JPH05192391A - Manufacture of blood treating equipment - Google Patents

Abstract

PURPOSE:To provide an improved manufacturing method for providing a blood treating vessel having less blood coagulation during use. CONSTITUTION:By use of a mixture of a polyisocyanate component containing 45% or less by weight of a polyisocyanate monomer and a polyhydric alcohol component, a selective transmitting film containing 3% or more by weight and less than 50% by weight of alcohol to organic high molecular polymer is adhesively bonded and solidified, whereby an urethane resin support body is formed.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for manufacturing a blood processing device. More specifically, it relates to a method for producing an improved blood treatment device in which a selectively permeable membrane such as a hollow fiber membrane is supported by a specific urethane resin support.

[0002]

2. Description of the Related Art Recently, various blood processing devices such as artificial kidneys, artificial livers, artificial lungs and plasma separators have been developed and many have been put to practical use. In particular, a so-called hollow fiber type blood treatment device using a hollow fiber-shaped selective permeable membrane is practically advantageous because it is easy to obtain a large-sized and compact membrane area.

When manufacturing this blood processing apparatus, for example, a hollow fiber bundle is housed in a cylindrical container, the gaps at both ends of the hollow fiber bundle are adhesively sealed with urethane resin, and a support is fixed to the inner surface of the container. Further, an operation of opening the hollow fiber by cutting a part of the outer side of the urethane resin support portion may be used, if necessary. Further, for example, in the case of a hollow fiber type artificial kidney, headers for blood inlet and outlet are attached to both open end portions of the hollow fibers, and dialysate inlet and outlet are provided on the side of the cylindrical container. Is provided.

Molding of such a urethane resin support is usually carried out by reacting a polyisocyanate component and a polyhydric alcohol component. The polyisocyanate component is mainly aromatic diisocyanate and the polyhydric alcohol component is mainly castor oil. Often used. In order to facilitate the cutting operation after molding, it is necessary to set the hardness of the urethane resin support after molding (curing) to an appropriate range. Therefore, as a polyisocyanate component, an -NCO-terminated prepolymer is used. The content of the prepolymer in that case was usually about 45% by weight or less, although the content was sometimes used.

In the conventional blood treatment apparatus thus obtained, for example, when blood is purified by circulating blood in the hollow portion of the hollow fiber, the hollow wall inside the hollow fiber, especially in the urethane resin support portion, becomes hollow. In many cases, blood coagulation easily occurs on the inner wall of the thread, and its solution has been strongly desired.

[0006]

OBJECTS OF THE INVENTION The present invention aims to remedy the drawbacks of such conventional blood processors. That is, the present invention provides an improved manufacturing method for obtaining a blood processing device which causes less blood coagulation during use. In particular, a method for easily and stably obtaining a blood processor with less blood coagulation even when the content of alcohol in the film during molding of the support molded body of the membrane housed in the blood processor is relatively high. It is intended to be provided. Further, the present invention is
It is an object of the present invention to provide a manufacturing method which can easily and stably obtain a blood treatment device with less blood coagulation even when heat sterilization is used as a sterilization method. Further, the present invention provides a method for producing a blood treatment device which can easily and stably obtain a blood processor with less blood coagulation even when heat sterilization is used as a sterilization method.

[0007]

The present inventors pay attention to the behavior of each component of the support raw material at the time of molding the membrane support, and can suppress a part of the raw material component from permeating or permeating the selective permeable membrane. The inventors have found that they are very effective in suppressing blood coagulation during use of the manufactured blood processing device, and arrived at the present invention.

That is, according to the present invention, when producing a blood treating apparatus comprising a selectively permeable membrane made of an organic polymer and a urethane resin support for supporting the membrane, 45% by weight or less of a polyisocyanate monomer is used. Characterized by supporting the selective permeable membrane by molding the urethane resin support by adhering and solidifying the alcohol-containing membrane using a mixture of a polyisocyanate component and a polyhydric alcohol component containing 45% by weight or less of a polyisocyanate monomer in the production of a blood treatment device; and a blood treatment device provided with a selectively permeable membrane made of an organic polymer and a urethane resin support for supporting the membrane. By adhering and solidifying the alcohol-containing film using a mixture of a polyisocyanate component containing a polyhydric alcohol and a polyhydric alcohol component The method of manufacturing a blood processing device, characterized in that heat sterilizing a material obtained by the blood processor and allowed molded urethane resin support, there is provided a.

