Agent a for hemodialysis and hemodialysis agent

Abstract

One purpose of the present invention is to provide an agent A for hemodialysis that has an excellent solubility.　This solid-state agent A for hemodialysis contains coated particles having coating layers that contain calcium chloride and / or magnesium chloride. Core particles of the coated particles contain potassium chloride. The coating layers substantially do not contain acetates.

Description

Hemodialysis agent A and hemodialysis agents

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

[0002] Currently, bicarbonate dialysis agents are mainly used as hemodialysis agents, and two types of hemodialysis agents are commonly available commercially: hemodialysis agent A, which contains numerous electrolyte components including sodium chloride and glucose, and hemodialysis agent B, which contains sodium bicarbonate. Conventionally, hemodialysis agent A has been classified into a liquid type containing electrolyte components in a concentrated liquid form and a solid type containing electrolyte components in a solid form, but the liquid type has been problematic in terms of transportation costs, storage space at hospitals, workability within 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-component type bicarbonate dialysis agent, agent A for hemodialysis contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, a pH adjuster, and glucose.

[0004] Furthermore, once solidification occurs, solid hemodialysis agents may aggregate and become insoluble when water is added to prepare the dialysis solution. In this case, insolubility refers to residual hemodialysis agents remaining when dissolving the hemodialysis agent to prepare the dialysis solution. The risk of insolubility increases with hemodialysis agents with slow dissolution rates. If residual hemodialysis agents remain during preparation of the dialysis solution, the electrolyte concentrations in the prepared dialysis solution will not reach the preset concentrations, resulting in concentration abnormalities. Dialysis using dialysis solution with such abnormal concentrations may prevent the body's electrolytes from being corrected within the normal range, potentially leading to serious electrolyte concentration abnormalities. To prevent this, hemodialysis agent dissolving devices and dialysis machines are equipped with safety devices, but activating such devices is undesirable in the first place. Therefore, to avoid insolubility, it is important to use formulations with good solubility (good dissolution rate). Existing dissolving devices must be designed to ensure that the entire amount of hemodialysis agent used is dissolved within the required dissolution time. An example of a dissolving device widely used in dialysis facilities is the fully automatic dissolving device DAD-50NX-ST (manufactured by Nikkiso Co., Ltd.), which has a dissolving time set to approximately 4 minutes. Another widely used dissolving device is the Agent A dissolving device AHI-502 (manufactured by DKK-TOA Corporation). This dissolving device employs a system in which a hemodialysis agent is gradually added to a predetermined amount of water stored in the device and the addition is automatically stopped when the dialysis solution reaches a predetermined electrical conductivity, and the dissolving time is set to approximately 9 minutes. If a hemodialysis agent with poor solubility (a slow dissolution rate) is used in this dissolving device, the remaining hemodialysis agent will dissolve slowly after the dialysis solution reaches the predetermined electrical conductivity and the addition of the hemodialysis agent is stopped, resulting in the supplied dialysis solution having a different electrical conductivity from the predetermined value, resulting in an abnormal concentration. Furthermore, poor dissolution of the hemodialysis agent can result in the inability to reach the specified conductivity within the set dissolution time, which may result in an alarm being triggered even if the correct amount is added to the dissolution device.Thus, in dissolving devices 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 impact on the quality of the obtained hemodialysis solution and the preparation efficiency.

[0005] Various techniques for increasing the solubility of hemodialysis agents have been investigated. 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 component selected from the group consisting of sodium chloride and potassium chloride as a main component, and a double salt layer containing a double salt formed by the reaction of sodium acetate and calcium chloride, another electrolyte composition, and a pH adjuster, and that the solid dialysis agent 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 for the development of a technology that can provide hemodialysis agent A with excellent solubility using a formulation technology different from these.

[0007] Japanese Patent Application Publication No. 9-40562

[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.

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

[0010] That is, the present invention provides the following aspects of the invention. Item 1. 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. 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. Item 9. A hemodialysis agent A according to any one of Items 1 to 7, further comprising glucose. Item 10. 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 11. 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 coating layer-forming solution in which calcium chloride and / or magnesium chloride is dissolved onto potassium chloride, and a second step of blending the coated particles obtained in the first step to produce a solid hemodialysis agent A.

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

[0012] Generally, the higher the solubility of a hemodialysis agent A, the lower its 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 reduce the volume per bag of hemodialysis agent A, thereby reducing transportation costs and storage space required in hospitals, etc.

