Source: http://www.google.com/patents/US5139529?dq=6,757,682
Timestamp: 2016-06-27 17:40:59
Document Index: 780876312

Matched Legal Cases: ['art 65', 'art 65', 'art 67', 'art 67', 'art 67', 'art                48']

Patent US5139529 - Porous polypropylene membrane and methods for production thereof - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsA porous polypropylene hollow fiber membrane is disclosed which is characterized by the fact that the solid phase in the inner surface region thereof is formed with particles of polypropylene closely fused and joined to give rise to a continuous phase while partially exposed through the surface thereof,...http://www.google.com/patents/US5139529?utm_source=gb-gplus-sharePatent US5139529 - Porous polypropylene membrane and methods for production thereofAdvanced Patent SearchPublication numberUS5139529 APublication typeGrantApplication numberUS 07/392,988PCT numberPCT/JP1988/000039Publication dateAug 18, 1992Filing dateJan 20, 1988Priority dateJan 20, 1987Fee statusPaidAlso published asDE3855721D1, DE3855721T2, EP0341309A1, EP0341309A4, EP0341309B1, US5354470, WO1988005475A1Publication number07392988, 392988, PCT/1988/39, PCT/JP/1988/000039, PCT/JP/1988/00039, PCT/JP/88/000039, PCT/JP/88/00039, PCT/JP1988/000039, PCT/JP1988/00039, PCT/JP1988000039, PCT/JP198800039, PCT/JP88/000039, PCT/JP88/00039, PCT/JP88000039, PCT/JP8800039, US 5139529 A, US 5139529A, US-A-5139529, US5139529 A, US5139529AInventorsYukio Seita, Shoichi Nagaki, Ken Tatebe, Kousuke KidoOriginal AssigneeTerumo Kabushiki KaishaExport CitationBiBTeX, EndNote, RefManPatent Citations (9), Referenced by (30), Classifications (22), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetPorous polypropylene membrane and methods for production thereof
As an amendment of such drawbacks as mentioned above, there has been proposed a porous polyolefin hollow fiber membrane produced by a process which comprises mixing polypropylene, an organic filler uniformly dispersible in the polypropylene while the polypropylene is in a molten state and readily soluble in an extractant to be used later, and a crystalline core forming agent, discharging the resultant mixture in a molten state through annular spinning orifices thereby forming hollow threads, cooling and solidifying the hollow threads by contact with a liquid of the aforementioned organic filler or a compound similar thereto, and then bringing the cooled and solidified hollow threads into contact with the extractant incapable of dissolving the polypropylene thereby removing the aforementioned organic filler from the hollow threads by extraction (Japanese Patent Application SHO 61(1986)-155,159). The hollow fiber membrane which is obtained by this method is free from the drawbacks enumerated above. During the course of cooling, however, the organic filler or the cooling and solidifying liquid is locally deposited on the outermost surfaces of the hollow fibers which have not yet been thoroughly cooled and solidified, to lower the ratio of distribution of the polypropylene composition on the outermost surfaces and consequently enlarge the pores in the outer surfaces of the hollow fibers and cause the polypropylene to continue in the form of a heavily rugged network. When the hollow fibers of this nature are used in an artificial lung of the type adapted to pass blood inside the hollow fibers and blow an oxygen-containing gas outside the hollow fibers to effect addition of oxygen to the blood and removal of carbon dioxide gas from the blood, no problem is raised. Conversely when the hollow fibers are used in an artificial lung of the type adapted to flow blood outside the hollow fibers and blow an oxygen-containing gas inside the hollow fibers, they entail a disadvantage that the outer surface of the hollow fibers, owing to their quality described above, inflict an injury on the blood cells and aggravate the pressure loss. Further, the artificial lung using such a hollow fiber membrane as described above, without reference to the choice between the two types of artificial lung, has a disadvantage that during the course of assembly of the artificial lung, the individual hollow fibers conglomerate to impair the workability thereof and jeopardize the effect of potting.
As concerns permeable membranes for use in the blood plasma separation, polyolefin type macromolecules have been attracting attention as materials experiencing activation of complements only to a nominal extent and excelling in bio-adaptability. At present, studies are underway on the feasibility of permeable membranes using such polyolefin type macromolecules. For example, there has been disclosed a method for the production of a porous membrane, which comprises preparing a molten mixture consisting of 10 to 80% by weight of a paraffin and 90 to 20% by weight of a polypropylene resin, extruding the molten mixture through a die in the form of a film, a sheet, or a hollow fiber, suddenly solidifying the molten extruded mixture in water kept at a temperature of not more than 50� C, and then separating the paraffin from the shaped article by extraction (Japanese Patent Unexamined Publication SHO 55(1980)-60,537). The porous membrane which is obtained by this method, however, does not fit speedy blood plasma separation because the membrane has been suddenly cooled with water, a substance of a large specific heat, and, as the natural consequence, the pores formed in the surfaces and those formed in the interior of the membrane have small diameters and the porosity is low and the speed of permeation is proportionately low.
As means of cooling and solidifying the aforementioned molten mixture, there has been proposed a method which uses a metallic roller and a method which uses a cooling and solidifying liquid such as a paraffin possessing highly desirable compatibility with the aforementioned organic filler (Japanese Patent Application SHO 60(1985)-237,069). The former method produces a porous membrane which possesses surface pores of an extremely small diameter and, therefore, passes blood plasma only at a low speed. In the latter method, since the cooling and solidifying liquid has a small specific heat as compared with water and, therefore, promotes the crystallization of polypropylene at a proper cooling rate, the membrane is enabled in the interior thereof to form micropores of a diameter large enough for the purpose of blood plasma separation and is suffered in the surface regions thereof to form a very large reticular structure which is believed to arise because the polypropylene in the surface regions is dissolved out into the cooling and solidifying liquid before it is allowed to solidify. In the porous membrane possessing such surface layers as described above, the surface layers each function as a prefilter. Thus, the porous membrane is capable of carrying out the blood plasma separation at a highly desirable speed without suffering proteins and blood cells to clog the micropores. When this porous membrane is brought into contact with blood, however, it is liable to occlude blood cells, which may possibly be forced to liberate homoglobin under application of pressure.
This invention also discloses a porous polypropylene hollow fiber membrane, wherein the index of birefringence thereof in the direction of axis is in the range of 0.001 to 0.01. This invention further discloses a porous polypropylene hollow fiber membrane, wherein the porosity thereof is in the range of 10 to 60% and the aperture ratio of the inner surface region thereof is in the range of 10 to 30% and the oxygen gas flux is in the range of 100 to 1,500 liters/min.m2.atm. This invention further discloses a porous polypropylene hollow fiber membrane, wherein the inside diameter is in the range of 150 to 300μm and the wall thickness in the range of 10 to 150μm. This invention also discloses a porous polypropylene hollow fiber membrane, wherein the average diameter of the particles of polypropylene is in the range of 0.1 to 2.0μm and the average diameter of the pores in the inner surface region is in the range of 0.1 to 1.0 μm. This invention further discloses a porous polypropylene hollow fiber membrane, wherein the membrane used in an artificial lung is substantially free from leakage of blood plasma or degradation of gas-exchange capacity within 30 hours of service. Further this invention discloses a porous polypropylene hollow fiber membrane, wherein the membrane used in an artificial lung sparingly inflicts injury on blood cells.