The present invention will be described in more detail below. That is, for example, in order to manufacture a hollow fiber blood treatment device using a hollow fiber membrane as a selective permeable membrane, a hollow fiber bundle prepared in advance is usually stored in a cylindrical container and centrifugal force or the like is used. There is used a method in which a liquid adhesive is fed to both ends of the membrane to be solidified and the both ends are sealed to form a membrane support. In the case of a dialysis type artificial kidney or the like, the hollow portions of the hollow fiber are opened while the sealing of the hollow fiber bundle gap is closed by cutting the solidified and molded membrane supports at both ends, and Attach a header for blood inlet and outlet that communicates with the hollow part of the hollow fiber at both ends,
A measuring pipe for dialysate inlet / outlet communicating with the hollow fiber bundle gap is attached to the side of the container.

According to the present invention, in the method for manufacturing such a liquid-liquid treatment device, a membrane support made of urethane resin is adopted, and the support made of the urethane resin, that is, the urethane resin support, is used in an amount of 45% by weight or less. It is characterized in that a polyisocyanate component containing an isocyanate monomer and a polyhydric alcohol component are reacted to solidify and mold. Strictly speaking, the membrane is supported by applying the urethane resin adhesive from the surface opposite to the surface directly contacting blood and solidifying and molding.

The polyisocyanate monomer contained in this polyisocyanate component is selected from aromatic polyisocyanate, aliphatic polyisocyanate, alicyclic polyisocyanate, etc., and has a carbon number of 20 excluding carbon in the --NCO group. The following are more preferable and those of 15 or less are more preferable. Among these, aromatic polyisocyanates can be preferably used, and specific examples thereof include diphenylmethane diisocyanate, tolylene diisocyanate, xylylene diisocyanate, ethylbenzene isocyanate, diethylbenzene isocyanate, phenylene diisocyanate, triphenylmethane diisocyanate,
Examples thereof include triphenylmethane diisocyanate and naphthylene diisocyanate. Among them, diphenylmethane diisocyanate and tolylene diisocyanate are preferable, and diphenylmethane diisocyanate is particularly excellent in blood affinity, moldability, adhesiveness and the like. Two or more of these polyisocyanate monomers may be used, but they are usually used alone.

The polyisocyanate component also contains a plurality of
A prepolymer having an NCO group at the end is contained,
The prepolymer is one in which two or more molecules of the compound are reacted and two or more —NCO groups are present at the terminal. As such a prepolymer, a polyhydric alcohol to which a plurality of polyisocyanate monomers are added, a polyisocyanate oligomer, and the like are preferable. Preferable polyhydric alcohols here include castor oils such as castor oil and castor oil derivatives, and glycols such as diethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. Among these polyhydric alcohols, those having a molecular weight of about 1000 or less are preferable. Further, as the polyisocyanate for the prepolymer referred to herein, in addition to the aromatic polyisocyanates exemplified above, aliphatic polyisocyanates such as tetramethylene diisocyanate and hexamethylene diisocyanate are preferable. The preferred molecular weight of the prepolymer referred to in the present invention is 1000 to 2000. Particularly preferable prepolymers in terms of blood affinity and moldability include those obtained by adding an aromatic polyisocyanate monomer to castor oil and having a molecular weight of 1500 to 2000, and further, an oligomer of an aliphatic polyisocyanate. By containing it, the viscosity may be lowered to improve the moldability.

The polyisocyanate component used in the present invention contains a polyisocyanate monomer in a range of 45% by weight or less. The polyisocyanate monomer content is 10% by weight or more, further 20% by weight or more. Is more practical because the polyisocyanate component as a whole and the viscosity at the time of forming the urethane resin can be properly controlled. When the content of the polyisocyanate monomer is 40% by weight or less, and further 35% by weight or less, the effect of preventing blood coagulation during use of the obtained blood treatment device is very large.

