JPH0987182A - Neutral peritoneal dialysis fluid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a dialysis fluid effective for decreasing the damage on the peritoneal mesothelium cell and peritoneal macrophage function and having excellent aging stability and safety to living body by adding bicarbonate ion to a basic solution in an amount to attain a specific concentration in mixed state and adjusting the pH of the mixture to a level within a specific range. SOLUTION: An acidic solution containing a reducing sugar, an organic acid, etc., is incorporated with various components to get a mixture containing 1-10W/V% of glucose, 5-40mEq/l of lactate ion, 50-150mEq/l of sodium ion, 0-5mEq/l of calcium ion and 0-5mEq/l of magnesium ion, the obtained basic solution is incorporated with bicarbonate ion in an amount to get a mixture having a bicarbonate ion content of 5-20mEq/l and the pH of the mixture is adjusted to 6.8-7.4.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a peritoneal dialysate. More specifically, it relates to a peritoneal dialysate having excellent stability and low damage to the peritoneum.

[0002]

2. Description of the Related Art Peritoneal dialysis, which is one of the symptomatic treatments for renal failure, does not require a large scale of equipment and instruments and is less restricted in terms of time compared with dialysis therapy performed by an artificial kidney, so that home medical care is possible. It is attracting attention as one of the. However, this therapy has always been associated with the risk of peritonitis, which has been thought to be the leading cause of impediment to continued peritoneal dialysis therapy. The incidence of peritonitis is decreasing year by year due to improvements in catheters and aseptic connection methods, and the number of long-term peritoneal dialysis patients is increasing.However, despite the absence of a history of peritonitis, the function as a peritoneal dialysis membrane. In some cases, it becomes difficult to continue the peritoneal dialysis due to a decrease in the amount of water removed or a decrease in the effect of removing waste products. Although the cause of this has not been determined yet, in general, direct contact between the tube and the peritoneum, mechanical stress on the peritoneum due to infusion / drainage of dialysate, and further the pH of the dialysate.
Damage and exfoliation of peritoneal mesothelial cells due to stimuli derived from properties such as osmotic pressure and osmotic pressure deviating from the physiological range,
It is considered to be caused by a series of tissue reactions such as peritoneal fibrosis (thickening).

Conventionally used peritoneal dialysis fluid is formulated to have a pH in the range of 5.0 to 5.5 in order to prevent glucose decomposition and coloration. It has been reported that a peritoneal dialysate of 5.0 to 5.5 substantially reduces the immune defense mechanism of peritoneal macrophages and increases the risk of peritonitis due to bacterial invasion. Further, the peritoneal dialysate having a pH value of 5.0 to 5.5 has a significantly high toxicity to the cultured peritoneal mesothelial cells, and the pH value is 6.
It has been reported that the disability can be reduced by setting the ratio to 5 or more. However, the pH of the peritoneal dialysate currently in use has a great influence on the stability of glucose contained in it, and if the pH is increased as it is, glucose is decomposed during production or storage and the dialysate is colored. However, the product value will be significantly reduced.

Therefore, as a method of increasing the pH while suppressing the decomposition and coloring of glucose, the glucose-containing component and the high-pH bicarbonate-containing component are separately stored until immediately before use, and aseptically mixed immediately before use. A dialysate solution has been developed. In such a dialysate, a certain amount of acid is added to the glucose-containing component in order to adjust the expected pH when the two components stored separately are mixed. The acid to be added is an inorganic acid such as hydrochloric acid or acetic acid or citric acid, and there is no example of adding lactic acid which has been used as an alkalizing agent in a conventional peritoneal dialysate. Further, the blending amount is an amount necessary only for adjusting the expected pH when the two components are mixed, and does not expect any other function.
This is because it is not necessary to add lactic acid by adding only bicarbonate having a high pH as an alkalizing agent. When bicarbonate is blended as the alkalizing agent, the blending amount thereof is basically 35-40 mEq / l which is the blending amount of the alkalizing agent in the conventional peritoneal dialysate. When this concentration is blended, the carbon dioxide gas partial pressure of the dialysate becomes 80 mmHg or more in the pH range of 6.8 to 7.4, and there is a risk of exhibiting symptoms such as abdominal pain and discomfort when injected into the abdominal cavity. Furthermore, it is pointed out that calcium and magnesium which are mixed in the conventional peritoneal dialysate may cause precipitation of carbonate.

