KR20160064181A - Three-pack type dialysis agent containing acetic acid and acetic acid salt - Google Patents

Abstract

It is an object of the present invention to provide a dialysis solution which can set the total acetic acid ion content in a dialysis solution to a low value, and is also excellent in storage stability of glucose and the like, can reduce acetic acid odor, A dialysis solution capable of arbitrarily changing the concentration of bicarbonate ions while keeping the concentration of trace metal ions such as ions constant.
A triple-acting dialysis solvent comprising an S agent comprising sodium chloride, a B agent comprising sodium bicarbonate, an electrolyte component other than sodium chloride and sodium bicarbonate, and an agent comprising glucose, wherein acetic acid and acetic acid salt And the molar ratio of acetic acid: acetic acid salt is 1: 0.5 to 2, it is possible to prepare a bicarbonate dialysis solution having a total acetic acid ion concentration of 2 mEq / L or more and less than 6 mEq / L, It is possible to reduce the odor of acetic acid in addition to the excellent stability of the component and furthermore, according to the three-dosage-type dialysis solvent, the concentration of the bicarbonate ion in the dialysis solution, / Or the sodium concentration may be varied.

Description

(THREE-PACK TYPE DIALYSIS AGENT CONTAINING ACETIC ACID AND ACETIC ACID SALT)

The present invention relates to a trifunctional dialysis solvent containing acetic acid and acetic acid salt. More specifically, the present invention relates to a dialysis solution which can be prepared so that the total acetic acid ion concentration in the dialysis solution is less than 6 mEq / L, and furthermore, the storage stability is excellent and acetic acid odor can be reduced, The present invention relates to a dialysis solution for three dosage forms,

Dialysis therapy has been established as a treatment for patients with renal failure and has been carried out for the purpose of controlling blood component concentrations of electrolytes, removing uremic substances, and correcting the acid base balance. The dialysis solution used in the dialysis treatment contains a plurality of components, and the components that are in conformity with the purpose of treatment and which are less burdened to the living body should be blended at appropriate concentrations.

Recently, a bicarbonate dialysis solution using sodium bicarbonate has become mainstream for the correction of the acid base equilibrium in the dialysis solution, and it is also necessary to form an acid to neutralize the dialysis solution. In addition, when they are co-existed in the same container and circulated, carbon dioxide gas is generated in the container and becomes very unstable. Therefore, the dialysis solution used for preparing the dialysis solution is divided into two components A and B, .

Normally, the agent A contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, a pH adjuster (a buffer component as an acid and optional components) and glucose, and the B agent includes sodium hydrogencarbonate. In addition, in order to prevent the precipitation of insoluble salts, mixing of calcium chloride and magnesium chloride is prohibited for the B-form.

Conventionally, these A and B agents have been used as a liquid filled in a polyethylene container, but problems such as transportation cost and workability in a hospital (weight, storage space, disposal method of polyethylene container, etc.) , A powdery dialysis solvent which is mixed with water at the time of use is put to practical use.

The dialysis solution in powder form was initially composed of an A-1 agent containing an electrolyte and a pH adjusting agent, and a B agent including an A-2 agent and a sodium bicarbonate containing only glucose. And A-2 are combined to form a two-dosage form containing A-agent and B-agent.

Today, the bicarbonate dialysis solvent is prescribed to have the following composition and concentration when used as a dialysis solution in clinical practice.

The dialysis solution is an A solution obtained by dissolving a liquid A or a powder A solution or a solution A solution obtained by dissolving powder A-1 agent and A-2 agent, and a liquid B As described above, in the bicarbonate dialysis solution, carbonic acid gas is generated over time due to the coexistence of an acid and sodium bicarbonate, as described above, and a B liquid obtained by dissolving a B- , And at the same time, the pH is also elevated to generate insoluble calcium carbonate or the like. Due to this phenomenon, there is a problem that the calcium concentration effective for treatment is reduced, or crystals adhere to the piping or hose of the dialysis apparatus.

On the other hand, acetic acid has been used for a long period of time as a pH regulator. However, in recent years, the peripheral vasodilating action of acetic acid, the inhibition of cardiac function, the induction of inflammatory cytokines, and the burden on patients suffering from acetic acid intolerance have been questioned. That is, since acetic acid is metabolized in a short time, it does not accumulate in the living body, but has an effect of suppressing cardiac function and capillary vasodilating effect and consequently lowering blood pressure. Since dialysis treatment is a treatment for removing moisture in the body, a blood pressure decrease due to water removal necessarily occurs during dialysis and after dialysis. In order to prevent this, coping therapies such as water removal control and the administration of a pressure-increasing agent are often used in combination. The presence or absence of symptoms due to these actions may also be attributed to the concentration of acetic acid contained in the dialysis solution, which differs from patient to patient. In recent years, a method called acetic acid (acetate-free) dialysis has been advocated as a way to overcome this situation.

Therefore, today, citric acid is incorporated as a pH controlling agent instead of acetic acid, and it is commercially available and clinically used (see, for example, Patent Documents 1 to 4). However, since citric acid has a strong chelating action, it chelates a part of calcium in the dialysis solution and lowers the ionized calcium concentration, and because it is stronger than acetic acid, the pH of the liquid A, which is a thick liquid, is lowered, There is a problem in that a large amount of an organic acid salt is added in order to raise the pH of the liquid A, and crystals of calcium citrate precipitate and affect the composition. That is, citric acid is liable to chelate with an alkaline earth metal, so it is chelated with calcium or magnesium in the dialysis solution component. This action is especially strong against calcium. In dialysis treatment, the control of the amount of calcium is very important, so that the reduction of the ionized calcium concentration by the chelate greatly affects the calcium resin of the patient. For example, when citric acid and calcium are contained at almost the same concentration (ion equivalence ratio) in the dialysis solution, about 35% of calcium is chelated, and the concentration of ionized calcium in the dialysis solution decreases accordingly, It is destroyed. In addition, since citric acid also enters the body by dialysis, calcium citrate is formed due to the combination of citric acid and calcium in the blood, so that there is a fear that calcium citrate is formed and deposited in blood vessels. Further, the dynamics of the components after citric acid and calcium enter the blood at the same time It is also noteworthy that it is difficult to manage calcium in the body, which is important in dialysis patients. In addition, the lowering of ionized calcium concentration by citric acid accelerates the relaxation of myocardial or vascular smooth muscle, resulting in hypotension, and the anticoagulant effect of citric acid is also problematic in that it is difficult to use for patients having bleeding tendency.

In addition, since citric acid is a solid, it is easy to handle in ordinary handling. However, since the concentrated liquid is strongly acidic, even when stored in powder form, when partial moisture absorption occurs, hydrogen chloride gas tends to be generated, Or resin deterioration may occur in some cases. For example, Patent Document 1 discloses a powdered dialysis solution of acetic acid which can prevent the formation of insoluble compounds, inhibit precipitation of calcium carbonate and decompose glucose by using citric acid, Lt; RTI ID = 0.0 > 2.2 to 2.9. ≪ / RTI > In this limited pH range, there is a problem in that there is a risk of corrosion of the dissolution apparatus and the dialysis apparatus, and also the concentration of ionized calcium is lowered due to the strong chelating action of citric acid, which may affect the therapeutic effect as described above.

For this reason, it is not optimal to use citric acid as an acid component other than acetic acid, and it is also conceivable to use a substance which is safe for living bodies such as lactic acid, malic acid, fumaric acid and gluconic acid as organic acids other than citric acid. However, It is important to consider the influence on the dialysate preparation apparatus and the dialysis apparatus by using these acid components as well as to minimize the use amount thereof since it is not clear about the behavior in the body after dialysis.

On the other hand, as described above, citric acid or the like may lower the ionized calcium concentration due to the strong chelating action, but strictly speaking, the acetic acid also lowers the ionized calcium concentration. Although the clinical problem has been underestimated in view of the rapid metabolism of acetic acid, the concentration of ionized calcium is lowered when the dialysis solution is used than when hydrochloric acid is used as the pH adjuster, and as the content of acetic acid is increased, The concentration is lowered. It is not known in general. If the content of acetic acid is large, it is certainly not a level of citric acid, but it is surely a factor to lower the concentration of ionized calcium in the dialysis solution. Even in this respect, it is clear that the acetic acid content is preferably as small as possible.

Acetic acid-containing dialysis agent A, which has been sold in Japan so far, has a total acetic acid content of 8 mEq / L or more, and a ratio of sodium acetate to acetic acid of at least 2.2, regardless of liquid or solid, Less than that is not used. In this condition, the solution A has a pH of 4.7 or more, which makes it difficult for the dialysis liquid preparation apparatus to corrode from the viewpoint of production of a liquid preparation, and is easy to handle.

The reason for the prescription of 8mEq / L in Japan is that when the concentration of acetate dialysis solution (sodium acetic acid is mixed more than 30mEq / L without using sodium bicarbonate) is changed to bicarbonate dialysis solution, the advantage of bicarbonate and acetate This is because it has the advantage of correcting the bicarbonate ion of the blood directly and correcting the bicarbonate ion slowly through metabolism of the acetate.

On the other hand, liquid preparations (liquid A) are mainly sold outside Japan. In Japan, sodium acetate is used as a part of the alkalizing agent, but since only sodium bicarbonate of sodium B is used as an alkalizing agent outside Japan, sodium acetate is not used. Therefore, as the acetic acid component, only acetic acid in an amount of usually not more than 4 mEq / L is used as a pH adjusting agent.

However, in the case where sodium acetate is not included, the pH of the liquid A becomes 3 or less, which causes adverse effects such as corrosion of the metal member of the dialysis liquid preparation apparatus and the dialysis apparatus, and strong irritation to the skin. In recent years, manufacturers of dialysate preparation apparatuses have been deemed to use a material resistant to corrosion as a component, because the pH of the solution A (including the solution prepared by dissolving the A powder) is 3 or less. , Their materials are expensive and therefore not economically desirable.

Further, in a dialysis solution containing acetic acid, it is also necessary to devise a dialysis solution which is handled in a large amount even in the case of a liquid, because it has a strong acetic acid odor and is uncomfortable.

