JPS63209663A - Method for sterilizing body fluid treatment apparatus and sterilized body fluid treatment apparatus - 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 (Industrial Application Field) The present invention can be used to treat body fluids such as blood, plasma, and lymph, and to change their composition ratio or change the function of structures. The present invention relates to a body fluid treatment device and a sterilization method thereof.

In recent years, due to advances in science and technology such as medicine and engineering, various types of body fluid treatment devices have been developed, such as body fluid treatment devices that return body fluid components that have changed due to various diseases to their normal state, and body fluid treatment devices that change the immune system of living bodies. body fluid treatment devices have been developed and are becoming more effective in treating various diseases. For example, artificial kidneys are used to restore blood components to normal in patients with renal failure, artificial lungs are used to send oxygen into the blood, and useful components such as albumin from ascites accumulated due to cancer or liver cirrhosis are added to the blood. A blood cell/plasma separator for filtering plasma containing malignant substances such as autoantibodies and immune complexes in the blood, which is used for collagen diseases, autoimmune diseases, etc., and malignant substances in plasma. filtration filters that remove only high molecular weight substances, including filtration, adsorbers that selectively adsorb only malignant substances in plasma, and adsorbers that adsorb poisoning-causing substances from the blood of drug-addicted patients. , an adsorbent that adsorbs bilirubin that increases in the blood of patients with liver disease, an adsorbent that adsorbs blood type substances in the blood of pregnant patients with incompatible blood types, and an adsorbent for removing white blood cells and lymphocytes from the blood of patients with autoimmune diseases. Blood cell separation filter, blood cell separation filter for removing leukemia cells from the blood of leukemia patients, stimulating immune cells in the blood,
Examples of body fluid processing devices include cell stimulation devices for inducing specific functions.

(Prior art) Body fluids treated with body fluid treatment devices are often re-infused into a living body, and body fluid treatment devices are sterilized before use in order to prevent denaturation of body fluids during body fluid treatment. is normal.

Sterilization methods include heating methods (flame method, dry heat method, high pressure steam method, flow steam method, boiling method, intermittent method), filtration method, irradiation method (radiation method, ultraviolet method, high frequency method), gas method, There are chemical liquid methods, etc. (Japanese Pharmacopoeia, 11th revision, general test methods (7) sterilization methods and aseptic operation methods), but sterilization of body fluid treatment equipment usually involves high-pressure steam sterilization, radiation (gamma ray) sterilization, Gas (ethylene oxide) method etc. are often used.

However, since sterilization means killing or removing all microorganisms in a substance, it is easy to imagine that the body fluid treatment device itself could be seriously damaged by sterilization. In fact, body fluid processing equipment is particularly damaged by high-pressure steam sterilization and radiation sterilization.
This causes problems such as decomposition and discoloration of the constituent materials of the body fluid treatment device, and that low-molecular substances are eluted from the body fluid treatment device to the body fluid side when body fluids are treated.

In particular, body fluid treatment devices (
This has been a problem in body fluid treatment devices that use polymers that are easily denatured by high-pressure steam or radiation (for example, adsorbents in which proteins, peptides, amino acids, etc. are immobilized on carriers, cell stimulators, etc.), and polymers that are easily denatured by high-pressure steam or radiation.

(Problems to be Solved by the Invention) In view of the above-mentioned problems, an object of the present invention is to sterilize a body fluid treatment device by significantly reducing damage to the body fluid treatment device while maintaining the sterilization effect. Another object of the present invention is to provide a body fluid treatment device that is safe and useful for living organisms and is sterilized by this sterilization method.

(Means for solving the problem) As a result of the inventors' extensive research in line with the above objectives,
We discovered that it is possible to prevent damage to body fluid treatment devices by sterilizing them in the presence of antioxidants, and furthermore, we found that body fluid treatment devices sterilized using this sterilization method are safe and useful for living organisms. It is now possible to make the present invention by confirming that this is the case.

