JP7372001B2 - Granules used in hemodialysis agents, hemodialysis agents A and hemodialysis agents containing the granules - Google Patents

Description

The present invention relates to a granulated product for use in hemodialysis agents, which contains an acetate and magnesium chloride and/or calcium chloride and has excellent storage stability. The present invention also relates to a hemodialysis agent A and a hemodialysis agent containing the granulated product.

Currently, bicarbonate dialysis agents are mainly used as hemodialysis agents, and they consist of two agents: agent A, which contains many electrolyte components including sodium chloride, and glucose, and agent B, which contains sodium bicarbonate. This type is commercially available as a general dialysis agent. In addition, in recent years, a three-drug type bicarbonate dialysis agent has been proposed, consisting of a drug A containing an electrolyte component other than sodium chloride, a drug S containing sodium chloride, and a drug B containing sodium bicarbonate. (See Patent Document 1).

Conventionally, there have been two types of dialysis agent A: a liquid type that contains electrolyte components in the form of a concentrated liquid, and a solid type that contains electrolyte components in a solid form. However, in recent years, solid dialysis agent A has become the mainstream in Japan.

Agent A for dialysis in a general two-drug type bicarbonate dialysis agent contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, a pH adjuster, and glucose, and these raw materials Among these, the content of sodium chloride is extremely large compared to other components, and is usually contained in an amount of 70% by weight or more. In order to increase the manufacturing efficiency of solid A agent for dialysis, in which sodium chloride accounts for the majority, at least a portion of the trace electrolyte components other than sodium chloride is granulated in advance, and the granules are combined with raw materials such as sodium chloride. It becomes effective to mix.

On the other hand, trace electrolyte components such as calcium chloride and magnesium chloride have the disadvantage of high hygroscopicity, and if these trace electrolyte components are made into granules and blended into dialysis agent A without using sodium chloride, storage There is a problem in that it absorbs moisture and becomes more likely to solidify. Therefore, when granules used in hemodialysis agents do not substantially contain sodium chloride and contain magnesium chloride and/or calcium chloride, it is necessary to Improvements are required.

Conventionally, there are several methods that can improve the storage stability of granules for hemodialysis agents containing trace electrolyte components such as sodium acetate, magnesium chloride, calcium chloride, potassium chloride, etc., without adding sodium chloride. It has been reported that For example, Patent Document 2 does not contain sodium chloride, contains sodium acetate, magnesium chloride, calcium chloride, and potassium chloride, and has a pore diameter of 2000 to 200000 nm relative to an integrated pore volume in a pore diameter of 3 to 200000 nm. It is described that a granulated material for agent A having an integrated pore volume ratio of 50% or less has excellent storage stability and can have high hardness and excellent solubility. Further, Patent Document 3 discloses that a first fraction which is a granulated product that substantially contains only one of magnesium chloride and potassium chloride and also contains calcium chloride, and a second fraction which contains acetic acid and acetate. It is described that the solid hemodialysis agent A containing the compound A has excellent storage stability.

According to the formulation techniques described in Patent Documents 2 and 3, it is possible to provide excellent storage stability, but in order to respond to improvements in manufacturing efficiency, diversification of formulation techniques, etc., formulation techniques different from these are required. Therefore, it is desired to develop a method that can provide granules for hemodialysis agents containing trace electrolyte components with excellent storage stability without the need to contain sodium chloride.

Patent No. 5099464 Japanese Patent Application Publication No. 2016-209485 International Publication No. 2018/079022

An object of the present invention is to provide a granulated product for a hemodialysis agent containing sodium acetate and magnesium chloride and/or calcium chloride and having excellent storage stability. Another object of the present invention is to provide a hemodialysis agent A and a hemodialysis agent using the granules.

The present inventors conducted intensive studies to solve the above problem, and found that magnesium chloride and/or calcium chloride was applied to the surface of core particles that contained acetate but did not substantially contain sodium chloride. It has been found that a granulated product formed with a coating containing the above-mentioned particles has reduced hygroscopicity and can have excellent storage stability. The present invention was completed through further studies based on this knowledge.

That is, the present invention provides the inventions of the following aspects.
Item 1. A granulated product used in a hemodialysis agent,
A granulated product having a core particle and a coating formed on the surface of the core particle,
the core particles contain acetate and are substantially free of sodium chloride;
A granulated material in which the coating portion contains magnesium chloride and/or calcium chloride.
Item 2. Item 2. The granulated product according to Item 1, wherein the acetate is sodium acetate and/or potassium acetate.
Item 3. Item 3. The granulated product according to Item 1 or 2, wherein the coating portion contains an acetate.
Item 4. A mixture of granules used in hemodialysis agents, comprising:
(A) The granulated material according to any one of items 1 to 3,
(B) A granulated mixture comprising: (B) a granulated material in which a coating containing magnesium chloride and/or calcium chloride is formed on the surface of a core particle containing magnesium chloride;
Item 5. A mixture of a first component group consisting of the granules according to any one of Items 1 to 3 or a mixture of the granules according to Item 4, and a second component group containing potassium chloride, acetic acid, and acetate. , Solid A agent for hemodialysis.
Item 6. 6. The solid agent A for hemodialysis according to item 5, wherein the second component group includes sodium chloride and/or glucose.
Section 7. Item 5. The solid state according to Item 5, wherein a coating containing magnesium chloride and/or calcium chloride is not formed on the surface of at least one of potassium chloride, acetic acid, and acetate included in the second component group. Agent A for hemodialysis.
Section 8. 7. The solid agent A for hemodialysis according to item 6, wherein the sodium chloride included in the second component group has no coating portion containing magnesium chloride and/or calcium chloride formed on its surface.
Item 9. Items 5 to 8, wherein the acetic acid and acetate contained in the second component group are at least one selected from the group consisting of a mixture of acetic acid and acetate, an alkali metal diacetate, and a higher acetate compound. A solid agent A for hemodialysis according to any one of the above.
Item 10. 10. The solid agent A for hemodialysis according to any one of Items 5 to 9, wherein the acetate included in the second component group is sodium acetate and/or potassium acetate.
Item 11. A solid hemodialysis agent comprising the solid hemodialysis agent A according to any one of Items 5 to 10 and a hemodialysis agent B containing sodium bicarbonate.
Item 12. A method for producing a solid hemodialysis agent A, comprising:
A first step of obtaining granules by spraying an aqueous solution for forming a coating portion containing magnesium chloride and/or calcium chloride onto core particles containing acetate and substantially free of sodium chloride and drying the mixture. , and a second step of obtaining a preparation containing the granules obtained in the first step, potassium chloride, acetic acid, and acetate;
A method for producing a solid agent A for hemodialysis, comprising:
Item 13. 13. The method for producing a solid agent A for hemodialysis according to item 12, wherein in the second step, the preparation further contains sodium chloride.
Section 14. 14. The method for producing a solid agent A for hemodialysis according to item 12 or 13, wherein in the second step, the preparation further contains glucose.
Item 15. Item 15. The method for producing a solid agent A for hemodialysis according to any one of Items 12 to 14, wherein the aqueous solution for forming the coating portion contains an acetate.

