CA1181206A

CA1181206A - Hollow fibre membrane for plasma separation

Info

Publication number: CA1181206A
Application number: CA000381723A
Authority: CA
Inventors: Klaus Gerlach; Erich Kessler; Werner Henne
Original assignee: Akzo NV
Current assignee: Akzo NV
Priority date: 1980-07-15
Filing date: 1981-07-14
Publication date: 1985-01-22
Also published as: ES503936A0; AU541863B2; EP0044405B1; ATE18262T1; AU7284081A; JPS5749467A; IL63302A0; BR8104510A; ZA814857B; US4708799A; ES8205359A1; EP0044405A1; IL63302A; DE3026718A1; AR228060A1

Abstract

ABSTRACT OF THE DISCLOSURE

A hollow porous fibre useful in a membrane for plasmapheresis is produced by extruding a homogeneous mixture of a fusible polymer and a liquid inert to the polymer through a hollow fibre nozzle, into a spinning tube containing liquid of the extruded mixture, the liquid being maintained below the segregation temperature; the fibre and liquid are guided through the spinning tube at the same or only slightly different linear velocities.

Description

The invention relates to hollow fibre membranes for plasma separation, i.e. blood plasmapheresis, mDre particularly human blood.
In order to improve therapeutical treatment, medical research is being devoted to an increasing degree, to the questior~ of what cor~onents the blood consists of.
Of interest in this connection i9 both the quantitat~vç
and the ~ualitative composition of the blood and changes therein, whether due to disease or other influences, and the effects produced by elimination processes, a typical example of which is hemodialysis.
Hemodialysis by means of artificial kidneys has increased signiflcantly over the past fifteen years, and the lives of those suffering from kidney diseases, and of those who for some reason have lost their kidneys, have been con-siderably extended. Many people owe their lives entirely to the functioning of a mernbrane which eliminates metabolic decomposition products from the blood by means of dialysis.
These chemically produced semi-perme ble membranes, the mosk important of which is the cuprophan mernbrane, made of regenerated cellulose simulate the separating process of natural mer~ranes in the human body so well that they can replace failed, diseased, sub-functional organs.
The difference in concentration of so called meta-bolites between the blood side and the water side of the membrane ensures constant diffusion from the blood of the substance, the molecular size of whlch is determined by the porosity of the dialysis mernbrane. The same principle applies to innumerable cell and organ membranes in the human body.
In this connection, nephrologists have learned to master the method of extra-corporeal circulation of the blood, i . e. the extension of human blood circulation to a branch outside the body, thus establishing the prerequisites for more extensive eliminating processes such as hemofiltration.
In hemofiltration with an artificial kidney, rnetabolites are removed by pressure îiltration through a mernbrane, in that metaboli tes passing -through the membrane are discarded in large quantities, for example 20 1 (litres).
The large amount of filtrate rnust be replaced as a physiolo-gical saline solution in order to prevent undue inspissation of the blood.
In either case, namely hemodialysis or hemofiltra-tion, however, the mernbrane must not allow any protein to pass, the most common of which is albumin (molecular weight about 69, 000), in other words the mernbrane must be impermeable to molecules of this size.
Medical research has established that very many diseases are caused by toxins frec~uently associated with proteins. These are often small molecules which can pass through the dialysis mernbrane or hemoEil-tration mernbrane if they are present in the free form.
However, protein combining produces molecules so larye -that they cannot be elim:inclted -through such rnembranes this applies to irnrnune comp:Le.~es and antigens.
In order -to rerrlove such protein cornbined tox:ins in the molecular weigh-t range betw:en about 100,000 arld 3,000,000, the only rnethod hi-ther to available has been plasrna separatio by ultracentrifuging. This involves ta~cing an admissible amount of blood from -the pati ent, placing it in a bag, feeding -the conten-ts thereof to an ultracen-trifuge, and thus separa-ting cellular cornponents from the blood plasrna.
Cellular components such as red and white blood corpuscles, and also blood pla-telets, were returned to the pa-tient a-fter dilution, the plasma and released or dissolved components being discarded, and the toxic substances thus eliminated.
The same process, among others, is still used with healthy blood donors in order to obtain plasma for patient plasmatransfusion.
Thus -the separation of blood into cells and plasrna has two different fields of application, namely elimination of protein combined toxins and obtaining plasma for plasma-transfusion.
In these two fields of application, it would be desirable to carry out extracorporeal hemofiltration on patients or donors which would make it possible to separate plasma still containing the released or dissolved substances, and to return directly to the blood circulation of the patient or donor, the fractions containing the cell components.
This, however, would require mernbranes having a limit of permeability to molecular weights of about 3,000,000.
A few types of membranes are used for this purpose, such as cellulose, acetate, cellulose nitrate, and polyvinyl alcohol membranes. However, these have a limited, or rather an overall partial permeab~li-ty to the proteins. Permeabil-ity may be expressecl by the so-called screen coeffic:ient:

