Hemodialysis agent A and hemodialysis agents

Abstract

One object of the present invention is to provide an agent A for hemodialysis having excellent solubility. A solid hemodialysis agent A comprising coated particles having a coating layer containing calcium chloride and / or magnesium chloride, wherein core particles of the coated particles contain potassium chloride, and the coating layer is substantially free of acetate.

Description

[Technical field]

[0001] The present invention relates to a hemodialysis agent A having excellent solubility, and a hemodialysis agent containing said hemodialysis agent A. [Background technology]

[0002] Currently, bicarbonate dialysis agents are mainly used as hemodialysis agents, and two types of hemodialysis agents are generally available on the market: hemodialysis agent A, which contains many electrolyte components including sodium chloride and glucose, and hemodialysis agent B, which contains sodium bicarbonate. Conventionally, hemodialysis agent A was available in two types: liquid type, which contains electrolyte components in a concentrated liquid form, and solid type, which contains electrolyte components in a solid form, but the liquid type has been problematic in terms of transportation costs, storage space in hospitals, workability in hospitals, disposal of containers after use, etc., and in recent years, solid hemodialysis agent A has become mainstream in Japan.

[0003] In a typical two-agent type bicarbonate dialysis agent, agent A for hemodialysis contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, a pH adjuster, and glucose.

[0004] In addition, if solid hemodialysis agents solidify, they may aggregate and cause poor solubility when water is added to prepare the dialysis solution. In this case, poor solubility refers to the residual hemodialysis agent that is left undissolved when the hemodialysis agent is dissolved to prepare the dialysis solution, and the risk of poor solubility increases with hemodialysis agents that have a slow dissolution rate. If residual hemodialysis agents are left undissolved when preparing the hemodialysis solution, the electrolyte concentrations in the prepared dialysis solution do not reach the preset concentrations, and concentration abnormalities occur. If dialysis is performed using a dialysis solution with such concentration abnormalities, the electrolytes in the body will not be corrected to within the normal range, and in some cases, serious electrolyte concentration abnormalities may occur. In order to prevent this, the dissolving device for the hemodialysis agent and the dialysis device are equipped with a safety device, but it is not desirable to activate the safety device in the first place. Therefore, in order to prevent poor solubility, it is important to use a preparation with good solubility (good dissolution rate), and it is necessary to design the existing dissolving device so that the entire amount of the hemodialysis agent used is reliably dissolved within the dissolution time required for the existing dissolving device. As a dissolving device widely used in dialysis facilities, for example, there is a fully automatic dissolving device DAD-50NX-ST (manufactured by Nikkiso Co., Ltd.), and the dissolving time required for this dissolving device is set to about 4 minutes. In addition, the A agent dissolving device AHI-502 (manufactured by DKK Toa Co., Ltd.) is also widely used as a dissolving device, and this dissolving device adopts a system in which a hemodialysis agent is added little by little to a specified amount of water stored in the device, and the addition is automatically stopped when the dialysis fluid reaches a specified conductivity, and the dissolving time is set to about 9 minutes. If a hemodialysis agent with poor solubility (slow dissolving rate) is used in this dissolving device, the remaining hemodialysis agent dissolves with a delay after the dialysis fluid reaches a specified conductivity and the addition of the hemodialysis agent is stopped, so the supplied dialysis fluid has a value different from the specified conductivity, and an abnormality in concentration occurs. In addition, poor dissolution of the hemodialysis agent also leads to the failure to reach the specified conductivity within the set dissolving time, so that even if the appropriate amount is put into the dissolving device, it may be detected as an abnormality and an alarm may be issued.Thus, in the case of a dissolving device generally used in clinical practice, if the solubility of the hemodialysis agent used is poor, there is a concern that this will have a significant effect on the quality of the obtained hemodialysis fluid and the preparation efficiency.

[0005] Conventionally, various techniques for increasing the solubility of hemodialysis agents have been studied. For example, Patent Document 1 describes that a solid dialysis agent containing an electrolyte composition consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium acetate and a pH adjuster has a two-layer structure consisting of a core layer containing at least one selected from the group consisting of sodium chloride and potassium chloride as a main component, and a double salt layer containing a double salt generated by the reaction of sodium acetate and calcium chloride, other electrolyte composition, and a pH adjuster, and has excellent solubility.

[0006] The formulation technology described in Patent Document 1 can provide excellent solubility, but in order to further improve solubility (improve dissolution rate), improve quality, and respond to the diversification of formulation technologies, there is a need to develop a technology that can provide hemodialysis agent A with excellent solubility using a formulation technology different from these. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 9-40562 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a hemodialysis agent A having excellent solubility, and a hemodialysis agent containing said hemodialysis agent A. [Means for solving the problem]

[0009] The present inventors have conducted intensive research to solve the above problems, and have found that by incorporating coated particles, in which the surface of a potassium chloride-containing core particle is covered with a coating layer containing calcium chloride and / or magnesium chloride, into a hemodialysis agent A, the hemodialysis agent A can be provided with excellent solubility. The present invention was completed through further research based on this finding.

[0010] That is, the present invention provides the following aspects. Item 1. A solid hemodialysis agent A comprising coated particles having a coating layer containing calcium chloride and / or magnesium chloride, The core particle of the coating particle contains potassium chloride, the coating layer is substantially free of acetate; Solid hemodialysis agent A. Item 2. The hemodialysis agent A according to Item 1, wherein the core particles are substantially free of sodium chloride. Item 3. The hemodialysis agent A according to Item 1 or 2, wherein the coating layer is substantially free of potassium chloride. Item 4. The hemodialysis agent A according to any one of Items 1 to 3, wherein the coating layer contains calcium chloride and magnesium chloride. Item 5. The hemodialysis agent A according to any one of Items 1 to 4, further comprising sodium chloride. Item 6. The hemodialysis agent A according to any one of Items 1 to 5, further comprising acetic acid and an acetate salt. Item 7. The hemodialysis agent A according to any one of Items 1 to 5, further comprising citric acid and / or a citrate salt. Item 8. The hemodialysis agent A according to any one of Items 1 to 7, further comprising glucose. Item 9. A bicarbonate-type hemodialysis agent comprising the hemodialysis agent A according to any one of items 1 to 8 and a hemodialysis agent B containing sodium bicarbonate. Item 10. A method for producing a solid hemodialysis agent A according to any one of Items 1 to 8, comprising the following first and second steps: A first step of obtaining coated particles by spraying an aqueous solution for forming a coating layer in which calcium chloride and / or magnesium chloride is dissolved into potassium chloride; and The second step is to prepare a solid hemodialysis agent A by blending the coated particles obtained in the first step. Effect of the Invention

[0011] The hemodialysis agent A of the present invention has excellent solubility, and therefore when preparing hemodialysis fluid, it dissolves quickly to prevent residual agent from remaining in the hemodialysis fluid, while at the same time reducing the risk of abnormality in the dialysis fluid concentration, making it possible to stably and efficiently prepare a safe dialysis fluid.

[0012] Generally, the higher the solubility of the hemodialysis agent A, the lower the density tends to be. However, in one embodiment of the hemodialysis agent A of the present invention, excellent solubility and high density can be achieved, making it possible to make the volume per bag of the hemodialysis agent A compact, thereby reducing transportation costs and saving storage space in hospitals, etc.

[0013] In addition, in one embodiment of the hemodialysis agent A of the present invention, the generation of dust can be suppressed when preparing the hemodialysis fluid, which not only reduces the risk of abnormalities in the dialysis fluid concentration but also leads to an improvement in the working environment of medical personnel. [Brief description of the drawings]

[0014] [Figure 1] 1 is a diagram showing an outline of a dust measuring device used for measuring dust weight, in which A is a photograph showing the exterior of the dust measuring device, and B is a schematic diagram showing the configuration of the dust measuring device. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] 1. Hemodialysis agent A The hemodialysis agent A of the present invention is characterized in that it contains coated particles having a coating layer containing calcium chloride and / or magnesium chloride, the core particles of the coated particles contain potassium chloride, and the coating layer is substantially free of acetate. The hemodialysis agent A of the present invention achieves excellent solubility in water by containing the coated particles having the specific structure. The hemodialysis agent A of the present invention will be described in detail below.

