction value of porcine
parvovirus at the time point by which further 5 liter/m2
has been permeated after 50 liter/m2 is permeated are 3
or more, and when 3 wt% bovine immunoglobulin having a
monomer ratio of 80 wt% or more is filtered at a
constant pressure of 0.3 MPa, an average permeation
rate (Iiter/m2/h) for 5 minutes from the start of
filtration (briefly referred to as globulin permeation
rate A) satisfies the following formula (1) and an
average permeation rate (Iiter/m2/h) for 5 minutes from
the time point of 55 minutes after the start of
filtration (briefly referred to as globulin permeation
rate B) satisfies the following formula (2):
Globulin permeation rate A > 0.0015 x maximum
pore size (nm)2'75 (1)
Globulin permeation rate B/globulin
permeation rate A > 0.2 (2).
BEST MODE FOR CARRYING OUT THE INVENTION
The maximum pore size of the hydrophilic
microporous membrane of the present invention measured
by the bubble point method is preferably 10 nm or more
and more preferably 15 nm or more from the viewpoint of
permeability of physiologically active substances such
as globulin and filtration rate. The upper limit of
the maximum pore size measured by the bubble point
method is preferably 100 nm or less, and although it
varies depending on the size of the virus and the like
to be removed, it is preferably 70 nm or less for
removing medium-sized viruses such as Japanese
encephalitis virus, and particularly 36 nm or less when
the object to be removed is a small virus such as
parvovirus. The maximum pore size as used herein is
the value measured by the bubble point method based on
ASTM F316-86.
It is preferable that a skin layer does not
exist on the surface of the hydrophilic microporous
membrane of the present invention. If a skin layer
exists, suspending substances contained in the solution
containing physiologically active substances such as
protein accumulate on the membrane surface, and
accordingly a rapid fall in the permeation capability
may occur. The skin layer as used herein refers to a
layer which exists adjacent to the membrane surface,
and whose pore size is smaller compared with the inside
of the membrane, and the thickness thereof is usually 1
jam or less.
The hydrophilic microporous membrane of the
present invention has an average permeation rate
(Iiter/m2/h) for 5 minutes from the start of filtration
(hereinafter briefly referred to as globulin permeation
rate A) when 3 wt% bovine immunoglobulin having a
monomer ratio of 80 wt% or more is filtered at a
constant pressure of 0.3 MPa which satisfies the
following formula (1):
Globulin permeation rate A > 0.0015 x maximum
pore size (nm) 2.75 (1) .
That is, the globulin permeation rate A of
the hydrophilic microporous membrane of the present
invention should be more than 0.0015 x maximum pore
size (nm)2.75, preferably not less than 0.0015 x maximum
pore size (nm)2.80, more preferably not less than 0.0015
x maximum pore size (nm)2"85, most preferably not less
than 0.0015 x maximum pore size (nm}2"90. When the
globulin permeation rate A is more than 0.0015 x
maximum pore size (nm)2.75, sufficient permeation rate to
carry out removing of viruses in the production of
plasma derivatives, biopharmaceuticals, etc. on an
industrial scale is securable.
In addition, the hydrophilic microporous
membrane of the present invention should have a
globulin permeation rate A and an average permeation
rate (Iiter/m2/h) for 5 minutes from the time point of
55 minutes after the start of filtration (hereinafter
briefly referred to as globulin permeation rate B) when
3 wt% bovine immunoglobulin having a monomer ratio of
80 wt% or more is filtered at a constant pressure of
0.3 MPa which satisfies the following formula (2):
Globulin-permeation rate B/globulin
permeation rate A > 0.2 (2).
In the hydrophilic microporous membrane of
the present invention, globulin permeation rate
B/globulin permeation rate A (hereinafter briefly
referred to as the ratio of filtration rates) is
preferably 0.3 or more, and more preferably 0.4 or
more. If the ratio of filtration rate is more than
0.2, filtration rate can be kept sufficiently and
removing of viruses in the production of plasma
derivatives, biopharmaceuticals, etc. on an industrial