CF~
CB
wherein:
CF is the concentration of substance X in the filtrate and CB is the concen-tratioll of subs-tance X in -the blood.
With S equal to 1, permeability is cort~lete, with S
equal -to less than 1, permeability is partial. Presently available membranes have screen coefficients which are already less than 0.~3 for albumin. This means that elimination of components to be separated takes place only to a reduced degree, and a lengthy treatment time is therefore necessary.
It is therefore necessary to work with larger amounts of reinfusion, or to use very large mernbranes. This has con-siderable disadvantages since it rneans -that the units have a very large extracorporeal volurne.
There is therefore a need for rnernbranes which do not have the above rnentioned disadvantages.
It is therefore the purpose of the invention to rna~e available a merr~rane by means of which it is possible to separate proteins dissolved in the blood up to molecular weights in the vicinity of 2.5 or even 3 million, i.e. mernbranes which, in the molecular weight range of about 60,000 to 3 million, preferably 60,000 to 2.5 million, have a high screen coefficient and also permit a large filtrate flow. It is therefore another purpose of the invention to make available mernbranes having a filtrate flow of at least l/5th of the flow of blood through the filter unit. In this way, patient treatment times and transfusion times remain within acceptable limits. The filtrate flow is determined at a pressure differ-ential of 0.1 bar.
According to -the invention there is provided a method for producing porous, hollow fibre membranes for p:lasma separation which is characterized in that a homogeneous mixture of at least two components, one being a fusible polyrner and being present in an amount of abou-t 1 to 30~/0, by weight, and the other being a liquid which is inert to the polymer and is present in an arnoun-t of abou-t 70 to ~0'~, by weiyht, -the -two components forming a binary system which, as a liquid aygre-gate, comprises a range of comple-te miscibility and a ranye having a rniscibility gap, is ex-truded, at a temperature above the segrega-tion temperature, through a hollow fibre nozzle, ~ _ into a spinniny tube containing the liquid of the extruded mixture of components, t'ne liquid in the said spinning tube being at a temperature below the segregation temperature, and the fibre and the inert liquid being guided, in the same direction, at approxirnately the same, or at a slightly different, linear velocity, throuyh the said spinning tube, the fibre beiny then rernoved frorn the said spinning tube under slight tension, and the hollow fibre structure thus formed beiny washed out with a solvent after solidification.

