JP2004283571A - Method for preparing peritoneal dialysate solution by tripartite method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve a preservation method for sterilization processing when an antioxidant or a reductant component is added in order to suppress the crosslinking reaction of protein by glucose to be used as an osmotic pressure agent in a peritoneal dialysis method. <P>SOLUTION: In a peritoneal dialysate solution preparing method, an acidic solution containing a saccharide osmotic pressure agent is stored in a first vessel, a solution containing the antioxidant or the reductant is stored in a second vessel, and a solution containing an electrolytic salt is stored in a third vessel. After the sterilization processing, they are mixed before usage, so as to prepare the peritoneal dialysate solution. Thus, an oxidation product by high temperature sterilization processing is prevented from being generated. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a peritoneal dialysate used for treating renal peritoneal dysfunction. More specifically, the present invention relates to a peritoneal dialysate which does not cause protein cross-linking by a sugar osmotic agent such as glucose added to the peritoneal dialysate.

  Peritoneal dialysis is one of the effective treatments for patients with renal failure. In the peritoneal dialysis method, a catheter is placed in the peritoneal cavity of a patient with renal insufficiency, peritoneal dialysate is infused into the peritoneal cavity from the dialysate bag through the peritoneal cavity, stored for a certain period of time, and then discharged out of the body through the catheter. Repeat several times a day.

  Unlike the hemodialysis method using an artificial membrane, the peritoneal dialysis method can continuously and continuously purify blood through the peritoneum, which is the patient's own biological membrane. It has the advantage of being easy and is widely used.

  However, in the case of peritoneal dialysis, the excess water in the blood excreted by a healthy person as urine is removed by a pressure difference between the extracorporeal blood circulation circuit and the outside of the membrane through a semipermeable membrane, as in hemodialysis. Can not be removed in a way that gives Therefore, in the peritoneal dialysis method, an osmotic agent is added to the dialysate to be injected into the peritoneal cavity to make the osmotic pressure of the dialysate higher than the osmotic pressure of blood, and water is removed by ultrafiltration. As a means for increasing the osmotic pressure, the electrolyte salt concentration cannot be increased, and thus glucose has been exclusively used as an osmotic agent.

Until now, glucose was considered to be the safest physiologically and had no metabolic problems even if it was absorbed into the body. However, if peritoneal dialysis is continued for a long time using a dialysate containing glucose, a large amount of glucose is absorbed into the body and reacts with amino acids, peptides and proteins in the body to cause cross-linking between protein molecules, resulting in peritoneal dialysis. It became clear that the peritoneal dialysis had to be stopped due to the progression of hardening and thickening of the peritoneal dialysis.
The mechanism of the cross-linking between protein molecules by glucose is presumed to be due to the following reaction.

  The sugar (I) having a carbonyl group, such as glucose, reacts with the amino acid, peptide, protein or the like (II) and, as shown in the formula (1), undergoes an intermediate of the Schiff base (III) and the Amadori compound (IV) to form an advanced It becomes a compound called Glycation Products (Advanced Glycation End Products: hereinafter referred to as AGE).

In using the dialysate, sterilization treatment is performed at high temperature and high pressure. During the sterilization treatment, glucose is partially denatured, and various glucose denatured products (Glucose Degradation Products: hereinafter referred to as GDP) are generated as follows. I do.
Glyoxal
Methylglyoxal
3-deoxyglucosone

The above-mentioned glucose-modified product is a substance having a higher AGE-forming reactivity than saccharides. When such a glucose-modified product is contained in the dialysate, it is several tens to several thousand times that of glucose alone. Crosslinking proceeds at a rate.
The following formula (2) shows an example of a cross-linked product of proteins that are cross-linked by bonding the carbonyl group of GDP or the saccharide itself to a protein and an amino group such as lysine or arginine of a protein component.

  As one method for solving this problem, a method of reducing the GDP content by improving the sterilization treatment process of the dialysate has been proposed, but it cannot completely suppress the production of GDP, and furthermore, glucose Since the cross-linking reaction of the protein by its own reaction cannot be ignored, an effective method for suppressing the cross-linking reaction is required in the peritoneal dialysis method using glucose as an osmotic agent.

