JPS607496B2 - Heat sterilization method for artificial kidneys - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for heat sterilization of an artificial kidney and an artificial kidney used for the heat sterilization. An artificial kidney having a container containing a hollow fiber made of a selectively permeable membrane, and having a closure in the container consisting of an inlet and an outlet for blood and an inlet and an outlet for dialysate. This method is known per se, and it replaces the function of the living kidney by removing waste products from the blood into the dialysate through dialysis and by passing excess water in the blood through an ultrafilter. Hollow fiber artificial kidneys are becoming increasingly important due to their advantages of being relatively small and easy to use.Artificial kidneys are sterilized during manufacturing to prevent bacterial contamination before being delivered to the user. Up until now, users have performed the necessary pretreatment on sterilized artificial kidneys before using them. Conventionally, artificial kidneys have been sterilized using the following two methods. The first method is that the manufacturer has placed a relatively high
The artificial kidney is usually sterilized and shipped by filling it with an aqueous formaldehyde solution with a concentration of 1 to 5%, and the user washes and removes the formaldehyde inside the artificial kidney. This is a method in which the membrane is subjected to necessary treatments such as filling with physiological saline and then subjected to dialysis. Although this method is an effective method for sterilization, the formaldehyde used as a sterilizing agent is toxic to the human body, so it is necessary to thoroughly wash and remove formaldehyde so that it does not remain in the artificial kidney. In order to do this, it is necessary to flush a large amount of water for a long period of time to clean it.However, such cleaning is a complicated operation and has the disadvantage of consuming a considerable amount of effort and time on the part of the user. Furthermore, even after the formaldehyde concentration in the cleaning wastewater has decreased and formaldehyde is virtually undetectable, if cleaning is stopped and left as it is, the formaldehyde remaining in the hollow fiber membranes etc. will gradually ooze out. In the second method, the manufacturer supplies a dry hollow fiber artificial kidney with a sterilizing gas, such as ethylene oxide or propylene oxide at a concentration of 10-30% as the sterilizing component, and the remaining percentage of Freon. or sterilized by passing through Namiai Gust containing carbon dioxide gas, and then shipped.
In this method, the user performs necessary treatments such as filling the dry sterilized artificial kidney with dialysate, physiological saline, etc., and then uses it for dialysis. This method has the problem that gases such as ethylene oxide and propylene oxide are adsorbed and remain on the hollow fiber membrane of the artificial kidney, and ``these residual gases react with chlorine ions in the dialysate and physiological saline. There are also problems such as the production of harmful chlorohydrin compounds.In order to clean these residual gases, it is necessary to pass a large amount of physiological saline (approximately 200ml or more) through the pipe.Furthermore, hollow fiber type artificial When passing fluid into the hollow fibers of the kidney, it is necessary to pass the fluid for a long time in order to completely remove air bubbles, or to replace the air in the hollow fibers with sterile carbon dioxide gas, as the tubes are capillary tubes. In the latter case, the user needs to prepare equipment such as a carbon dioxide cylinder, a sterilization filter, a pressure regulator, and a flow regulator. If so, there is a risk that microbubbles may flow into the body during dialysis, and this may cause blood clots within the hollow fibers, increasing the amount of blood remaining in the dialyzer after dialysis is completed, leading to greater blood loss. Furthermore, in this gas sterilization method, the performance of the artificial kidney is likely to change because the dry artificial kidney is brought into a moist state during pretreatment, and the reproducibility of the performance of the artificial kidney is unstable.
In addition to the different sterilization methods, a third method is 0.5 to 9
A method of sterilizing an artificial kidney by irradiating it with Mrad gamma rays has been proposed. This radiation sterilization method does not use a sterilizing agent, so there is no problem of residual toxicity. However, ``the pretreatment of filling a dry artificial kidney with physiological saline, dialysate, etc. tends to cause a change in the performance of the artificial kidney, similar to the second method. The materials that make up the kidney are easily degraded by radiation, and there are still unresolved issues in selecting suitable materials for material improvement.In general, sterilization methods include:
In addition to the above-mentioned methods, there is a heat sterilization method, which is widely used as a method for sterilizing syringes and surgical instruments. , 30 minutes; 12100, 2 minutes or 1
2600, which specifies a method of killing microorganisms by heating in saturated steam for 15 minutes. Furthermore, in the Japanese Pharmacopoeia mentioned above, 30 to 6 minutes each time in 80 to 10,000 water or under circulating steam every 2 hours.
