JP2018168147A - Agent a for hemodialysis - Google Patents

Abstract

To provide a solid agent A for hemodialysis that can reduce acetic acid smell, furthermore can suppress solidification due to storage, decomposition of glucose when glucose is allowed to coexist, and pH rise when dissolved in water, and has excellent storage stability.SOLUTION: A solid agent A for hemodialysis contains: a first fraction which substantially contains only one of magnesium chloride and potassium chloride and is constituted of granules containing calcium chloride; and a second fraction containing acetic acid and acetate.SELECTED DRAWING: None

Description

  The present invention relates to a hemodialysis agent A containing acetic acid and acetate and a method for producing the same. More specifically, the present invention includes acetic acid and acetate, can reduce acetic acid odor, and further suppresses solidification by storage, decomposition of glucose when coexisting with glucose, and increase in pH when dissolved in water. The present invention relates to a solid A-dialysis agent having excellent storage stability and a method for producing the same. Furthermore, this invention relates to the agent for hemodialysis using the said A agent for hemodialysis.

  Dialysis therapy for patients with renal insufficiency is performed for the purpose of adjusting the concentration of blood electrolyte components, removing uremic substances, correcting acid-base balance, and the like. The dialysis therapy generally performed is roughly classified into peritoneal dialysis and hemodialysis, and both methods use a dialysis solution.

  The dialysate contains a plurality of components, but components that have formulation stability, meet the purpose of treatment, and have a low burden on the living body should be blended at appropriate concentrations. For example, sodium lactate is generally used as an alkalizing agent in dialysate used for peritoneal dialysis, but sodium bicarbonate, sodium acetate, sodium citrate is used as dialysate for hemodialysis. From the viewpoints of difficulty in formulation, administration route, and biocompatibility, components suitable for each dialysis method are selected.

  In general, it is known that peritoneal dialysis has a slower dialysis efficiency than hemodialysis, has less burden on the heart and cells, and lowers renal function more slowly than hemodialysis. On the other hand, hemodialysis is generally performed about 3 times a week for about 4 to 5 hours per dialysis, and water removal and waste removal in the body progress at a relatively high rate during dialysis treatment. Therefore, it often causes imbalance syndrome and hypotension.

Due to the difference in dialysis efficiency, there is a difference in prescription between dialysates used for peritoneal dialysis and hemodialysis. For example, many hemodialysis agents currently marketed worldwide contain potassium, and no hemodialysis agent containing no potassium is sold in Japan. Hemodialysis is time efficient and contains potassium chloride at a concentration that does not fall below the lethal risk because there is a risk of hypokalemia due to rapid removal of potassium ions when potassium is not included It is necessary. On the other hand, since potassium is an electrolyte that should be sufficiently removed for patients with renal failure, it is reasonable not to include potassium in a peritoneal dialysis agent with a slow dialysis progression. For example, in Patent Document 1, glucose is used as the osmotic pressure adjusting substance, sodium ions (Na ⁺ ), calcium ions (Ca ⁺ ), and magnesium ions (Mg ⁺ ) are used as the cations, and chloro ions are used as anions. Renal failure requiring nutritional management and / or blood glucose management characterized in that (Cl ⁻ ) and / or organic acid ions are included, and the water removal performance is adjusted by changing the type and concentration of the organic acid. A peritoneal dialysis fluid for a patient is disclosed.

  When the hemodialysis agent is in a liquid state, its bulkiness makes it expensive to transport and also requires a storage space corresponding to it, so in recent years the use of solid preparations has become the mainstream in Japan. Since solid preparations are prepared in a predetermined amount of water by using a special device before dialysis treatment to prepare dialysate, it is not necessary to carry a large volume of dialysate, reducing the burden on medical personnel. Can do.

  The solid hemodialysis agent was initially composed of three agents: A-1 agent containing an electrolyte and a pH regulator, A-2 agent consisting of glucose alone, and B agent consisting of sodium bicarbonate. Many dialysis agents currently distributed in the country are two-part solid hemodialysis agents composed of an A agent and a B agent. Usually, agent A contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, pH regulator (acid and optional buffer component), and glucose, and agent B contains sodium bicarbonate. ing. In order to prevent the precipitation of insoluble salts, the B agent is contraindicated in calcium chloride or magnesium chloride. In addition, for example, Patent Document 2 discloses an electrolyte component (other than sodium bicarbonate and sodium chloride) that makes it possible to change the bicarbonate ion concentration and the sodium ion concentration according to the patient's condition during dialysis treatment. A three-drug hemodialysis agent comprising an A agent mainly containing, an S agent mainly containing sodium chloride, and a B agent mainly containing sodium bicarbonate has also been proposed.

Today, the bicarbonate dialysate used as a hemodialysis agent is formulated to have a composition and concentration as shown in Table 1 below when used as a dialysate in clinical practice.

  Hemodialysis agent A usually contains acetic acid as a pH regulator. Acetic acid is metabolized in a short time because it is metabolized in a short time, and since the pH when dissolving the hemodialysis agent A is higher than that containing citric acid and hydrochloric acid, The impact when touching the machine is small. Therefore, hemodialysis agents containing acetic acid are prevalent in liquid preparations as well as solid preparations.

  A general solid preparation in pharmaceuticals requires a special formulation technique different from a liquid preparation under the condition that necessary components are uniformly and stably maintained in a required amount at least partially. If it is liquid, all components are dissolved and in a uniform state, so there is no problem with the uniformity of the component content, but it is not easy to create a state where the content is uniformly contained in the solid preparation.

  In the case of a solid hemodialysis agent, in general, it is possible to improve the content uniformity by processing into a state where a part or all of the electrolyte component contained is mixed or granulated. The problem is solved. For example, Patent Document 3 discloses a dialysis agent and a method for producing the same that can improve the production efficiency while suppressing the problem that the amount of components contained in the granular material (granulated material) varies. Further, in Patent Document 4, if a specific cumulative pore volume ratio is set to 50% or less by granulation, a granulated product for agent A excellent in solubility, solidification suppression during storage, and the like can be obtained. It is disclosed.

  In recent years, the lower the total acetate ion content in the dialysate is physiologically desirable, less than 6 mEq / L or less than 4 mEq / L is reported in academic societies, etc., and hemodialysis that can be set to a low total acetate ion content There is an increasing demand for the development of preparations.

  When acetic acid is included as a pH regulator in a solid hemodialysis agent A, acetic acid odor often becomes a problem. In addition, acetic acid may react with other components to cause solidification. Acetic acid is also a factor that promotes the degradation of glucose, which is widely and generally contained in the A-dialysis agent.

