Agent A for hemodialysis and agent for hemodialysis

Abstract

One purpose of the present invention is to provide an agent A for hemodialysis, which has excellent solubility. A solid agent A for hemodialysis, which contains coated particles having a coating layer containing calcium chloride and / or magnesium chloride, the core particles of the coated particles containing potassium chloride, and the coating layer containing substantially no acetate.

Description

Technical Field

[0001] The present invention relates to an agent A for hemodialysis having excellent solubility, and a hemodialysis agent containing the agent A for hemodialysis. Background Art

[0002] At present, bicarbonate dialysis agents are mainly used as hemodialysis agents, and hemodialysis agents of two dosage forms, which are formed by combining hemodialysis agent A containing a large amount of electrolyte components including sodium chloride and glucose and hemodialysis agent B containing sodium bicarbonate, are sold on the market as common hemodialysis agents. In the past, hemodialysis agent A had a liquid type containing electrolyte components in the form of a concentrated liquid, and a solid type containing electrolyte components in a solid state, but the liquid type has attracted attention in terms of transportation costs, storage space in hospitals, etc., operability in hospitals, and disposal of containers after use. In recent years, solid hemodialysis agent A has become mainstream in Japan.

[0003] The hemodialysis agent A of the general two-dose bicarbonate dialysis agent contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, a pH adjuster, and glucose.

[0004] In addition, if the solid hemodialysis agent solidifies, there is also the following situation: when adding water to prepare the dialysate, it aggregates and causes poor solubility. Poor solubility in this case refers to the dissolution residue produced when the hemodialysis agent is dissolved in order to prepare the dialysate. For the hemodialysis agent with a slow dissolution rate, the risk of poor solubility increases. If the dissolution residue of the hemodialysis agent occurs when the hemodialysis agent is prepared, the concentration of each electrolyte in the prepared dialysate will not become the pre-set concentration, resulting in abnormal concentration. If the dialysate with this abnormal concentration is used for dialysis, the electrolyte in the body cannot be corrected to the normal range, and serious electrolyte concentration abnormality may be caused according to the situation. In order to prevent this situation, a safety device is equipped in the dissolving device and the dialysis device of the hemodialysis agent, but it is not originally desired to make the safety device work from the beginning. Therefore, in order not to cause poor solubility, it is important to use a preparation with good solubility (good dissolution rate), and it is necessary to design the whole amount of the hemodialysis agent used to be reliably dissolved within the required time for dissolution set by the existing dissolving device. As a dissolution device widely used in dialysis facilities, for example, there is a fully automatic dissolution device DAD-50NX-ST (manufactured by Nikkiso Co., Ltd.), in which the time required for dissolution is set to about 4 minutes. In addition, the A-agent dissolution device AHI-502 (manufactured by DKK-TOA CORPORATION) is also widely used as a dissolution device. In this dissolution device, a system is adopted 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 dialysate reaches a specified conductivity. The time required for dissolution is set to about 9 minutes. When a hemodialysis agent with poor solubility (slow dissolution rate) is used in this dissolution device, after the addition of the hemodialysis agent is stopped when the dialysate reaches a specified conductivity, the residual hemodialysis agent is dissolved slowly, so the supplied dialysate becomes a value different from the specified conductivity, resulting in abnormal concentration. In addition, since poor dissolution of the hemodialysis agent may result in failure to reach the specified conductivity within the set dissolution time, even if an appropriate amount is added to the dissolution device, it may be detected as abnormal and an alarm may be issued. Thus, in the dissolution device commonly used in clinical practice, if the solubility of the hemodialysis agent used is poor, there is a concern that the quality and preparation efficiency of the obtained hemodialysis fluid will be greatly affected.

[0005] In the past, various studies have been conducted on technologies that can improve the solubility of hemodialysis agents. For example, Patent Document 1 states that in a solid hemodialysis agent comprising an electrolyte composition formed of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate and a pH regulator, a solid hemodialysis agent having a two-layer structure can have excellent solubility, wherein the two-layer structure comprises: a core layer comprising at least one selected from the group consisting of sodium chloride and potassium chloride as a main component; and a double salt layer comprising a double salt generated by the reaction of sodium acetate and calcium chloride, other electrolyte compositions and a pH regulator.

[0006] According to the formulation technology described in Patent Document 1, it is possible to have excellent solubility. However, in order to cope with further improvement in solubility (increase in dissolution rate), improvement in quality, diversification of formulation technology, etc., it is desired to develop a technology that can make Agent A for hemodialysis have excellent solubility through a formulation technology different from them.

[0007] Prior art literature

[0008] Patent Literature

[0009] Patent Document 1: Japanese Patent Application Laid-Open No. 9-40562 Summary of the invention

[0010] Problems to be solved by the invention

[0011] An object of the present invention is to provide an agent A for hemodialysis having excellent solubility, and a hemodialysis agent containing the agent A for hemodialysis.

[0012] Means for solving problems

[0013] The inventors of the present application have conducted intensive research to solve the above-mentioned problems, and as a result, have found that by adding coated particles obtained by coating the surface of core particles containing potassium chloride with a coating layer containing calcium chloride and / or magnesium chloride to hemodialysis agent A, hemodialysis agent A can have excellent solubility. The present invention was completed through further repeated research based on the above-mentioned findings.

[0014] That is, the present invention provides the inventions of the following disclosed aspects.

[0015] Item 1. A solid hemodialysis agent A, comprising coated particles, wherein the coated particles have a coating layer comprising calcium chloride and / or magnesium chloride.

[0016] The core particle of the coated particle comprises potassium chloride,

[0017] The coating layer contains substantially no acetate.

[0018] Item 2. The agent A for hemodialysis according to Item 1, wherein the core particles contain substantially no sodium chloride.

[0019] Item 3. The agent A for hemodialysis according to Item 1 or 2, wherein the coating layer does not substantially contain potassium chloride.

[0020] Item 4. The agent A for hemodialysis according to any one of Items 1 to 3, wherein the coating layer contains calcium chloride and magnesium chloride.

[0021] Item 5. The agent A for hemodialysis according to any one of Items 1 to 4, further comprising sodium chloride.

[0022] Item 6. The agent A for hemodialysis according to any one of Items 1 to 5, further comprising acetic acid and an acetate.

[0023] Item 7. The agent A for hemodialysis according to any one of Items 1 to 5, further comprising citric acid and / or a citrate.

[0024] Item 8. The agent A for hemodialysis according to any one of Items 1 to 7, further comprising glucose.

[0025] 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.

[0026] Item 10. The method for producing the solid agent A for hemodialysis according to any one of Items 1 to 8, comprising the following first and second steps:

[0027] In a first step, a coating layer-forming aqueous solution in which calcium chloride and / or magnesium chloride is dissolved is sprayed onto potassium chloride to obtain coated particles; and

[0028] In the second step, the coated particles obtained in the first step are mixed to produce a solid agent A for hemodialysis.