Next, in Japan, a powder preparation becomes a mainstream from the flow of pulverization of a dialysis solvent, and many patents related to a bicarbonate dialysis solvent corresponding to pulverization are disclosed. For example, in Patent Document 5, in the powdered dialysis agent A, when the ratio (molar ratio) of sodium acetate to acetic acid is from 1.56 to 3.29, preferably from 2.49 to 3.29, sodium acetate easily adsorbs acetic acid, It is disclosed that the preparation of the powder preparation becomes easier because it is difficult to volatilize. However, even in the technique disclosed in Patent Document 5, the total acetic acid ion content in the finally prepared dialysis solution is assumed to be 8 mEq / L or more.

In addition, it is common that sodium acetate is mixed more than 2 times and 5 times or less with respect to acetic acid. For example, 2.2 times (2.5mEq / L of acetic acid: 5.5mEq / L of acetic acid) (2 mEq / L of acetic acid and 6 mEq / L of sodium acetate), 4.5 times (2 mEq / L of acetic acid and 9 mEq / L of sodium acetate), and 5 times of acetic acid (2 mEq / L of acetic acid, Sodium 10 mEq / L). The reason why the ratio of sodium acetate to acetic acid is not more than twice as large as the past prescription changes is that there is a problem of acetic acid odor. That is, the higher the ratio of sodium acetate to triplicate or quadruple, the smaller the odor of acetic acid as a powder preparation. On the contrary, when the temperature is close to 2 times or less than 2 times, odor of acetic acid is generated so that it is hard to bear, which is not practically usable.

Thus, in the case of dialysis solution using acetic acid, the total acetic acid ion content is 4 mEq / L or less, or 8 mEq / L or more is used all over Japan and abroad, and when the solid solution A is dissolved in water, Concentrate) is set to be about 4 and the total acetic acid ion content in the dialysis solution is set to be 4 to 8 mEq / L.

In the patent document 6, it is disclosed that acetic acid and sodium acetate are used, and the total acetic acid ion content in the dialysis solution is preferably at most 5 mEq / L. However, Patent Document 6 discloses basic concentrates (sodium hydrogencarbonate, sodium chloride and sodium acetate) and individual concentrates (sodium, potassium, calcium, magnesium, hydrochloric acid and / or acetic acid, glucose) In the final dialysis solution containing water, the molar ratio of acetate / sodium is 0.03 or less. That is, when the sodium content in the dialysis solution is generally set to 140 mEq / L, the total acetic acid ion content in the dialysis solution corresponds to 4.2 mEq / L or less. The sodium acetate to be added to the basic concentrate is less than 0.03 as acetate / sodium, and thereafter the acetic acid ion content in the dialysis solution is less than about 4 mEq / L. That is, Patent Document 6 discloses a dialysis solvent that is effective for manufacturing a dialysis solution having a total acetic acid ion content of less than about 4 mEq / L as the actual condition.

In addition, the dialysis solvent of Patent Document 6 enables various individual concentrates to be selected by individual patients, and its purpose of compounding sodium acetate is to improve the stability and preservability of basic concentrates at low temperatures. That is, a small amount of sodium acetate in the basic concentrate enhances the solubility of sodium hydrogencarbonate and suppresses the formation of a precipitate thereof.

That is, the dialysis solvent of Patent Document 6 is capable of various prescription dialysis (calcium, magnesium, potassium, etc.) according to individual patients, and requires a highly complicated system, so that acetic acid and acetic acid salt are mixed in different preparations It is different from the two-part formulation consisting of the general A and B agents or the three-part-type dialysis agent composed of the A-1 agent, the A-2 agent and the B agent in view of the formulation thereof and the preparation method of the dialysis liquid. In Patent Document 6, no technical means for reducing the odor of acetic acid in the dialysis solvent has been studied at all. Also, in the dialysis solution of Patent Document 6, since the individual concentrated solution contains hydrochloric acid or acetic acid and does not contain a basic component, it is exposed to a strong acidity of pH 3 or less. Therefore, , The stability of glucose and the like can never be said to be good.

As described above, in the combination of A (electrolyte, acid, glucose etc.) and B (sodium hydrogencarbonate), which are generally used as general two-dosage form dialysis solvents, the total acetic acid ion content in the dialysis solution is 4 to 8 mEq / L And there was no practical use due to strong acetic acid odor for powdered dialysis solvent. In addition, even in the case of the combination of A-1 agent (electrolytic acid), A-2 agent (glucose) and B agent (sodium hydrogencarbonate) which are commonly used as conventional three-dosage form dialysis solvents, the above problem was entirely the same.

In fact, there has been no practical application of a dialysis solution in powder form, in which the total acetic acid ion content in the dialysis solution is set to be less than 8 mEq / L, both in Japan and abroad. This is considered to be due to the difficulty in commercializing a powdery dialysis solvent that can withstand clinical use in terms of fluidity, stability, and acetic acid odor. Acetic acid, for example, has a large environmental impact in that it has an irritating odor. The preparation of the dialysis solution in clinical practice is generally performed by a clinical engineer, which is problematic in that an uncomfortable feeling accompanied by irritating odor is generated. Therefore, it is necessary to find out the optimal prescription while fully considering these problems.

In recent years, the lower the total acetic acid ion content in the dialysis solution is physiologically preferable, and the lower the total acetic acid ion content in the dialysis solution is preferably 6 mEq / L or 4 mEq / L, More and more is being demanded. Since the total acetic acid ion content is lowered in this way, acetic acid has a higher metabolic rate than other organic acids and has a lower content than that of the conventional products. Therefore, the concentration of acetic acid in the blood of the patient is not substantially increased during dialysis, The expression can be suppressed, and it is considered that the safety is remarkably improved. However, in the dialysis solution having a low total acetic acid ion content reported in the academic societies and the like, the amounts of acetic acid and sodium acetate added for dialysis are set at a total acetic acid ion content of 8 mEq / L, Therefore, the pH of the dialysis solution is inevitably increased. In such a high-pH dialysis solution, continued use may result in vascular calcification of the patient, and furthermore, there is a problem of calcium deposition in the dialysate preparation apparatus or dialysis apparatus.

On the other hand, the applicant of the present application has developed a three-dosage-type dialysis solution for preparing a dialysis solution capable of arbitrarily changing the concentration of bicarbonate ions according to the condition of a patient while keeping the trace metal ion concentration constant and developing a device for preparing such a dialysis solution (See Patent Document 7). As described above, it is possible to provide a three-dosage-type dialysis solvent capable of arbitrarily changing the concentration of bicarbonate ions and capable of setting the total acetic acid ion content in the dialysis solution to a low value, further having excellent storage stability of the A formulation and capable of reducing the odor of acetic acid The ability to develop pharmaceutical technology will bring good news to dialysis patients as well as dialysis therapists.

Japanese Patent Application Laid-Open No. 2003-104869 International Publication No. 2005/094918 Japanese Patent Laid-Open No. 10-087478 International Publication No. 2010/112570 Japanese Patent Application Laid-Open No. 7-24061 Japanese Patent Application Laid-Open No. 6-245995 Japanese Patent No. 5099464

It is an object of the present invention to provide a dialysis solution which can set the total acetic acid ion content in a dialysis solution to a low value, and is also excellent in storage stability of glucose and the like, can reduce acetic acid odor, A dialysis solution capable of arbitrarily changing the concentration of bicarbonate ions while keeping the concentration of trace metal ions such as ions constant.

As a result of diligent studies for solving the above problems, the present inventors have found that the above-mentioned problems can be solved by the present invention, and it is an object of the present invention to provide a sodium hypobromite solution containing an S agent containing sodium chloride, a B agent containing sodium bicarbonate, an electrolyte component other than sodium chloride and sodium bicarbonate, Wherein the total acetic acid ion concentration is 2 mEq / L or more and less than 6 mEq / L by containing acetic acid and acetic acid salt in Form A and satisfying a molar ratio of acetic acid: acetic acid salt of 1: 0.5 to 2 It is possible to prepare a bicarbonate dialysis solution, and it is possible to reduce the odor of acetic acid in addition to the excellent stability of components such as glucose in the agent A. In addition, according to the three-dosage-type dialysis solution, it is needless to say that the S agent and the A agent can be dissolved at the same time and used as a general two-dosage dialysis agent. However, It is possible to change the concentration of bicarbonate ion and / or the concentration of sodium in the dialysis solution. The present invention has been completed by repeatedly examining based on such knowledge.

That is, the present invention provides the invention in the form shown below.

Item 1. A three-component dialysis solution for preparing a dialysis solution, comprising an S agent containing sodium chloride, a B agent containing sodium bicarbonate, an electrolyte component other than sodium chloride and sodium bicarbonate, and an A agent containing glucose Lt;

Wherein the A agent comprises acetic acid and acetic acid salt, and the molar ratio of acetic acid: acetic acid salt is 1: 0.5 to 2,

A 3-dose dialysis solvent used for the preparation of a dialysis solution having a total acetic acid ion of 2 mEq / L or more and less than 6 mEq / L.

Item 2. The trivalent dialysis solvent according to Item 1, wherein the molar ratio of acetic acid: acetic acid salt in Form A is 1: 1 to 1.5.

Item 3. A three-dosage-type dialysis solvent according to Item 1 or 2, wherein the total acetic acid ion is used to prepare a dialysis liquid having a concentration of 2 mEq / L or more and 5 mEq / L or less.

Item 4. A three-dosage-type dialysis solution according to any one of Items 1 to 3, wherein the pH of the aqueous solution is in the range of 3.9 to 4.7 when the aqueous solution is concentrated to a concentration of 175 times the concentration of each component in the finally prepared dialysis solution .

Item 5. The trivalent dialysis solvent according to any one of Items 1 to 4, wherein the acetic acid salt is an alkali metal salt of acetic acid.

Item 6. The three-dosage-type dialysis solution according to any one of Items 1 to 5, further comprising a physiologically acceptable electrolyte component other than acetic acid, acetic acid salt, sodium chloride and sodium bicarbonate.

Item 7. The three-dosage-type dialysis solvent according to Item 6, wherein the electrolyte comprises potassium chloride, magnesium chloride, and calcium chloride.

Item 8. A three-dosage-type dialysis solvent according to Item 6 or 7, wherein the above-mentioned A further comprises an organic acid salt other than an acetate salt as said electrolyte and / or an organic acid other than acetic acid as a pH adjusting agent.

