JPS6328625B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for manufacturing an artificial organ. More specifically, the present invention relates to a method for manufacturing artificial organs such as an artificial kidney, an artificial liver, an artificial lung, and a blood separation device, which do not substantially cause transient leukopenia. (Prior art) Artificial organs such as artificial kidneys, artificial livers, artificial lungs, and blood separation devices have been used in the past, and especially in the dialysis area, they have been used as dialysis membranes such as hollow fiber membrane type and flat membrane type. Regenerated cellulose-based materials are widely used from the viewpoint of dialysis properties, mechanical strength, cost, etc. However, artificial organs using such regenerated cellulose-based membranes, such as regenerated cellulose-based artificial kidneys, suffer from so-called transient leukopenia (hemodialysis leukopenia), in which the number of white blood cells decreases temporarily and rapidly immediately after the start of dialysis. ) and other side effects on living organisms, and the impact this has on patients cannot be ignored. On the other hand, synthetic polymer membranes such as polymethyl methacrylate, polyacrylonitrile, ethylene-vinyl alcohol copolymer, and polycarbonate, which have recently been proposed as permeable membranes, are less likely to cause transient leukopenia than the regenerated cellulose-based membranes. These synthetic polymer membranes have a poor balance between physical properties such as mechanical strength, heat resistance, ultrafiltration rate (UFR), etc., and performance during processing, assembly, or use. There are problems such as not only limited patients, but also high costs, increased pinholes during use, and limited sterilization methods. In order to solve the above-mentioned problems, it has been proposed to modify the surface of the regenerated cellulose membrane using heparin or the like, but satisfactory results have not yet been obtained. Therefore, the present inventors first introduced a solution of fatty vitamins in an organic solvent (e.g., lower alcohol) into the body fluid circulation area in the artificial organ, and after making sure that the solution was thoroughly absorbed into the contact area with the solution. , manufacture of an artificial organ in which the surface of the body fluid circulation area in the artificial organ that can come into contact with the body fluid is coated with a film of fat-soluble vitamins by discharging the solution and then drying to remove the solvent. The authors proposed a method for manufacturing an artificial organ in which the solvent is similarly removed, and a liquid that is harmless to the living body is brought into contact with the side surface of the flow area to perform sterilization. However, since the organic solvent used in the above method is methanol, lower ethanol such as ethanol, diethyl ether, etc., not only does the drying time take a long time, but also fat-soluble vitamins tend to peel off and a sufficient film cannot be formed. It was hot.
Particularly when sterilized by autoclaving, the releasability was remarkable. (Problems to be Solved by the Invention) Therefore, an object of the present invention is to provide an improved method for manufacturing an artificial organ. Another object of the present invention is to provide a method for manufacturing an artificial organ with fewer side effects on living organisms. Still another object of the present invention is to provide a method for manufacturing an artificial organ that substantially does not cause transient leukopenia. Another object of the present invention is to provide a method for manufacturing an artificial organ with good durability (first invention). In addition to the above object, the present invention provides a method for manufacturing an artificial organ with good autoclave sterilization resistance. (Second invention). (Means for Solving the Problems) These objectives are achieved by flowing a solution of vitamin E in a chlorinated fluorocarbon or a fluorinated hydrocarbon solvent into a regenerated cellulose hollow fiber membrane type body fluid flow area in an artificial organ. After the solution is thoroughly applied to the contact area with the solution, the solution is discharged and then dried to remove the chlorinated fluorinated hydrocarbon or fluorocarbon hydrogen solvent. This is achieved by a method for manufacturing an artificial organ (first invention) in which the surface of a part of the body fluid circulation area that can come into contact with the body fluid is coated with a vitamin E film. Further, the present invention provides that the chlorofluorinated hydrocarbon solvent is 1,1,2-trichloro-1,
2,2-trifluoroethane, trichlorofluoromethane and 1,1,2,2-tetrachloro-
This is a method for producing an artificial organ made of at least one member selected from the group consisting of 1,2-difluoroethane. The present invention provides a method in which the concentration of vitamin E in a chlorinated fluorinated hydrocarbon or fluorinated hydrocarbon solvent solution is 0.01.