The drop in velocity between the fibre and the spin-ning liquid, during passage through the spinning tube, is pre-ferably less than 15%. In certain cases, it is even desirable -for the fibre and the inert liquid to be passed through the spinning tube at the same linear velocity.
It is desirable for the fibre to be taken from the spinning tube at a velocity which is between 5 and 15% higher than that achieved without take off as the fibre emerges from the spinning tube. This keeps the tension very low. It is advantageous to subject the fibre, af-ter it has solidified, to pressure washing in order to remove the inert liquid. The fibres are preferably wound parallel and then washed out.
It :is desirable to maintain an air gap between the outlet surface of the hollow f:ibre nozzle and the surface of the liquid, the said yap being between 3 and 5 mrn, i.e. as small as possible.
In another aspect of the invention there ls provided a hollow fibre and a mernbrane for plasrnapheresis formed from one or more of such fibres, the fibre being a porous, hollow fibre having a pore volume ratio of at least 7~/O~ an inside diameter of bc~tween 100 and 550 ~m, a wall thickness of between 15 and 300 ~rn, and a screen factor for human blood protein, in the molecular weight range of about 60,000 -to 3 million, o-f at least 0.7.
The mernbrane suitably comprises an assen~ly of the hollow fibres.
The screen factor is preferably between 0.9 and 1.
It may even be close to 1 for human blood protein in the molecular weight range of about l -to 2.5 million. The pore cavity or volumes of the membranes preferably amounts to at least 8~/o. Suitable rnert~ranes have an inside diarneter of between 250 and ~50 ~lm, preferably with a wall thickness of between 100 and 200 ~m. The membrane is impermeable to blood cells, namely exythrocytes, leucocytes and blood platelets.
The procedure for producing the hollow fibre mem-branes according to the invention may be as follows. The inert liquid, NN-bis-(2-hydroxyethyl)-hexadecylamine being particularly suitable, is mixed with the appropriate amount of the polymer, more particularly polypropylene, at the required temperature, e.g. 220C. Stirring is recommended and the application of a vacuum, in order to remove such low molecular weight components as amines from the solvent. This produces, after a certain tirne, for example, 2 hours, a homo-geneous, processable, viscous solution.
The fusible polyrtler is preferably polypropylene, however it is also possible -to use other hiyh molecular weight polyrners, more particular polyoleEins, for example, high molecular weight polyethylene, copolyrners of propy:Lene and ethylene, polymers based on 3-me-thyl-pentene-(1), po:lyethylenechlorotrifluoro-ethylene available under the trade mark "~lalar", and polye-thylerle sulphide.
In the case of con-tinuous operation, it is advisable, first of all, i.e. before the dissolving process, to free -the liquid from low molecular weight components by evacuation.
The polypropylene is melted in an extruder, the heated liquid ~8~

and molten polypropylene being then passed to a mixer, for example, a pir, mixer. For a more thorough mixing, the mixture is also suitably passed through a sintered metal cylinder.
The melt, preferably held under an inert gas, for example, nitrogen, then passes to the pump which delivers it.
A conventional hollow fibre no~zle is used, preceded by a filter, preferably a sintered metal filter. An air gap of between 3 and 5 mm is preferably located between the outlet surface of the nozzle and the surface o-f the liquid. Although it should be as srnall as possible, the gap, under certain circumstances, may also be larger, for example, about 30 mm.
The homogeneous mixture, at a temperature of about 220C, is then extruded through the hollow fibre nozzle and enters, after passing the air gap, the inert liquid in the spinning tube, below the segregation temperature of the extruded mixture, preferably at about 30 to 60C. Nitrogen is passed, in known fashion, through the interior of the hollow fibre in the hollow fibre nozzle.
Accurate control of the amount of nitrogen intro-duced is desirable since, by measuring the nitrogen consump-tion it is possible to control the uniformity of the fibre produced. Irregularities in nitrogen consurnp-tion indicate problems in the production of -the fibre, Eor example unduly thin walls and -the like. I.iquid is fed cons-tantly to the spinning -tube, and an overflow ensures that the level therein is always constan-t. The iner-t liquid ar.d the hollow fibre pass through the spinnirlg tube in the same direction a-t a velocity of, for example, 20 m/min. The velocity in -the spinning tube may be contr-olled by the viscosity of the inert liquid, and this may be controlled by varying the -teml-)erature thereof. It has been found particularly advantageous to rnain-tain temperatures of between 35 and 70C in the spinning tube.
The inert liquid and the hollow fibre leave the spinning tube at the lower end, the fibre being taken off at a velocity which suitably is only slightly above that at which the fibre would leave the spinning tube with a special mechanical ta]ce-off. This velocity may easily be determined by allowing the fibre to sag slightly below the def:Lecting roller, and by increasing the resulting veloci-ty by between 5 and 15%.
The deflecting roller preferably runs on ball bear-i.ngs and has grooves adapted to the cross-section of the fibre. The surface should be very smooth.
The deflecting roller is preferably followed by two further rollers, the purpose of which is to prevent fluctuations which may arise when the fibre is wound and taken off, from continuing into the spinning tube. Take-off is preferably effected by a three roller unit. The rollers may be covered with foamed material which ensures good ad-herence and prevents slip. The fibre is then passed to adancing arm which feeds the fibre in parallel turns to a winding element.
The spinning -tube :Ls preerably enclosed i:n a casiny containing a temperature regu:lating liquld. This :Liquid is p:referably at a telnperature lower than -tha-t a-t the beginning of the spinnirlg tube. This cools the :Eibre as it passes through the spinning tube, and furtherrnore p:revents the -ternperature in the spinnirlg tube from increasing.
It is desirable for the spinning tube to be accurately centred, so -that the fibre docs not touch the walls -thereof, since this might lead to spinnil-~g problems and fibre irreg-l-larities.