That is, the present invention is a method for sterilizing a body fluid treatment device, characterized in that the body fluid treatment device is sterilized in the presence of an antioxidant, and is a body fluid treatment device sterilized in the presence of an antioxidant.

The body fluid processing device referred to here refers to blood, plasma, lymph fluid,
Using body fluids such as bone marrow fluid as a material, we can change the composition of electrolytes, hormones, proteins, etc. of this body fluid, and change the composition of red blood cells, white blood cells, platelets, or monocytes, granulocytes, lymphocytes, and lymphocyte subsets in white blood cells. It is a processing device that induces helper function, suppressor function, killer function, etc. by stimulating some lymphocytes, even if the composition remains unchanged. This is a device that allows you to There are various mechanisms for causing changes in body fluids, such as physical mechanisms and chemical mechanisms, such as dialysis, filtration, adsorption, adhesion,
Various methods can be used, such as antigen-antibody reaction, use of specific gravity difference, salting out, and physical stimulation. Here are some examples of body fluid processing devices: an artificial kidney to restore normal blood components in patients with renal failure, an artificial lung to supply oxygen to the blood, and albumin in ascites that is concentrated and re-injected intravenously. Water intake treatment equipment for the purpose of water treatment, plasma filtration filters for separating blood cell and plasma components, centrifugal separators and blood cell separation filters for separating blood cells into their respective components, and selective adsorption of specific components in body fluids. Adsorbers for separating plasma components by molecular weight, filters for selectively removing specific blood cells, and stimulating immune cells in the blood to induce specific functions. There are stimulators and the like to do this, and all processing devices that cause some kind of change in body fluids are included even if they are not exemplified here.

In the present invention, sterilization refers to killing or removing all microorganisms in a substance.

Furthermore, the antioxidant referred to in the present invention refers to an atom, molecule, or ion that has the property of easily donating electrons to other molecules, but has the property of suppressing changes in body fluid treatment equipment caused by oxygen. It is something. Examples of antioxidants are shown below.

The functional classification of antioxidants is (1) chain initiation inhibitors (
UV absorbers, light stabilizers, metal deactivators, ozone deterioration inhibitors, etc.) (2) Radical chain inhibitors (phenolic,
amine-based compounds, etc.) (3) peroxide decomposers (sulfur-based, phosphorus-based compounds, etc.), and can also be categorized into (1) salicylic acid-based (2) benzophenone-based (3) benzotriazole-based (4) Phenol type (5) Phosphorus type (6
) Sulfur-based (7) Organometallic, etc. Specific examples of antioxidants according to functional classification include: UV absorbers and light stabilizers such as phenyl salicylate, monoglycol salicylate, P-tert-butylphenyl salicylate, and 2-hydroxy-4= methoxybenzophenone,
2-Hydroxy-4-octoxybenzophenone, 2(
2'-hydroxy-5'-methylphenyl)benzotriazole, 2(2'-hydroxy-3',5'-
di-tert-butylphenyl)benzotriazole, 2(2
'Hydroxy-3'-tert-butyl-5'-methylphenyl)benzotriazole, resorcinol monobenzoate, 2'-ethylhexyl-2-cyano-3-phenylcinnamate, bis(2,2,6,6, -tetramethyl-4-piperidine) sebacate, etc., and metal deactivators include N-salicyloyl-N'-aldehydehydrazine, N-salicyloyl-N'-acetylhydrazine, N,N'-diphenyl-oxamide, N-salicyloyl-N'-aldehydehydrazine,
, N'-di(2-hydroxyphenyl)oxamide, etc., and examples of ozone deterioration inhibitors include 6-nitoxy 2.2.4-trimethyl-1,2-dihydroquinoline,
Examples include N-phenyl-N'-isopropyl-p-phenylenediamine, and examples of amine antioxidants include phenyl-β-naphrylamine, α-naphthylamine, and N-phenyl-N'-isopropyl-p-phenylenediamine.
, N'-di-tert-butyl-p-phenylenediamine,
Examples include phenothiazine, N,N'-diphenyl-P-phenylenediamine, and the like. Examples of phenolic antioxidants include 2.6-di-tert-butyl-p-cresol;
6-di-tert-butyl-phenol, 2.4-di-methyl-6-tert-butyl-phenol, butylhydroxyanisole, 2.2'-methylenebis(4-methyl-6-tert-butylphenol), 4.4 '-Butylidene bis(3
-methyl-6-tert-butylphenol), 4,4'-thiobis(3-methyl-6-tert-butylphenol), tetrakis[methylene-3(3,5-di-tert-butylphenol)
-Hydroxyphenyl)propionate comethane, 1.
Examples include 1,3-tris(2-methyl-4-hydroxy-5-tert-butylphenyl)butane. Furthermore, dilauryl thiodipropionate, sulfur-based antioxidants,
Distearyl thiodipropionate, laurylstearyl thiodipropionate, simiristyl thiodipropionate, distearyl β, β'-thiodibutyrate, 2
-Mercaptobenzimidazole, dilauryl sulfide, sodium pyrosulfite, sodium bisulfite,
Examples include sodium sulfite, sodium bisulfite, acetone-sodium-bisulfite, sodium formaldehyde sulfoxylate, and sodium hydrosulfide. Examples of phosphoric acid-based antioxidants include triphenylphosphite, triotadecylphosphite, tridecylphosphite, trilauryltrithiophosphite, and the like. In addition, 2-ascorbic acid, cysteine, thioglycerol, thiomalate, thiosorbitol, glutathione, ethylenediaminetetraacetic acid, guaiac butter, isopropyl citrate, dibutylhydroxytoluene, d2-α-tocopherol,
Examples include nordihydroguaiaretic acid, butylhydroxyanisole, and propyl gallate. These antioxidants may be used alone or in combination of two or more.

