JPH0376971B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a composite membrane. More specifically, a monomolecular condensed film formed by spreading a copolymer of a hydrophilic monomer and a hydrophobic monomer on the liquid surface is laminated on a support layer with the side having many hydrophilic segments facing up. The present invention relates to a medical composite membrane that has excellent biocompatibility, particularly blood affinity. [Prior Art] In recent years, there has been remarkable progress in separation techniques using membranes, and some of them have been put into practical use on an industrial scale. Looking back at the history of these developments, we can see that improvements in separation efficiency and membrane mechanical, chemical,
It can be seen that the composite structure of membranes is being developed with the aim of achieving both biological durability and biological durability. The composite membrane in such a separation membrane consists of an active layer and a support layer, with the support layer maintaining membrane strength and the active layer controlling permeability. In general, the thinner the active layer is, the higher its permeability to substances;
Ultra-thin films are used. One of the methods for manufacturing such ultra-thin films is the so-called on-water casting method, in which a non-aqueous polymeric solvent is spread on the water surface to form an ultra-thin layer of the solution, and this is then removed. . Specifically, as a large-area ultra-thin layer manufacturing method, a pair of partition rods is installed above the water surface, and a polymer solution is dripped into the area separated by the partition rods, and the distance between the partition rods is increased. method (Japanese Patent Application Laid-Open No. 51-89564), a method in which a solvent with a higher density than water is used and the solution is forcefully spread on the water surface by passing a movable surface such as a rotating roll through a solution reservoir installed below the water surface. (U.S. Pat. No. 3,767,737), a method of spreading a polymer solution on the water surface by controlling the relative liquid surface position of the aqueous phase and the solution phase (Japanese Patent Laid-Open No. 58-92526)
No.) etc. are known. However, since these ultra-thin membranes are considered as active layers in reverse osmosis, liquid-liquid separation, gas separation, etc., they essentially have only a homogeneous and smooth structure and are not biocompatible. It cannot be said that it is excellent. Also, JP-A-57-
No. 159506 discloses a composite membrane in which the active layer is composed of molecules of a crosslinked monomolecular film. Although this film can be said to be a much more advanced film in that the active layer is an ultra-thin layer with a specific orientation and structure, the surface of the active layer is still only a homogeneous and smooth structure, and it has poor biocompatibility. It is insufficient in this respect. On the other hand, in terms of biocompatibility, in addition to conventional materials such as medical silicone rubber, polyhydroxyethyl methacrylate, and Teflon, blenders of hydrophilic polyether urethane and hydrophobic polydimethylsiloxane, and segmented copolyether -Urethane-Urea etc. are being studied. In particular, since the latter two have a microphase-separated structure of hydrophilic and hydrophobic parts, not only the primary structure of the polymer but also the higher-order structure of the surface is an important factor for antithrombotic properties. It is recognized that this is the case (Region of Chemistry, 34, 519). Another example of a highly biocompatible surface structure is a scattering layer. (Polym.
PrePrints, Japan, 28, 1542 (1979)). This is a higher-order structure in which flexible hydrophilic side chains protrude from the polymer surface into the water like seaweed, and have high blood compatibility due to the molecular movement and electrical repulsion of the hydrophilic layer. It is believed that it will be shown. As mentioned above, there are materials with high biocompatibility that exhibit their properties through a special chemical structure (primary structure) and those that exhibit their properties through a specific three-dimensional structure (higher-order structure). Some exhibit biocompatibility due to the above properties or both properties, and all of these have been developed as implantable biomaterials such as blood tubes, blood bags, artificial blood vessels, artificial hearts, and catheters. However, there have been no research examples of thinning the material to create a composite membrane with good substance permeability and excellent biocompatibility. [Problems to be solved by the invention] As mentioned above, conventional composite membranes made of ultra-thin films have poor biocompatibility, while the above-mentioned biocompatible materials have poor substance permeability. However, at present, a composite membrane that successfully combines the advantages of both is not yet known. In view of this situation, the present inventors formed an ultra-thin layer with excellent biocompatibility and used it as an active layer to create a composite membrane with excellent biocompatibility that can also exhibit substance permeability. As a result of intensive studies to obtain this, it was unexpectedly possible to spread a solution of a copolymer of a hydrophilic monomer and a hydrophobic monomer on the water surface and compress it with a predetermined surface pressure to release the hydrophilic segment of the copolymer. After forming a monomolecular condensed film submerged in water, or during molding, transfer the condensed film onto a support layer with the surface in contact with the water surface facing up, or
Alternatively, after the copolymer is diffused and developed on the non-aqueous solvent surface and compressed with a predetermined surface pressure to form a monomolecular condensed film in which the hydrophobic segments of the copolymer have penetrated into the non-aqueous solvent. The present inventors have discovered that it is possible to obtain a composite membrane that satisfies the above objectives by forming the condensed membrane and transferring the condensed membrane onto a support layer with the side not in contact with the non-aqueous solvent surface as the surface, and have thus arrived at the present invention. . [Means and effects for solving the problem] The present invention spreads a copolymer of a hydrophilic monomer and a hydrophobic monomer on a liquid surface to form a monomolecular condensed film, and makes the condensed film hydrophilic. Although this is a composite membrane formed by laminating a support layer with the surface having many segments facing up, the copolymerization type of the copolymer is not particularly limited, and a general-purpose random copolymer is generally used. The effects of the present invention are great when block copolymers and graft copolymers are used, and ethylene-vinyl alcohol copolymers are particularly preferred. Examples of the hydrophilic monomer used in the copolymer include those containing a hydroxyl group such as vinyl alcohol and cellulose, and known neutral hydrophilic monomers containing an aldehyde group, an ethylene oxide group, and the like. In addition, carboxyl groups, sulfate groups, sulfite groups,
It is also possible to use monomers containing nitrate groups, nitrite groups, phosphoric acid groups, phosphorous acid groups, hypophosphorous acid groups, and ester groups thereof, or monomers containing these ions that can be negatively ionized in water. Monomers containing amino groups, imino groups, etc. that can be positively charged in water can also be used, but since these have the property of easily adsorbing proteins in body fluids, when using the composite membrane of the present invention for such treatment, , it is necessary to inactivate the active center before use. Examples of methods for deactivating the active center include binding with a negatively charged substance such as heparin, binding with various enzymes, hormones, proteins, and physiologically active substances. Hydrophobic monomers used in the copolymer of the present invention include olefin, diene, acetylene, aromatic, organosiloxane, and fluoroethylene monomers. In the present invention, various membranes having so-called pores, such as membranes and dialysis membranes, are used as the support layer. Such a membrane is desirably a membrane whose surface in contact with the monomolecular condensed membrane has an average pore diameter of 1000 Å or less, preferably 400 Å or less. If a membrane with an average pore diameter larger than 1000 Å is used, defects will occur when a monomolecular condensation membrane is transferred to the membrane, and permselectivity will likely be impaired. Further, as the support layer, a material generally referred to as a film or sheet, which has a substantially pore-free structure and extremely low permeability to substances, is also used. A virtually pore-free structure means