~8~

The inside diameter of the spinning tube, filled with inert liquid, and the outside diameter of the ho]low fibre, must be matched, since this can control the flow velocity in the tube. The inside diameter of the spinning tube is prefer-ably about 2 to 10 times the outside diameter of the hollow fibre.
The leny-th of the splnning tube may vary within wide lirnits, a sui-table leng-th being between 1 and 3 m. However, other lengths are no-t excluded.
It is deslrable for the outlet velocity from, and the delivery to, the nozzle, and the condi-tions in the spinning tube, to be matched in such a manner that the flow velocity of the fibre and inert liquid in the spinning tube arnount to about 5 to 25 m/min..
The fibre is then passed to a dancing arm on a wind-ing unit, it being desirable to lay the fibre in parallel turns on the unit, especially on suitable spools. The fibre is then washed with a solvent in which the inert liquid is soluble.
In th.is connection, it is advantageous for the fibre to be sub]ected to pressure washiny on the spools. Suitable washing fluids are ethanol, isopropanol and acetone, e-thanol being preferred.
It was particularly surprisiny to find that the hollow fibre mernbranes of the invention are so outstandingly sui.table for plasrnapheresis, rendering possible simple and rapid separation of blood p.lasrna on the one hand and blood corpuscles and blood platelets on the other hand, and with no removal of substances such as pro-teins frorn the plasrna. It is possible -to produce hollow fibre mernbranes for plasrnapheresis having a screen factor of approximately 1 for rnost blood components, except blood corpuscles and blood platelets. Thus with the rner~ranes of the invention, it is possible to separ-_ g _ ate blood corpuscles, ~or example, erythrocytes, leucocytes and blood platelets from the blood, without also separating therefrom proteins dissolved in the plasrna. Thus, in the treatment of healthy blood, it is possible to recover valuable whole plasrna on the one hand and, on the other hand, to return again directly to the doner the blood corpuscles and blood platelets. Obviously the plasma may also be returned in this way to the donor, while blood ce].ls may be enriched and recovered.
This rneans that blood plasma may be subjected to fur-ther fractionating, thus making it possible to recover from the plasma practically all proteins by suitable fractionating methods.
The screen factor remains almost constant over long periods.
By means of the membranes of the invention, it is also possible to remove from sick patients toxins corr~ined with dissolved proteins and to return to the patients' blood healthy plasma or other suitable solutions. The treatment may be carried out in an extremely short time, so that the patient or donor spends only a short time in the unpleasant procedure o:E blood rernoval.
The hollow fi.bre merrlbranes of the inven-tion are extremely sirnple and economical -to produce, and -therefore represent an inexpensive but very valuable disposable article.
This elimi.na-tes the -tedious cleaning and sterilization re~uired in centrifuging.
The invention is illustrated by reference to the accompanying drawings in which:
FIGURE 1 illustrates schernatically a spinrling unit for carrying out the method of the inven-tion.