According to the present invention, a granulated product containing sodium acetate, magnesium chloride and/or calcium chloride, and having reduced hygroscopicity and excellent storage stability is provided. Therefore, the hemodialysis agent containing the granules of the present invention can suppress moisture absorption and solidification during storage.

Further, according to the present invention, excellent storage stability can be provided even without containing sodium chloride in the granulated product, and there is no need to granulate sodium chloride, which accounts for most of the hemodialysis agent. Since there is no oxidation, the manufacturing process can be simplified and manufacturing efficiency can be improved.

In addition, in a solid hemodialysis agent, it is important to create a state in which the content is uniformly contained, but in one embodiment of the granules of the present invention, it is incorporated into the hemodialysis agent together with other ingredients. In this case, each component can be distributed uniformly, so it is possible to improve the content uniformity in the hemodialysis agent and suppress fluctuations in the concentration of components in the dialysate each time the dialysate is prepared. I can do it.

1 is a diagram showing a powder X-ray diffraction pattern of a granulated product obtained in Example 1. FIG.

1. Granules for hemodialysis agents The granules of the present invention are used for hemodialysis agents, and include core particles and a coating formed on the surface of the core particles. The granulated product is characterized in that the core particles contain acetate and are substantially free of sodium chloride, and the coating portion contains magnesium chloride and/or calcium chloride. Hereinafter, the granulated material of the present invention will be explained in detail.

[Nuclear particle]
The granulated product of the present invention contains an acetate as a core particle. The acetate is not particularly limited as long as it is acceptable as a component of the hemodialysate, but examples include alkali metal acetates such as sodium acetate and potassium acetate; alkaline earth metal acetates such as calcium acetate and magnesium acetate. Salt is an example. These acetates may be either anhydrous or hydrated. Among these acetates, sodium acetate and potassium acetate are preferred, and sodium acetate is more preferred, from the viewpoint of safety and cost based on a long history of use. Sodium acetate may be in either a hydrate (eg, trihydrate) or anhydrous state.

In the granulated product of the present invention, the core particles do not substantially contain sodium chloride. As used herein, "the core particles do not substantially contain sodium chloride" refers to the fact that they do not contain sodium chloride, except for sodium chloride that is inevitably mixed in or produced as a by-product during the manufacturing process. For example, when sodium acetate is used as the core particle, the magnesium chloride and/or calcium chloride used in the coating may react with the sodium acetate during the manufacturing process, producing a small amount of sodium chloride. The core particles of the granulated product may contain a small amount of sodium chloride produced as a by-product during the manufacturing process.

In the granules of the present invention, the content of acetate contained as core particles is not particularly limited, but for example, the content of acetate contained as core particles per 100 parts by weight of the granules of the present invention in terms of anhydride weight. 8 to 95 parts by weight, preferably 15 to 85 parts by weight, more preferably 20 to 75 parts by weight, still more preferably 50 to 70 parts by weight, based on the weight of the anhydride of the acetate. In the present invention, "anhydrous weight conversion of granules" is a value obtained by converting all components contained in granules into anhydrous weights. When a component is included, it is the weight of the granulated product excluding the weight of crystallization water (water molecules in the hydrate) of the hydrate. In addition, in the present invention, "anhydride weight conversion of acetate" means that when acetate is in the form of a hydrate, the weight of the anhydride is excluded, excluding the weight of crystal water (water molecules in the hydrate). This is the value calculated by converting it to the weight of .

In addition to acetate, calcium ions, magnesium ions, sodium ions (other than sodium chloride), and chlorides may be added to the core particles of the granules of the present invention, as long as they do not impair the effects of the present invention. ion, acetate ion, citrate ion, lactate ion, gluconate ion, succinate ion, malate ion, etc.; other organic acid salts and/or inorganic salts; organic acids; Components may be included.

In the granulated product of the present invention, per 100 parts by weight of the total amount of core particles in terms of anhydride weight, 70 parts by weight or more, preferably 80 parts by weight or more, more preferably 90 parts by weight or more, in terms of anhydride of acetate, and Preferably it accounts for 95 parts by weight or more, particularly preferably 98 parts by weight or more. Further, in a preferred embodiment of the granulated product of the present invention, the core particles do not substantially contain components other than acetate. In the present invention, "anhydrous weight conversion of the core particle" is a value obtained by converting all components contained in the core particle to the weight of anhydride. For example, if the core particle contains a hydrate component, If it is, it is the weight of the core particle excluding the weight of the water of crystallization (water molecules in the hydrate) of the hydrate.

[Coated part]
In the granulated product of the present invention, a coating portion is formed on the surface of the core particle. In the granulated product of the present invention, it is preferable that the coating portion covers the entire surface of the core particle, but does not cover the entire surface of the core particle, and as long as the effect of the present invention is achieved. Part of the surface of the particle may be exposed. That is, in the granulated product of the present invention, a coating portion may be formed on at least a portion of the surface of the core particle. As will be described later, in the production of the granules of the present invention, the acetate serving as the core particles is sprayed with an aqueous coating solution for forming the coating in which the components for forming the coating are dissolved, and then dried. , most of the surface of the core particle can be covered with the coating part.

In the granulated product of the present invention, the coating portion is formed of magnesium chloride and/or calcium chloride.

In the granulated product of the present invention, magnesium chloride is a component that serves as a source of magnesium ions and chloride ions. Magnesium chloride forming the coating portion may be in either a hydrated or anhydrous state.

In the granules of the present invention, calcium chloride is a component that serves as a source of calcium ions and chloride ions. Calcium chloride forming the coating may be in either a hydrated or anhydrous state.

In the granulated product of the present invention, the coating portion may contain only one of magnesium chloride and calcium chloride, or may contain both of these. In one preferred embodiment of the granulated product of the present invention, a granulated product having a coating portion containing both magnesium chloride and calcium chloride; a granulated product having a coating portion containing magnesium chloride but not containing calcium chloride; , a mixture containing calcium chloride and a granulated material having a coating portion not containing magnesium chloride, and the like.

In the granulated product of the present invention, the ratio of acetate constituting the core particle to magnesium chloride and/or calcium chloride contained in the coating portion is determined by the magnesium ion concentration and/or calcium ion concentration of the dialysate to be prepared. It may be set appropriately depending on the situation. For example, in the case of magnesium chloride, 1 to 100 parts by weight, preferably 3 to 50 parts by weight of magnesium chloride contained in the coating, in terms of anhydride, per 100 parts by weight of acetate constituting the core particle, calculated in terms of anhydride. parts, more preferably 10 to 35 parts by weight, still more preferably 15 to 25 parts by weight. For example, in the case of calcium chloride, 1 to 200 parts by weight, preferably 5 to 200 parts by weight of calcium chloride contained in the coating, in terms of anhydride, per 100 parts by weight of acetate constituting the core particle, calculated in terms of anhydride. Examples include 200 parts by weight, more preferably 20 to 80 parts by weight, still more preferably 40 to 75 parts by weight, even more preferably 45 to 75 parts by weight. In the present invention, "magnesium chloride in terms of anhydrous weight" means, when magnesium chloride is in the form of a hydrate, the weight of the anhydrous product excluding the weight of crystal water (water molecules in the hydrate). "Anhydrous weight conversion of calcium chloride" means that when calcium chloride is in the form of a hydrate, the weight of crystal water (water molecules in the hydrate) is excluded. This is the value calculated by converting it to the weight of the anhydride.

