JPS5931345B2 - Method for producing artificial organs sterilized by high-pressure steam - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for manufacturing an artificial organ, that is, a method for manufacturing an artificial organ subjected to high-pressure steam sterilization.

The main body of an artificial organ is a functional part that replaces the function of a living organ.

Artificial organs including artificial kidneys, artificial livers, artificial lungs, etc.
It mainly replaces the mass transfer function of living organs.

That is, biological functions such as metabolism, regulation, excretion, and detoxification are complemented by physicochemical functions such as dialysis, filtration, adsorption, and exchange in artificial organs.

In the functional parts of artificial organs, membranes play an important role, playing a main role in dialysis, filtration, etc., and acting as a protective member in adsorption, exchange, etc.

The shape of the membrane function part may be a flat membrane, a tubular membrane (including laminated and coiled types), a capillary membrane, a hollow fiber membrane, a microcapsule membrane (a protective membrane for an adsorbent or an exchange agent), and the like.

The functional unit is designed to perform the above functions safely and efficiently by interposing a membrane between the body fluid to be processed (mainly blood) and the processing fluid (dialysis fluid, etc., but it may not be necessary). Designed and manufactured.

A compact and easy-to-use structure that reduces the amount of extracorporeal blood and prevents blood flow from stagnation is desirable.

In order to use artificial organs safely, it is necessary to prevent bacterial contamination during the manufacturing stage and to ultimately produce sterilized products.

It is also necessary to pre-treat the sterilized product before use.

Conventionally, artificial organs have been sterilized and used using the following two methods.

The first method is that the manufacturer sterilizes the artificial organ by filling it with a relatively concentrated aqueous formaldehyde solution, usually 1 to 5%, and then the user cleans the formaldehyde inside the artificial organ. Afterwards, necessary treatments such as filling the Tsukuda liquid side with a heparin-containing physiological saline solution are performed before use.

In the second method, the manufacturer sterilizes the dry artificial organ by passing a sterilizing gas into the artificial organ, for example, a gas containing ethylene oxide or propylene oxide at a concentration of lO to 30% as the sterilizing component. shipped,
The user fills the dry artificial organ with physiological saline, washes it, and uses it on the patient.

The first and second methods are typical methods using sterilizing agents, including alcohol, phenol, halogens, glutaraldehyde, quaternary ammonium salts, chlorhexidine, hydrogen peroxide, ozone, and hypochlorous acid. Sodium etc. can be used.

The action of sterilizing agents is based on mechanisms such as denaturing and destroying the proteins of pathogenic microorganisms, bacteria, and spores to be killed, inhibiting synthesis, metabolism, and enzymatic reactions, and damaging and destroying cell membranes.

When using artificial organs that have been sterilized with such agents, it is necessary to thoroughly wash and remove the sterilizing agent before use, but the sterilizing agents often remain and cause problems. be.

In addition, even if there is no apparent residual sterilization after cleaning the artificial organ, sterilization agents stored in functional parts such as membranes and adsorbents and other container components may enter the blood when the artificial organ is used. There is a strong possibility that it will elute.

It is known that residual sterilization agents act on the patient's living tissues, causing various side effects such as effects on blood components and allergic symptoms.

This is particularly a problem in long-term hemodialysis for patients with chronic renal failure.

In addition to sterilization using the sterilizing agents mentioned above, there are heat sterilization methods.

This method is generally practiced as a method of sterilizing surgical instruments and the like.

For example, the 9th revised Japanese Pharmacopoeia states that the high-pressure steam sterilization method is 115°C for 30 minutes, 121'C for 20 minutes, or
The method stipulates that microorganisms are killed by heating in saturated steam at 26° C. for 15 minutes.

Furthermore, the above-mentioned Japanese Pharmacy also describes an intermittent sterilization method in which heating is performed 3 to 5 times for 30 to 60 minutes every 24 hours in water or flowing steam at 80 to 100°C.

Other heat sterilization methods include dry heat sterilization and boiling sterilization.

Heat sterilization has the advantage that there is no residual toxicity of sterilizing agents and that pre-use treatment such as cleaning is easy, so it would be extremely convenient if heat sterilization could be applied to artificial organs.

However, to date, heat sterilization methods have hardly been applied to artificial organs.

The reason for this was that there were difficult problems with components, manufacturing, sterilization process, aseptic sealing after sterilization, safety, etc., and it was not put into practical use.