Item 9. The three-dosage-type dialysis solution according to any one of Items 1 to 8, wherein A is a solid.

Item 10. The three-dosage-type dialysis solvent according to Item 6, wherein the A is a solid phase, and the magnesium chloride and / or calcium chloride is a dried or anhydrous salt.

Item 11. The trivalent dialysis solvent according to Item 9 or 10, wherein the acetic acid and the acetic acid salt are contained as a mixture.

Item 12. The trivalent dialysis solvent according to any one of Items 9 to 11, wherein at least a part of the acetic acid and the acetic acid salt are contained in the form of an alkali metal diacetate.

Item 13. The trivalent dialysis solvent according to item 12, wherein the alkali metal diacetate salt is sodium diacetate and / or potassium diacetate.

Item 14. The trivalent dialysis solvent according to Item 8, wherein the organic acid salt is at least one member selected from the group consisting of sodium lactate, sodium gluconate, sodium citrate, sodium malate and sodium succinate.

Item 15. The trivalent dialysis solvent according to Item 8, wherein the organic acid is at least one selected from the group consisting of lactic acid, gluconic acid, glucono delta lactone, citric acid, malic acid and succinic acid.

16. The method according to item 16, wherein the A agent comprises a second raw material comprising a first raw material comprising a mixture of acetic acid and acetic acid salt and a composition comprising a physiologically acceptable electrolyte other than acetic acid and acetic acid salt,

The entirety of the acetic acid salt in the preparation A is contained in the first raw material or a part of the acetic acid salt in the dialysis aid A is contained in the second raw material,

A three-dosage-type dialysis solvent according to any one of items 9 to 15, wherein glucose is contained in the composition of the second raw material and / or a third raw material containing glucose is contained separately from the first raw material and the second raw material.

Item 17. The trivalent dialysis solvent according to Item 16, wherein the second raw material comprises, as electrolytes, potassium chloride, magnesium chloride, and calcium chloride.

Item 18. The three-dosage-type dialysis solvent according to item 16 or 17, wherein the second raw material further contains an organic acid salt other than an acetate salt as an electrolyte.

Item 19. The trivalent dialysis solvent according to any one of items 9 to 18, wherein the S agent, the B agent, and the A agent are accommodated in a packaging container having a moisture permeability of 0.5 g / m 2 24 h or less.

Item 20. The trivalent dialysis solvent according to any one of Items 9 to 19, wherein the S agent, the B agent, and the A agent are contained in a packaging container together with a desiccant.

Item 21. The trivalent dialysis solvent according to any one of items 1 to 20, which is used by varying the concentration of bicarbonate ion and / or the concentration of sodium in the dialysis liquid by controlling the addition amount of the S agent, B agent and A agent in use.

Item 22. A method for preparing a dialysis liquid,

An S agent containing sodium chloride,

A B agent containing sodium bicarbonate,

An A agent having an electrolyte component other than sodium chloride and sodium bicarbonate, acetic acid, acetic acid salt, and glucose and having a molar ratio of acetic acid: acetic acid of 1: 0.5 to 2,

And a mixing step of mixing water with an amount of total acetic acid ions of 2 mEq / L or more and less than 6 mEq / L.

Item 23. The method for preparing a dialysis liquid according to item 22, wherein in the mixing step, the dialysis solution is prepared so as to change the bicarbonate ion concentration and the sodium ion concentration to be constant in accordance with the condition of the patient during the dialysis treatment.

24. The method for preparing a dialysis liquid according to item 22, wherein in the mixing step, during the dialysis treatment, the dialysis solution is prepared so as to change the bicarbonate ion concentration and the sodium ion concentration at the same time according to the condition of the patient.

Since the dialysis solution for bicarbonate of the present invention can be used to prepare a bicarbonate dialysis solution so that the total acetic acid ion concentration is less than 6 mEq / L, it is possible to suppress symptoms such as blood pressure drop during dialysis, And the concentration of ionized calcium in the dialysis solution can be effectively suppressed. Further, the agent A in the three-dosage-type dialysis agent of the present invention is intended to improve the stability of other components such as glucose and to reduce the odor of acetic acid and furthermore to suppress the corrosion of the dialysate preparation apparatus and the dialysis apparatus Therefore, the quality is improved, the use environment in the medical field is improved, and the operability at the medical field is remarkably improved.

Particularly, by setting the total acetic acid ion concentration in the dialysis solution to be 2 to 5 mEq / L and further setting the molar ratio of acetic acid: acetic acid salt to about 1: 1 to 1.5 with respect to the agent A in the three- It is possible to make the pH of the liquid A (concentrated liquid) obtained by dissolving the solid phase A in water or the pH of the liquid phase A to be around 4.4, and furthermore, the three formulations which are more clinically safe, It becomes possible to provide a dialysis solvent.

As described above, according to the present invention, a bicarbonate dialysis solution can be prepared so that the total acetic acid ion concentration is less than 6 mEq / L, which is more clinically useful than the conventional dialysis solvent, Can be provided.

According to the present invention, the concentration of the bicarbonate ion and / or the sodium concentration in the dialysis solution can be freely changed by adjusting the addition amounts of the S agent, the B agent and the A agent, as required in the preparation of the dialysis liquid as in Patent Document 7 . For example, according to the present invention, it is possible to freely change the concentration of bicarbonate ions while controlling the concentration of trace metal ions such as potassium ions, calcium ions, and magnesium ions in the dialysis solution, It is possible to correct the metabolic acidosis suitable for the patient's condition. Therefore, the present invention can reduce the risk of death or hospitalization of dialysis patients and is extremely useful in future dialysis treatment.

In the present specification, the symbol " to " indicating the numerical range indicates that the numerical value is not less than the numerical value added to the left side of the numerical range, but not more than the numerical value added to the right side thereof. , X or more and Y or less.

The present invention relates to a three-dosage dialysis solution for preparing a bicarbonate dialysis solution, which comprises an agent comprising an S agent containing sodium chloride, a B agent containing sodium bicarbonate, and an electrolyte component other than sodium chloride and sodium bicarbonate, Characterized in that the A agent is used for the preparation of a dialysis solution containing acetic acid and acetic acid salt and further having a molar ratio of acetic acid: acetic acid salt of 1: 0.5 to 2 and total acetic acid ion of 2 mEq / L or more and less than 6 mEq / L. Hereinafter, the three-part type dialysis solution of the present invention will be described in detail.

S

The S agent includes sodium chloride. The S agent preferably contains no electrolytic component other than sodium chloride, and it is suitable that the contained component substantially contains only sodium chloride. The S agent may be provided in any form of a solid form or an aqueous solution, but is preferably solid in terms of ease of transportation and storage. Specific examples of the shape of the solid S-shape include powders and granules. In this specification, the solid S agent is referred to as a "solid S agent" and the aqueous solution S agent may be referred to as "liquid S agent".

When the liquid S agent is employed, the content of sodium chloride contained in the liquid S agent is, for example, 8 to 32 g / 100 ml, preferably 26 to 32 g / 100 ml, more preferably 30 to 31 g / 100 ml have.

There is no particular limitation on the packaging container accommodated in the case where the sealant is to be distributed, but for example, the same packaging container as the container for containing the A material can be mentioned.

B

B contains sodium bicarbonate. The agent B preferably contains no electrolyte component other than sodium bicarbonate, and it is preferable that the contained component substantially contains only sodium bicarbonate. B system, and S agent, it may be provided in any form of solid form or aqueous solution, but it is preferable that it is solid in terms of ease of transportation and storage. Specific examples of the shape of the solid form B include powders and granules. In the present specification, the solid B material is referred to as "solid B material", and the aqueous B liquid is sometimes referred to as "liquid B material".

In the case of employing the liquid B agent, the amount of sodium bicarbonate contained in the liquid B agent is such that it can satisfy the desired concentration of bicarbonate ions in the finally obtained dialysis liquid, and is preferably 7 to 12 g / 100 ml, Is 8 to 12 g / 100 ml, more preferably 9 to 11 g / 100 ml.

There is no particular limitation on the packaging container accommodated in the case of distributing the agent B, but for example, the same packaging container as the container for containing the agent A may be mentioned.

A

Agent A includes electrolyte components other than sodium chloride and sodium bicarbonate. The A agent includes at least acetic acid and acetic acid salt as electrolyte components, and the molar ratio of acetic acid: acetic acid salt is 1: 0.5 to 2.

Acetic acid contained in Form A may be glacial acetic acid. The acetate salt contained in the agent A is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include alkali metal salts of acetic acid such as sodium acetate and potassium acetate; And alkaline earth metal salts of acetic acid such as calcium acetate and magnesium acetate. Of these acetic acid salts, alkali metal salts of acetic acid, more preferably sodium acetate, are preferable from the standpoint of safety and cost due to years of use. These acetic acid salts may be used singly or in combination of two or more kinds.

Also, when A is a solid phase, the acetic acid and the acetic acid salt contained may be at least partially in the form of an alkali metal acetate diacetate. 2 Acetic acid alkali metal salt is a complex (MH (C ₂ H ₃ O ₂ ) _{2 wherein} M represents an alkali metal atom) in which 1 mole of an alkali metal acetate salt and 1 mole of acetic acid are combined, and from 1 mole of an alkali metal acetate diacetate, (Alkali metal acetate salt) and 1 mole of acetic acid are supplied. Specific examples of the alkali metal acetate diacetate include sodium diacetate, potassium diacetate, and the like. These alkali metal diacetate salts may be used singly or in combination of two or more. Among the alkali metal acetate diacetate, sodium diacetate is preferably used.

The A agent contains acetic acid and acetic acid salt so that the molar ratio of acetic acid: acetic acid salt is 1: 0.5 to 2. Even if the total acetic acid ion concentration in the dialysis solution is set to less than 6 mEq / L by satisfying such a molar ratio, the pH of the liquid A (concentrated liquid) obtained by dissolving the solid phase A in water or the pH of the liquid phase A is adjusted to about 3.9 to 4.7 And it is possible to suppress the corrosion of the dialysate preparation apparatus or the dialysis apparatus. By satisfying such a molar ratio, it is also possible to enhance the storage stability of the agent A and further reduce the odor of acetic acid.

