Abstract:
A process for the production of hydrophilic membranes using at least one hydrophobic polymer and polyvinyl pyrrolidone as a hydrophilic polymer, membrane-forming shaping of the polymers and immobilization of the polyvinyl pyrrolidone is characterized in that the polyvinyl pyrrolidone is immobilized on and/or in the membrane by treatment with an aqueous solution of peroxodisulphate in a hot condition. The solution of peroxodisulphate is kept substantially free of oxygen during immobilization by degassing the solution. The membranes are used for hemodialysis, hemodiafiltration and hemofiltration of blood.

Description:
This is a continuation-in-part of application Ser. No. 08/215,325, filed Mar. 18, 1994 now abandoned. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to processes for the production of hydrophilic membranes. More particularly, the present invention relates to processes for the production of hydrophilic membranes utilizing hydrophobic and hydrophilic polymers therefor. Still more particularly, the present invention relates to improved hydrophilic membranes, and their use in connection with processes such as hemodialysis, hemodiafiltration, and hemofiltration. 
     BACKGROUND OF THE INVENTION 
     Various publications, such as U.S. Pat. Nos. 3,615,024 and 3,691,068, and German laid-open application (DE-OS) No. 2,917,357, disclose hollow fibers and other membranes comprising a hydrophobic polymer. Such membranes, which are intended to be suitable for use in the hemodialysis, hemodiafiltration and hemofiltration of blood, cannot be wetted in the dry condition with water, so that they may either not be entirely dried, or they must be filled with a hydrophilic fluid, such as glycerin. 
     In order to eliminate the disadvantages of these requirements, and to improve the wettability, blood compatibility and diffusive permeability of these membranes, it is known to combine the hydrophobic polymers in the membrane with hydrophilic polymers, e.g., in European laid-open application Nos. 0,082,443; 0,168,782; and 0,305,787. In that respect, the hydrophobic polymers used are, for example, polysulphones, polyethersulphones, polycarbonates, polyaramides, polyamides, polyvinyl chloride, modified acrylic acid, polyethers, polyurethanes, polyacrylonitrile, polypropylene, polyetherimides, and copolymers thereof. In accordance with the above-mentioned patent specifications, the hydrophilic polymers used are polyvinylpyrrolidone, polyethyleneglycol, polyglycolmonoester, copolymers of polyethyleneglycol and polypropyleneglycol, cellulose derivatives, polysorbate and polyethylene-polypropyleneoxide copolymers. Polyvinylpyrrolidone is preferably used as the hydrophilic polymer. 
     Membranes of that type, in comparison with hydrophobic membranes, have the advantage of improved wettability with aqueous solutions, enhanced blood compatibility, and increased levels of diffusive permeability. There is, however, the problem that such membranes, upon reworking and use, gradually give off proportions of the hydrophilic polymer component, which, on the one hand, therefore results in a loss of the hydrophilic properties of the members; and, on the other hand, in medical use in vivo results in accumulation of the hydrophilic component, in particular polyvinylpyrrolidone, in the tissue of the patients. 
     In order to eliminate these disadvantages of hydrophilic membranes, the process of European laid-open application No. 0,261,734 immobilizes the hydrophilic polymer, such as polyvinylpyrrolidone, by cross-linking with heat treatment. Another known procedure is the cross-linking of polyvinylpyrrolidone with gel formation; for example, by irradiation with gamma rays. In that respect attention is directed, for example, to Macromol. Sci. Phys., B7 (2), pp. 209-244 (1973) . Also known is cross-linking by UV-irradiation (Poly. Sci. USSR, 11, p. 1638 [1968]) and chemical cross-linking (Tetrahedron, 19, pp. 1441-1454 [1963]). 
     In Journal of Applied Polymer Science 23, 2453 (1979) , the mechanism of cross-linking for PVP in solution with persulphate is disclosed as a radial reaction. Cross-linking is achieved by combining two macroradicals resulting in a polymeric gel which is virtually insoluble in the swollen condition. In this cross-linking reaction undesired byproducts are produced which may have reduced hemocompatibility. It has been found that OH-groups on surfaces of membranes produced in the known manner are contributing to increased complement activation in comparison with surfaces with OH-groups. 
     It is therefore the underlying object of the present invention to provide without undesired byproducts a process for the production of hydrophilic membranes using polyvinylpyrrolidone as a hydrophilic polymer, which give off the minimum amount (or none) of polyvinylpyrrolidone by virtue of extraction, and which exhibit improved efficiency. 