Intermittent sterilization with ~5 heating cycles is also permitted. Since heat sterilization has the advantages of no residual toxicity and easy cleaning, it would be extremely convenient if heat sterilization could be applied to artificial kidneys. However, heat sterilization methods have not been applied to artificial kidneys to date, and it was thought that heat sterilization methods would be impossible to implement, especially for artificial kidneys filled with filling liquid. It had not been attempted at all. The reason for this is that when an artificial kidney is heated, the artificial kidney is deformed, cracked, or destroyed due to the thermal expansion of the filling fluid and air contained within the artificial kidney, and the self-generating pressure of water vapor, resulting in leakage of the filling fluid. This is due to the fact that it is difficult to aseptically seal the artificial kidney after sterilization. The present invention has successfully solved the above problems, and an object of the present invention is to provide a method for heat sterilization of an artificial kidney filled with a filling liquid. An object of the present invention is to provide a user with an artificial kidney that substantially eliminates the need for pretreatment. A heat sterilization method for an artificial kidney in which an opening consisting of a blood inlet, a blood outlet, a dialysate inlet, and a dialysate outlet are provided in ``{b) Connect a pressure buffer tank to at least one of the closed openings, and seal the remaining openings □ not connected to the pressure buffer tank with a sealing means, and close the artificial kidney. Heat sterilize the artificial kidney by heating it to a temperature in the range of 80 to 13,000 degrees Celsius, and move the part of the filling liquid and gas inside the artificial kidney expanded by the heating to a pressure buffer tank, {e} After sterilization, the artificial kidney is cooled, thereby allowing the artificial kidney to recover the filling liquid that had been transferred to the pressure buffer tank. A heat sterilization method consisting of each step, and a container containing a hollow fiber made of a selectively permeable membrane, and the container has a closure consisting of a blood inlet, a blood outlet, a dialysate inlet, and a dialysate outlet. A method for heat sterilization of an artificial kidney equipped with an artificial kidney comprising: ``filling the artificial kidney with a filling liquid consisting of water or an aqueous solution, ``b} connecting a pressure buffer bag to at least one of the openings, {c} The remaining closure that is not connected to the pressure-absorbing bag is sealed using a sealing means, and the artificial kidney is sealed for 80 minutes.
Heat sterilize the artificial kidney by heating it to a temperature within the range of ~13,000° C. At that time, a part of the filling liquid and gas inside the artificial kidney expanded by heating are transferred to a pressure buffer bag,
} After sterilization, the artificial kidney is cooled, thereby allowing the artificial kidney to collect the filling liquid that had been transferred to the pressure buffer bag. Provided is a heat sterilization method comprising the steps of: sealing. FIG. 1 is a diagram schematically showing how the heat sterilization method of the present invention is carried out. FIG. 2 is a diagram schematically showing one embodiment of the heat sterilization method of the present invention, and FIG. 3 a or b is a diagram showing another embodiment of the heat sterilization method of the present invention. Figures 4 to 6 show typical examples of buffer bags used in the embodiment shown in Figure 3a. Fig. 8 shows a connecting tube suitable for use in the method shown in Fig. 7; 8a and ga are longitudinal sectional views, and 8b and gb are longitudinal sectional views. Each is a cross-sectional view taken along line A-A.
An important feature of the heat sterilization method of the present invention is that the pressure buffer tank or pressure buffer bag that performs special functions is connected to the "blood inlet", "blood outlet", "dialysate inlet" and "dialysate inlet" of the artificial kidney filled with filling fluid. Connect to at least one of the closed ports consisting of the outflow port, and seal the remaining ports.
The point is that sterilization is performed by heating to a temperature within the range of 0. When heating is carried out under such conditions, the filling liquid and gas components such as air present in the artificial kidney, which expand due to the rise in temperature, move into the pressure buffer tank or pressure buffer bag.