[0005]

DISCLOSURE OF THE INVENTION According to the present invention, the pH at the time of use can be maintained in a neutral range while the decomposition and coloring of reducing sugars typified by glucose are suppressed, and the carbon dioxide partial pressure is 60 m.
It is to provide a peritoneal dialysate having a physiological level of mHg or less.

[0006]

The above object is achieved by the present invention described below. (1) In a peritoneal dialysate used by mixing an acidic solution containing a reducing sugar, an organic acid, etc. and a basic solution containing bicarbonate ion, the amount of heavy solution of 5 to 20 mEq / l after mixing with the basic solution. Contains carbonate ions and has a pH of 6.8 after mixing
It is a peritoneal dialysate characterized by being in the range of to 7.4.

(2) In a peritoneal dialysate used by mixing an acidic solution containing a reducing sugar or an organic acid with a basic solution containing bicarbonate ion, glucose 1 is mixed with the acidic solution.
-10w / v%, preferably 1-5w / v%, lactate ion 5-
40 mEq / l, preferably 10-30 mEq / l, sodium ion 50-150 mEq / l, preferably 1
00-140 mEq / l, calcium ion 0-5 mE
q / l, preferably 2-4 mEq / l, magnesium 0
-5 mEq / l, preferably 0-3 mEq / l, in an amount of 5-20 mE after mixing with the basic solution.
The peritoneal dialysis solution according to (1) above, which contains bicarbonate ions in an amount of q / l, preferably 5 to 10 mEq / l.

(3) The acidic solution and the basic solution are individually housed in a soft plastic bag having water vapor impermeability and gas impermeability prior to mixing and heat sterilized. ) To (2). (4) The peritoneal dialysate as described in (1) to (3) above, wherein the carbon dioxide partial pressure after mixing is 60 mmHg or less.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The peritoneal dialysate of the present invention is prepared by mixing an acidic solution containing reducing sugar such as glucose and a basic solution containing bicarbonate ion after heat sterilization or immediately before use. By using it as a product, the decomposition and coloring of reducing sugar can be suppressed, and the pH can be maintained at 6.8 to 7.4. Further, even when calcium or magnesium is added to the composition, precipitation of carbonate can be prevented by adding calcium or magnesium to the acidic solution.

The peritoneal dialysate of the present invention has a pH of 6.8 to 7.4.
Therefore, the pH of the conventional peritoneal dialysate is 5.0 to 5.0.
It is possible to reduce the damage of peritoneal mesothelial cells and peritoneal macrophage function, which is derived from 5.5.

In the peritoneal dialysate of the present invention, the amount of bicarbonate ion is sufficient to adjust the pH after mixing to 6.8 to 7.4, and calcium and magnesium are added. In such a case, an amount that does not cause precipitation is mixed, and specifically, the amount is 5 to 20 mEq / l after mixing, and more preferably 5 to 10 mEq / l. In addition, the amount of the above-mentioned bicarbonate ion can keep the partial pressure of carbon dioxide gas after mixing at 60 mmHg or less and suppress symptoms such as abdominal pain and discomfort when injected into the abdominal cavity.

In the peritoneal dialysis solution of the present invention, the amount of the organic acid ion compounded is sufficient to maintain the pH after mixing at 6.8 to 7.4 and does not adversely affect metabolism in the living body. The amount, specifically 5-40 mEq / after mixing
1 and more preferably 10 to 30 mEq / l.
In addition, it is preferably 10 to 50 mEq / l, more preferably 25 to 40 mEq / l in combination with bicarbonate ions. Further, in the present invention, the organic acid is not particularly limited, but specific examples thereof include lactic acid, acetic acid, citric acid, malic acid, etc., and preferably lactic acid conventionally used as an alkalizing agent in an infusion solution or a dialysate. Is used.