[0029] Effects of the Invention

[0030] The hemodialysis agent A of the present invention has excellent solubility, and therefore dissolves rapidly when preparing hemodialysis fluid, thereby preventing dissolved residues and reducing the risk of abnormal dialysate concentration, thereby enabling stable and efficient preparation of safe dialysate.

[0031] In addition, generally speaking, the higher the solubility of Agent A for hemodialysis, the lower the density tends to be. However, in one embodiment of Agent A for hemodialysis of the present invention, it is possible to have both excellent solubility and high density, so that the volume of each bag of Agent A for hemodialysis can be made compact, which can reduce transportation costs and storage space in hospitals, etc.

[0032] In one embodiment of the hemodialysis agent A of the present invention, the generation of dust can be suppressed even when preparing the hemodialysis fluid, thereby reducing the risk of abnormal dialysate concentration and improving the working environment of medical practitioners. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] [ Figure 1 ] is a diagram showing an overview of a dust measuring device used for measuring dust weight. A is a photograph of the appearance of the dust measuring device, and B is a schematic diagram showing the structure of the dust measuring device. DETAILED DESCRIPTION

[0034] 1. Agent A for hemodialysis

[0035] The hemodialysis agent A of the present invention is characterized in that it comprises coated particles, the coated particles have a coating layer comprising calcium chloride and / or magnesium chloride, the core particles of the coated particles comprise potassium chloride, and the coating layer does not substantially contain acetate. By including the coated particles of the specific structure in the hemodialysis agent A of the present invention, excellent solubility in water is achieved. The hemodialysis agent A of the present invention is described in detail below.

[0036] In addition, in this specification, when expressing "coated particles", it means coated particles having a coating layer containing calcium chloride and / or magnesium chloride.

[0037] [Coated particles]

[0038] Coating layer

[0039] The coated particles used in the agent A for hemodialysis of the present invention have a coating layer formed on the surface of a core particle described later, which does not substantially contain acetate and contains calcium chloride and / or magnesium chloride.

[0040] In the present invention, the so-called "coating layer" refers to a layer (spray coating layer) formed by spraying an aqueous solution in which components forming the coating layer are dissolved on core particles and drying. That is, granulated materials that are in a state where other particles are attached to a part of the surface of the core particles while maintaining their shape (a state of aggregated granulated materials) by wet granulation, dry granulation, etc. do not have a coating layer and are not coated particles.

[0041] The coating layer in the coated particles does not contain substantially any acetate. Here, “does not contain substantially any acetate” means that the coating layer does not contain any acetate except for the case where it is inevitably mixed in the manufacturing process. Acetate refers to a salt having an acetate ion, such as an alkali metal salt of acetic acid, an alkaline earth metal salt of acetic acid, and more specifically, sodium acetate, or a complex salt generated by the reaction of sodium acetate and calcium chloride, etc.

[0042] In the coated particles, the 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, the calcium chloride used to form the coating layer may be in a hydrate or an anhydrous state.

[0043] In the coated particles, the magnesium chloride forming the coating layer is a component that serves as a supply source of magnesium ions and chloride ions in the hemodialysis fluid. In the coated particles, the magnesium chloride used to form the coating layer may be in a hydrate or an anhydrous state.

[0044] In the coated particles, the coating layer may contain only one of calcium chloride and magnesium chloride, or both. In a preferred embodiment of the coated particles of the present invention, there can be mentioned: 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, etc.

[0045] In the coated particles, the content of calcium chloride contained in the coating layer can be appropriately set by comprehensively considering the total calcium ion concentration of the dialysate to be prepared and the total chloride ions. Specifically, the content of calcium chloride contained in the coating layer is set so that the total calcium ion concentration in the hemodialysis fluid to be prepared becomes 1.5 to 4.5 mEq / L; preferably 2.5 to 3.5 mEq / L. For example, with respect to 100 parts by weight of the anhydrous conversion amount of the coated particles, the anhydrous conversion amount of calcium chloride contained in the coating layer can be 10 to 94 parts by weight, preferably 10 to 80 parts by weight, more preferably 20 to 60 parts by weight, and further preferably 30 to 50 parts by weight. In the present invention, the so-called "anhydrous conversion amount of the coated particles" refers to the value obtained by removing the weight of the crystal water of the hydrate (water molecules in the hydrate) and converting all the components contained in the coated particles into the weight of the anhydrous substance. The “anhydrous equivalent amount of calcium chloride” refers to a value obtained by removing the weight of crystal water (water molecules in the hydrate) and converting the result to the weight of the anhydrous form when the calcium chloride is in the form of a hydrate.

[0046] In the coated particles, the content of magnesium chloride contained in the coating layer can be appropriately set by comprehensively considering the total magnesium ion concentration and the total chloride ion of the dialysate to be prepared. Specifically, the content of magnesium chloride contained in the coating layer is set so that the total magnesium ion concentration in the hemodialysis fluid to be prepared becomes 0.5 to 2.0 mEq / L; preferably 0.75 to 1.5 mEq / L. For example, with respect to 100 parts by weight of the anhydrous conversion amount of the coated particles, the anhydrous conversion amount of magnesium chloride contained in the coating layer can be 1 to 85 parts by weight, preferably 10 to 60 parts by weight, more preferably 10 to 30 parts by weight, and further preferably 10 to 20 parts by weight. In the present invention, the so-called "anhydrous conversion amount of the coated particles" refers to the value obtained by removing the weight of the crystal water of the hydrate (water molecules in the hydrate) and converting all the components contained in the coated particles into the weight of the anhydrous substance. The “anhydrous equivalent amount of magnesium chloride” refers to a value obtained by removing the weight of crystal water (water molecules in the hydrate) and converting the result to the weight of the anhydrous form when the magnesium chloride is in the form of a hydrate.

[0047] In the coated particles, when the coating layer contains both calcium chloride and magnesium chloride, their ratio can be appropriately set by comprehensively considering the total calcium ion concentration and magnesium ion concentration in the hemodialysis fluid to be prepared. For example, the amount of magnesium chloride contained in the coating layer, as calculated as an anhydrous amount, can be 10 to 75 parts by weight, preferably 15 to 65 parts by weight, and more preferably 20 to 55 parts by weight, relative to 100 parts by weight of the anhydrous amount of the calcium chloride contained in the coating layer.

[0048] In the coated particles, in addition to calcium chloride and / or magnesium chloride, the coating layer may also contain, as needed, other organic acid salts and / or inorganic salts that serve as a source of sodium ions, potassium ions, chloride ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc.; organic acids; and constituent components of hemodialysis fluid such as glucose, in the range that does not hinder the effects of the present invention.

[0049] In the coated particles, there is no particular restriction on the ratio of the total amount of calcium chloride and magnesium chloride in the overall coating layer. The total amount of calcium chloride and magnesium chloride can be 20 parts by weight or more, preferably 30 parts by weight or more, more preferably 65 parts by weight or more, and further preferably 80 parts by weight or more, relative to the total amount of 100 parts by weight of the anhydrous conversion amount of the coating layer. In the present invention, the so-called "anhydrous conversion amount of the coating layer" refers to the value obtained by removing the weight of the crystal water of the hydrate (water molecules in the hydrate) and converting all the components contained in the coating layer into the weight of the anhydrous substance.