[0013] Furthermore, in one embodiment of the hemodialysis agent A of the present invention, dust generation can be suppressed when preparing the hemodialysis solution, which not only reduces the risk of abnormalities in the dialysate concentration but also leads to an improvement in the working environment of medical personnel.

[0014] 1A and 1B are diagrams showing an outline of a dust measuring device used to measure the dust weight, in which FIG. 1A is a photograph showing the exterior of the dust measuring device, and FIG. 1B is a schematic diagram showing the configuration of the dust measuring device.

[0015] 1. Hemodialysis Agent A The hemodialysis agent A of the present invention comprises coated particles having a coating layer containing calcium chloride and / or magnesium chloride, wherein the core particles of the coated particles contain potassium chloride, and the coating layer is substantially free of acetate. By including coated particles of the specific structure, the hemodialysis agent A of the present invention achieves excellent solubility in water. The hemodialysis agent A of the present invention is 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] [Coated Particles] Coating Layer The coated particles used in the hemodialysis agent A of the present invention have a coating layer formed on the surface of a core particle, which will be described later, that is substantially free of acetate and contains calcium chloride and / or magnesium chloride.

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

[0019] The coating layer of the coated particles is substantially free of acetate. Here, "substantially free of acetate" means that the coating layer does not contain acetate, except in cases where acetate is inevitably mixed in during the manufacturing process. Acetate is a salt containing an acetate ion, such as an alkali metal salt of acetic acid or an alkaline earth metal salt of acetic acid. More specifically, examples include sodium acetate and a double salt formed 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 solution. The calcium chloride used to form the coating layer in the coated particles may be in either a hydrated or anhydrous state.

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

[0022] In the coated particles, the coating layer may contain either calcium chloride or magnesium chloride, or may contain both of them. A preferred embodiment of the coated particles of the present invention includes 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 but not magnesium chloride, and coated particles having a coating layer containing magnesium chloride but not calcium chloride, etc.

[0023] The content of calcium chloride contained in the coating layer of coated particles may be appropriately determined taking into account the total calcium ion concentration and total chloride ions in the prepared dialysis solution. Specifically, the content of calcium chloride contained in the coating layer may be determined 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 form is 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 form. In the present invention, the "anhydrous equivalent amount of the coated particles" refers to, when the components contained in the coated particles are hydrates, the value obtained by converting all components contained in the coated particles to anhydrous weight, excluding the weight of the water of crystallization of the hydrate (water molecules in the hydrate). Furthermore, the "anhydrous equivalent amount of calcium chloride" is a value obtained by converting the amount of calcium chloride into the weight of anhydrous calcium chloride excluding the weight of water of crystallization (water molecules in the hydrate) when the calcium chloride is in the form of a hydrate.

[0024] The content of magnesium chloride contained in the coating layer of coated particles may be appropriately determined taking into account the total magnesium ion concentration and total chloride ions in the prepared dialysis solution. Specifically, the content of magnesium chloride contained in the coating layer may be determined 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 amount of magnesium chloride contained in the coating layer in anhydrous equivalent form 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 form. In the present invention, the "anhydrous equivalent amount of coated particles" refers to, when the components contained in the coated particles are hydrates, the value obtained by converting all components contained in the coated particles to anhydrous weight, excluding the weight of the water of crystallization of the hydrate (water molecules in the hydrate). Furthermore, the "anhydrous equivalent amount of magnesium chloride" is a value obtained by converting the amount of magnesium chloride into the weight of anhydrous magnesium chloride 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 the coating layer of the coated particles contains both calcium chloride and magnesium chloride, the ratio thereof may be appropriately set taking into consideration the total calcium ion concentration and magnesium ion concentration in the hemodialysate to be prepared. 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, in terms of anhydrous, per 100 parts by weight of calcium chloride contained in the coating layer in terms of anhydrous.

[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 needed, within the range that does not impair the effects of the present invention.

[0027] In 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, in terms of anhydrous, per 100 parts by weight of the total amount of the coating layer in terms of anhydrous, can be 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. In the present invention, the "anhydrous equivalent amount of the coating layer" refers to, when a component contained in the coating layer is a hydrate, the value obtained by converting all components contained in the coating layer into the weight of the anhydrous, excluding the weight of the water of crystallization of the hydrate (water molecules in the 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 solely of 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" means that potassium chloride is not contained in the coating layer except when it is unavoidably mixed in or by-produced in the production process.