scale is carried out.
The hydrophilic microporous membrane of the
present invention preferably has a logarithmic
reduction value of porcine parvovirus at the time point
by which 55 liter/m2 has been filtered from the start of
filtration (hereinafter referred to as the 0 to 55
liter/m2 filtered time) is 3 or more, and more
preferably 3.5 or more, and most preferably 4 or more.
When logarithmic reduction value of porcine parvovirus
at the 0 to 55 liter/m2 filtered time is 3 or more, it
can be equal to the use as a virus removal filter for
removing small viruses such as human parvovirus B19 and
poliomyelitis virus from a solution containing
physiologically active substances. Furthermore, the
fact that small viruses such as human parvovirus B19
and poliomyelitis virus can be removed means that
larger viruses such as hepatitis C and HIV can be:
removed with still.higher probability.
In addition, although a virus concentration
in a filtrate may vary depending on a filtered volume,
a membrane with no or a small, if any, decreasing ratio
in the virus removal ability as the filtered volume
increases is naturally desired. The hydrophilic
microporous membrane of the present invention
preferably has both of the logarithmic reduction value
of porcine parvovirus at the time point by which 5
liter/m2 has been filtered from the start of filtration
(hereinafter referred to as the 0 to 5 liter/m2 filtered
time) and the logarithmic reduction value of porcine
parvovirus at the time point by which further 5 liter/m2
has been filtered after 50 liter/m2 is filtered
(hereinafter referred to as the 50 to 55 liter/m2
filtered time) of 3 or more, and more preferably 3.5 or
more, and most preferably 4 or more. The fact that
each of the porcine parvovirus at 0 to 5 liter/m2
filtered time and 50 to 55 liter/m2 filtered time is 3
or more can be regarded as an index showing that
persistency of the virus removal ability of the
membrane is sufficiently high.
Proteins in a plasma derivative or a
biopharmaceutical are liable to be adsorbed to a
hydrophobic membrane, in other words, they are hardly
adsorbed to a hydrophilic membrane, and the
hydrophilicity of the membrane can be estimated by
contact angle of water. There are two methods for
measuring contact angle, static contact angle method
and dynamic contact angle method, and the dynamic
contact angle method, which provides information on
surface dynamics, is preferable. Among the dynamic
contact angle methods, the measuring method according
to the Wilhelmy method with high flexibility of sample
form is more preferable.
Among the contact angles of water, receding
contact angle of water serves as an important index for
estimating the hydrophilicity of the membrane, since
the receding contact angle directly reflects the
hydrophilicity of the membrane surface in water. The
hydrophilic microporous membrane of the present
invention preferably has a receding contact angle of
water of 0 to 20 degrees, more preferably 0 to 15
degrees, still more preferably 0 to 10 degrees and most
preferably 0 to 5 degrees. When the receding contact
angle of water exceeds 20 degrees, the hydrophilicity
of the membrane is insufficient and a rapid fall of the
filtration rate will be caused by adsorption of
protein.
Although the form of hydrophilic microporous
membrane of the present invention is applicable in any
form including a flat membrane, a hollow fiber, etc.,
hollow fiber is preferable from the viewpoint of
easiness of production.
The membrane thickness of hydrophilic
microporous membrane of the present invention is
preferably 15 mm to 1000 mm, more preferably 15 mm to
500 mm, and most preferably 20 mm to 100 mm. When the
membrane thickness is 15 mm or more, not only strength
of the microporous membrane is sufficient but also
certainty in virus removal is sufficient. Membrane
thickness exceeding 1000 mm is not preferable since the
permeation capability tends to fall.
The porosity of hydrophilic microporous
membrane in the present invention is 20 to 90%,
preferably 30 to 85%, and more preferably 40 to 80%.
When the porosity is less than 20%, filtration rate is
not enough and when the porosity exceeds 90%, there is
a tendency that the certainty of virus removal
decreases and the strength of microporous membrane
becomes insufficient and therefore it is not
preferable.
Although water permeativity of the
hydrophilic microporous membrane of the present
invention varies depending on the pore size, it is
preferably 2X10-11 to 3xl0-8, more preferably 4X10-11 to
1.5xlO-8, most preferably 5xlO-11 to 8.5xlO-9. The unit
of the water permeativity is m3/m2/second/Pa. When the
water permeativity is 2xlCT-11 or more, water
permeativity sufficient for use as a separation
membrane can be obtained and therefore it is
preferable. On the other hand, in consideration of
keeping the strength of hydrophilic microporous
membrane or securing the certainty of virus removal,
water permeativity.exceeding 3xlO-8 is not realistic.
The surface of the hydrophilic microporous
membrane of the present invention and the surface of
the micropores preferably show low adsorptivity for
proteins such as globulin. The degree of adsorptivity
can be evaluated by permeating a diluted solution of
globulin which is a typical plasma protein, and
quantifying the proteins contained in the unfiltered
solution and the filtrate by absorption spectrometer.
The amount of adsorption per 1 g of membrane when a
bovine immunoglobulin solution diluted to 100 mass ppm
is made to permeate is 3 mg or less, more preferably 2
mg or less, and most preferably 1 mg or less.
As for the hydrophilic microporous membrane
of the present invention, it is preferable that the
maximum pore size is 10 to 100 run and the structure of
the microporous membrane is not limited as long as it
satisfies the following formula (1) and formula (2).
It is preferable, however, that the microporous
membrane has a coarse structure layer with a higher
open pore ratio and a fine structure layer with a lower
open pore ratio, and the above-described coarse
structure layer exists on at least one side of the
membrane surface and has a thickness of 2 mm or more
and the thickness of the above-described fine structure
layer is 50% or more of the whole membrane thickness,
and the above-described coarse structure layer and the
above-described fine structure layer are formed in one
piece. This is because such a structure facilitates to
secure the initial filtration rate satisfying the
formula (1) and to keep the filtration rate satisfying
the formula (2).
Globulin permeation rate A > 0.0015 x maximum
pore size (nm)2.75 (1)
Globulin permeation rate B/globulin
permeation rate A > 0.2 (2).
Microporous membranes having a preferable
structure will be described below.
In the above-described microporous membrane,
the coarse structure layer preferably exists on at
least one side of the membrane surface and the
thickness of the coarse structure layer is preferably 2
mm or more, more preferably 3 mm or more, still more
preferably 5 mm or more and particularly preferably 8
mm or more. The coarse structure layer has a pre-
filter function, and alleviates decrease in the
filtration rate due to the blockade by impurities. As
the pore size of microporous membrane is smaller,
impurities contained in physiologically active
substances may more readily cause decrease in the
filtration rate, and thus the thickness of the coarse
structure layer is preferably large.
In the meantime, the thickness of the fine
structure layer is preferably 50% or more of the whole
membrane thickness. When the thickness of the fine
structure layer is 50% or more of the whole membrane
thickness, it can be used without reducing removing
performance such as for viruses. It is more preferably
55% or more, and particularly preferably 60% or more.
The above-described coarse structure layer is
a part where open pore ratio is relatively large in the
whole membrane thickness and improves processing
performance of the membrane by exhibiting a pre-filter
function on the suspending substances contained in a
protein solution or the like. On the other hand, the
above-described fine structure layer is a part where
open pore ratio is relatively small in the whole
membrane thickness and substantially defines the
membrane pore size. It is the layer which has the
function of removing particles in a microporous
membrane to remove particles such as viruses.
Both of the porosity and the open pore ratio
respectively correspond to the capacity ratio of the
pored portion in the microporous membrane of the
present invention and they are the same in the basic
concept but the porosity is a numerical value obtained
from an apparent volume calculated from the cross-
sectional area across the membrane and the length and
the mass of the membrane and the true density of the
membrane material, whereas the open pore ratio is an
area ratio of the pored portions to the cross-sectional
area of the membrane in the cross-section of the
membrane, which can be determined from the image
analysis of the electron microscope photograph of the
cross-section of the membrane. In the present
invention, open pore ratio is measured for every pre-
determined thickness in the membrane thickness
direction in order to investigate changes in the
capacity ratio of the pored portions in the membrane
thickness direction, and it is measured for every 1 mm
thickness in consideration of measurement accuracy.
Specifically, the open pore ratio is an
average open pore ratio determined by dividing
observation result of the cross-sectional structure in
the direction perpendicular to the membrane surface of
the microporous membrane for every 1 mm thickness in
the thickness direction, determining the open pore
ratio by image-processing analysis for each of the
divided regions and averaging these open pore ratios
for a predetermined membrane thickness region, and the
average open pore ratio of the whole membrane thickness
is a open pore ratio which is determined by averaging
the open pore ratios obtained for each of the divided
regions throughout the whole membrane thickness.
In the present invention, the coarse
structure layer is a layer with a higher open pore
ratio which exists adjacent to the membrane surface,
and preferably it is a layer in which (A) open pore
ratio is the average open pore ratio of the whole
membrane thickness + 2.0% or more (hereinafter referred
to as the coarse structure layer of (A)), more
preferably + 2.5% or more of layer, particularly
preferably + 3.0% or more. The upper limit of the open
pore ratio of the coarse structure layer is preferably
the average open pore ratio of the whole membrane
thickness + 30% or less, more preferably the average
open pore ratio of the whole membrane thickness + 25%
or less, particularly preferably the average open pore
ratio of the whole membrane thickness + 20% or less.
When the open pore ratio of the coarse structure layer
is the average open pore ratio of the whole membrane
thickness + 2.0% or more, the structural difference
from the fine structure layer is also sufficiently
large, which allows to exhibit pre-filtering effect and
provides an effect of increasing the processing
performance of the microporous membrane. On the other
hand, when the open pore ratio of the coarse structure
layer is more than the average open pore ratio of the
whole membrane thickness + 30%, the structure of the
coarse structure layer is unnecessarily coarse and may
have only insufficient pre-filter function and
therefore it is not preferable.
Furthermore, the coarse structure layer
preferably has a gradient structure where the open pore
ratio decreases continuously from the membrane surface
to the fine structure layer. The reason why this is
preferable is that the pore size decreases continuously
as the open pore ratio decreases continuously, thereby
large suspending substances are removed near the
surface and smaller suspending substances are gradually
removed as going deeper into the inside and thus the
pre-filter function of the coarse structure layer is
improved. It is not preferable that the open pore
ratio changes a lot discontinuously on the boundary
between the coarse structure layer and the fine
structure layer since the suspending substances
accumulate near the boundary and cause decrease in the
filtration rate. The gradient structure where the open
pore ratio decreases continuously as used herein means
an overall tendency in the membrane thickness
direction, and there may be some local inversions of
the open pore ratio resulting from structural variation
or measurement errors.
The coarse structure layer preferably
contains a layer where the open pore ratio is the
average open pore ratio of the whole membrane thickness
+ 5.0% or more, and still more preferably contains a
layer where the open pore ratio is the average open
pore ratio of the whole membrane thickness + 8.0% or
more. When the coarse structure layer contains a layer
where the open pore ratio is the average open pore
ratio of the whole membrane thickness + 5.0% or more,
it means that the coarse structure layer has a layer
having a sufficiently larger pore size than the fine
structure layer, the coarse structure layer can exhibit
sufficient pre-filter function. The layer which has
the maximum open pore ratio is preferably present on
the membrane surface or near the membrane surface.
In addition, the average pore size on the
surface of the membrane to which the coarse structure
layer is adjacent in the microporous membrane is
preferably twice more the maximum pore size determined
by the bubble point method, and more preferably three
times more the maximum pore size determined by the
bubble point method. If the average pore size on the
surface of the membrane to which the coarse structure
layer is adjacent is below twice the maximum pore size
determined by the bubble point method, the pore size is
too small and there is a tendency that suspending
substances deposit on the surface to cause decrease in
the filtration rate, which is not preferable. When the
microporous membrane is used for removing particles
such as viruses, the average pore size on the surface
of the membrane to which the coarse structure layer is
adjacent is preferably 3 pm or less, more preferably 2
fim or less. If the above-described average pore size
exceeds 3 mm, there is a tendency that the pre-filter
function deteriorates, which is not preferable.
The fine structure layer is a layer with a
lower open pore ratio, and preferably it is a layer in
which (B) open pore ratio is less than the average open
pore ratio of the whole membrane thickness + 2.0% and
in the range of (the average value of the open pore
ratio of the layer in which the open pore ratio is less
than the average open pore ratio of the whole membrane
thickness + 2.0%) ±2.0% (including both the ends)
(hereinafter referred to as the fine structure layer of
(B)). The fact that the open pore ratio of the fine
structure layer is in the range of (the average value
of the open pore ratio of the layer in which the open
pore ratio is less than the average open pore ratio of
the whole membrane thickness + 2.0%) ± 2.0% (including
both the ends) means that the fine structure layer has
a relatively homogeneous structure, and this is
important for removing a virus or the like by depth
filtration. The higher the homogeneity of the fine
structure layer, the more preferable, and the range of
variation of the open pore ratio is preferably within
the range of ±2%, still more preferably within the
range of ±1%. As an example of structure of the fine
structure layer, the void structure in spherocrystal
5 disclosed in the International Publication WO01/28667
pamphlet can be preferably applied.
An intermediate region belonging to neither
the above-described coarse structure layer of (A) nor
the fine structure layer of (B) may also exist in the
10 microporous membrane. The intermediate region as used
herein corresponds to a layer where the open pore ratio
is less than the average open pore ratio of the whole
membrane thickness + 2.0% but does not fall in the