  Conventionally, various methods for reducing the odor of acetic acid caused by volatilization of acetic acid contained in the agent A for hemodialysis have been proposed. For example, in Patent Document 5, the dialysis agent A used for the preparation of bicarbonate dialysis solution contains acetic acid and acetate, and the molar ratio of acetic acid: acetate satisfies 1: 0.5-2. This makes it possible to prepare a bicarbonate dialysis solution so that the total acetate ion concentration is 2 mEq / L or more and less than 6 mEq / L, and in addition to excellent stability of components in the dialysis agent A, acetic acid It is disclosed that odor can be reduced. Patent Document 6 discloses a solid dialysis agent A used for the preparation of bicarbonate dialysate, which contains glucose, acetic acid and acetate, and at least a part of acetic acid and acetate is alkali metal diacetate. In addition, by setting the acetic acid: acetate molar ratio to 1: 0.5 to 2, a bicarbonate dialysis solution having a total acetate ion concentration of 2 mEq / L or more and less than 6 mEq / L can be prepared. In addition to the excellent stability of the components in the dialysis agent A, the acetic acid odor can be reduced. As described above, some studies have been already made in the prior art so as to realize problems such as solidification suppression during storage, reduction of acetic acid odor, and glucose degradation suppression. However, the problem solving means of the prior art is limited to a method using a difference in physical properties depending on the manufacturing method and a coping method such as limiting the components contained, and the granulated product and other coexisting components However, there is still room for improvement in the method for reducing the odor of acetic acid.

Japanese Patent Laid-Open No. 2001-190662 Japanese Patent No. 5099464 JP 2012-105964 A Japanese Patent Laid-Open No. 2006-209485 Japanese Patent No. 5376480 Japanese Patent No. 5517321

  The object of the present invention is to reduce the odor of acetic acid, further suppress solidification by storage, degradation of glucose when coexisting with glucose, and pH increase when dissolved in water, and a solid state excellent in storage stability. It is to provide agent A for hemodialysis.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention, as a solid A hemodialysis agent, contains only one of magnesium chloride and potassium chloride, and contains calcium chloride. It has been found that the coexistence of the first fraction composed of the product and the second fraction containing acetic acid and acetate can suppress the volatilization of acetic acid and reduce the odor of acetic acid. Furthermore, the solid A agent for hemodialysis is capable of suppressing solidification due to storage, suppressing pH increase when dissolved in water, and suppressing glucose degradation and coloring even when coexisting with glucose. It was also found that it has excellent storage stability. In particular, the solid A agent for hemodialysis was dissolved in water by reducing the odor of acetic acid, suppressing solidification by storage, even when the first fraction and the second fraction were uniformly dispersed. It was found that the pH increase at the time, the decomposition of the glucose and the suppression of the coloring can be suppressed even when coexisting with glucose, and it has excellent storage stability. The present invention has been completed by further studies based on this finding.

That is, this invention provides the invention of the aspect hung up below.
Item 1. A solid hemodialysis agent A containing a first fraction and a second fraction,
The first fraction is a granulated product substantially containing only one of magnesium chloride and potassium chloride and containing calcium chloride;
The solid A agent for hemodialysis, wherein the second fraction contains acetic acid and acetate.
Item 2. Item 2. The solid A agent for hemodialysis according to Item 1, wherein the first fraction contains magnesium chloride.
Item 3. Item 3. The solid hemodialysis agent A according to Item 1 or 2, wherein the first fraction contains magnesium chloride and the second fraction contains potassium chloride.
Item 4. Item 2. The solid hemodialysis agent A according to Item 1, wherein the first fraction contains potassium chloride and the second fraction contains magnesium chloride.
Item 5. Item 5. The solid hemodialysis agent A according to any one of Items 1 to 4, comprising acetic acid and an alkali metal acetate as the acetic acid and acetate.
Item 6. Item 5. The solid hemodialysis agent A according to any one of Items 1 to 4, comprising an alkali metal diacetate as the acetic acid and acetate.
Item 7. Item 5. The solid hemodialysis agent A according to any one of Items 1 to 4, comprising a higher-order acetate compound as the acetic acid and acetate.
Item 8. Item 8. The solid hemodialysis agent A according to any one of Items 1 to 7, wherein the first fraction and / or the second fraction contains sodium chloride.
Item 9. Item 9. The solid hemodialysis agent A according to any one of Items 1 to 8, wherein the first fraction contains sodium chloride.
Item 10. Item 10. The solid hemodialysis agent A according to any one of Items 1 to 9, wherein the first fraction and / or the second fraction contains glucose.
Item 11. Item 11. The solid hemodialysis agent A according to any one of Items 1 to 10, wherein the second fraction contains glucose.
Item 12. Item 12. A two-agent hemodialysis agent comprising the solid hemodialysis agent A according to any one of items 1 to 11 and a hemodialysis agent B containing sodium bicarbonate.
Item 13. Solid A preparation for hemodialysis according to any one of Items 1 to 7, 10 and 11, which does not contain sodium chloride,
S-agent for hemodialysis containing sodium chloride,
B agent for hemodialysis containing sodium bicarbonate;
A three-drug hemodialysis agent.
Item 14. A first step of preparing a granulated product substantially containing only one of magnesium chloride and potassium chloride and containing calcium chloride; and a granulated product obtained in the first step; and acetic acid and acetate. A method for producing a solid hemodialysis agent A, comprising a second step of obtaining a solid hemodialysis agent A.

  The hemodialysis agent A of the present invention can effectively suppress the volatilization of acetic acid, and the acetic acid odor is reduced. Furthermore, the agent A for hemodialysis of the present invention can suppress solidification by storage, decomposition of glucose when coexisting with glucose, and pH increase when dissolved in water, and has excellent storage stability. Have. Therefore, according to the hemodialysis agent A of the present invention, it is possible to improve the quality of the hemodialysis agent, improve the use environment in the medical field, and the like.

1. Solid A Agent for Hemodialysis The A agent for hemodialysis of the present invention is a solid A agent for hemodialysis comprising a first fraction (first granule composition) and a second fraction (second composition). Wherein the first fraction is a granulated material substantially containing only one of magnesium chloride and potassium chloride and containing calcium chloride, and the second fraction contains acetic acid and acetate. It is characterized by. In this way, by formulating the A fraction for hemodialysis so that the first fraction formed from the granulated product of the specific component and the second fraction containing the specific component coexist. It is possible to reduce the odor of acetic acid, suppress solidification by storage, suppress degradation of glucose when coexisting with glucose, and suppress an increase in pH when dissolved in water. Hereinafter, the hemodialysis agent A of the present invention will be described in detail.

<First fraction>
The first fraction contained in the hemodialysis agent A of the present invention is a granulated product substantially containing only one of magnesium chloride and potassium chloride and containing calcium chloride. The “granulated product” in the present invention refers to not only a state in which each component particle is agglomerated or reacted to mix multiple component particles in one particle, but also an aggregated state in which one particle is bonded.

