CA1171615A

CA1171615A - Dialysis membrane of cellulose

Info

Publication number: CA1171615A
Application number: CA000379026A
Authority: CA
Inventors: Klaus Gerlach; Joachim Behnke; Alexander Brandner
Original assignee: Akzo NV
Current assignee: Akzo NV
Priority date: 1980-06-12
Filing date: 1981-06-04
Publication date: 1984-07-31
Also published as: ZA813985B; DD159527A5; DE3021943A1; ES502962A0; IL63068A0; JPH0460692B2; NO811958L; DK254081A; DE3021943C2; ES8203629A1; PT73167B; AU7147981A; JPS5724606A; BR8103677A; GR74574B; FI811840L; PT73167A; EP0042517A1; ATE7206T1; EP0042517B1

Abstract

ABSTRACT

A regenerated cellulose, dialysis membrane having a dialytic permeability to vitamin B12, adjustable as a function of the ultra-filtration power (UFP) and measured at 20°C, of at least the value calculated from the linear regression equation:

DL vitamin B12 = 5.3 (UFP) + 2.3 x 10-3 said ultra-filtration power being between 0 and 10 x 10-4 ml/min. N; the dialysis membrane of the invention has a higher vitamin B12 permeability than prior regenerated cellulose membranes, and still display a significant vitamin B12 permeability when ultra-filtration power is practically no longer measurable.

Description

6~L5 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, -~L~7~
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 . . , : , 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 ,~ , . .
, ~ .

~7~5 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 .: :

a.c 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 ~7~
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 . - ,: ' ' '':

6~
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:

, ~Ll71613j 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_ - ' ' ' ~ .

~7~
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 -10- ' . -, .
.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

1. An extruded regenerated cellulose dialysis membrane having a dialytic permeability to vitamin B12, adjustable as a function of the ultra-filtration power(UFP) and measured at 20°C, of at least the value calculated from the linear regression equation:

DLvitamin B12 = 5.3 (UFP) + 2.3 x 10-3, said ultra-filtration power being between 0 and 10 x 10-4 ml/
min. N.

2. A membrane according to claim 1 extruded in the form of a flat foil.

3. A membrane according to claim 1 extruded in the form of a tubular foil.

4. A membrane according to claim 1 extruded in the form of a hollow fibre.

5. A membrane according to claim 1, wherein said dialytic permeability is equal to said value calculated from said equation.

6. A membrane according to claim 1, wherein said dialytic permeability is greater than said value calculated from said equation.

7. A dialysis membrane according to claim 1, wherein the cellulose consists partly or wholly of substituted cellulose.

8. A dialysis membrane according to claim 7, wherein said substituted cellulose has a degree of substitution between 0.1 and 0.7.

9. A membrane according to claim 1, 5 or 6, formed by extruding a spinning solution comprising said cellulose and said tertiary amine oxide into a non-solvent.

10. A method for producing a dialysis membrane having a dialytic permeability to vitamin B12, adjustable as a func-tion of the ultra-filtration power (UFP) and measured at 20°C, of at least the value calculated from the linear regression equation:

DLvitamin B12 = 5.3 (UFP) + 2.3 x 10-3 said ultra-filtration power being between 0 and 10 x 10-4 ml/
min. N, comprising:
forming a spinning solution by dissolving a mixture of 7 to 25%, by weight, of cellulose, 93 to 50%, by weight, of tertiary amine oxide, related in each case to the weight of the spinning solution, in a mixer in a time of less than 8 minutes and at a temperature of be-tween 80 and 150°C, degasifying the solution thus bbtained, extruding the solution into a precipitation bath, washing the precipitated extrudate and, after the addition of a plasti-cizer, drying the extrudate at a temperature of between 50 and 110°C, without shrinkage, and reeling the dried extrudate.

11. A method according to claim 10, wherein the precipi-tatlon bath comprises a liquid or solution miscible with the tertiary amine oxide.

12. A method according to claim 11, wherein a major part of the liquid or solution is water, mono- or multi-valent alcohol, ketone, or a mixture thereof.

13. A method according to claim 11 or 12, wherein the precipitation bath contains between 1.0 and 25%, by weight, of tertiary amine oxide.

14. A method according to claim 10, 11 or 12, wherein the spinning solution contains a stabilizer as an additive.

15. A method according to claim 10, 11 or 12, wherein the spinning solution contains a plasticizer as an additive.

16. A method according to claim 10, 11 or 12, wherein the mixture is dissolved in said mixer in less than 4 minutes.

17. A method according to claim 10, 11 or 12, wherein-the mixture is dissolved at a temperature of between 90 and 110°C.

18. A method according to claim 10, wherein the dialysis membrane obtained is treated, prior to the addition of the plasticizer, for between 5 and 50 minutes, in a water-contain-ing liquid, at a temperature of between 50 and 105°C.

19. A method according to claim 18, wherein the water-containing liquid is a 75 to 85%, by weight, aqueous hydrazine solution.

20. A method according to claim 18, wherein the water-containing liquid is a mixture of glycerin and at least one of water and a monovalent alcohol having 1 to 3 carbon atoms.

21. A method according to claim 20, wherein the water-containing liquid contains between 10 and 40%, by weight, of glycerin.

22. A method according to claim 18. 19 or 20, wherein the treatment is carried out at a temperature of between 60 and 80°C.

23. A method according to claim 18, 19 or 20, wherein the duration of the treatment is between 10 and 20 minutes.

24. A method according to claim 10, wherein the mixer is a double-worm extruder comprising a degasification zone.

25. A method according to claim 24, wherein said extruder comprises worms which rotate in the same direction.

26. A method according to claim 10, 11 or 12, wherein said spinning solution further comprises up to 25%, by weight, of a non-solvent and up to 10%, by weight of conventional additives.