[0030] In addition, the coating layer of the coated particles may have either a single layer structure or a multi-layer 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 may be added as needed.

[0032] Furthermore, when the coating layer has a multilayer structure, the components forming the coating layer may be divided into two or more layers, and multiple coating layers may be laminated. When the coating layer has a multilayer structure, the number of coating layers may be, for example, 2 to 4 layers, preferably 2 or 3 layers, and more preferably 2 layers. Furthermore, for example, in one embodiment in which 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. Furthermore, for example, in another embodiment in which 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 (e.g., sodium chloride) that are optionally included.

[0033] Core 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 solution.

[0034] The content of potassium chloride contained as core particles in coated particles is not particularly limited, but may be, for example, 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, in terms of anhydrous potassium chloride contained as core particles per 100 parts by weight of coated particles in terms of anhydrous potassium chloride. In the present invention, the "amount of potassium chloride in terms of anhydrous potassium chloride" refers to, when potassium chloride is in the form of a hydrate, a value determined by converting the amount of potassium chloride into the weight of the anhydrous potassium chloride excluding the weight of water of crystallization (water molecules in the hydrate).

[0035] 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 ratio may be set so that the prepared hemodialysis fluid has a total potassium ion concentration of 0.5 to 3.0 mEq / L, a total magnesium ion concentration of 0.5 to 2.0 mEq / L, and a total calcium ion concentration of 1.5 to 4.5 mEq / L; preferably, a total potassium ion concentration of 1.5 to 2.5 mEq / L, a total magnesium ion concentration of 0.75 to 1.5 mEq / L, and a total calcium ion concentration of 2.5 to 3.5 mEq / 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, in anhydrous terms, per 100 parts by weight of potassium chloride forming the core particles.Furthermore, 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, in anhydrous terms, per 100 parts by weight of potassium chloride forming the core particles.

[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 in or by-produced in the manufacturing process.

[0037] Furthermore, in the coated particles, the core particles may contain, in addition to potassium chloride, as necessary, components of hemodialysis fluid such as other organic acid salts and / or inorganic salts that serve as sources of chloride ions, acetate ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc.; organic acids; glucose, etc., within the scope that does not impair the effects of the present invention. 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 the other component are aggregated as a core particle; a mixture of coated particles having potassium chloride as a core particle and coated particles having the other component as a core particle; or a mixture of coated particles having a particle in which potassium chloride and the other component are aggregated as a core particle, coated particles having potassium chloride as a core particle, and coated particles having the other 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, in terms of anhydrous equivalent, of potassium chloride per 100 parts by weight of the total amount of the core particles in terms of 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 core particles in all 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 water of crystallization of the hydrate (water molecules in the hydrate).

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

[0040] Furthermore, the ratio of the core particle to the coating layer in the coated particles may be appropriately set so that the components constituting the core particle and the coating layer have the desired ion concentrations 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 anhydrous weight of the coating layer may be 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 weight.

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

[0042] More specifically, the content of the coated 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 anhydrous equivalent of the coated particles per 100 parts by weight of the total amount of the electrolyte components contained in the hemodialysis agent A in anhydrous equivalent. In the present invention, the "anhydrous equivalent amount of the electrolyte components contained in the hemodialysis agent A" refers to, when the electrolyte components contained in the hemodialysis agent A are hydrates, the value obtained by converting the total electrolyte components contained in the hemodialysis agent A into anhydrous weight, excluding the weight of the water of crystallization of the hydrate (water molecules in the hydrate). The electrolyte components contained in the hemodialysis agent A also include organic acid salts, inorganic acid salts, organic acids, and inorganic acids contained in the hemodialysis agent A.

[0043] -Method for producing coated particlesThe 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 multilayer structure, two or more aqueous solutions for forming a coating layer corresponding to each layer of the coating layer may be prepared, and the two or more aqueous solutions for forming a coating layer may be 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, scale, etc. 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 wt %, preferably 20 to 45 wt %, 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 wt %, preferably 9 to 15 wt %, 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 determined 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 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] 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, the aqueous solution for forming a coating layer may be sprayed after at least a portion of the potassium chloride and at least a portion of the other components have been aggregated by, for example, heating and mixing.