  Magnesium chloride is a substance that serves as a source of magnesium ions and chloride ions. Magnesium chloride used as a raw material for producing the first fraction may be either a hydrate or an anhydride, but it is preferable that part or all of the magnesium chloride is in the form of a hydrate. When magnesium chloride hydrate is used, at least a part of the crystal water contained in the magnesium chloride hydrate is released by heating or heat generation during granulation, and serves as a binder, thereby efficiently using the electrolyte raw material. It becomes possible to granulate. Specific examples of magnesium chloride hydrate include magnesium chloride dihydrate, magnesium chloride tetrahydrate, magnesium chloride hexahydrate, magnesium chloride octahydrate, magnesium chloride dodecahydrate, etc. 1 to 12 hydrates. Among these magnesium chloride hydrates, magnesium chloride hexahydrate is preferable. These magnesium chloride hydrates may be used alone or in combination of two or more.

  Potassium chloride is a substance that is a source of potassium ions.

  In the first fraction, only one of magnesium chloride and potassium chloride is substantially contained. Here, “substantially containing only one” means that one of potassium chloride and magnesium chloride is contained, and the other is not substantially contained. That is, magnesium chloride and potassium chloride do not substantially coexist in the same fraction. Therefore, the first fraction contains two aspects of the first aspect containing magnesium chloride and substantially free of potassium chloride, and the second aspect containing potassium chloride and substantially free of magnesium chloride. It is divided into.

  When the first fraction is the first aspect, the magnesium ion content of the hemodialysis solution prepared by the agent A for hemodialysis is 0.5 to 2.0 mEq for the content of magnesium chloride in the first fraction. / L, preferably 0.75 to 1.5 mEq / L, and may be appropriately set in consideration of the content of other magnesium salts contained in the dialysis agent. For example, the first fraction 0.1 to 50 parts by weight, preferably 0.1 to 40 parts by weight, and more preferably 0.3 to 30 parts by weight in terms of anhydrous magnesium chloride per 100 parts by weight of the total. In the present invention, "anhydrous weight conversion of magnesium chloride" means that when magnesium chloride is in the form of hydrate, the weight of anhydride is excluded except for the weight of crystal water (water molecules in the hydrate). It is a value obtained by converting to.

  When the first fraction is the first aspect, the first fraction is substantially free of potassium chloride. Here, “substantially free of potassium chloride” means that it is allowed to contain a small amount of potassium chloride as long as the effects of the present invention are not impaired. Specifically, Potassium chloride is 1 part by weight or less, preferably less than 0.3 part by weight, more preferably 0 part by weight per 100 parts by weight of the first fraction.

  When the first fraction is the second aspect, the potassium chloride content in the second fraction is about 0.5 to 3 mEq of the hemodialysis solution prepared by the hemodialysis agent A. / L may be appropriately set in consideration of the content of other potassium salts contained in the dialysis agent, for example, potassium chloride is 0.1 per 100 parts by weight of the total amount of the first fraction. 1-50 weight part, Preferably it is 0.1-40 weight part, More preferably, 0.3-30 weight part is mentioned.

  When the first fraction is the second aspect, the first fraction is substantially free of magnesium chloride. Here, “substantially free of magnesium chloride” means that it is allowed to contain a small amount of magnesium chloride as long as the effects of the present invention are not impaired. Specifically, Magnesium chloride is 1 part by weight or less, preferably less than 0.3 part by weight, more preferably 0 part by weight in terms of anhydride weight per 100 parts by weight of the first fraction.

  Calcium chloride is a substance that is a source of calcium ions. The calcium chloride used as the raw material for producing the first fraction may be either a hydrate or an anhydride, but it is preferable that a part or all of the calcium chloride is in the form of a hydrate. When calcium chloride hydrate is used, depending on the heating or exothermic conditions during granulation, at least a portion of the crystal water contained in the calcium chloride hydrate may be released and serve as a binder. Specific examples of calcium chloride hydrates include 1 to 6 hydrates such as calcium chloride monohydrate, calcium chloride dihydrate, calcium chloride tetrahydrate, and calcium chloride hexahydrate. Can be mentioned. Among these calcium chloride hydrates, calcium chloride dihydrate is preferable. These calcium chloride hydrates may be used singly or in combination of two or more.

  Regarding the content of calcium chloride in the first fraction, the calcium ion concentration of the hemodialysis solution prepared by the agent A for hemodialysis is 1.5 to 4.5 mEq / L, preferably 2.5 to 3.5 mEq / L may be appropriately set in consideration of the content of other calcium salts contained in the dialysis agent, for example, the anhydrous weight of calcium chloride per 100 parts by weight of the first fraction. 0.1-70 weight part in conversion, Preferably 0.1-60 weight part, More preferably, 0.3-50 weight part is mentioned. In the present invention, “calcium chloride anhydrous weight conversion” means that when calcium chloride is in the form of hydrate, the weight of anhydride is excluded except for the weight of crystal water (water molecules in the hydrate). It is a value obtained by converting to.

  The first fraction is granulated together with other components that are blended as necessary, and is in the form of a granulated product. The particle diameter of the granulated material constituting the first fraction is not particularly limited. For example, the particle size passes through a 10 mesh (1700 μm opening) sieve with a Tyler standard sieve, but a 80 mesh (180 μm opening) sieve. The proportion of particles that do not pass through is 90% by weight or more, preferably 93% by weight or more, more preferably 95% by weight or more.

  Although there is no restriction | limiting in particular about the water content of a 1st fraction, For example, 3 weight% or less, Preferably it is 2 weight% or less, More preferably, it is 1.5 weight% or less. When such moisture content is satisfied, it is possible to more effectively suppress acetic acid odor, solidification by storage, degradation of glucose when coexisting with glucose, and increase in pH when dissolved in water. become. In the present invention, the water content of the first fraction is a value measured using a Karl Fischer moisture meter.

<Second fraction>
The second fraction is a fraction containing acetic acid and acetate. In the agent A for hemodialysis according to the present invention, all the components other than the granulated material constituting the first fraction are constituents of the second fraction.

  The acetic acid used in the second fraction may be glacial acetic acid. The acetate used in the second fraction is not particularly limited as long as it is acceptable as a component of the hemodialysis solution. For example, alkali metal acetates such as sodium acetate and potassium acetate; calcium acetate And alkaline earth metal acetates such as magnesium acetate. These acetate salts may be anhydrous acetate salts. Among these acetates, alkali metal acetates are preferable, and sodium acetate is more preferable, from the viewpoints of safety and cost due to many years of use. Moreover, these acetates may be used individually by 1 type, and may be used in combination of 2 or more type.

Further, at least part of acetic acid and acetate contained in the second fraction may be in the form of alkali metal diacetate. Use of alkali metal diacetate reduces the odor of acetic acid, suppresses solidification by storage, suppresses degradation of glucose when coexisting with glucose, and suppresses increase in pH when dissolved in water. It becomes possible to plan. The alkali metal diacetate is a complex (MH (C ₂ H ₃ O ₂ ) ₂ ; M represents an alkali metal atom) in which 1 mol of an alkali metal acetate and 1 mol of acetic acid are complexed. From 1 mol of the metal salt, 1 mol of acetate (alkali metal acetate) and 1 mol of acetic acid are supplied. Specific examples of the alkali metal diacetate used in the present invention include sodium diacetate and potassium diacetate. These alkali metal diacetates may be used individually by 1 type, and may be used in combination of 2 or more type. Among the alkali metal diacetates, sodium diacetate is preferable.