range of (the average value of the open pore ratio of
15 the layer in which the open pore ratio is less than the
average open pore ratio of the whole membrane thickness
+ 2.0%) ± 2.0% (including both the ends). Such a layer
usually exists in the boundary portions between the
coarse structure layer of (A) and the fine structure
20 layer of (B).
As for the microporous membrane, it is
preferable that the coarse structure layer and the fine
structure layer are formed in one piece. The
expression that the coarse structure layer and the fine
25 structure layer are formed in one piece means that the
coarse structure layer and the fine structure layer are
simultaneously formed at the time of production of the
microporous membrane. Under the present circumstances,
an intermediate region may exist in the boundary
portions between the coarse structure layer and the
fine structure layer. As compared to a membrane
produced by coating a comparatively small pore sized
layer on the large pore sized support or a laminated
membrane comprising laminated membranes having
different pore sizes, it is more preferable that the
coarse structure layer and the fine structure layer are
formed in one piece. The membrane produced by coating
and the laminated membrane comprising laminated
membranes having different pore sizes, in which the
connectivity of the pores becomes low or the pore size
changes discontinuously a lot between two layers, have
defects that suspending substances tend to deposit
between the support and the coating layer.
The process for producing a hydrophilic
microporous membrane of the present invention will be
described below.
The thermoplastic resin used for producing a
microporous membrane of the present invention is a
thermoplastic resin having crystallizing properties
which is used for usual compression, extrusion,
ejection, inflation and blow moldings and polyolefin
resins such as polyethylene resin, polypropylene resin
and poly 4-methyl-l-pentene resin; polyester resins
such as polyethylene terephthalate resin, polybutylene
terephthalate resin, polyethylene terenaphthalate
resin, polybutylene naphthalate resin,
polycyclohexylenedimethylene terephthalate resin;
polyamide resins such as nylon 6, nylon 66, nylon 610,
nylon 612, nylon 11, nylon 12, and nylon 46; fluoride
resins such as polyvinylidene fluoride resin,
ethylene/tetrafluoroethylene resin and
polychlorotrifluoroethylene resin; polyphenylene ether
resins; and polyacetal resins, etc. can be used.
Among the above-described thermoplastic
resins, polyolefin resins and fluoride resins have good
balance of heat resistance and molding processability
and therefore they are preferable, and inter alia
polyvinylidene fluoride resins are particularly
preferable. The polyvinylidene fluoride resin as used
herein refers to a fluoride resin containing vinylidene
fluoride units as a backbone structure, and is
generally referred to by the abbreviated name of PVDF.
As such a polyvinylidene fluoride resin, a homopolymer
of vinylidene fluoride (VDF), a copolymer of one or two
monomers selected from the monomer group consisting of
hexafluoropropylene (HFP), pentafluoropropylene (PFP),
tetrafluoroethylene (TFE), chlorotrifluoroethylene
(CTFE) and perfluoromethyl vinyl ether (PFMVE) with
vinylidene fluoride (VDF) can be used. The above-
described homopolymer and the above-described copolymer
can also be mixed and used. In the present invention,
polyvinylidene fluoride resin containing 30 to 100 wt%
of a homopolymer is preferably used since the
crystallinity of the microporous membrane will be
improved and the strength thereof will become high, and
it is still more preferable to use only homopolymer.
The average molecular weight of the
thermoplastic resin used in the present invention is
preferably 50,000 to 5,000,000, more preferably 100,000
to 2,000,000, still more preferably 150,000 to
1,000,000. Although this average molecular weight
indicates weight average molecular weight obtained by
gel permeation chromatography (GPC) measurement, since
correct GPC measurement is generally difficult for a
resin having an average molecular weight exceeding
1,000,000, viscosity average molecular weight by the
viscosity method can be adopted instead thereof. If
the weight average molecular weight is smaller than
50,000, the melt tension during melt molding becomes
small, with the result that shapability will be
deteriorated or the membranous mechanical strength will
become low, and therefore it is not preferable. If the
weight average molecular weight exceeds 5,000,000,
uniform melt-blending becomes difficult, and therefore
it is not preferable.
The polymer concentration of the
thermoplastic resin used in the present invention is
preferably 20 to 90 wt%, more preferably 30 to 80 wt%,
and most preferably 35 to 70 wt% in the composition
containing a thermoplastic resin and a plasticizer. If
the polymer concentration becomes less than 20 wt%,
problems will occur, for example, membrane forming
properties are deteriorated and sufficient mechanical
strength cannot be obtained. In addition, pore size of
the microporous membrane obtained becomes too large as
a membrane for removing viruses, and the virus removal
performance becomes insufficient. If the polymer
concentration exceeds 90 wt%, the porosity becomes
small while the pore size of microporous membrane
obtained becomes too small, and therefore the
filtration rate decreases and the membrane cannot be
used practically.
As a plasticizer used in the present
invention, a non-volatile solvent which can form a
uniform solution at a temperature not less than the
melting point of the crystal of a thermoplastic resin
when the plasticizer is mixed with the thermoplastic
resin with a composition for producing a microporous
membrane is used. The non-volatile solvent here has a
boiling point of 250°C or more under atmospheric
pressure. The form of a plasticizer may be a liquid or
a solid generally at a normal temperature of 20°C. It
is preferable to use a plasticizer of so-called solid-
liquid phase separation system for producing a membrane
which has a small pore sized and homogeneous fine
structure layer to be used for virus removal, which
plasticizer has a thermally induced solid-liquid phase
separation point at a temperature not lower than normal
temperature when a uniform solution with thermoplastic
resin is cooled. Some plasticizers have a thermally
induced liquid-liquid phase separation point at a
temperature not lower than normal temperature when a
uniform solution with a thermoplastic resin is cooled
but generally the use of a plasticizer of liquid-liquid
phase separation system tends to form obtained
microporous membrane in large pore sizes. The
plasticizer used here may be a single substance or a
mixture of two or more substances.
The method for measuring a thermally induced
solid-liquid phase separation point may comprise using
as a sample a composition containing a thermoplastic
resin and a plasticizer of the predetermined
concentration and melt-blended beforehand, and
measuring the exothermic peak temperature of this resin
by thermal analysis (DSC). The method of measuring the
crystallizing point of this resin may also comprise
using as a sample the resin melt-blended beforehand,
and conducting thermal analysis in a similar manner.
As a plasticizer used preferably for the
production of a membrane which has a small pore sized
and homogeneous fine structure layer and is used for
virus removal, a plasticizer disclosed in International
Publication WO01/28667 pamphlet can be mentioned. That
is, a plasticizer for which a depression constant of
the phase separation point of the composition defined
by the following formula is 0 to 40°C, preferably 1 to
35°C, still more preferably 5 to 30°C can be mentioned.
If the depression constant of the phase separation
point exceeds 40°C, homogeneity of the pore size and
strength are deteriorated and therefore such a
plasticizer is not preferable.
a = 100 x (Tc° - Tc)/(100 - C)
wherein a represents a depression constant of the phase
separation point (°C), Tc° represents a crystallizing
temperature (°C) of the thermoplastic resin, Tc
represents a thermally induced solid-liquid phase
separation point (°C) of the composition and C
represents a concentration (wt%) of the thermoplastic
resin in the composition.
For example, when polyvinylidene fluoride
resin is selected as a thermoplastic resin,
dicyclohexyl phthalate (DCHP), diamyl phthalate(DAP),
triphenyl phosphate (TPP), diphenylcresyl phosphate
(CDP), tricresyl phosphate (TCP), etc. are particularly
preferable.
In the present invention, the first method
for carrying out uniform dissolution of the composition
containing a thermoplastic resin and a plasticizer is a
method comprising feeding the resin into a continuous
resin blending machine such as an extruder, introducing
a plasticizer in an arbitrary ratio while heat melting
the resin and carrying out screw blending to obtain a
uniform solution. The form of the resin to be fed may
be in any shape of a powder, a granule and a pellet.
When carrying out the uniform dissolution by this
method, the form of the plasticizer is preferably a
liquid at a normal temperature. As an extruder, a
single axis screw extruder, two-axis opposite direction
screw extruder, two-axis same direction screw extruder,
etc. can be used.
The second method of carrying out uniform
dissolution of the composition containing a
thermoplastic resin and a plasticizer is a method
comprising mixing and dispersing a plasticizer in a
resin beforehand using a churning equipment such as a
Henschel mixer and feeding the resultant composition
into a continuous resin blending machine such as an
extruder and carrying out melt-blending to obtain a
uniform solution. The form of the composition to be
fed may be in a shape of slurry when the plasticizer is
a liquid at normal temperature, and in a shape of a
powder, a granule or the like when the plasticizer is a
solid at normal temperature.
The third method of carrying out uniform
dissolution of the composition containing a
thermoplastic resin and a plasticizer is a method of
using a simple form resin blending machine such as a
brabender and a mill, and a method of melt-blending
within a blending container of the other batch type.
According to these methods, it cannot be said that
productivity is good since they are batch type
processes, but there is an advantage that they are
simple and highly flexible.
In the present invention, after the
composition containing a thermoplastic resin and a
plasticizer is heated to a temperature not lower than
the melting point of the crystal of the thermoplastic
resin to form a uniform solution, the composition is
extruded in the form of a flat membrane or a hollow
fiber from a discharging orifice such as a T-die, a
circular die and an annular spinneret, and cooled to
solidification to shape a membrane form (step (a)). In
the step (a) in which the composition is cooled to
solidification to shape a membrane form, the fine
structure layer is formed while the coarse structure
layer is formed adjacent to the membrane surface.
In the present invention, the composition
containing a thermoplastic resin and a plasticizer
which is heated and uniformly dissolved is discharged
from a discharging orifice and the membrane is taken
over at a taking-over rate so that the draft ratio
defined below may be not less than 1 and not more than
12, while a non-volatile liquid heated to 100°C or more
which is capable of partially solubilizing the
thermoplastic resin is contacted with one membrane;
surface and the other side of the membrane is cooled to
form a coarse structure layer and a fine structure
layer.
Draft ratio = (membrane taking-over
rate)/(discharging rate of the composition at the
discharging orifice)
The above-described draft ratio is preferably
not less than 1.5 and not more than 9, more preferably
not less than 1.5 and not more than 7. If the draft
ratio is less than 1, no tension is loaded on the
membrane and the shapability is poor and if it exceeds
12, the membrane is extended and therefore it is
difficult to form a coarse structure layer having a
sufficient thickness. The discharging rate of the
composition at the discharging orifice as used herein
is given by the following formula:
Discharging rate of the composition at the
discharging orifice = (volume of composition discharged
per unit time)/(area of discharging orifice)
The preferable range of the discharging rate
is 1 to 60 m/min, more preferably 3 to 40 m/min. When
the discharging rate is less than 1 m/min, problems
occur such as increase in fluctuation of the
discharging volume in addition to decrease in
productivity. On the contrary, if the discharging rate
exceeds 60 m/min, since there is much discharging
volume, a turbulent flow may occur at the discharging
orifice, and the discharging state may become unstable.
Although the taking-over rate can be set
according to the discharging rate, it is preferably 1
to 200 m/min, more preferably 3 to 150 m/min. If the
taking-over rate is less than 1 m/min, productivity and
shapability are deteriorated, and if the taking-over
rate exceeds 200 m/min, cooling time becomes short,
tension loaded on the membrane increases and
accordingly rupture of the membrane tends to occur.
A preferable method of forming a coarse
structure layer is a method in which one side of the
surfaces of uncured membrane formed by extruding the
composition containing a thermoplastic resin and a
plasticizer from the extruding orifice into a membrane
of the shape of a flat membrane or a hollow fiber is
contacted with a non-volatile liquid which is capable
of partially solubilizing the thermoplastic resin., In
this case, a coarse structure layer is formed by
diffusion of the contacted liquid inside the membrane
and a partial dissolution of the thermoplastic resin.
The liquid which is capable of partially solubilizing
the thermoplastic resin as used herein is a liquid
which cannot form a uniform solution unless the
temperature is elevated to 100°C or more when it is
mixed with the thermoplastic resin in 50 wt%
concentration, and.preferably it is a liquid which can
form a uniform solution at a temperature not lower than
100°C and not higher than 250°C, and more preferably it
is a liquid which can form a uniform solution at a
temperature not lower than 120°C and not higher than
200°C. If the liquid which can achieve uniform
dissolution at a temperature lower than 100°C is used as
a contact liquid, cooling solidification of the
composition solution containing a thermoplastic resin
and a plasticizer is prevented, and consequently
problems may occur, for example, shapability may be
deteriorated, the coarse structure layer may become
unnecessarily thick, or the pore size becomes
excessively large. In the case of the liquid which
cannot form a uniform solution at a temperature lower
than 250°C, the solubility of the thermoplastic resin is
too low, and it is difficult to form a coarse structure
layer having a sufficient thickness. The non-volatile
liquid as used herein is a liquid having a boiling
point exceeding 250°C under 101325Pa.
For example, when polyvinylidene fluoride
resin is selected as a thermoplastic resin, phthalic
acid esters, adipic acid esters and sebacic acid esters
in which the carbon chain length of the ester chain is
seven or less, phosphoric acid esters and citric acid
esters in which the carbon chain length of the ester
chain is eight or less can be preferably used, and.
particularly, diheptyl phthalate, dibutyl phthalate,
diethyl phthalate,.dimethyl phthalate, dibutyl adipate,
dibutyl sebacate, tri(2-ethylhexyl) phosphate, tributyl
phosphate, acetyltributyl citrate, etc. can be used
suitably.
However, plasticizers having an annular
structure such as a phenyl group, a cresyl group, a
cyclohexyl group, etc. in the ester chain, i.e.,
dicyclohexyl phthalate, (DCHP), diamyl phthalate(DAP),
triphenyl phosphate (TPP), diphenylcresyl phosphate
(CDP), tricresyl phosphate (TCP), etc. do have
exceptionally poor capability to form a coarse