As a result, the internal pressure of the artificial kidney caused by the thermal expansion of the fluids (filling liquid and gaseous components) and the increase in water vapor pressure is buffered, which would otherwise be the case if such a buffering effect did not exist. It is also possible to effectively avoid deformation of the artificial kidney from cracking or destruction.That is, the pressure buffer tank and pressure buffer bag used in the present invention can effectively prevent the expanded fluid (filling liquid and gas components)
The pressure buffer tank used in the method of the present invention has a pressure buffering function to store the artificial kidney and a function to buffer the pressure increase in the artificial kidney that occurs during heating. Although it communicates with the outside (atmosphere), it is either a tank that is isolated from the outside (atmosphere) in terms of bacteria, or a tank that is isolated from the outside in terms of pressure and bacteria. In addition, the pressure buffer bag used in the method of the present invention is one that is sealed from the outside both in terms of pressure and bacteria, and includes, for example, a sealed bag. When used, this bag must be able to expand itself in response to the movement of expanded fluid (filling liquid and gas components) into its interior, so that it can exert a pressure-absorbing effect. Preferably. In the method of the present invention, when the connection between the artificial kidney and the pressure buffer tank is released after heat sterilization of the artificial kidney, "a means for preventing leakage of the filling liquid" is used for the opening connected to the pressure buffer tank. In addition, in the method of the present invention, even if a pressure buffer bag is used, "a means for preventing leakage of the filled liquid" is provided for the opening connected to the pressure buffer bag in the same manner as above. In some cases, it may be necessary to create a seal by using the method of the present invention.It is another important feature of the present invention that the method of the present invention allows this seal to be easily performed aseptically. Sterilization is preferably carried out based on the 9th revised Japanese Pharmacopoeia, and includes high-pressure steam sterilization (115 to 126°C) and intermittent sterilization (8
0 to 10,000) is also applied within the range of 80 to 130qC. The present invention will be explained below with reference to the drawings. Figure 1 is a diagram schematically showing how heat sterilization of an artificial kidney is carried out according to the method of the present invention. The artificial kidney 1 consists of a container 2 in which a large number of hollow fibers 3 having selectively permeable membranes are housed. 3
is supported by the partition wall 5. The container 2 has a blood inlet 6 and a blood outlet 6, which are usually thin side tubes with a barrier port.
', and a dialysate inlet and a dialysate outlet 7', usually consisting of thick side pipes with closed openings. Both ends of the container 2 are a blood distribution section 4 and a blood collection section, which are separated by a partition wall 51 from a dialysis room in the center of the container 2 where dialysis is performed. Container 2 Hollow fiber 3, partition wall 5, side pipes 6, 6
', 7 and 7' are all 80-130 for heat sterilization.
It is made of a material that does not substantially undergo thermal deformation in the temperature range of 0.000. Before heat sterilizing the artificial kidney 1 according to the method of the present invention, the artificial kidney 1 is first filled with a filling liquid of water or an aqueous solution. Thereby, the filling liquid fills all the spaces in the container 2, that is, the spaces in the hollow fibers that are blood passages, the spaces between hollow fibers that are dialysate passages, and the blood distribution part 4 and blood collection part 4'. and all the spaces within the side tubes 6, 6', 7 and 7'. At least one of the side pipes 6, 6', 7 and 7' (conduit 6' in FIG. 1) is connected to a pressure buffer tank or pressure buffer bag 101 via a pipe 9, and the other side pipes is provided with means 8 (such as a plug or a seal) for preventing leakage of the filling liquid. In this state, the artificial kidney 1 is heated to a temperature of 80 to 130 q0 to perform heat sterilization, but it may also be heated together with the artificial kidney 1 in the pressure buffer tank or pressure buffer bag. Alternatively, only the artificial kidney 1 may be heated by placing the pressure buffer tank or pressure buffer bag 10 outside the heater. When the artificial kidney 1 is heat sterilized, the expanded portion of these fluids leaves the artificial kidney 1 due to the expansion of the filling fluid and air in the artificial kidney due to the increase in temperature, and the self-generating pressure of water vapor, causing the pressure to rise. A buffer tank or pressure buffer bag 10 is entered, by which the pressure within the artificial kidney is buffered. If the artificial kidney is cooled after completing the specified sterilization, the fluid remaining in the artificial kidney will contract and the water vapor pressure will also decrease, resulting in a reduced pressure state inside the artificial kidney. As a result, the artificial kidney tries to return from this reduced pressure state to a normal pressure state and passes through the pressure buffer tank or pressure buffer bag 1 through the conduit 9.