With further reference to Figure 1, a small spinning unit comprises a storage tank 1, a hollow fibre nozzle 3, a spinning tube 4 and a winding unit 7.
Storage tank 1 includes an inlet line 11 for the homogeneous melt and a nitrogen line 12.
~ gear pump 2 is disposed in a line between storage tank 1 and nozzle 3, which line includes a sintered metal filter 14.
A nitrogen line communicates with nozzle 3 through a rnicrovalve 15 and a bore 19. A pressure sensor 18 is connected in this nitrogen line.
Spinning tube 4 includes a thermostat 8, and a line 22 recycles liquid from tube 4 to an overflow hopper 9 and back to tube 4. A thermostat 5 is provided between tube 4 and line 22. Line 23 conveys excess recycled liquid from hopper 9 to thermostat 5.
Winding unit 7 includes a ball bearing roller disposed below tube 4, a take-off roller 6, a danci-ng arm 7 and a disc spool 24.
~0 The operation of the spinning unit is more partic-ularly described in Exarnple 1.
The invention is explained in greater detail by the following exarnples which refer -to Figure 1.

Exarnpl _ 1600 g (80% by weight) of N,N-bis-2-hydroxyethyl-hexadecylamine (hereinafter referred to as N~H) and ~00 g (20% by weight) of natural type PPH 1050 polypropylene with a melt flow illdex of 1.5 (Hochst AG), are hea-ted in a 4-litre ground surface flask, with stirring and under a 20 -to 50 torr vacuum, to 220~C within an hour. Stirring is continued for another hour, until a hornogeneous melt is obtained.

The hot, homogeneous melt is then placed in the storage tank 1, heated to 200C, of a small spinning unit.
The whole unit is heated, from the tank 1 to the nozzle, at a temperature decreasing from 210C to 180C. The tank 1, is sealed and nitrogen pressure at 1 bar is applied. Gear pump 2 delivers the melt, through sintered metal filter 14 having a pore diameter of 50 to 70 urn~ into hollow fibre nozzle 3, frorn which it is extruded in the form of a hollow fibre. Nitrogen is fed into the hollow fibre, through a rnicrovalve 15 and bore 19 located in the middle of the flow of molten material, the nitrogen pressure being measured and recorded between microvalve 15 and nozzle 3. Pressure sensor 18, having a range of 0 to 10 rnbars, records fibre fluctua-tions and any varlation in the lumen.
The dimensions of the fibre are deterrnined by the throughput of molten material, the supply of nitrogen, and the take-off velocity:

inside diameter 0.3 mm outside diameter 0.6 wall thickness 0.15 melt density 0.89 g/cm rnelt throughput ~.2~ cm3/min.
3.78 g/min.
ni-trogen supply 1.~1 cm /min.NB
take-off veloci-ty 20 m/min.

W:i-th a no~zle bore of 1.8 mrn and a nozzle needle having an o~tside diameter of 0.9 tnm, the ve:Locity of the fibre at the ou-tlet from the nozzle is 2.7 m/~min.. The fibre is then spun in a spinning -tube ~ located a-t a dis~ance of 5 rnm ver-tically below -the nozzle 3 and filled with NBH, is deflected around ball bearing roller 20, is taken off at a constant rate of 20 m/min. by take-off roller 6 and is then wound, on a winding unit 7, in parallel -turns on a perforated disc spool 24, the winding speed being controlled by dancing arm 21. The N~H flowing through the spinning tube is cooled in thermostat 5 to 50C and is purnped through line 22, through an overflow hopper 9, into spinning tube ~. Excess N~H flows through line 23 back to thermostat 5, The inside diarne-ter of the spinning tube 4 is 5 mm and it is 2.30 m in length. It is a double walled tube, cooled to 35C by thermo-stat8, over A length of 2 m The ternperature of the melt at the outlet from the nozzle is ahout 180C. Under the aforesaid conditions the flow velocity in the spinning tube 4 is between 16 and 17 m/min.
In order to spin safely, with no sagging of the fibre at deflecting roller 20, the take-off speed is 20 m/min The hollow fibre, wound onto perforated disc spool 24, at about 4 km/spool, is then pressure washed with ethanol for 3 hours, the spool being flushed at a pressure of between 0.5 and 0.8 bar with between 5 and 8 litres of ethanol/min.

