JP2000051348A - Peritoneal dialysis solution - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve stability of glucose in heating sterilization and the subsequent storage and to make pH approach to physiological region by mixing a liquid containing glucose and sodium lactate with a specified concentration with a liquid containing alkali pH regulator, and specifying the pH after mixing. SOLUTION: This two-liquid type peritoneal dialysis is composed of a liquid containing glucose and a liquid containing no glucose but alkali pH regulator, which are mixed immediately before the use. 20 ppm-1000 ppm of sodium lactate is included in glucose-containing liquid, and pH of the mixture is set to 6.0-7.5. Thus, decomposition of glucose in heating sterilization and the subsequent storage can be restrained, and the stability and shelf life can be improved. The pH of the glucose-containing liquid is preferably set in a region of 4.5-6.5. Further. Alkali pH regulator, preferably sodium hydroxide, sodium hydrogencarbonate or the like are incleeded in the liquid containing the pH regulator.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention belongs to the technical field of peritoneal dialysate, and more particularly to a peritoneal dialysate having improved stability of glucose contained in peritoneal dialysate.

[0002]

2. Description of the Related Art Peritoneal dialysis, which is one of the symptomatic treatments for renal insufficiency, requires less equipment and instruments than dialysis therapy performed with artificial kidneys, and has less time constraints, so it is a home medical care. It is drawing attention as one of them.

[0003] However, peritoneal dialysis therapy is always associated with the risk of peritonitis. This has been thought to be the biggest factor preventing the continuation of peritoneal dialysis therapy.However, the incidence of peritonitis has been decreasing year by year due to improvements in catheters and aseptic connection methods, and the number of continuous peritoneal dialysis patients has increased I am doing it. However, despite no history of peritonitis,
In some cases, the function of the peritoneal membrane as a dialysis membrane gradually decreases, and the amount of water removed and the effect of removing waste products decrease, making it difficult to continue peritoneal dialysis.

The cause of this has not been determined yet, but in general, there is direct contact between the tube and the peritoneum, physical stress on the peritoneum due to injection and drainage of the drug solution, and furthermore, the pH and osmotic pressure of the drug solution. Stimuli, such as those that deviate from the physiological range, cause a series of tissue reactions, such as damage and detachment of peritoneal mesothelial cells and fibrosis (thickening) of the peritoneum, resulting in reduced peritoneal function. It is believed to be caused.

For example, conventionally used peritoneal dialysis solutions are formulated so that the pH of the drug solution is in the range of 5.0 to 5.5 in order to prevent the decomposition and coloring of glucose (glucose). However, recent studies show that such p
H peritoneal dialysate has been reported to substantially reduce the immune defense mechanisms of peritoneal macrophages and increase the risk of peritonitis for bacterial invasion. Further, the peritoneal dialysis solution having a pH of 5.0 to 5.5 has remarkably high impairment on cultured peritoneal mesothelial cells. Has been reported to be effective.

[0006] However, the pH of the peritoneal dialysis solution has a great effect on the stability of glucose contained in the currently used peritoneal dialysis solution. It decomposes to color the chemical solution, resulting in a significant reduction in product value. Therefore, while suppressing the decomposition and coloring of glucose,
As a method of increasing the pH of the peritoneal dialysis solution, a formulation has been developed in which a drug solution component containing glucose and a drug solution component having a high pH are separately stored until use, and aseptically mixed immediately before use.

[0007] As described above, a peritoneal dialysis solution having a high pH and suppressing the decomposition and coloring of glucose by separating a drug solution component is disclosed in, for example, Japanese Patent Application Laid-Open No. 7-500992, in which 10 to 50% There is disclosed a peritoneal dialysis solution obtained by separating the above high-concentration glucose solution from other electrolytes and alkaline agents. According to this peritoneal dialysis solution, although the absorbance at 228 nm caused by the degradation product of glucose is reduced, it is an indicator of 5-hydroxymethylfurfural (5-HMF), which is the main degradation product of glucose.
The absorbance at 4 nm increases with time, that is, it cannot sufficiently suppress the decomposition of glucose.