Among the above examples, sodium pyrosulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, sodium hydrosulfite,
- Ascorbic acid and the like are preferably used from the viewpoint of toxicity and ease of handling, with sodium pyrosulfite being particularly preferred.

A method of coexisting a body fluid treatment device and an antioxidant is to simply have the antioxidant exist around the body fluid treatment device, for example, by making antioxidant powder exist around the body fluid treatment device. Alternatively, the antioxidant may be placed in a breathable bag, or the antioxidant may be dissolved in a suitable solvent and brought into contact with a body fluid treatment device, such as water or physiological A method of dissolving an antioxidant in a target salt solution and filling or impregnating the body fluid treatment device, and a method of dissolving the antioxidant in a solvent such as glycerin or alcohol and filling or impregnating the body fluid treatment device are also used. In short, it is sufficient that the antioxidant is present near the body fluid treatment device and that the body fluid treatment device is in a state that can suppress changes in the body fluid treatment device due to oxygen.

When using an antioxidant in a solution state, the optimal concentration of the antioxidant should be determined depending on the material of the body fluid treatment device, the type of antioxidant, and sterilization conditions, but it is preferably 0. A concentration of .001% to 1%, more preferably 0.005% to 0.5%.

Sterilization methods used in the present invention include heating methods, irradiation methods, gas methods, chemical methods, etc. Among heating methods, high pressure steam methods,
Among the irradiation methods, gamma ray method is preferably used.

Hereinafter, embodiments of the present invention will be described in detail, taking as examples a case in which an adsorbent is sterilized with high-pressure steam, and a case in which a hollow fiber artificial kidney is sterilized with gamma rays.

Adsorbents, especially those used for autoimmune diseases, collagen diseases, blood incompatibility pregnancy, etc., adsorb proteins such as protein antibodies and immune complexes (antigen-antibody complexes) contained in blood. In many cases, the structure of the adsorbent is such that the porous carrier contains proteins (antibodies or proteins that interact with the adsorbed substance), amino acids, and ligands such as polysaccharides (supported for specific adsorption in affinity chromatography). A compound that is immobilized on the body is called a ligand) is often used. Among these adsorbents,
Let's take an example of an adsorbent in which amino acids are immobilized on a carrier.