An aqueous solution of the retained water enters the artificial kidney 1. The heat sterilization method of the present invention can be carried out by either of the two embodiments described below. The first embodiment uses a pressure buffer tank which can contain a filling liquid in advance, and allows the filling liquid in the artificial kidney and the filling liquid in the pressure buffer tank to communicate with each other. This is a method of heat sterilization by connecting the two. Figure 2 schematically shows an example of this first embodiment, and does not necessarily accurately depict the actual embodiment. In other words, the pressure buffer tank includes a pressure buffer bellows 14 as described later, a sterilization filter 15, etc.; Here, a plurality of artificial kidneys are each connected to one pressure buffer tank 10', and the filling liquid in each artificial kidney is transferred to the filling liquid phase 12 in the pressure buffer tank 10. A gas phase 13 exists above the liquid phase 12. In Fig. 2, 14 is a bellows for pressure buffering, and 15 is a sterilization filter for passing gas. It is preferable to use such bellows and/or sterilization filters to provide pressure buffering. In this first embodiment, during heat sterilization, the expanded fluid (filling liquid and Air) moves from the artificial kidney 1 to the pressure buffer tank 10, but during cooling, only the filling liquid returns to the artificial kidney 1, and the air remains in the gas phase 13 and does not return to the artificial kidney 1. After heat sterilization, the amount of gas components such as air that existed in the artificial kidney will decrease compared to before heat sterilization.The amount of gas components existing in the artificial kidney will be reduced as much as possible. The above-mentioned reduction in the content of gas components brought about by the heat sterilization process is advantageous since it is desirable that the amount of gas components be reduced, and herein it is referred to as "improvement of the filling condition of the artificial kidney". If the filling state of the artificial kidney is insufficient, air bubbles present in the blood flow path may cause blood clots, etc., and air bubbles present in the dialysate flow path may reduce the effective membrane area of the hollow fibers. This is not preferable because it reduces the dialysis efficiency.The first embodiment of the method of the present invention described above is an extremely preferred embodiment because it can improve the filling state of the artificial kidney.In the first embodiment, Preferably, the pressure buffer tank 10 is made of a material such as metal, glass, or heat-resistant resin, and the conduit 3 is made of a material such as silicone rubber or heat-resistant synthetic rubber. This shows an example of the second embodiment, in which a pressure buffer bag 10, such as a balloon bag, is connected to the side tube 7' of the artificial kidney. In this method, the pressure buffer bag itself expands to absorb the fluid inside the artificial kidney expanded by heat sterilization, buffering the pressure, and thereby reducing the load on the container and blood distribution and collection parts of the artificial kidney. Become. However, this second
In this embodiment, no improvement in filling condition can be achieved. In the embodiment shown in FIG. 3, there is no particular need to disconnect the artificial kidney from the pressure buffer bag after heat sterilization of the artificial kidney. However, if the artificial kidney is connected to the pressure buffer bag in the manner shown in Figure 2, it is necessary to release the connection after sterilization, in which case the same means for preventing leakage of the filling fluid as described above must be used. It is necessary to seal it by The material of the buffer bag is required to have physical properties that will prevent it from bursting upon expansion. Any non-toxic material may be used as long as it has green fever resistance at 80 to 130°C and is medically safe. For example, cushioning bags made of rubber-like elastic materials such as natural rubber, synthetic rubber such as polysoprene rubber and polybutadiene rubber, silicone rubber, polyurethane elastomer, etc., or polypropylene, polyester, nylon, polypropylene-polyester laminates, etc. Any buffer bag made of a non-elastomeric material, such as a film, can be used as the pressure buffer bag of the second embodiment.The volume of the buffer bag is defined as the maximum inflation volume within pressure limits. However, at least fluids due to expansion due to heating (filling liquid and air)
It is necessary that the increase in volume of Second
The shape of the buffer bag used in this embodiment can be various shapes such as a bag, a balloon, or a tube, but a particularly suitable buffer bag has an inner thick part 21 as shown in FIGS. It is a bag in which the inner thin part 22 is integrated, the inner thick part is the main part that engages with the side tube of the artificial kidney, the inner thin part is an inflatable part, and the inner thick part is the main part that engages with the side tube of the artificial kidney. Thickness T (ribs)
This is a buffer bag in which the thickness t (willow) of the inner thin portion has the relationship expressed by the following formula m to '3}. 0.05 Willow StS2. Vengeance...{1
}0.25 TS5. Comparison...■
・<Tei≦300-...-{31 The volume of the buffer bag at zero pressure (at normal pressure) is 2 to 100 mm, preferably 4 to 50 mm. The maximum inflation volume varies depending on the artificial kidney and its filling condition, but
If there are 400 artificial organs and their filling status is 400, and the remaining air volume is between 0 and 20, 2070 can be expected.
