JP4419904B2 - Peritoneal dialysate - Google Patents

Description

  The present invention belongs to the technical field of peritoneal dialysis fluid. More specifically, the present invention relates to a peritoneal dialysis solution that is composed of a two-component preparation that is mixed at the time of use and that suppresses the degradation of glucose.

It is known that peritoneal dialysis fluids used in the medical field contain glucose, and that glucose is degraded during the heat sterilization process and long-term storage to produce various degradation products.
On the other hand, since glucose is most stable around pH 3.0, it is known that adjusting the pH to a low level during the heat sterilization of glucose has less degradation of glucose and is more stable.
However, the peritoneal dialysis solution is in direct contact with the peritoneum, and on the other hand, since the living body pH is almost neutral, the heat sterilization of the peritoneal dialysis solution mixed with glucose is unavoidably 4.5 to close to the living body pH. It was prepared on the slightly acidic side of 5.5. Therefore, in the commercially available sterilized peritoneal dialysis solution, a degradation product of glucose is contained, and this degradation product of glucose enhances vascular permeability, and the peritoneal dialysis fluid has a reduced water removal ability, It is thought to cause a decrease in peritoneal function.

Accordingly, various studies have been made to suppress the production of this degradation product. As one method for increasing the pH of the peritoneal dialysis solution while suppressing the decomposition and coloring of glucose, a drug solution containing glucose and having a low pH is used. A formulation has been developed in which an ingredient and a liquid chemical ingredient having a high pH are separately stored until use, and aseptically mixed immediately before use.
As described above, various preparations have been disclosed as peritoneal dialysis fluids that have a high pH that is close to the biological pH during use by separating the chemical solution components to suppress glucose separation and coloring.

  For example, Patent Document 1 discloses a peritoneal dialysis solution obtained by separating a high-concentration glucose solution of 10 to 50% or more from other electrolytes and alkaline agents. 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 index 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.

  Patent Document 2 includes glucose and a first liquid having a pH of 4 to 5 that does not contain lactate ions, and a second liquid that contains sodium lactate and does not contain glucose. 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 has been increasing in recent years, and it has a physiological pH that does not affect the human body, and more suitably suppresses the degradation and coloring of glucose. The appearance of a stable peritoneal dialysis solution is desired.

  Further, Patent Document 3 includes a first liquid containing grapes and the like and 20 ppm to 1000 ppm of sodium lactate, and a second liquid containing an alkaline pH regulator, and after mixing the first liquid and the second liquid. Disclosed is a peritoneal dialysis solution that has a pH of 6.0 to 7.5, can maximize the stability of glucose during heat sterilization and subsequent storage, and has a pH close to a physiological range. Yes.

  Patent Document 4 is a peritoneal dialysis solution that is separated and accommodated in two solutions of an acidic side concentrated solution and an alkaline side concentrated solution, and contains glucose, calcium salt, and magnesium salt in the acidic side concentrated solution, By containing lactate and a small amount of bicarbonate ion in the alkali concentrate, it is possible to prevent the decomposition of glucose before use, and the dialysate after mixing is in a pH range that is biocompatible, and the pH is adjusted during production. A neutral peritoneal dialysis solution is disclosed.

Incidentally, 5-hydroxymethylfurfural (hereinafter abbreviated as 5-HMF), which is a typical degradation product of glucose, is considered to be harmful to the living body, but is another glucose degradation product and is a precursor of 5-HMF. 3-deoxyglucosone (hereinafter abbreviated as 3-DG), which is a body, is also known to be harmful because it causes increased peritoneal permeability and induces a decrease in peritoneal function (see Patent Document 5). . Moreover, 3-DG reacts with a protein to produce Advanced Glycation End Products (AGE), and is considered to be one of the causes of diabetic complications.
Patent Document 5 discloses a one-component type that does not contain 3-DG as a decomposition product of glucose produced by adding high-pressure steam sterilization to a preparation by adding cysteine to glucose or a combination drug containing glucose and sterilizing by heating. A peritoneal dialysis fluid formulation is disclosed.

However, since a step of adding cysteine as an additive is required in the peritoneal dialysate manufacturing process, the peritoneal dialysate is more complicated than before and suppresses the production of 3-DG that can be manufactured in a simpler process. A formulation was desired.
Moreover, the formulation which suppressed generation | occurrence | production of both decomposition products of 5-HMF and 3-DG is not disclosed, but safer peritoneal dialysis which suppressed generation | occurrence | production of both decomposition products of 5-HMF and 3-DG. It has been desired to provide a liquid formulation.