In addition, in the granulated product of the present invention, the content of magnesium chloride and/or calcium chloride contained in the coating part depends on the above-mentioned ratio, the magnesium ion concentration and/or calcium ion concentration of the dialysate to be prepared, etc. You can set it as appropriate. For example, in the case of magnesium chloride, 1 to 55 parts by weight, preferably 3 to 55 parts by weight of magnesium chloride contained in the coating, in terms of anhydride, per 100 parts by weight of the granulated product of the present invention in terms of anhydride. Examples include 35 parts by weight, more preferably 5 to 16 parts by weight, even more preferably 6 to 13 parts by weight. For example, in the case of calcium chloride, it is preferably 1 to 75 parts by weight of calcium chloride contained in the coated portion in terms of anhydride weight per 100 parts by weight of the granulated product of the present invention in terms of anhydride weight. Examples include 5 to 50 parts by weight, more preferably 15 to 35 parts by weight, and even more preferably 22 to 33 parts by weight.

Moreover, in the granulated product of the present invention, the coating portion may contain acetate in addition to magnesium chloride and/or calcium chloride. Specific examples of the acetate to be contained in the coating include sodium acetate and/or potassium acetate. The sodium acetate and/or potassium acetate forming the coating may be in either a hydrated or anhydrous state.

When acetate is contained in the coating portion of the granules of the present invention, the ratio of acetate contained in the coating portion includes the content of acetate contained as core particles, the sodium ion concentration of the dialysate to be prepared, and the proportion of acetate contained in the coating portion. It may be set as appropriate depending on/or potassium ion concentration and/or acetate ion concentration. For example, per 100 parts by weight of acetate constituting the core particle, the acetate contained in the coating part is 1 to 500 parts by weight, preferably 1 to 300 parts by weight, more preferably 1 to 150 parts by weight, and further Preferably, the amount is 1 to 100 parts by weight. More specifically, if sodium acetate is contained in the coating, 1 to 300 parts by weight, preferably in terms of anhydrous sodium acetate contained in the coating, per 100 parts by weight of acetate constituting the core particle. is 1 to 100 parts by weight, more preferably 1 to 75 parts by weight, even more preferably 1 to 50 parts by weight. If potassium acetate is contained in the coating, 1 to 360 parts by weight, preferably 1 to 120 parts by weight of potassium acetate contained in the coating in terms of anhydride, per 100 parts by weight of acetate constituting the core particle. Parts by weight, more preferably 1 to 2 parts by weight.

In addition, when acetate is contained in the coated portion of the granules of the present invention, the content of acetate contained in the coated portion includes the above-mentioned ratio, the sodium ion concentration and/or potassium ion concentration of the dialysate to be prepared. It may be set as appropriate depending on the concentration and/or acetate ion concentration. For example, per 100 parts by weight of the granulated product of the present invention in terms of anhydride weight, the acetate contained in the coating part is 1 to 90 parts by weight, preferably 1 to 70 parts by weight, more preferably 1 part by weight in terms of anhydride. ~55 parts by weight. More specifically, if sodium acetate is contained in the coating, the amount of sodium acetate contained in the coating in terms of anhydride is 1 per 100 parts by weight of the granulated product of the present invention in terms of anhydride. ~60 parts by weight, preferably 1 to 45 parts by weight, more preferably 1 to 35 parts by weight, still more preferably 16 to 20 parts by weight. In addition, if the coating part contains potassium acetate, 1 to 70 parts by weight of potassium acetate contained in the coating part in terms of anhydride per 100 parts by weight of the granulated product of the present invention in terms of anhydride weight. , preferably 1 to 55 parts by weight, more preferably 1 to 45 parts by weight.

In addition to magnesium chloride and/or calcium chloride, calcium ions, magnesium ions, sodium ions, potassium ions may be added to the coating portion of the granules of the present invention as long as the effects of the present invention are not impaired. , other organic and/or inorganic salts as sources of chloride ions, acetate ions, citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc.; organic acids; blood such as glucose; Components of the dialysate may also be included. Further, the coating portion may have a double salt of magnesium chloride and/or calcium chloride and any of the above components generated therein, or may contain the double salt generated in advance.

In one embodiment of the granulated product of the present invention, the total amount of magnesium chloride and/or calcium chloride contained in the coating part is 70 parts by weight or more in terms of anhydride weight per 100 parts by weight of the coating part in terms of anhydride weight, Preferably it accounts for 80 parts by weight or more, more preferably 90 parts by weight or more, still more preferably 95 parts by weight or more, particularly preferably 98 parts by weight or more. In the present invention, the "anhydride weight conversion of the coating part" is a value obtained by converting all components contained in the coating part to the weight of anhydride. For example, if the coating part contains hydrate components, If it is, it is the weight of the coated portion excluding the weight of crystal water (water molecules in the hydrate) of the hydrate. Further, as a preferred embodiment of the granulated product of the present invention, the coating portion does not substantially contain components other than magnesium chloride and/or calcium chloride; and the coating portion does not contain any components other than magnesium chloride, calcium chloride, and sodium acetate. One example is that it does not contain substantially any of the following components. In the present invention, "substantially free" refers to the absence of other components, except for components that are unavoidably mixed or by-produced during the manufacturing process. For example, when using sodium acetate as the core particle, during the manufacturing process, the magnesium chloride and/or calcium chloride used in the coating portion reacts with the sodium acetate, and a small amount of magnesium acetate and/or calcium acetate is deposited on the surface of the core particle or in the core. Although it may be generated at the boundary between the particles and the coating, the coating of the granules of the present invention contains small amounts of magnesium acetate and/or calcium acetate, which are produced as by-products in the manufacturing process. Good too.

Moreover, in the granulated product of the present invention, the coating portion may have either a single layer structure or a multilayer structure.

When the covering part has a single-layer structure, the single-layer covering part may be formed of a mixture containing magnesium chloride and/or calcium chloride and, if necessary, acetate.