[0050] As a preferred embodiment of the coated particles, an embodiment in which the coating layer contains calcium chloride and magnesium chloride can be given. As a further preferred embodiment of the coated particles, an embodiment in which the coating layer contains only calcium chloride and magnesium chloride can be given.

[0051] In addition, as another preferred embodiment of the coated particles, a method in which the coating layer does not substantially contain potassium chloride can be cited. In the present invention, the term "substantially containing potassium chloride as a coating layer" means that the coating layer does not contain potassium chloride except when it is inevitably mixed in the manufacturing process or produced as a by-product.

[0052] In the coated particles, the coating layer may have either a single-layer structure or a multi-layer structure.

[0053] When the coating layer has a single-layer structure, the coating layer may be formed using a mixture containing calcium chloride and / or magnesium chloride and other components as needed.

[0054] In addition, when the coating layer is a multilayer structure, the components forming the coating layer can be divided into two or more and multiple coating layers can be stacked. In the case of a multilayer structure, as the number of layers of the coating layer, for example, 2 to 4 layers, preferably 2 or 3 layers, and more preferably 2 layers can be cited. In addition, for example, in one embodiment in which calcium chloride and magnesium chloride are included in the coating layer and the coating layer is a two-layer structure, the surface of the core particle is 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 in which calcium chloride and magnesium chloride are included in the coating layer and the coating layer is a two-layer structure, after the surface of the core particle is coated with a first coating layer containing calcium chloride and magnesium chloride, it is coated with a second coating layer containing other components (for example, sodium chloride, etc.) as required.

[0055] Nuclear particles

[0056] The coated particles contain potassium chloride. Potassium chloride may be in a hydrate or anhydrous form. The potassium chloride contained in the coated particles is a component that serves as a supply source of potassium ions and chloride ions in the hemodialysis fluid.

[0057] In the coated particles, there is no particular limitation on the content of potassium chloride contained as the core particles. For example, the anhydrous equivalent amount of potassium chloride contained as the core particles can be 5 to 89 parts by weight, preferably 10 to 80 parts by weight, more preferably 20 to 70 parts by weight, and further preferably 30 to 50 parts by weight, relative to 100 parts by weight of the anhydrous equivalent amount of the coated particles. In the present invention, the so-called "anhydrous equivalent amount of potassium chloride" refers to a value obtained by removing the weight of crystal water (water molecules in the hydrate) and converting it to the weight of the anhydrous form when potassium chloride is in the form of a hydrate.

[0058] In addition, in the coated particles, the ratio of potassium chloride forming the core particles to calcium chloride and / or magnesium chloride forming the coating layer can be appropriately set by comprehensively considering the total potassium ion concentration, total magnesium ion concentration, total calcium ion concentration, and total chloride ion of the dialysate to be prepared. Specifically, the total potassium ion concentration in the hemodialysis fluid to be prepared 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. For example, the amount of calcium chloride forming the coating layer in terms of anhydrous conversion relative to 100 parts by weight of potassium chloride forming the core particle can be 50 to 500 parts by weight, preferably 50 to 300 parts by weight, more preferably 60 to 200 parts by weight, and further preferably 70 to 140 parts by weight. In addition, the amount of magnesium chloride forming the coating layer in terms of anhydrous conversion relative to 100 parts by weight of potassium chloride forming the core particle can be 1 to 100 parts by weight, preferably 5 to 80 parts by weight, more preferably 10 to 60 parts by weight, and further preferably 20 to 50 parts by weight.

[0059] 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 for the case where sodium chloride is inevitably mixed in the production process or generated as a by-product.

[0060] In addition, in the coated particles, within the range that does not hinder the effect of the present invention, the core particles may contain, in addition to potassium chloride, other organic acid salts and / or inorganic salts that serve as a supply source of chloride ions, acetate ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc.; organic acids; constituents of hemodialysis fluid such as glucose, etc., as needed. In the case where the core particles contain components other than potassium chloride, the coated particles may be: coated particles with particles aggregated with potassium chloride and other components as core particles; a mixture of coated particles with potassium chloride as core particles and coated particles with other components as core particles; or a mixture of coated particles with particles aggregated with potassium chloride and other components as core particles, coated particles with potassium chloride as core particles, and coated particles with other components as core particles.

[0061] In the coated particles, there is no particular restriction on the ratio of potassium chloride in the core particles. For the total amount of 100 parts by weight of the anhydrous equivalent of the core particles, the amount of potassium chloride in terms of anhydrous equivalent can be 80 parts by weight or more, preferably 90 parts by weight or more, and more preferably 95 parts by weight or more. In the present invention, the so-called "anhydrous equivalent of the core particles" refers to the anhydrous equivalent of the total amount of the core particles in all coated particles having a coating layer including potassium chloride. In the case where the components contained in the core particles are hydrates, it refers to the value obtained by removing the weight of the crystal water of the hydrate (water molecules in the hydrate) and converting all the components contained in the core particles into the weight of anhydrous.

[0062] As a preferred embodiment of the coated particles, there is mentioned an embodiment in which only potassium chloride is contained as the core particles.

[0063] In addition, in the coated particles, the ratio of the core particles to the coating layer can be appropriately set in such a way that the components constituting the core particles and the coating layer become the desired ion concentration in the dialysate to be prepared. Specifically, in terms of the ratio of the core particles to the coating layer, the total potassium ion concentration in the hemodialysate to be prepared 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, relative to 100 parts by weight of the anhydrous conversion amount of the core particles, the anhydrous conversion amount of the coating layer can be 10 to 300 parts by weight, preferably 20 to 200 parts by weight, and more preferably 100 to 180 parts by weight.

[0064] · Coated particle content

[0065] Regarding the content of the aforementioned coated particles in the hemodialysis agent A of the present invention, the amount of potassium chloride, magnesium chloride and / or calcium chloride contained in the coated particles is comprehensively considered, and the total potassium ion concentration, total magnesium ion concentration and total calcium ion concentration required in the hemodialysis fluid to be prepared can be appropriately set in a manner that satisfies the total potassium ion concentration, total magnesium ion concentration and total calcium ion concentration required in the hemodialysis fluid to be prepared. Specifically, the content of the aforementioned coated particles in the hemodialysis agent A of the present invention is set in a manner that the total potassium ion concentration in the hemodialysis fluid to be prepared 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.

[0066] More specifically, the content of the aforementioned 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, based on the anhydrous conversion amount of the aforementioned coated particles, relative to the total amount of 100 parts by weight of the anhydrous conversion amount of the electrolyte components contained in the hemodialysis agent A. In the present invention, the so-called "anhydrous conversion amount of the electrolyte components contained in the hemodialysis agent A" refers to the value obtained by removing the weight of the crystal water of the hydrate (water molecules in the hydrate) and converting all the electrolyte components contained in the hemodialysis agent A into the weight of the anhydrous substance 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.

