JP2003339853A - Stable dialysis agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an acetic acid-free physiological dialysis agent stable in pharmaceutical preparations, with respect to the dialysis agent including an electrolytic component for preparing the bicarbonate dialysis artificial perfusion liquid, a pH adjusting agent and/or glucose. <P>SOLUTION: This dialysis agent does not include acetic acid and/or acetate salt, includes citric acid or sodium citrate, and the concentration of citric acid ion in preparation is 1.4-2.0 mEq/L. The agent is a solid agent, and divisionally stored in a plural-chamber container. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a dialysis agent containing an electrolyte component, a pH adjusting agent and / or glucose for preparing an artificial perfusate for bicarbonate dialysis used for hemodialysis.

[0002]

2. Description of the Related Art Hemodialysis (artificial dialysis) is one of the most common blood purification therapies for patients with chronic renal failure. The hemodialysis treatment method aims to improve serum electrolyte concentration, correct acid-base balance, etc. in addition to removing waste products and removing water. The dialysate used for this requires a large amount of alkalizing agent, which is removed by dialysis due to the small molecule of bicarbonate ion, which is an alkalizing agent in the living body. Low HC
O ₃ ^- in order to prevent that lead to hyperlipidemia. Therefore, it is natural that bicarbonate is the most suitable alkalizing agent, but in bicarbonate dialysate, bicarbonate ion reacts with calcium ion and magnesium ion to form an insoluble compound (metal carbonate such as calcium carbonate or magnesium carbonate). However, there is a problem in that it is difficult to store for a long period of time because it produces salt and is unstable, and because bacteria are easily proliferated.

Therefore, a method for replenishing alkali has been established by utilizing the fact that acetic acid is metabolized in the liver and converted into bicarbonate, and a stable dialysate can be supplied. Therefore, acetic acid using an acetate salt as an alkalizing agent. Dialysis started. As a result, it became possible to set a high alkali concentration, and it became possible to replenish the bicarbonate sufficiently.
Acetic acid has vasodilatory and cardiac function suppressing effects, and in the case of acetic acid intolerance with slow acetic acid metabolism, the exacerbation of dialysis imbalance syndrome caused by acetic acid and a large amount of CO ₂ in the blood during dialysis are dialyzed. Lost inside, the problems such as respiratory depression appeared.

[0004] Thereafter, as the number of dialysis patients increases and the number of patients with diabetes mellitus and the like expands, the frequency and severity of dialysis imbalance syndrome increase, and asymptomatic dialysis is performed in which even normal dialysis patients have minimal discomfort during dialysis. Demand has increased, and because the involvement of acetic acid was strongly suspected as the cause of these symptoms,
At present, the mainstream is acetic acid dialysis which uses acetate as an alkalizing agent, and bicarbonate dialysis which uses sodium hydrogen carbonate.

[0005]

In bicarbonate dialysis, in general, "A agent" containing an electrolyte component containing calcium ions and magnesium ions, a pH adjuster and / or glucose, and bicarbonate hydrogen carbonate. It has a two-agent structure consisting of sodium "B agent". This is because bicarbonate ions react with calcium ions and magnesium ions to form metal carbonate, which is an insoluble compound. However, even though it is referred to as bicarbonate dialysis, it contains 8 to 12 mEq / L of acetic acid such as acetic acid or sodium acetate as a pH adjuster, though not as much as the previous acetic acid dialysis. Initially, it was thought that the addition of acetic acid in this amount was not a problem, but since acetic acid originally does not exist in the living body (0.1 mEq / L or less), recently, due to prolonged dialysis, The development of clinical symptoms such as headache during dialysis and lowering of blood pressure, which is thought to be caused by acetic acid, has become a problem.
Also, due to improvements in the performance of the dialyzer, acetic acid is overloaded and adversely affects the circulatory system, and it is recognized that the toxic effect of acetic acid, such as acetic acid intolerance, is stronger than expected. It's coming. Therefore, there is a demand for the development of a dialysis preparation that does not contain acetic acid.

[0006]

Means for Solving the Problems The present invention has been completed as a result of extensive studies to solve such problems, and it has been completed. An artificial perfusate for bicarbonate dialysis used for hemodialysis is prepared. The present invention provides a dialysis agent containing an electrolyte component, a pH adjuster and / or glucose, which does not contain acetic acid and acetate.