  In addition, the inventors of the present invention provide a method of recovering and concentrating a patient's own plasma protein eluted in peritoneal dialysis effluent as an osmotic agent and using it as an osmotic agent instead of all or a part of glucose. (JP-A-9-32751 and JP-A-11-137672). However, also in this method, when glucose is partially used, the problem of cross-linking of proteins similarly occurs.

  The inventors of the present invention believe that since the cross-linking reaction of protein by glucose and a denatured glucose proceeds by the above mechanism, it is possible to suppress the cross-linking reaction by adding a compound that inhibits this reaction. As a result of searching for additives, a large number of compounds that suppress the cross-linking reaction were found, and as a bond inhibitor, a reducing agent or an antioxidant is generally effective, and in particular, a reducing oxygen oxyacid salt is effective. It was found that this was the case (Japanese Patent Application Laid-Open No. 2002-315825).

  Furthermore, it has been proposed to add an amino acid or an oligomer of the amino acid, such as glutathione, to the dialysate (Japanese Patent Laid-Open No. 2000-107286).

JP-A-9-32751 JP-A-11-137672 JP-A-11-137672 JP-A-2002-315825

  The dialysate is produced by dissolving the raw material containing the pathogenic bacteria, but the bacteria are not allowed to remain in the product. Therefore, sterilization is performed at a high temperature of 120 ° C. or more for several tens minutes.

Regarding the method of sterilization, from the viewpoint that when a reducing agent is sterilized together with glucose, a denaturation reaction of glucose can be suppressed, in the above-mentioned JP-A-2002-315825, when the crosslinking inhibitor is a reducing agent that is stable at a high temperature, the electrolyte salt It has been proposed that a two-part sterilization method for a dialysate, in which a reducing agent is added to glucose and sterilized separately from the solution, can be used.

However, the two-split method in which [electrolyte salt + glucose] and [inhibitor] are separately stored and the two-split method in which [sugar + reducing agent] and [electrolyte salt] are separately stored (Comparative Examples 2 and 3 described later) It has since been found that the amount of addition required to reduce the oxidation component to zero does not become sufficiently low.

  In addition, when the dialysate containing the compound having an amino group as described above is sterilized at a high temperature, the AGE reaction proceeds in a state where it is mixed with a saccharide, and the condensate produced has a yellowish brown tint, which is not preferable.

  Therefore, the present inventor, the acidic solution containing the saccharide osmotic agent, the solution containing the antioxidant or reducing agent, and the solution containing the electrolyte salt are all separately stored in separate containers, and after sterilizing these separately, By mixing, it has been found that the progress of the AGE conversion reaction of saccharides is suppressed, whereby the protein cross-linking reaction is suppressed, and peritoneal dialysis treatment can be performed over a long period of time, and the present invention has been achieved.

  That is, the present invention contains an acidic solution containing a saccharide osmotic agent in a first container, a solution containing an antioxidant or a reducing agent in a second container, and a solution containing an electrolyte salt in a third container. This is a method of preparing a dialysate by mixing beforehand.

  After the above-mentioned respective component solutions of the dialysate are sterilized separately, they are taken out of the autoclave and cooled, and then mixed, or mixed immediately before use in dialysis. In any case, it is stored for several months to several years at room temperature until it is used for treatment, during which the amount of sugar denaturation and the amount of dicarbonyl compound produced is far less than that produced during sterilization. For this reason, it is important to store them separately for sterilization.

  In the peritoneal dialysis method, glucose or a denatured glucose used as an osmotic agent causes a protein cross-linking reaction, and the peritoneal dialysis cannot be continued due to hardening of the peritoneum. In order to solve this problem by adding, in the present invention, each component of the saccharide osmotic agent, antioxidant or reducing agent, and electrolyte salt is separately stored, sterilized, and then mixed to form an oxidizing agent. A peritoneal dialysis solution is obtained in which no components are generated and protein cross-linking is unlikely to occur.

  Examples of the saccharide used as the osmotic agent in the peritoneal dialysate of the present invention include monosaccharides such as glucose and mannose, disaccharides such as sucrose and fructose, and oligomers, and polymers such as dextran and dextrin.

Electrolyte salt is a mixture of sodium chloride, magnesium chloride, calcium chloride, sodium lactate, sodium bicarbonate, etc., preferably with a composition and concentration close to serum. Therefore, when the blood calcium and magnesium concentrations deviate from the normal values, it is preferable to use a dialysate in which these concentrations are adjusted.