-10 w/v%, especially 0.1-1 w/v%, is a method for producing an artificial organ. Furthermore, the present invention is a method for producing an artificial organ, in which drying is performed by flowing a gas inert to the vitamin E through the body fluid circulation area at a temperature of 10 to 80°C. In addition, these purposes are achieved by coating the body fluid flow area surface of a regenerated cellulose hollow fiber membrane-type body fluid permselective membrane in an artificial organ with a solution of vitamin E in a chlorinated fluorocarbon or a fluorinated hydrocarbon solvent; By a method for producing an artificial organ (second invention), which removes a chlorofluorinated hydrocarbon or a fluorinated hydrocarbon solvent, further brings a liquid harmless to living organisms into contact with the side surface of the flow area, and performs autoclave sterilization. achieved.
Further, the present invention provides that the chlorinated fluorohydrocarbon solvent has 1,
1,2-trichloro-1,2,2-trifluoroene, trichlorofluoromethane and 1,
This is a method for manufacturing an artificial organ made of at least one member selected from the group consisting of 2,2-tetrachloro-1,2-difluoroethane. Furthermore, the present invention provides that the concentration of vitamin E in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent is between 0.01 and 10 w/v%, especially
This is a method for producing an artificial organ with a concentration of 0.1 to 1 w/v%. Further, the present invention is a method for manufacturing an artificial organ, in which the liquid harmless to living bodies is water, physiological saline, or aqueous glycerin solution. The permselective membrane used in the present invention refers to a membrane that has the property of separating a specific substance from a fluid by selectively permeating it, and is used in a dialysis method or an ultrafiltration method. Refers to membranes used in microporous filtration methods, gas exchange methods, etc. (Function) The artificial organ in the present invention is one that has a circulation area for body fluids such as blood, such as an artificial kidney, an artificial liver, an artificial lung, a blood separation device, a blood circuit, and an artificial blood vessel. be. Note that the artificial organ includes not only tubes and connectors that connect the living body to the artificial organ, but also other blood circuits and the like. Next, one embodiment of the present invention will be described with reference to the drawings. FIG. 1 shows an example of an artificial organ, that is, a hollow fiber dialyzer. This dialyzer 1 is constructed by inserting a hollow fiber bundle 5 made of a large number of hollow fibers into a cylindrical body 4, which has an inlet pipe 2 and an outlet pipe 3 for dialysate near both ends. It has a structure similar to, for example, a shell-and-tube type device in a heat exchanger, in which both ends of the cylindrical body are sealed with potting agents 6 and 7 such as polyurethane, and both ends of the cylindrical body are sealed. Headers 10 and 11 each having an inlet 8 and an outlet 9 for blood are brought into contact with the headers 10 and 11, respectively.
The headers 10 and 11 and the cylindrical body 4 are fixed by caps 12 and 13, respectively. Tubes 14 and 15 connected to the human body are connected to the inlet 8 and the outlet 9. Therefore, the hollow fibers constituting the hollow fiber bundle 5 are dialysis membranes, for example, regenerated cellulose membranes,
Preferred is a copper alumonia regenerated cellulose membrane. According to the present invention, a body fluid of the artificial kidney as described above, for example, a contact site with the blood in the blood circulation area,
For example, the inner surface of the hollow fiber membrane, the inner surface of the space formed by the header 10 and the potting agent 6, the inner surface of the space formed by the header 11 and the potting agent 7, the inner surface of the blood inlet 8, the inner surface of the blood outlet 9,
The inner surfaces of the tubes 14 and 15, particularly the inner surfaces of the hollow fiber membranes, are coated with a vitamin E coating. For example, as shown in FIG. 2, the inner surface of a hollow fiber membrane 16 is coated with a vitamin E coating 17. The vitamin E used in the present invention includes α-