A structure in which the presence of pores cannot be confirmed even with a scanning electron microscope at a magnification of 100,000 times. In the present invention, when the above films and sheets are used as a support layer, the effect of the present invention is to modify their surfaces and impart high biocompatibility. When used as a layer, the effect is not only to simply modify the membrane surface, but also to provide excellent biocompatibility with high substance permeability. Therefore, when such a membrane is used as a support layer, the effect is more clearly expressed. Further, as a special support layer, for example, a monomolecular film of the same or different materials or a composite film in which a cumulative film thereof is fixed can be used, or a hollow fiber membrane can also be used. Although the thickness of these supports is not particularly defined in the present invention, they are practically used in the range of several μ to several mm. The composite membrane of the present invention is composed of these support layers and a monomolecular condensed layer, and the monomolecular condensed layer may be used as a single layer or as a multilayer as a cumulative membrane. However, in either case, it is necessary that the surface has a large number of hydrophilic segments. Next, a method for manufacturing the composite membrane of the present invention will be described. A monomolecular condensed film of a hydrophilic monomer and a hydrophobic monomer can be produced using a known method. For example, according to the Langmiuer method, a polymer copolymer is dissolved in a solvent that is as insoluble as possible and lighter than water, and the solution is spread on a water surface having a movable partition rod. When the solvent evaporates or dissolves, a monomolecular film of the copolymer remains on the water surface.
The partition rod is moved to reduce the area of the water surface and compress the monolayer on the water surface. As the compression rate is increased, the segments begin to be buried in water from the areas with the highest hydrophilic monomer density, forming a monomolecular condensed film in which the areas with the highest hydrophilic monomer density protrude into the water and the areas with the highest hydrophobic monomer density protrude into the air. is obtained. In the case where the copolymer is a block copolymer or a graft copolymer made of a hydrophilic monomer and a hydrophobic monomer, the effect appears more clearly because of the presence of long segments of the hydrophilic monomer. Also, if the above operation is performed using a non-aqueous solvent,
It is also possible to make the areas with high hydrophilic monomer density protrude into the air. The process by which such a monomolecular condensed film is produced on the water surface is schematically shown in FIGS. 2 to 4. Figure 2 shows a state in which a copolymer consisting of a hydrophilic monomer and a hydrophobic monomer is spread on the water surface;
The figure shows a state in which the hydrophilic segment protrudes into water by compression, and FIG. 4 is a schematic diagram in a state in which it is bonded to a support layer. Moreover, FIG. 1 is a schematic diagram of a composite membrane of the present invention manufactured by such a method. The degree of protrusion of the hydrophilic segments can be controlled with good reproducibility by determining a predetermined compression ratio and temperature depending on the composition and structure of the copolymer. In order to increase the strength of the obtained monomolecular condensed film, it is also an effective method to add salts or substances reactive with the copolymer in advance into the water or on the water surface. The monomolecular condensed film can be transferred onto the support by known methods such as the Langmuir-Blodget method, the rotating cylinder method, and the horizontal deposition method. In the composite membrane obtained as described above, the bond between the surface layer consisting of a monomolecular condensed membrane and the support layer may not be sufficient depending on the application. Therefore, it is also practically effective to firmly bond the monomolecular condensed film to the support layer using known techniques such as photocrosslinking, radiation crosslinking, and chemical reaction. Although it is not completely clear why the composite membrane of the present invention exhibits excellent biocompatibility, the composite membrane of the present invention has a surface that is similar to the conventional homogeneous surface as shown in FIG. Unlike a smooth structure, the monomolecular condensed film has a so-called scattering layer structure with protruding hydrophilic segments, so the movement of this layer eliminates approaching blood coagulants, Furthermore, it is considered that albumin is adsorbed onto the layer, thereby covering the surface of the layer, thereby reducing the adhesion of platelets, blood cells, and the like. Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples in any way. Example 1 An ethylene-vinyl alcohol copolymer with an ethylene content of 32 mol% and a degree of saponification of 99.8 mol% was dissolved in a mixed solvent of benzene and dimethyl sulfoxide, and the solution was dropped onto distilled water at room temperature and allowed to diffuse. A monomolecular condensed film was formed. After standing for 1 hour, the monomolecular film was compressed to a surface pressure of 20 dyne/cm.
As shown in Figure 5, according to the surface pressure-area curve of the ethylene-vinyl alcohol copolymer, the copolymer becomes a liquid expanding membrane when the surface pressure is 10 dyne/cm or less.
Below 15 dyne/cm, it becomes a liquid condensation film.
The occupied area per monomer in this condensed film state is approximately
The area is 2.5 Å ² , which is extremely small compared to the approximately 11 Å ² occupied area of the monomer according to the molecular model, and it is clear that the hydrophilic segment is buried in water or the hydrophobic segment is folded into the air. Next, a clean ethylene-vinyl alcohol copolymer film was gently placed on this monomolecular condensation film, and the monomolecular condensation film was transferred onto a support film by a horizontal adhesion method. The composite membrane obtained in this way was placed inside a cell with an internal volume of 1.5 cc, and fresh dog blood was injected into it in an airtight state.
After holding for 10 minutes, the blood was discarded, rinsed with phosphate buffer, fixed with glutaraldehyde, and then electron microscopic observation of the surface of the composite membrane revealed that there was little adhesion of platelets and almost no change in platelet morphology. It was not recognized at all. From the above results, it is clear that the composite membrane of the present invention has excellent blood compatibility. Example 2 An ethylene-vinyl alcohol film with a surface average pore diameter of approximately 300 Å (according to scanning electron microscopy) was used as the support layer, and a monomolecular condensation film was transferred onto the support by the Langmiur-Blodget method. Example 1
A composite membrane was obtained in the same manner as above, and the platelet adhesion behavior was examined. As a result, the number of platelets attached was small, and almost no change in platelet morphology was observed. Furthermore, the water permeability and albumin rejection rate of this composite membrane were measured, and the results were as shown in Table 1. For comparison, Table 1 also shows the results measured using only the support layer. From these results, it is clear that the composite membrane of the present invention exhibits excellent blood affinity and high permselectivity.