This invention also discloses a method for the production of a porous polypropylene hollow fiber membrane, wherein silicone oil or polyethylene glycol is used as the cooling and solidifying liquid. This invention also discloses a method for the production of a porous polypropylene hollow fiber membrane, wherein silicone oil possesses viscosity in the range of 2 to 50 cSt at 20� C. This invention also discloses a method for the production of a porous polypropylene hollow fiber membrane, wherein polyethylene glycol possesses an average molecular weight in the range of 100 to 400. This invention further discloses a method for the production of a porous polypropylene hollow fiber membrane, wherein liquid paraffin is used as the organic filler. This invention further discloses a method for the production of a porous polypropylene hollow fiber membrane, wherein the amount of the organic filler to be incorporated is in the range of 35 of to 150 parts by weight, based on 100 parts by weight of polypropylene. This invention also discloses a method for the production of a porous polypropylene hollow fiber. membrane, wherein the crystalline seed forming agent is an organic heat-resistant substance possessing a melting point of not less than 150� C. and a gelling point not less than the crystallization starting point of polypropylene. Further, this invention discloses a method for the production of a porous polypropylene hollow fiber membrane, wherein the amount of the crystalline seed forming agent to be incorporated is in the range of 0.1 to 5 parts by weight, based on 100 parts by weight of polypropylene.
The objects described above are further accomplished by an artificial lung provided with a hollow fiber membrane as a gas-exchange membrane, characterized by the fact that the hollow fiber membrane is a porous polypropylene hollow fiber membrane wherein the solid phase in the inner surface region thereof is formed with particles of polypropylene closely fused and joined to give rise to continuous phase while partially exposed through the surface thereof, the solid phase in the interior and the outer surface region thereof is formed with particles of polypropylene interconnected in the direction of axis of fiber to give rise to a multiplicity of lumps of polypropylene, and the interstices between these solid phases have continuous pores interconnected in the form of a three-dimensional network.
This invention also discloses a flat-film type porous polypropylene membrane, wherein the bubble point of the membrane is not more than 1.8 kgf.cm2. This invention further discloses a flat-film type porous polypropylene membrane, wherein the water permeability is not less than 140 ml/min.mmHg.m2. Further this invention discloses a flat-film type porous polypropylene membrane, wherein the shrinkage ratio after 120 minutes' heat treatment at 121� C. is not more than 6.0%.
This invention also discloses a method for the production of a flat-film porous polypropylene membrane, wherein the porous polypropylene membrane obtained after the aforementioned removal of the organic filler by extraction is fixed in a prescribed length is subjected to a heat treatment at a temperature in the range of 110� to 140� C. This invention further discloses a method for the production of a flat-film type porous polypropylene membrane, wherein the contact of the molten membrane with the cooling and solidifying liquid is effected by disposing a guide roller in the cooling and soldifying liquid, allowing part of the guide roller to emerge from the surface of the cooling and solidifying liquid, discharging the aforementioned mixture onto the guide roller, and allowing the mixture to be led into the cooling and solidifying liquid by the rotation of the guide roller. Further this invention discloses a method for the production of a flat-film type porous polypropylene membrane, wherein the cooling and solidifying liquid is a polyether. This invention also discloses a method for the production of a flat-film type porous polypropylene membrane, wherein the polypropylene is a polypropylene possessing a melt index in the range of 5 to 40 and having mixed therewith 0 to 50% by weight of a polypropylene possessing a melt index in the range of 0.05 to 5. This invention also discloses a method for the production of a flat-film type porous polypropylene membrane, wherein the crystalline seed forming agent is incorporated therein in an amount in the range of 0.1 to 1.0 part by weight. This invention further discloses a method for the production of a flat-film type porous polypropylene membrane, wherein the crystalline seed forming agent is an organic heat-resistant substance possessing a melting point of not less than 150� C. and a gelling point of not less than the crystallization starting point of the polypropylene. Further, this invention discloses a method for the production of a flat-film type porous polypropylene membrane, wherein the extractant is a halogenated hydrocarbon or a mixture of the halogenated hydrocarbon with a ketone.
FIGS. 1 through 6 are electron microscope photographs illustrating textures of porous polypropylene hollow fiber membranes of the present invention.
FIGS. 7 through 19 are electron microscope photographs illustrating textures of conventional porous hollow fiber membranes.
FIG. 20 is a schematic cross section of an apparatus to be used for the method of production of a porous polypropylene hollow fiber membrane the present invention.
FIG. 21 is a semi-cross section illustrating a typical hollow fiber membrane type artificial lung as one embodiment of this invention.
FIG. 22 is a cross section illustrating portions of the artificial lung relative to the hollow fiber membrane filling ratios.
FIG. 23 is a schematic diagram illustrating a typical apparatus to be used in working the method of production of flat-film type porous polypropylene membrane of this invention.
FIG. 24 is a circuit diagram for the measurement of the highest blood plasma separation speed.
FIGS. 25 and 26 are electron microscope photographs illustrating textures of typical flat-film type porous polypropylene membranes of the present invention.
FIGS. 27 and 28 are electron microscope photographs illustrating textures of flat-film-type porous membranes used for comparative experiments.
FIG. 29 is a graph showing the relation between the blood plasma separation speed (Qf) and the total membrane pressure (T.M.P.).
FIG. 30 is a graph showing the relating between the total membrane pressure and the amount of free hemoglobin (ΔHb).
FIG. 31 a through c illustrate relations of permeation of various components of blood plasma vs the blood plasma separation speed (Qf).
FIGS. 29 through 31C illustrate the data of Example 3 with blank cycles (◯) and the data of Control 5 with solid circles ( )
For the porous polypropylene hollow fiber membrane of this invention to be advantageously used in an artificial lung, the porosity is required to fall in the range of 10 to 60%, preferably 30 to 55%, the aperture ratio of the inner surface in the range of 10 to 30%, preferably 12 to 20%, and the oxygen gas flux in the range of 100 to 1,500 liters/min.m2.atm, preferably 300 to 800 liters/min.m2.atm. If the porosity is less than 10%, the membrane has the possibility of exhibiting an insufficient gas-exchange capacity. Conversely if the porosity exceeds 60%, the membrane has the possibility of leaking blood plasma. If the aperture ratio is less than 10%, the membrane has the possibility of exhibiting an insufficient gas-exchange capacity because of insufficient formation of continuous pores in the part of pores of the membrane. Conversely, if the aperture ratio exceeds 30%, the membrane has the possibility of suffering from leakage of blood plasma because of the lack of the complexity of continuous pores. If the oxygen gas flux deviates from the range of 100 to 1,500 liters/min.m2.atm, the membrane has the possibility of failing to fulfill the function as a gas-exchange membrane. The sizes and distribution degrees of the particles of polypropylene and the continuous pores, i.e. the interstices between the adjacent particles of polypropylene, which make up the porous polypropylene hollow fiber membrane of the present invention can be controlled to their respectively desirable conditions by the production conditions of the membrane and the composition of raw materials used therefor. Generally, the particles of polypropylene are required to possess an average diameter in the range of 0.1 to 2.0 μm, preferably 0.2 to 1.5 μm and the pores opening in the inner surface to possess an average diameter in the range of 0.1 to 1.0 μm, preferably 0.3 to 0.6 μm.