These include tocopherols such as tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol, and tocotrienols such as α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. The thickness of the vitamin E coating is 0.001 to 0.1 μm, preferably 0.002 to 0.05 μm. Such vitamin E has a concentration of 0.01 to 10w/v
%, preferably 0.1 to 1 w/v% of chlorinated fluorinated hydrocarbon or fluorinated hydrocarbon solvent solution to the regenerated cellulose hollow fiber membrane type body fluid flow area (first to
In the case of the artificial kidney shown in FIG. 2, the blood flow into the blood circulation area) and contact for a predetermined period of time, e.g. 30 seconds to 60 minutes, preferably 1 to 10 minutes, causes the inner surface of the area, e.g. tube 14, header 10 The vitamin E is sufficiently absorbed into the space formed between the hollow fiber and the potting agent 6, the space formed between the header 11 and the potting agent 7, and the inner surface of the tube 15. Then, after discharging the solution, a gas inert to the vitamin E, such as air, nitrogen, carbon dioxide, etc., is introduced at a temperature of 10 to 80°C, preferably 15 to 30°C to convert the solution into chlorinated fluoride. A coating of vitamin E is formed on the contact surface by evaporating and removing the hydrocarbon or fluorinated hydrocarbon solvent, which is further washed with water if necessary. In this case, it is of course possible to carry out the coating operation without connecting the tubes 14 and 15 to form a vitamin E coating on the main parts, especially the permeable membrane parts. Particularly in artificial organs using regenerated cellulose membranes that are prone to transient leukopenia, significant effects can be obtained by coating the permeable membrane portion with vitamin E. In addition, in the case of regenerated cellulose, especially regenerated cellulose produced by cuprammonium method, as the permeable membrane, glycerin can be included in the chlorinated fluorohydrocarbon or fluorinated hydrocarbon solvent solution of vitamin E, thereby allowing the permeation. It can impart hydrophilic properties to the membrane. Therefore, it is effective in artificial organs that use hydrophilic permeable membranes, such as artificial kidneys and artificial livers. The concentration of glycerin in the solution is 0.1 to 10 w/v%, preferably 1 to 5 w/v%.
v%. The chlorofluorinated hydrocarbon solvents used in the present invention include 1,2,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane,
Examples include 1,1,2,2-tetrachloro-1,2-difluoroethane, and preferably 1,1,2-trichloro-1,2,2-trifluoroethane. In addition, examples of fluorinated hydrocarbons include methyl fluoride,
Perfluorosicaroalkanes such as carbon tetrafluoride, tetrafluoroethane, tetrafluoroethylene, perfluoromethylpropylcyclohexane, perfluorobutylcyclohexane, perfluorodecane, perfluoromethyldecalin, perfluoroalkyltetrahydropyran, perfluorodecane etc. Artificial organs manufactured in this way can be sterilized and stored using autoclave sterilization, ethylene oxide sterilization, gamma ray sterilization, etc., or
Alternatively, a sterilized conventional artificial organ is coated with vitamin E as described above before use. In addition, the artificial organs manufactured in this way are
After removing the chlorinated fluorocarbon or fluorinated hydrocarbon solvent, an additional biologically harmless liquid, e.g.
At least one type of liquid selected from the group consisting of water, physiological saline, and aqueous glycerin solution is brought into contact with the side surface of the body fluid flow area, and sterilized using an autoclave. The above has mainly explained the artificial kidney, which is a dialyzer, but it can of course also be used for artificial livers, artificial lungs, artificial blood vessels, blood circuits, blood separation devices, etc. Among them, permeable membranes for body fluids, especially blood A remarkable effect can be obtained by forming the vitamin E coating on the area having the above-mentioned vitamin E coating. In addition, to check whether the membrane is coated with vitamin E, contact the membrane with a solvent again.
can be detected by elution. (Example) Next, the present invention will be described in further detail by giving examples. Example 1 Inner diameter approximately 200μm, outer diameter approximately 220μm, length 14-14.5cm
Using 368 cuprammonium regenerated cellulose hollow fibers, as shown in FIG.
