Note: Descriptions are shown in the official language in which they were submitted.
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The invention relates to dialysis membranes made
of regenerated cellulose, particularly in the form of flat
foils, tubular foils, or hollow fibres, and more particularly
such membranes produced by e~truding a spinning solution,
comprising cellulose and a tertiary amine oxide, into a non-
solvent.
It is known from Swiss Patent 191,822 that cellu-
lose is soluble in tertiary amine o~ide, and that the cellu-
lose can be regenerated by placing a solution of this kind
in an aqueous precipitation bath. Another method of dis-
solving cellulose in tertlary amine oxides is described in
.S. Patent 3,447,939.
Federal Republic of Germany Offenlegungsschriften
(Published Patent Specifications) 28 30 683, 28 30 684 and
28 30 685 describe methods of dissolving cellulose in a -tertiary amine oxide, the preferred amine oxide being ~-
methyl-morpholine and the tertiary amine oxide containing,
if necessary, a non-solvent diluent.
The product thus obtained, which is stable in
storage, may be used directly for extrusion into a non-
solvent, whereby foils or fibres of regenerated cellulose
occur.
Dialysis membranes made of cellulose in the form
of flat foil, tubular foil or hollow fibres have been known
for some time, the cellulose being regenerated by the CUOX~M
or viscose methods, or by hydrolysis of cellulose acetate.
Depending upon the method used, and the operating conditions,
the membranes obtained have different dialysis properties,
for example ultra-filtration,permeability to molecules of
different sizes, the ability to retain water, and different
proportions of a plurality of such properties. As a general
rule, hydrodynamic permeability is in a specific ratio to
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diffusive permeability.
For example, Federal Republic of German Offenle-
gungsschrift (Published Patent Specification) 28 23 985
claims a cellulose membrane, produced by the CUOXAM method,
which has greater hydrodynamic permeability (ultra-filtra-
tion power) than is otherwise obtained by this method.
Membranes of this kind are used in treating patients suffer-
ing from hypertension, in which case, for the purpose of
reinfusing larger quantities of fluid into the human circula-
tion, the membrane.. must have high hydrodynamic permeability
and, at the same time, adequately high diffusive permeability,
as achieved with cellulose regenerated by the CUOXAM method.
Dialysis membranes made of cellulose regenerated
by the CUO~AM method lose their dialytic permeability when
the ultra-filtration power is in excess of l x 10 4 ml/min.
to such a degree that the-y can no longer be used as
dialysis membranes, especially for haemodialysis.
In British Patent 1,14~,759, which describes the
regeneration of cellulose from spinning solutions consisting
mainly of cellulose and tertiary amine oxides, mention is
also made of the possibility of using the cellulose thus
regenerated for dialysis membranes, but without dealing in
any way with the numerous problems arising in this connec-
tion.
It was the purpose of the present invention to
provide a dialysis membrane, made of regenerated cellulose,
having sufficient strength-and, more particularly, hitherto
unknown dialysis properties.
.~his purpose is achieved by means of a membrane
of the type mentioned at the~beginning hereof and charac-
terized in that the permeability to vitamin Bl2, adjustable
as a function of ultra-filtration power and measured at 20C,
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is equal to, or greater than, the value calculated from
the linear regression equation DLVit min B12 = 5 3 IUFP)
+ 2.3 x 10 3, the ultra-filtration power being between
0 and 10 x 10 ml/min. N.
The dialysis membrane of the invention thus has
distinctly higher vitamin B12 permeability than hitherto
known dialysis membranes made of regenerated cellulose.
One particular advantage is that these membranes still show
considerable vitamin B12 permeability when practically no
ultra-filtration power can be measured.
Outstanding dialysis membranes of the invention
are those conslsting wholly or partly of substituted cellu-
lose, the degree of substitutlon being between 0.1 and 0.7.
Substituted celluloses which lead, within the
scope of the invention, to satisfactory dialysis mernbranes,
with comparatively low ultra-filtration power, are carboxy-
alkyl-cellulose, alkylated cellulose, for example methyl-
and ethyl-cellulose, and also mixed substituted celluloses,
for example hydroxypropylmethyl-cellulose.
The invention provides a method for producing a
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dialysis membrane, characterized in that a mixture of 7 to
25%, by weight, of cellulose, 93 to 50%, by weight, of
tertiary amine oxide, if necessary up to 25%, by weight, of
non-solvent, and up to 10%, by weight, of conventional
additives, related ln each case to the weight-of the spinn-
ing solution, is dissolved in a mixer in less than 8 minutes
and at a temperature between 80 and 150C, the solution
thus obtained being degasified, being extruded, in the
desired form, for example through a nozzle having a wide
slot, a nozzle having an annular slot, or a hollow fibre
nozzle, into a precipitation bath, being washed, and, after
the addition of a plasticizer, being dried at a temperature
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between 50 and 110C, care being taken to prevent shrinkage,
and then being reeled.