  Further, at least part of acetic acid and acetate contained in the second fraction may be in the form of a higher-order acetate compound. The higher order acetate compound is a compound formed by combining acetic acid (primary compound) and acetate (primary compound) with each other. By using alkali metal diacetate, it is more effective to reduce acetic acid odor, suppress solidification by storage, suppress degradation of glucose when coexisting with glucose, and suppress increase in pH when dissolved in water. It becomes possible to aim at.

  In the second fraction, the molar ratio of acetic acid and acetate is not particularly limited and may be appropriately set based on the pH range to be applied to the hemodialysis solution. For example, acetic acid in the second fraction The molar ratio of: acetate is preferably 1: 0.5 to 10, more preferably 1: 0.5 to 3.0, and particularly preferably 1: 0.7 to 2.0. Here, when acetic acid and acetic acid salt include alkali metal diacetate, acetic acid and acetic acid salt derived from 1 mol of alkali metal diacetate are calculated as 1 mol of acetic acid and 1 mol of acetate, and the molar ratio is calculated. The When acetic acid and a high-order acetate compound are included as the acetate, if the molar ratio of acetic acid: acetate in the high-order acetate compound is 1: X, it is derived from 1 mol of the higher-order acetate compound. As for acetic acid and acetate, the molar ratio is calculated as 1 mol of acetic acid and X mol of acetate.

  Regarding the content of acetic acid and acetate in the second fraction, the acetate ion concentration of the hemodialysis solution prepared by the agent A for hemodialysis is 0.5 to 12 mEq / L, preferably 1.5 to 10 mEq / L. More preferably, it may be appropriately set so as to be 2 to 6 mEq / L. For example, the total amount of acetic acid and acetate is 1 to 100 parts by weight, preferably 5 to 80 parts per 100 parts by weight of the second fraction. Parts by weight, more preferably 5 to 25 parts by weight.

  Moreover, when the said 1st fraction is a 1st aspect (namely, aspect which does not contain potassium chloride substantially), potassium chloride may be contained in the 2nd fraction. When potassium chloride is contained in the second fraction, the content of other potassium salts contained in the hemodialysis agent is adjusted so that the potassium ion concentration of the hemodialysis solution is 0.5 to 3 mEq / L. What is necessary is just to set suitably in consideration of content etc.

  Moreover, when the first fraction is in the second mode (that is, a mode that does not substantially contain magnesium chloride), the second fraction may contain magnesium chloride. When magnesium chloride is contained in the second fraction, the magnesium ion concentration of the hemodialysis solution is 0.5 to 2.0 mEq / L, preferably 0.75 to 1.5 mEq / L. In addition, the content of other magnesium salts contained in the agent A for hemodialysis may be appropriately set.

  The second fraction may be in the form of a non-granulated product containing the above components and other components blended as necessary, and the second fraction is prepared together with other components blended as necessary. It may be in the form of granules. Further, the second fraction may be a combination of a non-granulated product and a granulated product.

  In the container containing the hemodialysis agent A of the present invention, the second fraction may be present in a state where the above components and other components blended as necessary are uniformly dispersed. Moreover, the said component and the other component mix | blended as needed may exist in the state disperse | distributed or distributed unevenly.

<Sodium chloride>
The agent A for hemodialysis of the present invention may contain sodium chloride as a sodium ion supply source. When sodium chloride is contained in the hemodialysis agent A of the present invention, sodium chloride may be contained in either the first fraction or the second fraction, and the first fraction and the second fraction. May be included in both minutes.

  When sodium chloride is contained in the hemodialysis agent A of the present invention, the sodium ion concentration of the hemodialysis solution prepared by the hemodialysis agent A is 120 to 150 mEq / L, preferably 135 to 145 mEq. / L may be appropriately set in consideration of the content of other sodium salts contained in the dialysis agent.

<Glucose>
The agent A for hemodialysis of the present invention may contain glucose for the purpose of maintaining the blood glucose level of the patient. Glucose tends to be destabilized by contact with electrolytes such as calcium chloride and magnesium chloride, but in the agent A for hemodialysis according to the present invention, the first fraction is in the form of a granulated product. By coexisting with the fraction, glucose can be stably maintained even when glucose is contained.

  When glucose is included in the hemodialysis agent A of the present invention, glucose may be contained in either the first fraction or the second fraction, and both the first fraction and the second fraction. However, from the viewpoint of further improving the stability of glucose, it is preferably contained in the second fraction.

  When glucose is contained in the hemodialysis agent A of the present invention, the content is appropriately set according to the glucose concentration provided in the finally prepared hemodialysis solution. Specifically, the glucose content in the hemodialysis agent A is such that the glucose concentration in the finally prepared dialysate is 0 to 2.5 g / L, preferably 1.0 to 2.0 g / L. What is necessary is just to set suitably.

<Other ingredients>
In addition to the components described above, the agent A for hemodialysis according to the present invention includes calcium ion, magnesium ion, sodium ion, potassium ion, chloride ion, citrate ion, lactate ion, gluconate ion, succinate as necessary. Other organic acid salts and / or inorganic salts that serve as sources of acid ions, malate ions, and the like may be included. When these components are contained, they may be contained in any of the first fraction and the second fraction, and may be contained in both the first fraction and the second fraction.

  Examples of the compound serving as a source of calcium ions include calcium salts of organic acids such as calcium acetate, calcium lactate, calcium citrate, calcium gluconate, calcium succinate, and calcium malate. These calcium salts of organic acids may be used alone or in combination of two or more.

  Examples of the compound serving as a supply source of magnesium ions include magnesium organic acid salts such as magnesium acetate, magnesium lactate, magnesium citrate, magnesium gluconate, magnesium succinate, and magnesium malate. One of these organic acid salts of magnesium may be used alone, or two or more thereof may be used in combination.

  Examples of the compound serving as the supply source of sodium ions include sodium organic acid salts such as sodium lactate, sodium citrate, sodium gluconate, sodium succinate, and sodium malate. These organic acid salts of sodium may be used alone or in combination of two or more.

  Examples of the compound serving as a source of potassium ions include potassium organic acid salts such as potassium acetate, potassium lactate, potassium citrate, potassium gluconate, potassium succinate, and potassium malate. These organic acid salts of potassium may be used alone or in combination of two or more.

  These organic acid salts and / or inorganic acid salts may be appropriately selected according to the types of various ions to be contained in the finally prepared hemodialysis solution.

  In the hemodialysis agent A of the present invention, the content of these organic acid salts and / or inorganic salts is appropriately set according to each ion concentration provided in the hemodialysis solution to be finally prepared. Specifically, the content of the electrolyte component contained in the agent A for hemodialysis of the present invention may be appropriately set so that the finally prepared hemodialysis solution satisfies each ion concentration shown in Table 2 below. .