Therefore, the buffer bag must be able to expand when the pressurized volume does not reach the maximum inflation volume, and the buffer bag must be stretched flat to prevent gas from entering the bag during use. However, it must be filled with a small amount of water or an aqueous solution before installation. Therefore, the thickness (t) of the thin portion is 005 to 2 to allow expansion and flat expansion. ratio, preferably 0.10 to 1.0. Moreover, when it is necessary to expand, it is preferable that the elongation at break is in the range of 100 to 1500%. More preferably 300-1000%
is within the range of On the other hand, the neck, which is attached to the side tube of the artificial kidney, is the fixing part of the bag, and is thick so as to have a sealing effect to prevent leakage of filling liquid, etc. and secondary contamination after heat sterilization. This thickness (T) is 0.25 to 5.0 ribs, preferably 0.4
~3.0 sardines. Although the thin part and the thick part are molded into one piece, they can also be molded into two or more pieces and integrated by adhesive or the like. The relationship between the two thicknesses satisfies equation '3}. FIG. 4 shows a buffer bag suitable for a narrow side tube of an artificial kidney, such as a blood port. The length and length of the neck portion 21 that engages with the side tube may be dimensioned to engage and seal with the side tube. FIG. 5 shows a buffer bag suitable for a large side tube, such as a dialysate inlet. FIG. 6 shows that the inner surface 23 of the neck matches the outer shape of the side tube, and the thickness T in this case is defined as the average of the minimum dimension T and the maximum dimension T2. The shape may be substantially cylindrical, ellipsoidal, or entirely oval as shown in Figure 6. In the heat sterilization method of the present invention, after the heat treatment is completed, the artificial kidney and pressure Before disconnecting the buffer tank, it is necessary to aseptically seal the closure connected to the pressure buffer tank. There are two main methods for achieving this aseptic seal: The first method is to connect the conduit 9, which has a thick tip, with the side tube 6' of the artificial kidney 1, as shown in the artificial kidney 1 at the left end of FIG. Inside the thick part,
In this method, the stopper 11 for preventing leakage of the filling liquid is suspended, and after the heat sterilization process is completed, the stopper 11 is installed in the side pipe 6' before disconnecting the side pipe 6' and the conduit 9. After heat sterilization, the inside of the artificial kidney and the pressure buffer tank are in a sterile state, so the above operation can achieve aseptic sealing of the side tube 6'. 7, the side tube 7' of the artificial kidney 1 and the conduit 9 are connected via a connecting tube 30 having a melt-sealed part 31. This method achieves aseptic sealing by melt-sealing the melt-sealing portion 31 after the heat sterilization process is completed and before disconnecting the side pipe 7' and the conduit 9. Any material can be used as long as the sealing part 31 can be melt-sealed by heat, high frequency, or ultrasonic waves, and can be sterilized by high-pressure steam. Examples include polyvinyl chloride, polyolefin, polyurethane, etc. In addition to the above two methods, if the side tube or conduit 9 of the artificial kidney can be melt-sealed, it may be melt-sealed, as exemplified by the artificial kidney in the center of FIG. Alternatively, if the pressure buffer bag described above is used, the pressure buffer bag may be left on without being removed and used as a seal.Used in the second method described above. Connecting tubes suitable for
As shown in the figure, it is a cylindrical tube consisting of a cylindrical engaging part 32, a sealing part 31, and a cylindrical conduit part 33, and the engaging part 32 is connected to a side tube of an artificial organ. The welded part 31 has a narrow neck shape, and the maximum external dimension of its cross section is 2 to 15 ribs, and the maximum internal dimension of its cross section is 1.
The connecting tube 30 is made of a material that can be melt-sealed and has a thickness of ~14 mm. The melting part 31 is located in the center of the connecting tube 30, and the coupling part 32 and the conduit part 33 are located at both ends of the connecting tube 30. In addition, the engaging portion 32 and the conduit portion 33
The shapes and dimensions of the tubes may be determined in consideration of the shape and sealing properties of the respective mating tubes. For practicality as a conduit, the melt-sealed portion 31 should have an internal dimension of one side or more and a cross-sectional dimension of 14 willow or less considering the dimensions of the side tube of the artificial kidney and the melt-sealed area. It is preferable that the maximum outer dimension of the port sealing part 31 is 2 to 15 willows depending on the inner diameter, considering the aqueous solution retention and the welding area.More preferably, the maximum outer dimension of the welding part 31 is The dimensions are 3 to 8 ribs, and the inner dimension of the cross section is 2 to 7 sides.The cross-sectional shape may be circular, oval, oval, quadrilateral, etc.If the welded part 31 has a string diameter, the cross-section is circular, In the case of a relatively large size, a fan-flat oval shape, an oval shape, or a quadrilateral shape is preferable because the port sealing operation can be easily performed, but the shape is not limited to these shapes.
