JP3871442B2 - Peritoneal dialysate - Google Patents

Description

【００３４】
上記表１に示されるように、本発明に従って薬液処方を設定し、適切な加熱滅菌を行うことによって、加熱滅菌後、あるいは６０℃で１０日経過後も２８４ｎｍの吸光度において０．１以下の腹膜透析液を実現することができる。この事は従来技術からは予測なし得なかった事である。
以上の結果より、本発明の効果は明らかである。
【００３５】
【発明の効果】
以上、詳細に説明したように、本発明によれば、ｐＨを生理的な領域にできると共に、加熱滅菌およびその後の保管中のブドウ糖の分解を最大限に抑制し、非常に安定性に優れた腹膜透析液を得ることができる。
【図面の簡単な説明】
【図１】 ブドウ糖溶液の乳酸ナトリウム含有量に対する２８４ｎｍの吸光度の経時的な変化を示すグラフである。[0001]
BACKGROUND OF THE INVENTION
The present invention belongs to the technical field of peritoneal dialysis fluid, and particularly relates to a peritoneal dialysis fluid with improved stability of glucose contained in the peritoneal dialysis fluid.
[0002]
[Prior art]
Peritoneal dialysis, which is one of the symptomatic treatments for renal failure, is notable as a device for home care because it requires less equipment and instruments and less time constraints than dialysis performed with an artificial kidney. Has been.
[0003]
However, peritoneal dialysis always carries the risk of peritonitis. Although this has been considered to be the biggest cause of continuation of peritoneal dialysis therapy, the incidence of peritonitis has decreased year by year due to improvements in catheters and sterile connection methods, etc. I am doing.
However, despite the absence of a history of peritonitis, the function of the peritoneum as a dialysis membrane gradually declines, reducing the amount of water removed and the effect of removing waste products, making it difficult to continue peritoneal dialysis. An example came out.
[0004]
The cause of this has not yet been determined, but in general, the direct contact between the tube and the peritoneum, the physical stress on the peritoneum due to the injection and discharge of chemicals, and the pH and osmotic pressure of the chemicals are physiological. When stimulation derived from deviating from the range causes a series of tissue reactions such as peritoneal mesothelial cell damage and detachment, peritoneal fibrosis (thickening), and this causes a decrease in peritoneal function It is considered.
[0005]
For example, conventionally used peritoneal dialysis fluid has been 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). According to this study, it has been reported that peritoneal dialysis fluid having such a pH substantially reduces the immune defense mechanism of peritoneal macrophages and increases the risk of peritonitis against bacterial invasion.
Furthermore, the peritoneal dialysis solution having a pH of 5.0 to 5.5 has extremely high damage to the cultured peritoneal mesothelial cells. To reduce the damage, the pH of the peritoneal dialysis solution is set to 6.5 or more. It has been reported to be effective.
[0006]
However, the pH of the peritoneal dialysis solution has a great influence on the stability of glucose blended in the peritoneal dialysis solution currently used. If the pH is increased as it is, glucose will be degraded during production and storage. A chemical | medical solution will color and a product value will fall remarkably.
Therefore, as a method of increasing the pH of the peritoneal dialysis solution while suppressing the decomposition and coloring of glucose, the drug solution component containing glucose and the drug solution component having a high pH are separately stored until use, and aseptic before use. Formulations have been developed that mix with
[0007]
In this way, as a peritoneal dialysis solution having a high pH and suppressing the decomposition and coloring of glucose by separating the chemical solution components, for example, Japanese Patent Publication No. 7-500992 discloses a high permeation rate of 10 to 50% or more. A peritoneal dialysis solution obtained by separating a glucose solution at a concentration from other electrolytes and alkaline agents is disclosed.
According to this peritoneal dialysis solution, although the absorbance at 228 nm due to the degradation product of glucose decreases, the absorbance at 284 nm, which is an indicator of 5-hydroxymethylfurfural (5-HMF), which is the main degradation product of glucose, is However, it increases over time, that is, the degradation of glucose cannot be sufficiently suppressed.