     SUMMARY OF THE INVENTION 
     In accordance with the present invention, these and other objects have now been accomplished by the invention of a process for the production of hydrophilic microporous membranes by forming the membrane from at least one hydrophobic polymer and a hydrophilic polymer comprising polyvinylpyrrolidone, the membrane being formed by membrane-forming shaping of the polymers, and immobilizing the polyvinylpyrrolidone on and/or in the membrane by treating the membrane with an aqueous peroxodisulphate-containing solution, which solution is kept substantially free of oxygen during the immobilizing reaction. This can be accomplished by, inter alia, either continuously degassing the solution, preferably by means of vacuum treatment or by adding an oxygen binding substance to said solution. The latter is preferably accomplished by adding ascorbic acid or other non-toxic compound which reacts substantially irreversably with oxygen to the solution. In this case, the concentration of the oxygen binding substance should range from between about 1.0 and about 10.0, and preferably between about 2.0 and about 6.0 percent by weight of the peroxodisulphate-containing solution. If a vacuum treatment is selected, then the presssure used should generally be below 40 mm Hg, depending upon such factors as temperature, concentration, and pH. Preferably, the oxygen content is kept lower than 0.1 ml O 2  per liter of said solution. 
     In accordance with one embodiment of the process of the present invention, the process includes forming the membrane from a mixture of the hydrophobic and hydrophilic polymers. In another embodiment, the hydrophilic polymer is provided by coating the membrane with polyvinylpyrrolidone prior to the immobilizing step. 
     In accordance with another embodiment of the process of the present invention, treating of the membrane with the aqueous peroxodisulphate-containing solution is carried out at an elevated temperature, generally between about 50° and below 80° C., and preferably between about 60° and 75° C. 
     In accordance with another embodiment of the process of the present invention, treating of the membrane with the aqueous peroxodisulphate-containing solution is carried out for a period of between more than 5 and 30 minutes, preferably between about 5 and 20 minutes, and most preferably for a period of about 10 minutes. 
     In accordance with another embodiment of the process of the present invention, treating of the membrane with the aqueous peroxodisulphate-containing solution utilizes a peroxodisulphate-containing solution having a peroxodisulphate concentration of between about 0.1 and below 5% by weight, preferably between about 1 and 3% by weight. 
     In accordance with a preferred embodiment of the process of the present invention, treating of the membrane with the aqueous peroxodisulphate-containing solution comprises flowing the peroxodisulphate-containing solution over the membrane, preferably at a flow rate of between about 100 and 300 ml/min., and most preferably at a flow rate of between about 150 and 300 ml/min. 
     In accordance with another embodiment of the present invention, applicants have discovered a hydrophilic membrane comprising at least one hydrophobic polymer and a hydrophilic polymer comprising polyvinylpyrrolidone, the membrane being free of undesired byproducts and the polyvinylpyrrolidone being immobilized on the membrane whereby the membrane is substantially free of extractable polyvinylpyrrolidone. In a preferred embodiment the membrane included less than about 15 mg of extractable polyvinylpyrrolidone per 20 grams of membrane, preferably less than about 2 mg of the extractable polyvinylpyrrolidone per 20 grams of membrane. 
     On an overall basis, the process of the present invention generally takes place in the following manner: the hydrophobic and hydrophilic polymers to be used are dried and then dissolved in a suitable solvent, such a N-methylpyrrolidone. The polymer solution is then filtered and spun in the usual manner, employing the known phase inversion process to give hollow fibers, or cast in order to provide membranes in sheet form. When reference is made to membranes in this description, that term is also intended to include hollow fiber membranes. 
     The membrane is then possibly pre-coated with polyvinylpyrrolidone and rinsed. The immobilization step according to the present invention then follows. This is accomplished by treatment of the membrane with a peroxodisulphate solution in a hot condition, whereafter rinsing is again effected. When using polyethersulphone or polyaramide as the hydrophobic polymer, steam sterilization is then effected, whereupon the membrane is dried and is then ready for installation in a casing. In the case of hollow fibers, they are cast in a casing by means of polyurethane. 
    