[0016] In this specification, the term "coated particles" refers to coated particles having a coating layer containing calcium chloride and / or magnesium chloride.

[0017] [Coating particles] Coating layer The coated particles used in the hemodialysis agent A of the present invention have a coating layer that is substantially free of acetate and contains calcium chloride and / or magnesium chloride formed on the surface of a core particle described below.

[0018] In the present invention, the "coating layer" refers to a layer (sprayed coating layer) formed by spraying and drying an aqueous solution in which components forming the coating layer are dissolved on core particles. That is, granulated products in which other particles are attached to part of the surface of core particles while maintaining their shape (state of agglomerated granulated products) by wet granulation or dry granulation, etc., do not have a coating layer and are not considered coated particles.

[0019] The coating layer of the coated particle is substantially free of acetate. Here, "substantially free of acetate" means that acetate is not contained in the coating layer except when it is inevitably mixed in during the manufacturing process. Acetate is a salt having an acetate ion, such as an alkali metal salt of acetate or an alkaline earth metal salt of acetate, and more specifically, sodium acetate or a double salt produced by the reaction of sodium acetate and calcium chloride.

[0020] In the coated particles, calcium chloride forming the coating layer is a component that serves as a source of calcium ions and chloride ions in the hemodialysis fluid. In the coated particles, calcium chloride used to form the coating layer may be in either a hydrated or anhydrous state.

[0021] In the coated particles, magnesium chloride forming the coating layer is a component that serves as a source of magnesium ions and chloride ions in the hemodialysis solution. In the coated particles, the magnesium chloride used to form the coating layer may be in either a hydrated or anhydrous state.

[0022] In the coated particles, the coating layer may contain only one of calcium chloride and magnesium chloride, or may contain both of them. In a preferred embodiment of the coated particles of the present invention, there are coated particles having a coating layer containing both calcium chloride and magnesium chloride; a mixture of coated particles having a coating layer containing calcium chloride and not containing magnesium chloride and coated particles having a coating layer containing magnesium chloride and not containing calcium chloride, and the like.

[0023] In the coated particles, the content of calcium chloride contained in the coating layer may be appropriately set in consideration of the total calcium ion concentration and the total chloride ion of the prepared dialysis solution. Specifically, the content of calcium chloride contained in the coating layer may be set so that the total calcium ion concentration in the prepared hemodialysis solution is 1.5 to 4.5 mEq / L, preferably 2.5 to 3.5 mEq / L. For example, the amount of calcium chloride contained in the coating layer in anhydrous equivalent may be 10 to 94 parts by weight, preferably 10 to 80 parts by weight, more preferably 20 to 60 parts by weight, and even more preferably 30 to 50 parts by weight, per 100 parts by weight of the coated particles in anhydrous equivalent. In the present invention, the "anhydrous equivalent amount of the coated particles" refers to a value obtained by converting all the components contained in the coated particles into anhydrous weight, excluding the weight of the crystal water of the hydrate (water molecules in the hydrate), when the components contained in the coated particles are hydrates. In addition, the "anhydrous equivalent amount of calcium chloride" is the value obtained by converting the amount of calcium chloride in the form of a hydrate into the weight of the anhydrous form excluding the weight of water of crystallization (water molecules in the hydrate).

[0024] In the coated particles, the content of magnesium chloride contained in the coating layer may be appropriately set in consideration of the total magnesium ion concentration and the total chloride ion of the prepared dialysis solution. Specifically, the content of magnesium chloride contained in the coating layer may be set so that the total magnesium ion concentration in the prepared hemodialysis solution is 0.5 to 2.0 mEq / L; preferably 0.75 to 1.5 mEq / L. For example, the content of magnesium chloride contained in the coating layer in anhydrous equivalent is 1 to 85 parts by weight, preferably 10 to 60 parts by weight, more preferably 10 to 30 parts by weight, and even more preferably 10 to 20 parts by weight per 100 parts by weight of the coated particles in anhydrous equivalent. In the present invention, the "anhydrous equivalent amount of the coated particles" refers to a value obtained by converting all components contained in the coated particles into anhydrous weight, excluding the weight of the crystal water of the hydrate (water molecules in the hydrate), when the components contained in the coated particles are hydrates. In addition, the "anhydrous equivalent amount of magnesium chloride" is a value obtained by converting the amount of magnesium chloride into the weight of the anhydrous form excluding the weight of water of crystallization (water molecules in the hydrate) when the magnesium chloride is in the form of a hydrate.

[0025] When both calcium chloride and magnesium chloride are contained in the coating layer of the coated particles, the ratio between them may be appropriately set taking into consideration the total calcium ion concentration and magnesium ion concentration in the prepared hemodialysis fluid. For example, the magnesium chloride contained in the coating layer may be 10 to 75 parts by weight, preferably 15 to 65 parts by weight, and more preferably 20 to 55 parts by weight, calculated on an anhydrous basis, per 100 parts by weight of calcium chloride contained in the coating layer in an anhydrous basis.

[0026] In the coated particles, the coating layer may contain, in addition to calcium chloride and / or magnesium chloride, components of hemodialysis fluid such as other organic acid salts and / or inorganic salts that serve as sources of sodium ions, potassium ions, chloride ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc.; organic acids; and glucose, as necessary, within the scope that does not impair the effects of the present invention.

[0027] In the coated particles, the ratio of the total amount of calcium chloride and magnesium chloride to the entire coating layer is not particularly limited, but the total amount of calcium chloride and magnesium chloride is 20 parts by weight or more, preferably 30 parts by weight or more, more preferably 65 parts by weight or more, and even more preferably 80 parts by weight or more per 100 parts by weight of the total amount of the coating layer in anhydrous form. In the present invention, the "anhydrous amount of the coating layer" refers to a value obtained by converting all the components contained in the coating layer into the weight of the anhydrous form, excluding the weight of the crystal water of the hydrate (water molecules in the hydrate), when the component contained in the coating layer is a hydrate.

[0028] A preferred embodiment of the coated particles includes particles containing calcium chloride and magnesium chloride as a coating layer. A more preferred embodiment of the coated particles includes particles having a coating layer consisting of only calcium chloride and magnesium chloride.

[0029] Another preferred embodiment of the coated particles is one in which the coating layer is substantially free of potassium chloride. In the present invention, the phrase "the coating layer is substantially free of potassium chloride" refers to the absence of potassium chloride in the coating layer, except when potassium chloride is unavoidably mixed in or by-produced in the production process.

[0030] In the coated particles, the coating layer may have either a single layer structure or a multilayer structure.

[0031] When the coating layer has a single-layer structure, the single coating layer may be formed from a mixture containing calcium chloride and / or magnesium chloride and other components that are added as necessary.

[0032] In addition, when the coating layer has a multi-layer structure, the components forming the coating layer may be divided into two or more layers, and a plurality of coating layers may be laminated. In the case where the coating layer has a multi-layer structure, the number of layers of the coating layer may be, for example, 2 to 4 layers, preferably 2 or 3 layers, and more preferably 2 layers. In addition, for example, in an embodiment where the coating layer contains calcium chloride and magnesium chloride and has a two-layer structure, the surface of the core particle may be coated with a first coating layer containing calcium chloride and a second coating layer containing magnesium chloride in any order. In addition, for example, in another embodiment where the coating layer contains calcium chloride and magnesium chloride and has a two-layer structure, the surface of the core particle may be coated with a first coating layer containing calcium chloride and magnesium chloride, and then coated with a second coating layer containing other components (for example, sodium chloride, etc.) that are included as necessary.