, headers 10 and 11 were attached to both ends, and the caps 12 and 13 were used to secure the dialyzer (artificial kidney) 1. The inner membrane area of this product was 300 cm ² . On the other hand, vitamin E (DL-α-tocopherol)
0.5g of 1,1,2-trichloro-1,2,2-
Vitamin E dissolved in 100ml of trifluoroethane
A solution of 1,1,2-trichloro-1,2,2-trifluoroethane was prepared. A 50 ml syringe was connected to one end of the dialyzer 1, and the other end was immersed in the vitamin E solution. The plunger of the syringe was activated to fill the dialyzer with the vitamin E solution. In this state, it was left at room temperature for about 5 minutes. Next, the dialyzer was pulled up to discharge the vitamin E solution, an aspirator was connected, and the dialyzer was dried by blowing air at a temperature of 25°C. Furthermore, to ensure complete drying, it was left in an oven at 60°C overnight. The dialyzer thus produced was sterilized by autoclaving at 115° C. for 30 minutes. The theoretical thickness of the vitamin E coating in the dialyzer thus obtained was estimated to be approximately 0.025 μm. Example 2 In the method of Example 1, vitamin E 1,1,
A dialyzer was manufactured in the same manner as in Example 1 except that the concentration of vitamin E in the 2-trichloro-1,2,2-trifluoroethane solution was 0.7 w/v%. The theoretical thickness of the vitamin E coating in this dialyzer was estimated to be 0.035 μm. Comparative Example For comparison purposes, a dialyzer similar to Example 1, which was not treated with a solution of vitamin E in 1,1,2-trichloro-1,2,2-trifluoroethane, was wetted simply by autoclaving. Example 3 After measuring the weight of the rabbit, it was fixed in the dorsal position on a Kitajima fixation table. Next, the hair in the surgical field was trimmed with electric clippers and wiped with alcohol cotton. An incision was made along the midline from the submandible to the clavicle with scissors, the muscle limbs were further opened, and the right (left) common carotid artery was removed, being careful not to damage the meridian, branch vessels, and surrounding tissues. Then, the left (right) facial vein was carefully dissected in the same way, and a Surflow indwelling catheter with a rubber cap for mixed injection filled with 11 U/ml heparinized saline was inserted and tied off. Similarly, a catheter was also inserted into the artery, and the artery was tied off. The weights of the test rabbits at this time were as shown in Table 1. Table 1 Sample weight (Kg) VE 0.5% 2.63 VE 0.7% 2.54 No treatment 2.57 Regarding rabbit 20 prepared in this way,
The dialyzers 1 of Examples 1 and 2 and Comparative Example were opened to prepare experimental circuits. i.e. rabbit 2
The catheter 21 connected to the artery of
2, a bypass catheter 23 is connected to the catheter 21, and the bypass catheter 23 is connected to the catheter 21.
was connected to the chamber 24 that communicated with the out 25 side of the manometer, and the chamber 24 and the vein of the rabbit 20 were further connected with a catheter 26. The pump 22 and the dialyzer 1 are connected through a tube 27, and the tube 27 communicates with the inlet 28 side of the manometer. Further, the dialyzer 1 and the chamber 24 were connected through a tube 29. On the other hand, the dialysate inlet and outlet of the dialyzer 1 were connected through a tube 30, and a pump 31 was installed in the tube 30, and the dialyzer 1 was immersed in a water bath 32 at 37°C.
The thus constructed circuit was primed and washed with 1 IU/ml heparinized saline (100 ml). The collected blood was diluted 2 times with 1.5% EDTA-3K saline, and then
(manufactured by Instrument). The white blood cell counts (WBC), platelets (PLT) and hematocrit values (HCT) obtained as a result are shown in Tables 3 to 5.
In addition, the white blood cell count and platelet count are calculated using the following formula.
The HCT value was corrected and expressed as the HCT value immediately before the start of circulation. Cx=Co HCTx HCTo However, the symbols in the formula are as follows. Cx: Correction value Co: Actual measurement calculation value HCTx: Correction standard Hct value = initial Hct value HCTo: Hct value when Co value is obtained.
Initial count) indicates the change over time relative to the initial 100, with the percentage after the start of counting as 100.

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[Table] Figure 4 shows the changes over time in the number of white blood cells obtained from the above results. In the same figure, curve A is for vitamin E 0.5%, and curve B is for vitamin E.
Curve C shows the case of 0.7% E and the case of 0% vitamin E, respectively. Furthermore, the change in platelet count over time is shown in FIG. In the same figure, curve D is for vitamin E 0.5%, and curve E is for vitamin E.