As a result of intensive research into applying heat sterilization, particularly high-pressure steam sterilization, to the sterilization of artificial organs, we have solved one difficult problem after another.

For example, regarding member 1, JP-A-53-58194, JP-A-53-61576, and JP-A-53-99694; manufacturing and sterilization processes are JP-A-53-84394, JP-A-53-84395, and JP-A-53-53- 101889, JP-A No. 54-28495 and JP-A-54-28497, and for aseptic sealing and safety, JP-A-53-99695, JP-A-54-28496, and Utility Model Application No. 53-15528.
No. 9, No. 53-161595 and No. 53-1615
No. 96 discloses a heat sterilization technique for artificial organs.

Among high-pressure steam sterilized artificial organs, the type in which the sterilized product is filled with water or an aqueous solution is disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 53
No. -84394, No. 53-84395, JP-A-1983-
As shown in Nos. 28495 and 53-28496, highly safe and easy-to-use artificial organs have already been completed.

On the other hand, products that are not filled with water or an aqueous solution after sterilization have not yet been put to practical use.

Therefore, the present invention has been completed by making full use of the techniques disclosed in the above-mentioned publications regarding the members and the aforementioned Japanese Patent Application Laid-open No. 101889/1989 regarding the manufacturing process.

Conventional artificial organs have the advantage that they do not contain sterilizing agents and can be prepared for cleaning in a short time before use.

However, because the interior of the artificial organ is liquid-tight, special means are required to buffer the thermal expansion and contraction of the liquid during the high-pressure steam sterilization process, and the product itself becomes heavy, making it difficult to handle and transport. There are some inconveniences.

In particular, when storing in a cold region, management is required to prevent the water or aqueous solution filled in the cavity of the artificial organ from freezing, destroying the membrane, and preventing leakage from occurring in the artificial organ itself.

It is clear that these and other problems are all caused by the water or aqueous solution filled in the cavity of the artificial organ, and there has been a strong desire for the emergence of an autoclaved artificial organ that is not filled with water or an aqueous solution. .

An object of the present invention is to provide a sterilized artificial organ in which the membrane part of the artificial organ is swollen and moistened with water or an aqueous solution, but the container of the artificial organ is not filled with water or an aqueous solution. It is to be.

The artificial organ according to the present invention has the advantage that the membrane function and membrane performance are maintained because the dialysis membrane is not dried, and the transportation and storage of the artificial organ is extremely easy.

Moreover, it is easy to handle since there is no need to remove sterilizing agents before use.

That is, in the present invention, when subjecting a heat-resistant artificial organ to high-pressure steam sterilization, the membrane function part constituting the artificial organ is swollen in advance with water or an aqueous solution, and then the artificial organ is swollen in a saturated steam atmosphere. The membrane function part is substantially swollen with water or an aqueous solution, and the membrane function part is substantially swollen with water or an aqueous solution. A method for producing an artificial organ sterilized by high-pressure steam, characterized in that the container and the internal cavity are not filled with water or an aqueous solution.

The present invention will be explained.

Heat resistance in the present invention means that the entire artificial organ and the individual components constituting these can substantially withstand moist heat treatment at 40 to 130°C.

Examples of heat-resistant membrane materials include flat membranes, capillary membranes, and tube membranes made of cellulose, cellulose ester, polyacrylonitrile, polyvinyl alcohol, aromatic polyamide, polycarbonate, polysulfone, polyester, and the like.

In addition, polycarbonate, polyvinylidene fluoride, poly-4-methylpentene-1, and polypropylene are used for materials such as containers for artificial organs.

Examples include polysecure.

In the present invention, a membrane functional part, which is a main component of an artificial organ, is swollen or moistened in advance with water or a water bath.

The artificial organ having the membrane function part in a swollen state is then sterilized with high pressure steam.

If an artificial organ with a dry membrane is directly exposed to high-pressure steam without any pretreatment such as wetting, significant deterioration in membrane performance tends to occur.

In particular, the permeation efficiency of water or other substances decreases, and dimensional changes of the membrane occur.

In order to avoid the above-mentioned deterioration that tends to occur during steam sterilization, it is necessary to swell the membrane material before bombarding it with high-pressure, high-temperature steam.

In particular, it is advantageous to reach the maximum membrane moisture content by swelling the membrane itself with water or an aqueous solution.