[0033] ·Nuclear particles The coated particles contain potassium chloride. The potassium chloride may be in either a hydrated or anhydrous state. The potassium chloride contained in the coated particles is a component that serves as a source of potassium ions and chloride ions in the hemodialysis fluid.

[0034] In the coated particles, the content of potassium chloride contained as core particles is not particularly limited, but for example, the content of potassium chloride contained as core particles in anhydrous equivalent is 5 to 89 parts by weight, preferably 10 to 80 parts by weight, more preferably 20 to 70 parts by weight, and even more preferably 30 to 50 parts by weight per 100 parts by weight of the coated particles in anhydrous equivalent. In the present invention, the "content of potassium chloride in anhydrous equivalent" is a value obtained by converting the weight of potassium chloride into the weight of anhydrous equivalent excluding the weight of crystal water (water molecules in the hydrate) when potassium chloride is in the form of a hydrate.

[0035] In addition, the ratio of potassium chloride forming the core particles to calcium chloride and / or magnesium chloride forming the coating layer in the coated particles may be appropriately set in consideration of the total potassium ion concentration, total magnesium ion concentration, total calcium ion concentration, and total chloride ion concentration of the prepared dialysis fluid. Specifically, the total potassium ion concentration may be set to 0.5-3.0mEq / L, the total magnesium ion concentration to 0.5-2.0mEq / L, and the total calcium ion concentration to 1.5-4.5mEq / L in the prepared hemodialysis fluid; preferably, the total potassium ion concentration may be set to 1.5-2.5mEq / L, the total magnesium ion concentration to 0.75-1.5mEq / L, and the total calcium ion concentration to 2.5-3.5mEq / L. For example, the amount of calcium chloride forming the coating layer is 50 to 500 parts by weight, preferably 50 to 300 parts by weight, more preferably 60 to 200 parts by weight, and even more preferably 70 to 140 parts by weight, per 100 parts by weight of potassium chloride forming the core particles in terms of anhydrous. Also, the amount of magnesium chloride forming the coating layer is 1 to 100 parts by weight, preferably 5 to 80 parts by weight, more preferably 10 to 60 parts by weight, and even more preferably 20 to 50 parts by weight, per 100 parts by weight of potassium chloride forming the core particles in terms of anhydrous.

[0036] In a preferred embodiment of the coated particles, the core particles are substantially free of sodium chloride. Here, "substantially free of sodium chloride" means that the core particles do not contain sodium chloride except when it is unavoidably mixed or by-produced in the production process.

[0037] Furthermore, in the coated particles, the core particles may contain, as necessary, other organic acid salts and / or inorganic salts serving as sources of chloride ions, acetate ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc., other than potassium chloride, as long as the effects of the present invention are not impaired. When a component other than potassium chloride is contained as the core particle, the coated particle may be a coated particle having a particle in which potassium chloride and other components are aggregated as a core particle; a mixture of a coated particle having potassium chloride as a core particle and a coated particle having another component as a core particle; or a mixture of a coated particle having a particle in which potassium chloride and other components are aggregated as a core particle, a coated particle having potassium chloride as a core particle, and a coated particle having another component as a core particle.

[0038] In the coated particles, the ratio of potassium chloride in the core particles is not particularly limited, but may be 80 parts by weight or more, preferably 90 parts by weight or more, and more preferably 95 parts by weight or more, of potassium chloride in anhydrous equivalent per 100 parts by weight of the total amount of the core particles in anhydrous equivalent. In the present invention, the "anhydrous equivalent amount of the core particles" refers to the anhydrous equivalent amount of the total amount of the core particles in all the coated particles having a coating layer containing potassium chloride, and when the component contained in the core particles is a hydrate, it is a value obtained by converting all the components contained in the core particles into the weight of the anhydrous equivalent, excluding the weight of the crystallization water of the hydrate (water molecules in the hydrate).

[0039] A preferred embodiment of the coated particles includes core particles containing only potassium chloride.

[0040] In addition, the ratio of the core particle to the coating layer in the coated particle may be appropriately set so that the components constituting the core particle and the coating layer have the desired ion concentration in the prepared dialysis solution. Specifically, the ratio of the core particle to the coating layer may be set so that the total potassium ion concentration in the prepared hemodialysis solution is 0.5 to 3.0 mEq / L, the total calcium ion concentration is 1.5 to 4.5 mEq / L, and the total magnesium ion concentration is 0.5 to 2.0 mEq / L; preferably, the total potassium ion concentration is 1.5 to 2.5 mEq / L, the total calcium ion concentration is 2.5 to 3.5 mEq / L, and the total magnesium ion concentration is 0.75 to 1.5 mEq / L. For example, the amount of the coating layer in anhydrous equivalent is 10 to 300 parts by weight, preferably 20 to 200 parts by weight, and more preferably 100 to 180 parts by weight per 100 parts by weight of the core particle in anhydrous equivalent.

[0041] Coating particle content The content of the coated particles in the hemodialysis agent A of the present invention may be appropriately set so as to satisfy the total potassium ion concentration, total magnesium ion concentration, and total calcium ion concentration required in the hemodialysis solution to be prepared, taking into consideration the amount of potassium chloride, magnesium chloride, and / or calcium chloride contained in the coated particles. Specifically, the content of the coated particles in the hemodialysis agent A of the present invention may be set so that the total potassium ion concentration is 0.5 to 3.0 mEq / L, the total magnesium ion concentration is 0.5 to 2.0 mEq / L, and the total calcium ion concentration is 1.5 to 4.5 mEq / L, preferably the total potassium ion concentration is 1.5 to 2.5 mEq / L, the total magnesium ion concentration is 0.75 to 1.5 mEq / L, and the total calcium ion concentration is 2.5 to 3.5 mEq / L in the hemodialysis solution to be prepared.

[0042] More specifically, the content of the coating particles in the hemodialysis agent A of the present invention is 1 to 20 parts by weight, preferably 2 to 15 parts by weight, in terms of anhydrous of the coating particles per 100 parts by weight of the total amount of the electrolyte components contained in the hemodialysis agent A in terms of anhydrous. In the present invention, the "anhydrous equivalent amount of the electrolyte components contained in the hemodialysis agent A" refers to a value obtained by converting the total electrolyte components contained in the hemodialysis agent A into the weight of anhydrous, excluding the weight of the crystal water of the hydrate (water molecules in the hydrate), when the electrolyte components contained in the hemodialysis agent A are hydrates. In addition, the electrolyte components contained in the hemodialysis agent A include organic acid salts, inorganic acid salts, organic acids, and inorganic acids in the hemodialysis agent A.

[0043] ·Method of manufacturing coating particles The coated particles are produced by spraying or spraying and then drying an aqueous solution for forming a coating layer, in which calcium chloride and / or magnesium chloride is dissolved, onto core particles containing potassium chloride. When the coating layer has a multi-layer structure, two or more aqueous solutions for forming a coating layer are prepared according to the respective layers of the coating layer, and the two or more aqueous solutions for forming a coating layer are sprayed stepwise onto the core particles containing potassium chloride while drying, or sprayed and then dried.

[0044] The concentration of calcium chloride and / or magnesium chloride in the aqueous solution for forming a coating layer may be appropriately set depending on the type and scale of the production equipment. From the viewpoint of suppressing unevenness in the coating layer, the concentration of calcium chloride in the aqueous solution for forming a coating layer is 15 to 50% by weight, preferably 20 to 45% by weight, calculated as anhydrous calcium chloride. From the same viewpoint, the concentration of magnesium chloride in the aqueous solution for forming a coating layer is 5 to 25% by weight, preferably 9 to 15% by weight, calculated as anhydrous magnesium chloride.

[0045] The amount of the aqueous solution for forming a coating layer to be sprayed onto the core particles may be appropriately set depending on the concentration of calcium chloride and / or magnesium chloride in the aqueous solution for forming a coating layer, the ratio of core particles to the coating layer in the coated particles to be produced, etc.