  The hemodialysis agent A of the present invention contains acetic acid and acetate in the second fraction so that the prepared hemodialysis solution has an appropriate pH. The dialysis agent A may further contain a pH adjusting agent other than acetic acid and acetate, if necessary. The pH adjuster that can be used in the hemodialysis agent A of the present invention is not particularly limited as long as it is acceptable as a component of the dialysis solution. For example, liquid acids such as hydrochloric acid, lactic acid, and gluconic acid, Examples thereof include solid acids such as citric acid, succinic acid, fumaric acid, malic acid and glucono delta lactone, and sodium, potassium, calcium and magnesium salts thereof. Among these pH regulators, organic acids are preferably used. A pH regulator may be used individually by 1 type, and may be used in combination of 2 or more type.

  In addition, when the A agent for hemodialysis of the present invention contains a pH regulator other than acetic acid and acetate, the pH regulator may be contained in any of the first fraction and the second fraction, Further, it may be contained in both the first fraction and the second fraction.

  When the hemodialysis agent A of the present invention contains a pH regulator other than acetic acid and acetate, the pH of the hemodialysis solution to be finally prepared is 7.2 to 7.6, preferably May be appropriately set to be 7.2 to 7.5.

<Contained aspect of the first fraction and the second fraction>
The hemodialysis agent A of the present invention is contained in a state in which the first fraction and the second fraction coexist. In the hemodialysis agent A of the present invention, it is sufficient that the first fraction and the second fraction coexist in the contained container. For example, the first fraction and the second fraction are uniformly dispersed. Even in this state, the first fraction and the second fraction may be dispersed or distributed unevenly.

<Water content of agent A for hemodialysis>
The water content of the hemodialysis agent A of the present invention is not particularly limited and is determined by the water content of the first fraction and the second fraction. For example, the hemodialysis agent A of the present invention contains sodium chloride. If included, the water content of the hemodialysis agent A is 5.0% by weight or less, preferably 2.0% by weight or less, and more preferably 1.5% by weight or less. When the hemodialysis agent A of the present invention satisfies such a moisture content, acetic acid odor, solidification by storage, decomposition of glucose when glucose is allowed to coexist, and pH increase when dissolved in water, It becomes possible to suppress more effectively. In the present invention, the water content of the hemodialysis agent A is a value measured using a Karl Fischer moisture meter.

<Manufacturing method>
The agent A for hemodialysis of the present invention is produced by preparing a granulated product constituting the first fraction and mixing the components contained in the second fraction with the granulated product. Specifically, examples of the method for producing the hemodialysis agent A of the present invention include a method including the following first step and second step.
First step: A granulated product containing only one of magnesium chloride and potassium chloride and containing calcium chloride is prepared.
Second Step: A solid hemodialysis agent A containing the granulated product obtained in the first step, acetic acid and acetate is obtained.

  In the first step, granulation may be performed using the components contained in the first fraction. The granulation can be performed according to a method usually employed in the technical field.

  The granulated product obtained in the first step may be subjected to post-treatment such as drying, cooling, and sieving as necessary. In particular, when drying is performed, it is preferable to sufficiently remove moisture in consideration of formulation stability and fluidity. The amount of water in the granulated product greatly depends on the total amount of water of crystallization of the raw material used, but as a guideline, when water is added and granulated in the first step, the same amount of water as the added water is removed. Furthermore, 80 parts by weight to 20 parts by weight, more preferably 80 to 40 parts by weight, and particularly preferably 75 to 50 parts by weight of crystallization water per 100 parts by weight of the total water of crystallization originally retained by the raw material used. Drying to remove is preferred. By sufficiently drying the granulated material within a temperature range in which the raw material is not decomposed, reduction of acetic acid odor, suppression of solidification, and improvement of stability when glucose is contained are more effectively achieved. It becomes possible.

  In the second step, the granulated product (first fraction) obtained in the first step and the components constituting the second fraction may be mixed or added. In the second step, the component constituting the second fraction may be added separately to the granulated product (first fraction) obtained in the first step, and the second fraction is constituted. The mixture may be added after the components to be mixed are once mixed. When acetic acid and acetate are contained in the second fraction, in the second step, acetic acid and acetate are once mixed, and then added or mixed to the granulated product obtained in the first step. When the acetic acid odor is reduced, solidification is suppressed, and glucose is contained, the stability can be improved more effectively.

<Packaging aspect of agent A for hemodialysis>
The hemodialysis agent A of the present invention is provided by being housed in a packaging container. Although it does not restrict | limit especially as a packaging container used for the packaging of A agent for hemodialysis, For example, a flexible bag, a hard bottle, etc. are mentioned. Specific examples of the packaging container include a silica vapor deposition laminate bag, an aluminum vapor deposition laminate bag, an aluminum oxide vapor deposition laminate bag, an aluminum laminate bag, and a polyethylene hard bottle. In particular, a packaging bag (such as an aluminum laminate bag) using a metal foil such as an aluminum foil can reduce moisture permeability and more effectively suppress acetic acid volatilization. Further, the moisture permeability of these packaging containers is preferably 0.5 g / m ² · 24 h (40 ° C., 90% RH) or less, and more preferably, from the viewpoint of more effectively reducing the odor of acetic acid. 2 g / m ² · 24 h (40 ° C., 90% RH) or less. The said moisture permeability is a value measured based on the measuring method prescribed | regulated to the moisture permeability test method (cup method) of a JISZ0208 moisture-proof packaging material.

  Further, the packaging container for storing the hemodialysis agent A of the present invention may further contain a desiccant in order to effectively reduce the water content of the hemodialysis agent A. Although it does not restrict | limit especially as a desiccant, For example, a zeolite, magnesium sulfate, sodium sulfate, a silica gel, an alumina etc. are mentioned. When a desiccant is stored in a packaging container, a container in which these substances are blended with a part of plastic (for example, a polyethylene layer) constituting the container may be used, or a space in which the desiccant can be stored in the packaging container ( A separate room may be provided. Alternatively, the desiccant may be contained in a non-woven fabric or the like so as not to be mixed into the hemodialysis agent A and contained in a packaging container.

2. Hemodialysis agent The hemodialysis agent of the present invention contains the A agent for hemodialysis and the B agent for hemodialysis containing sodium bicarbonate.

  The hemodialysis agent B may contain glucose as necessary. When glucose is included in the hemodialysis agent B, the content thereof is such that the glucose concentration in the finally prepared hemodialysis solution is 0 to 2.5 g / L, preferably 1.0 to 1.5 g / L. What is necessary is just to set suitably so that it may become. However, it is desirable that the B agent for hemodialysis does not contain electrolyte components other than sodium bicarbonate, and it is preferable that the component is substantially composed of sodium bicarbonate. The hemodialysis agent B is preferably solid from the viewpoint of transportation and storage. Specific examples of the shape of the solid B agent for hemodialysis include powders and granules.

  What is necessary is just to set the usage-amount of the said B agent for hemodialysis suitably so that the bicarbonate ion in the hemodialysis liquid finally prepared may be 20-40 mEq / L, Preferably it is 25-35 mEq / L.

