JPS61143072A - Heat sterilization of artificial kidney - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

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 suitable for use in the heat sterilization.

An artificial kidney comprising a container containing a hollow fiber bundle made of a selectively permeable membrane, the container having openings consisting of an inlet and an outlet for blood and an inlet and an outlet for dialysate. This system is known per se, and it replaces the function of a living kidney by removing waste products from the blood into a dialysate through dialysis and by ultrafiltrating excess water in the blood. Hollow fiber artificial kidneys are becoming increasingly important because of their advantages of being small and easy to use relative to their effective membrane area. The artificial kidney is
It is necessary to sterilize the artificial kidney at the manufacturing stage to prevent bacterial contamination before supplying it to the user. Until now, the user had to perform the necessary pretreatment on the sterilized artificial kidney before using it. It is offered to

Conventionally, artificial kidneys have been sterilized using the following two methods.

The first method is that the manufacturer uses relatively concentrated
The artificial kidney is usually sterilized and shipped by filling it with a 1-5% formaldehyde aqueous solution at 11 degrees Celsius, and the user warms the artificial kidney after washing and removing the formaldehyde in the artificial kidney to body temperature, and the blood side contains heparin. In this method, the tube 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 completely wash and remove formaldehyde so that it does not remain in the artificial kidney. It is necessary, and for this purpose, large amounts of water must be flushed for a long period of time. However, such cleaning is a complicated operation, and has the drawback of requiring a considerable amount of effort and time on the part of the user.

Even after the formaldehyde concentration in the washed backwater has decreased and formaldehyde is virtually undetectable, if washing is stopped and left as it is, the formaldehyde remaining in the hollow fiber membrane will gradually ooze out. There is also.

In the second method, the manufacturer supplies the dry hollow fiber artificial kidney with a sterilizing gas, for example, ethylene oxide or propylene oxide at a concentration of 10 to 30% as sterilizing components, and the remaining percentage of freon or carbon dioxide. The artificial kidney is sterilized by passing a mixed gas through it before being shipped, and the user performs necessary processing such as filling the dry sterilized artificial kidney with dialysate, physiological saline, etc., and then uses it for dialysis. There is a method. 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 chloride ions in the dialysate and physiological saline, causing harmful effects such as rohydrin. There are also problems such as the formation of compounds. To clean these residual gases, it is necessary to pass a large amount of physiological saline of about 2f1 or more.

Furthermore, when passing liquid through the hollow fiber of a hollow fiber type artificial kidney, it is necessary to pass the liquid for a long time to completely remove air bubbles, or to replace the air inside the hollow fiber with sterile carbon dioxide, since the hollow fiber is a capillary tube. In the latter case, the user will need to prepare equipment such as a carbon dioxide cylinder, a sterilizing filter, a pressure regulator, and a flow regulator. If air bubbles remain inside the hollow fiber,
There is a risk of microbubbles flowing into the body during dialysis, and there is also a risk of causing blood clots within the hollow fibers, increasing the amount of blood remaining in the dialyzer after dialysis and increasing blood loss.

Furthermore, this gas sterilization method has the disadvantage that the performance of the artificial kidney tends 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 above two types of sterilization methods, a third method is 0.
A method of sterilizing an artificial kidney by irradiating it with gamma rays of 5 to 5 Hrad has been proposed. This radiation sterilization method does not use a sterilizing agent, so there is no problem of residual toxicity. However, in the pretreatment of filling a dry artificial kidney with physiological saline, dialysate, etc., this method tends to cause changes in the performance of the artificial kidney, similar to the second method. Moreover, the materials constituting the artificial kidney are easily degraded by radiation, and there are still unresolved problems in improving the materials and selecting suitable materials.

Generally, as a sterilization method, in addition to the above-mentioned methods, there is a heat sterilization method, and this method is widely used as a method for sterilizing syringes or surgical instruments. For example, the 9th revised Japanese Pharmacopoeia states that high-pressure steam, sterilization methods at 115℃,
30 minutes = 121℃, 20 minutes or 126℃915
It stipulates a method of killing microorganisms by heating in saturated steam under any of the following conditions: Furthermore, in the Japanese Pharmacopoeia mentioned above, 2
An intermittent sterilization method in which heating is performed 3 to 5 times for 30 to 60 minutes every 4 hours 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 could not be performed basolaterally, especially for artificial kidneys filled with filling fluid. , 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 difficulty in aseptically sealing 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.

Another object of the present invention is to provide a user with an artificial kidney that requires substantially no pretreatment before use.