[0046] The temperature conditions when spraying the aqueous solution for forming a coating layer onto the core particles are not particularly limited, but may be, for example, 15 to 300°C, preferably 60 to 250°C, and more preferably 100 to 200°C.

[0047] In order to spray the aqueous solution for forming a coating layer onto the core particles, for example, a fluidized granulation coating device such as a tumbling fluidized granulation coating device may be used.

[0048] In addition, when the core particles contain components other than potassium chloride, the aqueous solution for forming a coating layer may be sprayed onto potassium chloride and the other components. Alternatively, for example, at least a part of the potassium chloride and at least a part of the other components may be aggregated by heating and mixing, and then the aqueous solution for forming a coating layer may be sprayed.

[0049] [Sodium chloride] The hemodialysis agent A of the present invention preferably contains sodium chloride in addition to the coated particles.

[0050] In one embodiment of the hemodialysis agent A of the present invention, sodium chloride is in a state in which at least one of magnesium chloride, calcium chloride, and potassium chloride is not attached or coated on the surface.

[0051] When sodium chloride is contained in the hemodialysis agent A of the present invention, its content may be appropriately set so as to satisfy the total sodium ion concentration required in the hemodialysis solution to be prepared, taking into consideration the amount of sodium chloride contained as necessary in the coated particles, the contents of other sodium salts, etc. Specifically, the content of sodium chloride in the hemodialysis agent A of the present invention may be set so that the total sodium ion concentration of the hemodialysis solution to be prepared is 90 to 120 mEq / L, preferably 100 to 110 mEq / L.

[0052] For example, the total amount of sodium chloride is 40 to 95 parts by weight, preferably 55 to 90 parts by weight, per 100 parts by weight of the total amount of the electrolyte components contained in the hemodialysis agent A in terms of anhydrous basis.

[0053] [Acetic acid and acetate salts] The hemodialysis agent A of the present invention may contain acetic acid and an acetate salt in addition to the coated particles.

[0054] The acetic acid may be glacial acetic acid. The acetate is not particularly limited as long as it is acceptable as a component of a hemodialysis solution, and examples thereof include alkali metal acetates such as sodium acetate and potassium acetate; and alkaline earth metal acetates such as calcium acetate and magnesium acetate. These acetates may be anhydrous acetates. Among these acetates, from the viewpoints of safety and cost based on a long history of use, alkali metal acetates are preferred, and sodium acetate is more preferred. These acetates may be used alone or in combination of two or more, and acetic acid and acetates are preferably used in the form of a mixture.

[0055] In addition, at least a part of the acetic acid and the acetate may be in the form of an alkali metal diacetate. By using an alkali metal diacetate, it is possible to further improve the solubility and storage stability, reduce the acetic acid odor, and suppress the decomposition of glucose when glucose is coexisted. An alkali metal diacetate is a complex (MH(C2H3O2)2; M represents an alkali metal atom) in which 1 mole of an alkali metal acetate is complexed with 1 mole of acetic acid, and 1 mole of acetate (alkali metal acetate) and 1 mole of acetic acid are supplied from 1 mole of an alkali metal diacetate. Specific examples of the alkali metal diacetate used in the present invention include sodium diacetate and potassium diacetate. These alkali metal diacetate salts may be used alone or in combination of two or more. Among the alkali metal diacetates, sodium diacetate is preferred.

[0056] At least a portion of the acetic acid and acetate may be in the form of a higher acetate compound, which is a compound formed by combining acetic acid (a primary compound) and acetate (a primary compound) with each other.

[0057] The molar ratio of acetic acid and acetate contained in the hemodialysis A agent of the present invention is not particularly limited and may be appropriately set based on the pH range to be imparted to the hemodialysis solution, but it is desirable that the molar ratio of acetic acid contained in the hemodialysis A agent to acetate contained in the hemodialysis A agent is set to 1:0.5-10, preferably 1:0.5-6.0, more preferably 1:0.5-3.0, and even more preferably 1:0.7-2.0. Here, when an alkali metal diacetate salt is contained as the acetic acid and acetate salt, the molar ratio of acetic acid and acetate salt derived from 1 mole of the alkali metal diacetate salt is calculated as 1 mole of acetic acid and 1 mole of acetate salt. When a high-order acetate compound is contained as the acetic acid and acetate salt, if the molar ratio of acetic acid:acetate salt in the high-order acetate compound is 1:X, the molar ratio of acetic acid and acetate salt derived from 1 mole of the high-order acetate compound is calculated as 1 mole of acetic acid and X moles of acetate salt.

[0058] When acetic acid and acetate are contained in the hemodialysis agent A of the present invention, the content thereof may be appropriately set so as to satisfy the total acetate ion concentration and pH required in the hemodialysis solution to be prepared. Specifically, when acetic acid and acetate are contained in the hemodialysis agent A of the present invention, the content thereof may be appropriately set so that the total acetate ion concentration in the hemodialysis solution to be prepared is 0.5 to 12 mEq / L, preferably 1.5 to 10 mEq / L, more preferably 2 to 10 mEq / L, and even more preferably 10 mEq / L, 8 mEq / L, 6 mEq / L, or 4.2 mEq / L, etc.

[0059] For example, the total amount of acetic acid and acetate salts in anhydrous form is 0.1 to 25 parts by weight, preferably 0.3 to 20 parts by weight, and more preferably 4 to 12 parts by weight, per 100 parts by weight of the total amount of electrolyte components contained in the hemodialysis agent A in anhydrous form. In the present invention, the "amount of acetic acid and acetate salts in anhydrous form" refers to a value obtained by converting the total amount of acetic acid and acetate salts into the weight of anhydrous form, excluding the weight of the water of crystallization of the hydrate (water molecules in the hydrate), when the acetate salt is a hydrate.

[0060] [Citric acid and / or its salts] In the hemodialysis agent A of the present invention, when the coated particles do not contain citric acid and / or a salt thereof, or when the citric acid and / or a salt thereof contained in the coated particles cannot satisfy the desired citrate ion concentration, it is preferable that the agent A further contains citric acid and / or a salt thereof in addition to the coated particles.

[0061] The citrate salt is not particularly limited as long as it is acceptable as a component of a hemodialysis solution, and examples thereof include alkali metal citrates such as sodium citrate and potassium citrate; and alkaline earth metal citrates such as calcium citrate and magnesium citrate. Among these citrate salts, from the viewpoints of safety and cost based on a long history of use, alkali metal citrates are preferred, and sodium citrate is more preferred. These citrate salts may be used alone or in combination of two or more.

[0062] When citric acid and / or a salt thereof is contained in the hemodialysis agent A of the present invention, the content thereof may be appropriately set so as to satisfy the total citrate ion concentration and pH required in the hemodialysis solution to be prepared, taking into consideration the presence or absence of citric acid and / or a salt thereof, the content thereof, etc. Specifically, when citric acid and / or a salt thereof is contained in the hemodialysis agent A of the present invention, the content thereof may be appropriately set so that the total citrate ion concentration in the hemodialysis solution to be prepared is 0.1 to 18 mEq / L, preferably 0.5 to 3.5 mEq / L or 1 to 4 mEq / L, more preferably 1 to 3.3 mEq / L.

[0063] More specifically, the total amount of citric acid and / or its salts in anhydrous form per 100 parts by weight of the total amount of electrolyte components contained in the hemodialysis agent A in anhydrous form is 0.5 to 50 parts by weight, preferably 1 to 15 parts by weight, and more preferably 2 to 5 parts by weight. In the present invention, the "anhydrous amount of citric acid and / or its salts" refers to, when the citric acid salt is a hydrate, the value obtained by converting the total amount of citric acid and its salts into the weight of the anhydrous form, excluding the weight of the water of crystallization of the hydrate (water molecules in the hydrate).