Furthermore, when the covering part has a multilayer structure, the components forming the covering part may be divided into two or more parts, and a plurality of covering parts may be laminated. When the covering part has a multilayer structure, the number of layers in the covering part is, for example, 2 to 4 layers, preferably 2 or 3 layers, and more preferably 2 layers. In addition, as an embodiment when the coating part has a multilayer structure, a first coating part containing magnesium chloride and not containing calcium chloride is provided on the core particle side, and the surface of the first coating part (the core particle is a two-layered coating having a second coating that contains calcium chloride and does not contain magnesium chloride (on the opposite surface); a first coating that contains calcium chloride and does not contain magnesium chloride on the core particle side; core particle A first coating section containing magnesium chloride and/or calcium chloride is provided on the side, and a second coating section containing acetate is provided on the surface of the first coating section (the surface opposite to the core particle). Coating part with layered structure; Coating part with three-layer structure in which a coating part containing magnesium chloride, a coating part containing calcium chloride, and a coating part containing acetate are laminated in any order from the core particle side; core A four-layered coating section, etc., in which a coating section containing magnesium chloride, a coating section containing calcium chloride, a coating section containing sodium acetate, and a coating section containing potassium acetate are laminated in any order from the particle side. Can be mentioned.

[Particle size]
The particle size distribution of the granules of the present invention is not particularly limited, but for example, the ratio of particle diameters of more than 500 μm and 1700 μm or less is 50 to 100% by weight, preferably 67 to 100% by weight, more preferably 67 to 92% by weight. % by weight. Here, the value of the particle size distribution of the granules is determined using sieves (openings 1700 μm, 1000 μm, 850 μm, 710 μm, 500 μm, 355 μm, 250 μm, and 180 μm), and is the value measured according to “General Test Methods 3.04 Particle Size Measurement Method 2. Method 2 Sieving Method” described in the 18th edition of the Japanese Pharmacopoeia. The ratio of particle diameters of more than 500 μm and 1700 μm or less is the ratio of the weight of the granules that passed through a sieve with an opening of 1700 μm but did not pass through a sieve with an opening of 500 μm to the total weight of the granules. Calculated.

y(50)：中位径（D50）
x₁：重量累積が50％未満になる最後の篩（重量累積50％未満を満たす目 開きが最小の篩）までの重量累積量（％）
x₂：重量累積が50％以上になる最初の篩（重量累積50％以上を満たす目 開きが最大の篩）までの重量累積量（％）
y₁：重量累積が50％未満になる最後の篩の目開き（μｍ）
y₂：重量累積が50％以上になる最初の篩の目開き（μｍ）Further, the average particle diameter of the granulated product of the present invention is not particularly limited, but may be, for example, 300 to 2000 μm, preferably 400 to 1500 μm, and more preferably 500 to 1200 μm. Here, the value of the average particle diameter of the granules is the median diameter (D50, weight cumulative 50%) calculated from the particle size distribution, and specifically, the value of the particle size distribution measured by the method described above. This is the value calculated according to the following formula.

y(50): Median diameter (D50)
x ₁ : Cumulative weight amount (%) up to the last sieve where the cumulative weight is less than 50% (the sieve with the smallest opening that satisfies the cumulative weight of less than 50%)
x ₂ : Cumulative weight (%) up to the first sieve with a cumulative weight of 50% or more (the sieve with the largest opening that satisfies the cumulative weight of 50% or more)
y ₁ : The opening of the last sieve where the weight accumulation is less than 50% (μm)
y ₂ : The first sieve opening where the weight accumulation is 50% or more (μm)

[Production method]
Regarding the method for producing granules of the present invention, it is particularly important that a coating containing magnesium chloride and/or calcium chloride can be formed on the surface of core particles containing acetate and substantially free of sodium chloride. Although not limited thereto, a suitable example is a method in which core particles containing acetate are sprayed with an aqueous solution for forming a covering portion in which magnesium chloride and/or calcium chloride is dissolved and then dried. If the coating part is to have a multilayer structure, prepare two or more types of coating part forming aqueous solutions corresponding to each layer of the coating part, and apply two or more types of coating part forming aqueous solutions to the core particles containing acetate. This can be done by spraying an aqueous solution in stages and drying.

The concentration of magnesium chloride and/or calcium chloride in the aqueous solution for forming the coating part may be set appropriately depending on the type and scale of the manufacturing equipment, but it is said that it is necessary to suppress the occurrence of unevenness in the coating part that is formed. From this point of view, 1 to 60% by weight, preferably 1 to 50% by weight, more preferably 3 to 30% by weight, even more preferably 4 to 11% by weight, calculated as anhydrous magnesium chloride, and/or anhydrous calcium chloride. Examples include 1 to 50% by weight, preferably 3 to 45% by weight, more preferably 5 to 40% by weight, and still more preferably 10 to 40% by weight.

Further, when the coating portion contains an acetate, the acetate may be contained in the aqueous solution for forming the coating portion. The concentration of acetate in the aqueous solution for forming the coating portion may be set as appropriate depending on the type of acetate, the type and scale of the manufacturing equipment, etc., but for example, the concentration of acetate may be 1 to 70% by weight in terms of anhydride. , preferably 5 to 65% by weight, more preferably 5 to 55% by weight. More specifically, when the acetate is sodium acetate, the concentration of sodium acetate in the aqueous solution for coating part formation is 5 to 50% by weight, preferably 5 to 45% by weight, more preferably 5 to 45% by weight. Examples include 5 to 35% by weight. In addition, when the acetate is potassium acetate, the concentration of potassium acetate in the aqueous solution for forming the coating portion in terms of anhydride is 6 to 60% by weight, preferably 6 to 55% by weight, more preferably 6 to 42% by weight. % is mentioned.

The amount of the coating part forming aqueous solution to be sprayed onto the core particles containing acetate depends on the concentration of magnesium chloride and/or calcium chloride in the coating part forming aqueous solution, and the relationship between the core particles and the coating part of the granules to be produced. For example, the amount of the aqueous solution for forming the coating portion may be 100 to 6000 g, preferably 200 to 3000 g, and more preferably 300 to 2600 g per 1 kg of core particles containing acetate. Here, the "amount of aqueous solution for coating part formation to be sprayed" is the amount of aqueous solution for coating part formation required to form one layer of coating part. For example, when forming a coating part with a single layer structure, The above amount of the aqueous coating solution may be sprayed onto the core particles, and in the case of forming a multilayered coating, the above amount of the coating solution may be sprayed to form one layer of the coating. Just spray an aqueous solution.

Further, the temperature conditions when spraying the aqueous solution for forming the coating portion onto the core particles containing acetate are not particularly limited, but are, for example, 20 to 200°C, preferably 40 to 150°C, more preferably 80 to 150°C. For example, 130°C.

In order to spray the coating portion forming aqueous solution onto the core particles containing acetate, a fluid granulation coating device such as a tumbling fluid granulation coating device may be used, for example.

In the production of the granules of the present invention, drying may be carried out after spraying an aqueous solution for forming a coating on the core particles containing acetate. Drying may be performed while spraying the aqueous solution. The drying conditions may be appropriately set depending on the amount of core particles used, the amount of spraying of the aqueous solution for forming the covering portion, and the like. For example, the drying temperature may be 80 to 200°C, preferably 90 to 160°C, more preferably 100 to 150°C. Further, the drying time is 1 to 60 minutes, preferably 5 to 45 minutes, and more preferably 10 to 30 minutes.