According to the present invention, there is provided a container containing hollow fibers made of a selectively permeable membrane, and the container is provided with openings consisting of a blood inlet, a blood outlet, a dialysate inlet, and a dialysate outlet. 1. A method for heat sterilization of an artificial kidney, comprising: (a) filling the artificial kidney with a filling liquid consisting of water or an aqueous solution; (1)) providing a pressure buffer bag of substantially uniform thickness in at least one of the openings; (c) sealing the remaining opening that is not connected to the pressure buffer bag with a sealing means; (d) heating the artificial kidney to a temperature within the range of 80 to 13 ()°C to prepare the artificial kidney. (e) After sterilization, the artificial kidney is cooled, and a portion of the filling fluid and gas expanded by heating are transferred to the pressure buffer bag. A heat sterilization method is provided which includes the following steps: (f) aseptically sealing the opening connected to the pressure buffer bag, as necessary.

FIG. 1 is a diagram schematically showing how the heat sterilization method of the present invention is carried out. Figure 2 (a) or (b)
FIG. 1 is a diagram showing an embodiment of the heat sterilization method of the present invention. Third
Figures 3 and 4 show connecting tubes suitable for use in the present invention, 3(a) and 4(a) are longitudinal sectional views, respectively, and 3(b) and 4(b) are longitudinal cross-sectional views. FIG. 3 is a cross-sectional view of each tooth taken along line A-A.

An important feature of the heat sterilization method of the present invention is that a pressure buffer bag that exhibits a special function is made up of the blood inlet, blood outlet, dialysate inlet, and dialysate outlet of the artificial kidney filled with filling fluid. The opening is connected for at least one day, the remaining openings are sealed, and in this state the artificial kidney is heated to a temperature within the range of 80 to 130°C to sterilize it. When heating is carried out under these conditions, gas components such as the filling liquid, the artificial kidney, and the air present in the organs, which expand due to the rise in temperature, move into the pressure buffer bag, and as a result, the fluid (filling This buffers the internal pressure of the artificial kidney caused by thermal expansion of liquid and gaseous components and increases in water vapor pressure, which would otherwise occur if such buffering did not exist. It becomes possible to effectively avoid deformation, cracking, or destruction of the material. That is, the pressure buffer bag used in the present invention has the function of storing the expanded fluid (filling liquid and gas components) of the artificial kidney and the function of buffering the increase in pressure inside the artificial kidney that occurs during heating. .

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. However, when using a sealed bag, the bag will expand itself in response to the movement of expanded fluid (filling liquid and gas components) into its interior, so that pressure can be exerted. It is preferable that the bag is of a type that can be used.

In the method of the invention, it may be necessary to seal the opening connected to the pressure buffer bag with means for preventing leakage of the filling liquid.

In the present invention, heat sterilization is preferably performed based on the 9th revised Japanese Pharmacopoeia, and the high-pressure steam sterilization method (115-126
℃) and intermittent sterilization method (80 to 100℃), so the temperature is 80 to 130℃.

The present invention will be described below with reference to the drawings.

FIG. 1 is a diagram schematically showing how heat sterilization of an artificial kidney is performed according to the method of the present invention. In FIG. 1, an artificial kidney 1 consists of a container 2 containing a number of hollow fibers 3 having selectively permeable membranes. A pair of partition walls 5 are installed inside the container 2, and the hollow fibers 3 are supported by the partition walls 5. The container 2 is provided with a blood inlet 6 and a blood outlet 6' which are usually thin side pipes with openings, and a dialysate inflow lower and a dialysate outflow lower' which are usually thick side pipes with openings. .

I'm here. Both ends of the container 2 are a blood distribution section 4 and a blood collection section 4', which are separated by a partition wall 5 from a dialysis room in the center of the container 2 where dialysis is performed.

Container 2. Hollow fiber 3. Bulkhead 5. The side tubes 6.6', 7 and 7' are all made of a material that does not substantially undergo thermal deformation in the temperature range of 80 DEG to 130 DEG C. at which heat sterilization is carried out.

When 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, the blood origin 4 and the 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 the pressure buffer bag 10 via a conduit 9, and the other side pipes are filled with liquid. Leakage prevention means 8 (such as plugs or seals) are provided. In this condition, the artificial kidney 1 is 80 to 130
Heat sterilization is performed by heating to a temperature of °C. At this time, the pressure buffer bag 1o may be heated together with the artificial kidney 1,
Alternatively, the pressure buffer bag 10 may be placed outside the heater to heat only the artificial kidney 1. When the artificial kidney 1 is heat sterilized, the filling fluid and air inside the artificial kidney expand due to the rise in temperature, and due to the natural pressure of water vapor, the expanded portion of these fluids leaves the artificial kidney 1 and the pressure increases. A transition is made to the buffer bag 10, which buffers the pressure within the artificial kidney.