In addition to the above-mentioned composition, the peritoneal dialysis solution of the present invention contains, as electrolyte ions, electrolyte ions used in ordinary injectable solutions such as potassium ions and infusions, and reducing sugars such as glucose and fructose. , Lactose, galactose, etc. can be added.

The peritoneal dialysate of the present invention is characterized in that it is divided into an acidic solution and a basic solution after heat sterilization or immediately before use. However, a reducing sugar or a heavy sugar which causes decomposition or coloring in the neutral to alkaline range. Components such as calcium ions and magnesium ions that cause precipitation with carbonate ions are preferably added to the acidic solution. In addition, there is no particular problem even if a component that is inactive against reducing sugars such as sodium and potassium and bicarbonate ion is added to either solution.

The peritoneal dialysate of the present invention containing the above-mentioned composition is substantially acceptable for injections, compounds (bicarbonic acid, lactic acid, etc.) used for producing infusions, or pharmacologically acceptable thereof. Salts (sodium bicarbonate, sodium lactate, etc.), specifically, sodium hydrogen carbonate (NaHCO ₃ ), sodium chloride (NaCl), calcium chloride (CaCl ₂ ), magnesium chloride (MgC) as an electrolyte.
l ₂ ) etc., reducing sugars such as anhydrous glucose and anhydrous fructose are dissolved in water in a predetermined amount and sealed in a water vapor impermeable and gas (oxygen, carbon dioxide) impermeable soft plastic bag or glass bottle. It is obtained by

When calcium ions and magnesium ions are mixed in the peritoneal dialysis solution of the present invention, in order to prevent the formation of carbonates thereof and to ensure the stability of the reducing sugar, a soft plastic bag is used. In addition, it is preferable to perform vacuum packaging with a packaging material having a high gas barrier property. Also, by maintaining a vacuum between the packaging material with a high gas barrier property and the container, it can be stored more stably,
If the vacuum cannot be maintained, a deoxidizer that generates carbon dioxide may be enclosed. Specific examples of the oxygen scavenger include Ageless G (manufactured by Mitsubishi Gas Chemical Co., Inc.). In this case, it is preferable to minimize the space volume between the packaging material having a high gas barrier property and the soft bag.

The soft plastic bag may be made of any material that is compatible with the infusion solution plastic container test, and specific examples thereof include polyvinyl chloride, polypropylene, polyethylene, polyester and ethylene vinyl acetate copolymer. Specific examples include Telpack, blood bag, CAPD bag (each made by Terumo (polyvinyl chloride)), and the like.

As the packaging material having a high gas barrier property, those which are normally used may be used as long as they can withstand high-pressure steam sterilization or hot water sterilization, typically polyamide (nylon 610 etc.), A multilayer film made of a combination of materials such as ethylene vinyl alcohol copolymer (EVOH), polyethylene terephthalate (PET), and polyvinylidene chloride (PVDC),
Alternatively, these multilayer films can be exemplified by those obtained by vapor-depositing metal oxide or ceramic. Specifically, PET / EVOH / NY (nylon) / CPP (polypropylene), (Fuji Sangyo Co., Ltd.), PET / alumina vapor deposition PET / CPP (Fuji Sangyo Corp.), metal oxide vapor deposition P
ET / PVDC-MA (methyl acrylate) / PA
(Polyamide) / CPP (manufactured by Hosokawa Yoko), PET / S
Examples include iO _x vapor deposition PET / CPP (manufactured by Toppan Printing Co., Ltd.).

The peritoneal dialysate of the present invention is preferably used after heat sterilization, but when high-pressure steam sterilization is performed as heat sterilization, it is preferable that the temperature is 100 to 133 ° C. for 1 to 120 minutes. Specifically, 100 to 126 ° C,
It is carried out for 5 to 60 minutes.