[Application]
The granulated product of the present invention is used by being mixed into a hemodialysis agent. The type of hemodialysis agent to which the granules of the present invention are blended is not particularly limited, but it is preferably used in combination with a bicarbonate dialysis agent, particularly a dialysis agent A of a bicarbonate dialysis agent. .

[Form of mixture with other granules]
The granulated product of the present invention can also be provided in the form of a mixture with other granulated products. As one embodiment of a mixture of the granules of the present invention and other granules, a coating portion containing magnesium chloride and/or calcium chloride is provided on the surface of the core particles containing the granules of the present invention and magnesium chloride. A granulated material (hereinafter sometimes referred to as a "second granulated material") in which is formed is mentioned. When the granulated material of the present invention is mixed with the second granulated material, even if the water content is relatively high, hygroscopicity is reduced and excellent storage stability is provided. becomes possible.

In the second granule, the core particles contain magnesium chloride. Magnesium chloride forming the core particles of the second granules may be in either a hydrated or anhydrous state.

In the second granules, the content of core particles is not particularly limited, but for example, per 100 parts by weight of the second granules in terms of anhydride weight, magnesium chloride contained as core particles is The amount is 20 to 95 parts by weight, preferably 40 to 85 parts by weight, and more preferably 50 to 75 parts by weight.

In addition to magnesium chloride, the core particles of the second granulate are supplied with sodium ions (other than sodium chloride), citrate ions, lactate ions, gluconate ions, succinate ions, malate ions, etc., as necessary. Other organic and/or inorganic salts as sources; organic acids; constituents of the hemodialysate such as glucose may also be included.

In the second granule, a coating portion containing magnesium chloride and/or calcium chloride is formed on the surface of the core particle. In the second granule, the covering part preferably covers the entire surface of the core particle, but does not cover the entire surface of the core particle, leaving a part of the surface of the core particle exposed. It may be.

In the second granule, the magnesium chloride and/or calcium chloride contained in the coating portion may be in either a hydrated state or an anhydrous state. In the granulated product of the present invention, the coating portion may contain only one of magnesium chloride and calcium chloride, or may contain both of these.

In the second granule, the ratio of the core particles to the coating portion may be appropriately set depending on the composition required for the dialysate to be prepared. For example, if the coating part of the second granule contains magnesium chloride, the amount of magnesium chloride contained in the coating part is 1 to 200 parts by weight in terms of anhydride per 100 parts by weight of the core particles in terms of anhydride. parts, preferably 1 to 100 parts by weight, more preferably 1 to 75 parts by weight, still more preferably 30 to 70 parts by weight. In addition, if calcium chloride is contained in the coating part of the second granule, 1 to 200 weight parts of calcium chloride contained in the coating part in terms of anhydride per 100 parts by weight of the total amount of the core particles in terms of anhydride. parts, preferably 5 to 200 parts by weight, more preferably 10 to 100 parts by weight, still more preferably 20 to 80 parts by weight, even more preferably 30 to 70 parts by weight.

In addition, in the second granules, the content of magnesium chloride and/or calcium chloride contained in the coating portion varies depending on the ratio described above, the magnesium ion concentration and/or calcium ion concentration of the dialysate to be prepared, etc. You can set it as appropriate. For example, if the coating portion contains magnesium chloride, the amount of magnesium chloride contained in the coating portion is preferably 1 to 55 parts by weight in terms of anhydride per 100 parts by weight of the second granulated product in terms of anhydride. is 1 to 35 parts by weight, more preferably 1 to 15 parts by weight, even more preferably 1 to 10 parts by weight. For example, if the coating portion contains calcium chloride, 1 to 75 parts by weight of calcium chloride contained in the coating portion in terms of anhydride per 100 parts by weight of the second granulated product in terms of anhydride. , preferably 5 to 50 parts by weight, more preferably 10 to 45 parts by weight, still more preferably 20 to 40 parts by weight.

In addition to magnesium chloride and/or calcium chloride, the coating portion of the second granules may contain calcium ions, magnesium ions, sodium ions, potassium ions, chloride ions, acetate ions, citrate ions, lactic acid ions, etc. Other organic acid salts and/or inorganic salts that serve as sources of ions, gluconate ions, succinate ions, malate ions, etc.; organic acids; components of the hemodialysate such as glucose may also be included. Further, the coating portion may have a double salt of magnesium chloride and/or calcium chloride and any of the above components generated therein, or may contain the double salt generated in advance.

Moreover, in the second granulated product, the coating portion may have either a single layer structure or a multilayer structure.

Specific examples of the second granules include a granule in which a coating portion containing calcium chloride is formed on the surface of a core particle containing magnesium chloride; a granule containing calcium chloride and magnesium chloride on the surface of a core particle containing magnesium chloride; Examples include granules with a coating formed thereon; mixtures thereof; and the like.

The particle diameter of the second granulated product is the same as that of the granulated product of the present invention.

In the mixture of the granules of the present invention and the second granules, these ratios are not particularly limited, but for example, per 100 parts by weight of the total mixture of the granules of the present invention and the second granules, The ratio of the granulated material of the present invention is 1 to 50 parts by weight, preferably 2 to 25 parts by weight, and more preferably 3 to 15 parts by weight.

The second granulated product can be produced, for example, in the same manner as the granulated product of the present invention, except that magnesium chloride is used instead of acetate as the core particle.

Further, in the method for producing the granulated product of the present invention, the granulated product of the present invention and the second granulated product are mixed by mixing acetate and magnesium chloride, and spraying the aqueous solution for forming a coating portion thereon and drying the mixture. A mixture of granules can also be obtained directly. In such a method, when magnesium chloride is mixed with acetate in a sufficiently dried state, the granules of the present invention and particles containing magnesium chloride as the core particles and magnesium chloride and/or calcium chloride as the coating part are combined. A mixture with 2 granules is obtained. In addition, in this method, if magnesium chloride is mixed with acetate without being sufficiently dried, part of the magnesium chloride and part of the acetate may be mixed with each other before spraying the aqueous coating solution. Therefore, the granules of the present invention, the second granules containing magnesium chloride as the core particles and magnesium chloride and/or calcium chloride as the coating, and the granules of the present invention containing magnesium chloride and/or calcium chloride as the core particles, A mixture of the reaction product of magnesium and acetate and a second granulate containing magnesium chloride and/or calcium chloride as a coating may be obtained.

2. A preferred embodiment of the dialysis agent A in a solid state includes a first component group consisting of the granules (including the case of a mixture with a second granulate); , a solid dialysis agent A (hereinafter referred to as dialysis agent A of the present invention) which is a mixture with a second component group containing potassium chloride, acetic acid, and an acetate. That is, in the agent A for dialysis of the present invention, components other than the granules are included as the second component group. Hereinafter, agent A for dialysis of the present invention will be explained.