From the viewpoint of more effectively exhibiting the functions of improving the storage stability of the dialysis agent A, reducing the odor of acetic acid, and suppressing the corrosion of the dialysis solution and the dialysis apparatus, the ratio of the acetic acid to the acetic acid salt in the agent A Preferably 1: 0.75 to 1.75, more preferably 1: 0.75 to 1.5, more preferably 1: 1 to 1.5, and particularly preferably 1: 1 to 1.25. As described above, since the alkali metal diacetate is a complex of 1 mole of acetic acid and 1 mole of alkali metal acetate, if an alkali metal diacetate is used as at least a part of acetic acid and acetic acid salt, it may be derived from 1 mole of alkali metal acetate Acetic acid and acetic acid salt are calculated as 1 mole, respectively. That is, for example, when acetic acid and acetic acid salt consist solely of alkali metal diacetate, the molar ratio of acetic acid: acetic acid salt is 1: 1. Further, for example, when acetic acid and acetic acid salt include X mol of an alkali metal acetate, Y mol of acetic acid and Z mol of acetic acid, the molar ratio of acetic acid: acetic acid salt is 1: (X + Z) / (X + Y) .

The content of acetic acid and acetic acid salt contained in the agent A may be appropriately set depending on whether it is a solid phase or a liquid phase. Usually, the total acetic acid ion content in the finally prepared dialysis liquid is 2 mEq / L or more and less than 6 mEq / L, / L to 5.5 mEq / L or less, and more preferably 2 mEq / L to 5 mEq / L. As described above, according to the dialysis agent A of the present invention, since the total acetic acid ion content in the dialysis solution can be set to a low level that can not be realized by the conventional dialysis solvent, the symptom such as lowering of blood pressure caused by acetic acid ion The expression can be suppressed, and the safety can be remarkably improved.

In addition to the acetic acid and acetic acid salts, the electrolyte A constituting the supply source of the magnesium ion, the calcium ion, the sodium ion, the potassium ion, the chloride ion, the citrate ion, the lactate ion, the gluconate ion, the succinate ion, Or two or more of them may be included. It is preferable that the electrolytic component (other than the acetic acid and the acetate salt) contained in the agent A contains at least a source of the chloride ion, the magnesium ion and the calcium ion, and furthermore, the source of the potassium ion Is more preferable.

As the source of the magnesium ion, a magnesium salt can be mentioned. The magnesium salt used for the agent A is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include magnesium chloride, magnesium lactate, magnesium citrate, magnesium gluconate, magnesium succinate, magnesium malate and the like have. Of these magnesium salts, magnesium chloride is suitably used as a supply source of magnesium because of its high solubility in water. These magnesium salts may be in the form of a hydrate, or may be in the form of dehydrating the hydrate by drying. These magnesium salts may be used singly or in combination of two or more kinds.

A calcium salt may be used as a source of calcium ions. The calcium salt used for the agent A is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include calcium chloride, calcium lactate, calcium citrate, calcium gluconate, calcium succinate and calcium malate. Of these calcium salts, calcium chloride is suitably used as a source of calcium because of its high solubility in water. These calcium salts may be in the form of hydrates, or may also be in the form of dehydration of the hydrates by drying. These calcium salts may be used singly or in combination of two or more kinds.

As the source of the sodium ion, sodium salt can be mentioned. When sodium acetate is used as the acetic acid salt, the sodium acetate serves as the source of the sodium ion. However, by using the sodium salt other than the sodium acetate, the sodium ion can be supplemented so as to have the desired sodium ion concentration in the dialysis solution. The sodium salt is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include sodium lactate, sodium citrate, sodium gluconate, sodium succinate, and sodium malate. These sodium salts may be in the form of hydrates. These sodium salts may be used singly or in combination of two or more kinds.

As a source of potassium ions, potassium salts may be mentioned. The potassium salt to be compounded in Form A is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include potassium chloride, potassium lactate, potassium citrate, potassium gluconate, potassium succinate and potassium malate . Of these potassium salts, potassium chloride is suitably used as a source of potassium since chloride ions are the most physiological substances. These potassium salts may be in the form of hydrates. These potassium salts may be used singly or in combination of two or more.

As the source of the chloride ion, a chloride salt can be mentioned. The chloride salt to be compounded in the agent A is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include calcium chloride, magnesium chloride and potassium chloride. These chloride salts are suitably used because they have high solubility in water and can also serve as a source of potassium, magnesium, or potassium. These chloride salts may be in the form of hydrates. These chloride salts may be used alone or in combination of two or more. It is also possible to use hydrochloric acid, which also acts as a pH adjusting agent, as a source of chloride ions.

As described above, each of the electrolyte components to be mixed with the agent A may be in the form of a hydrate, but is preferably in the form of an anhydride from the viewpoint of further reducing the odor of acetic acid and improving the storage stability.

The kinds and combinations of the electrolyte components to be mixed in the agent A are appropriately set according to the composition of each ion to be contained in the dialysis liquid finally prepared. As a suitable example of the electrolyte component (other than acetic acid and acetic acid salt) contained in the agent A , Magnesium chloride, calcium chloride and potassium chloride. When magnesium chloride, calcium chloride, and potassium chloride are used in combination as an electrolytic component, an organic acid salt (other than an acetate salt) may be further contained. Examples of such organic acid salts include sodium lactate, sodium gluconate, sodium citrate, sodium malate and sodium succinate. These organic acid salts may be used singly or in combination of two or more kinds.

The content of each electrolyte component contained in the agent A is appropriately set in accordance with each ion concentration to be provided in the finally prepared dialysis liquid. Concretely, the content of the electrolyte component (other than acetic acid and acetate) contained in the agent A is determined in consideration of the kind and content of the acetate salt, the amount of the electrolyte component contained in the S agent and the B agent, The dialysis solution may be appropriately set so as to satisfy the respective ion concentrations shown in Table 2 below.

Each ion concentration shown in Table 2 includes each ion derived from an acetate salt, and the amount of each electrolyte component contained in the agent A is determined in consideration of the amount of ions supplied from the acetate salt. The amount of the electrolyte component (other than sodium acetate) which is the source of sodium contained in the agent A is the amount of sodium supplied from the sodium hydrogen carbonate in the dialysis agent B and the amount of sodium acetate when sodium acetate is used as the salt The sodium ion concentration shown in Table 2 is determined.

For example, in the case where A contains acetic acid and sodium acetate, and other electrolytic components include potassium chloride, magnesium chloride, and calcium chloride, in order for each ion concentration contained in the dialysis solution to satisfy the range shown in Table 1, 0.08 to 1.5 mol, preferably 0.3 to 1.25 mol, of potassium chloride per 1 mol of the total molar amount of sodium acetate; 0 to 0.5 mol, preferably 0.05 to 0.38 mol, of magnesium chloride; It may be set at a ratio such that the calcium chloride is in the range of 0.13 to 1.13 mol, preferably 0.25 to 0.88 mol.

In addition to the above electrolyte components, the A agent includes glucose for the purpose of maintaining the blood sugar value of the patient. The content of glucose in the preparation A is appropriately set in accordance with the concentration of glucose to be provided in the dialysis solution finally prepared. Concretely, the content of glucose in the dialysis agent A may be suitably set so that the glucose concentration in the finally prepared dialysis solution is 0 to 2.5 g / L, preferably 1.0 to 2.0 g / L.

The agent A contains acetic acid and acetic acid salt in a predetermined ratio so that the pH of the finally prepared dialysis liquid is adjusted to have a suitable range. However, the pH agent may be further included if necessary. The pH adjuster which can be used for the agent A is not particularly limited as long as it is acceptable as a component of the dialysis solution, and examples thereof include a liquid acid such as hydrochloric acid, lactic acid, gluconic acid, citric acid, succinic acid, fumaric acid, malic acid, Lactones and the like, and sodium, potassium, calcium and magnesium salts of these acids. Of these pH adjusting agents, organic acids are suitably used. The pH adjusting agent may be used alone or in combination of two or more. When the pH adjusting agent is contained in the agent A, the content thereof is appropriately adjusted so as to satisfy the pH of the liquid A or the liquid A obtained by dissolving the solid phase A described later in water and the pH of the dialysis solution finally obtained You can set it.

The formulation form of agent A is not particularly limited, and may be either solid or liquid. In this specification, the solid form A agent is referred to as a solid phase agent A, and the liquid phase dialysis agent A is referred to as a " liquid phase A agent ". As the preparation form A, from the viewpoint of space saving and less burden on the operator, a solid phase A agent is preferably used.

The shape of the solid shape A agent is not particularly limited, and examples thereof include powders and granules. The content of each component in the solid phase agent A may be suitably set so as to satisfy the respective ion concentrations in the above-mentioned dialysis solution.

Although the content of each component in the liquid phase A agent is not particularly limited, in consideration of practicality, for example, the concentration of each component in the finally prepared dialysis solution is 150 to 200 times, preferably 170 to 180 times .

Since the pH of the liquid A or the liquid A obtained by dissolving the solid phase A in water is 4, by satisfying the above-mentioned ratio of the acetic acid and the acetic acid salt, the agent A can corrode the dialysis liquid preparation apparatus or the dialysis apparatus In addition, safety is assured when it comes into contact with the skin of a patient such as a worker at a clinic or a manufacturing site or a home dialysis.

More specifically, when the pH of the liquid A or liquid A obtained by dissolving the solid phase A in water is adjusted to be more than 175 times the concentration of each component in the finally prepared dialysis liquid Hereinafter, referred to as " 175-fold concentrated A-solution "), and the pH thereof is usually from 3.9 to 4.7, preferably from 4.1 to 4.4, more preferably about 4.3. Here, the pH of the 175-fold concentrated A-solution is a value measured at 25 占 폚.

By satisfying the above-described pH range, it is also possible to further improve the stability of glucose. Glucose is generally considered to be the most stable around pH 3 (interactions of food ingredients, published by Shoichi Norma, pp. 5-15, edited by Mamiko Namiki and Satsuo Matsushita, issued May 1, 1980) , And the glucose in Form A is set so that the ratio of acetic acid: acetic acid salt is 1: 0.5 to 2 and the total acetic acid ion concentration of the finally prepared dialysis solution is 6 mEq / L or less, It has been confirmed that it remains extremely stable.