As the polyhydric alcohol component used in the urethane resin support of the present invention, castor oils such as castor oil and castor oil derivatives, glycols such as polyethylene glycol and polypropylene glycol are preferable, and among them, the molecular weight is 200 to 1500, Furthermore, 500-
Those in the range of 1000 are practical. As the polyhydric alcohol component of the present invention, one or more of these may be used. Among them, castor oils are superior in blood affinity and moldability. Incidentally, in this polyhydric alcohol component, a compound functioning as a polymerization reaction accelerator may be added, and specific examples thereof include ethylenediamine,
Examples include amines such as triethylamine, triethanolamine, and tetrakishydroxypropylethylenediamine.

In the molding of the urethane resin support in the production method of the present invention, the polyisocyanate component and the polyhydric alcohol component are added in such a manner that the total --NCO groups and the total --OH groups are almost equivalent or the --NCO groups are slightly excessive. A mixture of both components having a viscosity of about 500 to 2500 cps at 30 ° C. immediately after mixing is disclosed in, for example, JP-B-56-40603 and JP-B-57-58963.
In this method, both ends of a hollow fiber bundle housed in a tubular container are adhered and solidified by the centrifugal molding method disclosed in Japanese Patent Publication No. 57-58964.

In the production method of the present invention, the selective permeable membrane represented by hollow fibers is made of an organic polymer, and the liquid adhesive is a strict liquid adhesive at least during the molding of the urethane resin support. It is characterized in that it contains alcohols which mainly function as a plasticizer and a structure-retaining agent when they come into contact with each other. Conversely, by applying the above adhesive to a film containing alcohol,
An excellent effect of preventing the occurrence of blood coagulation during use can be obtained.

The organic high molecular weight polymer referred to in the present invention includes
Cellulose, cellulose acetate, cellulose propionate, cellulose such as cellulose ester such as cellulose nitrate, polyacrylonitriles, polyvinyl alcohols, polyaromatic acid amides, polycarbonates, ethylene-vinyl alcohol copolymers, Examples thereof include polymethylmethacrylates and polysulfones including polyether sulfone, and among them, cellulose and cellulose ester can be preferably used. Although two or more of these may be used, usually only one is used. The shape of the selectively permeable membrane may be any of a flat shape, a hollow fiber shape, a tube shape, and the like, but the hollow fiber shape is practical because the membrane area can be increased with a constant volume.

The alcohol contained in the film is usually used as a plasticizer or a film structure-retaining agent, and may be either a monohydric alcohol or a divalent or higher polyhydric alcohol. However, a polyhydric alcohol is usually used due to its function. As such polyhydric alcohol,
As described above, other erythritols such as glycerins and glycols, pentitols such as arabitol, hexitols such as sorbitol, and pentaerythritol are preferable. Among them, glycerins and glycols are practical, and glycerin is particularly stable. Excellent in terms of sex. Two or more of these alcohols may be used together, but it is usually preferable to use one.

In the production method of the present invention, the amount of such alcohol contained in the membrane may be selected under conditions suitable for molding the urethane resin support while maintaining the membrane structure and membrane performance. Even when the amount of alcohol produced is relatively large, there is an advantage that a blood processor with reduced blood coagulation can be obtained by using the urethane resin raw material. The alcohol content of such a membrane is 3% by weight based on the weight of the organic high molecular weight polymer constituting the membrane.
As described above, the effect of the present invention is remarkable when the content is 50% by weight or more. Regarding the upper limit of the alcohol content, it is usually about 450% by weight or less from the viewpoint of adhesive moldability, but if it is 200% by weight or less, a blood processor without blood coagulation can be obtained more reliably, which is preferable. .
The alcohol contained in the film is mainly impregnated in the film, but may be adhered to the film surface in some cases. The membrane may contain a larger amount of water as the water content per weight of the organic polymer than in the conventional case. For example, bubbles are generated in the range of 15% by weight or less, preferably 10% by weight or less. There is no adverse effect due to the above, and there is an advantage that the water management of the hollow fiber membrane becomes easy.

The combination of the amount of alcohol contained in the membrane of the present invention and the content of polyisocyanate monomer in the polyisocyanate component represents a particularly preferable range mainly in terms of the effect of preventing blood coagulation. become that way. The amount of alcohol contained in the film is 3% by weight
If it is less than the above, it is often difficult to properly maintain the membrane performance.