The porous polypropylene hollow fiber described above is produced, for example, as follows. As illustrated in FIG. 20, a mixture 11 of polypropylene, an organic filler, and a crystalline seed forming agent is fed through a hopper 12 into a kneader such as, for example, a uniaxial extruding machine 13, there to be fused, blended, and extruded. Then, the extruded mixture is forwarded to a spinning device 14, discharged through an annular spinning orifice (not shown) of a spinneret 15 into a gaseous atmosphere such as, for example, air. A hollow thread 16 emanating from the spinneret 15 is introduced into a cooling tank 18 filled with a cooling and solidifying liquid 17, and cooled and solidified by contact with the cooling and solidifying liquid 17. In this case, the contact of the hollow thread 16 and the cooling and solidifying liquid 17 is desired to be effected by causing the aforementioned cooling and solidifying liquid 17 to flow down the interior of a cooling and solidifying liquid flow tube 19 disposed as directed downwardly through the bottom of the aforementioned cooling tank 18 as illustrated in FIG. 20 and allowing the aforementioned hollow thread 16 to fall down along the flow of the cooling and solidifying liquid and come into parallel contact therewith. The cooling and solidifying liquid 17 which has flowed down is received and stored in a solidifying tank 20. The hollow thread 16 is vertically introduced into the solidifying tank 20 and caused to change to course of travel by a deflection bar 21 so as to be solidified through ample contact therewith. The cooling and solidifying liquid 16 accumulating in the solidifying tank 20 is discharged via a circulation line 23 and circulated by a circulation pump 24 to the aforementioned cooling tank 18. Subsequently, the solidified hollow thread 16 is led to a shower conveyor type extruding machine 27 onto which an extractant 25 capable of dissolving the aforementioned organic filler and incapable of dissolving the polypropylene is dropped in the form of shower. In this extruding machine 27, the hollow thread 16 is brought into ample contact with the extractant and consequently deprived of the remaining organic filler while it is being advanced on a belt conveyor 26. The hollow thread which is led out of the extruding machine 27 by a drive roll 22, when necessary, is passed through the steps of re-extraction and heat treatment for drying and is finally taken up in a roll.
The polypropylene to be used as one of the raw materials for this invention need not be limited to homopolymer of propylene. It may be a block polymer using propylene as the main component and additionally incorporating therein another monomer. The polypropylene is required to possess a melt index (M.I.) in the range of 5 to 70, preferably 10 to 40. In the various forms of polypropylene mentioned above, the homopolymer of propylene proves to be .particularly desirable. In the various species of homopolymer of propylene, that which has a high degree of crystallinity proves to be most desirable.
The organic filler is required to be uniformly dispersible in the polypropylene which is in a molten state and to be easily soluble in an extractant to be used later. Examples of the filler which fulfills this requirement include liquid paraffin (number average molecular weight 100 to 2,000), α-olefin oligomers [such as, for example, ethylene oligomer (number average molecular weight 100 to 2,000), propylene oligomer (number average molecular weight 100 to 2,000), and ethylene oligomer (number average molecular weight 100 to 2,000)], paraffin wax (number average molecular weight 200 to 2,500), and various hydrocarbons. In the organic fillers enumerated above, the liquid paraffin proves to be particularly desirable.
The crystalline seed forming agent to be included in the raw materials for this invention is an organic heat-resistant substance possessing a melting point of not less than 150� C. (preferably in the range of 200� to 250� C.) and a gelling point of not less than the crystallization starting point of polyolefin. The crystalline seed forming agent of this description is used as one of the raw materials for the purpose of causing contraction of the particles of polypropylene thereby narrowing the interstices namely the continuous pores between the particles and heightening the pores density. As examples of the crystalline seed forming agent, there can be cited 1,3,2,4-dibenzylidene sorbitol, 1,3,2,4-bis(p-methylbenzylidene) sorbitol, 1,3,2,4-bis(p-ethylbenzylidene) sorbitol, bis(4-t-butylphenyl) sodium phosphate, sodium benzoate, adipic acid, talc and kaolin.
Among other crystalline seed forming agents cited above, benzylidene sorbitols, especially 1,3,2,4-bis(p-ethylbenzylidene) sorbitol and 1,3,2,4-bis(p-methylbenzylidene) sorbitol prove to be particularly desirable because they are not significantly dissolved in the blood.
The mixture of raw materials prepared as described above is fused and blended in a uniaxial extruding machine, for example, at a temperature in the range of 160� C. to 250� C., preferably 180� to 220� C., extruded through an annular orifice of a spinning device into gaseous atmosphere, when necessary, by the use of a gear pump enjoying high accuracy of measurement, to give rise to a hollow thread. To the center of the interior of the annular orifice mentioned above, an inactive gas such as, for example, nitrogen, carbon dioxide, helium, argon, or air may be delivered through spontaneous suction or, when necessary, forced introduction. Subsequently, the hollow thread discharged through the annular orifice is allowed to fall down into contact with the cooling and solidifying liquid held inside the cooling tank. The distance of this fall of the hollow thread is in the range of 5 to 1,000 mm, preferably 10 to 500 mm. If this distance is less than 5 mm, the hollow thread is caused to pulsate and is possibly crushed at the time the hollow thread enters the cooling and solidifying liquid. Inside this cooling tank, the hollow thread has not yet been thoroughly solidified and it is liable to be deformed by an external force because the central part of the membrane is formed with a gas. The aforementioned hollow thread can be forced to move and the deformation of the hollow thread by the external force (such as fluid pressure) can be precluded by allowing the aforementioned solidifying liquid 17 to flow down the interior of the cooling and solidifying tube 19 disposed as directed downwardly through the bottom of the cooling tank 18 as illustrated in FIG. 20 and allowing the hollow thread to fall parallelly to the flow of the liquid. For the flow of the cooling and solidifying liquid to fulfill the purpose thereof, the flow rate obtained by gravitational attraction suffices. The cooling temperature used in this case is in the range of 10� to 90� C., preferably 20� to 75� C. If the cooling temperature is less than 10� C., the cooling and solidifying speed is unduly high and the greater part of the thick wall part of the membrane assumes the form of a closely packed layer and the gas-exchange capacity of the membrane is proportionately lowered. If this temperature exceeds 90� C., the hollow thread is not sufficiently cooled and solidified and is possibly broken within the cooling and solidifying tank.
As the cooling and solidifying liquid for this invention, a solution exhibiting no compatibility with the organic filler is used which possesses a specific heat capacity in the range of 0.2 to 0.7 cal/g, preferably 0.3 to 0.6 cal/g. As concrete examples of the cooling and solidifying liquid, there can be cited silicone oils such as dimethyl silicone oil and methylphenyl silicone oil possessing a kinetic viscosity in the range of 2 to 50 cSt, preferably 8 to 40 cSt, and polyethylene glycols possessing an average molecular weight in the range of 100 to 400, preferably 180 to 330. A liquid exhibiting no compatibility with the organic filler and possessing a specific heat capacity in the range of 0.2 to 0.7 cal/g is used as the cooling and solidifying liquid for the following reason.
When liquid paraffin is used as the organic filler and a halogenated hydrocarbon is used as the cooling and solidifying liquid capable of dissolving the organic filler mentioned above, it is inferred that the organic filler will be dissolved and extracted out and will pass from the inner to the outer side of the hollow thread while the phase separation of the polypropylene and the organic filler is proceeding in the cooling and solidifying liquid, the proportion of the organic filler near the inner surface of the hollow thread is lowered after the hollow thread has been thoroughly cooled and solidified, and the ratio of openings in the inner surface is unduly lowered and the gas-exchange capacity of the membrane is suffered to fall after the organic filler has been thoroughly dissolved and extracted out. Further, in the present case, there is the possibility that even the low molecular weight component of the polypropylene in the hollow thread is extracted out and suffered to accumulate and deposit on the inner wall of the cooling and solidifying liquid flow tube 19 shown in FIG. 20 and induce reduction of the inside diameter of the cooling and solidifying liquid flow tube 19 and consequent deformation of the hollow thread. When a compound identical or similar to the aforementioned organic filler is used as the cooling and solidifying agent, namely when a species of liquid paraffin is used as the organic filler and another species of liquid paraffin having a number average molecular weight approximating that of the first liquid paraffin is used as the cooling and solidifying agent, the organic filler (liquid paraffin) in the hollow thread is allowed to give rise to pores in a prescribed density without being significantly migrated within the hollow thread and the specific heat is not unduly large and, as the result, the polypropylene is crystallized at a proper cooling speed and enabled to acquire a stable form finally. During the course of the cooling, however, the organic filler or the cooling and solidifying liquid is suffered to occur locally on the outermost surface of the hollow thread which has not yet been thoroughly cooled and solidified and the ratio of the polypropylene composition is lowered on the outermost surface, and, as the result, the pores in the outer surface of the hollow thread are large and the solid phase finally assumes a heavily rugged surface condition because it is formed with particles of polypropylene spread out in the form of a network. When an inactive liquid which is incompatible with the organic filler and possesses a large specific heat capacity is used as the cooling and solidifying liquid, namely when liquid paraffin is used as the organic filler and water having a large specific heat capacity of about 1.0 cal/g is used as the cooling and solidifying agent, there is the possibility that the polypropylene will be quickly cooled and the outer surface will assume a state of low crystallinity because the cooling effect of water is high. The possible consequence is that the polypropylene will fail to form minute particles and the produced hollow fiber membrane will contain unduly small pores in the outer surface thereof and exhibit a small gas-exchange capacity. If the cooling and solidifying liquid to be used possesses a small specific heat capacity, there is the possibility that no sufficient cooling effect will be obtained and the extruded mixture will not be converted into a hollow thread as desired.