    
     DETAILED DESCRIPTION 
     The hydrophobic and hydrophilic polymers to be utilized for the preparation of the membranes hereof can be used in quantitative ratios which are known from the state of this art. Desirably, the procedure uses from about 80 to 99.5% by weight of the hydrophobic polymer or polymers, and from about 0.5 to 20% by weight, and preferably from about 0.5 to 10% by weight, of the hydrophilic polymer or polymers, of which one comprises polyvinylpyrrolidone. 
     The hydrophobic and hydrophilic polymers can therefore be used in a mixture for production of the membranes according to the present invention. The membrane of hydrophobic polymer, or of a mixture of hydrophobic and hydrophilic polymer, can be coated with polyvinylpyrrolidone. 
     The hydrophobic polymers to be used in accordance with the present invention are those which are also used for membranes in accordance with the state of the art, such as polysulphone, polyethersulphone, polyaramide, polycarbonate, polyamide, polyvinyl chloride, modified acrylic acid, polyether, polyurethane, polyacrylonitrile, polypropylene, polyetherimide, and mixed polymers of these polymers. Preferred hydrophobic polymers are polysulphone, polyethersulphone, polyaramide and polyamide. 
     A hydrophilic polymer which is necessarily used in accordance with the present invention is polyvinylpyrrolidone. In addition to polyvinylpyrrolidone, however, it is also possible to use other hydrophilic polymers which are known to be useful for the production of membranes, such as polyethyleneglycol, polyglycolmonoester, copolymers of polyethyleneglycol with polypropyleneglycol, water-soluble cellulose derivatives, polysorbate and polyethylene-polypropylene oxide copolymers. 
     The polyvinylpyrrolidone used in accordance with this invention preferably has a molecular weight (weight-average) of at least about 8000 daltons, wherein the molecular chains comprise repetitive structural units of the following formula: ##STR1## in which n is greater than 120. 
     In order to produce membranes therefrom, the polymers are dissolved in a suitable solvent, such as dimethylformamide, N-methylpyrrolidone or dimethylacetamide. N-methylpyrrolidone is preferred. Precipitation of the membrane occurs in a precipitation path from pure water or a mixture of water with N-methylpyrrolidone or dimethylsulphoxide. The temperature of the precipitation bath is desirably between about 18° and 65° C. The membranes obtained are usually of a thickness in the range of from about 45 to 50 μm. 
     Immobilization of the polyvinylpyrrolidone in order to prevent portions of this component from being extracted in the rising operation, and in subsequent use, is effected with a aqueous solution of at least one peroxodisulphate, with heating and degassing by vacuum treatment. Desirably, K 2  S 2  O 8 , Na 2  S 2  O 8  or (NH 4 ) 2  S 2  O 8  are used as the peroxodisulphates. The temperature of the peroxodisulphate solution during treatment of the membrane is preferably in the range of from about 50° to below 80° C., preferably in the range of from about 60° to 75° C. The treatment time is usually in the range of from more than 5 to 30 minutes, preferably in the range of from about 5 to 20 minutes, and in particular of the order of magnitude of about 10 minutes. A dilute peroxodisulphate solution is used for the treatment, desirably with a concentration of from about 0.1 to below 5% by weight, preferably from about 1 to 3% by weight. Preferably, the pH of the solution is kept at pH 4 to 7 by the addition of alkali. The peroxodisulphate solution is preferably passed over, or in the case of hollow fibers through, the membranes, more specifically usually at a flow rate of from about 100 to 300 ml/min, preferably from about 150 to 200 ml/min. 
     In a particularly preferred embodiment in accordance with the present invention, sodiumperoxodisulphate in a concentration of 3 percent in water is used having a pH of 4.9. The immobilizing treatment is conducted at 65° C. during 15 minutes residence time at a vacuum of about 40 mm Hg. 
     After this immobilization treatment is completed, the membranes are preferably rinsed with deionized water, and then dried with air at 45° C., and with a water content of less than about 1 g/m 3  until the weight is constant. 
     The following procedure is usually employed for determining the extractable polyvinylpyrrolidone contents: the sheet membranes or hollow fibers to be investigated, with a dry weight of from about 0.5 to 20 g, are cut into pieces and treated with deionized water for 16 hours at 60° C. in a defined volume. In the extract, the concentration of polyvinylpyrrolidone is measured using the procedure described by K. Muller (Pharm. Acta. Helv. 42, p. 107 [1968]) and J. Breinlich (Pharm. Ztg. 118 [12], p. 330 [1973]). The extractable amount of polyvinylpyrrolidone is converted to the polyvinylpyrrolidone overall weight of the polymer of the dry membrane of 20 g. 
     The membranes produced in accordance with the present invention are particularly suitable as membranes for medical purposes, in particular for hemodialysis, hemodifiltration and hemofiltration of blood, since as a result of the effective immobilization of the polyvinylpyrrolidone in accordance with this invention, the membranes not only substantially maintain their efficiency, but they also do not give off any polyvinylpyrrolidone into the tissue of the patient. 
     In the following Examples, the membrane properties listed below were all measured at 37° C. 
     Furthermore, the following have the specified definitions: 
     Lp 1: Hydraulic permeability for pure water (10 -4  cm/s/bar), measuring method as described in &#34;Evaluation of Hemodialysis and Dialysis Membranes,&#34; NIH-publication 77-1294 (1977). 
     Lp (Alb): Hydraulic permeability for a 6% albumin solution (10 -4  cm/s/bar), measuring method as described in &#34;Evaluation of Hemodialysis and Dialysis Membranes,&#34; NIH-publication 77-1294 (1977). 
     Lp 2: Hydraulic permeability for pure water after the Lp-(Alb)-measurement (10 -4  cm/s/bar), measuring method as described in &#34;Evaluation of Hemodialysis and Dialysis Membranes,&#34; NIH-publication 77-1294 (1977). 
     P (C1): Diffusive Permeability for a 0.9% NcCl-solution (cm/s×10 -4  ), measuring method as described in &#34;Evaluation of Hemodialysis and Dialysis Membranes,&#34; NIH-publication 77-1294 (1977) . 
     SK (Myo): Sieve coefficient for a 0.002% myoglobin solution after 15 minutes (%), measuring method in accordance with DIN 58 353 , part 2 C 3, 1988. 
     SK (Alb): Sieve coefficient of a 6% albumin solution after 15 minutes (%), measuring method in accordance with DIN 58 343, part 2 C 3, 1988. 
     Moreover, in the following Examples 1 to 8 , the treatment according to the invention was the following immobilizing treatment. In the event of the use of sheet membranes, the membranes were submerged during a special residence time in the peroxodisulphate-containing solution, whereas in the event of the use of hollow fiber membrane bundles, the peroxodisulphate-containing solution was pumped through a bundle of hollow fiber membranes having a surface of the total bundle of 1.4 m 2 . The solution was pumped through the hollow fibers with a velocity of 200 ml/min. In all examples as peroxodisulphate sodiumperoxodisulphate Na 2  S 2  O 8  was used, the pH value was adjusted by addition of NaOH. 
     The following parameters have been used in the Examples 1 through 8: 
     
