JPH1171273A - Peritoneum dialysing fluid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a peritoneum dialysing fluid excellent in water-removing performance and capable of prolonging effective dialysing time and low in glucose absorption ratio, compared with a dialysing fluid consisting essentially of glucose. SOLUTION: This peritoneum dialysing fluid comprises at least one of N- acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid and ascorbic acid as an osmoticum or at least one of N-acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid and ascorbic acid and glucose as osmoticums.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a peritoneal dialysis solution used for peritoneal dialysis which is applied in cases such as renal failure.

[0002]

2. Description of the Related Art Peritoneal dialysis therapy is one of the blood purification methods for patients with end-stage renal failure. In this therapy, the peritoneal dialysate in the container is infused into the abdominal cavity using gravity or a pump through a tube placed in the body, and after a certain period of time, the stored fluid is discharged out of the body using gravity or a pump. Removes water and waste accumulated in the body. This therapy is performed continuously for a long period of time. However, compared to hemodialysis therapy performed by artificial kidneys, the device and equipment are not large, time constraints are small, and medical expenses are also expensive. .
The principle of peritoneal dialysis is that an osmotic pressure regulating substance contained in the peritoneal dialysis fluid forms an osmotic pressure gradient with the body (blood), and ultrafiltration transfers the water in the body into the dialysate in the peritoneal cavity. Let it. Waste products (eg, urea, creatinine, etc.) do not contain these components in the peritoneal dialysate, and are transferred to and removed from the dialysate (reservoir) in the peritoneal cavity by diffusion due to the concentration gradient.

[0003] In this therapy, peritoneal dialysate exchange is inadequate at the time of clinical introduction, near the catheter and catheter implantation (skin).
The incidence of peritonitis, which was thought to be due to bacterial infection, decreased year after year due to thorough disinfection and improvement of peripheral equipment and machinery to prevent infection. This has made it possible to continue peritoneal dialysis therapy for a long period of time. However, despite no previous history of peritonitis due to infection, the function of the peritoneal membrane as a dialysis membrane gradually decreases, making it impossible to remove water (ultrafiltration) or remove waste (diffusion), making it difficult to continue peritoneal dialysis. An example has emerged. Although the cause has not been determined yet, it has been speculated that physical stimulation of the peritoneum by infusion and discharge of the peritoneal dialysate, and low pH and high osmotic pressure of the peritoneal dialysate itself may damage the peritoneum.

[0004] The present peritoneal dialysis solution is composed of an osmotic pressure regulating substance for performing ultrafiltration, various electrolytes for maintaining electrolyte balance, and an alkalizing substance for correcting acidosis. Among them, glucose is used because the osmotic pressure regulating substance is metabolized, does not accumulate in the body, and is inexpensive, but has the following problems.

[0005] Since glucose is rapidly absorbed through the peritoneum, the osmotic pressure gradient disappears immediately after injecting the dialysate, and water is not removed (ultrafiltration). Along with this, waste removal (diffusion) also decreases. In order to increase the amount of water removal (ultrafiltration amount) or prolong the time of water removal, the glucose concentration must be increased or the infusion volume must be increased. Increase the burden on QO
If L is reduced and the peritoneal dialysate is set to a high osmotic pressure, this increase in osmotic pressure will damage the peritoneum and adversely affect the continuation of therapy.

[0006] Glucose in the peritoneal dialysate is mostly absorbed into the body via the peritoneum. The absorbed large amount of glucose causes obesity in dialysis patients and is a serious problem for diabetic renal failure patients who have been increasing in recent years.

The peritoneal dialysate is usually subjected to heat sterilization such as high-pressure steam sterilization or hot water sterilization. However, when heat sterilization is performed at a pH around neutrality, many glucose degradants (eg, 5-hydroxymethylf
urfural (5-HMFs) are produced. The current peritoneal dialysis solution is set to a slightly acidic pH in order to suppress the production of this decomposition product. However, it has been reported that this acidic pH damages the peritoneum.