structure layer and they are not preferable.
The temperature of the contacting liquid used
to introduce a coarse structure layer is a temperature
not lower than 100°C, preferably not lower than 120°C,
and not higher than the temperature of the uniform
solution of a thermoplastic resin and a plasticizer,
still more preferably a temperature not lower than
130°C, and not higher than (the temperature of the
uniform solution of a thermoplastic resin and a
plasticizer - 10°C). If the temperature of the
contacting liquid is lower than 100°C, the solubility of
the thermoplastic resin is too low, and therefore it
tends to be difficult to form a coarse structure layer
having a sufficient thickness. If the temperature
exceeds the temperature of the uniform solution of the
thermoplastic resin and the plasticizer, shapability is
deteriorated.
When a coarse structure layer is introduced
only on one side of the microporous membrane, the
cooling method of the surface of the other side
corresponding to the fine structure layer side can
follow any conventional method. That is, it can be
carried out by contacting a heat conducting object to
effect cooling. As the heat conducting object, metal,
water, air, or the plasticizer itself can be used.
Specifically, a method of introducing a coarse
structure layer is possible which comprises extruding a
uniform solution containing a thermoplastic resin and a
plasticizer in the shape of a sheet through a T-die
etc., carrying out contact cooling with a metal roll,
and bringing the other side of the membrane which does
not contact with the roll into contact with a non-
volatile liquid which is capable of partially
solubilizing the thermoplastic resin. Alternatively a
method is possible which comprises extruding a uniform
solution containing a thermoplastic resin and a
plasticizer in the shape of a cylinder or a hollow
fiber through a circular die, annular spinneret, etc.,
and passing a non-volatile liquid which is capable of
partially solubilizing the thermoplastic resin through
inside the cylinder or hollow fiber to form a coarse
structure layer in the inner surface side while
contacting the outside with a cooling media such as
water to effect cooling.
When the coarse structure layer is introduced
on both the sides of the microporous membrane, a
uniform solution containing a thermoplastic resin and a
plasticizer is extruded in a predetermined shape
through a T-die, a circular die, annular spinneret,,
etc., a circular die, annular spinneret, and the
solution is contacted with a non-volatile liquid which
is capable of partially solubilizing the thermoplastic
resin on both the sides to form a coarse structure
layer, which is then cooled to solidification. Cooling
method in this process can follow any conventional
method. When the time after contacting the non-
volatile liquid which is capable of partially
solubilizing the thermoplastic resin until the cooling
starts is too long, problems may occur, for example,
shapability may be deteriorated, the strength of the
membrane is deteriorated, etc., and therefore the time
period after contacting the contacting liquid till the
start of the cooling is preferably 30 seconds or less,
more preferably 20 seconds or less, and particularly
preferably 10 seconds or less.
In the production method of the microporous
membrane of the present invention, in order to form a
small pore sized and homogeneous fine structure layer,
it is preferable to make the cooling rate at the time
of effecting cooling solidification sufficiently high.
The cooling rate is preferably 50°C/min or more, more
preferably 100 to 1x105 °C/min, still more preferably
200 to 2x104 °C/min. Specifically, the method of
contacting with a metal cooling roll and water is
preferably used, and particularly, the method of
contacting with water is preferable since it can attain
rapid cooling by evaporation of water.
In the step (b) which removes the substantial
portion of the plasticizer, in order to remove a
plasticizer, an extracting solvent is used. It is
preferable that the extracting solvent is a poor
solvent for the thermoplastic resin and is a good
solvent for the plasticizer, and the boiling point
thereof is lower than the melting point of microporous
membrane. Examples of such an extracting solvent
include hydrocarbons such as hexane and cyclohexane;
halogenated hydrocarbons such as methylene chloride and
1,1,1-trichloroethane; alcohols such as ethanol and
isopropanol; ethers such as diethyl ether and
tetrahydrofuran; ketones such as acetone and 2-
butanone; or water.
In the present invention, the first method of
removing a plasticizer is performed by immersing and
fully washing the microporous membrane cut off in the
predetermined size in a container containing an
extracting solvent and making the adhering solvent air-
dried or dried by hot air. Under the present
circumstances, the immersing and washing operations are
preferably repeated many times since the plasticizer
remaining in the microporous membrane will decrease
accordingly. It is preferable to constrain the ends of
the microporous membrane, which suppresses contraction
of the microporous membrane during a series of
operations of immersion, washing and drying.
The second method of removing a plasticizer
comprises continuously feeding the microporous membrane
into a bath filled with an extracting solvent,
immersing the membrane in the tub over sufficient time
to remove a plasticizer, and then drying the solvent
adhered to the membrane. Under the present
circumstances, it is preferable to apply well-known
techniques such as a multi-stage method in which the
inside of the tub is divided into plural stages and the
microporous membranes are fed one by one into each tub
having different concentrations, or a counter-flow
method in which the extracting solvent is supplied in
the direction opposite to the running direction of the
microporous membrane, and thereby a concentration
gradation is provided, in order to enhance extraction
efficiency. It is important that a plasticizer is
removed from the microporous membrane substantially in
either of the first and second methods. Removing
substantially means that the plasticizer in the
microporous membrane is removed to an extent which does
not spoil the performance as a separation membrane and
the amount of the plasticizer remaining in the
microporous membrane is preferably 1 wt% or less, more
preferably 100 mass ppm or less. The quantification of
the amount of the plasticizer which remains in the
microporous membrane can be carried out by gas
chromatography, liquid chromatography, etc. It is
further preferable to raise the temperature of the
extracting solvent to a temperature lower than the
boiling point of the solvent, preferably in the range
of not higher than (the boiling point - 5°C) , since the
diffusion of the plasticizer and the solvent can be
promoted, and the extraction efficiency is improved.
In the present invention, the microporous
membrane may be heat-treated before, or after, or both
before and after the step for removing a plasticizer,
which provides effects such as reduction of contraction
of the microporous membrane at the time of removing a
plasticizer, improvement in the strength and
improvement in heat resistance of the microporous
membrane. There are some methods of performing heat-
treatment such as a method of disposing the microporous
membrane in a hot air, a method of immersing the
microporous membrane in a heat medium, or a method of
contacting the microporous membrane with a metal roll
which has been heated and heat-controlled. When the
size is fixed and the membrane is heat-treated,
particularly, blockades of minute holes can be
prevented and therefore such a method is preferable.
Although the temperature of heat-treatment
varies depending on the purpose and the melting point
of the thermoplastic resin, in the case of the
vinylidene fluoride membrane used for a virus removal,
121 to 175°C is preferable, more preferably 125 to
170°C. The temperature 121°C is used by general high-
pressure steamy sterilization, and the contraction and
modification during high-pressure steamy sterilization
can be prevented if heat-treatment is conducted at this
temperature or higher. If the temperature exceeds
175°C, which is close to the melting point of vinylidene
fluoride, disadvantages may occur, for example, the
membrane may be ruptured or minute pores may be closed
during the heat-treatment.
The microporous membrane which consists of a
hydrophobic resin excellent in physical strength is
excellent in that it can be endured against high
filtration pressure as compared with a microporous
membrane which consists of hydrophilic resin such as
cellulose while the former tends to cause adsorption of
a protein or the like, contamination and clogging of
the membrane, etc., resulting in a rapid fall of
filtration rate. Therefore, when a microporous
membrane which consists of a hydrophobic resin is used,
it is preferable to impart the membrane with
hydrophilicity in order to prevent blockade due to the
adsorption of protein, etc. In the production method
of the present invention, it is preferable to introduce
a hydrophilic functional group into the surface of the
pores of the hydrophobic membrane by graft
polymerization method, and to reduce adsorptivity such
as that of protein.
The graft polymerization method is a reaction
in which radicals are generated on the polymer
microporous membrane by means such as ionizing
radiation and chemical reaction and a monomer is graft
polymerized onto the membrane using the radical as a
starting point.
In the present invention, although any means
can be adopted in order to generate radicals on the
polymer microporous membrane, but in order to generate
radicals uniformly over the whole membrane, irradiation
of ionizing radiation is preferable. As a kind of
ionizing radiation, y-ray, electron beam, p-ray, neutron
beam, etc. can be used, but electron beam or y-ray is
most preferable in the implementation on an industrial
scale. Ionizing radiation can be obtained from
radioactive isotopes such as cobalt 60, strontium 90,
and cesium 137, or by X-ray photography equipment,
electron beam accelerator, ultraviolet ray irradiation
equipment, etc.
The irradiation dose of the ionizing
radiation is preferably not less than 1 kGy and not
more than 1000 kGy, more preferably not less than 2 kGy
and not more than 500 kGy, most preferably not less
than 5 kGy and not more than 200 kGy. Radicals are not
generated uniformly below 1 kGy while the strength of
the membrane may be deteriorated over 1000 kGy.
The graft polymerization method by
irradiation of ionizing radiation is generally roughly
divided into a pre-irradiation method in which radicals
are generated in the membrane and subsequently the
membrane is contacted to the reactant compounds and a
simultaneous irradiation method in which radicals are
generated in the membrane while the membrane is
contacted to the reactant compounds. In the present
invention, any method can be applied, but the pre-
irradiation method is preferable since it generates
less amount of oligomers.
A hydrophilic vinyl monomer which has one
vinyl group as a reactant compound, and a cross-linking
agent used if needed are made to contact with a polymer
microporous membrane in which radicals have been
generated in the present invention. Although the
method of carrying out contact can be performed also
either on a gaseous phase or a liquid phase, the method
of carrying out contact in a liquid phase in which a
graft reaction progresses uniformly is preferable. For
the purpose of making the graft reaction still more
uniformly, it is preferable that a hydrophilic vinyl
monomer which has one vinyl group or a hydrophilic
vinyl monomer and a cross-linking agent when a cross-
linking agent is used are dissolved in a solvent
beforehand and then the contact with a polymei:
microporous membrane is carried out.
As described above, the hydrophilic
microporous membrane of the present invention comprises
a polymer microporous membrane on which a hydrophilic
vinyl monomer having one vinyl group is graft
polymerized to impart the surface of the micropores
with hydrophilicity thereby reducing adsorption of
physiologically active substances such as protein. The
hydrophilic vinyl monomer which has one vinyl group in
the present invention is a monomer which has one vinyl
group and uniformly dissolves in a pure water of 25°C
when mixed therein at 1 vol% under atmospheric
pressure. Examples of the hydrophilic vinyl monomer
include vinyl monomers having a hydroxyl group or a.
functional group used as a precursor thereof such as
hydroxypropyl acrylate, hydroxybutyl acrylate; vinyl
monomers having an amide bond such as vinyl
pyrrolidone; vinyl monomers having an amino group such
as acrylics amide; vinyl monomers having a
polyethyleneglycol chain such as polyethyleneglycol
monoacrylate; vinyl monomers having an anion exchange