[0008]
Further, JP-A-8-131542 includes a first liquid having a pH of 4 to 5 that contains glucose and does not contain lactate ions, and a second liquid that contains sodium lactate and does not contain glucose. Thus, a peritoneal dialysis solution is disclosed in which the degradation of glucose is suppressed, that is, the absorbance at 284 nm, which is an indicator of 5-HMF, is reduced.
However, the demand for the stability of peritoneal dialysis fluid and the safety of peritoneal dialysis fluid has become increasingly higher in recent years, at a physiological pH that does not adversely affect the human body, and more glucose degradation and Appearance of a stable peritoneal dialysis solution in which coloring is suitably suppressed is desired.
[0009]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems of the prior art, to maximize the stability of glucose during heat sterilization and subsequent storage, and peritoneal dialysis whose pH is close to a physiological range. To provide liquid.
[0010]
[Means for Solving the Problems]
As a result of intensive studies in order to achieve the above object, the present inventors have obtained a peritoneal dialysis solution (hereinafter, for convenience, which separates and stores a drug solution component containing glucose and a drug solution component having a high pH). In a two-part peritoneal dialysis solution), by adding a trace amount of sodium lactate in a specific concentration range to a solution containing glucose, an increase in absorbance at 284 nm over time of the peritoneal dialysis solution can be suppressed, that is, The present inventors have found that a peritoneal dialysis solution excellent in stability can be obtained in which the degradation of glucose during heat sterilization and subsequent storage is greatly suppressed.
[0011]
That is, the present invention comprises a first liquid containing glucose and 10 ppm to 500 ppm sodium lactate, and a second liquid containing an alkaline pH adjuster, and the pH of the second liquid is 6.7-7. a .4, pH after mixing provide peritoneal dialysate is 6.0 to 7.5.
[0012]
Moreover, it is preferable that the alkaline pH adjuster of the second liquid contains at least one of sodium hydroxide and sodium hydrogen carbonate, and it is preferable that the pH of the first liquid is 4.5 to 6.5. .
[0013]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the peritoneal dialysis solution of the present invention will be described in detail.
[0014]
The peritoneal dialysis solution of the present invention comprises a first solution containing glucose and a second solution that does not contain glucose and contains an alkaline pH adjuster, and the first solution and the second solution are mixed immediately before use. In the peritoneal dialysis fluid of (2 compartments), the first fluid containing glucose contains 10 ppm to 500 ppm of sodium lactate, and the pH after mixing is 6.0 to 7.5.
[0015]
FIG. 1 shows the relationship between changes over time in absorbance at 284 nm and sodium lactate concentration of a solution containing glucose and sodium lactate.
In the example shown in FIG. 1, 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) Preparations), and 14 mL each of each aqueous solution is filled into a test tube with a stopper and sterilized by heating (110 ° C., 12 minutes) in a constant temperature bath at 60 ° C. and stored. The absorbance at 284 nm was measured after 5, 10, and 15 days.
That is, the 284 nm absorbance change with time of a glucose solution having sodium lactate concentrations of 0 ppm, 5 ppm, 10 ppm, 50 ppm, 350 ppm, and 500 ppm is shown.
[0016]
As shown in FIG. 1, by adding a small amount of sodium lactate to a glucose solution, it is possible to suppress an increase in absorbance of the solution at 284 nm over time, that is, to suppress glucose degradation. On the other hand, as the amount of sodium lactate added increases, the increase in absorbance increases.
[0017]
According to the study by the present inventors, in the two-part peritoneal dialysis solution, the first solution containing glucose contains 10 ppm to 500 ppm, preferably 10 ppm to 350 ppm of sodium lactate. Glucose degradation during sterilization and subsequent storage can be suitably suppressed, and a peritoneal dialysis solution that is stable and excellent in storage stability can be realized.
[0018]
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, and is preferably 0.5 g / dl to 10 g / dl.