In order to overcome these problems, maltodextrin, glucose polymer, glycerol, maltitol, lactitol, cyclodextrin, polypeptide, amino acid, hydroxyethyl starch, Peritoneal dialysis solutions using galactose, trehalose, mucopolysaccharide, palatinose, neutral polysaccharide, cysteine, raffinose and the like have been developed and proposed, but have not yet been put to practical use.

[0009]

Accordingly, an object of the present invention is to secure a water removal amount and a water removal time at a lower osmotic pressure than conventional peritoneal dialysis solutions, and to improve and remove a water removal amount at the same osmotic pressure. An object of the present invention is to provide a novel peritoneal dialysis solution capable of extending water time and suppressing the amount of glucose absorbed into the body.

[0010]

The above-mentioned objects are attained by the present invention described below. The present invention is a peritoneal dialysis solution containing at least one of N-acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid, and ascorbic acid as an osmotic pressure regulating substance. Further, the present invention is a peritoneal dialysis solution containing at least one of N-acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid, and ascorbic acid, and glucose as an osmotic pressure regulating substance.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The peritoneal dialysis solution of the present invention comprises N-acetylamino acid and N-acetyl-D
-At least one of glucosamine, glucuronic acid and ascorbic acid is included. The N-acetyl amino acid is not particularly limited, but includes acetylated derivatives of essential and non-essential L-amino acids. Particularly, amino acid derivatives such as histidine, proline, leucine, arginine, and tyrosine are desirable. In the present invention, the above-mentioned osmotic pressure regulating substance can be used in combination with glucose. The peritoneal dialysate of the present invention has a lower osmotic pressure, increases the amount of water removed (ultrafiltration), reduces the amount of glucose absorbed in the body, and prolongs the dialysis time compared to peritoneal dialysis performed with glucose alone. be able to.

The peritoneal dialysate of the present invention may contain, in addition to the above-mentioned osmotic substances, components usually used in peritoneal dialysates, for example, sodium ion, calcium ion, magnesium ion, and chloride ion as an electrolyte; Acetic acid, bicarbonate and salts thereof may be used alone or in combination. The amount of the above-mentioned osmotic pressure adjusting substance and other components can be appropriately selected depending on the osmotic pressure of the peritoneal dialysis solution, pH and the condition of the patient. It looks like this:

As osmotic pressure regulators, N-acetylamino acid 0-7.2 g / dl, N-acetyl-D-glucosamine 0-6.5 g / dl, glucuronic acid 0-5.7 g / dl, ascorbic acid 0- It can contain 5.2 g / dl and glucose 0-5.3 g / dl. As electrolytes, sodium ions 50 to 150 mEq / l, calcium ions 0 to 5 mEq / l, magnesium ions 0 to 3 mEq / l, chlor ions 30 to 1
10mEq / l, lactate ion 0-50m as alkalizing substance
Eq / l, acetate ion 0-50mEq / l bicarbonate ion 0-50m
Eq / l can be contained.

[0014] The peritoneal dialysis solution of the present invention has a neutral pH range, specifically pH 6.0 to 7.5, more preferably pH 6.0.
Adjust to 5 to 7.4 before use. By performing the treatment in this range, it is possible to maintain peritoneal macrophage immunity, suppress the onset of peritonitis due to bacterial infection, and suppress damage to peritoneal cells due to low pH. In addition, the osmotic pressure is not particularly limited, but the removal of waste products,
In consideration of the burden on the peritoneum, it is prepared and used at 280 to 600 mOsm / kg, preferably 280 to 400 mOm / kg.

The peritoneal dialysis solution of the present invention is obtained by dissolving these osmotic pressure regulating substances and other components in water, and is aseptically sealed in a soft plastic bag or a glass container. It is desirable to perform high-pressure steam sterilization or hot water sterilization. Examples of the material of the soft plastic include polyvinyl chloride and ethylene-vinyl acetate copolymer.