  In the case where sodium chloride is contained in the hemodialysis agent A, the hemodialysis agent of the present invention is a two-agent type comprising the hemodialysis agent A and the hemodialysis agent B containing sodium bicarbonate. It is used as a hemodialysis agent.

  In addition, when sodium chloride is not contained in the hemodialysis agent A, the hemodialysis agent of the present invention includes the hemodialysis agent A, hemodialysis agent S containing sodium chloride, and sodium bicarbonate. It is used as a three-drug hemodialysis agent comprising a B agent for hemodialysis. As described in Patent Document 2, the three-drug hemodialysis agent is prepared by adjusting the ratio of the addition amount of hemodialysis agent S and hemodialysis agent B during hemodialysis. Accordingly, it is possible to prepare a hemodialysis solution capable of maintaining a constant electrolyte concentration such as sodium, potassium, calcium, magnesium, etc. while freely changing the bicarbonate ion concentration even during hemodialysis.

  The S agent for hemodialysis may contain glucose as necessary. When glucose is contained in the S-agent for hemodialysis, the content thereof is such that the glucose concentration in the finally prepared hemodialysis solution is 0 to 2.5 g / L, preferably 1.0 to 1.5 g / L. What is necessary is just to set suitably so that it may become. However, it is desirable that the S-agent for hemodialysis does not contain electrolyte components other than sodium chloride, and those containing substantially sodium chloride are preferred. The S-agent for hemodialysis is preferably solid from the viewpoint of transportation and storage. Specific examples of the solid S-dialysis agent include powders and granules.

  The amount of the S agent for hemodialysis is appropriately determined so that the hemodialysis solution finally prepared satisfies the sodium concentration shown in Table 1 in consideration of the amount of sodium salt in the agent A for hemodialysis. You only have to set it.

  The hemodialysis agent of the present invention is used to prepare a bicarbonate hemodialysis solution. Specifically, when sodium chloride is not contained in the hemodialysis agent A, the hemodialysis agent B, and the hemodialysis agent A, the hemodialysis agent S is added with a predetermined amount of water ( Bicarbonate hemodialysate is prepared by mixing with and preferably diluting with purified water.

  Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not construed as being limited to the following examples.

Test example 1
1. Production of solid A agent for hemodialysis
Example 1
Weigh 928.8 g of sodium chloride, 28.2 g of calcium chloride dihydrate, and 18.0 g of magnesium chloride hexahydrate, put each in a separate plastic bag and seal it in a blow-type shelf dryer. And heated to 70 ° C. After heating, these raw materials and 18.0 g of purified water were put in one plastic bag and sealed, and after sufficiently mixing, they were again placed in a blow type shelf dryer and left at 70 ° C. for 20 minutes. Next, the entire contents of the plastic bag were spread uniformly on a stainless steel bat, placed in a 130 ° C. blown shelf dryer and dried for 2 hours. Since the granulated product was solidified by drying, it was pulverized with a spoon twice during drying, and after completion of drying, it was passed through a sieve having an opening of 2000 μm to produce a granulated product (first fraction).

  118.70 g of the obtained granulated product (first fraction), 5.27 g of a solid mixture of acetic acid and sodium acetate having a molar ratio of acetic acid: sodium acetate of 1: 1 (second fraction), glucose (second Fraction) 26.25 g was weighed and thoroughly mixed in a plastic bag, and then sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain a solid A agent for hemodialysis.

Example 2
Weighing 928.8 g of sodium chloride, 25.3 g of potassium chloride, and 28.2 g of calcium chloride dihydrate, and placing each in a separate plastic bag and sealing it to 70 ° C. with a blow-type shelf dryer Warmed up. After heating, these raw materials and 18.0 g of purified water were put in one plastic bag and sealed, and after sufficiently mixing, they were again placed in a blow type shelf dryer and left at 70 ° C. for 20 minutes. Next, the entire contents of the plastic bag were spread uniformly on a stainless steel bat, placed in a 130 ° C. blown shelf dryer and dried for 2 hours. Since the granulated product was solidified by drying, it was pulverized with a spoon twice during drying, and after completion of drying, it was passed through a sieve having an opening of 2000 μm to produce a granulated product (first fraction).

  118.70 g of the obtained granulated product (first fraction), 5.27 g of a solid mixture of acetic acid and sodium acetate having a molar ratio of acetic acid: sodium acetate of 1: 1 (second fraction), glucose (second Fraction) 26.25 g was weighed and thoroughly mixed in a plastic bag, and then sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain a solid A agent for hemodialysis.

Comparative Example 1
Weighing 928.8 g of sodium chloride, 25.3 g of potassium chloride, and 18.0 g of magnesium chloride hexahydrate, respectively, put each in a separate plastic bag, and sealed it in a fan-type shelf dryer at 70 ° C. Warmed up. After heating, these raw materials and 18.0 g of purified water were put in one plastic bag and sealed, and after sufficiently mixing, they were again placed in a blow type shelf dryer and left at 70 ° C. for 20 minutes. Next, the entire contents of the plastic bag were spread uniformly on a stainless steel bat, placed in a 130 ° C. blown shelf dryer and dried for 2 hours. Since the granulated product was solidified by drying, it was pulverized with a spoon twice during drying, and after completion of drying, it was passed through a sieve having an opening of 2000 μm to produce a granulated product (first fraction).

  118.70 g of the obtained granulated product (first fraction), 5.27 g of a solid mixture of acetic acid and sodium acetate having a molar ratio of acetic acid: sodium acetate of 1: 1 (second fraction), glucose (second Fraction) 26.25 g was weighed and thoroughly mixed in a plastic bag, and then sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain a solid A agent for hemodialysis.

Comparative Example 2
Weighing 928.8 g of sodium chloride, 25.3 g of potassium chloride, 28.2 g of calcium chloride dihydrate, and 18.0 g of magnesium chloride hexahydrate, and placing each in a separate plastic bag and sealing, blow It heated to 70 degreeC with the type | formula shelf dryer. After heating, these raw materials and 18.0 g of purified water were put in one plastic bag and sealed, and after sufficiently mixing, they were again placed in a blow type shelf dryer and left at 70 ° C. for 20 minutes. Next, the entire contents of the plastic bag were spread uniformly on a stainless steel bat, placed in a 130 ° C. blown shelf dryer and dried for 2 hours. Since the granulated product was solidified by drying, it was pulverized with a spoon twice during drying, and after completion of drying, it was passed through a sieve having an opening of 2000 μm to produce a granulated product (first fraction).

  118.70 g of the obtained granulated product (first fraction), 5.27 g of a solid mixture of acetic acid and sodium acetate having a molar ratio of acetic acid: sodium acetate of 1: 1 (second fraction), glucose (second Fraction) 26.25 g was weighed and thoroughly mixed in a plastic bag, and then sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain a solid A agent for hemodialysis.