Suitable tertiary amine oxides for use in the
invention include, for example, triethyl amine oxide, di-
methylcyclohexyl amine oxide, dimethyl ethanol amine oxide,
dimethyl-benzyl amine oxide, methylpiperidine oxide, methyl-
pyrolidine oxide, or pyridine oxide. N-Methylmorpholine-~-
oxide is the preferred tertiary amine oxide.
The spinning solution may suitably contain, if
necessary, between 10 and 25%, by weight, OL a non-solvent,
for example water, lower mono- and multi-valent alcohols,
dimethyl formamide, dimethyl sulphoxide, high boiling point
amines, more particularly the amine corresponding to the
tertiary amine oxide.
One parameter affecting the ultra-filtration power
of the dialysis membrane is the concentration of cellulose
in the spinning solution, the lower the concentration, the
higher the ultra-filtration power. High cellulose concentra--
tions lead to high viscosities and this impairs spinnability.
Up to 10% of additives may, if necessary, be added
to the spinning solution, for instance additives affecting
viscosity, stabilizers and/or plasticizers. Stabilizers
prevent excessive reduction in the degree of polymerization
and other problems causing discolouration in regenerated
cellulose. Citric acid and/or glucose have hitherto been
found satisfactory. Inorganic and/or organic salts, soluble
in the spinning solution, may also be used as additives,
for example to influence pore structure.
Whereas for hitherto known dialysis membranes, the
cellulose used has always been a high quality cellulose with
a high degree of polymerization, for example cotton linters,
in the case of the dialysis membrane of the invention, the
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use of celluloses having a low degree of polymerization
presents no problems. It is merely necessary to ensure,
for toxicological reasons, that no substances passing into
the blood remain in the cellulose, i.e. care must be taken
to eliminate resin and hemicellulose.
The temperature in the extruder should be set as
high as possible, since this reduces the period of residence,
furthermore, as a result of lower viscosity, there is an
improvement in processability - for example degasification,
higher cellulose concentration, and -thus lower ultra-filtra-
tion power, with outstanding values of dialytic permeability
to vitamin B12.
It is found to be possible to process the mixture
for the spinning solution at temperatures of up to 150C,
without seriously damaging the cellulose, especially if 3%,
by weight, of citric acid, for example, is added to the
mixture as a stabilizer. The operating temperature should,
in any case, be higher than the melting temperature of the
tertiary amine oxide selected. The admixture of non-sol~ents
lowers the melting point of most of the suitable tertiary
amine oxides to such an extent that temperatures of around
80C are sufficient to produce the spinning solution.
Suitable precipitation baths include liquids and
solutions which are miscible with the tertiary amine oxide,
for instance water, lower mono- and multi-valent alcohols,
ketones, amines and, more particularly, aqueous solutions.
Such substances may be used alone or mixed together. For
the purpose of influencing coagulation, the precipitation
bath preferably contains between 1 and 25%, by weight, of
tertiary amine oxide.
Salts, for example sodium sulphate or sodium
acetate may be added to the precipitation bath in order to
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limit swelling o~ the regenerated cellulose upon coagula-
tion.
The precipitation bath is usually operated at
room temperature. Higher temperatures should be avoided
in order to prevent any reduction in the dialytic perform-
ance of the membrane.
Under the conditions indicated above, a 2 minute
period of residence in the precipitation bath is sufficient.
Residues of tertiary amine oxides, and possible additives,
are washed out as usual with water in counterflow at
between 12 and 40C, requiring a period of residence of
between 2 and 4 minutes at the most.
In order to avoid the formation of a crust, as
by keratinization, and embrittlement during drying, a plas-
ticizer or softener is suitably added to the washed and still
wet dialysis membrane. This may be done by immersion in an
a~ueous and/or alcoholic solution of a plasticizer, or ~y
spraying or pressing the solution onto the membrane. Where
haemodialysis is involved, only clpounds which can be used
unrestrictedly may be considered. The following have been
found suitable: glycerin, polyethylene glycols, 1,3-butane-
diol, glucose and mixtures thereof.
The dialysis membranes of the invention are dried
at temperatures of between 50 and 110C in the manner used
for other dialysis membranes made of regenerated cellulose.
Drum driers, bel-t driers, or other types of driers which
ensure that drying takes place without shrinkage, are suit-
able for the purpose. Prevention of shrinkage is to be
understood to mean that steps are taken which largely
eliminate any reduction in longitudinal and transverse di-
mensions. Reduction in thickness is admissible. As a rule,
drying is lnitiated at a higher temperature which is lowered
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towards the end of the drying section.
In one particular embodiment of the invention,
the mixture for the spinning solution is dissolved in less
than 4 minutes, mainly as a result of the use of a suitably
high temperature in the extruder.
However, the high temperature in the extruder is
possible only if the spinning solution already contains a
stabilizer. The preferred temperature range in the extruder
for mixtures of spinning solutions containing no stabilizer
is between 90 and 110C.