The adsorbent is usually filled with water or a physiological solution into a container with an outlet and an outlet, and then subjected to autoclaving after forming the adsorbent device. At this time, 121℃, IKg/cm''
Because the amino acids are exposed to high temperature conditions for 20 minutes, some of the amino acids, even though they are covalently bonded to the carrier, break their bonds and are released into the solution. The amino acids that are released are
At this point, it is no longer an amino acid but a decomposition product of an amino acid. According to the present invention, which was made to solve such problems, for example, in order to contain an antioxidant in the filling liquid used when filling a container with the above-mentioned adsorbent, 1.
Even under high temperature conditions of 21°C, the bond between the amino acid and the carrier becomes difficult to break, and desorption of amino acid decomposition products into the solution is greatly reduced. This is thought to be due to the fact that the oxidative hydrolysis of amino acids was suppressed by adding the antioxidant. In particular, when the amino acid is inherently thermally weak like tryptophan, the tryptophan becomes even more thermally unstable after it is immobilized on the carrier, so it is recommended to autoclave it in high-pressure steam sterilization in the presence of an antioxidant. is preferred.

Next, the structure of the adsorbent will be described in more detail using an example in which a ligand is immobilized on a carrier.

The carrier must be insoluble in water, and both hydrophobic and woody carriers can be used. However, when a hydrophobic carrier is used, albumin adsorption to the carrier sometimes occurs, so a woody carrier gives more preferable results.

As for the shape of the carrier, any of the shapes such as spherical, granular, filamentous, hollow fiber, and flat membrane shapes can be effectively used, but spherical or granular shapes are preferably used from the viewpoint of flow of body fluid during extracorporeal circulation. Spherical or granular particles having an average diameter of 10 to 2,500 μm are easily used, but a range of 25 to 300 μm is preferably used.

Particulate carriers that can be used include agarose-based, dextran-based, cellulose-based, polyacrylamide-based, glass-based, and activated carbon-based carriers, but wood-philic carriers having a gel structure give good results. Furthermore, known carriers commonly used for immobilized enzymes and affinity chromatography can be used without any particular limitations.

Porous particles, especially porous polymers, can also be used as particulate carriers. The porous polymer particles used in the present invention have a ligand immobilized on their surface, and the exclusion limit molecular weight of the carrier can be selected depending on the size of the substance to be adsorbed. As the polymer composition, known polymers having a porous structure such as polyamide, polyester, polyurethane, vinyl compound polymers, etc. can be used, but in particular, vinyl compounds made hydrophilic by woody polymers can be used. Systemic porous polymer particles give favorable results.

Any known method such as covalent bonding, ionic bonding, physical adsorption, embedding, or precipitation insolubilization on the surface of a polymer can be used to bond the ligand to the carrier. It is preferable to use it after fixation and insolubilization. Therefore, it is possible to use commonly known methods for activating immobilized enzymes, carriers used in affinity chromatography, and binding methods for ligands.

Examples of activation methods include a cyanogen halide method, an epichlorohydrin method, a bisepoxide method, a halogenated triazine method, a bromoacetyl bromide method, an ethyl chloroformate method, a 1,1'-carbonyldiimidazole method, etc. can. The activation method of the present invention is not limited to the above examples as long as it can perform a substitution and/or addition reaction with a nucleophilic reactive group having active hydrogen such as an amino group, a hydroxyl group, a carboxyl group, or a thiol group of the ligand. .

Examples of ligands supported on the carrier are shown below.

For the treatment of systemic lupus erythematosus, homopolymers or copolymers of mono-, di-, and trinucleotides such as adenine, guanine, cytosine, uracil, and thymine, and naturally occurring DAN are used for adsorption and removal of anti-nuclear antibodies and anti-DNA antibodies. , nucleic acids such as RNA, hydrophobic compounds, etc. can be used.