As the extractant, there can be used any of the liquids which are incapable of dissolving the propylene which forms the backbone of the hollow fiber membrane and capable of dissolving and extracting the organic filler. Examples of the liquid so usable include alcohols such as methanol, ethanol, propanols, butanols, pentanols, hexanols, octanols, and lauryl alcohol and halogenated hydrocarbons such as 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane, dichlorofluoromethane, and 1,1,2,2-tetrachloro-1,2-difluoroethane. In all these extractants, halogenated hydrocarbons prove to be desirable from the standpoint of extraction capacity and chloro-flucrinated hydrocarbons prove to be especially desirable from the standpoint of safety on the human system.
The hollow fiber membrane which is obtained as described above, when necessary, is further subjected to a heat treatment. The heat treatment is carried out in a gaseous atmosphere such as air, nitrogen or carbon dioxide at a temperature in the range of 50� to 160� C., preferably 70� to 120� C., for a period in the range of 5 seconds to 120 minutes, preferably 10 seconds to 60 minutes. By this heat treatment, the hollow fiber membrane is structurally and dimensionally stabilized. Further, in this case, the hollow fiber membrane may be stretched prior to or during the heat treatment.
The tubular main body 57 of the aforementioned housing 56 is desired to be provided on the inner surface thereof halfway along the direction of axis with a projected constricting part 65. This constricting part 65 is integrally formed with the tubular main body 57 on the inner surface and adapted to squeeze the overall outer periphery of a hollow fiber bundle 66 consisting of the multiplicity of hollow fiber membranes 1 inserted inside the tubular main body 57. As the result, the aforementioned tubular fiber bundle 66 is constricted at the center in the direction of axis to form a constricted part 67 as illustrated in FIG. 21. The packing ratio of the hollow fiber membranes 1, therefore, varies along the direction of axis and reaches the maximum at the center. For the reason to described later on, the packing ratios of varying parts of the hollow fiber bundle 66 are desired to be as follows. First, the packing ratio A in the constricted part 67 at the center is approximately in the range of 60 to 80%, the packing ratio B within the tubular main body 57 except for the constricted part 67 in the range of 30 to 60%, and the packing ratio C at the opposite ends of the hollow fiber bundle 66, namely on the outer surfaces of the diaphragms 60, 61 in the range of 20 to 40% as illustrated in FIG. 22.
Now, the formation of the aforementioned diaphragms 60, 61 will be described below. As described above, the diaphragms 60, 61 fulfill an important function of isolating the interiors from the exteriors of the hollow fiber membranes 1. Generally, these diaphragms 60, 61 are formed by centrifugally casting a macromolecular potting material of high polarity such as, for example, polyurethane, silicone, or epoxy resin in the inner wall surfaces at the opposite ends of the housing 56 and allowing the cast macromolecular material to harden. To be more specific, a multiplicity of hollow fiber membranes 1 of a length greater than that of the housing 56 are prepared and, with the openings thereof at the opposite ends blocked up with highly viscous resin, parallelly disposed inside the tubular main body 57 of the housing 56. Subsequently, the opposite ends of the hollow fiber membranes 1 are completely concealed with pattern covers of a diameter larger than that of the fitting covers 58, 59 and the housing 56 is set rotating about the axis thereof and, at the same time, the macromolecular potting material is cast into the housing 56 through the opposite ends thereof. After the cast resin has been hardened, the aforementioned pattern covers are removed and the outer surface parts of the resin are cut off with a sharp blade to expose the open ends of the hollow fiber membranes 1 from the surfaces. In this manner, the diaphragms 60, 61 are formed.
In the flat-film type porous polypropylene membrane of the present invention, the pores formed therein are desired to have an average diameter in the range of 0.1 to 5.0 μm, preferably 0.2 to 3.0 μm. If the average pore diameter is less than 0.1 μm, the membrane is liable to exhibit an insufficient permeation speed to the blood plasma and the pores are liable to be clogged. Conversely, if the average pore diameter exceeds 5.0 μm, the porous membrane has the possibility of permitting not only the blood plasma component but also the blood cell component (erythrocytes leukocytes, and platelets) to permeate therethrough. So long as the average pore diameter falls in the aforementioned range, the porous membrane is capable of passing not less than 95% of the total proteins, namely the blood plasma component, without passing the blood cell component. The term "average pore diameter" as used herein means the average diameter of all the pores contained throughout the entire volume of the membrane as actually measured with a mercury porosimeter and not the average diameter of the pores contained only in the surface layers. In the flat-film type porous polypropylene membrane of the present invention, the bubble point is required not to exceed 2.0 kgf/cm2, preferably 1.8 kgf/cm2. The term "bubble point" as used herein means to define the largest allowable pore diameter of the membrane. If the bubble point exceeds 2.0 kgf/cm2, the pores in the membrane have too small diameters for the porous membrane to fit speedy filtration of blood plasma and exhibit sufficient permeability to the blood plasma component.
Further, in the flat-film type porous polypropylene membrane of the present invention, the porosity is in the range of 60 to 85%. If the porosity is less than 60%, the porous membrane is liable to exhibit insufficient permeability and offer no sufficient blood plasma separation speed. Conversely, if the porosity exceeds 85%, the porous membrane to be produced is liable to acquire no sufficient working strength. Further in the flat-film type porous polypropylene membrane of the present invention, the amount of water to be passed therethrough is required to exceed 100 ml/min.mmHg.cm2, preferably 140 ml/min.mmHg.cm2. If the amount of water passed therethrough is less than 100ml/min.mmHg.cm2, the porous membrane is liable to offer no sufficient blood plasma separation speed. The flat-film type porous polypropylene membrane of this invention is required to have a wall thickness in the range of 30 to 300 μm. If the wall thickness is less than 30μm, the porous membrane is liable to be deficient in strength. conversely, if the wall thickness exceeds 300μm, the module to be obtained by incorporating a multiplicity of such porous membranes is liable to occupy too large a volume to suit practical use.
The shrinkage which the flat-film type porous polypropylene membrane of this invention exhibits after 120 minutes' heat treatment at 121� C. is required not to exceed 6.0%, preferably 3.0%. The expression "120 minutes' heat treatment at 121� C." represents the high-pressure steam sterilization specified by the Japanese Pharmacopoeia. The term "shrinkage" as used herein means the degree of change in amount of the porous membrane before and after the aforementioned heat treatment. Since the flat-film type porous polypropylene membrane of the present invention is a flat film in shape, the foregoing requirement dictates that the change to be brought about by the heat treatment in the length of the porous membrane in the direction perpendicular to the axis of molding should be not more than 6.0%. If the shrinkage exceeds 6.0%, the porous membrane is liable to offer no sufficient separation of the blood component because of decrease in the amount of water to be passed and decrease in the blood plasma separation speed.
The flat-film type porous polypropylene membrane of the present invention which possesses the characteristic properties described above is produced, for example, as follows.