[First component group]
The dialysis agent A of the present invention includes the granules as the first component group. Regarding the content of the granules in the dialysis agent A of the present invention, the amount of magnesium chloride and/or calcium chloride contained in the granules, the amount of other magnesium salts and/or calcium contained in the second component group, Taking into consideration the salt content, etc., the concentration may be appropriately set so as to satisfy the magnesium ion concentration and/or calcium ion concentration required in the hemodialysate to be prepared. Specifically, the content of the granules in the dialysis agent A of the present invention is such that the magnesium ion concentration in the prepared hemodialysate is 0.5 to 2.0 mEq/L, preferably 0.75 to 2.0 mEq/L. The concentration may be set to 1.5 mEq/L and/or the calcium ion concentration to be 1.5 to 4.5 mEq/L, preferably 2.5 to 3.5 mEq/L.

More specifically, when the dialysis agent A contains sodium chloride, the content of the granules in the dialysis agent A of the present invention is per 100 parts by weight of the total electrolyte component contained in the dialysis agent A. Examples include 1 to 15 parts by weight, preferably 5 to 13 parts by weight, and more preferably 7 to 11 parts by weight. In addition, when the dialysis agent A does not contain sodium chloride, 45 to 75 parts by weight, preferably 53 to 68 parts by weight, more preferably 57 to 64 parts by weight, per 100 parts by weight of the total electrolyte component contained in the dialysis agent A. What is necessary is just to set it so that it becomes a weight part.

[Second component group]
- Potassium chloride Potassium chloride, included as the second component group, is a substance that serves as a source of potassium ions. Regarding the content of potassium chloride in agent A for dialysis of the present invention, the amount of potassium salt contained as necessary in the granules of the first component group, and the content of other potassium salts contained in the second component group. Taking these factors into consideration, the potassium ion concentration may be appropriately set so as to satisfy the required potassium ion concentration in the hemodialysate to be prepared. Specifically, the content of potassium chloride in agent A for dialysis of the present invention is such that the potassium ion concentration is 0.5 to 3 mEq/L and 1.5 to 2.5 mEq/L in the hemodialysate to be prepared. Just set it so that

More specifically, when the agent A for dialysis contains sodium chloride, the content of potassium chloride contained as the second component group is 1 to 4 parts by weight per 100 parts by weight of the total amount of electrolyte components contained in the agent A for dialysis. Parts by weight, preferably 2 to 4 parts by weight, more preferably 2 to 3 parts by weight. In addition, when the dialysis agent A does not contain sodium chloride, the potassium chloride content is 1 to 20 parts by weight, preferably 8 to 20 parts by weight, per 100 parts by weight of the total electrolyte component contained in the dialysis agent A. More preferably, it is 12 to 18 parts by weight.

- Acetic acid and acetate The acetic acid included as the second component group may be glacial acetic acid. The acetate included as the second component group is not particularly limited as long as it is acceptable as a component of the hemodialysate, but examples include alkali metal acetates such as sodium acetate and potassium acetate; calcium acetate, and acetate. Examples include acetic acid alkaline earth metal salts such as magnesium. These acetates may be acetate anhydrides. Among these acetates, from the viewpoint of safety and cost based on a long history of use, alkali metal acetates are preferred, and sodium acetate is more preferred. Moreover, these acetates may be used alone or in combination of two or more types, and it is preferable that acetic acid and acetate are used in the form of a mixture.

Furthermore, at least a portion of the acetic acid and acetate included in the second component group may be in the form of an alkali metal diacetate salt. By using an alkali metal diacetate salt, it becomes possible to further improve storage stability, reduce acetic acid odor, and suppress decomposition of glucose when glucose is present. Alkali metal diacetate is a complex of 1 mole of alkali metal acetate and 1 mole of acetic acid (MH(C ₂ H ₃ O ₂ ) ₂ ; M represents an alkali metal atom). One mole of metal salt supplies one mole of acetate (alkali metal acetate) and one mole of acetic acid. Specific examples of the alkali metal diacetate used in the present invention include sodium diacetate, potassium diacetate, and the like. These alkali metal diacetic acid salts may be used alone or in combination of two or more. Among the alkali metal salts of diacetate, sodium diacetate is preferred.

Furthermore, at least a portion of the acetic acid and acetate included in the second component group may be in the form of a higher acetate compound. A higher acetate compound is a compound produced by combining acetic acid (primary compound) and acetate (primary compound) with each other.

Furthermore, the molar ratio of acetic acid and acetate contained in the second component group is not particularly limited and may be set appropriately based on the pH range to be applied to the hemodialysate. The molar ratio of acetic acid contained: acetate contained in agent A for dialysis is 1:0.5 to 10, preferably 1:0.5 to 6.0, more preferably 1:0.5 to 3.0. , more preferably 1:0.7 to 2.0. Here, the acetic acid contained in agent A for dialysis is the total amount of acetic acid contained as necessary in the granules of the first component group and acetic acid contained as the second component group, and the amount of acetic acid contained in agent A for dialysis is The acetate contained in the granules is the total amount of acetate contained as the core particles of the granules in the first component group, acetate contained in the coating as necessary, and acetate contained in the second component group. be. In addition, when acetic acid and acetate include an alkali metal salt of diacetate, the acetic acid and acetate derived from 1 mole of alkali metal diacetate are calculated as follows: 1 mole of acetic acid and 1 mole of acetate. . In addition, when acetic acid and acetate include a higher order acetate compound, if the molar ratio of acetic acid:acetate in the higher order acetate compound is 1:X, the origin is derived from 1 mole of the higher order acetate compound. The molar ratio of acetic acid and acetate is calculated assuming that 1 mole of acetic acid and X moles of acetate.

In the dialysis agent A of the present invention, the content of acetic acid and acetate contained in the second component group is as follows: The concentration of acetic acid may be appropriately set in consideration of the amount of acetic acid contained in the hemodialysate to be prepared. Specifically, in the dialysis agent A of the present invention, the content of acetic acid and acetate included as the second component group is such that the acetate ion concentration is 0.5 to 12 mEq/L in the prepared hemodialysate, It may be appropriately set to preferably 1.5 to 10 mEq/L, more preferably 2 to 10 mEq/L, still more preferably 10 mEq/L, 8 mEq/L, 6 mEq/L, or 4.2 mEq/L. .

More specifically, when the dialysis agent A contains sodium chloride, the total amount of acetic acid and acetate contained as the second component group is 1 to 100 parts by weight of the total electrolyte component contained in the dialysis agent A. 6 parts by weight, preferably 3 to 6 parts by weight, more preferably 4 to 5 parts by weight. In addition, when the dialysis agent A does not contain sodium chloride, the total amount of acetic acid and acetate is 1 to 33 parts by weight, preferably 18 to 33 parts by weight, per 100 parts by weight of the total electrolyte component contained in the dialysis agent A. , more preferably 22 to 29 parts by weight.

- Sodium chloride Sodium chloride may be included as the second component group in the agent A for dialysis of the present invention. When the dialysis agent A of the present invention contains sodium chloride as the second component group, the dialysis agent A of the present invention can be combined with the dialysis agent B containing sodium bicarbonate to form a two-drug type bicarbonate dialysis. It can be provided as a dosage form. In addition, when sodium chloride is not included as the second component group in the dialysis agent A of the present invention, the dialysis agent A of the present invention can be used as a hemodialysis agent S containing sodium chloride and a blood serum containing sodium bicarbonate. In combination with agent B for dialysis, it can be provided as a three-drug type bicarbonate dialysis agent.