In addition, for the adsorption and removal of DNA, RNA, and ENA present in the blood, anti-Ippon 3F (DNA antibody, anti-nucleic acid antibodies such as anti-two-stranded DNA antibody, anti-RNA antibody, and anti-ENA antibody, methylated albumin Basic compounds such as actinomycin D can be used.Furthermore, for adsorption and removal of immune complexes in the blood, complement components such as ctq, specific proteins such as protein A, anti-heavy chain constant part 2 phase Antibodies to immune complexes such as antibodies can be used.

For the treatment of chronic rheumatoid arthritis and malignant rheumatoid arthritis,
Modified γ-globulin and aggregation modified by chemical denaturation (aggregation) methods such as urea, guanidine hydrochloride, mercaptoethanol, surfactants, and organic solvents, and physical denaturation (aggregation) methods such as heat, ultrasound, and gas bubbling. Using antigen-like substances against rheumatoid factor, such as immunoglobulin, Fc region of immunoglobulin, second phase of heavy chain constant region of immunoglobulin, and modified products thereof by the above-mentioned modification method, anti-rheumatoid factor antibody, hydrophobic compound, etc. Can be done. In addition, C1q is used to remove rheumatoid immune complexes.
Antibodies against immune complexes such as complement components such as, specific proteins such as protein A, and anti-heavy chain constant region second phase antibodies can be used.

Thyroglobulin, a microsomal fraction of the thyroid gland, can be used to treat Hashimoto's disease.

For the treatment of myasthenia gravis, tryptophan, a neuromuscular acetylcholine receptor fraction component, can be used.

Glomerular basement membrane components for the treatment of glomerulonephritis, platelet membrane components and platelet granule fraction components for the treatment of idiopathic thrombocytopenic purpura, and transcortisin and anti-cortiscin antibodies for the treatment of Cushing's syndrome. Can be used.

For the prevention and treatment of hepatitis, antibodies against surface antigens of viruses such as hepatitis A virus and hepatitis B virus can be used.

For the treatment of hypertension, anti-angiotensin antibody can be used, and for the treatment of hyperlipidemia, polyanion and anti-riboprotein antibodies can be used.

For treatment of immune diseases based on lymphocyte abnormalities, anti-lymphocyte antibodies such as anti-B cell antibodies, anti-pressor T antibodies, and anti-lymphocyte antibodies can be used.

Protein A and anti-immunoglobulin antibodies can be used to treat cancer such as breast cancer.

Ligands that can be used are not limited to the above examples, but include congnitinin, concanavalin A,
Known substances capable of binding to the absorbed substance, such as lectins such as phytohemaagglutinin, nucleic acids, amino acids, lipids, protamine, heparin, antigens, antibodies, enzymes, substrates, and coenzymes, can be used.

It is also possible to use a carrier holding two or more types of ligands. Furthermore, two or more types of carriers holding ligands can be used in combination.

Next, the case of gamma ray sterilization of a hollow fiber type artificial kidney will be described.

In the case of gamma ray sterilization, a hollow fiber artificial kidney is generally irradiated with gamma rays of 1 to 5 Mrad, but at this time, the hollow fibers may deteriorate and produce low-molecular substances. When body fluids are treated with this hollow fiber artificial kidney, the possibility of such low-molecular substances being eluted into the body fluid side cannot be denied, which poses a problem. According to the present invention, which was made to solve this problem, for example, the container of the hollow fiber artificial kidney is filled with a liquid in which an antioxidant is dissolved, so that even when irradiated with gamma rays, the hollow fiber This prevents yarn deterioration and greatly suppresses the production of low molecular weight substances. This is because the use of antioxidants prevents oxidative deterioration of the hollow fiber material.
This is thought to be due to the suppression of the production of low molecular weight substances.

Methods for making the antioxidant coexist with the hollow fiber artificial kidney are not limited to the above methods; methods include dissolving the antioxidant in a solution such as glycerin and impregnating it into the hollow fiber, and adding the antioxidant powder to the hollow fiber. It is also possible to use a method of dispersing them around the area.