That is, the present invention is as follows: A dialysis agent containing an electrolyte component, a pH adjuster and / or glucose for preparing an artificial perfusate for bicarbonate dialysis, which does not contain acetic acid and / or acetate salt,
Contains citric acid and / or sodium citrate,
Citrate ion concentration at the time of preparation is 1.4 to 2.0 mEq /
1. A dialysis agent which is L. The citrate ion concentration derived from citric acid at the time of preparation is 1.3 mEq / L or more.
2. the described dialysis agent, 3. The dialysis agent according to claim 1 or 2, which is a solid agent. The dialysis agent according to claim 3, which is separately stored in a multi-chamber container.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a dialysis agent containing an electrolyte component, a pH adjuster and / or glucose for preparing an artificial perfusate for bicarbonate dialysis, which contains acetic acid and / or acetate. However, it is characterized by using citric acid and sodium citrate, which are acids that also exist in the body. As a result, an acetic acid-free artificial perfusion solution for bicarbonate dialysis can be obtained.

The dialysis agent in the present invention is a preparation for preparing an artificial perfusion solution for bicarbonate dialysis by diluting and mixing with a sodium hydrogen carbonate solution, and its dosage form may be a liquid agent or a solid agent. However, since citric acid is a solid organic acid, a solid agent is particularly desirable. A granulation method of the solid agent may be a general method, and all components may be made into one agent, or may be divided into two agents, three agents and the like. The solid agent may be granulated or may be granulated without being granulated.

Further, in the case of a solid formulation, if all the components are combined into one formulation, glucose and citric acid may react with each other. Therefore, it is desirable to separately store the components that react with each other. At that time, it is particularly preferable to use a multi-chamber container in which one chamber is divided into several chambers, because it is possible to forget to put each component. For example, divide into two compartments, electrolyte and glucose, or electrolyte and glucose and citric acid
It may be divided into chambers, or may be granulated separately without being granulated.

This dialysis agent contains an electrolyte component, a pH adjuster and / or glucose. As the electrolyte component, other than citrate such as sodium citrate, for example,
Sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, potassium lactate, calcium lactate and the like are used. Preferred electrolyte compositions include sodium chloride, potassium chloride, calcium chloride,
Magnesium chloride and sodium citrate.

The amount of each component of the dialysate, when diluted and mixed to an appropriate concentration, is an artificial perfusate for bicarbonate dialysis,
The following concentrations are preferred. Na ⁺ 120 to 150 mEq / L K ⁺ 0 to 4 mEq / L Ca ⁺⁺ 0 to 4 mEq / L Mg ⁺⁺ 0 to 1.5 mEq / L Cl ⁻ 55 to 135 mEq / L HCO ₃ ⁻ 20 to 45 mEq / L citric acid 1.4-2.0 mEq / L glucose 0-3.0 g / L

In the present invention, citric acid is used as the pH adjusting agent. The pH of the artificial perfusate for bicarbonate dialysis may be adjusted to about 7-8.

The present invention is a dialysis agent containing citric acid and / or sodium citrate and having a citrate ion concentration of 1.4 to 2.0 mEq / L at the time of preparation. Further, at the time of preparation, the concentration of citric acid ion derived from citric acid is preferably 1.3 mEq / L or more. The "citrate ion concentration during preparation" is
It is the total citrate ion concentration when an artificial perfusate for bicarbonate dialysis was prepared. In the conventional so-called “agent A”, an acetic acid salt was contained, whereas in the present invention, by containing citric acid and / or sodium citrate, acetic acid is not contained at all, and sodium hydrogen carbonate alone is used as an alkali. Since it can be used as an agent, it has an advantage of a more physiological formulation.

Also, the use of citric acid can be expected to have an effect of suppressing precipitation. Two agents, a so-called "A agent" containing an electrolyte component, a pH adjuster and / or glucose, and a "B agent" consisting of sodium bicarbonate of bicarbonate ion, are produced by reacting bicarbonate ion with calcium ion and magnesium ion. In order to produce a metal carbonate which is an insoluble compound, it is generally diluted and mixed at the time of use to obtain an artificial perfusate for bicarbonate dialysis. Since the time required for actual hemodialysis is generally about 5 hours, it is desirable that the solution prepared as the artificial perfusion solution for bicarbonate dialysis is stable for 5 hours or more.
In this example, the stability of the artificial perfusate for bicarbonate dialysis was determined to be stable when no precipitation was observed for 8 hours or longer. In the present invention, the inclusion of citrate ions also has the advantage that stability is maintained for a long time due to the effect of suppressing the precipitation.