When sodium chloride is included as the second component group in agent A for dialysis of the present invention, the content should be such that the sodium ion concentration of the hemodialysate to be prepared is 120 to 150 mEq/L, preferably 135 to 145 mEq/L. It may be set as appropriate, taking into consideration the content of other sodium salts contained in the dialysis agent.

When sodium chloride is contained as the second component group in the dialysis agent A of the present invention, more specifically, the chloride contained as the second component group per 100 parts by weight of the total electrolyte component contained in the dialysis agent A. The total amount of sodium is 70 to 95 parts by weight, preferably 78 to 89 parts by weight, and more preferably 80 to 87 parts by weight.

- Glucose In the dialysis agent A of the present invention, glucose may be included as the second component group for the purpose of maintaining the patient's blood sugar level.

When glucose is contained as the second component group in the dialysis agent A of the present invention, the content is adjusted by taking into consideration the amount of glucose contained in the granules of the first component group as necessary. It may be set as appropriate to satisfy the glucose concentration required in the hemodialysate. Specifically, the glucose content in the dialysis agent A of the present invention is such that the glucose concentration in the prepared hemodialysate is 0 to 2.5 g/L, preferably 1.0 to 2.0 g/L. You can set it as appropriate.

More specifically, the content of glucose contained as the second component group is 5 to 30 parts by weight, preferably 7 to 25 parts by weight, per 100 parts by weight of the total amount of electrolyte components contained in agent A for dialysis. Preferably, the amount is 10 to 20 parts by weight.

- Magnesium chloride In the A agent for dialysis of the present invention, when magnesium chloride is not contained in the granules of the first component group, or when magnesium chloride is contained in the granules of the first component group, hemodialysis is prepared. If the required magnesium ion concentration in the liquid cannot be satisfied, it is preferable to include magnesium chloride as the second component group.

When magnesium chloride is contained as the second component group in agent A for dialysis of the present invention, its content is determined based on the content of magnesium chloride in the granules of the first component group, and the content of magnesium chloride in the granules of the first component group, and the content of magnesium chloride in the granules of the first component group. Taking into consideration the content of magnesium salt, etc., the concentration may be appropriately set so as to satisfy the required magnesium ion concentration in the hemodialysate to be prepared. Specifically, when magnesium chloride is contained as the second component group in agent A for dialysis of the present invention, the content is such that the magnesium ion concentration is 0.5 to 2.0 mEq/in the hemodialysate to be prepared. L, preferably 0.75 to 1.5 mEq/L.

- Calcium chloride In the dialysis agent A of the present invention, when calcium chloride is not included in the granules of the first component group, or when calcium chloride is contained in the granules of the first component group, hemodialysis is performed. If the required calcium ion concentration cannot be satisfied in the liquid, it is preferable to include calcium chloride as the second component group.

When calcium chloride is contained as the second component group in the dialysis agent A of the present invention, the content is determined based on the content of calcium chloride in the granules of the first component group, and the content of other calcium chloride contained in the second component group. Taking into consideration the content of calcium salt, etc., the concentration may be appropriately set so as to satisfy the calcium ion concentration required in the hemodialysate to be prepared. Specifically, when calcium chloride is contained as the second component group in the dialysis agent A of the present invention, the content is such that the calcium ion concentration in the prepared hemodialysate is 1.5 to 4.5 mEq/ L, preferably 2.5 to 3.5 mEq/L.

・Other components In addition to the above-mentioned components, the second component group in the dialysis agent A of the present invention may include calcium ions, magnesium ions, sodium ions, potassium ions, chloride ions, acetate ions, citric ions, Other organic acid salts serving as sources of acid ions, lactate ions, gluconate ions, succinate ions, malate ions, etc. may also be included.

Examples of compounds that serve as sources of calcium ions include calcium salts of organic acids such as calcium lactate, calcium citrate, calcium gluconate, calcium succinate, and calcium malate. These calcium salts of organic acids may be used alone or in combination of two or more.

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

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

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

These organic acid salts may be appropriately selected depending on the types of various ions to be contained in the finally prepared dialysate. Moreover, in the second component group of the agent A for dialysis of the present invention, the content of these organic acid salts is appropriately set according to the concentration of each ion with which the dialysate to be prepared is prepared. Specifically, the content of the organic acid salt, which is optionally included as the second component group of the agent A for dialysis of the present invention, is such that the final dialysate has a concentration of each ion shown in Table 1 below. It may be set as appropriate to satisfy the following.

The second component group in the agent A for dialysis of the present invention may contain a pH adjuster other than acetic acid and acetate, if necessary. The pH regulator that can be used in Agent A for hemodialysis of the present invention is not particularly limited as long as it is acceptable as a component of the dialysate, but examples include liquid acids such as hydrochloric acid, lactic acid, and gluconic acid; Examples include solid acids such as citric acid, succinic acid, fumaric acid, malic acid, and glucono delta-lactone, and their sodium, potassium, calcium, and magnesium salts. Among these pH adjusters, organic acids are preferably used. The pH adjusters may be used alone or in combination of two or more.

In one embodiment of the dialysis agent A of the present invention, at least one of the components included in the second component group has no coating containing magnesium chloride and/or calcium chloride formed on its surface. . More specifically, as an embodiment of the dialysis agent A of the present invention, at least one (preferably all) of potassium chloride, acetic acid, and acetate included as the second component group has magnesium chloride and /Or a covering portion containing calcium chloride is not formed. Further, when sodium chloride is included as the second component group, magnesium chloride and/or a coating containing magnesium chloride is not formed on the surface of the sodium chloride. Here, "a coating containing magnesium chloride and/or calcium chloride is not formed on the surface of at least one of the components included in the second component group" means that the components included in the second component group are , refers to not being coated (coated) with magnesium chloride and/or calcium chloride, for example, "spraying a solution in which magnesium chloride and/or calcium chloride is dissolved onto the components included in the second component group". This means that "dried particles" are not included.

[pH characteristics]
Agent A for dialysis of the present invention may have a pH of 7.2 to 7.6, preferably 7.2 to 7.5, when a hemodialysate is prepared. The pH of the hemodialysate can be adjusted by adjusting the amount of acetic acid and acetate contained in the agent A for dialysis of the present invention, and the amount of a pH adjuster added as necessary.

[form]
The dialysis agent A of the present invention is a solid preparation in which the first component group and the second component group are mixed in predetermined amounts. In the dialysis agent A of the present invention, each component included in the second component group may be either a powder or a granule, or a mixture of powder and granules.

[Production method]
The dialysis agent A of the present invention is produced by mixing a predetermined amount of the granulated material used as the first component group and each component used as the second component group.

3. Hemodialysis agent The dialysis agent A is combined with a dialysis agent B containing sodium bicarbonate to provide a hemodialysis agent (hereinafter referred to as the hemodialysis agent of the present invention).