The material of the hollow fiber is cellulose acetate, cellulose,
There are various types such as polyacrylonitrile, methyl methacrylate, polysulfone, decellulose acetate, and ethylene vinyl alcohol, but to varying degrees they deteriorate due to gamma ray sterilization and produce low molecular weight substances, and antioxidants are used to suppress this. The thing is very useful.

Furthermore, the use of an antioxidant is very effective in preventing deterioration of the surface of the container and deterioration of the adhesive used to bind and bond the hollow fibers.

(Effects of the Invention) As described above, by sterilizing body fluid treatment devices in the coexistence of antioxidants, the deterioration of the constituent materials of body fluid treatment devices, which has conventionally occurred, and the release of low-molecular substances due to deterioration can be avoided. It has become possible to significantly reduce generation, etc., and the body fluid treatment device sterilized by the present invention has become a body fluid treatment device that is safe and useful for living organisms.

The present invention will be explained in more detail with reference to Examples below.

(Example) [Example 1 and Comparative Example 1] An adsorbent in which tryptophan was immobilized on a carrier was produced, and the adsorbent was tested in the presence of an antioxidant (Example 1) and in the absence of an antioxidant (Comparative Example 1). ) and compared the amount of substances released into the solution.

Vinyl acetate 100g, triallyl isocyanurate 64
．． 3g, ethyl acetate 100g, heptane 100g, polyvinyl acetate (degree of polymerization 500) 7.5g and 2.2'-
A homogeneous liquid mixture consisting of 3.8 g of azobisisobutyronitrile, 1% by weight of polyvinyl alcohol, 0.05% by weight of sodium dihydrogen phosphate dihydrate, and 1.5% by weight of disodium hydrogen phosphate dodecane hydrate. 400m of water dissolved in
Pour 1 liter of water into a flask, stir thoroughly, and heat at 65°C.
Suspension polymerization was carried out by heating and stirring for 8 hours and then at 75° C. for 5 hours to obtain a granular copolymer. After filtering, washing with water, and then extracting with acetone, 46.5 g of caustic soda and 2 methanol were added.
The transesterification reaction of the copolymer was carried out at 40° C. for 18 hours in a solution consisting of ft.

The average particle size of the obtained gel was 100 μm, and the vinyl alcohol unit per unit weight (qOH) was 9.0 meq/g.
The specific surface area was 60rn'/g, and the molecular weight exclusion limit by dextran was 8x105.

Next, the resulting gel! Og (dry weight) of dimethyl sulfoxide 120ml! To this was added 78.3 ml of epichlorohydrin, 30% sodium hydroxide i 0
mIL was added and the activation reaction was carried out with stirring at 30° C. for 5 hours. After the reaction, the mixture was washed with dimethyl sulfoxide, water, and dehydrated under suction.

Next, this activated gel was mixed with 0.1 M sodium carbonate buffer (pH 9,8) containing 1.63 g of tryptophan.
Suspended in 0 mJl. The immobilization reaction was carried out at 50°C for 14 hours with stirring, and then ao, smg, /mI1
．． Tris(hydroxyethyl)aminomethane solution 33
mIL was added, and a blocking reaction (to block remaining active groups) was further carried out at 50° C. for 5 hours with stirring.

Thereafter, it was thoroughly washed with water to obtain an adsorbent for body fluid purification. The amount of tryptophan fixed on this adsorbent is 400μm01
/g (dry weight).

This adsorbent was packed into a column with an inner diameter of 10 mm and a length of 50 mm, and ACD-added rheumatoid patient plasma was applied at 0°4 mu/min.
The flow rate was 12 m2. No decrease in column packing volume, clogging, or decrease in flow rate was observed, and the pressure difference before and after the column was 10 mmHg or less for plasma.