Further, by satisfying the above-mentioned pH range of A, it is also possible to effectively reduce the odor of acetic acid. When the amount of the acetic acid salt per 1 mole of acetic acid in the liquid phase A agent is more than 2 moles, the odor of acetic acid tends to increase. Further, in the case of the solid phase A agent, the acetic acid salt tends to increase when the acetic acid salt is less than 0.5 mol per 1 mol of acetic acid and the pH is below the above-mentioned range.

From the viewpoint of further improving the functions such as the reduction of the odor of acetic acid and the storage stability of the glucose, the molar ratio of acetic acid and acetic acid salt is preferably 1: 0.5 to 2, and the total amount of acetic acid An A agent whose ion is set to 2 mEq / L or more and less than 6 mEq / L, and the pH of the 175-fold concentrated A solution is 3.9 to 4.7; More preferably, the molar ratio of acetic acid and acetic acid salt is 1: 0.75 to 1.5 (more preferably, 1: 1 to 1.5), and the total acetic acid ion as the dialysis solution is set to 2 mEq / L to 5.5 mEq / L , And the A solution having a pH of 4.1 to 4.4 in the 175-fold concentrated A solution; Particularly preferably, the molar ratio of acetic acid and acetic acid salt is 1: 1 to 1.25, the total acetic acid ion in the dialysis solution is set to 2 mEq / L or more and 5 mEq / L or less, A, which is about the same as A, can be mentioned.

When A is a solid phase agent, by reducing its moisture content, the odor of acetic acid can be further effectively reduced and the storage stability can be further improved.

The production method of the agent A is not particularly limited, and is appropriately set according to the form of the agent. Hereinafter, a suitable method for producing the solid phase A and the liquid phase A will be described.

As a suitable method for producing the solid phase A, there can be mentioned a first step of mixing acetic acid and acetic acid salt, and a second step of mixing the mixture obtained in the first step with another compounding component.

In the first step, by preparing a mixture of acetic acid and acetic acid salt (hereinafter sometimes referred to as a first raw material) in advance, it is possible to greatly reduce the acetic acid odor of the finally obtained solid phase A agent. In particular, when sodium acetic anhydride is used, acetic acid odor can be more effectively suppressed. Therefore, in the production of the solid phase A, it is preferable to use glacial acetic acid as the acetic acid and sodium acetic anhydride as the acetic acid salt.

It is also possible to provide the total amount of the acetate salt contained in the solid phase A agent to the preparation of the mixture in the first step and also to provide a part of the acetate salt contained in the solid phase A agent to the preparation of the mixture in the first step, The negative acetic acid salt may be mixed in the second step. The amount of the acetic acid salt to be provided in the first step of the acetic acid salt contained in the solid phase A agent is not particularly limited. For example, the amount of the acetic acid salt added to the first step, The amount of the salt is usually 20 to 100 parts by weight, preferably 50 to 100 parts by weight.

It is also possible to provide the total amount of acetic acid contained in the solid phase A agent to the preparation of the mixture in the first step and also to provide a part of the acetic acid contained in the solid phase A agent to the preparation of the mixture in the first step, The negative acetic acid may be mixed in the second step. The greater the amount of acetic acid contained in the solid phase A agent, the more the amount of acetic acid to be provided in the first step can be more effectively reduced, and the total amount of acetic acid contained in the solid phase A agent is preferably provided in the first step. As the amount of acetic acid to be supplied to the first step among the acetic acid contained in the solid phase A, specifically, the amount of acetic acid to be supplied to the first step is usually 50 to 100 weight parts per 100 weight parts of the total amount of acetic acid contained in the solid phase A agent, 100 parts by weight, preferably 75 to 100 parts by weight, more preferably 100 parts by weight.

In the first step, the method of mixing acetic acid and acetic acid salt is not particularly limited. From the viewpoint of further effectively reducing the odor of acetic acid, a method of mixing in a low moisture state such as heat mixing, drying, blowing, Suitable.

The mixture obtained in the first step has a low moisture content and does not emit only a small amount of acetic acid in a low humidity environment. However, since it tends to emit strong acetic acid in a high moisture content or in a high humidity environment, By lowering the moisture content and the humidity at the time of storage, the odor of acetic acid can be further suppressed. For example, the water content may be removed by heating sodium acetate to about 50 to 150 ° C to sufficiently lower the water content, and adding gaseous adsorbent such as molecular sieve to glacial acetic acid. It is possible to obtain a mixture having a low acetic acid odor by mixing them under the conditions of 60% RH or less, preferably 50% RH or less, more preferably 40% RH or less (all at 25 ° C). Further, by using a means for removing extra moisture, such as heating to 30 to 90 ° C at the time of mixing, or blowing dry air having a low absolute humidity, for example, 1.5 g / m 3 or less, or reducing the pressure, Thereafter, the effect of suppressing the odor of acetic acid can be further improved by temporarily storing or warming the mixture in an airtight container.

In the second step, the solid raw material A is prepared by mixing the first raw material obtained in the first step with other blending ingredients. The mixing of the mixture obtained in the first step and the other mixing components in the second step may be simple mixing or may be carried out by a combination of dry mixing such as stirring granulation, fluidized bed granulation, rotary fluidized bed granulation, Or may be carried out using a wet assembly method.

In the second step, the other mixing components to be mixed may be individually mixed with the first raw material, and a composition containing a part or all of other mixing components to be mixed may be prepared in advance, 1 raw material. Preferably, a method of preparing a composition containing an electrolyte component other than acetic acid and an acetate and, if necessary, an acetate (hereinafter sometimes referred to as a second raw material) may be prepared in advance and mixed with the first raw material . When the dialysis agent A of the present invention contains an organic acid salt, it is preferable that the organic acid salt is contained in the second raw material. The glucose may be contained in the second raw material, or may be mixed with the first raw material and the second raw material as a third raw material separately from the first raw material and the second raw material. Further, a part of glucose may be contained in the second raw material, and the remaining part may be mixed as a third raw material. When a part of the acetic acid is mixed in the second step, the acetic acid may be mixed into the second raw material, but separately from the first raw material and the second raw material and the third raw material to be mixed as required, 4 may be mixed as a raw material. The organic acid other than acetic acid may be contained in any one of the second raw material, the third raw material and the fourth raw material, or may be mixed as a fifth raw material separately from these organic acids.

The composition to be provided in the second step as the second raw material may be a mixture of electrolyte components, but is preferably in the form of an assembly. The method for producing the second raw material in the form of an assembly is not particularly limited. For example, in the case of producing a granular material (second raw material) containing potassium chloride, calcium chloride and magnesium chloride as electrolytic components, At least a part of calcium chloride and magnesium chloride is used as an aqueous solution and, if necessary, the remainder is added as a powder, and the mixture is heated and mixed at 50 to 90 캜, and then other components (organic acid salt, glucose or the like) Followed by heating and mixing to form a granulated product. Further, instead of adding an aqueous solution of calcium chloride and magnesium chloride in the formation of the granulated product, calcium chloride and magnesium chloride in powder form may be added, and an appropriate amount of water may be added before or after the addition. However, it is preferable that the granules are sufficiently dried regardless of any assembly operation. Further, magnesium chloride and calcium chloride, which are anhydrides, may be used, and further, their hydrates may be dehydrated by drying.

As a suitable example of the second step, a first raw material (a mixture of acetic acid and acetic acid salt), a second raw material (a composition containing an electrolyte other than acetic acid and acetic acid salt), a third raw material (glucose) (60% RH or less, preferably 50% RH or less, more preferably 40% RH or less (both 25 ° C or lower) at a low humidity In the case of the above method). When mixing in the second step, by using means for removing excess moisture such as heating to 30 to 90 占 폚 or blowing dry air having a low absolute humidity or reducing the pressure, as in the first step, The effect of suppressing the odor of acetic acid can be further enhanced. Also, it is preferable that the first raw material, the second raw material, the third raw material and the like have a low moisture content from the viewpoint of further reducing the odor of acetic acid produced by the solid phase A produced. Examples of the method for reducing the moisture content include a method in which each raw material provided in the mixing of the second step is previously dried at 90 to 140 캜 and cooled by a cold air having an absolute humidity of 1.5 g / have.

Further, as described above, since the alkali metal diacetate is a complex of acetic acid and acetic acid salt, an alkali metal diacetate may be used as a mixture of acetic acid and acetic acid salt as the first raw material. The alkali metal diacetate salt may be either a commercially available product or obtained by a known method (for example, a reaction product of acetic acid and an alkali metal hydroxide, a reaction product of acetic acid and an alkali metal carbonate, or an alkali metal acetate impregnated with acetic acid) .

The solid phase A thus produced is provided in a packaging container after being provided for a drying treatment, if necessary. For example, a flexible bag or a hard bottle is used as the packaging container used for packaging of the solid phase A agent. Specific examples of the packaging container include a silica-deposited laminate bag, an aluminum-deposited laminate bag, an aluminum oxide-deposited laminate bag, an aluminum laminate bag, and a polyethylene hard bottle. Particularly, a packaging bag (such as an aluminum laminate bag) in which a metal foil such as an aluminum foil is used can lower the moisture permeability and can more effectively suppress volatilization of acetic acid and moisture absorption from the environment. The moisture permeability of these packaging containers is preferably not more than 0.5 g / m 2 24 h (40 캜, 90% RH), more preferably not more than 0.2 g / m 2 24 h (40 DEG C, 90% RH) or less. The moisture permeability is a value measured in accordance with the measurement method specified in the moisture permeability test method (cup method) of the moisture-proof packaging material according to JIS Z0208.

In order to more effectively reduce the moisture content of the solid phase A contained in the packaging container, a desiccant may be contained in the packaging container together with the solid phase A agent. The drying agent is not particularly limited, and examples thereof include zeolite, magnesium sulfate, sodium sulfate, silica gel and alumina. When a desiccant is contained in a packaging container, a container in which these materials are mixed with a part of the plastic (for example, a polyethylene layer) constituting the container may be used, or a space (separate room) You may. It is also possible to store the drying agent in a packaging container so as not to be mixed with the solid phase agent in a state in which the drying agent is placed in a nonwoven fabric or the like.