The organic filler is required to be uniformly dispersible in the polypropylene which is in a molten state and to be easily soluble in an extractant to be used later. Examples of the filler which fulfills this requirement include liquid paraffin (number average molecular weight 100 to 2,000), α-olefin oligomers [such as, for example, ethylene oligomer (number average molecular weight 100 to 2,000), propylene oligomer (number average weight 100 to 2,000), and ethylene oligomer (number average molecular weight 100 to 2,000)], paraffin wax (number average molecular weight 200 to 2,500), and various hydrocarbons. On the organic fillers enumerated above, the liquid paraffin proves to be particularly desirable.
The mixing ratio of the polypropylene and the aforementioned organic filler is such that the proportion of the organic filler to 100 parts by weight of the propylene is in the range of 200 to 600 parts by weight, preferably 300 to 500 parts by weight. If the proportion of the organic filler is less than 200 parts by weight, the flat-film type porous polypropylene membrane to be produced possesses unduly low porosity and water permeability and fails to acquire sufficient permeation properties. If this proportion exceeds 600 parts by weight, the produced membrane exhibits unduly low viscosity and deficiency in workability. For the formulation of raw materials mentioned above, the mixture consisting of raw materials in a prescribed percentage composition is prepared (designed) by the premix method which comprises melting and blending the mixture, extruding the resultant blend, and pelletizing the extruded blend by the use of biaxial type extruding machine, for example.
The crystalline seed forming agent to be included in the raw materials for this invention is an organic heat-resistant substance possessing a melting point of not less than 150� C., preferably in the range of 200� to 250� C., and a gelling point of not less than the crystallization starting point of polyolefin. The crystalline seed forming agent of this description is used as one of the raw materials for the purpose causing contraction of the particles of polypropylene thereby controlling the gap between the solid phases, namely the diameter of micropores to be formed. As examples of the crystalline seed forming agent, there can be cited 1,3,2,4-dibenzylidene sorbitol, 1,3,2,4-bis(p-methylbenzylidene) sorbitol, 1,3,2,4-bis(p-ethylbenzylidene)sorbitol, bis(4-t-butylphenyl)sodium phosphate, sodium benzoate, adipic acid, talc and kaoline. Among other crystalline seed forming agents enumerated above, 1,3,2,4-dibenzylidene sorbitol, 1,3,2,4-bis(p-ethylbenzylidene) sorbitol, and 1,3,2,4-bis(p-methylbenzylidene) sorbitol prove to be advantageous because they do not appreciably dissolve out into the blood.
In contrast, when a liquid exhibiting no compatibility with the aforementioned organic filler and possessing a specific heat capacity in the range of 0.2 to 0.7 cal/g is used as the cooling and solidifying liquid, the propylene is not suffered to dissolve out in the surface parts, the cooling speed of the polypropylene is proper, and the polypropylene is smoothly crystallized even in the surface parts with the composition ratio thereof retained intact. As the result, there can be formed a reticular structure which is not enlarged unduly even in the surface parts and which is enabled to contain amply large pores fit for blood plasma separation even within the interior thereof.
The temperature of the cooling and solidifying liquid is desired to be in the range of 10� to 80� C., preferably 30� to 60� C., for the following reason. If this temperature is less than 10� C., the cooling and solidifying speed is so fast that the micropores to be formed consequently have a very small diameter. Conversely, if the temperature exceeds 80� C., the cooling and solidifying treatment does not proceed amply and the molten membrane is liable to break in the cooling and solidifying liquid.
The membrane which has been thoroughly cooled and solidified in the cooling and solidifying tank is brought into contact with the extractant to permit removal of the organic filler therefrom by extraction. This solution and extraction of the organic filler may be effected by the extraction tank method or the shower method which comprises advancing the membrane on a belt conveyor and causing the extractant to fall in the form of shower onto the membrane in motion.
The flat-film type porous polypropylene membrane which is obtained as described above, when necessary, may be further subjected to a heat treatment. This heat treatment is carried out at a temperature 10� to 15� C. lower than the melting point of the polypropylene, specifically a temperature in the range of 110� to 150� C., preferably 130� to 140� C., for a period in the range of 30 to 180 seconds, preferably 60 to 20 seconds. Preparatory to the heat treatment, the porous membrane must be fixed in a prescribed length. The flat-film type porous polypropylene membrane which is produced as described above is useful as a membrane for the separation of blood into blood cells and blood plasma and as a microfilter for the removal of bacteria from blood. It is used particularly advantageously as a membrane for the separation of blood plasma where the separated blood plasma is put to use as in the treatment of donorpheresis.
EXAMPLES 1 AND 2 AND CONTROLS 1 THROUGH 3
In a twin-screw extruder (produced by Ikeqai Iron Works, Ltd. and marketed under trademark designation of PCM-30-25), 100 parts by weight of propylene homopolymer possessing a melt index (M.I.) of 23, a varying proportion of liquid paraffin (number average molecular weight 324) indicated in Table 1, and 0.5 part by weight of dibenzylidene sorbitol were melted and blended and extruded. The extruded mixture was pelletized. By the use of a device illustrated in FIG. 20, namely a single screw extruder (produced by kasamatsu Seisakusho and marketed under produce code "WO-30"), the pellets were melted at a varying temperature indicated in Table 1 and discharged through an annular spinning hole possessing a core diameter of 4 mm, an inside diameter of 6 mm, an outside diameter of 7 mm, and a land length of 15 mm at a varying discharge volume indicated in Table 1 into the air to cause fall of a continuous hollow thread 16. The distance of this fall was varied as shown in Table 1. Then, the hollow thread 16 was brought into contact with a varying cooling and solidifying liquid indicated in Table 1 held in a cooling tank 18 and then cooled by parallel-flow contact with the cooling and solidifying liquid 17 spontaneously flowing down the interior of the cooling and solidifying liquid flow tube 19. In this case, the temperature of the cooling and solidifying liquid was varied as shown in Table 1. Then, the aforementioned hollow thread 16 was led into the cooling and solidifying liquid inside a solidification tank 20, caused to change the course of its travel by a deflection bar 21, then led to a drive roll 22 operated at a varying winding speed indicated in Table 1, continuously treated on a shower conveyor type extracting machine 27 with Freon 113 (1,1,2-trichloro-1,2,2-trifluoroethane) to effect through removal of the aforementioned liquid paraffin by extraction, passed around a drive roll 22, passed through a heat-treating device 30 under varying temperature and time conditions indicated in Table 1, and taken up on a bobbin 32 by a winder 31. Then hollow fiber thus taken up on the bobbin 32 was rewound on a skein by a rewinding device to obtain a hollow fiber bundle about 30 cm in length. The hollow fiber membrane thus obtained was examined with respect to shape (wall thickness), porosity, opening ratio in the inner surface, gas flux, ability to add oxygen gas, ability to remove carbon dioxide gas, leakage of blood plasma, and speed of blood plasma permeation. The results are shown in Tables 2 and 3.
To determine the microstructure of the hollow fiber membrane obtained, various portions of the hollow fiber membrane were observed under a scanning electron microscope (produced by JEOL and marketed under product code of "JSM-840"). Specifically, FIG. 1 is a photomicrograph of the outer surface (�10,000) of the hollow fiber membrane of Example 1, FIG. 2 of the inner surface (�10,000) of the hollow fiber membrane of Example 1, FIG. 3 of the cross section (�10,000) of the hollow fiber membrane of Example 1, FIG. 4 of the longitudinal cross section (�10,000) of the hollow fiber membrane of Example 1, FIG. 5 of the outer surface (�10,000) of the hollow fiber membrane of Example 2, FIG. 6 of the inner surface (�10,000) of the hollow fiber membrane of Example 2, FIG. 7 of the outer surface (�10,000) of the hollow fiber membrane of Control 1, FIG. 8 of the inner surface (�10,000) of the hollow fiber membrane of Control 1, FIG. 9 of the cross section (�10,000) of the hollow fiber membrane of Control 1, FIG. 10 of the longitudinal cross section (�10,000) of the hollow fiber membrane of Control 1, FIG. 11 of the outer surface (�10,0000) of the hollow fiber membrane of Control 2, FIG. 12 of the inner surface (�10,000) of the hollow fiber membrane of Control 2, FIG. 13 of the cross section (�3,000) of the hollow fiber membrane of Control 1, FIG. 14 of the outer surface (�3,000) of the hollow fiber membrane of Control 3, and FIG. 15 of the cross section (�3,000) of the hollow fiber membrane of Control 3, respectively taken under an electron microscope. In each of the microphotographs, the direction of axis of fibers in the relevant hollow fiber membrane is shown on the right.