[0067] ·Method for producing coated particles

[0068] The coated particles are manufactured by spraying a coating layer-forming aqueous solution in which calcium chloride and / or magnesium chloride is dissolved on a core particle containing potassium chloride, or drying the core particle after spraying a coating layer-forming aqueous solution in which calcium chloride and / or magnesium chloride is dissolved. If the coating layer is made into a multilayer structure, two or more coating layer-forming aqueous solutions corresponding to each layer of the coating layer are prepared, and the core particle containing potassium chloride is dried while spraying two or more coating layer-forming aqueous solutions in stages, or drying the core particle after spraying two or more coating layer-forming aqueous solutions.

[0069] About the concentration of calcium chloride and / or magnesium chloride in the coating layer forming aqueous solution, it is possible to appropriately set it according to the type, scale, etc. of the manufacturing device. Consider from the viewpoint of suppressing uneven generation in the coating layer, as the concentration of calcium chloride in the coating layer forming aqueous solution, in terms of the anhydrous conversion amount of calcium chloride, 15 to 50% by weight, preferably 20 to 45% by weight can be cited. In addition, from the same viewpoint, as the concentration of magnesium chloride in the coating layer forming aqueous solution, in terms of the anhydrous conversion amount of magnesium chloride, 5 to 25% by weight, preferably 9 to 15% by weight can be cited.

[0070] The amount of the coating layer forming aqueous solution sprayed onto the core particles may be appropriately set depending on the concentration of calcium chloride and / or magnesium chloride in the coating layer forming aqueous solution, the ratio of the core particles to the coating layer of the produced coated particles, and the like.

[0071] The temperature conditions when spraying the layer-forming aqueous solution onto the core particles are not particularly limited, and examples thereof include 15 to 300°C, preferably 60 to 250°C, and more preferably 100 to 200°C.

[0072] In order to spray the aqueous solution for coating layer formation onto the core particles, for example, a fluidized bed granulation coating apparatus such as a tumbling fluidized bed granulation coating apparatus may be used.

[0073] In addition, when the core particles contain components other than potassium chloride, the coating layer forming aqueous solution can be sprayed on potassium chloride and other components. In addition, for example, after at least a portion of potassium chloride and at least a portion of other components are aggregated by heating and mixing, the coating layer forming aqueous solution can be sprayed.

[0074] [Sodium chloride]

[0075] The agent A for hemodialysis of the present invention preferably contains sodium chloride in addition to the above-mentioned coated particles.

[0076] In one embodiment of the agent A for hemodialysis of the present invention, the sodium chloride may be in a state where at least one of magnesium chloride, calcium chloride, and potassium chloride is not attached to or coated on the surface.

[0077] When sodium chloride is contained in the hemodialysis agent A of the present invention, its content can be appropriately set in a manner that satisfies the total sodium ion concentration required in the hemodialysis fluid to be prepared, taking into account the amount of sodium chloride contained in the aforementioned coated particles as needed, the content of other sodium salts, etc. Specifically, the content of sodium chloride in the hemodialysis agent A of the present invention can be set in a manner that the total sodium ion concentration of the hemodialysis fluid to be prepared becomes 90 to 120 mEq / L, preferably 100 to 110 mEq / L.

[0078] For example, the total amount of sodium chloride is 40 to 95 parts by weight, preferably 55 to 90 parts by weight, based on 100 parts by weight of the total amount of the anhydrous equivalent of the electrolyte components contained in Agent A for hemodialysis.

[0079] [Acetic acid and acetates]

[0080] The agent A for hemodialysis of the present invention may further contain acetic acid and an acetate salt in addition to the coated particles.

[0081] The acetic acid may be glacial acetic acid. In addition, the acetate is not particularly limited as long as it is an acetate permitted as a component of the hemodialysis solution, and examples thereof include: alkali metal acetates such as sodium acetate and potassium acetate; alkaline earth metal acetates such as calcium acetate and magnesium acetate. These acetates may be anhydrous acetates. Among these acetates, from the perspective of safety and cost based on years of use, alkali metal acetates are preferred, and sodium acetate is more preferred. In addition, 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.

[0082] In addition, at least a portion of acetic acid and acetate may be in the form of alkali metal diacetate. By using alkali metal diacetate, it is possible to further improve solubility and storage stability, reduce the odor of acetic acid, and inhibit the decomposition of glucose when glucose coexists. The so-called alkali metal diacetate refers to a complex formed by 1 mole of alkali metal acetate and 1 mole of acetic acid (MH(C2H3O2)2; M represents an alkali metal atom), and 1 mole of acetate (alkali metal acetate) and 1 mole of acetic acid can be supplied from 1 mole of alkali metal diacetate. As the alkali metal diacetate used in the present invention, specifically, sodium diacetate, potassium diacetate, etc. can be cited. These alkali metal diacetates can be used alone or in combination of two or more. Among the alkali metal diacetates, sodium diacetate is preferably cited.

[0083] At least a portion of acetic acid and acetate may be in the form of a higher acetate compound. The higher acetate compound refers to a compound formed by bonding acetic acid (primary compound) and acetate (primary compound).

[0084] In addition, the molar ratio of acetic acid and acetate contained in the hemodialysis agent A of the present invention is not particularly limited, and can be appropriately set based on the pH range to be given to the hemodialysis fluid, etc. It is desirable to set the molar ratio of acetic acid contained in the hemodialysis agent A to acetate contained in the hemodialysis agent A to satisfy 1:0.5 to 10, preferably 1:0.5 to 6.0, more preferably 1:0.5 to 3.0, and further preferably 1:0.7 to 2.0. Here, in the case where an alkali metal diacetate is included as acetic acid and acetate, the acetic acid and acetate derived from 1 mole of the alkali metal diacetate are regarded as 1 mole of acetic acid and 1 mole of acetate to calculate the above molar ratio. In addition, in the case where a higher acetate compound is included as acetic acid and acetate, if the molar ratio of acetic acid to acetate in the higher acetate compound is 1:X, the acetic acid and acetate derived from 1 mole of the higher acetate compound are regarded as 1 mole of acetic acid and X moles of acetate to calculate the above molar ratio.

[0085] When the hemodialysis agent A of the present invention contains acetic acid and acetate, the content thereof can be appropriately set in a manner that satisfies the total acetate ion concentration and pH required in the hemodialysis fluid to be prepared. Specifically, when the hemodialysis agent A of the present invention contains acetic acid and acetate, the content thereof can be appropriately set in a manner that the total acetate ion concentration in the hemodialysis fluid to be prepared becomes 0.5 to 12 mEq / L, preferably 1.5 to 10 mEq / L, more preferably 2 to 10 mEq / L, further preferably 10 mEq / L, 8 mEq / L, 6 mEq / L, or 4.2 mEq / L.

[0086] For example, the total amount of acetic acid and acetate in terms of anhydride conversion 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, relative to 100 parts by weight of the total amount of the electrolyte components contained in the hemodialysis agent A in terms of anhydride conversion. In the present invention, the "anhydride conversion amount of acetic acid and acetate" refers to a value obtained by converting the total amount of acetic acid and acetate into the weight of anhydride by removing the weight of crystal water of the hydrate (water molecules in the hydrate) when the acetate is a hydrate.