FIG. 8 shows a connecting tube 30 suitable for engagement with a narrow side tube (blood port) of an artificial kidney. The engaging portion 32 and the conduit portion 33 have a cylindrical shape so as to form a sealing engagement. A of the melting part 31
-A' cross section is circular. FIG. 9 shows a connecting tube 30 suitable for engagement with a thick side tube (dialysate port) of an artificial kidney. The shape of the engaging part 32 is cylindrical with a conical top part 34, and it engages and seals with the side tube, and is also designed to facilitate the work of attaching and detaching the connecting tube when using this artificial kidney on a patient. A collar 35 is attached. In this connecting tube, the A-A' cross section of the sealing portion 31 is shaped like a square oval. According to the method of the present invention, heat sterilization of an artificial kidney can be easily carried out. In addition, this needle does not cause destruction, deformation, or poor sealing of the artificial kidney filled with water or an aqueous solution by heating for heat sterilization, and the blood flow path can be maintained. This has the advantage of preventing cross-contamination. Furthermore, the artificial kidney heat sterilized by the method of the present invention has an improved filling state and can exhibit excellent mass exchange performance and blood compatibility. Artificial kidneys heat sterilized by the method of the invention have an overall high degree of sterility guarantee, there is no risk of residual toxicity and are easy to prepare for cleaning. Further, according to the present invention, there is provided a hollow fiber type artificial kidney comprising a hollow fiber, a septum, and a container as an artificial kidney suitable for heat sterilization, in which the hollow fiber, the septum, and the container contain 40 to 13,000 particles. The partition wall member has substantially heat resistance within a range of linear expansion coefficient a [1/00]
is in the range of 40 to 13000, and the coefficient b[1
/00] and temperature t

[00], and (4.13 x 10-5), 0.0076 orbital diameter 2b and the partition wall member do not undergo secondary transition in the range of 50 to 120q0. An artificial kidney with features is provided. The artificial kidney configured as described above does not cause deformation or destruction of the capital material or seal failure due to heat sterilization heating, and can maintain the blood flow path and the treatment liquid flow path. As a result, combined with the heat resistance of the hollow fibers, excellent performance can be achieved. In order to create an artificial kidney that satisfies the above conditions, it is usually necessary to construct the artificial kidney using the following materials by a method known per se. That is, as the material for the hollow fibers, cellulose, cellulose ester, polyacrylonitrile, polyvinyl alcohol, polyaromatic acid amide (for example, polyamide benzhydrazide isophthalamide), polycarbonate, polyether polysulfone, etc. can be used. Particularly preferred materials are cellulose, polyacrylonitrile, and polycarbonate to polysulfone. As the material of the container, for example polycarbonate, polysulfone, poly-4-methylbentene-1, polyvinyridine fluoride and polyacetal can be used, in particular highly transparent polycarbonate Mt, polysulfone "Poly4-1", etc. Methylbentene-1 is a preferred material. A high molecular weight polymer is preferred as the material for the partition walls. Among high molecular weight polymers, two or more components (i.e., one or more prepolymers, a curing agent, etc.) can be formed by addition polymerization. Preferred are polymers that are polymerized and crosslinked and whose total mass does not substantially change.Such polymers include urethane resins and epoxy resins.Among urethane resins, prepolymers with isocyanate terminals and ,
Poly(ester type urethane), which is produced by addition polymerization of a fatty acid having a hydroxyl group and a polyol (curing agent) consisting of a glycerin ester, is preferable. Embodiments of the present invention will be explained in detail below using examples. Example 1 and Comparative Example 1 Cellulose hollow fiber with an inner diameter of 250 mm and a membrane thickness of 30 mm
The blood distribution plate made of polypropylene was tightened and fixed with a bag cap made of polycarbonate, and the blood distribution plate made of polypropylene was fixed with a polycarbonate bag cap. The thread-type artificial kidney was set up on a rope. Distilled water was filled on the blood side and the dialysate side of the hollow-fiber type artificial kidney assembled in this way, and a silicone rubber tube was connected to one place at the dialysate port. With the other end of the tube connected to 200ml of distilled water placed in a glass pressure buffer tank, heat sterilize it for 30 minutes with ilyo using an autoclave, then slowly cool it to room temperature and heat it under high pressure. The artificial kidney was taken out from the steam sterilizer.The weight of the artificial kidney thus obtained before filling {a} and the weight after filling 'b) and the weight of the artificial kidney after heat sterilization treatment {c} were measured. From the measured values, the amount of filling liquid before and after heat sterilization was calculated. The results are shown in Table 1 below. As Comparative Example 1, the amount of filling liquid before and after heat sterilization was calculated. The results are also shown in which the air on the blood side and the dialysate side was replaced with carbon dioxide gas and then filled with distilled water, which shows that the heat-sterilized artificial kidney obtained according to the present invention has been improved in both the actual filling volume and the appearance. Table 1 Also, as a result of conducting a sterility test on the artificial kidney obtained according to the present invention,