The liquid phase A agent is prepared by weighing predetermined amounts of acetic acid, acetic acid salts, other electrolytes, and glucose, mixing them in water and dissolving them. It may also be prepared by dissolving a predetermined amount of the above-mentioned solid phase A in water. Further, after each compounding component is dissolved in water, it may be provided for treatment such as filtration if necessary.

The liquid A agent thus prepared is accommodated in a packaging container. As a packaging container used for packaging of the liquid phase A, for example, a plastic container such as a polyethylene bottle may be used.

Preparation of dialysate

The dialysis solution is prepared through the steps of adding and mixing desired amounts of S, B, A, and if necessary, water.

In the preparation of the dialysis solution using the dialysis solvent of the invention, water is added as necessary in order to adjust the concentration of each component of the dialysis solution finally obtained. The water to be used in preparing the dialysis solution from the dialysis solution of the present invention in the form of a tablet of the present invention may be any one that has been refined to a pharmaceutically acceptable level and concretely satisfies quality with purified water prescribed in Japanese Pharmacopoeia. For example, as the water used for preparing the dialysis solution, tap water or ground water is pretreated with an activated carbon treatment or a softening treatment, and then treated with reverse osmosis membrane filtration, distillation, ultrafiltration or the like. The water used for preparing the dialysis solution may be purified water or distilled water which is commercially available.

The pH of the dialysis liquid prepared by the three-dosage-type dialysis solution of the present invention is not particularly limited as long as it satisfies the allowable range as the dialysis liquid, but from the viewpoint of avoiding the risk of excessively correcting the acidosis of dialysis patients, Is 7.2 to 7.6, more preferably 7.3 to 7.5, particularly preferably 7.3 to 7.4. The agent A used in the present invention is set so as to be able to prepare a dialysis liquid having a pH in the above range by the buffering action of the acetic acid-acetic acid salt provided by satisfying the specific composition of the acetic acid and the acetic acid salt in addition to the buffering action of the bicarbonic acid.

The concentration of bicarbonate ions in the dialysis solution prepared by the dialysis solution of the present invention is set within a range of, for example, 20 to 40 mEq / L, preferably 25 to 35 mEq / L, more preferably 27 to 33 mEq / L do. The total acetic acid ion concentration and other ion concentrations of the dialysis solution prepared by the three-dosage-type dialysis solution of the present invention are as described above.

The dialysis solution of the present invention can be used to prepare a dialysis solution (ion concentration constant type) in which different ion concentrations with different bicarbonate ions are kept constant over time, and the ion concentration of potassium, calcium, magnesium, (Ion concentration fluctuation type) in which the concentration of bicarbonate ion and / or the sodium ion can be freely changed while maintaining the pH of the dialysis solution.

Preparation of dialysate with constant ion concentration

The preparation of the dialysis solution having a constant ionic concentration can be carried out by uniformly adding the amounts of S, B, A, and optionally water added to the total amount of the dialysis solution finally obtained, collectively, intermittently or intermittently By continuously mixing them. In the case of producing a dialysis solution of a constant ion concentration, the S agent, the B agent and the A agent may be mixed in any order. For example, S solution and A solution are simultaneously dissolved to prepare a pre-concentrated solution A, which can be used as a general dual-formulation dialysis solution containing the solution A and the solution B to prepare a dialysis solution of a constant ion concentration.

Preparation of dialysis solution of ion concentration variation type

The preparation of the dialysis solution of the ion concentration variation type is carried out by appropriately adjusting the addition amounts of the S agent, the B agent and the A agent. For example, with respect to the total amount of the dialysis solution finally obtained, by controlling the addition amount of the agent B while keeping the ratio of the addition amount of the agent A constant, the concentration of the trace metal ions such as potassium, calcium, and magnesium in the dialysis solution is kept constant The bicarbonate ion concentration can be freely changed. The sodium ion concentration can be freely changed while maintaining the trace metal ion concentration in the dialysis solution by adjusting the addition amount of the S agent while maintaining the ratio of the addition amount of agent A constant with respect to the total amount of the dialysis solution finally obtained . Also, by adjusting the addition amount of the S agent and the B agent while maintaining the ratio of the addition amount of the agent A constant, the concentration of the metal ion in the dialysis solution is kept constant and the sodium ion concentration and the sodium ion It is also possible to change both of the concentrations or to keep the other constant while changing the other.

Concretely, the concentration of bicarbonate ions in the dialysis solution can be set individually according to the condition of the patient within the above-mentioned range. For example, the concentration of bicarbonate ion can be set to be varied within the above-described range during the dialysis treatment have. The conditions of the patient referred to herein include the degree of metabolic acidosis of the patient, the nutritional status, and the condition during dialysis.

Examples of changing the concentration of bicarbonate ions in the dialysis solution during dialysis include the following (1) to (8).

(1) The concentration of bicarbonate ions is lowered from the start to the end of the dialysis treatment.

(2) The bicarbonate ion concentration is increased from the start to the end of the dialysis treatment.

(3) The bicarbonate ion concentration is lowered from the beginning of the dialysis treatment to the middle, and then the bicarbonate ion concentration is kept constant until the end.

(4) The bicarbonate ion concentration is increased from the beginning of the dialysis treatment to the middle, and then the bicarbonate ion concentration is kept constant until the end.

(5) The bicarbonate ion concentration is kept constant from the start of the dialysis treatment to the middle, and then the bicarbonate ion concentration is increased until the end.

(6) The bicarbonate ion concentration is kept constant from the initiation of the dialysis treatment to the middle, and then the bicarbonate ion concentration is lowered until the completion.

(7) The bicarbonate ion concentration is lowered from the initiation of the dialysis treatment to the middle, and then the bicarbonate ion concentration is increased until the end.

(8) The bicarbonate ion concentration is increased from the beginning of the dialysis treatment to the middle, and then the bicarbonate ion concentration is lowered until the end.

The mode of changing the concentration of bicarbonate ions is an example only and the concentration of bicarbonate ions may be continuously, stepwise, intermittently, or gradually changed during dialysis in the forms other than the above (1) to (8) Of course, can be repeatedly changed.

Also, the sodium ion concentration in the dialysis liquid may be set to a constant value within the above-mentioned range according to the conditions of individual patients or the condition during dialysis, or may be set to be changed during dialysis within the above-mentioned range.

For example, it is sometimes difficult to sufficiently remove moisture from the sodium ion concentration (140 mEq / L) of the dialysis solution currently in widespread use for patients suffering from hypotension, diabetes, or the like, which are likely to become flooded. For such patients, a high sodium dialysis solution having a sodium concentration of about 145 to 160 mEq / L may be used. It is thought that it is useful for prevention of decrease of blood pressure during dialysis because increasing the plasma osmotic pressure by high sodium dialysis increases the circulating plasma amount by extracting water in cell efficiently into the blood, Therefore, there is a method in which the sodium ion concentration at the initial stage of dialysis is set high, and thereafter the sodium ion concentration is gradually decreased, or a method in which the high sodium concentration and the normal sodium concentration or the low sodium concentration are alternately switched It is preferable for the patient that the sodium ion concentration depending on the patient can be changed and the bicarbonate ion concentration can also be changed at the same time.

3 formulation The conditions for preparing the dialysis solution of the ion concentration variation type using the dialysis solvent are described in detail in Patent Document 7 and the preparation of the dialysis solution of the ion concentration variation type using the three- May be appropriately set with reference to the disclosure contents of Patent Document 7. [ In addition, in the preparation of the dialysis solution of the ion concentration variation type, it is preferable that the kind of the ion to be changed and the change in the concentration thereof are determined before the dialysis treatment according to the patient's condition and the like.

The preparation of the dialysis solution using the three-dosage-type dialysis solution of the present invention can be carried out by using a dialysis solution preparation device capable of mixing the components B, S, A and, if necessary, water at a predetermined ratio. When the concentration of bicarbonate ions in the dialysis solution is changed over time, a dialysis solution preparation device having a means for controlling the amount of addition of the agent B or a means for controlling the ratio of the amount of the addition of the agent S and the agent B may be used. The device is disclosed in Patent Document 7, and is known.

Example

Hereinafter, the present invention will be described in detail with reference to Examples. However, the present invention is not limited to the following examples.

Test Example  One

(1) Preparation of liquid phase A agent

(Predetermined amount shown in Table 3) and sodium acetic anhydride (a predetermined amount shown in Table 3) were dissolved in water, and the total amount was adjusted to 100 mL. The amount of sodium chloride To prepare a dialysis liquid A agent. This liquid phase agent A for dialysis is in the state of an aqueous solution (potassium ion concentration: 350 mEq / L) concentrated to 175 times the concentration of each component in the finally prepared dialysis solution.

(2) Evaluation of pH, volatile acetic acid concentration, 5-HMF amount and corrosivity of liquid A agent

The pH of each liquid phase A obtained above was measured. The pH was measured at a liquid temperature of 25 캜 using a pH meter (manufactured by Horiba Seisakusho, model number: F-73).

The volatile acetic acid concentration of each of the liquid phase A obtained above was measured by the following method. Specifically, regarding the concentration of the volatile acetic acid, each liquid A agent was contained in a triple flask, and after standing for 15 minutes, a detector tube for measuring acetic acid was set on the liquid surface, and a predetermined amount of the sample gas was passed through the detector tube , And a detector tube gas meter (GASTEC, model number: GV-100S).

The amount of 5-hydroxymethyl furfural (hereinafter referred to as 5-HMF), which is a degradation product of glucose, was measured for each liquid phase A immediately after preparation. The amount of 5-HMF was measured after each liquid A agent was contained in a polyethylene bottle and stored at 40 캜 and 75% RH for 1 month. For the amount of 5-HMF, the absorbance of 5-HMF at an absorption wavelength (wavelength of 284 nm) was measured for a liquid filtered through a 0.2 mu m filter using a spectrophotometer.