[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 where at least one of magnesium chloride, calcium chloride, and potassium chloride is not attached to 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 determined 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 determined 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 anhydrous electrolyte components contained in hemodialysis agent A.

[0053] [Acetic Acid and Acetate Salt] 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 acetate. Among these acetates, alkali metal acetates are preferred, with sodium acetate being more preferred, from the viewpoints of safety and cost, based on a long track record of use. These acetates may be used alone or in combination of two or more. It is also preferred to use acetic acid and acetates as a mixture.

[0055] Furthermore, at least a portion of the acetic acid and acetate salt may be in the form of an alkali metal diacetate. The use of an alkali metal diacetate can further improve solubility and storage stability, reduce the acetic acid odor, and inhibit the decomposition of glucose when glucose is coexistent. An alkali metal diacetate is a complex (MH(C2H3O2)2; M represents an alkali metal atom) formed by complexing 1 mole of an alkali metal acetate salt with 1 mole of acetic acid, and 1 mole of an alkali metal diacetate provides 1 mole of acetate salt (alkali metal acetate salt) and 1 mole of acetic acid. Specific examples of the alkali metal diacetate salt 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 diacetate salts, sodium diacetate is preferred.

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

[0057] The molar ratio of acetic acid and acetate contained in the hemodialysis agent A 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, etc. However, it is desirable that the molar ratio of acetic acid contained in the hemodialysis agent A to acetate contained in the hemodialysis agent A 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. When an alkali metal diacetate salt is contained as the acetic acid and acetate salt, the molar ratio of acetic acid and acetate derived from 1 mole of the alkali metal diacetate salt is calculated as 1 mole of acetic acid and 1 mole of acetate. When a higher-order acetate compound is contained as the acetic acid and acetate salt, if the molar ratio of acetic acid:acetate in the higher-order acetate compound is 1:X, the molar ratio of acetic acid and acetate derived from 1 mole of the higher-order acetate compound is calculated as 1 mole of acetic acid and X moles of acetate.

[0058] When acetic acid and acetate salts are contained in the hemodialysis agent A of the present invention, their contents 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 salts are contained in the hemodialysis agent A of the present invention, their contents 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.

[0059] For example, the total amount of acetic acid and acetate salts in anhydrous equivalent 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 in hemodialysis agent A in anhydrous equivalent form. In the present invention, the "amount of acetic acid and acetate salts in anhydrous equivalent form" refers to, when the acetate salt is a hydrate, the value obtained by converting the total amount of acetic acid and acetate salts into the weight of the anhydrous form, excluding the weight of water of crystallization of the hydrate (water molecules in the hydrate).

[0060] [Citric acid and / or a salt thereof] In the hemodialysis agent A of the present invention, if the coated particles do not contain citric acid and / or a salt thereof, or if the citric acid and / or a salt thereof contained in the coated particles cannot satisfy the desired citrate ion concentration, it is preferable that citric acid and / or a salt thereof is further contained 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, alkali metal citrates are preferred, and sodium citrate is more preferred, from the viewpoints of safety and cost, based on a long history of use. Furthermore, 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 as to provide a total citrate ion concentration in the hemodialysis solution to be prepared of 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 equivalent is 0.5 to 50 parts by weight, preferably 1 to 15 parts by weight, and more preferably 2 to 5 parts by weight per 100 parts by weight of the total amount of the electrolyte components contained in hemodialysis agent A in anhydrous equivalent. In the present invention, the "amount of citric acid and / or its salts in anhydrous equivalent" 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 equivalent, 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, if the calcium chloride contained in the coated particles is insufficient to satisfy the total calcium ion concentration required in the prepared hemodialysis solution, calcium chloride can be further contained in addition to the coated particles. Furthermore, in the hemodialysis agent A of the present invention, if the magnesium chloride contained in the coated particles is insufficient to satisfy the total magnesium ion concentration required in the prepared hemodialysis solution, magnesium chloride can be further contained in addition to the coated 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 during storage.