Both bacteria and fungi were negative. Furthermore, a hollow fiber leak test was conducted to confirm that there was no leak, and then dialysis performance was evaluated. At this time, in order to confirm the effect of improving the filling condition, measurements were taken with the filling condition of the present invention, and after the filling liquid on the dialysate side was drained for 10, 20, and 30 minutes, the artificial kidney was shaken well to remove air bubbles. The measurements were carried out after making the particles smaller and making the distribution more uniform.The results are shown in Table 2 below.Table 2 Dialysis performance model of ureaBlood: 0.01% urea aqueous solution (QB=200min) Dialysate; Water (Qo =500 screams'mjn)
From the results in Table 2, it is clear that the filling state affects the dialysis performance. Examples 2 to 4 A hollow fiber type artificial kidney assembled under the same conditions as in Example 1 and filled with distilled water was heat sterilized using a high-pressure steam sterilizer in the same manner as in Example 1 while varying the temperature. did. Regarding the artificial kidney thus obtained, the same procedure as in Example 1 was carried out.
The weight of the artificial kidney before and after filling (a and b) and the weight of the artificial kidney after heat sterilization were measured, and from these measurements, the amount of filling liquid after heat wave germination was determined by calculation. The results are shown in Table 3. Furthermore, the result of conducting a sterility test on the artificial kidney thus obtained was that it was negative for both bacteria and fungi.In other words, the present invention made it possible to obtain an artificial kidney with an improved t-filling state. Example 5 A hollow fiber artificial kidney was assembled in the same manner as in Example 1.Next, the blood side and the dialysate side of the artificial kidney were filled with 2,000 ml of distilled water, and one place near the dialysate inlet was filled with "thickness of the inner thin part". A buffer bag made of silicone rubber with a diameter of 0.5 willow and a volume of 50' as shown in Fig. 6 was attached so as to prevent gas from entering the buffer bag.The amount of liquid filled in the artificial kidney was was above 422, and the residual air amount was measured after heat sterilization and was 17 [. Prevented leakage.
The artificial kidney with the buffer bag attached in this way was sterilized using an autoclave at 115°C under a pressure of 2.0k9'.
The powder was heat sterilized, the internal pressure of the sterilizer was maintained at 2.0 kg' by introducing sterilized air, and the material was slowly heated to room temperature, and then taken out from the high-pressure steam sterilizer. There was no weight change at all - there was no leakage of the filling liquid. In addition, the results of a sterility test were negative for both bacteria and fungi. Furthermore, a test for leaks from the hollow fibers was carried out.
There was no leakage and an artificial kidney could be manufactured. Examples 6 to 12 and Comparative Examples 2 to 4 A hollow fiber artificial kidney assembled under the same conditions as Example 5 was heated at 20°C on the blood side and dialysate side.
Fill with distilled water of Heat sterilization was carried out under various conditions as shown below. The results are shown in Table 4 below. In addition, Examples 6 to 1
All sterility tests conducted on the artificial kidney shown in 2 were negative. That is, very good results were obtained in the present invention. The silicone rubber buffer bag used was an inflatable balloon type and had the shape shown in FIGS. 5 and 6. A bag-shaped polypropylene buffer bag was made from polypropylene film. In Comparative Examples 2 to 4 in Table 4, "The reason why the buffer bag was damaged by heat sterilization is that the volume of the buffer bag was smaller than the increase in volume of water and residual air in the artificial kidney due to expansion due to heating. This is thought to be due to the fact that. After filling the dialysate with saline, a connecting tube made of medical polyvinyl chloride and shaped as shown in Figure 9 was attached to the dialysate port, and piping was connected as shown in Figure 7.The buffer tank was sterilized. A filter was attached, and the three powders were heat sterilized at 115°C.After cooling, the melt-sealed part of the connecting tube was sealed using an ultrasonic welder, and the artificial kidney and the buffer were aseptically isolated. Then, the conduit side of the connecting tube was cut to prepare a product.A sterility test of the product showed negative results for both bacteria and fungi.