The peritoneal dialysate of the present invention contains an acidic solution and a basic solution separately in the above-mentioned soft plastic bag or the like after heat sterilization or immediately before use, and aseptically sterilizes both solutions after heat sterilization or immediately before use. A means for mixing is necessary, and as an example, a soft plastic bag is disclosed in Japanese Patent Publication No. 6-26563.
And a container having a separable partition wall as disclosed in JP-A-4-242647, and JP-A-3-195556.
Examples include a method of molding into a shape such as a container having a communication member such as No. 1 and the like. Alternatively, the tubes communicating with the bag containing the acidic solution and the basic solution may be joined together by an aseptic joining device such as TSCD (registered trademark, manufactured by Terumo Corp.).

[0021]

The present invention will be described in more detail with reference to the following examples. (Example 1) Glucose 5.0 g / dl, sodium chloride 123.8 mM, calcium chloride 1.875 mM, magnesium chloride 0.3125 mM, sodium lactate 28.7
1600 ml of acidic solution containing 5 mM and 2.5 mM lactic acid
And a basic solution 40 containing 50 mM sodium hydrogen carbonate
0 ml was made. Both solutions were stored in a polyvinyl chloride soft plastic bag (made by Terumo Corp.). This was vacuum-packed with a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 24 hr · atm), manufactured by Fuji Sangyo Co., Ltd.), and then high-pressure steam sterilization was performed at 105 ° C.
It went for 25 minutes. After sterilization, both solutions were mixed. P immediately after mixing
H was 7.0 and carbon dioxide partial pressure was 50 mmHg.

The composition of this example after mixing was 4.0 w / v glucose, 25 mEq / l lactate ion, 132 mEq / l sodium ion, and 3.0 m calcium ion.
Eq / l, magnesium 0.5 mEq / l, chloride ion 102.5 mEq / l, bicarbonate ion 10 mEq / l. In addition, in this example and each of the following examples and comparative examples, pH was measured at room temperature using a pH meter MH-20E (TOA), and carbon dioxide partial pressure was measured with ABL50 (Radiometer).

Example 2 Glucose 20 g / dl, calcium chloride 6.25 mM, magnesium chloride 1.25 m
400 ml of an acidic solution containing M, 140 mM of sodium lactate and 10 mM of lactic acid, and 12.5 m of sodium hydrogen carbonate
1600 ml of a basic solution containing M and 118.75 mM of sodium chloride was prepared. Both solutions were stored in a polyvinyl chloride soft plastic bag (made by Terumo Corp.). This is a gas barrier packaging material (Eval film (R
T-grate) (oxygen permeability 0.8 ml / m ² · 24 hr · atm), manufactured by Fuji Sangyo Co., Ltd.
It was carried out at 5 ° C for 25 minutes. After sterilization, both solutions were mixed. The pH immediately after mixing was 7.0, and the carbon dioxide partial pressure was 50 mmHg.
Met.

The composition of this example after mixing was 4.0 w / v glucose, 30 mEq / l lactate ion, 133 mEq / l sodium ion, 2.5 m calcium ion.
Eq / l, magnesium 0.5 mEq / l, chloride ion 98 mEq / l, bicarbonate ion 10 mEq / l.

Example 3 Glucose 5.0 g / dl,
Sodium chloride 194 mM, calcium chloride 4.0 m
M, magnesium chloride 0.5 mM, sodium lactate 56
1000 ml of an acidic solution containing mM and 4.0 mM lactic acid,
1000 basic solution containing 20 mM sodium hydrogen carbonate
ml was made. Both solutions were stored in a polyvinyl chloride soft plastic bag (made by Terumo Corp.). After vacuum packaging this with a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 24 hr · atm), Fuji Sangyo Co., Ltd.), high pressure steam sterilization was performed at 105 ° C, 2
Performed for 5 minutes. After sterilization, both solutions were mixed. PH immediately after mixing
Was 7.0 and the carbon dioxide partial pressure was 50 mmHg.

The composition of this example after mixing was 2.5 w / v% glucose, 30 mEq / l lactate ion, 135 mEq / l sodium ion, 4.0 m calcium ion.
Eq / l, magnesium 0.5 mEq / l, chloride ion 101.5 mEq / l, bicarbonate ion 10 mEq / l.