groups such as triethylammoniumethyl methacrylate;
vinyl monomers having a cation exchange groups such as
sulfopropyl methacrylate,
In the present invention, among the
hydrophilic vinyl monomers, the above-described
hydrophilic vinyl monomer which has one or more
hydroxyl group or a functional group used as a
precursor thereof is preferably used since the use
thereof reduces a receding contact angle of the
membrane. More preferably, esters of acrylic acid or
methacrylic acid and a polyhydric alcohol such as
hydroxypropyl acrylate and 2-hydroxyethyl methacrylate;
alcohols having an unsaturated bond such as allyl
alcohol; and enol esters such as vinyl acetate and
vinyl propionate are used and most preferably esters of
acrylic acid or methacrylic acid and a polyhydric
alcohol such as hydroxypropyl acrylate and 2-
hydroxyethyl methacrylate are used. The hydrophilic
microporous membrane to which hydroxypropyl acrylate is
grafted has a low receding contact angle and provides a
sufficient globulin permeating ability.
A vinyl monomer which has two or more vinyl
groups has a tendency to perform cross-linking in the
hydrophilic diffusive layer through copolymerization
and reduce the permeability of protein even if it is
hydrophilic, and accordingly it is not preferable from
the viewpoint of protein permeativity, but it is
possible to use such a monomer if needed as a cross-
linking agent since it has an effect of preventing
adherence between membranes and reducing dissolution-
out from the membrane.
The vinyl monomer which has two or more vinyl
groups used as a cross-linking agent is advantageous
when the receding contact angle is lower taking into
consideration the adsorptivity of the micropore
surfaces for protein and therefore it is preferable to
use a hydrophilic cross-linking agent. The hydrophilic
cross-linking agent is a monomer which has two or more
vinyl groups and uniformly dissolves in a pure water of
25°C when mixed therein at 1 vol% under atmospheric
pressure.
When such a cross-linking agent, i.e., vinyl
monomer which has two or more vinyl groups is used, it
is copolymerized at a proportion to the hydrophilic
vinyl monomer which has one vinyl group of preferably
10 mol% or less, more preferably 0.01 to 10 mol%,
further preferably 0.01 to 7 mol% and most preferably
0.01 to 5 mol%. The permeability of protein is not
enough if it exceeds 10 rnol%.
The cross-linking agent used in the present
invention has preferably a number average molecular
weight of 200 or more and 2000 or less, more preferably
a number average molecular weight of 250 or more and
1000 or less, most preferably a number average
molecular weight of 300 or more and 600 or less. It is
preferable from the viewpoint of the filtration rate of
a protein solution that the number average molecular
weight of the cross-linking agent is 200 or more and
2000 or less.
Specific examples of the cross-linking agent
used in the present invention, i.e., the vinyl monomer
which has two or more vinyl groups, include, for
example, ethylene glycol dimethacrylate, polyethylene
glycol dimethacrylate, ethylene glycol diacrylate,
polyethylene glycol diacrylate, etc., and as other
vinyl monomer which has two or more vinyl groups,
cross-linking agents having three reactive groups such
as divinylbenzene derivatives and trimethylolpropane
trimethacrylate can also be used. Although these
cross-linking agents can also be used as a mixture of
two or more kinds of compounds, it is preferable that
they are hydrophilic. Polyethylene glycol diacrylate is
particularly preferable from the viewpoint of the
receding contact angle or protein permeativity.
A solvent which dissolves the hydrophilic
vinyl monomer which has one vinyl group, and the cross-
linking agent used if needed is not particularly
limited as long as the uniform dissolution can be
carried out. Examples of such a solvent include
alcohols such as ethanol, and isopropanol, t-butyl
alcohol; ethers such as diethyl ether and
tetrahydrofuran; and ketones such as acetone and 2-
butanone; water or a mixture thereof.
The concentration of a hydrophilic vinyl
monomer which has one vinyl group, and the cross-
linking agent used if needed at the time of dissolving
them is preferably from 3 vol% to 30 vol%, more
preferably from 3 vol% to 20 vol%, most preferably from
3 vol% to 15 vol%. When it is a concentration not less
than 3 vol%, sufficient hydrophilicity can be obtained
and such a concentration is preferable. If it exceeds
30 vol%, the micropores may be filled with the
hydrophilized layer and there is a tendency that
permeation capability is deteriorated and therefore
such a concentration is not preferable.
The amount of the reaction liquid in which
the hydrophilic vinyl monomer which has one vinyl group
and the cross-linking agent used if needed are
dissolved in a solvent used at the time of graft
polymerization is preferably 1x10-5 m3 to 1x10-3 m3 per 1
g of the polymer microporous membrane. If the amount
of the reaction liquid is 1x10-5 m3 to 1x10-3 m3,
membranes with enough homogeneity can be obtained.
The reaction temperature at the time of graft
polymerization is not particularly limited, although
generally carried out at 20°C to 80°C.
The present invention introduces the optimal
hydrophilized layer to a hydrophobic microporous
membrane, and realizes high protein permeativity. The
ratio of the graft grafted to the hydrophobic
microporous membrane for this purpose is preferably 3%
or more and 50% or less, more preferably 4% or more and
40% or less, and most preferably 6% or more and 30% or
less. If the graft ratio is less than 3%,
hydrophilicity of the membrane runs short and a rapid
fall in the filtration rate resulting from adsorption
of protein is caused. If it exceeds 50%, relatively
small pores will be filled with the hydrophilized layer
and sufficient filtration rate cannot be obtained. The
graft ratio as used herein is a value defined by the
following formula:
Graft ratio (%) = 100 x ((membrane mass after
grafted - membrane mass before grafted)/membrane mass
before grafted)
To the composition which constitutes the
hydrophilic microporous membrane of the present
invention may be further blended, according to the
purpose, additives such as anti-oxidant, crystal core
agent, antistatic agent, flame retardant, lubricant,
and ultraviolet ray absorbent if necessary.
The hydrophilic microporous membrane which
has a heat resistance of the present invention can be
used for a wide range of applications including a
separation membrane for medical use such as for
removing, concentrating or as a culture medium of a
virus, bacterium, etc., a filter for industrial
processes which removes particles from a pharmaceutical
liquid or processed water, etc., a separation membrane
for oil-water separation or liquid-gas separation, a
separation membrane aiming at purification of city
water and sewerage, and a separator for lithium ion
battery, and a support for solid electrolyte polymer
batteries.
Hereafter, the present invention will be
described in detail by way of Examples but the present
invention is not limited thereto. The testing methods
shown in Examples are as follows.
(1) Outer diameter, inner diameter of hollow fiber,
thickness of membrane
The outer diameter, inner diameter of a
hollow fiber is determined by photographing the
perpendicular section of the membrane at 210 times
magnification using a substance microscope
(SCOPEMAN503, product of Moriteq Co., Ltd.). The
thickness of the membrane was calculated as 1/2 of the
difference of the outer diameter and the inner diameter
of a hollow fiber.
(2) Porosity
The volume and mass of the microporous
membrane were measured and the void ratio was
calculated using the following formula from the
obtained results.
Porosity (%) = (1 - mass/(density x volume of
resin)) x 100
(3) Water permeativity
The volume of permeated pure water at 2 5°C was
measured by constant-pressure dead-end filtration and
the water permeativity was calculated as the following
formula from the area of the membrane, filtration
pressure (0.1 MPa) and filtration time.
Water permeativity (m3/m2/second/Pa) =
permeation volume/(area of membrane x differential
pressure x filtration time)
(4) Maximum pore size
The bubble point (Pa) which can be determined
by the bubble point method based on ASTM F 316-8 6 was
converted to the maximum pore size (run) . As a testing
liquid in which the membrane is immersed, a
fluorocarbon liquid having a surface tension of 12 mN/m
(Perfluorocarbon coolant FX-3250 (trademark), product
of Sumitomo 3M) was used. The bubble point was
determined by setting a hollow fiber having an
effective length of 8 cm in a bubble point measurement
equipment, gradually raising the pressure of the hollow
side and reading the pressure when the gas flow rate
permeating the membrane reaches 2.4 E-3 liter/min.
(5) Structure observation of microporous membrane
The microporous membrane cut off in a
suitable size was fixed onto the sample stand with a
conductive double-sided tape, and coated with gold to
prepare a sample for microscopic observation. A high
resolution scanning electron microscope (HRSEM) (S-900,
product of Hitachi, Ltd.) was used and structure
observation of the surface and a section of the
microporous membrane was performed at an acceleration
voltage of 5.0 kV and predetermined magnification.
(6) Open pore ratio and average open pore ratio
The open pore ratio was determined by
dividing the observation result of the cross-sectional
structure of the microporous membrane in the thickness
direction for every 1 pm thickness, and obtaining as an
area ratio of void to each divided region by image-
processing analysis. Electron microscope photography
at this time was performed at 15,000 times
magnification. The average open pore ratio is the
average value of open pore ratio measured for the whole
membrane thickness.
(7) Thickness of coarse structure layer and ratio of
fine structure layer to the whole thickness of membrane
In the measurement of the above open pore
ratio, it was judged whether each divided region agreed
with the definition of the fine structure layer defined
and the coarse structure layer as described. That is,
the coarse structure layer is a continuous region
existing adjacent to the membrane surface and in which
the open pore ratio measured in the thickness direction
is higher by 2% or more than the average value of the
open pore ratio for the whole membrane thickness, and
the fine structure layer is a region other than the
coarse structure layer and in which the open pore: ratio
measured in the thickness direction is within the range
of less than ±2% of the average value of the open pore
ratio for the region excluding the coarse structure
layer. The ratio of the fine structure layer to the
whole thickness of membrane is a value obtained by
dividing the sum of the thicknesses of the agreeing
regions by the whole membrane thickness.
(8) Average pore size of the coarse structure layer
side surface
From the structure observation result of the
coarse structure layer side surface, the number and
area of pores which exist in the surface were measured
by image-processing analysis, and a circle equivalent
diameter of the pore was determined from the average
area per pore assuming that the pore is a true circle.
This circle equivalent diameter was regarded as the
average pore size of the coarse structure layer side
surface. Electron microscope (S-900, product of
Hitachi, Ltd.) photography at this time was performed
at 6,000 times magnification.
(9) Measurement of contact angle on membrane
The receding contact angle of the water on
the membrane was measured by using a water for
injection (product of Otsuka Pharmaceutical Co., Ltd.;
Japanese Pharmacopoeia) with the dynamic contact angle
measuring instrument (DCAT11, product of DataPhysics
Instruments GmbH). A hollow fiber membrane was cut to
about 2 cm, and mounted on the equipment. The receding
contact angle was measured using the principle of the
Wilhelmy method. The motor speed at the time of
measurement was 0.10 mm/second, the immersing depth was
10 mm, and 5-cycle measurement was carried out by
regarding the advance and retreat as one cycle. The
receding contact angle used was the average value of
the value acquired by 5 measurements.
(10) Amount of adsorption of bovine immunoglobulin
The bovine immunoglobulin solution from Life
Technology, Ltd. was diluted with a physiological
saline solution (product of Otsuka Pharmaceutical Co.,
Ltd.; Japanese Pharmacopoeia) to a concentration of
0.01 wt%, and this was used as a source solution for
filtration. The source solution for filtration was
subjected to constant-pressure dead-end filtration
under a filtration pressure of 0.3 MPa and a filtration
temperature of 25°C, and the filtrate at 50 liter/m2
from the start of filtration was sampled. Absorption
at a wavelength of 280 nm was measured for the source
solution for filtration and the filtrate, and the