The maximum moisture content here is the constant weight (W2) of the membrane material dried at 100 to 110°C, and the amount of water that adheres to the membrane surface when the membrane material is immersed in water at room temperature for 12 hours or more. The weight (W3) when wiped with filter paper etc. is divided by t and expressed as follows.

In other words, the maximum membrane moisture content refers to the state in which there is substantially no adhered water on the membrane surface, and the membrane-to-membrane gap, the contact area, and its vicinity E are the conditions in which the adhered water is only slightly resistant to adhesion. Except for water landing, only the membrane is swollen with water or a water mixture.

In the sterilization method of the present invention, first, the membrane functional members (flat membrane, tube membrane, hollow fiber membrane, etc.) of an artificial organ are sterilized with distilled water for injection or 6 liters of water.
Inject an aqueous solution such as saline to thoroughly clean the artificial organ.

In this way, the membrane member also becomes sufficiently swollen.

Either the water or aqueous solution in the artificial organ is replaced by extrusion with a sterilizing gas, or the artificial organ is placed in a saturated steam atmosphere or with steam aeration, whereby the membrane reaches its maximum membrane water content.

Of course, a dry artificial organ can be brought into the swollen state of the membrane member by applying a saturated steam atmosphere or ventilation.

Next, the artificial organ (in which the membrane member is swollen) is placed under high-pressure steam for a predetermined period of time to sterilize it.

A known autoclave can be used as the high-pressure steam sterilizer.

After sterilization, the autoclave is used to lower the temperature and pressure while maintaining the saturated vapor pressure corresponding to the internal temperature of the artificial organ.

During the cooling process of the artificial organ, a portion of the steam in the autoclave is replaced with dry air, making it possible to remove condensed moisture equivalent to the amount of heat absorbed by the artificial organ during high-pressure steam sterilization.

By adjusting the amount of dry air replaced, the membrane moisture content of the membrane member can be appropriately selected.

In the present invention, it is necessary to cool the interior of the artificial organ to such an extent that water (aqueous solution) accompanying steam treatment does not remain in the void area.

At the same time, the moisture content of the membrane must be such that the membrane member does not dry out more than necessary and its performance deteriorates.

The amount of dry air is adjusted while observing the cooling process after sterilization.

The effect of the present invention is to reduce the weight of the product (artificial organ) while maintaining its performance and safety, compared to a steam sterilized artificial organ filled with water or an aqueous solution.

As a result, advantages such as ease of handling and easy storage are obtained, and since no sterilizing agent is used, it is convenient for use in hospitals, patients, etc.

The present invention will be further explained below with reference to Examples.

Example l Cellulose hollow fiber 11 with an inner diameter of 260μ and an outer diameter of 320μ
After 1,000 bundles were bundled and stored in a polycarbonate container, a hollow fiber type artificial organ with a membrane area of 1.57712 was assembled by fixing both ends of the hollow fiber bundle with urethane resin.

After washing this assembly (artificial organ) using distilled water for injection, the entrance and exit of the artificial organ was sealed with a rubber stopper.

The weight of the artificial organ at this time was 900 g.

Next, distilled water remaining inside the hollow fiber (blood chamber) and outside (processing chamber), which is the cavity inside the container of the artificial organ, was removed using one breath of sterilized air, and the weight was 450 g. Ta.

If you measure the water content of the membrane in this state separately, it will be 170%.
Met.

The maximum water content of this cellulose hollow fiber membrane is 180%.
It can be seen that the condition was almost close to that of .

The artificial organ that had undergone the above sterilization pretreatment was subjected to the usual high-pressure saturation/steam sterilization treatment (115°C, trowel for 30 minutes), and then cooled.

In one cooling tank, the internal pressure of the sterilization can increases as cooling progresses.
Partial replacement of dry hot air with saturated steam was performed to reduce the pressure but not exceed the saturated steam pressure corresponding to the temperature at the center of the artificial organ.

After the temperature was completely lowered to room temperature and cooling was completed, the artificial organ was taken out from the heat sterilizer and its weight was measured.
g, and heat sterilization was completed while substantially maintaining the membrane water content (160%).

Furthermore, when the performance (water removal rate, material permeability) of the artificial organ was actually measured, the water removal rate retention rate was 91% and the material permeability (urea) retention rate was 97%. No substantial difference was observed compared to sterile artificial organs.

Further, no air bubbles remained in the film during brimming.