When we investigated the changes in plasma proteins and blood cell components before and after passing through the column, we found that albumin was only slightly adsorbed in plasma, and the decrease in complement component C3 was also small, but rheumatoid factors (sensitized hemagglutination, RAHA test, (manufactured by Fuji Organisation), the titer before adsorption was positive at a 1280-fold dilution, but the titer after adsorption became negative at a 40-fold dilution.

In addition, the immune complex (based on C+q solid-phase EIA) was 18 mg/m It before adsorption, but it normalized (below 3 μg/m j2) after adsorption. No significant differences were observed in the concentrations of white blood cells and platelets.

The above-mentioned adsorbent was placed in two heat-resistant bottles each containing 1.5 ml (wet distillation dehydration capacity) and subjected to the following treatment.

(Example 1) Add 150 g/dl of sodium sulfite aqueous solution as an antioxidant to a heat-resistant bottle containing 1.5 mfl of adsorbent.
m! After addition, autoclave sterilization was performed at 121° C. and 1 g/crn', and after cooling, the supernatant was collected and used as a test solution.

(Comparative Example 1) Add 150 m of distilled water to a heat-resistant bottle containing 1.5 mR of adsorbent.
After adding R, high-pressure steam sterilization was performed in the same manner as in Example 1, and a test liquid was collected in the same manner as in Example 1.

In order to determine the amount of substance eluted into the two test solutions, the absorbance of ultraviolet rays was measured. The measurement cell is 1
0mm is used, and the measurement wavelength is from 220nm to 350nm.
The absorbance at the point where the absorption was strongest between nm was determined. As the comparative liquid, in Example 1, a 0.05 g/dj2 sodium sulfite solution was sterilized under high pressure steam under the same conditions as in Example 1, and in Comparative Example 1, distilled water was used. As a result, the absorbance was 0.048 in Example 1 and 0°140 in Comparative Example 1.
It can be seen that in Example 1, in which sodium pyrosulfite was present as an antioxidant, much less substance was eluted than in Comparative Example, in which no antioxidant was present.

In addition, in Example 1, there was no coloration of the adsorbent, but in Comparative Example 1
Now, I colored it a light brown color.

Furthermore, adsorption performance was measured using adsorbents sterilized under the same conditions as in Example 1 and Comparative Example 1, but in both cases, the adsorption performance did not change before and after sterilization.

(Examples 2 to 7) Using the same adsorbent as in Example 1, 0.0001 g/dn of sodium pyrosulfite (Example 2), 0.
．． 001g/dJ2 (Example 3), O, O1g/di
(Example 4), 0.1 g/dI1. c Example 5), I
The experiment was conducted in the same manner as in Example 1, except that aqueous solutions of g/di (Example 6) and 10 g/dJ2 (Example 7) were used.

However, when measuring absorbance, comparative solutions of each concentration were used. The results are shown in Table-1. The data for Comparative Example 1 was used for the data when the antioxidant concentration was 0.

In all the data, it can be seen that the amount of eluted substances is smaller when sodium pyrosulfite is used as an antioxidant than when no antioxidant is used.

(Examples 8 to 11) Using the same adsorbent as in Example 1, the antioxidants were sodium sulfite (Example 8), acetone sodium bisulfite (Example 9), and sodium formaldehyde sulfoxylate (Example 10). ) and sodium hydrosulfide (Example 11) were used at a concentration of 0.1 g/di. However, solutions of each antioxidant were used as comparison solutions when measuring absorbance. The results are shown in Table-2. The data of Comparative Example 1 was used for the data without antioxidant.

(Margins below) Table 2 It can be seen that the amount of eluted substances is reduced for all antioxidants.

(Example 12) Cuproammonium rayon hollow fiber (inner diameter 200 μm
After assembling the artificial kidney by potting both ends of 7,300 fibers (film thickness: 11 μm) with polyurethane resin and incorporating them into a cylindrical outer tube, the blood side and the dialysate side were heated at 1,500 mJ2 each.
Washed and filled with an aqueous solution of sodium pyrosulfite.