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 the water or aqueous solution that had accumulated in the pressure buffer bag 1o passes through the conduit 9 and is transferred to the artificial kidney 1.
Come inside.

FIG. 2 shows an example of an embodiment of the method of the invention, in which a pressure buffer bag 10, such as a balloon bag, is connected to a side tube 7' of an artificial kidney. In this method, the pressure buffer itself expands to absorb the fluid inside the artificial kidney, which has been expanded by heat sterilization, and buffers the pressure, thereby reducing the load on the container and blood distribution and collection parts of the artificial kidney. Become. However, in the embodiment illustrated in FIG. 2, the filling condition cannot be improved. In the embodiment shown in FIG. 2, there is no particular need to release the connection between the artificial kidney and the pressure buffer bag after heat sterilization of the artificial kidney. However, if the artificial kidney is connected to the pressure buffer bag via the connecting conduit in the manner shown in Figure 1, the connection must be released after sterilization, and in that case It is necessary to seal the container with a means to prevent the filling liquid from leaking.

The material of the buffer bag is required to have physical properties that will not burst upon expansion. Any non-toxic material may be used as long as it has heat and humidity resistance at 80 to 130°C and is medically safe. For example, buffer bags made of rubber-like elastic materials such as natural rubber, synthetic rubber such as polyisoprene rubber and polybutadiene rubber, silicone rubber, polyurethane elastomer, etc.
Alternatively, any buffer bag made of a non-elastomeric material such as polypropylene, polyester, nylon, polypropylene-polyester laminate film, etc. can be used as the pressure buffer bag in this embodiment. The volume of the buffer bag is determined by the maximum inflation volume within the pressure resistance limit.
It needs to be at least larger than the increase in volume (filling liquid and air) due to expansion due to heating.

The buffer bag used in the embodiments of the present invention can have various shapes such as a bag, a balloon, or a tube.

As mentioned earlier, in the heat sterilization method of the present invention, after the heat treatment is completed, before disconnecting the artificial kidney from the pressure buffer bag, it is necessary to aseptically seal the opening connected to the pressure buffer bag. There are cases where

The main method for performing this aseptic seal is to connect the side tube of the artificial kidney to the pressure buffer via a connecting tube 30 having a welded part 31, as shown in FIGS. 3 and 4. This method achieves aseptic sealing by melt-sealing the melt-sealed portion 31 after the heat sterilization process is completed and before disconnecting the side pipe and the pipe.

Any material can be used for the connecting tube 30 as long as the melt-sealing portion 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, and the like.

In addition to the methods described above, if the side tube or conduit of the artificial kidney can be melt-sealed, it may be melt-sealed.

Alternatively, if the pressure buffer bag described above is used, the pressure buffer bag may be left on without being separated and used as a seal.

A suitable connecting tube for use in the method described above includes a cylindrical engagement portion 32. as shown in FIGS. 3 and 4. It is a cylindrical tube consisting of a melt-sealed part 31 and a cylindrical conduit part 33, the engaging part 32 can be engaged with a side pipe of an artificial organ, and the melt-sealed part 31 has a thin neck-like shape. and the maximum outer dimension of the cross section is 2 to 15 IllllI and the maximum inner dimension of the cross section is 1 to 14 mm,
The connecting tube 30 is made of a material that can be melt-sealed. The melting part 31 is located at the center of the connecting tube 30, and the engaging part 32 and the conduit part 33 are located at both ends of the connecting tube 30. Further, the shapes and dimensions of the engaging portion 32 and the conduit portion 33 may be determined in consideration of the shape and sealing properties of the respective mating tubes.

From the viewpoint of practicality as a conduit, the melt-sealed portion 31 preferably has an internal dimension of 1111111 or more in its cross section, and a cross-sectional dimension of 141III11 or less in consideration of the dimensions of the side tube of the artificial kidney and the melt-sealed area. . Further, the maximum outer dimension of the welded portion 31 is preferably 2 to 15 mm depending on the inner diameter, taking into consideration the aqueous solution retention and the welded area. Roughly preferred melted part 3
The maximum outer dimension of the cross-sectional view of No. 1 is 3 to 8 mm, and the inner dimension of the cross section is 2 to 7 mm. The cross-sectional shape may be circular, oval, oval, quadrilateral, or the like. If the melting part 31 has a small diameter, it is preferable to have a circular cross section, and if it is relatively large, it is preferable to have a flat oval, oval, or quadrilateral shape because it facilitates the melting operation, but it is not limited to this. do not have.