[0087] [Citric acid and / or its salts]

[0088] In the hemodialysis agent A of the present invention, when the aforementioned coated particles do not contain citric acid and / or its salt, or when the desired citrate ion concentration cannot be satisfied by the citric acid and / or its salt contained in the aforementioned coated particles, it is preferred that citric acid and / or its salt be contained in addition to the aforementioned coated particles.

[0089] The salt of citric acid is not particularly limited as long as it is a citrate that is permitted as a component of hemodialysis fluid, 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 salts of citric acid, from the perspective of safety and cost based on long-term use performance, alkali metal citrates are preferably used, and sodium citrate is more preferably used. In addition, these salts of citric acid may be used alone or in combination of two or more.

[0090] When the hemodialysis agent A of the present invention contains citric acid and / or its salt, the content thereof can be appropriately set in a manner that satisfies the total citrate ion concentration and pH required in the hemodialysis fluid to be prepared, taking into account the presence or absence of citric acid and / or its salt, its content, etc. Specifically, when the hemodialysis agent A of the present invention contains citric acid and / or its salt, the content thereof can be appropriately set in a manner that the total citrate ion concentration in the hemodialysis fluid to be prepared becomes 0.1 to 18 mEq / L, preferably 0.5 to 3.5 mEq / L or 1 to 4 mEq / L, and more preferably 1 to 3.3 mEq / L.

[0091] More specifically, the total amount of citric acid and / or its salt in terms of anhydrous equivalents is 0.5 to 50 parts by weight, preferably 1 to 15 parts by weight, and more preferably 2 to 5 parts by weight, relative to 100 parts by weight of the total amount of the electrolyte components contained in the hemodialysis agent A in terms of anhydrous equivalents. In the present invention, the "anhydrous equivalents of citric acid and / or its salt" refers to a value obtained by converting the total amount of citric acid and its salt into the weight of anhydrous equivalents by removing the weight of the crystal water of the hydrate (water molecules in the hydrate) when the salt of citric acid is a hydrate.

[0092] [Calcium chloride and magnesium chloride]

[0093] In the hemodialysis agent A of the present invention, when the total calcium ion concentration required in the hemodialysis solution to be prepared cannot be satisfied by the calcium chloride contained in the aforementioned coated particles, calcium chloride may be contained in addition to the aforementioned coated particles. In addition, in the hemodialysis agent A of the present invention, when the total magnesium ion concentration required in the hemodialysis solution to be prepared cannot be satisfied by the magnesium chloride contained in the aforementioned coated particles, magnesium chloride may be contained in addition to the aforementioned coated particles.

[0094] [glucose]

[0095] The hemodialysis agent A of the present invention may contain glucose for the purpose of maintaining the blood sugar level of the patient. When the hemodialysis agent A of the present invention contains glucose, the decomposition of glucose due to storage can also be suppressed.

[0096] When the hemodialysis agent A of the present invention contains glucose, its content can be appropriately set in a manner that satisfies the glucose concentration required in the hemodialysis fluid to be prepared. Specifically, the content of glucose in the hemodialysis agent A of the present invention can be appropriately set in a manner that the glucose concentration in the hemodialysis fluid to be prepared becomes 0.1 to 2.5 g / L, preferably 1.0 to 2.0 g / L.

[0097] For example, the amount of glucose is 0.5 to 60 parts by weight, preferably 10 to 25 parts by weight, based on 100 parts by weight of the total amount of the anhydrous electrolyte components contained in the agent A for hemodialysis.

[0098] [Other ingredients]

[0099] The hemodialysis agent A of the present invention may contain, in addition to the aforementioned components, other organic acid salts that serve as a supply source of calcium ions, magnesium ions, sodium ions, potassium ions, chloride ions, acetate ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc., as necessary.

[0100] Examples of the compound that serves as a source of calcium ions include calcium salts of organic acids such as calcium lactate, calcium gluconate, calcium succinate, and calcium malate. These calcium salts of organic acids may be used alone or in combination of two or more.

[0101] Examples of the compound that serves as a source of magnesium ions include organic acid salts of magnesium such as magnesium lactate, magnesium gluconate, magnesium succinate, and magnesium malate. These organic acid salts of magnesium may be used alone or in combination of two or more.

[0102] Examples of the compound that serves as a source of sodium ions include organic acid salts of sodium such as sodium lactate, sodium gluconate, sodium succinate, and sodium malate. These organic acid salts of sodium may be used alone or in combination of two or more.

[0103] Examples of the compound that serves as a source of potassium ions include organic acid salts of potassium, such as potassium lactate, potassium gluconate, potassium succinate, and potassium malate. These organic acid salts of potassium may be used alone or in combination of two or more.

[0104] These organic acid salts can be appropriately selected according to the types of various ions to be contained in the dialysate to be finally prepared. In addition, in the hemodialysis agent A of the present invention, the content of these organic acid salts can be appropriately set according to the concentration of each ion to be possessed in the dialysate to be prepared. Specifically, the content of the aforementioned organic acid salt contained in the hemodialysis agent A of the present invention as required can be appropriately set in a manner such that the hemodialysate to be finally prepared satisfies the concentration of each ion shown in Table 1 below.

[0105] [Table 1]

[0106] Concentration in dialysate The case of sodium ions 120 to 150 mEq / L, preferably 135 to 145 mEq / L Potassium ion situation 0.5 to 3 mEq / L, preferably 1.5 to 2.5 mEq / L The situation of calcium ions 1.5 to 4.5 mEq / L, preferably 2.5 to 3.5 mEq / L The situation of magnesium ions 0 to 2.0 mEq / L, preferably 0.5 to 1.5 mEq / L The case of citrate ion 0 to 18 mEq / L, preferably 0 to 3 mEq / L Chloride ion situation 90 to 135 mEq / L, preferably 100 to 120 mEq / L The case of lactate ion 0 to 10 mEq / L The situation of malate ion 0 to 10 mEq / L The situation of gluconate ion 0 to 10 mEq / L The case of the succinate ion 0 to 10 mEq / L

[0107] In the hemodialysis A agent of the present invention, as required, a pH adjusting agent other than the aforementioned can be included. As the pH adjusting agent that can be used in the hemodialysis A agent of the present invention, as long as it is a pH adjusting agent that is allowed as a component of the hemodialysis solution, there is no particular restriction, for example, liquid acids such as hydrochloric acid, lactic acid, gluconic acid, solid acids such as succinic acid, fumaric acid, malic acid, glucono-δ-lactone, and their sodium, potassium, calcium, magnesium salts, etc. can be cited. Among these pH adjusting agents, organic acids can be preferably used. The pH adjusting agent can be used alone, and more than two kinds can also be used in combination.

[0108] [pH characteristics]

[0109] The agent A for hemodialysis of the present invention may be set so that the pH becomes 6 to 8, preferably 7.1 to 7.6, when preparing a hemodialysis fluid.