Modules of the type adapted to pass blood outside hollow fiber membranes were assembled with the hollow fiber membranes of Example 1 and Control 1 and tested for hemolysis of blood and pressure loss of blood. The results are shown in Table 5.
For the purpose of comparison, a commercially available artificial lung-grade polypropylene hollow fiber membrane produced by the stretching method was tested for shape (inside diameter/wall thickness), porosity, opening ratio in inner surface, gas flux, ability to add oxygen gas, ability to remove carbon dioxide gas, leakage of blood plasma, and blood plasma permeation speed in the same manner as in Examples 1 and 2 and Controls 1 through 3. The results are shown in Tables 2 and 3. The microstructure of the hollow fiber membrane was observed under a scanning electron microscope (made by JEOL and marketed under product code of "JSM-840"). FIG. 16 is a photomicrograph of the outer surface (�10,000) of this hollow fiber membrane, FIG. 17 of the inner surface (�10,000) thereof, FIG. 18 of the cross section (�10,000) thereof, and FIG. 19 of the longitudinal cross section (�10,000) thereof, taken under the electron micrograph. In each of these figures, the direction of axis fibers in the hollow fiber membrane is shown on the right.
TABLE 1__________________________________________________________________________       Liquid       paraffin       content              Temperature           Heat       in raw               of cooling  Amount    treatment  Melting       material             and    Distance                                        dis- Winding                                                  Temperature  point       (part by            Cooling and     solidifying                                   of fall                                        charged                                             speed                                                  (�C.)/time  (�C.)       weight)            solidifying liquid                            liquid (�C.)                                   (mm) (g/min)                                             (m/min)                                                  (sec)__________________________________________________________________________Example 1  180  120  Polyethylene glycol                            50     35   3.43 80   100-110/19            (Mn = 200)Example 2  180  120  Polydimethyl siloxane                            50     30   3.66 80   100-110/19            (TORAY SILICONE SH 200,            20 cSt)Control 1  180  120  Liquid paraffin 35     30   3.60 80   100-110/19            (Mw = 299)Control 2  210   60  1,1,2-trichloro-                            27     24   2.76 100   70-80/15            1,2,2-trifluoroethaneControl 3  200   80  Water           35     30   7.6  170   70-80/15__________________________________________________________________________
TABLE 2______________________________________ShapeInside diameter/   Gas flux    PorosityWall thickness (&#956;m)              (lit/min.m2.atm)                          (%)______________________________________Example 1   200/45         432         41.1Example 2   200/45         361         42.8Control 1   200/45         416         38Control 2   209/26           16.9      17.8Control 3   177/44          0          --Control 4   200/25         1200        45______________________________________
TABLE 3__________________________________________________________________________Opening ratio        Ability to                Ability to remove   Blood plasmain inner     add oxygen gas                carbon dioxide gas                          Leakage of blood                                    permeating speedsurface (%)  (m./min.m2)                (ml/min.m2)                          plasma    (ml/min.m2.atm)__________________________________________________________________________Example 1 16.0   42.1    45.0      No sign of leakage                                    116                          after 30 hoursControl 1 17.6   40.9    47.6      No sign of leakage                                    73.8                          after 30 hoursControl 2  5.1   29.6    43.3      False positive                                    42.5                          reaction after 30                          hoursControl 3 20.1   41.8    49.8      First sign seen                                    332                          after 17 hours and                          heavy leakage after                          20 hours.__________________________________________________________________________
TABLE 4______________________________________               Ratio of               birefringence(&#916;n)______________________________________Example 1             0.004Control 1             0.003Control 4             0.014Completely oriented polypropylene                 0.035  (As reported                        in literature)______________________________________
It is clearly noted from the results shown in Tables 2 through 4 that the hollow fiber membranes of Examples 1 and 2 according with the present invention exhibited proper properties for artificial lung-grade hollow fiber membranes as the hollow fiber membrane of Control 1 and possessed smooth outer surface conditions. Thus, even in the modules adapted to circulate blood outside hollow fiber membranes, they induced neither hemolysis nor pressure loss so heavily as the counter type module of Control 1 as noted from Table 5. When the hollow fibers wound on bobbins in Examples 1 and 2 and Controls 1 and 2 were observed, the fibers spun simultaneously in Controls 1 and 2 were liable to cohere fast, whereas the fibers spun in Examples 1 and 2 were found to induce absolutely no such phenomenon. Further in Control 2, the low molecular component of polypropylene adhered to the interior of the cooling bath and continued to accumulate thereon to cause a gradual decrease in the diameter of the tube. In Examples 1 and 2, absolutely no such phenomenon was observed.
TABLE 6__________________________________________________________________________          Cooling               Compati-                     Specific          temper-               bility with                     heatCooling and    ature               liquid                     capacity                          Outer surface condition ofsolidifying liquid          (�C.)               paraffin                     (cal/g)                          hollow fiber Photograph__________________________________________________________________________Example 1 Polyethylene          50   X     0.51 Orderly arranged                                       FIG. 1 glycol                   particulate polypropylene (Mn = 200)               (0.1 to 0.2 &#956;m)Example 2 Polydimethyl          50   X     0.36 Orderly arranged                                       FIG. 5 silioxane (Toray         particulate polypropylene Silicone SH 200,         and ample presence of 20 cSt)                  poresControl 1 Liquid paraffin          35   &#9711;                     0.48 Particulate polypropylene                                       FIG. 7 (Mn = 200)               connected in the form of                          network (0.1 to 1.0 &#956;m)Control 2 Freon 113          27   &#9711;                     0.21 Lumps of polypropylene                                       FIG. 11                          interconnected in the form                          of network (several &#956;m)Control 3 Water    35   X     1.0  Skin layer of                                       FIG. 14                          polypropylene__________________________________________________________________________  &#9711;  compatible X incompatible
TABLE 7__________________________________________________________________________   Membrane         Inside.outside                Number of                      Available   surface         diameter                hollow                      length/total                            Packing ratio* (%)   (m2)         (&#956;m)                fibers                      length (cm)                            Part A                                Part B                                    Part C__________________________________________________________________________Examples 1 and   1.6   200/290                19700 13/16 60  50  432 and Control 1Control 4   1.6   200/245                19700 13/16 64  42  33__________________________________________________________________________ *The term "packing ratio" means the ratio of the crosssectional area (inclusive of empty spaces) of hollow fiber membrane to the crosssectiona area inside the cylinder proper in a varying part indicated in FIG. 22.
