The expression "plasmapheresis" is intended to mean a blood separation procedure in which blood cells are separated from plasma by means of a membrane which is permeable to the plasma but which retains, i.e., is not permeable, to the blood cells. Such a procedure differs from other similar types of blood separation procedures, such as hemofiltration, with respect to the cut-off point with regard to the passage of molecules for the specific membrane which is utilized therein. In hemofiltration, for example, that cut-off point is usually of the order of magnitude of 10.sup.3 -5.times.10.sup.4 Dalton, while the corresponding cut-off point in connection with plasmapheresis is about 3.times.10.sup.6 Dalton.
In the literature various membranes (as well as processes for their preparation) are described which are of the above-mentioned kind. For example, in Trans. Am. Soc. Artif. Inter. Org. 1978, pp. 21-26 the use of a hydrophobic polycarbonate membrane having pores which are formed through neutron radiation and etching in association therewith is described. This membrane displays a regular pore structure, but has a low porosity. Furthermore, the pore openings comprise a sharp edge which may cause the destruction of blood cells (hemolysis), when such membranes are used in plasmapheresis. Furthermore, due to its low porosity as well as the polymeric characteristics thereof, said membrane also has a low filtration capacity, such as about 0.004 ml/sec. x at x cm.sup.2.
In the above-noted article, as well as in DE-OS 22 57 697 and DE-OS 28 28 616, plasmapheresis membranes which are prepared from cellulose acetate are described, both in the form of hollow fibers and in the form of flat sheets. Again, however, there is also a risk of hemolysis with these membranes. A further disadvantage in connection with these prior membranes is the fact that they have a low permeability for substances having molecular weights of between 1.times.10.sup.6 and 3.times.10.sup.6 Dalton. For example, the permeability coefficient for factor VIII (having a molecular weight of 2.times.10.sup.6) is as low as 0.2-0.4. Furthermore, the Nieviny coefficient for high molecular weight substances (above about 500,000 Dalton) drastically decreases after filtrations for about 15 to 30 minutes.
In British Pat. No. 1,556,898 a polycarbonate membrane is described for use in hemodialysis. These hemodialysis membranes are prepared from polymers having recurring units of the formula ##STR1## in which A can be --CH.sub.2 CH.sub.2 O-- or --CH.sub.2 CH.sub.2 O-- and/or --C.sub.3 H.sub.6 O--, etc. The membranes discussed in this patent are useful in connection with hemodialysis, and thus by definition must have pore sizes which are quite small and which can only pass molecular sizes of up to about 20,000 Dalton. Specifically, they have pore sizes of up to about 0.008.mu. (about 80 .ANG.), i.e., between about 0.002 and 0.008.mu.. Furthermore, these membranes have hydraulic permeabilities generally of between about 2 and 6 ml/hr/m.sup.2 /mmHg. Furthermore, the membranes set forth in this patent are prepared by a wet phase inversion technique employing an aqueous gelation system with water as the gelling medium and a water-miscible organic solvent as the casting solvent. These polycarbonate membranes are thus prepared by casting a layer of the polyether-polycarbonate block copolymer onto a smooth substrate surface with a water-miscible organic solvent, together with a co-solvent which acts as a swelling agent for the copolymer, then drying that layer to partially evaporate the solvents and immersing the partially dried layer in water to form a gelled membrane which can then be stripped from the substrate surface. The preferred solvents used therein are 1,3-Dioxolane, 1,3-Dioxan, 1,4-Dioxan, dimethyl formamide, pyridine, and several others. The additional swelling agents can include dimethyl formamide, dimethyl acetamide, acetamide, formamide, pyridine, etc.
In the procedure set forth in patents such as the above-noted British patent, the evaporation step is important to partially remove the solvent and form a dense membrane structure. The membrane can then be immersed in the water bath to both gell and precipitate same, and during this entire procedure the solvent is completely removed from the membrane.
Furthermore, in a recent patent application, Ser. No. 257,929, filed on Apr. 23, 1981 assigned to Gambro Inc., modified polycarbonate membranes are disclosed for use in hemofiltration processes. These membranes are similar to those set forth above, but are produced by a process which permits the membrane to be used in hemofiltration processes, and have ultrafiltration rates of at least about 7 ml/hr/m.sup.2 /mmHg. These membranes, like those of the aforementioned British patent, have pore sizes of up to about 0.008.mu., i.e. between about 0.002 and 0.008.mu.. In the procedure disclosed in this co-pending application, the layer of polyether-polycarbonate block copolymer and water-miscible organic solvent are again dried by partial evaporation of the solvent subsequent to casting, and prior to immersion in water to gell the membrane. In one embodiment of that invention, an aqueous solution of an oxidizing agent is contacted with the membrane either subsequent to gelation or as part of the gelation process itself, while in yet another embodiment subsequent to gelation and precipitation of the membrane the gelled membranes are treated with swelling agents, such as glycerine or other polyols or polyethylene glycols, and/or mixtures of these compounds with various alcohols.
One of the objects of the present invention is therefore to provide a microporous membrane of a biocompatible polymer comprising a hydrophilic polycarbonate for use in plasmapheresis, which in contrast to the above-noted prior art membranes displays a regular pore structure comprising smoothly rounded pore openings without sharp edges. Furthermore, it is another object of this invention to provide such membranes having a high permeability or filtration capacity for high molecular substances of up to 3.times.10.sup.6 Dalton, to therefore also provide a high filtration rate for plasma, without drastically decreasing permeability coefficients.
A further object of this invention is to provide a process for the preparation of such an improved membrane for plasmapheresis.