[Brief explanation of drawings]

Figure 1 is a schematic diagram showing an example of the present invention, and Figure 2 is also a schematic diagram showing an embodiment of the heat sterilization method of the present invention. Figure 3 a or b shows another embodiment of the present invention. FIG. 4 is a perspective view showing a typical example of a buffer bag used in an embodiment of the present invention. FIG. FIG.
In the drawing, 1 is an artificial kidney, 2 is a container, 3 is a hollow fiber to 8G filled liquid leak prevention means, 9 is a conduit, IQ is a pressure buffer tank or pressure buffer bag, 14 is a bellows, 1 is a container This is the tube for connecting the bacteria filter and 3Q!

Claims (1)

[Scope of Claims] 1. A container containing hollow fibers made of a selectively permeable membrane, and an opening in the container consisting of a blood inlet, a blood outlet, a permeate inlet, and a dialysate outlet. 1. A method for heat sterilizing an artificial kidney provided, comprising: (a) filling the artificial kidney with a filling liquid consisting of water or an aqueous solution; and (b) filling at least one of the openings.
(c) sealing the remaining opening not connected to the pressure buffer tank with a sealing means; (d)
) Heat sterilize the artificial kidney by heating the artificial kidney to a temperature within the range of 80 to 130°C, and at that time, move a part of the filling liquid and gas in the artificial kidney expanded by heating to a pressure buffer tank. (e) cooling the artificial kidney after sterilization, thereby allowing the artificial kidney to collect the filling liquid that had been transferred to the pressure buffer tank, and (f) aseptically opening the opening connected to the pressure buffer tank. A heat sterilization method consisting of each step of sealing. 2. The method according to claim 1, wherein after the step (f), the connection made in the step (b) is released. 3. Before the step (b), the filling liquid is introduced into the pressure buffer tank to form two phases, a filling liquid phase and a gas phase, in the pressure buffer tank, and then the filling liquid phase is introduced into the pressure buffer tank before the step (b). 2. The method of claim 1, wherein said connection is made, thereby communicating the filling fluid within said artificial kidney with said filling fluid phase in said pressure buffer tank. 4. The method according to claim 3, wherein the pressure buffer tank is a tank that communicates with the outside in terms of pressure, but is isolated from the outside in terms of bacteria. 5. In the step (b), by interposing a conduit between the opening and the pressure buffer tank, and connecting one end of the conduit to the opening and the other end of the conduit to the pressure buffer tank, 2. The method of claim 1, wherein said opening and said pressure buffer tank are connected. 6. Heat sterilization of an artificial kidney having a container containing hollow fibers made of a selectively permeable membrane, and having openings in the container consisting of a blood inlet, a blood outlet, a dialysate inlet, and a dialysate outlet. A method comprising: (a) filling the artificial kidney with a filling fluid comprising water or an aqueous solution; and (b) filling at least one of the openings.
(c) sealing the remaining opening not connected to the pressure buffer bag with a sealing means; (d)
) Heat sterilize the artificial kidney by heating the artificial kidney to a temperature within the range of 80 to 130°C, and at that time, move a part of the filling liquid and gas inside the artificial kidney expanded by heating to a pressure buffer bag. (e) cooling the artificial kidney after sterilization, thereby allowing the artificial kidney to collect the filling liquid that had been transferred to the pressure buffer bag; and (f) opening, if necessary, further connected to the pressure buffer bag. A heat sterilization method consisting of each step of aseptically sealing. 7. The method of claim 6, wherein the pressure buffer bag is a sealed bag made of rubber elastic material so as to be inflatable by increasing internal pressure. 8. The bag is an integrated bag with a thick wall portion and a thin wall portion, the thick wall portion is a neck portion that engages with the opening of the artificial kidney, and the thin wall portion is an inflatable portion, and Claim 7, wherein the thickness T (mm) of the thick portion and the thickness t (mm) of the thin portion satisfy the relationships of the following formulas (1) to (3).
The method described in section. 0.05mm≦t≦2mm...(1) 0.25mm≦T≦5mm...(2) 1<T/t≦30...(3) 9 After the step (f), in the step (b) 7. The method according to claim 6, wherein the connection that has been made is canceled. 10 In the step (b), by interposing a conduit between the opening and the pressure buffer bag, and connecting one end of the conduit to the opening and the other end of the conduit to the pressure buffer bag, 7. The method of claim 6, wherein said opening and said pressure buffer bag are connected.