amount of adsorption of bovine immunoglobulin was
calculated from the following formula.
Amount of adsorption of bovine immunoglobulin
(mg/g) = (absorption of source solution for filtration
- absorption of filtrate)/absorption of source solution
for filtration x 0.005/membrane weight
(11) Filtration test of 3 wt% bovine immunoglobulin
solution
The bovine immunoglobulin solution from Life
Technology, Ltd. was diluted with a physiological
saline solution (product of Otsuka Pharmaceutical Co.,
Ltd.; Japanese Pharmacopoeia) to a concentration of 3
wt%, and this was pre-filtered further by the
filtration membrane (product of Asahi Kasei
Corporation, PLANOVA35N) for removing impurities and
then used as a source solution for filtration. As a
result of measuring the molecular weight distribution
of the bovine immunoglobulin in this source solution
for filtration using liquid chromatography (product of
TOSOH CORP., CCP&8020 series, product of Amersham
Biosciences Company, Superdex by 200 HR 10/30), the
ratio of polymer of dimer or larger was not more than
20 wt%. Constant-pressure dead-end filtration was
performed for this source solution for filtration on
conditions of a filtration pressure of 0.3 MPa and a
filtration temperature of 25°C, and the permeation rate
for 5 minutes after the start of filtration and for 55
to 60 minutes after the start of filtration (Iiter/m2/h)
was measured.
(12) Logarithmic reduction value of porcine parvovirus
As a source solution for filtration,
supernatant of a culture solution of ESK cell (pig
kidney cell) cultured in a Dulbecco's MEM culture-
medium solution (product of Nihon Biopharmaceutical
Research Institute) supplemented with 5% fetal bovine
serum (product of Upstate, Ltd.) and infected with
porcine parvovirus was used after pre-filtered by
microporous membrane (product of Asahi Kasei
Corporation, PLANOVA35N). Constant-pressure dead-end
filtration was performed for this source solution for
filtration under the condition of a filtration pressure
of 0.3 MPa and a filtration temperature of 25°C. The
filtrate was sampled as 11 fractions for every 5 ml (5
liter/m2) , and in order to measure the logarithmic
removing rate of porcine parvovirus at the time point
by which 55 liter/m2 has been filtered from the start of
filtration, 1 ml was respectively sampled from each
fraction and mixed. The concentration of the porcine
parvovirus in the source solution for filtration and
the filtrate (the mixed solution and the first and the
last fractions) was determined by TCID50 measuring
method using agglutination reaction of chicken fresh
erythrocyte (product of Nippon Biotest Laboratories,
Inc.) after adding each liquid to ESK cell and
culturing 10 days.
Example 1
After a composition consisting of 49 wt% of
polyvinylidene fluoride resin (SOLEF1012, product of
SOLVAY Company, Crystal melting point: 173°C) and 51 wt%
of dicyclohexyl phthalate (product of Osaka Organic
Chemical Industry, Ltd., industrial grade product) was
churned and mixed at 70°C using a Henschel mixer, the
mixture was cooled into the shape of a powder and was
supplied from the hopper and melt-blended using a two-
axis extruder (Laboplast mill MODEL 50C 150, product of
Toyo Seiki Seisaku-Sho, Ltd.) at 210°C so that the
mixture was homogeneously dissolved. Then, the
solution was extruded in the shape of a hollow fiber
from a spinneret which consists of an annular orifice
with an inner diameter of 0.8 mm and an outer diameter
of 1.1 mm at a discharging rate of 17m/min while
passing through the inside hollow part dibutyl
phthalate (product of Sanken Kakoh Company) at a
temperature of 130°C at a rate of 8 ml/min. The
extruded solution was cooled and solidified in a water
bath heat-controlled to 40°C and rolled up to a spinner
at a rate of 60 m/min. Then dicyclohexyl phthalate and
dibutyl phthalate were extracted and removed with 99%
methanol modified ethanol (product of Imazu Chemical
Co., Ltd., industrial grade product) and the attached
ethanol was replaced with water, and a heat-treatment
at 125°C was conducted for 1 hour using high-pressure
steamy sterilization equipment (HV-85, product of
Hirayama Factory, Ltd.) in the state where it was
immersed in water. Then, after replacing attached
water with ethanol, hollow fiber microporous membrane
was obtained by drying at a temperature of 60°C in the
oven. In order to prevent contraction during the steps
from the extraction step to drying step, the membrane
was fixed in a fixed size state and processed.
Then, hydrophilizing treatment by the graft
method was performed to the above microporous membrane.
Hydroxypropyl acrylate (product of Tokyo Chemicals,
Ltd., reagent grade) was dissolved in 25 vol% solution
of 3-butanol (Pure Science, Ltd., special reagent
grade) so that the former might be 8 vol%. The mixture
was held at 40°C while subjected to nitrogen bubbling
for 20 minutes, and then used as a reaction liquid.
First, 100 kGy irradiation of y-ray was carried out by
using Co60 as a radiation source, while cooling the
microporous membrane at - 60°C with dry ice under
nitrogen atmosphere. After allowing to stand still the
irradiated membrane under a reduced pressure of 13.4 Pa
or less for 15 minutes, it was contacted with the
above-described reaction liquid and the membrane was
allowed to stand still at 40°C for 1 hour. Then, the
membrane was washed with ethanol, vacuum drying at 60°C
was performed for 4 hours, and the microporous membrane
was obtained. It was confirmed that water
spontaneously permeates into the pores when the
obtained membrane was contacted with water. As a
result of evaluating the performance of the obtained
membrane, high performance was shown as in Table 1.
Example 2
A hollow fiber microporous membrane was
obtained according to Example 1 except that a
composition consisting of 39 wt% of polyvinylidene
fluoride resin and 61 wt% of dicyclohexyl phthalate was
extruded from a spinneret which consists of an annular
orifice with an inner diameter of 0.8 mm and an outer
diameter of 1.2 mm.
Then, the above microporous membrane was
subjected to hydrophilizing treatment according to
Example 1. As a result of evaluating the performance
of the obtained membrane, high performance was shown as
in Table 1.
Example 3
A hollow fiber microporous membranes was
obtained according to Example 2 except that a
composition consisting of 4 6 wt% of polyvinylidene
fluoride resin and 54 wt% of dicyclohexyl phthalate was
homogeneously dissolved and the solution was extruded
in the shape of a hollow fiber from a spinneret which
consists of an annular orifice with an inner diameter
of 0.8 mm and an outer diameter of 1.2 mm at a
discharging rate of 5.5 m/min while passing through the
inside hollow part diphenylcresyl phosphate (product of
Daihachi Chemical Industry Co., Ltd., industrial grade
product) at a rate of 7 ml/min.
Then, the above microporous membrane was
subjected to hydrophilizing treatment according to
Example 1. As a result of evaluating the performance
of the obtained membrane, high performance was shown as
in Table 1.
Example 4
Hydrophilizing treatment was performed to the
membrane obtained in Example 1. The hydrophilizing
treatment was performed according to Example 1 except
that 7.52 vol% of hydroxypropyl acrylate, 0.15 vol% (1
mol% to hydroxypropyl acrylate) of polyethylene glycol
diacrylate (product of Aldrich Co., average molecular
weight 258) and 0.33 vol% (1 mol% to hydroxypropyl
acrylate) of polyethylene glycol diacrylate (product of
Aldrich Co., average molecular weight 575) were
dissolved in 25 vol% solution of 3-butanol and used as
a reaction liquid. As a result of evaluating the
performance of the obtained membrane, high performance
was shown as in Table 1.
Example 5
Hydrophilizing treatment was performed to the
membrane obtained in Example 1. The hydrophilizing
treatment was performed according to Example 1 except
that 4-hydroxybutyl acrylate (product of Tokyo
Chemicals Industry), was dissolved in 25 vol% solution
of 3-butanol so that the former might be 8 vol% and
used as a reaction liquid. As a result of evaluating
the performance of the obtained membrane, high
performance was shown as in Table 2.
Example 6
A hollow fiber microporous membrane: was
obtained according to Example 1 except that a
composition consisting of 48 wt% of polyvinylidene
fluoride resin and 52 wt% of dicyclohexyl phthalate was
homogeneously dissolved and the solution was extruded
in the shape of a hollow fiber from a spinneret which
consists of an annular orifice with an inner diameter
of 0.8 mm and an outer diameter of 1.05 mm at a
discharging rate of 20 m/min while passing through the
inside hollow part dibutyl phthalate at a rate of 10
ml/min. Then, the above microporous membrane was
subjected to hydrophilizing treatment according to
Example 1. As a result of evaluating the performance
of the obtained membrane, high performance was shown as
in Table 2.
Example 7
A hollow fiber microporous membrane was
obtained according to Example 1 except that a
composition consisting of 50 wt% of polyvinylidene
fluoride resin and 50 wt% of dicyclohexyl phthalate was
used.
Then, the above microporous membrane was
subjected to hydrophilizing treatment according to
Example 1. As a result of evaluating the performance
of the obtained membrane, high performance was shown as
in Table 2.
Comparative Example 1
Hydrophilizing treatment was performed to the
membrane obtained in Example 1 according to Example 1
except that 1.23 vol% of hydroxypropyl acrylate, 0.61
vol% (25 mol% to hydroxypropyl acrylate) of
polyethylene glycol diacrylate (product of Aldrich Co.,
average molecular weight 258), 1.36 vol% (25 mol% to
hydroxypropyl acrylate) of polyethylene glycol
diacrylate (product of Aldrich Co., average molecular
weight 575) was dissolved in 25 vol% solution of 3-
butanol and used as a reaction liquid. As a result of
evaluating the performance of the obtained membrane, as
shown in Table 3 it turns out that the decrease in the
filtration rate of 3% bovine immunoglobulin solution
with time is remarkable. It is considered that this
was because the hydrophilizing treatment was performed
using a reaction liquid containing a lot of cross-
linking agent, and even though a sufficient coarse
structure layer for the membrane exists, the filtration
rate was reduced by adsorption of globulin.
Comparative Example 2
A hollow fiber microporous membrane was
obtained according to Example 1 except that a
composition consisting of polyvinylidene fluoride resin
and dicyclohexyl phthalate was homogeneously dissolved
and the solution was extruded in the shape of a hollow
fiber from a spinneret which consists of an annular
orifice with an inner diameter of 0.8 mm and an outer
diameter of 1.2 mm at a discharging rate of 5.5 m/min
while passing through the inside hollow part diheptyl
phthalate at a rate of 7 ml/min.
Then, the above microporous membrane was
subjected to hydrophilizing treatment. The
hydrophilizing treatment was performed according to
Example 1 except that hydroxypropyl acrylate and
polyethylene glycol dimethacrylate (product of Aldrich
Co., average molecular weight 550) was dissolved in 25
vol% solution of 3-butanol so that the acrylate and the
dimethacrylate might respectively be 1.1 vol% and 0.6
vol%. It was confirmed that water spontaneously
permeates into the pores when the obtained membrane was
contacted with water. As a result of evaluating the
performance of the obtained membrane, as shown in Table
3 it turns out that the permeation ability of 3% bovine
globulin was very low.
Example 8
As a result of evaluating the removing
ability of porcine parvovirus of the hydrophilic
microporous membrane obtained in Example 1, high
performance was exhibited as shown in Table 4.
Example 9
As a result of evaluating the removing
ability of porcine.parvovirus of the hydrophilic
microporous membrane obtained in Example 4, high
performance was exhibited as shown in Table 4.
Example 10
As a result of evaluating the removing
ability of porcine parvovirus of the hydrophilic
microporous membrane obtained in Example 5, high
performance was exhibited as shown in Table 4.
Example 11
As a result of evaluating the removing
ability of porcine parvovirus of the hydrophilic
microporous membrane obtained in Example 6, high
performance was exhibited as shown in Table 4.
Example 12
As a result of evaluating the removing
ability of porcine parvovirus of the hydrophilic
microporous membrane obtained in Example 7, high
performance was exhibited as shown in Table 4.
68
INDUSTRIAL APPLICABILITY
According to the hydrophilic microporous
membrane of the present invention, a separation
membrane can be provided which can attain both virus
5 removal performance and permeation capability of
physiologically active substances on a practical level
in the filtration of medical supplies which may have a
risk of virus contamination or physiologically active
substance solution which is the material thereof.