The corrosion resistance of each of the liquid phase A obtained above to stainless steel was evaluated by the following method. 100 mL of each liquid phase A was put into a transparent plastic container of 200 mL in volume, and further, an area of approximately half of a stainless steel (SUS304) plate of 40 mm x 100 mm was immersed in each liquid phase A agent, And the mixture was allowed to stand at room temperature for 2 months. Two months after storage, the iron concentration in the liquid phase A agent was measured. The measurement of the iron concentration was carried out in accordance with the method A specified in " General test method 1. Chemical test method 1.10 Iron test method " of the 16th Japanese Pharmacopoeia. Specific measurement conditions are as follows. To 5 mL of the liquid phase A, 5 mL of acetic acid-sodium acetate buffer solution for iron test and 2 mL of L-ascorbic acid solution (1 g? 100 mL) were added and mixed and allowed to stand for 30 minutes. Next, 1 mL of a solution (0.25 g? 50 mL) of 2,2'-bipyridyl in ethanol (95) was added, and the volume of the solution was adjusted to exactly 50 mL with water, followed by mixing and leaving for 30 minutes to prepare a sample solution. For the standard solution, 2 mL of the Japanese Pharmacopoeia standard solution (0.01 mg / mL in Japan) was used. After the sample solution was subjected to blank correction, the absorbance of the sample solution and the standard solution was measured at an absorption wavelength (wavelength 522 nm) using a spectrophotometer, and iron concentration was calculated. Further, the corrosion was evaluated by n = 2, and the average value of the iron concentration in the liquid phase A agent was calculated.

The obtained results are shown in Table 4. As can be seen from Table 4, the liquid phase A agents (Examples 1 to 4) having a molar ratio of acetic acid: sodium acetate within the range of 1: 0.5 to 2 had a pH of 3.9 or more, so that they can be safely handled in a clinical field, There was no fear of corrosion of the apparatus or the dialysis apparatus. On the other hand, in the liquid phase A (Comparative Example 1) in which the molar ratio of acetic acid: sodium acetate was 1: 0, the pH was stronger than 3, and sufficient safety for handling was not ensured.

The liquid phase A agents (Examples 1 to 4) in which the molar ratio of acetic acid: sodium acetate was 1: 0.5 to 2 were lower in the concentration of the volatile acetic acid than in Comparative Example 2, and the concentration of the volatile acetic acid could be remarkably reduced.

In addition, the liquid phase A agents (Examples 1 to 4) in which the molar ratio of acetic acid: sodium acetate was 1: 0.5 to 2 exhibited a small amount of 5-HMF, which was a decomposed product of glucose, particularly when the molar ratio was 1: 0.5 to 1.5 In Examples 1 to 3, the amount of 5-HMF was remarkably decreased, and the decomposition of glucose was effectively suppressed. In the conventional dialysis agent A (the total acetic acid concentration in the dialysis solution is 8 mEq / L or more), it is possible to improve the transportation cost and the workability in the hospital when the concentration is increased to 175 times the concentration of each component in the dialysis solution finally prepared On the other hand, since electrolyte components other than sodium chloride and sodium bicarbonate and glucose are concentrated at a high concentration, they are easily affected by each electrolyte component, and when the total amount of acetic acid and acetic acid salt is increased, (See, for example, the results of Comparative Example 2). In the liquid phase A agents of Examples 1 to 4, the acetic acid ion concentration in the finally prepared dialysis solution was set to be less than 6 mEq / L, And the amount of acetic acid salt is small, it is possible to effectively decompose glucose even if it is liquid A agent concentrated at 175 times It is thought to be.

In addition, in the liquid phase A agent (Comparative Example 1) in which the molar ratio of acetic acid: sodium acetate was 1: 0, the iron concentration after storage was high and the corrosion of the stainless plate was proceeding. On the other hand, in the liquid phase A agents (Examples 1 to 4) in which the molar ratio is 1: 0.5 to 2, the iron concentration after storage is kept at a low value, and corrosion of the dialysis liquid preparation apparatus or the dialysis apparatus can be suppressed .

(3) Preparation and evaluation of bicarbonate dialysis solution

2 mL of each of the dialyzable liquid phase A obtained above was precisely weighed and purified water was added to make 300 mL. Sodium chloride (a predetermined amount shown in Table 5) for dialysis and sodium bicarbonate (sodium hydrogencarbonate) (Bicarbonate ion concentration of the dialysis solution: 30 mEq / L), purified water was added to make exactly 350 mL, and a bicarbonate dialysis solution was prepared. L of sodium ion, 2 mEq / L of potassium ion, 3 mEq / L of calcium ion and 1 mEq / L of magnesium ion were added to each of the obtained bicarbonate dialysis solutions (using the dialyzed liquid phase A of Examples 1 to 4 and Comparative Examples 1 and 2) L is included. The pH and ionized calcium concentration of the obtained bicarbonate dialysis solution were measured. The pH was measured at a liquid temperature of 25 캜 using a pH meter (manufactured by Horiba Seisakusho, model number: F-73), and the ionized calcium concentration was measured with a blood gas analyzer cobas b121 Gonesticks).

Table 6 shows the total acetic acid ion concentration, pH and ionized calcium concentration in the obtained bicarbonate dialysis solution. The bicarbonate dialysis solution prepared using the dialysis liquid agent A of Examples 1 to 4 had a total acetic acid ion concentration of 2 mEq / L or more and less than 6 mEq / L, maintained a pH suitable as a dialysis solution, The calcium concentration could be kept high.

Test Example  2

(1) Preparation of solid phase A agent

2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, and further 0.53 g of water were added and mixed and dried at 150 캜 to obtain an electrolyte composition. 17.50 g of glucose, acetic acid (a predetermined amount shown in Table 7), sodium diacetate (a predetermined amount shown in Table 7) and sodium acetate (a predetermined amount shown in Table 7) were mixed with the above electrolyte composition to obtain a solid phase A .

(2) Evaluation of solid phase A agent

(PH of the 175-fold concentrated A solution)

Each of the solid phase A obtained above was dissolved in purified water, and the solution was concentrated to a concentration of 175 times the concentration of each component in the finally prepared dialysis solution to prepare a 175-fold concentrated solution A. Specifically, the total amount of each of the solid phase A obtained above was dissolved in purified water to 100 mL to prepare a 175-fold concentrated A-solution. The pH of the obtained 175-fold concentrated A-solution was measured at a liquid temperature of 25 캜 using a pH meter (manufactured by Horiba Seisakusho, model number: F-73).

(Volatile acetic acid concentration and 5-HMF content)

For each solid phase A, the obtained total amount of the solid phase A was contained in a bag made of polyethylene. The bag was sealed in the packaging bag shown in Table 8 and stored at 25 캜 and 60% RH and at 40 캜 and 75% RH for 2 months.

Before the storage, two weeks after the storage and one month after the storage, a detector tube was set in a bag made of polyethylene containing each of the solid phase A agents, and a predetermined amount of the sample gas was passed through a detector tube for measuring acetic acid, The concentration of volatile acetic acid was measured by Gastec (model number: GV-100S).

Each of the solid phase agents before storage, two weeks after storage and one month after storage was dissolved in purified water to obtain 100 mL of the total amount of each of the solid phase agents obtained above. The concentration of each solid phase A was 175 times of the concentration of each component in the dialysis liquid finally prepared A 175-fold concentrated A-solution was prepared. The amount of 5-HMF in the 175-fold concentrated A-solution thus obtained was measured by the same method as described above.

The results of measurement of the pH of the 175-fold concentrated A solution are shown in Table 9, the measurement results of the concentrations of volatile acetic acid are shown in Tables 10 and 11, and the measurement results of the amount of 5-HMF are shown in Tables 12 and 13.

In the solution of the 175-fold concentrated A solution prepared from the solid phase A agent for dialysis having a molar ratio of acetic acid: acetic acid salt of 1: 0 (Comparative Example 3), the pH was as low as about 2.2 and the acid was strong, Further, there was a prescription for corrosion of the dialysate preparation apparatus or the dialysis apparatus. Further, in the solid phase A for dialysis of Comparative Example 3, the concentration of volatile acetic acid exceeded 1000 ppm, which was not acceptable in a clinical field. Also, the absorbance at 284 nm, which is the absorption wavelength of 5-HMF, was higher in the storage period than in the other examples, and glucose was not stably maintained. In the dialysis solid phase A of Comparative Example 4, the concentration of volatile acetic acid was as high as 900 ppm, even though the molar ratio of acetic acid: acetic acid salt was 1: 3.

On the other hand, in the 175-fold concentrated A solution prepared from the dialyzate solid phase A (Examples 5 to 8) in which the molar ratio of acetic acid: acetic acid salt was in the range of 1: 0.5 to 2, the pH was 3.9 or more, And there was no fear of corrosion of the dialysate preparation apparatus or the dialysis apparatus. Further, in the solid phase A agents for dialysis of Examples 5 to 8, the concentration of volatile acetic acid was lower than those of Comparative Examples 3 and 4. Further, the 175-fold concentrated A-solution prepared in Examples 5 to 8 of the solid phase A for dialysis exhibited an absorbance at a wavelength of 284 nm which is an absorption wavelength of 5-HMF after the preparation was sufficiently low as compared with Comparative Example 3, It was possible to sufficiently inhibit the decomposition of glucose. In particular, in Examples 6 to 8 (acetic acid: acetic acid salt = 1: 1 to 2), the concentration of volatile acetic acid and the absorbance at a wavelength of 284 nm were significantly low.

(3) Preparation of dialysate

2 ml of the 175-fold concentrated A-solution prepared above was precisely weighed and purified water was added thereto to make about 300 ml. To this was added S (sodium chloride) (a predetermined amount shown in Table 14) for dialysis and sodium bicarbonate ) Was added to the solution (bicarbonate ion concentration of the dialysis solution was 30 mEq / L), purified water was added to make exactly 350 mL, and a bicarbonate dialysis solution was prepared. L of sodium ions, 2 mEq / L of potassium ions, 3 mEq / L of calcium ions and 1 mEq / L of magnesium ions (all of which were added to the obtained bicarbonate dialysis solution (using the solid phase A agents of Examples 5 to 8 and Comparative Examples 3 to 4) .

The total acetic acid ion concentration included in the obtained bicarbonate dialysis solution (using the solid phase A of Examples 5 to 8 and Comparative Examples 3 to 4) is as shown in Table 15, and the molar ratio of acetic acid: sodium acetate was 1: 0.5 to 2 It was confirmed that the concentration of the acetic acid ion in the dialyzate solution of bicarbonate prepared using the solid phase A agent can satisfy the range of 2 mEq / L or more and less than 6 mEq / L.