         ______________________________________  1    2      3      4    5    6    7    8______________________________________Temperature    75     50     65   75   75   75   65   65of the solu-tion, °C.Concentra-    2.5    5      3.5  2.5  2.5  2.5  3    3tion of thesolution, %Residence    12     20     15   12   12   12   15   15time, min.pH       5      6.5    5.5  5    5    5    4.9  4.8Vacuum, mm    40     30     40   40   40   40   40   40Hg______________________________________ 
    
     EXAMPLES 
     Example 1 
     Sheet membrane from a spinning solution with 14% polyethersulphone and 4% polyvinylpyrrolidone (PVP) in N-methylpyrrolidone, precipitated in pure water at 18° C. 
     
         ______________________________________         Extractable PVPMembrane type (mg/filter)   Lp1     P (Cl)______________________________________untreated     320            7      10.9treated according to the         &lt;2            10      11.3invention______________________________________ 
    
     Example 2 
     Sheet membranes from a spinning solution with 11% polyamide and 3% PVP in N-methylpyrrolidone, precipitated in pure water at 18° C. 
     
         ______________________________________         Extractable PVPMembrane type (mg/filter)   Lp1     P (Cl)______________________________________untreated     104            4      4.2treated according to the          6            120     4.5invention______________________________________ 
    
     Example 3 
     Sheet membranes from a spinning solution with 11% polyaramide, 3% PVP and 1 to 4% CaCl 2  in N-methylpyrrolidone, precipitated in a mixture of 70% water and 30% N-methylpyrrolidone at 65° C. 
     