[0110] [form]

[0111] The hemodialysis agent A of the present invention is a solid preparation in which the coated particles and the components contained in addition to the coated particles are mixed in a predetermined amount. In the hemodialysis agent A of the present invention, the components other than the coated particles may be any of powders or granules, and may also be in a state where powders and granules are mixed.

[0112] [Tap density]

[0113] In one embodiment of the hemodialysis agent A of the present invention, it has a high density, and the volume of each bag of hemodialysis agent A can be compact. In the hemodialysis agent A of the present invention, from the viewpoint of having such advantages, 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 Bulk density and tap density determination method" of the 18th revised edition of the Japanese Pharmacopoeia.

[0114] [Manufacturing method]

[0115] The agent A for hemodialysis of the present invention is produced by mixing the coated particles and each component contained in addition to the coated particles in predetermined amounts.

[0116] 2. Hemodialysis agents

[0117] 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 the hemodialysis agent B containing sodium bicarbonate.

[0118] From the viewpoint of transportation and storage, the aforementioned hemodialysis agent B is preferably in a solid state. Specifically, the shape of the solid hemodialysis agent B includes powders, granules, etc. The amount of the aforementioned hemodialysis agent B used can be appropriately set so that the bicarbonate ion in the hemodialysis solution to be prepared becomes 20 to 40 mEq / L, preferably 25 to 35 mEq / L.

[0119] In the case where the hemodialysis agent A of the present invention does not contain glucose, or in the case where the glucose contained in the aforementioned hemodialysis agent A cannot satisfy the required glucose concentration in the hemodialysis fluid to be prepared, the aforementioned hemodialysis agent B may contain glucose as needed. In the case where the aforementioned hemodialysis agent B contains glucose, the content of glucose can be appropriately set in such a way that the glucose concentration in the hemodialysis fluid finally prepared becomes 0.1 to 2.5 g / L, preferably 1.0 to 1.5 g / L. However, the aforementioned hemodialysis agent B preferably does not contain electrolyte components other than sodium bicarbonate, and the components contained are preferably substantially formed of sodium bicarbonate.

[0120] In addition, 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 cannot satisfy the glucose concentration required in the hemodialysis fluid to be prepared, the hemodialysis agent A of the present invention can also be provided as the hemodialysis agent A-1, and further combined with the hemodialysis agent A-2 formed of glucose. That is, the hemodialysis agent A of the present invention (including both the cases of containing glucose or not containing glucose) can be provided in the form of a two-dose hemodialysis agent in combination with the aforementioned hemodialysis agent B, or in the form of a three-dose hemodialysis agent in combination with the aforementioned hemodialysis agent A-2 and the aforementioned hemodialysis agent B.

[0121] When the hemodialysis agent A-2 is provided in the hemodialysis agent of the present invention, the content of glucose in the hemodialysis agent A-2 may be appropriately set so that the glucose concentration in the finally prepared hemodialysis fluid becomes 0.1 to 2.5 g / L, preferably 1.0 to 1.5 g / L.

[0122] The hemodialysis agent of the present invention can be used to prepare a bicarbonate hemodialysis solution. Specifically, each agent included in the hemodialysis agent of the present invention is dissolved in a predetermined amount of water (preferably purified water) for dilution to prepare a bicarbonate hemodialysis solution.

[0123] Example

[0124] Hereinafter, the present invention will be specifically described with reference to Examples, but the present invention is not to be construed as being limited to the following Examples.

[0125] Test Example 1: Preparation and evaluation of agent A for hemodialysis

[0126] 1. Manufacture of Agent A for Hemodialysis

[0127] [Example 1]

[0128] 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 coating layer formation. 5.22 kg of potassium chloride was added to a composite fluidized bed granulation coating device (manufacturer: Freund Industry Co., Ltd., model: SFC-15), and the device was operated under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm). After the hot air temperature (air supply) became about 150-160° C. and the product temperature became above 120° C., the entire amount of the aqueous solution for coating layer formation was sprayed onto potassium chloride under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm, a block crusher: 669 rpm) to form a coating layer. After spraying, the hot air temperature (air supply) was about 160-165° C., and the rotating body (rotor: 150 rpm, agitator: 210 rpm, lump crusher: 669 rpm) was dried until the product temperature reached 125° C. to obtain coated particles. The obtained coated particles had a structure including potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0129] 158.5 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, 108.8 g of anhydrous sodium acetate and 2.178 kg of sodium chloride were put into a plastic bag, mixed and sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0130] [Example 2]

[0131] Solid hemodialysis agent A was obtained under the same conditions as in Example 1 except that 437.5 g of glucose was additionally added to the plastic bag and mixed.

[0132] [Example 3]

[0133] The 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. In addition, the 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 152.1 g. It should be noted that the coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is included as a core particle, and calcium chloride and magnesium chloride are used as a coating layer to cover the surface of the core particle.

[0134] [Example 4]

[0135] Solid hemodialysis agent A was obtained under the same conditions as in Example 3 except that 437.5 g of glucose was additionally added to the plastic bag and mixed.

[0136] [Example 5]

[0137] The 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 coating layer formation. In addition, the amount of coated particles was changed to 177.8 g, and 437.5 g of glucose was added and mixed. Solid hemodialysis agent A was obtained under the same conditions as in Example 1. It should be noted that the coated particles contained in the hemodialysis agent A have a structure containing potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0138] [Example 6]

[0139] 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 coating layer formation, and coated particles were obtained under the same conditions as in Example 1. In addition, the amount of coated particles was changed to 169.9 g, and 437.5 g of glucose was added and mixed. Under the same conditions as in Example 1, a solid hemodialysis agent A was obtained. It should be noted that the coated particles contained in the hemodialysis agent A have a structure containing potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0140] [Example 7]

[0141] 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 coating layer formation, and coated particles were obtained under the same conditions as in Example 1. In addition, the amount of coated particles was changed to 195.6 g, and solid hemodialysis agent A was obtained under the same conditions as in Example 1. It should be noted that the coated particles contained in the hemodialysis agent A have a structure containing potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0142] [Example 8]

[0143] Solid hemodialysis agent A was obtained under the same conditions as in Example 7 except that 437.5 g of glucose was additionally added to the plastic bag and mixed when obtaining solid hemodialysis agent A.

[0144] [Example 9]

[0145] 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 coating layer formation. 10.80 kg of potassium chloride was added to a composite fluidized bed granulation coating device (manufacturer: Freund Industry Co., Ltd., model: SFC-15), and the device was operated under the conditions of a rotating body (rotor: 200 rpm, agitator: 300 rpm). After the hot air temperature (air supply) became about 160 to 190° C. and the product temperature became above 120° C., the entire amount of the aqueous solution for coating layer formation was sprayed onto potassium chloride under the conditions of a rotating body (rotor: 200 rpm, agitator: 300 rpm, a block crusher: 669 rpm) to form a coating layer. After the spraying is completed, the hot air temperature (air supply) is about 190° C., and the rotating body (rotor: 150 rpm, agitator: 210 rpm, block crusher: 669 rpm) is dried until the product temperature reaches 120° C. to obtain coated particles. The obtained coated particles have a structure containing potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0146] 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 put into a plastic bag, mixed, and sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0147] [Example 10]

[0148] Solid hemodialysis agent A was obtained under the same conditions as in Example 9 except that 525 g of glucose was additionally added to the plastic bag and mixed.