The dialysismembranes of the invention have high
dialytic permeability in the so-called medium molecular
range (500 - 5000 Dalton), and this is e~pressed by the
vitamin B12 clearance as a test molecule. This high
dialytic permeability is even largely retained when hydrau-
lic permeability to water (= ultra-filtration power) is
drasticàlly reduced, by an after-treatment, to the optimal
value for haemodialysis.
~his after treatment consists in treating the
20 dialysis membrane obtained, prior to the addition of plas-
ticizers, in liquids containing water, for between 5 and `~
SO minutes, preferably between 10 and 20 minutes, at a
temperature of between 50 and 105C, preferably between 60
and 80C.
Apart from water, a preferred water-containing
liquid is a 75 to 85%, by wei~ht, aqueous hydrazine solu
tion, or a mixture of water and/or monovalent alcohol ha~ing
1 to 3 carbon atoms and glycerin; the liquid suitably con-
tains between 10 and 40%, by weight, of glycerin.
A double worm extruder, with a degasifica~ion
area, has been found to be particularly suitable for mixing
the spinniny solution, with a particularly brief period of
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residence, to form a homogeneously degasified solution.
The worms in the said extruder should rotate in the same
direction.
The inventlon is further explained hereinafter
in particular and preferred embodiments by reference to
the following examples.
Example l
36 g/min. of a mixture of 20%, by weight, of beech sulphite
cellulose having an average degree of polymerization of
795 anhydroglucose units (weight means), 68%, by weight,
of M-methylmorpholine-N-oxide, and 12% of water, were fed
continuously, through a double metering worm, to a double-
worm extruder having worms running in the same direction and
a degasification zone. The extruder, with the exception of
the inlet zone, wàs heated to 100C. The mixture was
degassed in the degasification zone at a pressure of lO
mbars, the air and some of the water being removed. After
4 minutes in the extruder, the clear solution thus obtained
was filterèd and passed to a spinneret through a metering
pump. The spinneret, having a slot-wldth of 180 mm and a
gap adjustment of 600 ~m, was heated to 130 and was arranged
at a distance of lO mm above the surface of the preclpita-
tion bath. The membrane was precipitated at a take-off
velocity of 4 m/min. and with a 2.5 minute period of resi-
dence in the precipitation bath. It was then washed and
immersed in a plasticizer bath consisting of 35%, by weight,
of glycerin, 45%, by weight, of ethanol, and 20% of water,
and s~ueezed out~in a~two-high roll-stand. This was
followed by drying in a belt drier, at a chamber temperature
of 65C, with precautions against shrinkage, and by reeling.
The membrane thus obtained was transparent and had the
following dialysis properties:
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UFP = 3.2 x 10 [ ]
min M
DL(Vitamin B12)= 3.9 x 10 ~ _
lmin
+ UFL = '`Ultrafiltrationsleistuny"
i.e. UFP - ultra-filtration power
The breaking strain according to DIN 53455 in the longitu-
dinal direction was 1836 c~, the elongation at rupture
25.9%. The thickness of the membrane in the dry condition
was 13 ~m, the water content 7.9%, and the glycerin content
25%.
Example 2
A spinning solution havlng a cellulose content of 14% was ~:
processed into a membrane in a manner similar to that des-
cribed in Example 1. The drled membrane produced the
following values:
::
UFP = 6.3 x 10 4 ~ m
` : L min
D ~it B12 = 6.1:x 10 r cm 1 ;
lmin ~J
DL Urea = 37.3 x 10 r cm 1
.Thickness = 13 ~m Lmln J
Breaking strain - long= lSOO cN transverse = 500 c~ ~- .
: Elongation at rupture
: - long = 23% " - 140 % : :
Water content = 8 %:by weight -;:.
Glycerin content = 22 % by welght ~ ~:
Example 3 : :
The wide slot nozzle of Example 1 was replaced by a core
skin, symmetrically heatable bicomponent nozzle, The out-
_g_
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side diameter of the nozzle bore was 1100 ~m, that of the
core needle 700 ~m. The cavity-forming fluid was paraffin
oil (Primol* 340, available from Esso ~G). The cellulose
concentration of the spinning solution was 22%. With a
delivery of 1.8 g./min. per spinneret and a take-off velocity
of 15 m./min., the hollow fibres obtained,had an outside
diameter of 300 ~m and a wall thickness of 20 ~m. After
removal of the internal fluid with methylene chloride, and
blow drying, the dialytic properties of the hollow fibre
were checked~ The ultra-filtration rate was measured and
converted to ultra-filtration power for better comparability:
The UFR (measured at 20C) amounts to 3.5
m h Torr
correspondlng to a
UFP of 4.3 x 10 ~ ml
Lmin N J
D ~ it B12 = 5-5 10
Example 4
A membrane, produced as in Example 1, was after treated with
water for 12 minutes, at 75C, before adding the plasticizer.
It was then plasticized as usual and dried. The UFP could
practically no longer be measured, while the D ~it B12 was
equal to 2.6 x 10 3 cm./min.
* trademark
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