         ______________________________________         Extractable PVPMembrane type (mg/filter)   Lp1     P (Cl)______________________________________untreated     35            15      10.3treated according to the          2            15      13.3invention______________________________________ 
    
     Example 4 
     Hollow fiber membrane bundle with 100 fibers from a spinning solution with 14% polyethersulphone and 11% PVP in N-methylpyrrolidone, precipitated with a centrally through-flowing precipitation bath comprising 50% water, 25% dimethylsulphoxide and 25% N-methylpyrrolidone at 60° C. 
     
         __________________________________________________________________________     Lp (Alb)  P (Cl)                   SK   SK  ExtractedMembrane Lp 1     (10.sup.-4 cm/-           Lp 2               (10.sup.-4                   (Myo) 15                        (Alb)                            PVP (mg/-type  (H.sub.2 O)     s/bar)           (H.sub.2 O)               cms)                   min (%)                        (%) filter)__________________________________________________________________________untreated 120 4.5   67  13.6                   73   2.2 30-50treated 290 5.4   99  15.1                   93   8.2 &lt;1accordingto theinvention__________________________________________________________________________ 
    
     Example 5 
     Hollow fiber membrane bundle with 100 fibers from a spinning solution with 12% polyethersulphone and PVP in N-methylpyrrolidone, precipitated with a precipitation bath comprising 70% waster and 30% N-methylpyrrolidone at 60° C. 
     
         __________________________________________________________________________     Lp (Alb)  P (Cl)                   SK   SK  ExtractedMembrane Lp 1     (10.sup.-4 cm/-           Lp 2               (10.sup.-4                   (Myo) 15                        (Alb)                            PVP (mg/-type  (H.sub.2 O)     s/bar)           (H.sub.2 O)               cms)                   min (%)                        (%) filter)__________________________________________________________________________untreated 20  4.9   21  16.5                   26   0.4 30-50treated 32  4.3   21  13.5                   94   1.3 &lt;1accordingto theinvention__________________________________________________________________________ 
    
     Example 6 
     Hollow fiber membrane bundle with 100 fibers from a spinning solution with 14% polyethersulphone and 5% PVP in N-methylpyrrolidone, precipitated with a precipitation bath comprising 55% water and 45% N-methylpyrrolidone at 60° C. 
     
         __________________________________________________________________________     Lp (Alb)  P (Cl)                   SK   SK  ExtractedMembrane Lp 1     (10.sup.-4 cm/-           Lp 2               (10.sup.-4                   (Myo) 15                        (Alb)                            PVP (mg/-type  (H.sub.2 O)     s/bar)           (H.sub.2 O)               cms)                   min (%)                        (%) filter)__________________________________________________________________________untreated 120 4.5   64  15.1                   84   1.3 31treated 420 5.8   90  13.0                   95   6.6 &lt;1accordingto theinvention__________________________________________________________________________ 
    
     Example 7 
     Sheet membranes from a spinning solution with 14% polyethersulphone and 7% PVP in N-methylpyrrolidone, precipitated in a precipitation bath comprising 70% water and 30% N-methylpyrrolidone at 65° C. 
     
         ______________________________________         Extractable PVPMembrane type (mg/filter)   Lp 1    P (Cl)______________________________________Immobilized according         &lt;1            110     10.1to the invention withoutpreliminary PVP coatingImmobilized according         &lt;1             10     15.3to the invention with apreliminary coating ofa 5% PVP-solution______________________________________ 
    
     Example 8 
     Sheet membranes from a spinning solution with 14% polyethersulphone and 4% PVP in N-methylpyrrolidone, precipitated in a precipitation bath comprising 70% water and 30% N-methylpyrrolidone at 65° C. 
     
         ______________________________________         Extractable PVPMembrane type (mg/filter)   Lp 1    P (Cl)______________________________________Immobilized according         20            12.0    &lt;1to the invention withoutpreliminary PVP coatingImmobilized according         11            11.4    5-15to the invention with apreliminary coating ofa 2% PVP-solutionImmobilized according          1            11.3    5-15to the invention with apreliminary coating ofa 5% PVP-solution______________________________________ 
    
     Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.