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

[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 Components] In addition to the components described above, the hemodialysis agent A of the present invention may contain, if 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 calcium ion supply sources 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 organic acid salts of magnesium such as magnesium lactate, magnesium gluconate, magnesium succinate, magnesium malate, etc. These organic acid salts of magnesium 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 potassium ion supply source 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 selected appropriately depending on the types of ions to be contained in the final dialysis solution. Furthermore, the content of these organic acid salts in the hemodialysis agent A of the present invention is appropriately set depending on the concentrations of each ion to be contained in the dialysis solution to be prepared. Specifically, the content of the organic acid salts optionally contained in the hemodialysis agent A of the present invention may be appropriately set so that the final hemodialysis solution satisfies the ion concentrations shown in Table 1 below.

[0074]

[0075] The hemodialysis agent A of the present invention may contain a pH adjuster other than those described above, if necessary. pH adjusters that can be used in the hemodialysis agent A of the present invention are not particularly limited as long as they are acceptable as components of hemodialysis fluids, and examples include liquid acids such as hydrochloric acid, lactic acid, and gluconic acid, solid acids such as succinic acid, fumaric acid, malic acid, and glucono-delta-lactone, and sodium, potassium, calcium, and magnesium salts thereof. Among these pH adjusters, organic acids are preferably used. The pH adjusters 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 components contained separately from the coated particles are mixed in predetermined amounts. In the hemodialysis agent A of the present invention, each component other than the coated particles may be in the form of either a powder or granules, or a mixture of powder and granules.

[0078] [Tap Density] In one embodiment of the hemodialysis agent A of the present invention, the hemodialysis agent A has a high density, allowing the volume per bag of the hemodialysis agent A to be 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 Method 3 specified in Section "2. Tap Density" of "3.01 Bulk Density and Tap Density Measurement Method" in the Japanese Pharmacopoeia, 18th Edition.

[0079] [Production 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 Agent The hemodialysis agent A of the present invention is provided as a hemodialysis agent (hereinafter referred to as the hemodialysis agent of the present invention) in combination with a hemodialysis agent B containing sodium bicarbonate.

[0081] From the viewpoint of transportation and storage, the hemodialysis agent B is desirably in a solid form. 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 determined so that the bicarbonate ion concentration 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 is insufficient to achieve the required glucose concentration in the hemodialysis solution to be prepared, the hemodialysis agent B may contain glucose as needed. When the hemodialysis agent B contains glucose, the glucose content may be appropriately set so that the glucose concentration in the final hemodialysis solution is 0.1 to 2.5 g / L, preferably 1.0 to 1.5 g / L. However, the hemodialysis agent B desirably contains no electrolyte components other than sodium bicarbonate, and preferably contains components consisting essentially of sodium bicarbonate.

[0083] Furthermore, when the hemodialysis agent A of the present invention does not contain glucose, or when the glucose contained in the hemodialysis agent A of the present invention is insufficient to achieve the required glucose concentration in the prepared hemodialysis solution, the hemodialysis agent A of the present invention may be provided as hemodialysis agent A-1, in combination with hemodialysis agent A-2 comprising glucose. That is, the hemodialysis agent A of the present invention (including both cases with and without glucose) may be provided in combination with the hemodialysis agent B as a two-agent type hemodialysis agent, or the hemodialysis agent A-2 and the hemodialysis agent B as a three-agent type hemodialysis agent.

[0084] When the hemodialysis agent of the present invention includes the hemodialysis agent A-2, the glucose content in the hemodialysis agent A-2 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.

[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).

[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. Production of Hemodialysis Agent A [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 hybrid fluidized bed granulation coating apparatus (manufacturer: Freund Corporation, model number: SFC-15) and operated under conditions of rotor: 150 rpm, agitator: 210 rpm. After the hot air temperature (inlet air) reached approximately 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 the potassium chloride under conditions of rotor: 150 rpm, agitator: 210 rpm, ramp breaker: 669 rpm to form a coating layer. After spraying, the particles were dried under conditions of a hot air temperature (intake air) of approximately 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 125°C, yielding coated particles. The resulting coated particles contained potassium chloride as core particles, with calcium chloride and magnesium chloride forming a coating layer covering the surfaces of the core particles.

[0088] 158.5 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and sodium acetate anhydride in which the molar ratio of acetic acid:sodium acetate was 1:1.1, 108.8 g of sodium acetate anhydride, and 2.178 kg of sodium chloride 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.

[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 preparing the solid hemodialysis agent A.