TABLE 8______________________________________Blood         Fresh heparin-added bovine bloodHematocrit value         35% (as prepared with physiological         Saline solution)Hemoglobin concen-         12 � 1 g/dltrationBase Excess    0 � 2 mEq/liter (as prepared with         sodium hydrogen carbonate)Degree of oxygen         65 � 5%saturationCarbon dioxide         45 � 5 mmHgpartial pressureTemperature   37 � 2� C.______________________________________
From 10 hollow fiber membranes randomly extracted from a given lot, central portions 3 cm in length were cut out. The segments thus obtained had their ends on one side cut aslant and used as a sample. The hollow fiber membranes thus prepared were placed on a slide glass, wetted with an immersing liquid (liquid paraffin), and the slide glass thus prepared was set on a rotary stage in a polarizing microscope. With a monochromatic light source or a light source equipped with a filter as substitute, under a cross nicol exclusive of a compensator, the specimen on the rotary stage was rotated to the brightest position (reached by a 45� rotation from the darkest position) and immobilized at this brightest position. Then, the compensator was inserted, and the analyzer was rotated to find the angles producing the darkest (θ) black, and the retardation (R) was calculated in accordance with the formula represented below. Further the ratio of birefringence of the hollow fiber membrane was calculated in accordance with the following formula. The average of the numerical values obtained for 10 samples was reported. ##EQU1## wherein λ stands for the wavelength of light used. ##EQU2## wherein d stands for the thickness of sample (compensated with the porosity),
______________________________________Conditions of determination:______________________________________Polarizing microscope              Nikon OPTIPHTO-POLWavelength of Light source              546 nmCompensator        Senarmont type compensator______________________________________
TABLE 9______________________________________Number of hollow fiber membranes                48,160Available length     80 mmOverall length       135 mmPacking ratio in the central part                48%(Part A)______________________________________
By the use of a twin-screw extruder (produce by Ikegai Iron Works, Ltd. and marketed under trademark designation of PCM-30-25), 100 parts by weight of a mixture of two polypropylene species possessing melt flow indexes of 30 and 0.3 (mixing ratio 100:40 by weight), varying proportions of liquid paraffin (number average molecular weight 324), and 1,3,2,4-bis(p-ethylbenzylidene)sorbitol as a crystalline seed forming agent indicated in Table 10 were melted and kneaded and pelletized. By the aforementioned extruder, the pellets were melted at a varying temperature in the range of 150� to 200� C., extruded through a T die 0.6 mm in slit width into the air, allowed to fall onto a guide roller in a cooling liquid tank disposed directly below the T die, led into the cooling and solidifying liquid by the rotation of the roller to be cooled and solidified therein, and thereafter taken up. The kind and temperature of the cooling and solidifying liquid used in this case were as shown in Table 1. From the film thus taken up, a square (about 200 x 200 mm) was cut off, fixed in both the longitudinal and lateral directions, immersed four times in 1,1,2-trichloro-1,2,2-trifluoroethane (liquid temperature 25� C.) for 10 minutes each to effect expulsion of the liquid paraffin, and then heat treated in the air at 135� C. for 2 minutes.
Then, to determine the microstructure of the flat-film type porous polypropylene membrane, various portions of the membrane were observed under a scanning electron microscope (produced by JEOL and marketed under product code of "JSM-840"). FIG. 25 is a photomicrograph of the surface (�1,000) of the flat-film type porous polypropylene membrane of Example 1, FIG. 26 of the partial cross section (�2,500) of the flat-film type porous polypropylene membrane of Example 3, FIG. 27 of the surface (�1,000) the flat-film type porous polypropylene membrane of Control 5, and FIG. 28 of the partial cross section (�3,000) of the flat-film type porous polypropylene membrane of Control 1, respectively taken under the electron microscope. It is clearly noted from FIG. 25, and FIG. 26 that the flat-film type porous polypropylene membrane of Example 3 according with the present invention possessed practically equal reticular structure in the surface parts and in the interior of the membrane, the surface layers had a virtually negligible thickness (about 0.5% of the total membrane thickness), and the reticular structure had attained full development even in the interior of the membrane. In contrast, the flat-film type porous polypropylene membrane obtained by using liquid paraffin as the cooling and solidifying liquid (Control 5), as clearly noted from FIG. 27 and FIG. 28, possessed as fully developed a reticular structure in the interior of the membrane as in the membrane of Example 1, possessed fairly rough reticular structure in the surface parts, and had surface layers of a fairly large thickness (about 24.0% of the total thickness of the membrane). The comparison offers a definite evidence that the flat-film type porous polypropylene membrane of Example 3 according with the present invention suffered sparingly from occlusion of blood cells.
Separately, life-size laminate modules severally incorporating therein the flat-film type porous polypropylene membrane of Example 3 and Control 5 were operated to effect blood plasma separation of bovine blood, to compare the flat-film type porous polypropylene membrane in ability of blood plasma separation. Results are shown in FIG. 29-31. FIG. 29 shows the relation between the speed of blood plasma separation (Qf) and the total intermembranous pressure (T.M.P.) and FIG. 30 the relation between the T.M.P. and the amount of free hemoglobin (ΔHb).
TABLE 10__________________________________________________________________________                    Additive              Tempera-                    volume of                           Mem-                     HighestLiquid             ture of the                    crystalline                           brane                    Plasmaparaffin           cooling                    seed forming                           thick-                               Bubble     Volume of                                                    separation(part by           liquid                    agent (part                           ness                               point Porosity                                          Permeation                                                    Speedweight)    Cooling liquid              (�C.)                    by weight)                           (&#956;m)                               (kgf/cm2)                                     (%)  (ml.min.mmHg.m2)                                                    (ml/min)__________________________________________________________________________Example 3 400  Polyethylene              35    0.3    146 1.1   66   162       40      glycolExample 4 400  Polyethylene              20    0.3    140 1.1   65   158       --      glycolExample 5 456  Polyethylene              35    0.3    143 0.9   68   229       --      glycolControl 5 400  Liquid paraffin              38    0.3    120 0.7   71   330       40Control 6 400  1,1,2-trichloro-              30    0.3    150 0.9   73   305       40      1,2,2-trifluoro-      ethaneControl 7 150  Liquid paraffin              30    0.3    120 3.1   55   90        40Control 8 Cellulose Acetate         162 3.2   72   320       35 Membrane__________________________________________________________________________
Water at 25� C. was caused to permeate a give membrane measuring 1.45�10-3 m2 in area under application of a pressure of 0.7 kgf/cm2. The time required for 100 ml of water to pass through the membrane was clocked and reported as water permeation.
This property was determined by use of a circuit illustrated in FIG. 24. In a module 30 possessing a membrane surface area of 0.4 m2, fresh bovine blood incorporating therein heparin of a hematocrit value of 40% (5,000 U/liter) was circulated in a flow volume of 100ml/min at a pressure loss of 30 mmHg, with the flow volume of the filtration pump successively increased from 10 ml/min to 10, 15, 20, 25, 30, 40, and 42 at intervals of 30 minutes. The amount of filtrate immediately before the increase of T.M.P. within an interval of 30 minutes surpassed 20 mmHg was found and reported as Qf max.
As described above, this invention concerns a porous polypropylene hollow fiber membrane wherein the solid phase in the inner surface region thereof is formed with particles of polypropylene closely fused and joined to give rise to a continuous phase while partially exposed through the surface thereof, the solid phase in the interior and the outer surface region thereof is formed with particles of polypropylene interconnected in the direction of axis of fiber to give rise to a multiplicity of lumps of polypropylene, and the interstices between these solid phases has continuous pores interconnected in the form of a three-dimensional network. When this porous polypropylene hollow fiber membrane is used in an artificial lung, therefore, it induces no leakage of blood plasma and yet retains a high gas-exchange capacity even during a protracted service and, without reference to the choice of the type of the artificial lung on account of the mode of circulation of blood either inside or outside the hollow fiber membrane, neither imparts any injury to blood cells nor aggravates pressure loss of the blood. Since the porous polypropylene hollow fiber membrane possesses a smooth outer surface, it proves to be highly advantageous in respect that it is free from various drawbacks otherwise incurred during the assembly of an artificial lung such as cohesion of adjacent hollow fiber membranes or impairment of the work of potting due to adhesive agent. These characteristic features are manifested all the more to advantage when the ratio of birefringence in the direction of axis thereof is in the range of 0.001 to 0.01, the porosity in the range of 10 to 60%, the opening ratio in the inner surface in the range of 10 to 30%, the oxygen gas flux in the range of 100 to 1,500 liters/min.m2 atm, the inside diameter in the range of 150 to 300 μm, the wall thickness in the range of 10 to 150 μm, the average diameter of polypropylene particles in the range of 0.1 to 2.0 μm, and the average pore diameter in the inner surface in the range of 0.1 to 1.0 μm.