[0064] [Calcium chloride and magnesium chloride] In the hemodialysis agent A of the present invention, when the calcium chloride contained in the coating particles cannot satisfy the total calcium ion concentration required in the hemodialysis solution to be prepared, calcium chloride can be further contained in addition to the coating particles.In addition, in the hemodialysis agent A of the present invention, when the magnesium chloride contained in the coating particles cannot satisfy the total magnesium ion concentration required in the hemodialysis solution to be prepared, magnesium chloride can be further contained in addition to the coating particles.

[0065] [Glucose] The hemodialysis agent A of the present invention may contain glucose for the purpose of maintaining the blood glucose level of the patient. When the hemodialysis agent A of the present invention contains glucose, it is also possible to suppress the decomposition of glucose due to storage.

[0066] When glucose is contained in the hemodialysis agent A of the present invention, its content may be appropriately set so as to satisfy the glucose concentration required in the hemodialysis fluid to be prepared. Specifically, the glucose content in the hemodialysis agent A of the present invention may be appropriately set so as to provide a glucose concentration of 0.1 to 2.5 g / L, preferably 1.0 to 2.0 g / L in the hemodialysis fluid to be prepared.

[0067] For example, the amount of glucose is 0.5 to 60 parts by weight, preferably 10 to 25 parts by weight, per 100 parts by weight of the total amount of the electrolyte components contained in the hemodialysis agent A in terms of anhydrous form.

[0068] [Other ingredients] In addition to the above-mentioned components, the hemodialysis agent A of the present invention may contain, as necessary, other organic acid salts that serve as sources of calcium ions, magnesium ions, sodium ions, potassium ions, chloride ions, acetate ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc.

[0069] Examples of compounds that serve as a supply source of calcium ions include calcium salts of organic acids such as calcium lactate, calcium gluconate, calcium succinate, calcium malate, etc. These calcium salts of organic acids may be used alone or in combination of two or more.

[0070] Examples of compounds that serve as a supply source of magnesium ions include magnesium organic acid salts such as magnesium lactate, magnesium gluconate, magnesium succinate, magnesium malate, etc. These magnesium organic acid salts may be used alone or in combination of two or more.

[0071] Examples of compounds that serve as a source of sodium ions include organic acid salts of sodium such as sodium lactate, sodium gluconate, sodium succinate, sodium malate, etc. These organic acid salts of sodium may be used alone or in combination of two or more.

[0072] Examples of compounds that serve as a supply source of potassium ions include potassium organic acid salts such as potassium lactate, potassium gluconate, potassium succinate, potassium malate, etc. These potassium organic acid salts may be used alone or in combination of two or more.

[0073] These organic acid salts may be appropriately selected depending on the types of ions to be contained in the finally prepared dialysis solution. In addition, the content of these organic acid salts in the hemodialysis agent A of the present invention may be appropriately set depending on the concentration of each ion to be contained in the finally prepared dialysis solution. Specifically, the content of the organic acid salts, which are optionally contained in the hemodialysis agent A of the present invention, may be appropriately set so that the finally prepared hemodialysis solution satisfies the concentration of each ion shown in Table 1 below.

[0074] [Table 1]

[0075] The hemodialysis agent A of the present invention may contain a pH regulator other than the above, if necessary. The pH regulator usable in the hemodialysis agent A of the present invention is not particularly limited as long as it is acceptable as a component of hemodialysis fluid, and examples thereof include liquid acids such as hydrochloric acid, lactic acid, gluconic acid, etc., solid acids such as succinic acid, fumaric acid, malic acid, glucono delta lactone, etc., and their sodium, potassium, calcium, magnesium salts, etc. Among these pH regulators, organic acids are preferably used. The pH regulator may be used alone or in combination of two or more.

[0076] [pH characteristics] The hemodialysis agent A of the present invention may be adjusted so that the pH of the hemodialysis solution when prepared is 6 to 8, preferably 7.1 to 7.6.

[0077] [form] The hemodialysis agent A of the present invention is a solid preparation in which the coated particles and a component contained separately from the coated particles are mixed in a predetermined amount. In the hemodialysis agent A of the present invention, each component other than the coated particles may be either a powder or a granule, or may be a mixture of a powder and a granule.

[0078] [Tap Density] In one embodiment of the hemodialysis agent A of the present invention, the agent A has a high density, and the volume per bag of the agent A can be made compact. From the viewpoint of providing such advantages to the hemodialysis agent A of the present invention, the tap density of the hemodialysis agent A of the present invention is preferably 0.8 to 2.0 g / mL, and more preferably 1.0 to 1.5 g / mL. In the present invention, the tap density of the hemodialysis agent A is a value measured according to the third method specified in "2. Tap density" of "3.01 Measurement method of bulk density and tap density" of the Japanese Pharmacopoeia, 18th Edition.

[0079] [Manufacturing method] The hemodialysis agent A of the present invention is produced by mixing the coated particles with predetermined amounts of each component contained separately from the coated particles.

[0080] 2. Hemodialysis agents The hemodialysis agent A of the present invention is provided in combination with a hemodialysis agent B containing sodium bicarbonate as a hemodialysis agent (hereinafter referred to as the hemodialysis agent of the present invention).

[0081] The hemodialysis agent B is desirably in a solid form from the viewpoint of transportation and storage. Specific examples of the form of the solid hemodialysis agent B include powder and granules. The amount of the hemodialysis agent B used may be appropriately set so that the bicarbonate ion in the prepared hemodialysis solution is 20 to 40 mEq / L, preferably 25 to 35 mEq / L.

[0082] When the hemodialysis agent A of the present invention does not contain glucose, or when the glucose contained in the hemodialysis agent A cannot satisfy the glucose concentration required in the hemodialysis solution to be prepared, the hemodialysis agent B may contain glucose as necessary. When the hemodialysis agent B contains glucose, the content of glucose may be appropriately set so that the glucose concentration in the finally prepared hemodialysis solution is 0.1 to 2.5 g / L, preferably 1.0 to 1.5 g / L. However, the hemodialysis agent B desirably does not contain any electrolyte components other than sodium bicarbonate, and it is preferable that the components contained are substantially composed of sodium bicarbonate.

[0083] In addition, when the hemodialysis A agent of the present invention does not contain glucose, or when the glucose contained in the hemodialysis A agent of the present invention cannot satisfy the glucose concentration required in the hemodialysis fluid to be prepared, the hemodialysis A agent of the present invention may be provided as the hemodialysis A-1 agent and further combined with the hemodialysis A-2 agent consisting of glucose. That is, the hemodialysis A agent of the present invention (including both cases containing or not containing glucose) may be provided in combination with the hemodialysis B agent as a two-agent type hemodialysis agent, or the hemodialysis A-2 agent and the hemodialysis B agent as a three-agent type hemodialysis agent.

[0084] In the hemodialysis agent of the present invention, when the hemodialysis agent A-2 is provided, the glucose content in the hemodialysis agent A-2 may be appropriately set so that the glucose concentration in the finally prepared hemodialysis fluid is 0.1 to 2.5 g / L, preferably 1.0 to 1.5 g / L.

[0085] The hemodialysis agent of the present invention is used to prepare a bicarbonate hemodialysis solution. Specifically, the bicarbonate hemodialysis solution is prepared by dissolving and diluting each agent contained in the hemodialysis agent of the present invention in a predetermined amount of water (preferably purified water). EXAMPLES

[0086] The present invention will be specifically described below with reference to examples, but the present invention should not be construed as being limited to the following examples.

[0087] Test Example 1: Production and evaluation of hemodialysis agent A 1. Manufacture of Agent A for Hemodialysis [Example 1] 7.07 kg of calcium chloride dihydrate and 3.56 kg of magnesium chloride hexahydrate were dissolved in 4.63 kg of purified water to prepare an aqueous solution for forming a coating layer. 5.22 kg of potassium chloride was placed in a composite fluidized bed granulation coating device (manufacturer: Freund Corporation, model number: SFC-15) and operated under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm). After the hot air temperature (intake air) reached about 150 to 160°C and the product temperature reached 120°C or higher, the entire amount of the aqueous solution for forming a coating layer was sprayed onto potassium chloride under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) to form a coating layer. After spraying, the product was dried under conditions of a hot air temperature (intake air) of about 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 125°C, to obtain coated particles. The obtained coated particles have a structure in which potassium chloride is contained as core particles, and calcium chloride and magnesium chloride cover the surfaces of the core particles as a coating layer.