In addition, it is preferable to add amino acids, peptides, proteins, and the like as osmotic agents other than sugars to the dialysate to reduce the load of sugars.
However, in order to solve the above-mentioned problem, it is necessary to separately store and sterilize the two components that easily cause the mutual reaction. Therefore, when the above-mentioned non-saccharide osmotic agent is used, it is desirable to add it to the second container.
Furthermore, it is important to satisfy conditions such as pH and salt concentration that minimize the degradation and denaturation of saccharides.

  On the other hand, it is desirable that the dialysate at the time of use be adjusted to a physiological pH. Therefore, the problem can be solved by separately storing the components for neutralization and mixing them before using the sterilization degree.

  The antioxidant or reducing agent added to the dialysate as a protein cross-linking inhibitor can be inhibited at any stage of the AGE-forming reaction, and any physiologically harmless agent can be used. The protein cross-linking dissociation agent can be used as long as it dissociates the protein cross-linking in a physiological environment and its product is harmless.

  Examples of the antioxidant or reducing agent include mercapto compounds, sulfides, hydrosulfides, reducing oxygen oxyacid salts, thiourea and its derivatives, cyclic compounds having a hydroxyl group and / or a carboxyl group, flavonoid compounds, Examples thereof include a nitrogen-containing heterocyclic compound, a hydrazyl group compound, and a mucopolysaccharide having a uronic acid group. Particularly, a reducing oxygen oxyacid salt is effective.

  Reducing sulfur oxyacid salts include the sodium, potassium, or other physiologically safe salts of sulfurous acid, bisulfite, thiosulfate, metabisulfite, or dithionite. These salts may be acidic sulphite (bisulphite).

  In addition, since amino acid is mixed with sodium acid sulfite as a reducing agent in a commercially available amino acid infusion, such an amino acid infusion as such is an osmotic agent other than saccharides, or a protein cross-linking inhibitor is further added. It can also be used.

  As the reducing agent, one having a low oxidation-reduction potential is effective, and in particular, a reducing agent having a potential lower than the oxidation-reduction potential (+160 mV to +180 mV) of physiological saline is effective.

  In the present invention, it is essential to have first to third three containers, but further containers can be added as necessary. By increasing the number of containers, sterilizers having different sterilization conditions can be separately performed in the case of an inhibitor having low heat resistance. Further, it is preferable that a solution containing an amino acid, a peptide, a protein or other non-saccharide osmotic substances be contained in a fourth container and sterilized under milder conditions than the first to third containers.

  The containers used for storage and sterilization of each component may be separate ones, but as shown in FIG. 1, the first container and the second container are adjacent by a partition that can easily penetrate, and after mixing both, It is advantageous that the saccharide osmotic agent and the antioxidant or the reducing agent are easily mixed when housed in a container having a structure that can be mixed with the solution in the third container.

[Example 1]
400 ml of dilute hydrochloric acid solution (pH 3.5) containing glucose (20 g / dl) in the first chamber,
Sodium chloride in the second room: 132 mM / l
Magnesium chloride: 0.75 mM / l
Calcium chloride: 1.25 mM / l
Sodium lactate: 35mM / l
Solution (pH 8) containing 1500 ml
Sodium bisulfite solution (500ml) in room 3
Were separately sterilized in an autoclave at a maximum temperature of 121 ° C. and a maximum temperature maintenance time of 30 minutes. After cooling to room temperature, the three solutions were mixed, and an oxidation-reduction potentiometer (Toa Denpasha Co., Ltd.) , A fixed amount of excess sodium thiosulfate (Na ₂ S ₂ O ₃ ) was added thereto, and titration analysis was performed by a reverse titration method in which methylglyoxal was added dropwise to quantify the oxidized components.
In this, ten experiments were conducted in which the concentration of the sodium bisulfite solution (500 ml) was changed in the range of 1 to 10 mM / l. The addition amount of sodium bisulfite required for the component showing the value to become zero was determined. Table 1 shows the results.

[Comparative Example 1]
The mixture of the solutions in the respective chambers used in the examples was stored in one bag, subjected to high-temperature sterilization under the same conditions as in Example 1, and subjected to redox titration analysis. Table 1 shows the results.