(Example 4) Glucose 5.0 g / dl,
Sodium chloride 118.75 mM, calcium chloride 1.5
1600 ml of an acidic solution containing 625 mM, 0.3125 mM of magnesium chloride, 22.5 mM of sodium lactate and 2.5 mM of lactic acid, and 400 ml of a basic solution containing 100 mM of sodium hydrogen carbonate were prepared. Both liquids are each made of polyvinyl chloride soft plastic bag (made by Terumo)
Housed. This is a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 24 hr · at
m), manufactured by Fuji Sangyo Co., Ltd., and then vacuum-sterilized at 105 ° C. for 25 minutes. After sterilization, both solutions were mixed. The pH immediately after mixing was 7.4, and the carbon dioxide partial pressure was 4
It was 0 mmHg.

The composition of this example after mixing was 4.0 w / v% glucose, 20 mEq / l lactate ion, 133 mEq / l sodium ion, and 2.5 m calcium ion.
Eq / l, magnesium 0.5 mEq / l, chloride ion 98 mEq / l, bicarbonate ion 20 mEq / l.

(Example 5) Glucose 5.0 g / dl,
Sodium chloride 118.75 mM, calcium chloride 1.5
1600 ml of an acidic solution containing 625 mM, 0.3125 mM of magnesium chloride, 21.25 mM of sodium lactate and 3.75 mM of lactic acid, and 400 ml of a basic solution containing 100 mM of sodium hydrogen carbonate were prepared. Both solutions were stored in a polyvinyl chloride soft plastic bag (made by Terumo Corp.). This is a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 24 h
r * atm), manufactured by Fuji Sangyo Co., Ltd., and vacuum-sterilized at 105 ° C. for 25 minutes. After sterilization, both solutions were mixed. The pH immediately after mixing was 7.2, and the carbon dioxide gas partial pressure was 50 mmHg.

The composition of this example after mixing was 4.0 w / v% glucose, 20 mEq / l lactate ion, 133 mEq / l sodium ion, and 2.5 m calcium ion.
Eq / l, magnesium 0.5 mEq / l, chloride ion 98 mEq / l, bicarbonate ion 20 mEq / l.

(Example 6) Glucose 5.0 g / dl,
Sodium chloride 118.75 mM, calcium chloride 1.5
1600 ml of an acidic solution containing 625 mM, magnesium chloride 0.3125 mM, sodium lactate 35.625 mM, lactic acid 1.875 mM, and sodium bicarbonate 50 mM
400 ml of a basic solution containing was prepared. Both solutions were stored in a polyvinyl chloride soft plastic bag (made by Terumo Corp.). This is a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 2
4 hr.atm), manufactured by Fuji Sangyo Co., Ltd., and vacuum-sterilized at 105 ° C. for 25 minutes. After sterilization, both solutions were mixed. The pH immediately after mixing was 7.2 and the carbon dioxide partial pressure was 40 mmHg.

The composition of this example after mixing was 4.0 w / v% glucose, 30 mEq / l lactate ion, 133.5 mEq / l sodium ion, and 2.5 calcium ion.
mEq / l, magnesium 0.5 mEq / l, chloride ion 98 mEq / l, bicarbonate ion 10 mEq / l.

Example 7 Glucose 5.0 g / dl,
Sodium chloride 118.75 mM, calcium chloride 1.5
800 ml of an acidic solution containing 625 mM, 0.3125 mM of magnesium chloride, 36.25 mM of sodium lactate and 1.25 mM of lactic acid, and 200 ml of a basic solution containing 50 mM of sodium hydrogen carbonate were prepared. Both liquids are each made of polyvinyl chloride soft plastic bag (made by Terumo)
Housed. This is a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 24 hr · at
m), manufactured by Fuji Sangyo Co., Ltd., and then vacuum-sterilized at 105 ° C. for 25 minutes. After sterilization, both solutions were mixed. The pH immediately after mixing was 7.4 and the carbon dioxide partial pressure was 3
It was 0 mmHg.