Moreover, although there is no limitation in particular also in the pH of a 1st liquid, the range of pH4.5-6.5 is preferable. In the first solution of the peritoneal dialysis solution of the present invention, it is not necessary to adjust pH unless a component that causes a large pH change is blended, but if necessary, for example, hydrochloric acid or lactic acid is used. PH adjustment may be performed.
[0019]
In the second liquid of the peritoneal dialysis liquid of the present invention, the pH of the mixed liquid after mixing the first liquid and the second liquid in addition to sodium lactate or lactic acid blended as an alkalizing agent is 6.0 to 7. 5, Preferably, in order to adjust pH to 6.5-7.5, an alkaline pH adjuster, preferable examples include sodium hydroxide and sodium bicarbonate.
In the peritoneal dialysis solution of the present invention, if the pH after mixing is less than 6.0, the immune defense mechanism of macrophages is reduced and the peritoneal mesothelial cells are highly impaired. Concerned.
[0020]
In consideration of the fact that the first liquid contains sodium lactate in a predetermined range, the pH of the second liquid is usually pH 6.7 or higher, but is set to pH 9 or lower from the viewpoint of safety during misuse. It is desirable to do.
[0021]
In the peritoneal dialysis fluid of the present invention, the content of lactate ions is not particularly limited, and may be the same as that of a normal peritoneal dialysis fluid. Preferably, the total of the first fluid and the second fluid is 30 mEq / L to 45 mEq / L.
[0022]
In addition to these components, the peritoneal dialysate of the present invention contains various components contained in normal peritoneal dialysate, that is, sodium ions, calcium ions, magnesium ions, chloro ions, and the like.
These contents may be the same as the normal peritoneal dialysis solution. The total of the first and second fluids is 100mEq / L to 200mEq / L for sodium ions and 0mEq / L to 5mEq / L for calcium ions. However, the magnesium ion is preferably 0 mEq / L to 5 mEq / L, and the chloro ion is preferably 50 mEq / L to 180 mEq / L.
[0023]
These components may be contained in either the first liquid or the second liquid, but in terms of the stability of the peritoneal dialysis liquid such as suppression of glucose degradation, it may be added to the second liquid that does not contain glucose. preferable.
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 a normal peritoneal dialysis solution.
However, it is natural that the first liquid should not contain sodium lactate that exceeds the scope of the present invention, and the lactic acid added to the first liquid is preferably only for pH adjustment. .
[0024]
In such a 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 immediately before use. And the second liquid are mixed aseptically. In addition, sterilization is performed before or after packaging.
The method of sterilization is not particularly limited, and examples thereof include a method using heating or radiation using steam, electron beam, and a method of filling a container after aseptic filtration.
[0025]
The peritoneal dialysis solution of the present invention has been described in detail above, but 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]
【Example】
Hereinafter, the present invention will be described in more detail with reference to specific examples of the present invention. Needless to say, the present invention is not limited to the following examples.
[0027]
[Example 1]
Glucose were dissolved 2000 g, 50% sodium lactate solution 4.0 g, water for injection 40L, and the first solution was prepared (sodium lactate concentration 5 0 ppm).
Further, 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, each dissolved in 20 L of water for injection, The pH was adjusted and a second liquid was prepared.
800 mL of the first solution and 200 mL of the second solution are filled in a polypropylene multi-chamber container, put in a three-sided polypropylene / nylon / polypropylene bag, degassed, and then heat sterilized using an autoclave (115 ° C., 11 After that, the pH of the first 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.
[0028]
The change over time of the absorbance at 284 nm of the obtained product (peritoneal dialysate) was measured. The results are shown in Table 1 below.
The product was stored in a constant temperature bath at 60 ° C., and the first liquid and the second liquid were mixed immediately before measuring the absorbance.
[0029]
[Example 2]
Glucose was dissolved in 2000 g, 50% sodium lactate solution in 8.0 g and 40 L of water for injection to prepare a first solution (sodium lactate concentration of 100 ppm).