[0088] 158.5 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and anhydrous sodium acetate in which the molar ratio of acetic acid:sodium acetate was 1:1.1, 108.8 g of anhydrous sodium acetate, and 2.178 kg of sodium chloride were placed in a plastic bag and mixed, and then sieved through an 8 mesh sieve (mesh opening 2.36 mm) to obtain a solid hemodialysis agent A.

[0089] [Example 2] A solid hemodialysis agent A was obtained under the same conditions as in Example 1, except that 437.5 g of glucose was added to the plastic bag and mixed when obtaining a solid hemodialysis agent A.

[0090] [Example 3] Except for changing the amount of calcium chloride dihydrate used to 6.43 kg, coated particles were obtained under the same conditions as in Example 1. Except for changing the amount of coated particles to 152.1 g, solid hemodialysis agent A was obtained under the same conditions as in Example 1. The coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is contained as a core particle, and calcium chloride and magnesium chloride are coated on the surface of the core particle as a coating layer.

[0091] [Example 4] A solid hemodialysis agent A was obtained under the same conditions as in Example 3, except that 437.5 g of glucose was added to the plastic bag and mixed when obtaining a solid hemodialysis agent A.

[0092] [Example 5] Coated particles were obtained under the same conditions as in Example 1, except that 9 kg of calcium chloride dihydrate was dissolved in 5.34 kg of purified water to prepare an aqueous solution for forming a coating layer. Then, a solid hemodialysis agent A was obtained under the same conditions as in Example 1, except that the amount of coated particles was changed to 177.8 g and 437.5 g of glucose was added and mixed. The coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is contained as a core particle, and calcium chloride and magnesium chloride cover the surface of the core particle as a coating layer.

[0093] [Example 6] Coated particles were obtained under the same conditions as in Example 1, except that 6.43 kg of calcium chloride dihydrate and 5.34 kg of magnesium chloride hexahydrate were dissolved in 6.94 kg of purified water to prepare an aqueous solution for forming a coating layer. Then, a solid hemodialysis agent A was obtained under the same conditions as in Example 1, except that the amount of the coated particles was changed to 169.9 g and 437.5 g of glucose was added and mixed. The coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is contained as a core particle, and calcium chloride and magnesium chloride cover the surface of the core particle as a coating layer.

[0094] [Example 7] Coated particles were obtained under the same conditions as in Example 1, except that 9 kg of calcium chloride dihydrate and 5.34 kg of magnesium chloride hexahydrate were dissolved in 6.94 kg of purified water to prepare an aqueous solution for forming a coating layer. Then, a solid hemodialysis agent A was obtained under the same conditions as in Example 1, except that the amount of the coated particles was changed to 195.6 g. The coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is contained as a core particle, and calcium chloride and magnesium chloride cover the surface of the core particle as a coating layer.

[0095] [Example 8] A solid hemodialysis agent A was obtained under the same conditions as in Example 7, except that 437.5 g of glucose was added to the plastic bag and mixed when obtaining a solid hemodialysis agent A.

[0096] [Example 9] 12.04 kg of calcium chloride dihydrate and 7.68 kg of magnesium chloride hexahydrate were dissolved in 9.99 kg of purified water to prepare an aqueous solution for forming a coating layer. 10.80 kg of potassium chloride was placed in a composite fluidized bed granulation coating device (manufacturer: Freund Corporation, model number: SFC-15) and operated under the condition of a rotor (rotor: 200 rpm, agitator: 300 rpm). After the hot air temperature (intake air) reached about 160 to 190°C and the product temperature reached 120°C or higher, the entire amount of the aqueous solution for forming a coating layer was sprayed onto potassium chloride under the condition of a rotor (rotor: 200 rpm, agitator: 300 rpm, lamp breaker: 669 rpm) to form a coating layer. After spraying, the product was dried under conditions of a hot air temperature (intake air) of about 190°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 120°C, obtaining coated particles. The obtained coated particles have a structure in which potassium chloride is contained as core particles, and calcium chloride and magnesium chloride cover the surfaces of the core particles as a coating layer.

[0097] 169.6 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and anhydrous sodium acetate in a molar ratio of acetic acid:sodium acetate of 1:1.1, and 2.205 kg of sodium chloride were placed in a plastic bag and mixed, and then sieved through an 8 mesh sieve (mesh opening 2.36 mm) to obtain a solid hemodialysis agent A.

[0098] [Example 10] A solid hemodialysis agent A was obtained under the same conditions as in Example 9, except that 525 g of glucose was added to the plastic bag and mixed when obtaining a solid hemodialysis agent A.

[0099] [Example 11] 6.43 kg of calcium chloride dihydrate and 3.56 kg of magnesium chloride hexahydrate were dissolved in 5.55 kg of purified water to prepare an aqueous solution for forming a coating layer. 6.00 kg of potassium chloride was placed in a composite fluidized bed granulation coating device (manufacturer: Freund Corporation, model number: SFC-15) and operated under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm). After the hot air temperature (intake air) reached about 150 to 160°C and the product temperature reached 120°C or higher, the entire amount of the aqueous solution for forming a coating layer was sprayed onto potassium chloride under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) to form a coating layer. After spraying, the product was dried under conditions of a hot air temperature (intake air) of about 160-165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 120°C, to obtain coated particles. The obtained coated particles have a structure in which potassium chloride is contained as core particles, and calcium chloride and magnesium chloride cover the surfaces of the core particles as a coating layer.

[0100] 159.9 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and anhydrous sodium acetate in a molar ratio of acetic acid:sodium acetate of 1:1.1, and 2.205 kg of sodium chloride were placed in a plastic bag and mixed, and then sieved through an 8 mesh sieve (openings 2.36 mm) to obtain a solid hemodialysis agent A.

[0101] [Example 12] 169.6 g of the coated particles prepared under the conditions described in Example 9, 2,205 g of sodium chloride, 56.0 g of anhydrous citric acid, and 525 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (openings 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0102] [Example 13] A solid hemodialysis agent A was obtained under the same conditions as in Example 11, except that 525 g of glucose was added to the plastic bag and mixed when obtaining a solid hemodialysis agent A.

[0103] [Example 14] 9.01 kg of calcium chloride dihydrate and 5.34 kg of magnesium chloride hexahydrate were dissolved in 8.33 kg of purified water to prepare an aqueous solution for forming a coating layer. 6.00 kg of potassium chloride was placed in a composite fluidized bed granulation coating device (manufacturer: Freund Corporation, model number: SFC-15) and operated under the condition of a rotor (rotor: 200 rpm, agitator: 300 rpm). After the hot air temperature (intake air) reached about 150 to 165°C and the product temperature reached 120°C or higher, the entire amount of the aqueous solution for forming a coating layer was sprayed onto potassium chloride under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) to form a coating layer. After spraying, the product was dried under conditions of a hot air temperature (intake air) of about 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 125°C, to obtain coated particles. The obtained coated particles have a structure in which potassium chloride is contained as core particles, and calcium chloride and magnesium chloride cover the surfaces of the core particles as a coating layer.

[0104] 203.5 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and anhydrous sodium acetate in a molar ratio of acetic acid:sodium acetate of 1:1.1, and 2,205 kg of sodium chloride were placed in a plastic bag and mixed, and then sieved through an 8 mesh sieve (mesh opening 2.36 mm) to obtain a solid hemodialysis agent A.

[0105] [Example 15] A solid hemodialysis agent A was obtained under the same conditions as in Example 14, except that 525 g of glucose was added to the plastic bag and mixed when obtaining a solid hemodialysis agent A.