[0090] [Example 3] Coated particles were obtained under the same conditions as in Example 1, except that the amount of calcium chloride dihydrate used was changed to 6.43 kg. Then, a solid hemodialysis agent A was obtained under the same conditions as in Example 1, except that the blending amount of coated particles was changed to 152.1 g. The coated particles contained in hemodialysis agent A had a structure in which potassium chloride was contained as core particles, and calcium chloride and magnesium chloride formed a coating layer covering the surfaces of the core particles.

[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 preparing the 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 had a structure in which potassium chloride was contained as core particles, and calcium chloride and magnesium chloride coated the surfaces of the core particles as coating layers.

[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 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 had a structure in which potassium chloride was contained as core particles, and calcium chloride and magnesium chloride coated the surfaces of the core particles as coating layers.

[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. 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 195.6 g. The coated particles contained in the hemodialysis agent A had a structure in which potassium chloride was contained as core particles, and calcium chloride and magnesium chloride coated the surfaces of the core particles as coating layers.

[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 preparing the 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 hybrid fluidized bed granulation coating apparatus (manufacturer: Freund Corporation, model number: SFC-15) and operated under conditions of rotor: 200 rpm, agitator: 300 rpm. After the hot air temperature (inlet air) reached approximately 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 the potassium chloride under conditions of rotor: 200 rpm, agitator: 300 rpm, ramp breaker: 669 rpm to form a coating layer. After spraying, the particles were dried under conditions of a hot air temperature (intake air) of approximately 190°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 120°C, yielding coated particles. The resulting coated particles contained potassium chloride as core particles, with calcium chloride and magnesium chloride forming a coating layer covering the surfaces of the core particles.

[0097] 169.6 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and sodium acetate anhydride in an acetic acid:sodium acetate molar ratio of 1:1.1, and 2.205 kg of sodium chloride 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.

[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 preparing the solid hemodialysis agent A.

[0099] Example 11 An aqueous solution for forming a coating layer was prepared by dissolving 6.43 kg of calcium chloride dihydrate and 3.56 kg of magnesium chloride hexahydrate in 5.55 kg of purified water. 6.00 kg of potassium chloride was placed in a hybrid fluidized bed granulation coating apparatus (manufacturer: Freund Corporation, model number: SFC-15) and operated under conditions of rotor: 150 rpm, agitator: 210 rpm. After the hot air temperature (inlet air) reached approximately 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 the potassium chloride under conditions of rotor: 150 rpm, agitator: 210 rpm, ramp breaker: 669 rpm to form a coating layer. After spraying, the particles were dried under conditions of a hot air temperature (intake air) of approximately 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 120°C, yielding coated particles. The resulting coated particles contained potassium chloride as core particles, with calcium chloride and magnesium chloride forming a coating layer covering the surfaces of the core particles.

[0100] 159.9 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and anhydrous sodium acetate in an acetic acid:sodium acetate molar ratio of 1:1.1, and 2.205 kg of sodium chloride 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.

[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 sieve (openings 2.36 mm) 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 preparing the solid hemodialysis agent A.

[0103] Example 14 An aqueous solution for forming a coating layer was prepared by dissolving 9.01 kg of calcium chloride dihydrate and 5.34 kg of magnesium chloride hexahydrate in 8.33 kg of purified water. 6.00 kg of potassium chloride was placed in a hybrid fluidized bed granulation coating apparatus (manufacturer: Freund Corporation, model number: SFC-15) and operated under conditions of rotor: 200 rpm, agitator: 300 rpm. After the hot air temperature (inlet air) reached approximately 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 the potassium chloride under conditions of rotor: 150 rpm, agitator: 210 rpm, ramp breaker: 669 rpm to form a coating layer. After spraying, the particles were dried under conditions of a hot air temperature (intake air) of approximately 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 125°C, yielding coated particles. The resulting coated particles contained potassium chloride as core particles, with calcium chloride and magnesium chloride forming a coating layer covering the surfaces of the core particles.

[0104] 203.5 g of the obtained coated particles, 105.2 g of a mixture of acetic acid and anhydrous sodium acetate in an acetic acid:sodium acetate molar ratio of 1:1.1, and 2,205 kg of sodium chloride 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.

[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 preparing the 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 sieve (openings 2.36 mm) 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 sieve (openings 2.36 mm) 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 sieve (openings 2.36 mm) 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 sieve (openings 2.36 mm) 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 sieve (openings 2.36 mm) to obtain a solid hemodialysis agent A.