The peritoneal dialysate of the present invention containing at least one osmolyte comprising N-acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid and ascorbic acid contains glucose as a main component of the osmolyte. When compared with a peritoneal dialysis solution under the same conditions, the amount of water removed (ultrafiltration amount) is large, and the water removal time can be extended. That is, by using the present peritoneal dialysis solution, the peritoneal dialysis solution injection amount can be reduced as compared with the existing peritoneal dialysis solution, and the exchange time of the stored solution can be made wider. Further, the peritoneal dialysate in which glucose is used in combination with the above-mentioned osmotic pressure-regulating substance of the present invention, other than the above-mentioned osmotic pressure-regulating substance, for example, amino acid, fructose, glycerol, peritoneal dialysate in which glucose is used in combination with D-glucosamine, or When compared with a peritoneal dialysis solution containing glucose as a main component of the osmotic pressure regulating substance under the same conditions, the amount of water removed (ultrafiltration amount) is large, and the water removal time is prolonged. Furthermore, glucose absorption is low.

Therefore, the peritoneal dialysis solution of the present invention enables downsizing (reduction) of the bag for enclosing the peritoneal dialysis solution, reduction of the storage space for the peritoneal dialysis solution bag, and reduction of waste.
Furthermore, since the low osmotic pressure does not impose a burden on the peritoneum, the present therapy can be continued for a long period of time, and the time required for replacing the peritoneal dialysate has a wide range.
It makes a great contribution to OL. Furthermore, since the present invention can significantly reduce or eliminate the amount of glucose absorbed into the body, it is expected to be applied to diabetic patients and obese dialysis patients, and by selecting N-acetylamino acid, renal failure It can correct the patient's serum aminogram.

Since the peritoneal dialysis solution of the present invention does not contain the above-mentioned glucose at all or is reduced in weight and has a composition containing N-acetylamino acid, etc. In addition, the production of 5-HMF can be reduced, and the composition is stable as a single liquid formulation.
Therefore, in order to maintain the pharmaceutical stability at the time of sterilization, the components can be divided into two or more and used without mixing at the time of use. In order to ensure the stability of the components other than the osmotic pressure regulating substance, the components may be divided into two or more and mixed at the time of use without any problem. The method of using the peritoneal dialysis solution of the present invention is not limited at all, and is performed by a known technique of peritoneal dialysis therapy.

[0019]

The present invention will be described in more detail with reference to the following examples. (Example 1) (1-1. Preparation of peritoneal dialysate) Peritoneal dialysate: N-acetyl-L as an osmotic pressure regulating substance
-Arginine dihydrate was dissolved and adjusted in distilled water for injection to a final concentration of 1.75 g / dl. The osmotic pressure was adjusted to 350 mOsm / kg with sodium chloride, and the pH was adjusted to 7.0 with sodium hydroxide. Peritoneal dialysate: Ascorbic acid as an osmotic pressure adjusting substance was dissolved in distilled water for injection to a final concentration of 1.22 g / dl and adjusted. The osmotic pressure was adjusted to 350 mOsm / kg with sodium chloride, and the pH was corrected to 7.1 with sodium hydroxide. Comparative peritoneal dialysate: Glucose was dissolved in distilled water for injection to a final concentration of 1.25 g / dl as an osmotic pressure adjusting substance and adjusted. The osmotic pressure was adjusted to 350 mOsm / kg with sodium chloride, and the pH was adjusted to 7.0 with sodium hydroxide.