[0021]

[Table 1]

The present invention also includes a method for obtaining a sterilized blood processing apparatus by subjecting the blood processing apparatus manufactured by the method having the above-described characteristics to heat sterilization. This heat sterilization operation may be performed in a state in which the blood processing device is filled with water or an aqueous solution, or may be performed in a state in which the liquid is not particularly filled. The heat sterilization method of the blood treatment device mainly includes a high-pressure steam sterilization method, an intermittent sterilization method and the like, but the high-pressure steam sterilization method is advantageous in terms of sterilization reliability and operability. High-pressure steam sterilization is usually performed in the range of 110 to 130 ° C.

During such a heat sterilization operation, a substance that is likely to be eluted by heating is observed to elute. Therefore, when heat sterilization is carried out especially when water or an aqueous solution is filled, it is safe to remove the eluate. It is important in manufacturing a high blood processor. To remove this eluate, a method of washing with hot water or an organic solvent such as ethanol in advance before heat sterilization, or performing a washing operation such as filling liquid replacement during or after heat sterilization There is.

In the case of the blood treating apparatus of the present invention assembled as described above, since the polyisocyanate monomer, which is a raw material of the adhesive, hardly penetrates into the membrane, a reaction with alcohol in the membrane or on the membrane surface occurs. Since it is difficult to carry out a predetermined addition reaction of —NCO group and —OH group in the urethane resin support part, the elution of by-products resulting from the —NCO group from the urethane resin support and the film in the vicinity thereof is liable to occur. Tend to be less. Therefore, the cleaning operation for removing the eluate accompanying the heat sterilization of the blood processor of the present invention can be relatively simple. A typical membrane material suitable for heat sterilization is cellulose.

The blood processing apparatus manufactured according to the present invention may be sterilized by heat sterilization as described above, but other than that, ethylene oxide gas sterilization, formalin sterilization,
Sterilization may be performed by any method such as radiation sterilization. In any of the sterilization methods, since the specific raw material as described above is used, the original flatness of the film can be easily maintained properly without being disturbed particularly on the surface of the urethane resin support film. The effect of preventing blood coagulation is obtained.

Examples of the blood treatment device in the present invention include artificial kidneys and artificial livers for performing hemodialysis and hemofiltration, plasma separators, artificial lungs and the like, but other devices may be used.

[0027]

EXAMPLES The present invention will be described in more detail below with reference to examples.

[0028]

Examples 1 to 7 and Comparative Examples 1 to 3 Approximately 12000 cellulose diacetate hollow fiber membranes for hemodialysis having an inner diameter of 200 μm and an outer diameter of 225 μm and containing the amount of glycerin shown in Table 2 were converged and dialyzed. A prepolymer in which a diphenylmethane diisocyanate (hereinafter referred to as MDI) monomer was added to castor oil, which was housed in a cylindrical cylindrical container having a side tube portion for liquid inlet and outlet, and a polypolymer containing the amount of MDI monomer shown in Table 2 Use a mixed solution of isocyanate component and polyhydric alcohol component containing castor oil as a main component and a polymerization reaction accelerator in a ratio such that the --NCO group and the --OH group are equivalent to solidify both ends of the mixture. To form a urethane resin support, cut the ends of both supports to open the hollow fiber, and then attach the respective headers for blood inlet and outlet. A hemodialyzer for an artificial kidney having an effective surface area of about 1.2 m ² was molded.

The blood chamber side and the dialysis chamber side of the hemodialyzer thus obtained were filled with about 100 ml / well of physiological saline at about 37 ° C.
After washing for about 10 minutes at a flow rate of 10 minutes, about 10 liters of fresh blood from a pig is circulated for 1 hour at a flow rate of 200 ml / minute, and the blood in the dialyzer is dialyzed with 100 ml of physiological saline. After substituting from the upper side to the lower side of the vessel at a flow rate of 200 ml / min and further flowing air at a flow rate of 200 ml / min,
The upper header was removed and the percentage of hollow fibers clogged with blood was evaluated.

The results are also shown in Table 2. Most of the residual blood is due to blood coagulation in the vicinity of the membrane surface of the urethane resin support.