Further, JP-A-8-131542 discloses a first liquid containing glucose and not containing lactate ions, which has a pH of 4 to 5, and a second liquid containing sodium lactate and not containing glucose. A peritoneal dialysis solution that suppresses the decomposition of glucose, that is, reduces the absorbance at 284 nm, which is an index of 5-HMF, is disclosed. However, the demand for the stability of peritoneal dialysis solution and the safety of peritoneal dialysis solution has become increasingly higher in recent years, and at physiological pH that does not adversely affect the human body, and at the same time, glucose degradation and There is a demand for the appearance of a stable peritoneal dialysis solution in which coloring is suitably suppressed.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems of the prior art, and to maximize the stability of glucose during heat sterilization and subsequent storage, and to improve pH. Is to provide a peritoneal dialysate that is close to a physiological region.

[0010]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, a peritoneum which separates and stores a drug solution component containing glucose and a drug solution component having a high pH. In a dialysate (hereinafter, for convenience, referred to as a two-part peritoneal dialysate), a solution containing glucose contains a trace amount of sodium lactate in a specific concentration range,
It has been found that an increase in absorbance at 284 nm over time of the peritoneal dialysate can be suppressed, that is, a highly stable peritoneal dialysate can be obtained, which significantly suppresses degradation of glucose during heat sterilization and subsequent storage. The present invention has been accomplished.

That is, the present invention relates to glucose and 20
Provided is a peritoneal dialysis solution comprising a first solution containing 1 to 1000 ppm of sodium lactate and a second solution containing an alkaline pH adjuster, and having a pH of 6.0 to 7.5 after mixing.

Preferably, the alkaline pH adjuster of the second liquid contains at least one of sodium hydroxide and sodium hydrogencarbonate, and the pH of the first liquid is 4.5 to 6.5. Is preferred.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the peritoneal dialysis solution of the present invention will be described in detail.

The peritoneal dialysis solution of the present invention comprises a first solution containing glucose and a second solution containing no glucose and containing an alkaline pH adjuster. The first solution and the second solution are mixed immediately before use. A two-pack (two-compartment) peritoneal dialysis solution in which the first solution containing glucose is 20 ppm to 1000 pp
It is a peritoneal dialysis solution containing m-sodium lactate and having a pH after mixing of 6.0 to 7.5.

FIG. 1 shows the relationship between the change over time in the absorbance at 284 nm and the concentration of sodium lactate in a solution containing glucose and sodium lactate. The example shown in FIG.
In 250 mL (liter) of water for injection, 12.5 g of glucose, 0 mg, 2.5 mg, 5.0 mg, 25.0
mg, 175 mg, and 250 mg of 50% sodium lactate solution (external standard product) were prepared, and each aqueous solution was filled into a test tube with a stopper in a volume of 14 mL and sterilized by heating (110 ° C., 12 minutes). The sample was stored in a thermostat at 60 ° C., and the absorbance at 284 nm after 5, 10, and 15 days was measured. That is, when the sodium lactate concentration is 0 ppm, 10 ppm, 20 ppm, 100 pp
5 shows the time course of the absorbance at 284 nm for glucose solutions of m, 700 ppm and 1000 ppm.

As shown in FIG. 1, by adding a trace amount of sodium lactate to a glucose solution, two
It is possible to suppress an increase in absorbance at 84 nm over time, that is, to suppress the decomposition of glucose. On the other hand, when the added amount of sodium lactate increases, the increase in absorbance increases.

According to the study of the present inventors, in a two-pack type peritoneal dialysis solution, 20 ppm or less is contained in the first solution containing glucose.
1000 ppm, preferably 20 ppm to 700 pp
By containing m sodium lactate, the decomposition of glucose during heat sterilization and subsequent storage can be suitably suppressed, and a peritoneal dialysis solution that is stable and excellent in storage stability can be realized.

The content of glucose contained in the first solution is not particularly limited, and may be the same as that of a normal peritoneal dialysis solution.
g / dl to 10 g / dl are preferred. The pH of the first liquid is not particularly limited, but is preferably in the range of pH 4.5 to 6.5. In addition, in the first solution of the peritoneal dialysis solution of the present invention, unless a component causing a large pH change is blended, there is no particular need to adjust the pH, but if necessary, for example, hydrochloric acid or lactic acid is used. PH adjustment may be performed.

The second solution of the peritoneal dialysis solution of the present invention contains, in addition to sodium lactate and lactic acid blended as an alkalizing agent,
The pH of the mixed liquid after mixing the first liquid and the second liquid is 6.0 to 6.0.
To adjust the pH to 7.5, preferably to 6.5 to 7.5, an alkaline pH adjuster, as a preferred example,
Contains sodium hydroxide, sodium bicarbonate and the like. In the peritoneal dialysate of the present invention, the pH after mixing is 6.
If it is less than 0, the immune defense mechanism of macrophages is reduced,
It is highly toxic to peritoneal mesothelial cells.