WE CLAIM;
1. A hydrophilic microporous membrane comprising a thermoplastic
resin, which is subjected to a hydrophilizing treatment by a graft
polymerization reaction of a hydrophilic vinyl monomer
containing a hydroxyl group and one vinyl group in a graft ratio of
6 to 24%, wherein the graft polymerization reaction is performed
in a condition where a vinyl monomer which has two or more vinyl
groups is not contained at a proportion to the hydrophilic vinyl
monomer of more than 2 mol%,
wherein the hydrophilic microporous membrane has a maximum
pore size of 10 to 100 nm, and has a coarse structure layer and a
fine structure layer, which are formed in one piece, wherein the
above described coarse structure layer has a higher open pore ratio
and exists on at least one side of the membrane surface and has a
thickness of 2 mm or more, and the above described fine structure
layer has a lower open pore ratio and has a thickness of 50% or
more of the whole membrane thickness.
2. The hydrophilic microporous membrane as claimed in claim 1
having a maximum pore size of 10 to 70 nm.
3. The hydrophilic microporous membrane as claimed in claim 1
having a maximum pore size of 10 to 36 nm.
The hydrophilic microporous membrane as claimed in any one of
claims 1 to 3 having a receding contact angle of water of 0 to 20
degrees.
The hydrophilic microporous membrane as claimed in any one of
claims 1 to 4, wherein the thickness of coarse structure layer is 3
mm or more.
The hydrophilic microporous membrane as claimed in any one of
claims 1 to 4, wherein the thickness of the coarse structure layer is
5 mm or more.
The hydrophilic microporous membrane as claimed in any one of
claims 1 to 6, wherein the thermoplastic resin is polyvinylidene
fluoride.
The hydrophilic microporous membrane as claimed in any one of
claims 1 to 7 the use in removing viruses from a liquid containing
a physiologically active substance.