[0016]

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

(Example 1) Regarding the dialysis agent containing an electrolyte component, a pH adjusting agent and glucose for preparing an artificial perfusate for bicarbonate dialysis, the following 5 formulations containing citric acid and having different pHs were prepared. To do. That is, 214.8 g of sodium chloride (NaCl), potassium chloride (KCl)
5.22 g, calcium chloride (CaCl ₂ · 2H ₂ O)
7.72 g, magnesium chloride (MgCl ₂ · 6H
₂ O) 3.56 g, dextrose 52.5g and citric acid as a pH adjusting agent _{(C 6 H 8 O 7 ·} H 2 O) 1.23g
Was dissolved in water to make 1 L and prescription a (pH 2.
0), in this prescription a, the one prepared by changing the citric acid to 2.45 g was a prescription (pH 1.8), and the one prepared by changing the citric acid to 3.43 g was a prescription (pH).
1.8), the one prepared by changing the citric acid to 3.68 g is the formulation D (pH 1.7), and the one prepared by changing the citric acid to 4.90 g is the formulation E (pH 1.6). . Next, 29.4 g of sodium hydrogen carbonate was dissolved in water to make 1 L, water was further added to 35 mL of this aqueous solution, 10 mL of prescription a was added thereto, and water was added to make 350 mL, for acetic acid-free bicarbonate dialysis according to prescription a. An artificial perfusate was prepared. In addition, an acetic acid-free artificial perfusion solution for bicarbonate dialysis was prepared in the same manner for the formulations Ro to E. These were stored at room temperature and the properties were observed.

As a result, the artificial perfusate for bicarbonate dialysis according to the prescription a produced a precipitate after 2 hours, and the artificial perfusion solution for a bicarbonate dialysis according to the prescription b produced a precipitate after 6 hours. With the artificial perfusate for bicarbonate dialysis according to the formulations C, D, and E, no precipitate was formed even after 24 hours. From this,
It was revealed that the artificial perfusate for bicarbonate dialysis containing citric acid of 1.4 mEq / L or more is stable.

Example 2 A dialysis agent containing an electrolyte component, a pH adjuster and glucose for preparing an artificial perfusate for bicarbonate dialysis, containing citric acid and sodium citrate, and having a total citrate ion concentration. The following 8 formulations are prepared with the following formula: 1.4 mEq / L. That is, 214.8 g of sodium chloride (NaCl), potassium chloride (KCl)
5.22 g, calcium chloride (CaCl ₂ · 2H ₂ O)
7.72 g, magnesium chloride (MgCl ₂ · 6H
₂ O) 3.56 g, glucose 52.5 g, and citric acid (C ₆ H ₈ O ₇ .H ₂ O) 3.432 as a pH adjuster.
What was dissolved in water to make 1 L was prescribed (pH 1.
7), the pH adjusting agent of this formulation is citric acid 3.187.
g and sodium citrate _{(C 6 H 5 Na 3 O} 7 · 2
H ₂ O) was changed to 0.343 g to prepare (pH 1.9), and citric acid was changed to 2.942 g and sodium citrate to be changed to 0.686 g to prepare (pH 2.2). What was prepared by changing to 2.697 g of acid and 1.029 g of sodium citrate was prescribed (pH 2.4), and what was prepared by changing to 2.452 g of citric acid and 1.372 g of sodium citrate was prescribed (pH 2. 7), the one prepared by changing to 2.206 g of citric acid and 1.716 g of sodium citrate was prescribed (pH 2.9), the one prepared by changing to 1.961 g of citric acid and 2.059 g of sodium citrate. What was prepared by changing the formulation (pH 3.1) to 1.716 g of citric acid and 2.402 g of sodium citrate was designated as the formulation (pH 3.3). That. Next, 29.4 g of sodium hydrogen carbonate was dissolved in water to make 1 L, 35 mL of this aqueous solution was further added with water, 10 mL of the formulation was added thereto, and water was added to make 350 mL, and acetic acid-free artificial perfusion for bicarbonate dialysis according to the formulation. A liquid was prepared. An acetic acid-free artificial perfusion solution for bicarbonate dialysis was prepared in the same manner from the formulation. These were stored at room temperature and the properties were observed.