Example 2.
Hollow fibres of Exarnple 1 are gathered into bundles of about 2000 fibres, 30 crn in length and are cast in a tubu-lar housing, liquid t:iyht, with polyuretharle, at both head ends to :Eorm a filter un:i.t.
Human plasrna was passed through this filter unit having an active filter surface o:E 0.3 m , a-t a rate of 50 ml/min.. The -transmembrane pressure was set to 50 mrn Hg, a-t -the o-ltlet, by means of a clarnp. Sarnples were -taken :Erorn the filtrate, delivered a-t a rate of 15 rnl/rnin., at 10 mi.nute intervals, in order -to determ:ine the concer-ltra-tion of pro-teins, the remainder of -the f:iltrate heiny re-tu.rrled to -the starting receptacle. The human prote.ins in the fi.l-trate samples were f~

determined by laser nephelometry and were compared with the plasma concentrations, in order to determine screen coeffic-ients. The following values were obtained:

Alburnin = 0.98 IgG = 0.92 S = 0.90 IgM
S~ Lipoprotein = 0.96 The time pattern for ~Lipoprotein alone was deter-mined, the result being as follows:
S
After 10 min 0.98 " 20 " 0.96 " 30 " 0.95 " 40 " 0.93 " 50 " 0.90 " 60 " 0.89 `'120 " 0.90 No blood cells could be detected in the filtrate.
Example 3.
From the hollow fibres of Exarnple 1, a small test unit, with a capacity of 100 cm , 20 cm in length, was con-structed, -through which fresh stored human blood was dilvered at 3 ml/min. in a single pass.
The filtrate was collected for 60 rninutes and was -then checke~ for protein components. The screen fac-tors were as follows:

Albumin 0-95 IgG 0.91 IgA 0.90 a 2 Macroglobulin 0.91 IgM 0.9 Lipopro-tein 0.96 It may be gathered from the screen factors that the proteins passed almost totally through the membrane wall. No blood cells were detected in the filtrate.

Claims

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

1. A method for producing a porous, hollow fibre membrane for plasma separation, comprising extruding a homogeneous mixture of at least two components, one being a fusible polymer and being present in an amount of about 10 to 30%, by weight, and the other being a liquid which is inert to said polymer and is present in an amount of about 70 to 90%, by weight, the two components forming a binary system which, as a liquid aggregate, comprises a range of complete miscibility and a miscibility gap, at a temperature above the segregation temperature, through a hollow fibre nozzle, into a spinning tube containing liquid of the extru-ded mixture of components, the liquid in said spinning tube being at a temperature below the segregation temperature, and the fibre and the liquid being guided, in the same direction and at about the same, or at a slightly different linear velocity, through said spinning tube, the fibre being then removed from the said spinning tube under a slight tension, and the hollow fibre structure thus formed being washed with a solvent after solidification.

2. A method according to claim 1, wherein the fibre and the liquid are guided at about the same linear velocity through said tube.

3. A method according to claim 1, wherein the fibre and the liquid are guided at slightly different linear velocities through said tube.

4. A method according to claim 1, wherein a drop in velocity between the fibre and the liquid, as they pass through the spinning tube, is less than 15%.

5. A method according to claim 1, wherein the fibre leaves the spinning tube at a linear velocity 5 to 15% greater than that of the liquid.

6. A method according to claim 1, wherein the fibre is taken from the spinning tube at a velocity which is about 5 to 15% higher than that at which the fibre would emerge from the spinning tube without take-off.

7. A method according to claim 1, 4 or 6, wherein the fibre is subjected to pressure washing after solidification, to remove the liquid.