2. Evaluation of hemodialysis agent A Measurement and solidification of volatile acetic acid concentration at the start of each hemodialysis agent A when stored at 40 ° C / 75% RH and after 1 month, 2 months, 3 months, and 5 months Confirmation of coloring and measurement of pH and 5-HMF amount when 35-fold concentrated A solution was obtained were performed by the following methods. Moreover, the granulated material (1st fraction) used as a raw material of each A dialysis agent and the water content of each A dialysis agent were measured by the method shown below.

(1) Measurement of volatile acetic acid concentration A detector tube is set in a bag containing each hemodialysis agent A, and a certain amount of sample gas is passed through the detector tube for measuring acetic acid. The volatile acetic acid concentration was measured by a manufacturer: GASTEC, model number: GV-100S.

(2) Confirmation of solidification and coloring The inside of the bag which accommodated each agent A for hemodialysis was confirmed visually, and the presence or absence of solidification and coloring was confirmed. Solidification refers to a state in which the fluidity is lost due to changes in the contents, resulting in moisture.

(3) Measurement of pH and 5-HMF Each A-dialysis agent for hemodialysis is dissolved in purified water, and the solution is concentrated 35 times the concentration of each component in the dialysate to be finally prepared. Concentrated solution A was prepared. Specifically, a 35-fold concentrated A solution was prepared by dissolving the total amount of each A-dialysis hemodialysis agent in purified water to 500 mL. About each 35 times concentrated A liquid, pH was measured at the liquid temperature of 25 degreeC using the pH meter (Manufacturer: Horiba, model number: F-73). The amount of 5-hydroxymethylfurfural (hereinafter referred to as 5-HMF), which is a degradation product of glucose, is the absorbance at the absorption wavelength (wavelength 284 nm) of 5-HMF using a spectrophotometer for the liquid filtered with a 0.2 μm filter. (Abs) was measured.

(4) Measurement of water content About the granulated product (first fraction) used as a raw material for each hemodialysis agent A and each hemodialysis agent A immediately after production, Karl Fischer moisture meter (manufacturer: Hiranuma Sangyo, The water content was measured using a model number: AQV-2200).

  The results are shown in Tables 3-8. As a result, when the granulated product containing magnesium chloride and potassium chloride (first fraction) and acetic acid and acetate (second fraction) were mixed (Comparative Examples 1 and 2), the storage period passed. Along with this, the increase in the concentration of volatile acetic acid, solidification, coloring, and decomposition of glucose were remarkable. On the other hand, when the granulated material (first fraction) containing only one of magnesium chloride or potassium chloride and calcium chloride is mixed with acetic acid and acetate (second fraction) (Examples 1 and 2). ), The increase in the concentration of volatile acetic acid was sufficiently suppressed even after 5 months of storage, and further, the solidification, coloring, the increase in pH when dissolved in water, and the decomposition of glucose were also sufficiently suppressed. In any of the examples and comparative examples, the water content of the granulated product (first fraction) used as a raw material for the hemodialysis agent A and the hemodialysis agent A was sufficiently low. .

Test example 2
1. Production of solid A agent for hemodialysis
Example 3
1000 kg of sodium chloride, 33.4 kg of calcium chloride dihydrate, 22.3 kg of magnesium chloride hexahydrate, and an appropriate amount of purified water are placed in a Nauta mixer (manufacturer: Hosokawa Micron Corporation, model number: DBX-5000RW) and mixed for 30 minutes. A granulated product was obtained. Subsequently, the granulated material was continuously supplied to the vibrating sieve, and the discharged granulated material was continuously transferred. After continuous drying at a drying temperature of 155 ° C., the mixture was cooled to produce a granulated product (first fraction).

  The resulting granulated product (first fraction) 115.70 g, acetic acid: sodium acetate molar ratio 1: 1 solid mixture of acetic acid and sodium acetate (second fraction) 5.27 g, potassium chloride (second fraction) Fractions) 3.0 g was weighed and thoroughly mixed in a plastic bag, and then sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain a solid A agent for hemodialysis.

Comparative Example 3
Sodium chloride 1000kg, potassium chloride 28.9kg, calcium chloride dihydrate 33.4kg, magnesium chloride hexahydrate 22.3kg and appropriate amount of purified water to Nauta mixer (manufacturer: Hosokawa Micron Corporation, model number: DBX-5000RW) The mixture was mixed for 30 minutes to obtain a granulated product. Subsequently, the granulated material was continuously supplied to the vibrating sieve, and the discharged granulated material was continuously transferred to a dryer. After continuous drying at a drying temperature of 155 ° C., the mixture was cooled to produce a granulated product (first fraction).

  118.70 g of the obtained granulated product (first fraction), 5.27 g of a solid mixture of acetic acid and sodium acetate (second fraction) having a molar ratio of acetic acid: sodium acetate of 1: 1 (second fraction) were weighed. After mixing in the bag, the mixture was sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain a solid hemodialysis agent A.

2. Evaluation of Hemodialysis Agent A (1) Content Measurement of Granulated Product (First Fraction) The granulated product (first fraction) used in Example 3 and Comparative Example 3 was 115.72 g and 118. 72 g was weighed and dissolved in water to make a total volume of 500 mL, and each granulated concentrate was obtained. The contents of each major component were measured by liquid ion chromatography for these granulated concentrates.

  The results are shown in Table 9. As a result, it was confirmed that the granulated product (first fraction) produced in Example 3 and Comparative Example 3 had the electrolyte content as intended.

(2) Measurement of concentration of volatile acetic acid, confirmation of solidification and coloration, measurement of pH and water content Start of each A-agent for hemodialysis of Example 3 and Comparative Example 3 when stored at 40 ° C./75% RH Measurement result of 1 hour and storage, measurement of volatile acetic acid concentration after 5 days storage at 50 ° C (no humidity control), confirmation of solidification and coloration, pH and 5-HMF amount when used as 35-fold concentrated solution A Was measured. Moreover, the water content of each granulated product (first fraction) used as a raw material for each hemodialysis agent A and each hemodialysis agent A immediately after production was measured. Specific measurement conditions are the same as in Test Example 1.

  The results are shown in Tables 10-13. As a result, when a granulated product containing magnesium chloride, potassium chloride and calcium chloride (first fraction), and acetic acid and acetate (second fraction) were mixed (Comparative Example 3), after storage, volatile acetic acid was used. The increase in concentration, solidification, and coloration were remarkable. On the other hand, in the case where a granulated product containing magnesium chloride and calcium chloride (first fraction) and potassium chloride, acetic acid and acetate (second fraction) are mixed (Example 3), after storage However, the increase in the concentration of volatile acetic acid can be sufficiently suppressed, and further, the increase in pH when solidified, colored, or dissolved in water can be sufficiently suppressed. In both Example 3 and Comparative Example 4, the water content of the granulated product (first fraction) used as a raw material for hemodialysis agent A and the hemodialysis agent A is sufficiently low. It was.