[0106] [Example 16] 158.5 g of the coated particles prepared under the conditions described in Example 1, 2,178 g of sodium chloride, 56.0 g of anhydrous citric acid, and 437.5 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (mesh opening 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0107] [Example 17] 158.5 g of the coated particles prepared under the conditions described in Example 1, 2,178 g of sodium chloride, 22.4 g of anhydrous citric acid, and 437.5 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (mesh opening 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0108] [Example 18] 158.5 g of the coated particles prepared under the conditions described in Example 1, 2,178 g of sodium chloride, 89.7 g of anhydrous citric acid, and 437.5 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (openings 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0109] [Example 19] 152.1 g of the coated particles prepared under the conditions described in Example 3, 2,178 g of sodium chloride, 53.8 g of anhydrous citric acid, and 437.5 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (2.36 mm opening) sieve to obtain a solid hemodialysis agent A.

[0110] [Example 20] 177.8 g of the coated particles prepared under the conditions described in Example 5, 2,178 g of sodium chloride, 53.8 g of anhydrous citric acid, and 437.5 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (mesh opening 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0111] [Example 21] 6.43 kg of calcium chloride dihydrate and 3.56 kg of magnesium chloride hexahydrate were dissolved in 4.63 kg of purified water to prepare an aqueous solution for forming a coating layer. 6.53 kg of potassium chloride was placed in a composite fluidized bed granulation coating device (manufacturer: Freund Corporation, model number: SFC-15) and operated under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm). After the hot air temperature (intake air) reached about 150 to 165°C and the product temperature reached 120°C or higher, the entire amount of the aqueous solution for forming a coating layer was sprayed onto potassium chloride under the condition of a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) to form a coating layer. After spraying, the product was dried under conditions of a hot air temperature (intake air) of about 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 125°C, to obtain coated particles. The obtained coated particles have a structure in which potassium chloride is contained as core particles, and calcium chloride and magnesium chloride cover the surfaces of the core particles as a coating layer.

[0112] The obtained coated particles (165.2 g), sodium chloride (2,178 g), anhydrous citric acid (53.8 g) and glucose (437.5 g) were placed in a plastic bag, mixed and then sieved through an 8 mesh sieve (openings 2.36 mm) to obtain a solid hemodialysis agent A.

[0113] [Example 22] Coated particles were obtained under the same conditions as in Example 21, except that the amount of calcium chloride dihydrate used was changed to 9.00 kg. Then, a solid hemodialysis agent A was obtained under the same conditions as in Example 21, except that the amount of coated particles was changed to 190.9 g. The coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is contained as a core particle, and calcium chloride and magnesium chloride are coated on the surface of the core particle as a coating layer.

[0114] [Example 23] 169.6 g of the coated particles prepared under the conditions described in Example 9, 2,205 g of sodium chloride, 22.4 g of anhydrous citric acid, and 525 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (openings 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0115] [Example 24] 169.6 g of the coated particles prepared under the conditions described in Example 9, 2,205 g of sodium chloride, 89.7 g of anhydrous citric acid, and 525 g of glucose were placed in a plastic bag, mixed, and then sieved through an 8 mesh (openings 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0116] [Comparative Example 1] 4,000 kg of sodium chloride, 98.3 kg of potassium chloride, and 327.4 kg of anhydrous sodium acetate heated to 70°C were placed in a double-tube stirring mixer (steam heating), and while stirring, an aqueous solution of 134.2 kg of calcium chloride dihydrate and 67.8 kg of magnesium chloride hexahydrate dissolved in 81.4 kg of purified water was added and mixed. After that, the mixture was granulated and dried to obtain a mixture. 42 g of acetic acid was added to 2508.5 g of the obtained mixture and mixed to obtain a solid hemodialysis agent A.

[0117] [Comparative Example 2] 42 g of acetic acid was added to 2508.5 g of the mixture prepared under the conditions described in Comparative Example 1 and mixed, and then 437.5 g of glucose was added and mixed to obtain a solid hemodialysis agent A.

[0118] [Comparative Example 3] 12.3 kg of potassium chloride, 9.54 kg of magnesium chloride, 40.68 kg of anhydrous sodium acetate, and 9.4 kg of purified water were placed in a double-tube stirring mixer (steam heating), and heated while stirring until the temperature of the contents reached 73°C. 16.24 kg of calcium chloride was added to this mixture and mixed. After the calcium chloride was added, the contents became slightly whiter, and when heating and mixing were continued while maintaining the temperature of the contents at 70°C or higher, a unique viscosity was developed in the contents, the particles of the contents adhered to each other, and the entire contents took on a mochi-like shape. Therefore, the obtained contents could not be subjected to the subsequent granulation process, drying process, and sodium chloride and acetic acid addition process, and a solid hemodialysis agent A could not be obtained.

[0119] [Comparative Example 4] 25.02 kg of sodium chloride, 615 g of potassium chloride, 427 g of magnesium chloride, 2,034 g of sodium acetate, and 0.47 liters of pure water, all with an average particle size of about 350 μm, were placed in a double-tube stirring mixer (steam heating), and heated while stirring until the temperature of the contents reached 70°C. 907 g of calcium chloride was added to this mixture and mixed. 15 minutes after the addition of calcium chloride, the contents became slightly whiter, and when heating and mixing were continued while maintaining the temperature of the contents at 70°C, a unique viscosity was developed in the contents, and the particles of the contents began to adhere to each other. The contents were then removed and sized, after which 9.29 kg was dried, and 159 g of acetic acid was added and mixed. 350 g of glucose was added to 2,506 g of this mixture and mixed to obtain a solid hemodialysis agent A.

[0120] 2. Evaluation of Agent A for Hemodialysis 2-1.Evaluation method [Dissolution rate] 9 kg of water (24-25°C) was placed in a 12.7 L beaker, and while stirring with a stirrer (stirring speed 160 rpm), solid hemodialysis agent A (equivalent to one bag of solid hemodialysis agent A) in the amount shown in the column "Amount of agent A to be dissolved in 350 L (g)" in Table 3 was added, and the time (seconds) from addition until complete dissolution was measured.

[0121] [Tap Density] The measurement was carried out in accordance with the third method stipulated in "2. Tapped density" of "3.01 Bulk density and tapped density measurement method" of the 18th revised Japanese Pharmacopoeia. Using a powder property evaluation device (manufacturer: Hosokawa Micron Corporation, model number: Powder Tester PT-X), the "packed bulk density" of the device was selected, a cylinder for tapped density measurement (inner diameter 2.2 cm, height 3.2 cm) was attached to the top of the cup, and the cup capacity was 10 cm. 3 Under the conditions of a sieve with a mesh size of 1700 μm, a vibration time of 30 seconds, and an amplitude of 0.5 mm, the hemodialysis agent A (sample) was dropped into the cylinder through a sieve with a mesh size of 1700 μm vibrating at an amplitude of 0.5 mm, and the sample was filled up to about 80% of the cylinder's capacity. In this state, tapping was started at 60 times / min, and 200 taps were performed. During tapping, when the sample in the cylinder was compressed to about 20% of the cylinder's capacity, the sample was dropped into the cylinder again through a sieve with a mesh size of 1700 μm vibrating at an amplitude of 0.5 mm, according to the display of the device, to refill the cylinder with the sample up to about 80% of the cylinder's capacity. After tapping was completed, the cylinder was removed, the raised sample on the cup was scraped off, and the weight of the cup containing the sample was measured. The weight of the empty cup was subtracted from this weight to obtain the powder weight in the cup. After the measurement, the cylinder was reattached, the sample was filled to about 80% of the capacity, and tapping was performed another 400 times under the same conditions to determine the powder weight in the cup. If the difference between the two powder weight measurements obtained after 200 and 400 taps exceeded 2%, tap density was measured by tapping another 200 times each until the difference between two consecutive measurements was less than 2%. When the difference between two consecutive measurements was less than 2%, the tap density was measured by measuring the difference between the powder weight and the measured powder weight by 1 cm. 3 The powder weight per unit area was calculated, and the tap density (g / mL) was obtained.