[0149] [Example 11]

[0150] 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 coating layer formation. 6.00 kg of potassium chloride was added to a composite fluidized bed granulation coating device (manufacturer: Freund Industry Co., Ltd., model: SFC-15), and the device was operated under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm), and after the hot air temperature (air supply) became about 150-160° C. and the product temperature became above 120° C., the entire amount of the aqueous solution for coating layer formation was sprayed onto potassium chloride under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm, a block crusher: 669 rpm) to form a coating layer. After spraying, the mixture was dried under the conditions of hot air temperature (air supply) of about 160 to 165° C. and rotating bodies (rotor: 150 rpm, agitator: 210 rpm, lump crusher: 669 rpm) until the product temperature reached 120° C. to obtain coated particles. The obtained coated particles had a structure including potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0151] 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 put into a plastic bag, mixed, and sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0152] [Example 12]

[0153] 169.6 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0154] [Example 13]

[0155] Solid hemodialysis agent A was obtained under the same conditions as in Example 11 except that 525 g of glucose was additionally added to the plastic bag and mixed when obtaining solid hemodialysis agent A.

[0156] [Example 14]

[0157] 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 coating layer formation. 6.00 kg of potassium chloride was added to a composite fluidized bed granulation coating device (manufacturer: Freund Industry Co., Ltd., model: SFC-15), and the device was operated under the conditions of a rotating body (rotor: 200 rpm, agitator: 300 rpm). After the hot air temperature (air supply) became about 150-165° C. and the product temperature became above 120° C., the entire amount of the aqueous solution for coating layer formation was sprayed onto potassium chloride under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm, a block crusher: 669 rpm) to form a coating layer. After spraying, the hot air temperature (air supply) was about 160-165° C., and the rotating body (rotor: 150 rpm, agitator: 210 rpm, lump crusher: 669 rpm) was dried until the product temperature reached 125° C. to obtain coated particles. The obtained coated particles had a structure including potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0158] 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 put into a plastic bag, mixed, and sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0159] [Example 15]

[0160] Solid hemodialysis agent A was obtained under the same conditions as in Example 14 except that 525 g of glucose was additionally added to the plastic bag and mixed when obtaining solid hemodialysis agent A.

[0161] [Example 16]

[0162] 158.5 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0163] [Example 17]

[0164] 158.5 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0165] [Example 18]

[0166] 158.5 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0167] [Example 19]

[0168] 152.1 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0169] [Example 20]

[0170] 177.8 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0171] [Example 21]

[0172] 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 coating layer formation. 6.53 kg of potassium chloride was added to a composite fluidized bed granulation coating device (manufacturer: Freund Industry Co., Ltd., model: SFC-15), and the device was operated under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm). After the hot air temperature (air supply) became about 150-165° C. and the product temperature became above 120° C., the entire amount of the aqueous solution for coating layer formation was sprayed onto potassium chloride under the conditions of a rotating body (rotor: 150 rpm, agitator: 210 rpm, a block crusher: 669 rpm) to form a coating layer. After spraying, the hot air temperature (air supply) was about 160-165° C., and the rotating body (rotor: 150 rpm, agitator: 210 rpm, lump crusher: 669 rpm) was dried until the product temperature reached 125° C. to obtain coated particles. The obtained coated particles had a structure including potassium chloride as a core particle, and calcium chloride and magnesium chloride as a coating layer covering the surface of the core particle.

[0173] 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 put into a plastic bag, mixed and sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0174] [Example 22]

[0175] Except that the amount of calcium chloride dihydrate used was changed to 9.00 kg, coated particles were obtained under the same conditions as in Example 21. In addition, except that the amount of coated particles was changed to 190.9 g, a solid hemodialysis agent A was obtained under the same conditions as in Example 21. It should be noted that the coated particles contained in the hemodialysis agent A have a structure in which potassium chloride is included as a core particle, and calcium chloride and magnesium chloride are used as a coating layer to cover the surface of the core particle.

[0176] [Example 23]

[0177] 169.6 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0178] [Example 24]

[0179] 169.6 g of 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 sieved with an 8-mesh (mesh size 2.36 mm) sieve to obtain a solid hemodialysis agent A.

[0180] [Comparative Example 1]

[0181] 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 added to a double-tank stirring 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. Then, granulation was performed and then 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.

[0182] [Comparative Example 2]

[0183] To 2508.5 g of the mixture prepared under the conditions described in Comparative Example 1, 42 g of acetic acid was added and mixed, and then 437.5 g of glucose was additionally added and mixed to obtain a solid agent A for hemodialysis.

[0184] [Comparative Example 3]

[0185] 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 added to a double-tank stirring mixer (steam heating), and heated while stirring to make the content temperature 73°C. 16.24 kg of calcium chloride was added to the mixture and mixed. After adding calcium chloride, the content turned slightly white. When further heating and mixing were continued while maintaining the content temperature at 70°C or above, the content produced a specific stickiness, the particles of the content adhered to each other, and the content was in a cake shape as a whole. Therefore, the obtained content could not be supplied to the subsequent granulation process, drying process, sodium chloride and acetic acid addition process, and a solid hemodialysis agent A could not be obtained.

[0186] [Comparative Example 4]

[0187] 25.02kg of sodium chloride with an average particle size of about 350μm, 615g of potassium chloride, 427g of magnesium chloride, 2,034g of sodium acetate and 0.47 liters of pure water were added to a double-pot stirring mixer (steam heating), and heated while stirring to make the content temperature 70°C. 907g of calcium chloride was added to the mixture and mixed. 15 minutes after the addition of calcium chloride, the contents turned slightly white. When the contents were further heated and mixed while maintaining the content temperature at 70°C, the contents became specifically sticky and the particles of the contents began to adhere to each other. Then, the contents were taken out and granulated, and then 9.29kg was dried, 159g of acetic acid was added and mixed. 350g of glucose was added to 2,506g of the mixture and mixed to obtain a solid hemodialysis agent A.

[0188] 2. Evaluation of Agent A for Hemodialysis

[0189] 2-1. Evaluation method

[0190] [Dissolution rate]

[0191] Add 9 kg of water (24-25°C) to a 12.7 L beaker, and while stirring with a stirrer (stirring speed 160 rpm), add the amount of solid hemodialysis agent A recorded in the "Amount of A dissolved in 350 L (g)" column in Table 3 (equivalent to 1 bag of solid hemodialysis agent A), and measure the time (seconds) from the time of addition until complete dissolution.