As a result, the artificial perfusate for bicarbonate dialysis by the prescriptions ,,, and produced a precipitate after 4 hours, whereas the artificial perfusate for bicarbonate dialysis by the prescriptions, and showed no precipitation even after 8 hours. Did not generate. From this, it is judged that the formulations containing 1.3 mEq / L or more of citric acid are stable.

(Example 3) Preparation of artificial perfusate for bicarbonate dialysis
Electrolyte components for manufacturing, pH adjuster and glucose
For the dialysis agent containing citric acid,
PH by changing the sodium citrate concentration
Prepare the following 8 formulations that differ. That is, Natri chloride
214.8 g of sodium (NaCl), potassium chloride (KC
l) 5.22 g, calcium chloride (CaCl_Two・ 2H_Two
O) 7.72 g, magnesium chloride (MgCl_Two・ 6H
_TwoO) 3.56 g, glucose 52.5 g and pH adjustment
Citric acid (C₆H₈O₇・ H_TwoO) 3.432
Formulation A (pH 1.
7), this formulation A, sodium citrate (C₆H₅N
a _ThreeO₇・ 2H_TwoO) was prepared by adding 0.343 g
Formulation B (pH 1.9), sodium citrate 0.6
Formulation C (pH 2.1) prepared by adding 86 g,
Prepared by adding 1.029 g of sodium citrate
Formulation D (pH 2.3), sodium citrate 1.37
Prepared by adding 2 g to the formulation E (pH 2.4),
What was prepared by adding 1.716 g of sodium enoate
Formula F (pH 2.6), sodium citrate 2.059
What was prepared by adding g was formulated G (pH 2.7),
The product prepared by adding 2.402 g of sodium acidate was treated.
Method H (pH 2.8). Next, sodium bicarbonate
Dissolve 29.4g in water to make 1L, 35mL
To the water, add 10 mL of Formulation A, and add water.
Addition to 350 mL, acetic acid-free heavy carbon according to formula A
An artificial perfusate for acid dialysis was prepared. About prescriptions B to H
In the same manner, an acetic acid-free artificial perfusion solution for bicarbonate dialysis
Prepared. These were stored at room temperature and the properties were observed.

As a result, in the artificial perfusate for bicarbonate dialysis according to the formulations A and B, no precipitate was formed even after 8 hours. No precipitates were formed in the artificial perfusates for bicarbonate dialysis according to the formulations C, D, E, F, G and H even after 48 hours. From this, it was judged that the stability of the artificial perfusate for bicarbonate dialysis was stable even in the formulations according to the formulations A and B, but C, D, E, F, G and H were more excellent.

[0023]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, an electrolyte component and pH for preparing an artificial perfusate for bicarbonate dialysis are used.
A dialysis agent containing a regulator and / or glucose, containing citric acid and / or sodium citrate, and having a citrate ion concentration of 1.4 to 2.0 mE at the time of preparation.
By setting q / L, it is possible to provide a physiologically dialysis agent that is stable in terms of formulation and is acetic acid-free.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 33/14 A61K 33/14 A61P 7/08 A61P 7/08 F term (reference) 4C077 AA05 BB01 DD12 EE03 GG08 HH02 HH12 HH17 JJ12 JJ18 KK30 LL01 NN14 NN18 PP29 4C086 AA01 EA01 HA02 HA04 HA16 MA03 MA04 NA05 NA06 ZA52 4C206 AA01 DA34 MA03 MA05 MA85 NA05 NA06 ZA52

Claims (4)

[Claims] 1. A dialysis agent containing an electrolyte component, a pH adjusting agent and / or glucose for preparing an artificial perfusate for bicarbonate dialysis, which does not contain acetic acid and / or acetate salt and contains citric acid and / or Alternatively, it contains sodium citrate and has a citrate ion concentration of 1.4 to 2.0 at the time of preparation.
A dialysis agent, which is mEq / L. 2. The dialysis agent according to claim 1, wherein the citrate ion concentration derived from citric acid is 1.3 mEq / L or more during preparation. 3. The dialysis agent according to claim 1, which is a solid agent. 4. The dialysis agent according to claim 3, which is separately stored in a multi-chamber container.