[0111] Example 21 An aqueous solution for forming a coating layer was prepared by dissolving 6.43 kg of calcium chloride dihydrate and 3.56 kg of magnesium chloride hexahydrate in 4.63 kg of purified water. 6.53 kg of potassium chloride was placed in a hybrid fluidized bed granulation coating apparatus (manufacturer: Freund Corporation, model number: SFC-15) and operated under conditions of rotor: 150 rpm, agitator: 210 rpm. After the hot air temperature (inlet air) reached approximately 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 the potassium chloride under conditions of rotor: 150 rpm, agitator: 210 rpm, ramp breaker: 669 rpm to form a coating layer. After spraying, the particles were dried under conditions of a hot air temperature (intake air) of approximately 160 to 165°C and a rotor (rotor: 150 rpm, agitator: 210 rpm, lamp breaker: 669 rpm) until the product temperature reached 125°C, yielding coated particles. The resulting coated particles contained potassium chloride as core particles, with calcium chloride and magnesium chloride forming a coating layer covering the surfaces of the core particles.

[0112] 165.2 g of the obtained coated particles, 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 sieve (openings 2.36 mm) to obtain 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. 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 hemodialysis agent A had a structure in which potassium chloride was contained as core particles, and calcium chloride and magnesium chloride formed a coating layer covering the surfaces of the core particles.

[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 sieve (openings 2.36 mm) 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 sieve (openings 2.36 mm) 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, all heated to 70°C, were placed in a double-barrel agitator mixer (steam heating), and 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 while stirring. The mixture was then sized 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-barrel agitator mixer (steam heating) and heated with stirring until the content temperature reached 73°C. 16.24 kg of calcium chloride was added to this mixture and mixed. After the calcium chloride addition, the content became slightly more white. Further heating and mixing was continued while maintaining the content temperature at 70°C or higher, resulting in a unique viscosity of the content, with the particles adhering to each other and the entire content taking on a rice cake-like appearance. Therefore, the resulting content could not be subjected to the subsequent sizing step, drying step, or step of adding sodium chloride and acetic acid, 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 L of pure water, each having an average particle size of approximately 350 μm, were placed in a double-barrel agitator mixer (steam heating) and heated with stirring until the content temperature reached 70°C. 907 g of calcium chloride was added to this mixture and mixed. 15 minutes after the addition of calcium chloride, the content became slightly more white. Further heating and mixing while maintaining the content temperature at 70°C caused the content to develop a unique viscosity, and the particles began to adhere to each other. The content was then removed and sized. 9.29 kg of the mixture 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 Hemodialysis Agent A 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), the amount of solid hemodialysis agent A (equivalent to one bag of solid hemodialysis agent A) 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] Measurement was carried out in accordance with Method 3 specified in "2. Tap Density" of "3.01 Bulk Density and Tap Density Measurement Method" of the 18th Edition of the Japanese Pharmacopoeia. Using a powder property evaluation device (manufacturer: Hosokawa Micron Corporation, model number: Powder Tester PT-X), the "packed bulk density" setting was selected, and a cylinder (inner diameter 2.2 cm, height 3.2 cm) for tap density measurement was attached to the top of the cup, and the cup capacity was 10 cm. 3Under conditions of a 1700 μm mesh sieve, a vibration time of 30 seconds, and an amplitude of 0.5 mm, hemodialysis agent A (sample) was dropped into the cylinder through a 1700 μm mesh sieve vibrating at an amplitude of 0.5 mm, filling the cylinder to approximately 80% of its capacity. Tapping was started in this state at 60 times / min, and 200 taps were performed. During tapping, when the sample in the cylinder was compressed to approximately 20% of its capacity, the sample was dropped into the cylinder again through a 1700 μm mesh sieve vibrating at an amplitude of 0.5 mm, according to the display on the device, to replenish the cylinder with sample to approximately 80% of its capacity. After tapping was completed, the cylinder was removed, the raised sample on the cup was leveled off, and the weight of the cup containing the sample was measured. The weight of the empty cup was subtracted from this weight to determine the weight of the powder in the cup. After the measurement, the tube was reattached, the sample was filled up 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 measured powder weights obtained after 200 and 400 taps exceeded 2%, the tap density was measured by tapping another 200 times each until the difference between two consecutive measurements became less than 2%. When the difference between two consecutive measurements became less than 2%, the tap density was measured by subtracting 1 cm from the last measured powder weight. 3 The powder weight per unit area was calculated, and the tap density (g / mL) was determined.