[0192] [Tap density]

[0193] The measurement was carried out according to the third method specified in "2. Tap density" of "3.01 Bulk density and tap density determination method" of the 18th revised edition of the Japanese Pharmacopoeia. A powder property evaluation device (manufacturer: Hosokawa Micron Co., Ltd., model: Powder Tester PT-X) was used, and the "packed bulk density" of the device was selected. A cylinder for tap density measurement (inner diameter 2.2 cm, height 3.2 cm) was installed on the top of the cup. The cup capacity was 10 cm 3 , a sieve with a mesh size of 1700μm, a vibration time of 30 seconds, and an amplitude of 0.5mm, the hemodialysis agent A (sample) is dropped into the cylinder through a sieve with a mesh size of 1700μm vibrating at an amplitude of 0.5mm, and the sample is filled to about 80% of the cylinder capacity. In this state, tapping is started at 60 times / minute and 200 taps are performed. During the tapping, when the sample in the cylinder is compressed to about 20% of the cylinder capacity, according to the display of the device, the sample is dropped into the cylinder again through a sieve with a mesh size of 1700μm vibrating at an amplitude of 0.5mm, and the sample is replenished to about 80% of the cylinder capacity. After the tapping is completed, the cylinder is removed, the excess sample on the cup is scraped off, and the weight of the cup containing the sample is measured. The weight of the empty cup is subtracted from this weight to obtain the weight of the powder in the cup. After the measurement, install the cylinder again, fill the sample to about 80% of the capacity, and tap it 400 times under the same conditions to find the weight of the powder in the cup. If the difference between the two powder weights obtained after 200 and 400 taps is greater than 2%, further tap the cup every 200 times until the difference between the two consecutive measured values ​​is less than 2%. At the time when the difference between the two consecutive measured values ​​is less than 2%, calculate the density per 1cm based on the last measured value of the powder weight. 3 Calculate the tap density (g / mL) based on the weight of the powder.

[0194] [Dust weight]

[0195] Prepare Figure 1A dust measuring device with the structure shown. 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 and closable input part 3 for inputting solid hemodialysis agent A 2, a 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 top surface. One end of a suction pipe 42 equipped with a filter 41 (10 μm) for capturing dust is connected to the aforementioned suction part 4, and an aspirator 43 is connected to the other end of the suction pipe 42. The aspirator 43 is started to operate, and the inside of the acrylic box 1 is adjusted to -10 kPa. While the inside of the acrylic box 1 is maintained at -10 kPa, the amount of hemodialysis agent A recorded in the column "Amount of A dissolved in 350 L (g)" in Table 3 is input from the input part 3 into the acrylic box 1. After the input is completed, the input part 3 is closed, and the filter 41 is recovered after 5 minutes. The weight (mg) of dust captured by the filter 41 was measured.

[0196] 2-2. Evaluation results

[0197] Regarding each of the hemodialysis agents A of Examples 1, 3, 5, 6, 7, 9, 11, 14, 21, and 22, the theoretical values ​​(values ​​calculated from the compounding 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 are shown in Table 2. In addition, the hemodialysis agents A of Examples 1 to 24 and Comparative Examples 1 to 4 were dissolved in water in the amounts described in the column "Amount of A dissolved in 350 L (g)" in Tables 3 and 4, and adjusted to a total of 350 L of dialysate, and the theoretical concentrations (values ​​calculated from the compounding amounts) of sodium ions, potassium ions, magnesium ions, calcium ions, acetic acid, and citric acid at this time are shown in Tables 3 and 4.

[0198] [Table 2]

[0199]

[0200] [Table 3]

[0201]

[0202] [Table 4]

[0203]

[0204] In addition, the dissolution rate (dissolution time), tap density, and dust weight of each agent A for hemodialysis were evaluated and the results are shown in Tables 5 to 7.

[0205] The hemodialysis agent A (Examples 1 to 24) containing the following coated particles has a fast dissolution rate and excellent solubility. The coated particles contain potassium chloride as core particles, and calcium chloride and magnesium chloride as coating layers covering the surface of the core particles. In addition, the hemodialysis agent A containing the aforementioned coated particles has excellent solubility not only when acetic acid and its salts are contained, but also when citric acid is contained as a component other than the coated particles.

[0206] In contrast, the hemodialysis agent A (Comparative Examples 1, 2 and 4) comprising the following coated particles has a slow dissolution rate and poor solubility, wherein the coated particles have sodium chloride as a core particle and are coated with potassium chloride, calcium chloride, magnesium chloride and sodium acetate as a coating layer on their surface. It should be noted that the hemodialysis agent A of Comparative Example 4 is manufactured using the same manufacturing method as Example 1 shown in Patent Document 1 (Japanese Patent Laid-Open Gazette No. 9-40562).

[0207] In addition, in Comparative Example 3, the technology disclosed in Patent Document 1 (Japanese Patent Publication No. 9-40562) was used to attempt to produce a two-layer structure solid hemodialysis agent A containing potassium chloride as core particles. However, the particles aggregated and dissolved during the production process and became cake-like, and it was impossible to obtain a granulated material that could be used as a solid hemodialysis agent A.

[0208] From the above results, it was confirmed that Agent A for hemodialysis containing coated particles in which the surface of core particles containing potassium chloride was coated with a coating layer containing calcium chloride and magnesium chloride had an excellent dissolution rate.

[0209] In addition, it was confirmed that the tap density of the hemodialysis agent A of Examples 1, 2, 9 and 10 was high, reaching a level that could make the volume of each bag of hemodialysis agent A compact. From this result, it can be seen that the hemodialysis agent A of the present invention can reduce the volume during circulation and storage, and has the possibility of reducing transportation costs and storage space.

[0210] In addition, the weight of dust generated during operation was reduced in the hemodialysis agent A of Examples 2 and 9. From this result, it can be seen that the hemodialysis agent A of the present invention can suppress the electrolyte concentration of the hemodialysis fluid from deviating from the set value and becoming an abnormal value when preparing the hemodialysis fluid at the medical site, and can also suppress the deterioration of the working environment.

[0211] [Table 5]

[0212]

[0213] [Table 6]

[0214] [Table 7]

[0215]

[0216] Description of Reference Numerals

[0217] 1 acrylic box

[0218] 2Solid hemodialysis agent A

[0219] 3 Input Department

[0220] 4 Suction section

[0221] 41 Filters

[0222] 42 Suction tube

[0223] 43 Aspirator

[0224] 5. Pressure gauge

Claims

1. A solid hemodialysis agent A, comprising coated particles, wherein the coated particles have a coating layer comprising calcium chloride and / or magnesium chloride, The core particle of the coated particle comprises potassium chloride, 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 includes calcium chloride and magnesium chloride.

5. The hemodialysis agent A as claimed in 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.

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

8. The agent A for hemodialysis 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. The method for producing the solid agent A for hemodialysis according to claim 1, comprising the following first and second steps: In a first step, a coating layer-forming aqueous solution in which calcium chloride and / or magnesium chloride is dissolved is sprayed onto potassium chloride to obtain coated particles; and In the second step, the coated particles obtained in the first step are mixed to produce a solid agent A for hemodialysis.

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