FIG. 3 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.

The AA' cross section of the melt-sealed portion 31 is circular. FIG. 4 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, which engages and seals the side tube, and is also designed to facilitate the work of attaching and detaching the connecting tube when using the powder artificial kidney on a patient. A collar 35 is attached. In this connecting tube, the AA cross section of the melt-sealed portion 31 is shaped like a flat oval.

According to the method of the present invention, heat sterilization of an artificial kidney can be easily carried out. Furthermore, heat sterilization does not cause destruction, deformation, or poor sealing of the artificial kidney filled with water or an aqueous solution, and the blood flow path can be maintained. This has the advantage of preventing secondary contamination.

Furthermore, the artificial kidney heat sterilized by the method of the present invention may have an improved filling state, and can exhibit excellent mass exchange performance and blood compatibility.

The artificial kidney tooth heat sterilized by the method of the invention has an overall high degree of sterility guarantee, there is no risk of residual bacterial toxicity, and it is easy to prepare for cleaning.

In summary, 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, including a cough hollow fiber.

The partition wall and the container have substantially heat resistance in the range of 40 to 130°C, and the partition wall member has a linear expansion coefficient a [1/°C]
is 40 to 130°C, the coefficient b[1/
'C] and temperature t['c] have the following relationship, (4,13x 10-5) e' 0O769t≦
Provided is an artificial kidney characterized in that a≦2b and the partition member does not undergo secondary metastasis in a temperature range of 50 to 120°C.

The artificial kidney configured as described above does not cause deformation or destruction of members or seal failures due to heat sterilization and heating, and can maintain the blood flow path and 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 generally necessary to assemble the artificial kidney using the following materials and by a method known per se.

That is, examples of the material for the hollow fibers include cellulose, cellulose ester, polyacrylonitrile, polyvinyl alcohol, and polyaromatic acid amide (for example, polyamide benzhydrazide isophthalamide).

Polycarbonate, polyether polysulfone, etc. can also be used. Particularly preferred materials are cellulose, polyacrylonitrile, polycarbonate, and polysulfone.

An example of the material for the container is polycarbonate.

Except for the use of polysulfone, poly-4-methylpentene-1° polyvinylidene fluoride and polyacetal, in particular highly transparent polycarbonate,
Polysulfone, poly-4-methylpentene-1, is a preferred material.

The material for the partition walls is preferably a high molecular weight polymer.

Among high-molecular polymers, preferred are polymers that are polymerized and crosslinked by addition polymerization from two or more components, ie, one or more prepolymers, a curing agent, etc., and whose total mass does not substantially change. Such polymers include urethane resins and epoxy resins. Among urethane resins, poly(ester-type urethane) is preferable, which is obtained by addition polymerizing a prepolymer whose terminal end is an isocyanate and a polyol (curing agent) consisting of a fatty acid having a hydroxyl group and an ester of glycerin or ester.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing an embodiment of the present invention. FIGS. 2(a) and 2(b) are perspective views showing embodiments of the present invention. FIGS. 3 and 4 show a connecting tube used in the present invention. (a) in longitudinal section (a) and transverse section (b), respectively.
The relationship is as shown in the A-A arrow view in the figure.

Claims (1)

[Scope of Claims] 1. It has a container containing hollow fibers made of a selectively permeable membrane, and the container has openings consisting of a blood inlet, a blood outlet, a dialysate inlet, and a dialysate outlet. 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; (b) filling at least one of the openings with a substantially uniform film thickness; (c) sealing the remaining opening not connected to the pressure buffer bag with a sealing means; (d) heating the artificial kidney to a temperature within the range of 80 to 130°C; heat sterilizing the artificial kidney and transferring a portion of the filling fluid and gas inside the artificial kidney expanded by heating to a pressure buffer bag; A heat sterilization method comprising the following steps: (f) aseptically sealing the opening connected to the pressure buffer bag as necessary; 2. The method according to claim 1, wherein the pressure buffering bag is a sealed bag made of rubber elastic material so as to be inflatable by increasing internal pressure. 3. The method according to claim 1, wherein after the step (f), the connection made in the step (b) is released. 4. 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. 2. The method of claim 1, further comprising connecting the opening and the pressure buffer bag.