This invention further concerns a method for the production of a porous polypropylene hollow fiber membrane, which is characterized by mixing polypropylene, an organic filler uniformly dispersible in the polypropylene in a molten state and easily soluble in an extractant to be used later, and a crystalline seed forming agent, discharging the resultant mixture in a molten state through annular spinning orifices, cooling and solidifying the resultant hollow threads by contact with a cooling and solidifying liquid having no compatibility with the aforementioned organic filler and possessing a specific heat capacity in the range of 0.2 to 0.7 cal/g, and then bringing the cooled and solidified hollow threads into contact with an extractant incapable of dissolving polypropylene thereby removing the organic filler therefrom by extraction. While the spinning dope obtained by melting and uniformly dispersing the raw materials is cooled and solidified, therefore, the phase separation of the polypropylene and the organic filler in the spinning dope can be effected at a proper cooling speed without inducing any local presence of the organic filler in the outer surface part and, as the result, numerous micropores can be produced in the interstices of properly crystallized and grown particles of polypropylene and, moreover, the outer surface part as well as the thick wall part of the hollow fiber can form a solid phase having particles of polypropylene orderly arranged in the direction of axis of fiber and assume a smooth surface. As the result, there can be produced a hollow fiber membrane which exhibits the aforementioned outstanding properties stably and uniformly. By the method of this invention, the porous polypropylene hollow fiber membrane possessing still better properties can be obtained when a silicone oil or polyethylene glycol, preferably a silicone oil possessing a viscosity in the range of 2 to 50 cSt or a polyethylene glycol possessing an average molecular weight in the range of 100 to 400, is used as the cooling and solidifying liquid, liquid paraffin is used as the organic filler, the proportion of the organic filler to 100 parts by weight of polypropylene is in the range of 35 to 150 parts by weight, an organic heat-resistance substance possessing a melting point of not less than 150� C. and a gelling point of not less than the crystallization starting point of polypropylene is used as the crystalline seed forming agent, and the proportion of the crystalline seed forming agent to 100 parts by weight of polypropylene is in the range of 0.1 to 5 parts by weight.
This invention also concerns an artificial lung provided with a hollow fiber membrane as a gas-exchange membrane, characterized by the fact that the hollow fiber membrane is a porous polypropylene hollow fiber membrane wherein the solid phase in the inner surface region thereof is formed with particles of polypropylene closely fused and joined to give rise to a continuous phase while partially exposed through the surface thereof, the solid phase in the interior and the outer surface region thereof is formed with particles of polypropylene interconnected in the direction of axis of fiber to give rise to a multiplicity of lumps of polypropylene, and the interstices between these solid phases has continuous pores interconnected in the form of a three-dimensional network. In the artificial lung of either the type adapted to circulate the blood inside the hollow fiber membrane and blow the oxygen-containing gas outside the hollow fiber membrane or the type adapted to circulate the blood outside the hollow fiber membrane and blow the oxygen-containing gas inside the hollow fiber membrane, therefore, the ability of the membrane to add oxygen and the ability to remove carbon dioxide gas are not degraded even during a protracted service in the extra-corporeal circulation of blood, no leakage of blood or blood plasma is induced, and neither infliction of injury upon blood cells nor aggravation of pressure loss is entailed. Thus, the artificial lung deserves to be esteemed highly. Typically in 30 hours' extra-corporeal circulation of blood, the artificial lung of the present invention incurs neither leakage of blood plasma nor degradation of gas-exchange capacity. The properties of the artificial lung are manifested more to advantage when the ratio of birefringence in the direction of axis of fiber is in the range of 0.001 to 0.01, the porosity in the range of 10 to 60%, the opening ratio in the inner surface in the range of 10 to 30% , the oxygen gas flux in the range of 10 to 1,500 liters/min.m2.atm., and inside diameter in the range of 150 to 300 μm, the wall thickness in the range of 10 to 100 μm, the average diameter of polypropylene particles in the range of 0.1 to 2.0 μm, and the average pore diameter in the inner surface in the range of 0.1 to 1.0 μm.
Further, this invention concerns a flat-film type porous polypropylene membrane possessing a microreticular structure, characterized by the fact that either or both of the opposite surface region of the porous membrane form a surface layer possessing an average pore diameter in the range of 0.1 to 5.0 μm, a bubble point of not more than 2.0 kgf/cm2, a porosity in the range of 60 to 85%, and a water permeability of not less than 100 ml/min.mmHg.m2, and the membrane possesses a wall thickness in the range of 30 to 300μm. Thus, the flat-film type porous polypropylene membrane exhibits high porosity and water permeability. When it is used for blood plasma separation, it suffers sparingly from clogging of pores with proteins or blood cells, effects separation of blood plasma at a high speed, and entails only slight occlusion of blood cells and hardly includes hemolysis. Owing to these features, the flat-film type porous polypropylene membrane is used advantageously for blood plasma separation, i.e. the separation of blood into blood cells and blood plasma.. It is particularly useful as a membrane for blood plasma separation where the separated blood plasma is put to use as in donorpheresis. The flat-film type porous polypropylene membrane of this invention is enabled to manifest these highly desirable properties still more to advantage when the bubble point is not more than 1.8 kgf/cm2, the water permeation not less than 140ml/min.mmHg.m2, and the ratio of shrinkage due to 120 minutes' heat treatment at 121� C. is not more than 6.0%.
This invention also concerns a method for the production of a flat-film type porous polypropylene membrane, characterized by mixing 100 parts by weight of polypropylene, 200 to 600 parts by weight of an organic filler uniformly dispersible in the polypropylene in the molten state, and 0.1 to 5.0 parts by weight of a crystalline seed forming agent, discharging the resultant mixture in a molten state through a die thereby producing a molten membrane in the form of a flat film, cooling and solidifying liquid exhibiting no compatibility to the organic filler and possessing a specific heat capacity in the range of 0.2 to 0.7 cal/g, and then bringing the cooled and solidified membrane into contact with an extractant incapable of dissolving the polypropylene and capable of dissolving the organic filler thereby removing the organic filler from the membrane by extraction. This method is capable of easily producing the flat-film type porous polypropylene membrane possessing the aforementioned outstanding properties. The properties of the flat-film type porous polypropylene membrane are stabilized to a great extent when the method described above further comprises causing the flat-film type porous polypropylene membrane which results from the removal of the organic filler by extraction to be fixed in a prescribed length and subjected to a heat treatment at a temperature in the range of 110� to 140� C. The flat-film type porous polypropylene membrane of high grade can be obtained easily when the contact of the molten membrane with the cooling and solidifying liquid is effected by having a guide roller disposed in the cooling and solidifying liquid, discharging the molten mixture onto the guide roller, and causing the molten mixture to be led into the cooling and solidifying liquid by the rotation of the guide roller. The properties of the flat-film type porous polypropylene membrane are further enhanced when the cooling and solidifying liquid is a polyether, the polypropylene consists of a species of polypropylene possessing a melt index in the range of 5 to 40 and 0 to 50% by weight of another species of polypropylene possessing a melt index in the range of 0.05 to 5, the crystalline seed forming agent is incorporated in the mixture in a proportion falling in the range of 0.2 to 1.0 part by eight, the crystalline seed forming agent is an organic heat-resistant substance possessing a melting point of not less than 150� C. and a gelling point not less than the crystallization starting point of polypropylene, and the extractant is either a halogenated hydrocarbon or a mixture of a halogenated hydrocarbon with a ketone.
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