[0122] [Dust weight] A dust measuring device having the structure shown in FIG. 1 was prepared. The dust measuring device is a rectangular acrylic box 1 (size: height about 36 cm, width about 31 cm, depth about 33 cm), and is provided with an openable input part 3 for inputting a solid hemodialysis A agent 2, an suction part 4 for sucking dust in the acrylic box 1, and a pressure gauge 5 for measuring the pressure inside the acrylic box 1, on the ceiling surface. One end of a suction tube 42 to which a filter 41 (10 μm) for collecting dust is attached is connected to the suction part 4, and an aspirator 43 is connected to the other end of the suction tube 42. The operation of the aspirator 43 was started, and the pressure inside the acrylic box 1 was adjusted to -10 kPa. While maintaining the pressure inside the acrylic box 1 at -10 kPa, the amount of hemodialysis A agent described in the column "Amount of agent A to be dissolved in 350 L (g)" in Table 3 was input from the input part 3 to the acrylic box 1, and after the input was completed, the input part 3 was closed, and the filter 41 was collected after 5 minutes. The weight (mg) of dust trapped on the filter 41 was measured.

[0123] 2-2.Evaluation results For each of the hemodialysis A agents of Examples 1, 3, 5, 6, 7, 9, 11, 14, 21, and 22, the theoretical values ​​(values ​​calculated from the blending amounts) of the ratio of calcium chloride in the coated particles to the potassium chloride in the coated particles and the ratio of magnesium chloride in the coated particles to the potassium chloride in the coated particles are shown in Table 2. In addition, the theoretical concentrations (values ​​calculated from the blending amounts) of sodium ions, potassium ions, magnesium ions, calcium ions, acetic acid, and citric acid when the hemodialysis A agents of Examples 1 to 24 and Comparative Examples 1 to 4 were dissolved in water in the amounts shown in the column "Amount of A agent (g) to be dissolved in 350 L" in Tables 3 and 4 to prepare a dialysis solution of 350 L in total are shown in Tables 3 and 4.

[0124] [Table 2]

[0125] [Table 3]

[0126] [Table 4]

[0127] Tables 5 to 7 show the results of evaluating the dissolution rate (dissolution time), tap density, and dust weight of each hemodialysis agent A.

[0128] The hemodialysis agent A (Examples 1 to 24) containing coated particles in which potassium chloride is contained as a core particle and calcium chloride and magnesium chloride are coated on the surface of the core particle as a coating layer had a high dissolution rate and excellent solubility. Furthermore, the hemodialysis agent A containing the coated particles showed excellent solubility not only when it contained acetic acid and its salts as a component other than the coated particles, but also when it contained citric acid.

[0129] In contrast, the hemodialysis agent A (Comparative Examples 1, 2, and 4) containing coated particles in which sodium chloride is used as a core particle and the surface of the coated particles is coated with potassium chloride, calcium chloride, magnesium chloride, and sodium acetate as a coating layer had a slow dissolution rate and poor solubility. The hemodialysis agent A of Comparative Example 4 was produced by the same production method as Example 1 shown in Patent Document 1 (JP Patent Publication 9-40562).

[0130] In addition, in Comparative Example 3, an attempt was made to produce a two-layered solid dialysis agent A containing potassium chloride as core particles by utilizing the technology disclosed in Patent Document 1 (JP Patent Publication 40562 / 1997). However, the particles aggregated and dissolved during the production process, resulting in a sticky texture, and it was not possible to obtain a granulated product that could be used as a solid hemodialysis agent A.

[0131] From the above results, it was confirmed that hemodialysis agent A, which contains coated particles in which the surface of core particles containing potassium chloride is covered with a coating layer containing calcium chloride and magnesium chloride, has an excellent dissolution rate.

[0132] It was also confirmed that the tap densities of the hemodialysis agent A of Examples 1, 2, 9, and 10 were high enough to make the volume per bag of the hemodialysis agent A compact. This result revealed that the hemodialysis agent A of the present invention can reduce the volume during distribution and storage, and may reduce transportation costs and storage space.

[0133] Furthermore, the weight of dust generated during work was small for the hemodialysis agents A of Examples 2 and 9. From these results, it became clear that the hemodialysis agent A of the present invention can prevent the electrolyte concentration of the hemodialysis solution from deviating from the set value and becoming an abnormal value when preparing the hemodialysis solution in the medical field, and can also prevent the deterioration of the work environment.

[0134] [Table 5]

[0135] [Table 6]

[0136] [Table 7] [Explanation of symbols]

[0137] 1 Acrylic Box 2. Solid hemodialysis agent A 3 Input section 4 Suction part 41 Filters 42 Suction tube 43 Aspirator 5. Pressure gauge

Claims

1. a solid hemodialysis agent A comprising coated particles having a coating layer containing calcium chloride and / or magnesium chloride; the core particles of the coated particles contain potassium chloride and are substantially free of sodium chloride; the coating layer is substantially free of acetate; Solid hemodialysis agent A.

2. A solid hemodialysis agent A comprising coated particles having a coating layer containing calcium chloride and / or magnesium chloride, the core particles of the coating particles contain potassium chloride, the coating layer is substantially free of acetate and potassium chloride; Solid hemodialysis agent A.

3. A solid hemodialysis agent A comprising coated particles having a coating layer containing calcium chloride and / or magnesium chloride, acetic acid, and an acetate salt, the core particles of the coating particles contain potassium chloride, the coating layer is substantially free of acetate; Solid hemodialysis agent A.

4. A solid hemodialysis agent A containing coated particles having a coating layer containing calcium chloride and / or magnesium chloride, and glucose, the core particles of the coating particles contain potassium chloride, the coating layer is substantially free of acetate; Solid hemodialysis agent A.

5. The hemodialysis agent A according to any one of claims 2 to 4, wherein the core particles are substantially free of sodium chloride.

6. The hemodialysis agent A according to claim 1 , 3 or 4, wherein the coating layer is substantially free of potassium chloride.

7. The hemodialysis agent A according to any one of claims 1 to 4, wherein the coating layer contains calcium chloride and magnesium chloride.

8. The hemodialysis agent A according to any one of claims 1 to 4, further comprising sodium chloride.

9. The hemodialysis agent A according to claim 1, 2 or 4, further comprising acetic acid and an acetate salt.

10. The hemodialysis agent A according to any one of claims 1 to 4, further comprising citric acid and / or a citrate salt.

11. The hemodialysis agent A according to any one of claims 1 to 3, further comprising glucose.

12. A bicarbonate-type hemodialysis agent comprising the hemodialysis agent A according to any one of claims 1 to 4 and a hemodialysis agent B containing sodium bicarbonate.

13. A method for producing the solid hemodialysis agent A according to claim 1 or 2, comprising the following first and second steps: A first step of obtaining coated particles by spraying an aqueous solution for forming a coating layer in which calcium chloride and / or magnesium chloride is dissolved onto potassium chloride; and The second step is to compound the coated particles obtained in the first step to produce a solid hemodialysis agent A.

14. A method for producing the solid hemodialysis agent A according to claim 3, comprising the following first and second steps: A first step of obtaining coated particles by spraying an aqueous solution for forming a coating layer in which calcium chloride and / or magnesium chloride is dissolved onto potassium chloride; and A second step of producing a solid hemodialysis agent A by blending the coated particles obtained in the first step with acetic acid and an acetate salt.

15. A method for producing the solid hemodialysis agent A according to claim 4, comprising the following first and second steps: A first step of obtaining coated particles by spraying an aqueous solution for forming a coating layer in which calcium chloride and / or magnesium chloride is dissolved onto potassium chloride; and The second step is to blend the coated particles obtained in the first step with glucose to produce a solid hemodialysis agent A.

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