Test Example  3

(1) Preparation of solid phase A agent

(Example 9)

2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, and further 0.53 g of water were added and mixed and dried at 150 캜 to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. 17.5 g of glucose, 3.48 g of sodium diacetate, and 1.49 g of acetic acid and sodium acetate mixture were mixed with stirring to obtain a solid A for dialysis. The molar ratio of acetic acid: sodium acetate in the resulting solid phase A agent for dialysis was 1: 1.

(Example 10)

2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, and further 0.53 g of water were added and mixed and dried at 150 캜 to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. 17.50 g of glucose, 2.49 g of sodium diacetate, and 2.49 g of acetic acid and sodium acetate mixture were mixed with stirring to obtain a solid A for dialysis. The molar ratio of acetic acid: sodium acetate in the resulting solid phase A agent for dialysis was 1: 1.

(Example 11)

2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, and further 0.53 g of water were added and mixed and dried at 150 캜 to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. 17.5 g of glucose, 0.99 g of sodium diacetate, and 3.98 g of acetic acid and sodium acetate mixture were mixed with stirring to obtain a solid A for dialysis. The molar ratio of acetic acid: sodium acetate in the resulting solid phase A agent for dialysis was 1: 1.

(Example 12)

2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, and further 0.53 g of water were added and mixed and dried at 150 캜 to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. 17.5 g of glucose and 4.97 g of acetic acid and sodium acetate mixture were mixed with stirring to obtain a solid phase A agent for dialysis. The molar ratio of acetic acid: sodium acetate in the resulting solid phase A agent for dialysis was 1: 1.

Table 16 shows the kinds and amounts of components added as acetic acid and / or acetic acid salt, and the molar ratio of acetic acid and sodium acetate to each of the solid phase A agents for dialysis (Examples 9 to 12).

(2) Evaluation of long term and accelerated stability of solid phase A for dialysis

For each of the dialysis agent A (Examples 9 to 12), the obtained total amount of the solid phase A was contained in a bag made of polyethylene. Further, it was housed in a PET / AL / PE bag shown in Table 8, sealed, and stored at 25 占 폚 and 60% RH, 40 占 폚 and 75% RH for 2 months.

The concentrations of volatile acetic acid were measured in the same manner as in Test Example 2 for each dialysis agent A before storage, two weeks after storage and one month after storage. The total amount of dialyzed A for each dialyzing before preservation, two weeks after preservation and one month after the preservation was dissolved in purified water to 100 mL to prepare a 175-fold concentrated A-solution concentrated at 175 times the concentration of each component in the dialysis solution finally prepared And the pH and 5-HMF amount of the obtained 175-fold concentrated A-solution were measured by the same method as in Test Example 2. [

The obtained results are shown in Tables 17 and 18. From these results, it was found that the solid phase A for dialysis of Examples 9 to 12 can sufficiently inhibit the volatilization of acetic acid and decomposition of glucose even after the organs and accelerated tests, and had excellent storage stability.

Test Example  4

(1) Preparation of solid phase A agents (Examples 13 to 15)

2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, and 1.78 g of magnesium chloride hydrate were added and mixed to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. 8.25 g of the electrolyte composition, 17.50 g of glucose, a mixture of acetic acid and acetic acid salt (a predetermined amount shown in Table 19) and sodium acetate (a predetermined amount shown in Table 19) were mixed with stirring to obtain a solid phase A agent for dialysis.

(2) Preparation of solid phase A (Examples 16 to 18)

2.61 g of potassium chloride, 2.91 g of anhydrous calcium chloride and 0.83 g of anhydrous magnesium chloride were added and mixed to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. A mixture of 6.35 g of the electrolyte composition, 17.50 g of glucose, a mixture of acetic acid and acetic acid salt (a predetermined amount shown in Table 19) and sodium acetate (a predetermined amount shown in Table 19) were mixed with stirring to obtain a solid A for dialysis.

(3) Evaluation of solid phase A

(PH of the 175-fold concentrated A solution)

The pH, volatile acetic acid concentration and amount of 5-HMF in the solution of the concentrate A were measured in the same manner as in Test Example 2, using each of the solid phase A obtained above.

The results of measurement of the pH of the 175-fold concentrated A solution are shown in Table 20, the measurement results of the concentration of volatile acetic acid are shown in Table 21, and the measurement results of the amount of 5-HMF are shown in Table 22.

In the 175-fold concentrated A-solution prepared by using the solid phase A (Examples 13 to 18) in which the molar ratio of acetic acid: sodium acetate was 1: 1 to 1.5, all of the solutions were pH 4 or more, And there was no fear of corrosion of the dialysate preparation apparatus or the dialysis apparatus. In Examples 13 to 15 in which hydrate was used as calcium chloride and magnesium chloride and the drying step was not included, the concentration of volatile acetic acid before storage was lower than that in Comparative Examples 3 and 4 in Test Example 2 including a drying step. In Examples 16 to 18, in which anhydrides were used as calcium chloride and magnesium chloride, the hydrates of these hydrates were used and compared with those of Examples 13 to 15 which did not include a drying step, The amount of volatile acetic acid and the absorbance at a wavelength of 284 nm which is the absorption wavelength of 5-HMF showed a low value even during the storage period. By using an anhydride as the electrolyte component to be compounded, the stability of the dialysis solvent and the acetic acid odor It is possible to reduce the amount of waste.

Claims (24)

A dialysis solution for three dosage forms for preparing a dialysis solution, comprising an S agent containing sodium chloride, a B agent containing sodium bicarbonate, an electrolyte component other than sodium chloride and sodium bicarbonate, and an agent comprising glucose,
Wherein the A agent comprises acetic acid and acetic acid salt, and the molar ratio of acetic acid: acetic acid salt is 1: 0.5 to 2,
A 3-dose dialysis solvent used for the preparation of a dialysis solution having a total acetic acid ion of 2 mEq / L or more and less than 6 mEq / L. The three-part dialysis solution according to claim 1, wherein the molar ratio of acetic acid: acetic acid salt in Form A is 1: 1 to 1.5. 3. The three-dosage-type dialysis solution according to claim 1 or 2, wherein the total acetic acid ion is used to prepare a dialysis liquid having a concentration of 2 mEq / L or more and 5 mEq / L or less. 4. The dialysis solution according to any one of claims 1 to 3, wherein the agent A is an aqueous solution concentrated to a concentration of 175 times the concentration of each component in the finally prepared dialysis solution, solvent. The three-part type dialysis solution according to any one of claims 1 to 4, wherein the acetic acid salt is an alkali metal salt of acetic acid. The formulation according to any one of claims 1 to 5, wherein the agent A further comprises physiologically acceptable electrolyte components other than acetic acid, acetate, sodium chloride and sodium bicarbonate. The three-part-type dialysis solution according to claim 6, wherein the electrolyte comprises potassium chloride, magnesium chloride and calcium chloride. The three-part type dialysis solution according to claim 6 or 7, wherein the agent A further comprises an organic acid salt other than the acetate salt as the electrolyte and / or an organic acid other than acetic acid as the pH adjusting agent. 9. The dialytic agent according to any one of claims 1 to 8, wherein the A is a solid phase. The three-part-type dialysis solution according to claim 6, wherein said A is a solid phase, and said magnesium chloride and / or calcium chloride is a dried or anhydrous solution. The three-part dialysis solution according to claim 9 or 10, wherein the acetic acid and the acetate salt are contained as a mixture. 12. A three-dosage-type dialysis solution according to any one of claims 9 to 11, wherein at least a part of the acetic acid and the acetic acid salt are contained in the form of an alkali metal acetate salt. The three-part type dialysis solution according to claim 12, wherein the alkali metal diacetate salt is sodium diacetate and / or potassium diacetate. 9. The dialysis solution according to claim 8, wherein the organic acid salt is at least one member selected from the group consisting of sodium lactate, sodium gluconate, sodium citrate, sodium malate and sodium succinate. 9. The dialysis solution according to claim 8, wherein the organic acid is at least one member selected from the group consisting of lactic acid, gluconic acid, glucono delta lactone, citric acid, malic acid and succinic acid. 16. A method according to any one of claims 9 to 15, wherein the agent A comprises a first raw material comprising a mixture of acetic acid and acetic acid salt, and a composition comprising a physiologically acceptable electrolyte other than acetic acid and acetate 2 raw materials,
The entirety of the acetic acid salt in the preparation A is contained in the first raw material or a part of the acetic acid salt in the dialysis aid A is contained in the second raw material,
Wherein the glucose is contained in the composition of the second raw material and / or a third raw material containing glucose is contained separately from the first raw material and the second raw material. 17. The three-dosage-type dialysis solvent according to claim 16, wherein the second raw material contains potassium chloride, magnesium chloride, and calcium chloride as an electrolyte. The three-part type dialysis solution according to claim 16 or 17, wherein the second raw material further contains an organic acid salt other than an acetate salt as an electrolyte. 19. The three-dosage-type dialysis solution according to any one of claims 9 to 18, wherein the S agent, the B agent and the A agent are accommodated in a packaging container having a moisture permeability of 0.5 g / m < 2 > The three-part dialysis solution according to any one of claims 9 to 19, wherein the S agent, the B agent, and the A agent are contained in a packaging container together with a desiccant. 21. The method according to any one of claims 1 to 20, wherein the amount of the S agent, the B agent, and the A agent is adjusted so as to change the bicarbonate ion concentration and / or the sodium concentration in the dialysis liquid, . As a method for preparing a dialysis solution,
An S agent containing sodium chloride,
A B agent containing sodium bicarbonate,
An A agent having an electrolyte component other than sodium chloride and sodium bicarbonate, acetic acid, acetic acid salt, and glucose and having a molar ratio of acetic acid: acetic acid of 1: 0.5 to 2,
And a mixing step of mixing water with an amount of total acetic acid ions of 2 mEq / L or more and less than 6 mEq / L. 23. The method for preparing a dialysis liquid according to claim 22, wherein in the mixing step, the dialysis solution is prepared so as to change the concentration of bicarbonate ion in accordance with the condition of the patient during the dialysis treatment and maintain the sodium ion concentration constant. 23. The method for preparing a dialysis liquid according to claim 22, wherein in the mixing step, during the dialysis treatment, the dialysis solution is prepared so as to change the bicarbonate ion concentration according to the condition of the patient and simultaneously change the sodium ion concentration.