Further, 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, dissolved in 20 L of water for injection, and pH with sodium hydroxide The second liquid was prepared.
After packaging 1600 mL of the first solution and 400 mL of the second solution in the same manner as in Example 1, and then sterilizing by heating (115 ° C., 12 minutes) using an autoclave, the first, second, and both The pH of the liquid mixture 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.
For the obtained product, the change with time in the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.
[0030]
[Example 3]
Glucose was dissolved in 2000 g, 50% sodium lactate solution in 16.0 g, and 40 L of water for injection to prepare a first solution (sodium lactate concentration of 200 ppm).
Further, 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, dissolved in 20 L of water for injection, and pH with sodium hydroxide The second liquid was prepared.
After packaging 800 mL of the first liquid and 200 mL of the second liquid in the same manner as in Example 1, and then sterilizing by heating (115 ° C., 11 minutes) using an autoclave, the first liquid, the second liquid, and both The pH of the liquid mixture was measured. The pH of the first liquid was 5.7, the pH of the second liquid was 7.4, and the pH of the mixed liquid was 6.8.
For the obtained product, the change with time in the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.
[0031]
[Comparative Example 1]
Glucose was dissolved in 2000 g of 40 L of water for injection to prepare a first solution.
Further, 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, dissolved in 20 L of water for injection, and pH with sodium hydroxide The second liquid was prepared.
After packaging 1600 mL of the first liquid and 400 mL of the second liquid in the same manner as in Example 1, and then sterilizing by heating (115 ° C., 12 minutes) using an autoclave, the first liquid, the second liquid, and both The pH of the liquid mixture 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.
For the obtained product, the change with time in the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.
[0032]
[Comparative Example 2]
A first solution was prepared by dissolving 2000 g of glucose in 40 L of water for injection and adjusting the pH to 4.5 with dilute hydrochloric acid.
In addition, 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, dissolved in 20 L of water for injection to prepare a second solution did.
After packaging 1600 mL of the first liquid and 400 mL of the second liquid in the same manner as in Example 1, and then sterilizing by heating (115 ° C., 11 minutes) using an autoclave, the first liquid, the second liquid, and both The pH after mixing of the liquid was measured. The pH of the first solution was 4.3, the pH of the second solution was 7.2, and the pH of the mixed solution was 6.2.
For the obtained product, the change with time in the absorbance at 284 nm was measured in the same manner as in Example 1. The results are also shown in Table 1.
[0033]

[0034]
As shown in Table 1 above, by setting a chemical formulation according to the present invention and performing appropriate heat sterilization, peritoneal dialysis of 0.1 or less at an absorbance of 284 nm even after 10 days at 60 ° C. after heat sterilization. Liquid can be realized. This is something that could not have been predicted from the prior art.
From the above results, the effects of the present invention are clear.
[0035]
【The invention's effect】
As described above in detail, according to the present invention, the pH can be set in a physiological region, and the decomposition of glucose during heat sterilization and subsequent storage is suppressed to the maximum, and the stability is excellent. Peritoneal dialysate can be obtained.
[Brief description of the drawings]
FIG. 1 is a graph showing the change with time of absorbance at 284 nm with respect to the sodium lactate content of a glucose solution.

Claims (4)

A first liquid containing glucose and 10 ppm to 500 ppm sodium lactate (excluding those containing a lactic acid buffer solution comprising lactic acid and sodium lactate) and a second liquid containing an alkaline pH adjuster; A peritoneal dialysis solution in which the pH of the second solution is 6.7 to 7.4 and the pH after mixing is 6.0 to 7.5.   The peritoneal dialysis solution according to claim 1, wherein the first solution contains 50 to 200 ppm of sodium lactate. The peritoneal dialysis fluid according to claim 1 or 2 , wherein the alkaline pH adjuster of the second fluid contains at least one of sodium hydroxide and sodium bicarbonate. The peritoneal dialysis solution according to any one of claims 1 to 3, wherein the pH of the first solution is 4.5 to 6.5.

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