(1-2. Water Removal Test) The above-described water removal test of the peritoneal dialysate and the comparative peritoneal dialysate was performed using rats as a control. Male Sprague-Dawley (S
D) Rats were preliminarily reared for 6 days, then fasted for 24 hours and used for the test. Food and water were available ad libitum during the pre-breeding period, and only water was provided ad libitum during the fasting period. The test was performed under ether anesthesia, but was awake during the dialysis period. The body weight (A) was measured immediately before administration of the peritoneal dialysate, and then the peritoneal dialysate (5
0 ml / kg) was intraperitoneally administered using a 24G injection needle. Immediately after the administration, the body weight (B) was measured and dialyzed for 4 hours.
After completion of the dialysis, the body weight (C) was measured, the abdomen was immediately opened, and a part of the stored liquid was collected using a 2.5 ml syringe. afterwards,
The stored liquid was completely removed using absorbent cotton, and the body weight (D) was measured. The amount of water removed (ml / kg) was determined from Equation 1 with the specific gravity of the stored liquid as 1.

Formula 1: Water removal amount (ml / kg) = [(CD) −
(BA)] / A × 1000

(1-3. Results) The results of the water removal test after 4 hours of dialysis show that the peritoneal dialysate is 20.8 ml / kg and the peritoneal dialysate is 14.6 ml / kg, whereas the control is 14.6 ml / kg. The comparative peritoneal dialysis solution had a low value of 12.3 ml / kg, and the peritoneal dialysis solution and the comparative peritoneal dialysis solution were superior in water removal effect. In addition, instead of peritoneal dialysate and N-acetylglycine 0.81 g / dl (pH 7.0, osmotic pressure 350 mOsm / kg)
Peritoneal dialysis solution containing N-acetyl-L-tryptophan 1.71 g / dl (pH 7.0, osmotic pressure 350 mOsm / kg)
Peritoneal dialysis solution containing N-acetyl-L-histidine monohydrate 1.49 g / dl (pH 7.0, osmotic pressure 350 mOsm / k
g) containing 1.53 g / dl of N-acetyl-D-glucosamine (pH 7.0, osmotic pressure 350 mOsm / k)
g) containing peritoneal dialysis solution, glucuronic acid 1.35 g / dl
(PH 7.0, osmotic pressure 350 mOsm / kg) containing peritoneal dialysis solution was prepared, and the same test was carried out. As a result, the same excellent water removal effect as that of the peritoneal dialysis solution was obtained.

(Example 2) (2-1. Preparation of peritoneal dialysate) Peritoneal dialysate: N-acetyl-L as osmotic pressure regulating substance
-Proline and glucose were prepared at a final concentration of N-acetyl-L-proline of 0.545 g / dl and glucose of 0.62.
It was dissolved in distilled water for injection to adjust to 5 g / dl and adjusted. The osmotic pressure was adjusted to 350 mOsm / kg with sodium chloride, and the pH was adjusted to 7.0 with sodium hydroxide. Peritoneal dialysate: N-acetyl-D as osmolyte
-Glucosamine and glucose were dissolved in distilled water for injection at final concentrations of 0.767 g / dl of N-acetyl-D-glucosamine and 0.625 g / dl of glucose, respectively. The osmotic pressure was adjusted to 350 mOsm / kg with sodium chloride, and the pH was adjusted to 7.0 with sodium hydroxide.

(2-2. Water removal test) The above peritoneal dialysate and the water removal test were performed using rats as a control with the comparative peritoneal dialysate prepared in Example 1 as a control. The test was performed in the same manner as the water removal test.

(2-3. Measurement of Glucose Absorption and Glucose Absorption Rate) Approximately 1 ml of the retained solution obtained in the above-described water removal test was filtered through a 0.45 μm filter, and the enzyme was analyzed using an automatic biochemical analyzer. The glucose concentration was measured by the method. Next, the glucose absorption rate was determined according to Equations 2 to 5.
A, B, C and D in the formula are the same as in Example 1-2. It is the same as Equation 1 in the water removal test.