Test example 3
1. Production of solid A agent for hemodialysis
Example 4
486 kg of the granulated product used in Example 3 (first fraction), 12.4 kg of potassium chloride, 21.5 kg of a solid mixture of acetic acid and sodium acetate having a molar ratio of acetic acid: sodium acetate of 1: 1, and glucose 106 4 kg in Nauta mixer (manufacturer: Hosokawa Micron Corporation, model number: DBX-5000RW), mixed for 60 minutes, discharged, weighed 150.2 g, sealed in a moisture-proof packaging material containing an aluminum laminate layer, and hemodialyzed A preparation A was obtained.

Comparative Example 4
581 kg of the granulated product (first fraction) used in Comparative Example 3, 25.7 kg of a solid mixture of acetic acid and sodium acetate, and 127.2 kg of glucose were added to a Nauta mixer (manufacturer: Hosokawa Micron Corporation, model number: DBX-5000RW). After mixing for 60 minutes and discharging, 150.2 g was weighed and sealed in a moisture-proof packaging material containing an aluminum laminate layer to obtain agent A for hemodialysis.

2. Evaluation of hemodialysis agent A For each of hemodialysis agent A of Example 4 and Comparative Example 4, the measurement results at the start and storage of one month when stored at 40 ° C / 75% RH, and 50 ° C (humidity control) None), the concentration of volatile acetic acid after storage for 5 days, confirmation of solidification and coloring, and the pH and the amount of 5-HMF when a 35-fold concentrated solution A was obtained. Specific measurement conditions are the same as in Test Example 1.

  The results are shown in Tables 14-16. As a result, when a granulated product containing magnesium chloride, potassium chloride and calcium chloride (first fraction), and acetic acid and acetate (second fraction) were mixed (Comparative Example 4), volatile acetic acid was stored after storage. The increase in concentration, solidification, coloring, increase in pH when dissolved in water, and degradation of glucose were remarkable. On the other hand, when the granulated product containing magnesium chloride and calcium chloride (first fraction) and potassium chloride, acetic acid, and acetate (second fraction) are mixed (Example 4), storage is performed. Even after that, the increase in the concentration of volatile acetic acid was sufficiently suppressed, and further, solidification, coloring, increase in pH when dissolved in water, and decomposition of glucose were also sufficiently suppressed.

Production example
1. Production of solid A agent for hemodialysis
Example 5
Weighing 928.8 g of sodium chloride, 32.5 g of calcium chloride dihydrate, and 22.5 g of magnesium chloride hexahydrate, respectively, weighed each in a separate plastic bag, and sealed it in a blow-type shelf dryer At 70 ° C. After heating, these raw materials and 18.0 g of purified water were put in one plastic bag and sealed, and after sufficiently mixing, they were again placed in a blow type shelf dryer and left at 70 ° C. for 20 minutes. Next, the entire contents of the plastic bag were spread uniformly on a stainless steel bat, placed in a 130 ° C. blown shelf dryer and dried for 2 hours. Since the granulated product was solidified by drying, it was pulverized with a spoon twice during drying, and after completion of drying, it was passed through a sieve having an opening of 2000 μm to produce a granulated product (first fraction).

  4. The resulting granulated product (first fraction) 118.70 g, potassium chloride 27.5 g, acetic acid: sodium acetate molar ratio 1: 1, solid mixture of acetic acid and sodium acetate (second fraction) 27 g and glucose (second fraction) 26.25 g are weighed and mixed thoroughly in a plastic bag, then sealed in a moisture-proof packaging material containing an aluminum laminate layer, and a solid A agent for hemodialysis Got.

Example 6
Weighing 928.8 g of sodium chloride, 37.9 g of calcium chloride dihydrate, and 30.0 g of magnesium chloride hexahydrate, respectively, weighed each in a separate plastic bag, and sealed it in a blow-type shelf dryer At 70 ° C. After heating, these raw materials and 18.0 g of purified water were put in one plastic bag and sealed, and after sufficiently mixing, they were again placed in a blow type shelf dryer and left at 70 ° C. for 20 minutes. Next, the entire contents of the plastic bag were spread uniformly on a stainless steel bat, placed in a 130 ° C. blown shelf dryer and dried for 2 hours. Since the granulated product was solidified by drying, it was pulverized with a spoon twice during drying, and after completion of drying, it was passed through a sieve having an opening of 2000 μm to produce a granulated product (first fraction).

  4. The obtained granulated product (first fraction) 118.70 g, potassium chloride 33.0 g, acetic acid: sodium acetate molar ratio 1: 1, solid mixture of acetic acid and sodium acetate (second fraction) 27 g and glucose (second fraction) 26.25 g are weighed and mixed thoroughly in a plastic bag, then sealed in a moisture-proof packaging material containing an aluminum laminate layer, and a solid A agent for hemodialysis Got.

Claims (14)

A solid hemodialysis agent A containing a first fraction and a second fraction,
The first fraction is a granulated product that substantially contains only one of magnesium chloride and potassium chloride, contains calcium chloride, and contains neither acetic acid nor acetate.
The solid A agent for hemodialysis, wherein the second fraction contains acetic acid and acetate.   The solid A agent for hemodialysis according to claim 1, wherein the first fraction contains magnesium chloride.   The solid A preparation for hemodialysis according to claim 1 or 2, wherein the first fraction contains magnesium chloride and the second fraction contains potassium chloride.   The solid A agent for hemodialysis according to claim 1, wherein the first fraction contains potassium chloride and the second fraction contains magnesium chloride.   The solid A preparation for hemodialysis according to any one of claims 1 to 4, wherein the second fraction contains acetic acid and an alkali metal acetate as the acetic acid and acetate.   The solid A preparation for hemodialysis according to any one of claims 1 to 4, wherein the second fraction contains an alkali metal diacetate as the acetic acid and acetate.   The solid A preparation for hemodialysis according to any one of claims 1 to 4, wherein the second fraction contains a higher-order acetate compound as the acetic acid and the acetate.   The solid A preparation for hemodialysis according to any one of claims 1 to 7, wherein the first fraction and / or the second fraction contains sodium chloride.   The solid A preparation for hemodialysis according to any one of claims 1 to 8, wherein the first fraction contains sodium chloride.   The solid A preparation for hemodialysis according to any one of claims 1 to 9, wherein the first fraction and / or the second fraction contains glucose.   The solid A agent for hemodialysis according to any one of claims 1 to 10, wherein the second fraction contains glucose.   A two-agent type hemodialysis agent comprising the solid A agent for hemodialysis according to any one of claims 1 to 11 and a B agent for hemodialysis containing sodium bicarbonate. Solid A preparation for hemodialysis according to any one of claims 1 to 7, 10 and 11, which does not contain sodium chloride,
S-agent for hemodialysis containing sodium chloride,
B agent for hemodialysis containing sodium bicarbonate;
A three-drug hemodialysis agent. A first step of preparing a granulated product substantially containing only one of magnesium chloride and potassium chloride, containing calcium chloride, and containing neither acetic acid nor acetate; and the granulation obtained in the first step A method for producing a solid A agent for hemodialysis, comprising a second step of obtaining a solid A agent for hemodialysis comprising a product, acetic acid and acetate.