The composition of this example after mixing was 4.0 w / v% glucose, 30 mEq / l lactate ion, 134 mEq / l sodium ion, 2.5 m calcium ion.
Eq / l, magnesium 0.5 mEq / l, chloride ion 98 mEq / l, bicarbonate ion 10 mEq / l.

Comparative Example Glucose 5.0 g / dl, sodium chloride 118.75 mM, calcium chloride 1.56
25 mM, magnesium chloride 0.3125 mM, acetic acid 3.
1600 ml of an acidic solution containing 75 mM and 400 ml of a basic solution containing 150 mM of sodium hydrogen carbonate were prepared. Both solutions were stored in a polyvinyl chloride soft plastic bag (made by Terumo Corp.). After vacuum-packing this with a gas barrier packaging material (Eval film (RT Great) (oxygen permeability 0.8 ml / m ² · 24 hr · atm), manufactured by Fuji Sangyo Co., Ltd.), high-pressure steam sterilization is performed at 105 ° C for 25 minutes. went. After sterilization, both solutions were mixed. The pH immediately after mixing was 7.2, and the carbon dioxide gas partial pressure was 90 mmHg.

The composition of this comparative example after mixing was 4.0 w / v% glucose, 3.0 mEq / l acetate ion, 125 mEq / l sodium ion, 2.5 calcium ion.
mEq / l, magnesium 0.5 mEq / l, chloride ion 98 mEq / l, bicarbonate ion 30 mEq / l.

(Test Example) The dialysate of each Example after mixing and the dialysate of Comparative Example 1 were stored at 60 ° C. for 10 days.
Precipitation occurred in the comparative examples, but not in each example. When the dialysate of each Example was stored at 60 ° C. for 10 days without being mixed after sterilization, no precipitation occurred, and neither glucose decomposition nor coloring was observed.

[0038]

INDUSTRIAL APPLICABILITY The peritoneal dialysis solution of the present invention decomposes reducing sugars such as glucose by using an acidic solution containing reducing sugars and a basic solution containing bicarbonate ions after sterilization or just before use.・ P when used while suppressing coloring
H can be maintained at 6.8 to 7.4, and damage of peritoneal mesothelial cells and peritoneal macrophage function can be reduced. In addition, the amount of bicarbonate ion after mixing is 5 to 20 mEq.
/ L and the carbon dioxide partial pressure of 60 mmHg or less can suppress symptoms such as abdominal pain and discomfort when injected into the abdominal cavity. That is, the peritoneal dialysis solution of the present invention has excellent stability over time and safety to living bodies.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61L 2/06 A61M 1/28 A61M 1/14 523 A61K 9/08 E 1/28 A61J 1/00 335C // A61K 9/08 3/00 314Z (A61K 31/70 31:19) (A61K 33/14 33:00)

Claims (4)

[Claims] 1. A peritoneal dialysate used by mixing an acidic solution containing a reducing sugar, an organic acid or the like with a basic solution containing bicarbonate ion, and the peritoneal dialysis solution is mixed with the basic solution in an amount of 5 to 20 mEq /
A peritoneal dialysis solution containing bicarbonate ion in an amount of 1 and having a pH after mixing in the range of 6.8 to 7.4. 2. A peritoneal dialysate used by mixing an acidic solution containing a reducing sugar, an organic acid and the like with a basic solution containing bicarbonate ions, and glucose 1 to 10 after being mixed with the acidic solution.
w / v%, lactate ion 5-40 mEq / l, sodium ion 50-150 mEq / l, calcium ion 0-5
mEq / l, magnesium 0-5mEq / l in an amount of each component, and after mixing with a basic solution 5-20mEq / l
The peritoneal dialysis solution according to claim 1, which contains bicarbonate ion in an amount of 1. 3. The acidic solution and the basic solution are separately housed in a soft plastic bag having water vapor impermeability and gas impermeability and heat-sterilized before mixing. The peritoneal dialysis solution according to 2. 4. The peritoneal dialysate according to claim 1, wherein the partial pressure of carbon dioxide gas after mixing is 60 mmHg or less.