Formula 2: amount of administered glucose (mg / kg) = [glucose concentration of administered peritoneal dialysate (mg / dl) × amount of administered solution (body weight B-body weight A) (ml)] / body weight A (g) × 100
0/100

Formula 3: Amount of residual glucose (mg / kg) = [glucose concentration of stored liquid (mg / dl) × amount of stored liquid (body weight C−
Body weight D) (ml) / body weight A (g)] x 1000/100

Formula 4: Glucose absorption (mg / kg) = Dose glucose (mg / kg) -Residual glucose (mg / kg)

Equation 5: Glucose absorption rate (%) = glucose absorption amount (mg / kg) / administered glucose amount (mg / kg) × 10
0

(2-4. Results) The water removal rate of the comparative peritoneal dialysate was 12.3 ml / kg, whereas the peritoneal dialysate was 1 ml.
It was 6.0 ml / kg and that of peritoneal dialysis solution was 16.1 ml / kg.
The glucose absorption rate and absorption amount were 78.1% and 491 mg / kg for the comparative peritoneal dialysate, whereas 67.0% and 212 mg / kg for the peritoneal dialysate and 6% for the peritoneal dialysate.
It was 1.7% and 195 mg / kg, and the peritoneal dialysate and the comparative peritoneal dialysate were superior in the water removal effect, the glucose absorption rate and the suppression of the absorption amount.

The peritoneal dialysis solution was replaced with 0.611 g / dl of ascorbic acid and 0.625 g / dl of glucose.
Peritoneal dialysate containing dl (pH 7.0, osmotic pressure 350 mOsm / kg), 0.709 g of N-acetyl-L-tryptophan
/ dl and glucose 0.625 g / dl (pH 7.0, osmotic pressure 350 mOsm / kg) peritoneal dialysate, N-acetyl-L-arginine dihydrate 0.875 g / dl and glucose 0.625 g / dl (PH 7.0, osmotic pressure 350 mOsm / kg)
Peritoneal dialysate, 0.601 g / dl N-acetyl-L-leucine and 0.625 g / dl glucose (pH 7.
0, peritoneal dialysis solution containing osmotic pressure 350 mOsm / kg), N
-Acetyl glycine 0.406 g / dl and glucose 0.6
Peritoneal dialysate containing 25 g / dl (pH 7.0, osmotic pressure 350 mOsm / kg), 0.273 g of N-acetyl-L-proline
/ dl, 0.306 g / dl of ascorbic acid and 0.3 g of glucose.
As a result of preparing a peritoneal dialysis solution containing 625 g / dl (pH 7.0, osmotic pressure 350 mOsm / kg) and conducting the same test,
As with the peritoneal dialysis solution, the same excellent water removal effect, glucose absorption rate, and suppression of absorption were exhibited.

(Example 3) (3-1. Water removal test) A water removal test of the peritoneal dialysate prepared in Example 2 was performed using the comparative peritoneal dialysate prepared in Example 1 as a control and using rats. did. Male Spr weighing about 200g
After pre-breeding ague-Dawley (SD) rats for 6 days, 2
They were fasted for 4 hours and used for the test. Food and water were available ad libitum during the pre-breeding period, and only water was provided ad libitum during the fasting period. The test was performed under ether anesthesia, but was awake during the dialysis period. After measuring the body weight (A) immediately before administration of the peritoneal dialysate, the peritoneal dialysate (50 ml / kg) was administered intraperitoneally using a 24G injection needle. Immediately after the administration, the body weight (B) was measured and 1, 2,
Dialysis was performed for 4 to 6 hours. After completion of the dialysis, the body weight (C) was measured, the abdomen was immediately opened, and a part of the stored solution was collected using a 2.5 ml syringe. Thereafter, the stored liquid was completely removed using absorbent cotton, and the body weight (D) was measured. The amount of water removed (ml / kg) was determined from the equation 1 described in Example 1, assuming that the specific gravity of the stored liquid was 1.

(3-2. Measurement of Glucose Absorption and Glucose Absorption Rate) Approximately 1 ml of the stored solution obtained in the above-mentioned water removal test was filtered through a 0.45 μm filter, and the enzyme was analyzed using an automatic biochemical analyzer. After administration, 1, 2, 4,
The glucose concentration after dialysis for 6 hours was measured. Next, the glucose absorption rate was determined according to the formulas 2 to 5 described in Example 2.