[0122] [Dust Weight] A dust measuring device having the structure shown in Figure 1 was prepared. The dust measuring device comprises a rectangular acrylic box 1 (size: height approximately 36 cm, width approximately 31 cm, depth approximately 33 cm), and is provided on the ceiling with an openable inlet 3 into which solid hemodialysis agent A 2 can be introduced, a suction unit 4 for suctioning dust inside the acrylic box 1, and a pressure gauge 5 for measuring the pressure inside the acrylic box 1. One end of a suction tube 42 equipped with a dust-collecting filter 41 (10 µm) is connected to the suction unit 4, and the other end of the suction tube 42 is connected to an aspirator 43. 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 agent A shown in the "Amount of agent A (g) to be dissolved in 350 L" column in Table 3 was introduced into the acrylic box 1 through the introduction port 3. After the introduction was completed, the introduction port 3 was closed, and after 5 minutes, the filter 41 was recovered. The weight (mg) of dust collected on the filter 41 was measured.

[0123] 2-2. Evaluation Results Table 2 shows the theoretical values ​​(values ​​calculated from the blending amounts) of the ratio of calcium chloride in the coated particles to potassium chloride in the coated particles and the ratio of magnesium chloride in the coated particles to potassium chloride in the coated particles for each of the hemodialysis agents A of Examples 1, 3, 5, 6, 7, 9, 11, 14, 21, and 22. Tables 3 and 4 also show 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 agents A of Examples 1 to 24 and Comparative Examples 1 to 4 were dissolved in water in the amounts shown in the "Amount of agent A (g) to be dissolved in 350 L" column in Tables 3 and 4 to prepare a dialysis solution with a total volume of 350 L.

[0124]

[0125]

[0126]

[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] Hemodialysis agents A (Examples 1 to 24) containing coated particles, each of which contained potassium chloride as a core particle and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle, exhibited a fast dissolution rate and excellent solubility. Furthermore, hemodialysis agents A containing the coated particles exhibited excellent solubility not only when they contained acetic acid and its salts as components other than the coated particles, but also when they contained citric acid.

[0129] In contrast, hemodialysis agent A (Comparative Examples 1, 2, and 4) containing coated particles in which sodium chloride was used as core particles and the surface of the particles was coated with potassium chloride, calcium chloride, magnesium chloride, and sodium acetate as a coating layer showed 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-A-9-40562).

[0130] In Comparative Example 3, an attempt was made to produce a two-layer solid dialysis agent A containing potassium chloride as core particles by utilizing the technology disclosed in Patent Document 1 (JP 9-40562 A). 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 containing 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 agents A of Examples 1, 2, 9, and 10 were high enough to enable the volume per bag of the hemodialysis agent A to be made compact. These results demonstrate that the hemodialysis agent A of the present invention can reduce its volume during distribution and storage, potentially reducing transportation costs and storage space.

[0133] Furthermore, the weight of dust generated during work was reduced for the hemodialysis agents A of Examples 2 and 9. These results demonstrate 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 a medical setting, and can also prevent the working environment from becoming worse.

[0134]

[0135]

[0136]

[0137] REFERENCE SIGNS LIST 1 Acrylic box 2 Solid hemodialysis agent A 3 Input part 4 Suction part 41 Filter 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, wherein a core particle of the coated particles contains potassium chloride, and the coating layer is substantially free of acetate.

2. The hemodialysis agent A according to claim 1, wherein the core particles are substantially free of sodium chloride.

3. The hemodialysis agent A according to claim 1 or 2, wherein the coating layer is substantially free of potassium chloride.

4. The hemodialysis agent A according to claim 1 or 2, wherein the coating layer contains calcium chloride and magnesium chloride.

5. The hemodialysis agent A according to claim 1 or 2, further comprising sodium chloride.

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

7. The hemodialysis agent A according to claim 1 or 2, further comprising citric acid and / or a citrate salt.

8. The hemodialysis agent A according to claim 1 or 2, further comprising glucose.

9. A bicarbonate-type hemodialysis agent comprising the hemodialysis agent A according to claim 1 or 2 and a hemodialysis agent B containing sodium bicarbonate.

10. A method for producing a solid hemodialysis agent A according to claim 1, 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.

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