JP 7-500992 A JP-A-8-131542 JP 2000-51348 A JP 2000-245826 A JP-A-5-105633

An object of the present invention is to provide a two-liquid type peritoneal dialysate preparation that suppresses the production of 3-DG, which is a degradation product of glucose, as compared with a conventional two-liquid type peritoneal dialysate preparation .

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the glucose solution (first solution) of the two-liquid type peritoneal dialysis solution contains no salt and contains about 0.5 to about glucose. It has been found that by containing 20 w / v%, no sodium lactate, and 50-100 μg / mL of lactic acid, the production of 3-DG is suppressed without requiring any special additive. Reached.

That is, the present invention
(1) A glucose solution of a two-component peritoneal dialysis solution that does not contain salts, contains 0.5 to 20 w / v% glucose and 50 to 100 μg / mL lactic acid, and does not contain sodium lactate.
(2) The glucose solution of the two-liquid type peritoneal dialysis solution according to (1) having a pH of 3.5 to 4.5.
(3) The glucose solution of the two-liquid type peritoneal dialysate according to (1), wherein the osmotic pressure ratio is 0.7 to 1.6.
About.

The peritoneal dialysis fluid of the present invention can suppress 3-DG after heat sterilization and during long-term storage , as compared with the conventional two-component peritoneal dialysis fluid preparation, and has the effect of suppressing the decrease in peritoneal function. Have.
That is, this invention can provide the formulation which can maintain a dialysis effect over a long period of time.

Further, the present invention comprises an acidic solution (first liquid) containing glucose and an organic acid and a basic solution (second liquid) containing salts, and the pH after mixing is in a neutral range (about 6.4-7. Since it is adjusted to 4), it is a peritoneal dialysis solution that is close to the pH of serum and is gentler to the living body.
Furthermore, since the osmotic pressure of the 1st liquid and the 2nd liquid is closer to the osmotic pressure of the physiological saline, even if it is administered unmixed due to a medical error, the safety is high. When a second liquid having a pH of about 7.0 to 7.6 is stored in a chamber on the drainage port side stored in a multi-chamber container made of resin or the like, the pH of the second liquid depends on the pH of the living body. Because it is close, it is even safer.

  The peritoneal dialysis solution of the present invention is a two-liquid type peritoneum that does not contain salts, and comprises an acidic first solution containing glucose and an organic acid, and a basic second solution containing salts and a pH regulator. Dialysate.

The glucose concentration in the first liquid is preferably about 0.5 to 20 w / v%, more preferably about 4 to 16 w / v%.
The acid of the present invention includes various inorganic acids and organic acids, but organic acids are preferred. Examples of the organic acid include lactic acid, citric acid, acetic acid, succinic acid, and tartaric acid. Among these, lactic acid, citric acid, and acetic acid are preferable, and lactic acid is most preferable.
The concentration of lactic acid in the first liquid is preferably 50 to 100 μg / mL.

The pH of the first liquid is preferably about 3.5 to 4.5.
Moreover, it is preferable not to contain pH adjusters other than lactic acid in the first liquid.
The osmotic pressure ratio of the first liquid is usually about 0.2 to 2.0 with respect to the physiological saline, and about 0.7 if the safety when administered without communication due to a medical error is taken into consideration. It is preferable that it is -1.6.

  The salts of the present invention include organic salts and inorganic salts, and are not particularly limited as long as they are usually used in peritoneal dialysis fluid. Examples of inorganic salts include sodium chloride, calcium chloride, magnesium chloride and the like. Examples of organic salts include sodium lactate and sodium citrate.

Although it will not specifically limit if it is a pH adjuster normally used for a peritoneal dialysate, for example, lactic acid, a citric acid, an acetic acid, hydrochloric acid etc. are mentioned for the pH adjuster used for this invention. Of these, preferred are lactic acid, citric acid, and acetic acid.
The pH of the second liquid is preferably about 6.8 to 8.5, and more preferably about 7.0 to 7.6.
The osmotic pressure ratio of the second liquid is usually about 1.0 to 6.0 with respect to the physiological saline, and about 1.0 when taking into account safety when administered without communication due to a medical error. It is preferable that it is -1.6.