(3-3. Results) Changes in the water removal amount, glucose absorption amount and glucose absorption rate of the peritoneal dialysate and the comparative peritoneal dialysate are shown in FIGS. In each figure, ● indicates a peritoneal dialysate, and □ indicates a comparative peritoneal dialysate. As a result, the peritoneal dialysate was superior to the comparative peritoneal dialysate at all dialysis times, and the amount of glucose absorbed and the rate of absorption were suppressed. In addition, a peritoneal dialysate using the substances shown in Examples 1 and 2 as an osmotic pressure adjusting substance instead of the peritoneal dialysate was prepared, and the same test was carried out. As a result, the same excellent water removal as the peritoneal dialysate was performed. The effect and the suppression of glucose absorption and absorption were shown.

[0035]

The peritoneal dialysis solution using at least one of N-acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid and ascorbic acid as the osmotic pressure regulating substance of the present invention is characterized by using glucose as an osmotic pressure regulating substance. It has superior water removal performance as compared with the peritoneal dialysis solution as the main component. It has superior water removal performance and effective dialysis time as compared with a peritoneal dialysate containing glucose as a main component of the osmotic pressure regulating substance. That is, compared with a peritoneal dialysis solution containing glucose as a main component of the osmotic pressure regulating substance, a water removal amount and an effective dialysis time can be secured at a lower osmotic pressure. Alternatively, at the same osmotic pressure, the amount of water removed can be improved and the effective dialysis time can be extended. Furthermore, since the peritoneal dialysis solution of the present invention does not contain glucose, which is a reducing sugar, it contains few decomposed products and is stable in terms of formulation, so that the pH can be set to a neutral range with a one-solution formulation.

A peritoneal dialysate using glucose as the osmotic pressure regulating substance of the present invention and at least one of N-acetylamino acid, N-acetyl-D-glucosamine, glucuronic acid, and ascorbic acid is used to convert glucose into an osmotic pressure regulating substance. Has a water removal performance, an effective dialysis time and a low glucose absorption compared with a peritoneal dialysate using glucose and other osmotic pressure regulating substances. In other words, compared to a peritoneal dialysis solution comprising only glucose or glucose and another osmotic pressure regulating substance, the amount of water removed and the effective dialysis time can be secured at a lower osmotic pressure. Further, the water removal amount can be improved and the effective dialysis time can be extended with the same osmotic pressure.

Furthermore, since the peritoneal dialysis solution of the present invention can significantly reduce or eliminate the amount of glucose absorbed in the body, it is expected to be applied to diabetic patients and obese dialysis patients. In addition, since glucose can be reduced, the amount of decomposed products derived from glucose is small and the composition is stable, and the pH can be set to a neutral range with a one-part preparation.

[Brief description of the drawings]

FIG. 1 is a line graph showing the difference in the amount of water removed during the dialysis time between a peritoneal dialysate of the present invention and a comparative peritoneal dialysate.

FIG. 2 is a line graph showing the difference in glucose absorption between the peritoneal dialysate of the present invention and the comparative peritoneal dialysate during dialysis time.

FIG. 3 is a line graph showing the difference in the rate of glucose absorption between the peritoneal dialysate of the present invention and the comparative peritoneal dialysate during the dialysis time.

Claims (4)

[Claims] (1) N-acetylamino acid, N-acetyl-D
-A peritoneal dialysis solution containing at least one of glucosamine, glucuronic acid and ascorbic acid as an osmotic pressure regulating substance. 2. N-acetyl amino acid, N-acetyl-D
-A peritoneal dialysate comprising at least one of glucosamine, glucuronic acid and ascorbic acid and glucose as an osmotic pressure regulating substance. 3. The peritoneal dialysis solution according to claim 1, wherein the N-acetylamino acid is an acetylated derivative of an L-amino acid. 4. The peritoneal dialysate according to claim 2, wherein the N-acetylamino acid is an acetylated derivative of an L-amino acid.