[Comparative Example 2]
In the first chamber, the glucose and the electrolyte salt used in Comparative Example 1 were 1500 ml. In the second chamber, a series of experiments in which the concentration of the sodium bisulfite solution (500 ml) was changed in the range of 1 to 10 mM / l was performed at the highest temperature in the autoclave. A high-pressure steam sterilization treatment was performed at 121 ° C. and a maximum temperature maintenance time of 30 minutes, and after cooling to room temperature, the two solutions were mixed, and redox titration analysis was performed under the same conditions as in Example 1. Table 1 shows the results.

[Comparative Example 3]
A dialysate bag containing a solution of glucose and sodium bisulfite (500 ml) in the first chamber and an electrolyte salt solution (1500 ml) in the second chamber is subjected to high-pressure steam sterilization in an autoclave at a maximum temperature of 121 ° C. and a maximum temperature maintenance time of 30 minutes. In the experiments to be performed, a series of experiments in which the concentration of sodium bisulfite was changed in the range of 1 to 10 mM / l was performed. After cooling to room temperature, the two solutions were mixed and subjected to redox titration analysis under the same conditions as in Example 1. Table 1 shows the results.

[Example 2]
In Example 1, 200 ml of an amino acid infusion (Kidmin manufactured by Otsuka Pharmaceutical Co., Ltd.) was stored in the third chamber in place of the sodium bisulfite solution, and high-temperature sterilization was performed in the same manner as in Example 1 except for the other conditions. Table 1 shows the results.
Amino acid transfusion (Kidmin manufactured by Otsuka Pharmaceutical Co., Ltd.) consists of total amino acids 14.41g / 200ml
Sodium bisulfite 40mg / 200ml (0.2g / l = 1,92mM / l)
It is.

[Example 3]
400 ml of dilute hydrochloric acid solution (pH 3.5) containing glucose (20 g / dl) in the first chamber,
NaCl: 132 mM / l in the second chamber
MgCl ₂ : 0.75 mM / l
CaCl ₂ : 1.25 mM / l
Na lactate: 35mM / l
Solution (pH 8) containing 1800 ml
A series of experiments in which the amino acid mixture was stored in the third chamber, the NaHSO solution (100 ml) was stored in the fourth chamber, and the concentration was changed in the range of 1 to 10 mM / l, were subjected to high-temperature sterilization under the same conditions as in Example 1. Was.

  As is clear from the results in Table 1, when component solutions containing a saccharide osmotic agent, a reducing agent, and an electrolyte salt are mixed and subjected to high-temperature sterilization, a large amount of oxidized components is generated. After the solution is stored and sterilized, no oxidized component is generated in the mixed solution. By performing the sterilization in this way, it is expected that a peritoneal dialysis solution that does not easily cause protein cross-linking will be obtained.

  Further, as is apparent from the results in Table 1, the three-split method and the four-split method of the present invention greatly increase the required amounts of reducing agents and antioxidants to be added, as compared with the two-split method of JP-A-2002-315825. Can be reduced.

  By using such a peritoneal dialysis solution, it is possible to perform peritoneal dialysis treatment for a long period of time without causing peritoneal sclerosis, and it is possible to supply a dialysis solution that maintains the water removal ability. Therefore, the present invention is extremely useful as a means for continuously performing treatment by peritoneal dialysis without any trouble.

1 shows an example of the structure of a container for storing each component of the peritoneal dialysate of the present invention.

Claims (5)

An acidic solution containing a saccharide osmotic agent in the first container, a solution containing an antioxidant or a reducing agent in the second container, a solution containing an electrolyte salt in the third container, and after sterilization, mixed before use. A method for preparing a peritoneal dialysate. The method for preparing a peritoneal dialysate according to claim 1, wherein a non-saccharide osmotic agent is added to the second container. The method for preparing a peritoneal dialysate according to claim 2, wherein the non-saccharide osmotic agent is any one of amino acids, peptides, or proteins or a mixture thereof. The method for preparing a peritoneal dialysate according to any one of claims 1 to 3, wherein a solution containing an amino acid, a peptide, a protein, or another non-saccharide osmotic substance is stored in the fourth container. The first container and the second container are adjacent to each other with a partition that can easily penetrate, and after mixing both, the container is housed in a container having a structure that can be mixed with the solution of the third container. A method for preparing a peritoneal dialysate.

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