The first liquid and the second liquid of the present invention are preferably prepared so that the pH after mixing is about 6 to 8, more preferably about 6.3 to 7.6.
Moreover, it is preferable that the osmotic pressure of the chemical | medical solution after mixing 1st liquid and 2nd liquid is about 1.0-2.0 with respect to physiological saline.

  When the peritoneal dialysis fluid of the present invention is accommodated in a multi-chamber container made of various resins, the second fluid is accommodated in a chamber that leads to the drainage port, and the first fluid is a chamber other than the chamber that leads to the drainage port. It is preferable to be accommodated in This is because the second liquid is highly safe because it is close to the biological pH even if the multi-chamber container is administered without communication due to a medical error.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

  Glucose was dissolved in water for injection to a concentration of 5.0 w / v% and lactic acid at a concentration of 50 μg / mL to obtain a first solution of the peritoneal dialysis solution of the present invention.

  Glucose was dissolved in water for injection to a concentration of 5.0 w / v% and lactic acid at a concentration of 100 μg / mL to obtain a first solution of the peritoneal dialysis solution of the present invention.

(Comparative Example 1)
An aqueous solution in which butter sugar was dissolved in water for injection so as to have a concentration of 5 w / v% without containing any pH regulator or the like was prepared.

(Comparative Example 2)
An aqueous solution in which glucose was dissolved in water for injection to a concentration of 5.0 w / v% and sodium lactate at 50 μg / mL was prepared.
In addition, this comparative example is a chemical | medical solution included in the 1st liquid (liquid containing glucose) in the peritoneal dialysis liquid of invention of patent document 3. FIG.

(Comparative Example 3)
An aqueous solution in which glucose was dissolved in water for injection to a concentration of 5.0 w / v%, lactic acid 10 μg / mL, and calcium chloride 294 μg / mL was prepared.

(Comparative Example 4)
Glucose was dissolved in water for injection to a concentration of 5.0 w / v% and lactic acid at a concentration of 5 μg / mL to obtain a first solution of the peritoneal dialysis solution of the present invention.

(Comparative Example 5)
Glucose was dissolved in water for injection to a concentration of 5.0 w / v% and lactic acid at 10 μg / mL to obtain a first solution of the peritoneal dialysis solution of the present invention.

(Test Example 1) Lactic acid concentration and glucose stability The effect of lactic acid concentration on the stability of butter sugar in the first liquid was examined.
For each of Examples 1-2 and Comparative Examples 1-5 , 10 mL of glass vials were filled and autoclaved (105 ° C., 30 minutes). Each vial filling solution was measured for ultraviolet absorbance (absorption wavelengths: 228 nm and 284 nm) and pH before sterilization, after sterilization, and after storage at a temperature of 60 ° C. for 1 week and after storage for 2 weeks. Table 1 shows the measurement results of each test solution.

（滅菌前：n=1、その他：n=3）
Effect of lactic acid concentration on the stability of glucose solution

(Before sterilization: n = 1, other: n = 3)

(Results and discussion)
As can be seen from the results in Table 1, the absorbance at 228 nm, which is an index of 3-DG, was lower in all Examples than in Comparative Example 1 which was a simple glucose aqueous solution.
Moreover, when 50 microgram / mL sodium lactate is added like the comparative example 2, it turns out that the production | generation of 3-DG is hardly suppressed.
Furthermore, even if it contains 10 μg / mL of lactic acid as in Comparative Example 3, it can be seen that the effect of suppressing the production of 3-DG is low as compared with any of the Examples.
Moreover, even if it contains a small amount of lactic acid such as 5 μg / mL or 10 μg / mL as in Comparative Examples 4 and 5, it can be seen that the effect of suppressing the production of 3-DG is low compared to any of the Examples.

From the above results, as a preferable condition for obtaining a 5 w / v% glucose solution stabilizing effect (decomposition inhibiting effect), a very excellent 3-DG production inhibiting effect is obtained in a lactic acid concentration range of 50 to 100 μg / mL. You can see that

  The present invention provides a peritoneal dialysis solution that can be used for various peritoneal dialysis treatments for medical purposes.

Claims (3)

A glucose solution of a two-component peritoneal dialysis solution that does not contain salts, contains 0.5 to 20 w / v% glucose and 50 to 100 μg / mL lactic acid , and does not contain sodium lactate. The glucose solution of the two-component peritoneal dialysis solution according to claim 1, which has a pH of 3.5 to 4.5. The glucose solution of the two-liquid type peritoneal dialysis solution according to claim 1, wherein the osmotic pressure ratio is 0.7 to 1.6.