Incidentally, the pH of the second liquid is usually set in consideration of the fact that the first liquid contains a predetermined range of sodium lactate.
pH 6.7 or more, but p
It is desirable to set H9 or less.

In the peritoneal dialysis solution of the present invention, the content of lactate ion is not particularly limited and may be the same as that of a normal peritoneal dialysis solution. Preferably, the total amount of the first solution and the second solution is 3
0 mEq / L to 45 mEq / L.

[0022] In addition to these components, the peritoneal dialysate of the present invention contains various components contained in ordinary peritoneal dialysates, that is, sodium ions, calcium ions, magnesium ions, chlor ions, and the like. These contents may be the same as those of a normal peritoneal dialysis solution, and may be the first solution and the second solution.
The total amount of sodium ions is 100 mEq / L to 20
0mEq / L, calcium ion is 0mEq / L-5mEq / L
However, magnesium ions are preferably 0 mEq / L to 5 mEq / L, and chlor ions are preferably 50 mEq / L to 180 mEq / L.

These components may be contained in either the first solution or the second solution. However, in terms of stability of the peritoneal dialysis solution such as suppression of glucose degradation, the components are mixed with the second solution containing no glucose. Is preferred. In addition, these components may be added to the peritoneal dialysis solution of the present invention as lactic acid, sodium lactate, calcium chloride, magnesium chloride, sodium chloride, etc. in the same manner as ordinary peritoneal dialysis solution. However, it is natural that sodium lactate exceeding the range of the present invention should not be blended in the first liquid, and lactic acid blended in the first liquid is preferably used only for pH adjustment. .

In the peritoneal dialysis solution of the present invention, the first solution and the second solution are separately filled and packaged in a container made of polypropylene or polyvinyl chloride and stored. The first liquid and the second liquid are aseptically mixed. Also, sterilization is performed before or after packaging. The method of sterilization is not particularly limited, and examples include a method using heating or radiation with steam or an electron beam, and a method of filling a container after aseptic filtration.

Although the peritoneal dialysis solution of the present invention has been described in detail above, the present invention is not limited to this, and various improvements and modifications may be made without departing from the gist of the present invention.

[0026]

Hereinafter, the present invention will be described in more detail with reference to specific examples of the present invention. It goes without saying that the present invention is not limited to the following embodiments.

Example 1 2000 g of glucose, 50
The first solution was prepared by dissolving 4.0 g of a 40% sodium lactate solution in 40 L of water for injection.
pm). Also, 887 g of 50% sodium lactate solution, 555 g of sodium chloride, and 1 g of calcium chloride / dihydrate
8.3 g and 5.08 g of magnesium chloride hexahydrate were each dissolved in 20 L of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second liquid. 800 mL of the first liquid,
200 mL of the second liquid was filled in a polypropylene double-chamber container, placed in a polypropylene / nylon / polypropylene three-sided bag, degassed and packaged, and then heat-sterilized (115 ° C., 11 minutes) using an autoclave. First
The pH of the liquid, the second liquid, and the mixture of both liquids was measured. The pH of the first liquid was 5.6, the pH of the second liquid was 7.2, and the pH of the mixed liquid was 6.8.

284 n of the obtained product (peritoneal dialysis solution)
The change in absorbance over time was measured. The results are shown in Table 1 below. The product was stored in a thermostat at 60 ° C., and the first liquid and the second liquid were mixed immediately before the measurement of the absorbance.

Example 2 2000 g of glucose, 50 g
% Sodium lactate solution was dissolved in 8.0 g of 40 L of water for injection to prepare a first solution (sodium lactate concentration of 200 p).
pm). Also, 887 g of 50% sodium lactate solution, 555 g of sodium chloride, and 1 g of calcium chloride / dihydrate
8.3 g, 5.08 g of magnesium chloride hexahydrate, 2
The second solution was prepared by dissolving in 0 L of water for injection and adjusting the pH with sodium hydroxide. 1st liquid 1600mL, 2nd liquid 4
00 mL each was packaged in the same manner as in Example 1, and then heat-sterilized (115 ° C., 12 ° C.) using an autoclave.
Minutes), p of the first liquid, the second liquid, and the mixture of the two liquids
H was measured. The pH of the first liquid was 5.6, the pH of the second liquid was 7.4, and the pH of the mixed liquid was 6.9. About the obtained product, the change with time of the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.