A hydrophilic microporous membrane comprising a thermoplastic resin, which
is subjected to a hydrophilizing treatment by a graft polymerization reaction
of a hydrophilic vinyl monomer containing a hydroxyl group with a cross-
linking agent in a graft ratio of 6 to 30%, wherein the cross-linking agent is
used at a proportion to the hydrophilic vinyl polymer of 0 to 10 mol%,
wherein the hydrophilic microporous membrane has a maximum pore size of
10 to 100 nm, and has a coarse structure layer and a fine structure layer,
which are formed in one piece, wherein the above-described coarse structure
layer has a higher open pore ratio and exists on at least one side of the
membrane surface and has a thickness of 2 m or more, and the above-
described fine structure layer has a lower open pore ratio and has a thickness
of 50% or more of the whole membrane thickness.

Documents:

927-KOLNP-2005-FORM-27.pdf

927-kolnp-2005-granted-abstract.pdf

927-kolnp-2005-granted-assignment.pdf

927-kolnp-2005-granted-claims.pdf

927-kolnp-2005-granted-correspondence.pdf

927-kolnp-2005-granted-description (complete).pdf

927-kolnp-2005-granted-examination report.pdf

927-kolnp-2005-granted-form 1.pdf

927-kolnp-2005-granted-form 13.pdf

927-kolnp-2005-granted-form 18.pdf

927-kolnp-2005-granted-form 2.pdf

927-kolnp-2005-granted-form 26.pdf

927-kolnp-2005-granted-form 3.pdf

927-kolnp-2005-granted-form 5.pdf

927-kolnp-2005-granted-form 6.pdf

927-kolnp-2005-granted-gpa.pdf

927-kolnp-2005-granted-reply to examination report.pdf

927-kolnp-2005-granted-specification.pdf

927-kolnp-2005-granted-translated copy of priority document.pdf


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Patent Number 234018
Indian Patent Application Number 927/KOLNP/2005
PG Journal Number 18/2009
Publication Date 01-May-2009
Grant Date 29-Apr-2009
Date of Filing 18-May-2005
Name of Patentee ASAHI KASEI MEDICAL CO., LTD.
Applicant Address 9-1 KANDA MITOSHIRO-CHO, CHIYODA-KU, TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 ICHIRO KOGUMA 75-1-207, SACHIGAOKA, ASAHI-KU, YOKOHAMA-SHI KANAGAWA
2 FUJIHARU NAGOYA 4-76-105, NAKAJIMACHO, MINAMI-KU, YOKOHAMA-SHI, KANAGAWA
PCT International Classification Number B01D 61/04
PCT International Application Number PCT/JP2003/013329
PCT International Filing date 2003-10-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2002-304766 2002-10-18 Japan
2 2002-376767 2002-12-26 Japan
3 2003-023709 2003-01-31 Japan