Curve F shows the case of 0.7% E and the case of 0% vitamin E, respectively. (Effects of the Invention) As described above, the method for manufacturing an artificial organ according to the present invention (first invention) provides a method for producing an artificial organ using a regenerated cellulose hollow fiber membrane-type body fluid distribution area in an artificial organ. Injecting a hydrocarbon solvent solution and thoroughly blending the solution into the contact area with the solution, discharging the solution, and then drying to remove the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent. Since the coating process is carried out by Less is. Furthermore, the action of the vitamin E used can reduce side effects on living organisms, such as transient leukopenia, and also exhibits an excellent effect on inhibiting platelet expansion. In particular, in the method of the present invention, chlorinated fluorinated hydrocarbons or fluorinated hydrocarbons are used as the solvent, so compared to the case where organic solvents such as alcohol are used, vitamin A is delivered to the body fluid distribution area within the artificial organ. E
It has the advantage of having strong coating strength, making it difficult to peel off and having good durability. In addition, in the method for manufacturing an artificial organ (second invention) in which after removing the solution, a liquid that is harmless to the living body is brought into contact with the side surface of the body fluid circulation area, and then sterilized in an autoclave, vitamin E
Since it is coated, there is no need to sterilize it before dialysis. Furthermore, compared to the case of using an organic solvent such as alcohol, since a chlorofluorinated hydrocarbon is used as a solvent, there is no peeling of vitamin E even when sterilization is performed by heating in the presence of the liquid.
Durability is significantly increased.

[Brief explanation of the drawing]

FIG. 1 is a perspective view with a partial cutout showing an embodiment of the position of the artificial organ according to the present invention, FIG. 2 is a longitudinal cross-sectional view of a hollow fiber, and FIG. In the experimental circuit, FIG. 4 is a graph showing changes over time in the number of white blood cells, and FIG. 5 is a graph showing changes over time in the number of platelets. 1... dialyzer, 4... cylindrical body, 5...
...Hollow fiber bundle, 6,7...Potting agent, 10,
11... Header, 12, 13... Cap.

Claims (1)

[Scope of Claims] 1. A solution of fat-soluble vitamin E in a chlorinated fluorohydrocarbon or a fluorinated hydrocarbon solvent is introduced into a regenerated cellulose hollow fiber membrane-type body fluid circulation area in an artificial organ, and the solution is introduced into a region in contact with the solution. After thoroughly blending the solution, the chlorinated fluorinated hydrocarbon or fluorinated hydrocarbon solvent is removed by drying. A method for producing an artificial organ coated with a vitamin E film. 2 The chlorofluorinated hydrocarbon solvent is from the group consisting of 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane and 1,1,2,2-tetrachloro-1,2-difluoroethane. The method for manufacturing an artificial organ according to claim 1, which is at least one selected type. 3. The method for manufacturing an artificial organ according to claim 1 or 2, wherein the concentration of vitamin E in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent solution is 0.01 to 10 w/v%. 4. The artificial organ according to any one of claims 1 to 3, wherein the concentration of vitamin E in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent solution is 0.1 to 1 w/v%. Production method. 5. The drying method according to any one of claims 1 to 4, wherein the drying is performed by flowing a gas inert to the vitamin E at a temperature of 10 to 80°C in the body fluid circulation area. Method for manufacturing artificial organs. 6. The side surface of the body fluid flow area of a regenerated cellulose hollow fiber membrane-type body fluid permselective membrane in an artificial organ is coated with a solution of vitamin E in a chlorinated fluorinated hydrocarbon or fluorinated hydrocarbon solvent, and then A method for producing an artificial organ, which comprises removing a hydrogenated hydrocarbon solvent, contacting a side surface of the flow area with a liquid that is harmless to living organisms, and performing autoclave sterilization. 7 The chlorofluorinated hydrocarbon solvent is from the group consisting of 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane and 1,1,2,2-tetrachloro-1,2-difluoroethane The method for manufacturing an artificial organ according to claim 6, which is at least one selected type. 8. The method for manufacturing an artificial organ according to claim 6 or 7, wherein the concentration of vitamin E in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent solution is 0.01 to 10 w/v%. 9. The artificial organ according to any one of claims 6 to 8, wherein the concentration of fat-soluble vitamins in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent is 0.1 to 1 w/v%. Production method. 10. The method for manufacturing an artificial organ according to any one of claims 6 to 9, wherein the liquid harmless to living organisms is water, physiological saline, or aqueous glycerin solution.