Example 2 In the same manner as in Example 1, after thoroughly washing the assembled cellulose hollow fiber artificial organ with distilled water, a 50% glycerin aqueous solution was passed through and filled inside the hollow fiber (blood chamber) and outside (processing chamber). , the hollow fiber membrane was swollen with an aqueous glycerin solution.

Next, the glycerin aqueous solution in the blood chamber and processing chamber was replaced with sterilized air to obtain an artificial organ in which only the cellulose hollow fiber membranes were swollen with the glycerin aqueous solution.

The weight of the artificial organ in this state was 430 g (membrane water content 125%).

In addition, the maximum membrane water content of the cellulose hollow fibers was separately measured with respect to a 50% glycerin aqueous solution and was found to be 130.

Artificial organs that have undergone the above pre-sterilization swelling treatment (Example 1)
Similarly, after high-pressure saturation sterilization and cooling, the weight of the artificial organ was measured and found to be 400I (membrane water content 65%).
).

Since glycerin acts as a dimensional stabilizer for the cellulose membrane, it was possible to reduce the membrane moisture content after sterilization to 7/8 to 1/2 of the maximum membrane moisture content.

When the performance of the artificial organ was actually measured, as in Example 1, there was no difference from the conventional heat-sterilized artificial organ filled with water or an aqueous solution.

Example 3 A cellulose membrane tube (1,000 membrane area: 1.1 m2) having blood communication ports at both ends and a polypropylene network membrane support were laminated, wound in a spiral shape, and the membrane tube was stored in a polycarbonate container. In addition, blood ports were provided at both ends using silicone elastomer, and the membrane tube was fixed in the container.

In this way, a coil-type artificial kidney was assembled.

Distilled water for injection was passed through the blood inlet into the cellulose tube to wash the membrane, and then a 30% aqueous sorbitol solution was delivered.

Next, the sorbitol aqueous solution remaining in the tube was expelled with sterilized air to obtain a coiled artificial kidney in which only the cellulose membrane tube was swollen with the sorbitol aqueous solution.

The measured value of the membrane water content was 130%, and the weight was 720 g.

The maximum membrane water content of the same cellulose membrane for sorbitol was 140.

After high-pressure saturated steam sterilization and cooling in the same manner as in Example 1, the weight was measured to be 720 g (membrane water content: 130 g).
%).

The physical properties of the artificial kidney described above (water removal rate, material permeability, blood resistance, blood residual degree) and the coiled artificial kidney made of the same membrane were immersed in hot water and subjected to high-pressure sterilization ( 115
When comparing the various physical property values after the test (at 30°C for 30 minutes), no substantial differences were observed.

Example 4 An artificial organ was manufactured by micro-encapsulating 150 g of spherical activated carbon with an average particle size of 650 μm with a polyvinyl alcohol membrane, storing it in a container made of polycarbonate and polypropylene, and attaching an activated carbon leak-prevention screen and a blood distribution collection unit to both ends. did.

First, distilled water for injection was passed through the artificial organ to wash it, and the activated carbon and the polyvinyl alcohol film were sufficiently swollen with water.

Next, sterilized air was blown through the blood distribution section and 150 g of water filled in the cavity inside the artificial organ container was removed from the blood collection section, thereby obtaining an artificial organ in which only the activated carbon and the membrane were swollen with water.

The weight in this state was 440 g, which reached the maximum film and active water content of the activated carbon and film that were measured separately.

Then, in the same manner as in Example 1, high-pressure steam sterilization was performed,
After cooling, the weight of the artificial organ was measured and the weight was 440 g.

When we measured the adsorption capacity, residual air bubbles during priming, blood resistance, blood remaining amount, etc. of the artificial organ, we found no substantial difference compared to the same artificial organ that had been pre-filled with water and sterilized with high-pressure steam. There wasn't.

Therefore, it has become clear that an artificial organ not filled with water can be obtained.

Claims (1)

[Claims] 1. When subjecting a heat-resistant artificial organ to high-pressure steam sterilization, the membrane functional part constituting the artificial organ is swollen in advance with water, an aqueous solution, or steam, and then the artificial organ is subjected to high-pressure steam sterilization in a saturated steam atmosphere. Thereafter, the membrane function part, which consists of cooling the artificial organ while suppressing the adhesion of water to the artificial organ and performing dehumidification and water removal as necessary, is substantially swollen with water or an aqueous solution, and the artificial organ is cooled. A method for producing an artificial organ sterilized by high-pressure steam, characterized in that the container and internal cavity of the organ are not filled with water or an aqueous solution.