[0031]

[Table 2]

[0032]

Examples 8 to 10, Comparative Example 4 A cylinder similar to that of Example 1 was prepared by concentrating 10000 cellulose dialyzer hollow fibers for dialysis having an inner diameter of 210 μm, an outer diameter of 250 μm and containing the amount of glycerin shown in Table 3. The mixture was placed in a cylindrical container, and a support using a mixture of the polyisocyanate component and the polyhydric alcohol component similar to that of Example 1 was formed except that the content of the MDI monomer in the polyisocyanate component was shown in Table 3, and further carried out. A hemodialyzer was molded in the same manner as in Example 1.

The hemodialyzers thus obtained were each washed with distilled water at 95 ° C. at a flow rate of 50 ml / min for about 1 hour, and then filled with distilled water almost at 115 ° C. in an autoclave.
Heat sterilization was performed for 0 minutes. Further, these dialyzers were subjected to the same residual blood volume evaluation test as in Example 1, and the results shown in Table 3 were obtained.

[0034]

[Table 3]

[0035]

Example 11 A hemodialyzer molded in the same manner as in Example 1 was subjected to EO gas sterilization and then subjected to the same washing with distilled water and residual blood evaluation test as in Example, and the residual blood hollow fiber was obtained. The result was 0%.

[0036]

Examples 12 to 14 and Comparative Example 5 The same dialysis cellulosic hollow fibers as in Example 8 were adjusted to the glycerin content shown in Table 4, and 10000 fibers were bundled into Example 1.
The sample was placed in the same container as above, and a support was formed in the same manner as in Example 1 to form a hemodialyzer.

Each of the obtained dialyzers was washed with distilled water at 95 ° C. at a flow rate of 50 ml / min for about 1 hour, and then heat-sterilized at 115 ° C. for 30 minutes in an autoclave in a state in which the distilled water was packed almost completely. did.

The UFR and urea clearance, which are the performance of the dialyzer thus obtained, were measured using distilled water and fresh pig blood, and the results shown in Table 4 were obtained.
For the measurement of urea clearance, the blood flow rate is 200 ml /
And the dialysate flow rate was 500 ml / min.

[0039]

[Table 4]

[0040]

According to the manufacturing method of the present invention, there is an excellent advantage that a blood treatment device with less blood coagulation can be reliably obtained when used for blood treatment. Such an improvement in anticoagulant property also makes it possible to reduce the amount of residual blood, which reduces the blood loss of the patient who uses it, and is a very significant improvement in safety.

Claims (5)

[Claims] 1. A blood processor comprising a selective permeable membrane composed of an organic high molecular polymer and a urethane resin support for supporting the membrane, which contains 45% by weight or less of a polyisocyanate monomer. By using a mixture of polyisocyanate component and polyhydric alcohol as a component, the selective permeable membrane containing 3% by weight or more and less than 50% by weight of alcohol with respect to the organic polymer is adhered and solidified to obtain the urethane. A method for manufacturing a blood treatment device, which comprises molding a resin support. 2. The polyisocyanate component is 10 to 4
2. The method for producing a blood treating apparatus according to claim 1, wherein the preservative comprises a prepolymer having a diphenylmethane diisocyanate monomer in the range of 5% by weight and the other mainly comprises a plurality of --NCO terminals. 3. The organic high molecular polymer is cellulose, cellulose ester, polyacrylonitrile, polyvinyl alcohol, polyaromatic acid amide, polycarbonate,
The method for producing a blood processing apparatus according to claim 1, wherein the blood processing apparatus is at least one selected from the group consisting of ethylene-vinyl alcohol copolymer, polymethylmethacrylate, and polysulfone. 4. The method for manufacturing a blood processing apparatus according to claim 1, wherein the alcohol is at least one selected from polyhydric alcohols. 5. A blood processing apparatus comprising a selectively permeable membrane made of an organic polymer and a urethane resin support for supporting the membrane, wherein the blood treatment apparatus contains 45% by weight or less of a polyisocyanate monomer. By using a mixture of a polyisocyanate component and a polyhydric alcohol component, the selective permeable membrane containing alcohol in an amount of 3% by weight or more and less than 50% by weight with respect to the organic high molecular weight polymer is adhered and solidified to obtain the urethane resin. A method for manufacturing a blood processing apparatus, comprising heat-sterilizing a blood processing apparatus obtained by molding a support.