〔Effect of the invention〕

According to the present invention, a composite membrane can be provided in which a monomolecular condensed membrane of a copolymer of a hydrophilic monomer and a hydrophobic monomer is laminated on a support layer with the surface having many hydrophilic segments facing the surface. When a so-called film or sheet that is substantially non-porous and exhibits no substance permeability is used as the support layer of the composite membrane, it exhibits good biocompatibility, particularly excellent blood compatibility. Furthermore, when a membrane with so-called pores, such as a permeable membrane or a dialysis membrane, is used as the support layer, it exhibits not only excellent biocompatibility but also high substance permeability. The composite membrane of the present invention is widely used in medical applications such as artificial organs such as artificial kidneys and artificial lungs, biomaterials for implantation such as blood tubes, blood bags, and artificial blood vessels, and detection ends of medical sensors.

[Brief explanation of drawings]

FIG. 1 is a schematic diagram showing a composite membrane of the present invention. Figure 2 shows the state in which a copolymer consisting of a hydrophilic monomer and a hydrophobic monomer is spread on the water surface, Figure 3 shows the state in which hydrophilic segments protrude into the water by compression, and Figure 4 shows the support layer. FIG. FIG. 5 is a curve showing the surface pressure-area of the ethylene-vinyl alcohol copolymer used in the examples. 1... Monomolecular condensed film whose surface has a surface having many hydrophilic segments, 2... Protruding hydrophilic segments, 3... Support layer, 4... Hydrophilic group, 5... Hydrophobic group, 6
...Water surface.

Claims (1)

[Claims] 1 A copolymer of a hydrophilic monomer and a hydrophobic monomer is spread on the liquid surface to form a monomolecular condensed film with many hydrophilic segments on one surface and many hydrophobic segments on the other surface. , a composite membrane formed by laminating the condensed membrane on a support layer with the side having many hydrophilic segments facing up.