The concentration of the sodium sulfite aqueous solution in the aqueous solution is 0.
O1g/di, 0.1g/dIt, 0.5g/d J2
There were three levels. Thereafter, the artificial kidney was sealed in a polyethylene bag, packaged in a cardboard case, and in this state was sterilized by irradiation with gamma rays of 2.5 Mrad. Measurements were carried out using the sterilized filling liquid as a test liquid.

(Comparative Example 2) After assembling a cuproammonium rayon hollow fiber artificial kidney, the same procedure as in Example 12 was carried out using pure water.
The sample was subjected to Mrad's gamma ray sterilization treatment, and the filling liquid was used as a test liquid for measurement.

The absorbance in the ultraviolet region and the absorbance in the visible region of the above test solution was measured. The method for measuring ultraviolet absorbance was the same as in Example 1, and filled water of each concentration was used as a comparison liquid when measuring absorbance.

The absorbance in the visible region was measured at a wavelength of 420 nm for the purpose of measuring the degree of yellowing of the solution. The measurement results are shown in Table 3.

Table 3 In all data, the amount of eluted substances was smaller in the solution using sodium pyrosulfite than in Comparative Example 2 (when no antioxidant was used), and the degree of yellowing of the solution was also lower. It turns out that there are few.

(Example 13) Using the same artificial kidney as in Example 12, sodium bisulfite (0.01 g/dj2), acetone sodium bisulfite (0.1 g/dJ2), and sodium formaldehyde sulfoxylate were used as antioxidants. (0.1g/
The same experiment as in Example 12 was conducted except that each aqueous solution of di,) was used. The results are shown in Table 4. The data of Comparative Example 2 was used for the data without antioxidant. Gamma ray irradiation 19ffi was set to 2.5 Mrad.

It can be seen that for all antioxidants, the amount of eluted substances was reduced and the degree of yellowing of the solution was also improved.

(Example 14) Cellulose hollow fiber for artificial kidney (inner diameter 200 μm, membrane thickness 1
1 μm) was immersed in an aqueous solution of sodium sulfite (0.1 g/dfi) in a glass beaker, wrapped in polyethylene film, and exposed to gamma rays of 2.5 Mrad in this state.
was irradiated. Thereafter, the hollow fibers were taken out of the solution and the tensile strength and elongation of the hollow fibers were measured.

(Comparative Example 3) Cellulose hollow fibers (same as in Example 14) were immersed in distilled water in a glass beaker, and in this state 265 Mrad gamma rays were irradiated to measure the tensile strength and elongation of the hollow fibers. Ta. The measurement results are shown in Table-5.

Those using sodium pyrosulfite as an antioxidant are
Both tensile strength and elongation were superior to that in which no antioxidant was used (Comparative Example 3).

(Example 15) Cupro ammonium rayon hollow fibers were immersed in a 0.5 wt % sodium pyrosulfite aqueous solution and then dried to produce cupro ammonium rayon hollow fibers containing 0.25 wt % sodium pyrosulfite. An artificial kidney was assembled using this hollow fiber and sterilized by irradiation with gamma rays of 1.5, 2.5 and 3.5 Mrad in a dry state.

Thereafter, the blood side and dialysate side of the artificial kidney were filled with distilled water, and after being left at 40°C for 24 hours, the filled liquid was taken out and used as a test liquid.

(Comparative Example 4) An artificial kidney was assembled using cuproammonium rayon hollow fibers containing no antioxidant, and a test solution was collected in the same manner as in Example 15. The test results are shown in Table-6.

(Margins below) Table 6: Products using sodium pyrosulfite as an antioxidant:
Comparative Example 4) Compared to the case in which no antioxidant was used, the amount of the eluted substance was small, and the degree of yellowing of the solution was also small.

Even in gamma ray irradiation in a dry state, the effect of antioxidants is observed as in wet irradiation.

Claims (2)

[Claims] (1) A method for sterilizing a body fluid treatment device, comprising sterilizing the body fluid treatment device in the presence of an antioxidant. (2) A body fluid treatment device sterilized in the presence of an antioxidant.