Example 3 2000 g glucose, 50 g
1% sodium lactate solution was dissolved in 40 L of water for injection to prepare a first solution (sodium lactate concentration of 400%).
ppm). Also, 887 g of 50% sodium lactate solution,
555 g of sodium chloride, 18.3 g of calcium chloride / dihydrate, 5.08 g of magnesium chloride / hexahydrate,
The second solution was prepared by dissolving 20 L in water for injection and adjusting the pH with sodium hydroxide. 800 mL of the first liquid and 200 mL of the second liquid were respectively packed in the same manner as in Example 1, and then heat-sterilized (115 ° C., 1
After 1 minute), the pH of the first liquid, the second liquid, and the mixed liquid of both liquids were measured. PH of the first liquid is 5.7, pH of the second liquid
Was 7.4 and the pH of the mixture was 6.8. About the obtained product, the change with time of the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.

Comparative Example 1 2000 g glucose, 40 g
L was dissolved in L of water for injection to prepare a first liquid. Also, 50
887 g of sodium lactate solution and 55% of sodium chloride
5 g, 18.3 g of calcium chloride dihydrate and 5.08 g of magnesium chloride hexahydrate were dissolved in 20 L of water for injection, and the pH was adjusted with sodium hydroxide to prepare a second liquid. Each of 1600 mL of the first liquid and 400 mL of the second liquid was packaged in the same manner as in Example 1, and then heat-sterilized (115 ° C., 12 minutes) using an autoclave.
The pH of the liquid, the second liquid, and the mixture of both liquids was measured. The pH of the first liquid was 5.5, the pH of the second liquid was 7.2, and the pH of the mixed liquid was 6.7. About the obtained product, the change with time of the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.

Comparative Example 2 2000 g of glucose and 40
L was dissolved in L of water for injection, and the pH was adjusted to 4.5 with dilute hydrochloric acid to prepare a first liquid. Also, 887 g of 50% sodium lactate solution, 555 g of sodium chloride, 18.3 g of calcium chloride / dihydrate, 5.08 g of magnesium chloride / hexahydrate, and dissolved in 20 L of water for injection to prepare a second solution. did. First liquid 1600mL, Second liquid 400mL
Were packaged in the same manner as in Example 1, and then heat-sterilized (115 ° C., 11 minutes) using an autoclave, and then the pH of the first solution, the second solution, and the pH after mixing both solutions were measured. . The pH of the first liquid is 4.3, the pH of the second liquid is 7.2,
The pH of the mixture was 6.2. About the obtained product, the change with time of the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.

[0033]

As shown in Table 1 above, by setting a drug solution formulation according to the present invention and performing appropriate heat sterilization, the heat treatment is performed after heat sterilization or after 10 days at 60 ° C.
A peritoneal dialysate of 0.1 or less at an absorbance of 4 nm can be realized. This could not have been predicted from the prior art. From the above results, the effect of the present invention is clear.

[0035]

As described above in detail, according to the present invention, the pH can be brought to a physiological range, and the decomposition of glucose during heat sterilization and subsequent storage can be suppressed to the utmost. A stable peritoneal dialysis solution can be obtained.

[Brief description of the drawings]

FIG. 1 is a graph showing the change over time of the absorbance at 284 nm with respect to the sodium lactate content of a glucose solution.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Naoya Amemiya 1727, Tsukiji Arai, Showa-cho, Nakakoma-gun, Yamanashi Prefecture Inside Terumo Corporation (72) Inventor Megumi Kunimasa 2-44-1, Hatagaya, Shibuya-ku, Tokyo Terumo Co., Ltd. F term (reference) 4C077 AA06 BB01 GG09 KK30

Claims (3)

[Claims] 1. Glucose and 20 ppm to 1000 pp
A first liquid containing sodium lactate and alkaline p
A peritoneal dialysis solution comprising a second solution containing an H adjuster and having a pH after mixing of 6.0 to 7.5. 2. The peritoneal dialysis solution according to claim 1, wherein the alkaline pH adjuster of the second solution contains at least one of sodium hydroxide and sodium hydrogen carbonate. 3. The peritoneal dialysis solution according to claim 1, wherein the pH of the first solution is 4.5 to 6.5.