8. A method according to claim 1, 4 or 6, wherein the fibres are wound in parallel turns and are flushed.

9. A method according to claim 1, wherein an air gap is maintained between an outlet surface of the hollow fibre nozzle and the surface of the liquid in the spinning tube.

10. A method according to claim 9, wherein the air gap has a length of 3 to 5 mm.

11. A method according to claim 1, 4 or 6, wherein said polymer is polypropylene.

12. A porous hollow fibre membrane for plasmapheresis, comprising a porous, hollow fibre having a pore volume of at least 70%, an inside fibre diameter of between 100 and 550 µm, a wall thickness of between 15 and 300 µm, and a screen factor for human blood proteins, in the molecular weight range of about 60,000 to 3 million, of at least 0.7 obtained by a method comprising, extruding a homogeneous mixture of at least two components, one being a fusible polymer and being present in an amount of about 10 to 30%, by weight, and the other being a liquid which is inert to said polymer and is present in an amount of about 70 to 90%, by weight, the two components forming a binary system which, as a liquid aggregate, comprises a range of complete miscibility and a miscibility gap, at a temperature above the segregation temperature, through a hollow fibre nozzle, into a spinning tube containing liquid of the extruded mixture of components, the liquid in said spinning tube being at a temperature below the segregation temperature, and the fibre and the liquid being guided, in the same direction and at about the same, or at a slightly different linear velocity, through said spinning tube, the fibre being then removed from the said spinning tube under a slight tension, and the hollow fibre structure thus formed being washed with a solvent after solidification.

13. A hollow fibre membrane for plasmapheresis, comprising a porous, hollow fibre having a pore volume of at least 70%, an inside fibre diameter of between 100 and 550 µm, a wall thickness of between 15 and 300 µm, and a screen factor for human blood proteins, in the molecular weight range of about 60,000 to 3 million, of at least 0.7.

14. A membrane according to claim 13, wherein said hollow fibre is a polypropylene fibre.

15. A membrane according to claim 14, having a screen factor of between 0.9 and 1Ø

16. A membrane according to claim 15, having a screen factor of about 1 for human blood proteins in the molecular weight range of about 1 to 2.5 million.

17. A membrane according to claim 13, 14 or 16, having a pore volume of at least 80%.

18. A membrane according to claim 13, 14, or 16, having an inside diameter of between 250 and 450 µm.

19. A membrane according to claim 13, 14 or 16, having a wall thickness of between 100 and 200 µm.

20. A membrane according to claim 13, 14 or 15, which is impervious to blood cells.

21. A membrane according to claim 13, 14 or 15, having a filtrate flow of at least 1/5th of the flow of blood through a filter unit, containing the membrane, said filtrate flow being determined at a pressure difference of 0.1 bar.

22. A hollow fibre membrane for plasmapheresis comprising porous hollow fibres of polypropylene, impervious to blood cells, having a pore volume of at least 80%, an inside diameter of from 250 to 450 µm, a wall thickness of from 100 to 200 µm, and a screen factor of from 0.9 to 1.0 for human blood proteins having a molecular weight in the range from 60,000 to 3 million.

23. A membrane according to claim 22, wherein said fibres have a screen factor of about 1 for human blood proteins having a molecular weight in the range of 1 to 2.5 million.

24. A membrane according to claim 22 or 23, having a filtrate flow of at least 1/5th of the flow of blood through a filter unit, containing the membrane, said filtrate flow being determined at a pressure difference of 0.1 bar.

25. A method for separating macromolecules from biological cells in a liquid blood mixture containing both which comprises filtering said liquid blood mixture with a membrane as defined in claim 13 or 14.

26. A method for separating macromolucules from biological cells in a liquid blood mixture containing both which comprises filtering said liquid blood mixture with a membrane as defined in claim 22 or 23.

27. A method of plasma separation which comprises passing plasma through a membrane as defined in claim 13 or 14.

28. A method of plasma separation which comprises passing plasma through a membrane as defined in claim 22 or 23.