The B agent for dialysis is preferably in solid form from the viewpoint of transportation and storage. Specific examples of the form of the solid B agent for dialysis include powders, granules, and the like. The amount of the B agent for dialysis to be used may be appropriately set so that the bicarbonate ion in the prepared hemodialysate is 20 to 40 mEq/L, preferably 25 to 35 mEq/L.

When the dialysis agent A contains sodium chloride, the hemodialysis agent of the present invention can be provided by combining the dialysis agent A and the dialysis agent B.

In addition, when the dialysis agent A does not contain sodium chloride, the hemodialysis agent of the present invention is a dialysis agent containing sodium chloride in addition to the dialysis agent A and the dialysis agent B. A combination of agents can be provided. As described in Patent Document 1, the hemodialysis agent provided with the S agent for dialysis can be prepared by adjusting the ratio of the amounts of the S agent for dialysis and the B agent for dialysis during hemodialysis. It becomes possible to prepare a hemodialysate that can maintain a constant concentration of electrolytes such as sodium, potassium, calcium, and magnesium while freely changing the bicarbonate ion concentration even during hemodialysis depending on the patient's pathological condition. The S agent for dialysis is preferably in solid form from the viewpoint of transportation and storage. Specific examples of the solid S agent for dialysis include powders, granules, and the like. The amount of the S agent for dialysis to be used is appropriately set, taking into account the amount of sodium salt in the A agent for hemodialysis, etc., so that the final hemodialysate prepared satisfies the sodium concentration shown in Table 1. do it.

If the dialysis agent A does not contain glucose, or if the glucose contained in the dialysis agent A cannot satisfy the glucose concentration required in the hemodialysate to be prepared, the dialysis agent The B agent or the S agent for dialysis may contain glucose as necessary. When the B agent for dialysis or the S agent for dialysis contains glucose, the glucose content is such that the glucose concentration in the final hemodialysate is 0 to 2.5 g/L, preferably 1.0 to 2.5 g/L. What is necessary is just to set it suitably so that it may become 1.5 g/L. However, the agent B for dialysis desirably does not contain any electrolyte components other than sodium bicarbonate, and it is preferable that the contained components consist essentially of sodium bicarbonate. Further, it is desirable that the S agent for dialysis does not contain any electrolyte components other than sodium chloride, and it is preferable that the contained components consist essentially of sodium chloride.

In addition, if the dialysis agent A does not contain glucose, or if the glucose contained in the dialysis agent A cannot satisfy the glucose concentration required in the hemodialysate to be prepared, The dialysis A agent may be provided in combination with the dialysis A-1 agent and the dialysis A-2 agent consisting of glucose. That is, when the dialysis agent A contains sodium chloride, the hemodialysis agent of the present invention contains the dialysis agent A (including both glucose-containing and non-glucose containing cases) and the dialysis agent A of the present invention. A two-drug type hemodialysis agent consisting of agent B; or consisting of the agent A-1 for dialysis (the agent A for dialysis that does not contain glucose), the agent A-2 for dialysis, and the agent B for dialysis It can be provided as a three-drug type hemodialysis drug. Further, when the dialysis agent A does not contain sodium chloride, the hemodialysis agent of the present invention includes the dialysis agent A (including both glucose-containing and non-containing cases) and the dialysis agent A. A three-drug type hemodialysis agent consisting of the S agent for dialysis and the B agent for dialysis; or the A-1 agent for dialysis (the A agent for dialysis that does not contain glucose) and the A-2 agent for dialysis; , it can be provided as a four-drug type hemodialysis agent consisting of the S agent for dialysis and the B agent for dialysis.

In the hemodialysis agent of the present invention, when the dialysis A-2 agent is provided, the glucose content in the dialysis A-2 agent is such that the glucose concentration in the final hemodialysis fluid is 0 to 2. It may be appropriately set to .5 g/L, preferably 1.0 to 1.5 g/L.

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

The present invention will be specifically described below with reference to Examples. However, the present invention should not be construed as being limited to the following examples.

Test example 1
1. Preparation of granules for hemodialysis agents
Example 1
283.0 g of calcium chloride dihydrate and 142.3 g of magnesium chloride hexahydrate were dissolved in 185.0 g of purified water to prepare an aqueous solution for forming a covering portion. 436.4 g of anhydrous sodium acetate was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and operation was started at a rotation speed of 170 rpm and an air temperature of 80° C., and the coating portion forming aqueous solution was The entire amount was sprayed onto anhydrous sodium acetate to perform surface coating. Thereafter, drying was performed at 130° C. for 10 minutes in a fluidized bed dryer (manufacturer: Nagato Electric Works Co., Ltd., model number: 10F model) to obtain a granulated product.

Example 2
283.0 g of calcium chloride dihydrate and 142.3 g of magnesium chloride hexahydrate were dissolved in 185.0 g of purified water to obtain an aqueous solution 1 for forming a coating portion. Further, 145.5 g of anhydrous sodium acetate was dissolved in 334.5 g of purified water to prepare aqueous solution 2 for forming a coating portion. 290.9 g of anhydrous sodium acetate was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and operation was started at a rotation speed of 170 rpm and an air temperature of 80° C., and the coating portion forming aqueous solution was After spraying the entire amount of 1 onto anhydrous sodium acetate, the entire amount of the aqueous solution 2 for forming a coating portion was sprayed to perform surface coating. Thereafter, drying was performed at 130° C. for 10 minutes in a fluidized bed dryer (manufacturer: Nagato Electric Works Co., Ltd., model number: 10F model) to obtain a granulated product.

Example 3
283.0 g of calcium chloride dihydrate, 142.3 g of magnesium chloride hexahydrate, and 145.5 g of anhydrous sodium acetate were dissolved in 1162.1 g of purified water to obtain an aqueous solution for forming a coating portion. 290.9 g of anhydrous sodium acetate was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and operation was started at a rotation speed of 170 rpm and an air temperature of 80° C. The entire amount was sprayed onto anhydrous sodium acetate to perform surface coating. Thereafter, drying was performed at 130° C. for 10 minutes in a fluidized bed dryer (manufacturer: Nagato Electric Works Co., Ltd., model number: 10F model) to obtain a granulated product.

Example 4
707.0 g of calcium chloride dihydrate and 356.0 g of magnesium chloride hexahydrate were dissolved in 498.4 g of purified water to prepare an aqueous solution for forming a coating portion. 1089.3 g of anhydrous sodium acetate was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and the device was operated at a rotational speed of 750 rpm and an air temperature of 80° C. to coat the coating portion forming aqueous solution. The entire amount was sprayed onto anhydrous sodium acetate to perform surface coating, and then the air temperature was set to 130°C and drying was performed for 5 minutes to obtain a granulated product.

Example 5
353.5 g of calcium chloride dihydrate and 178.0 g of magnesium chloride hexahydrate were dissolved in 249.2 g of purified water to prepare an aqueous solution for forming a covering portion. 544.7 g of anhydrous sodium acetate was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and the device was operated at a rotational speed of 750 rpm and an air temperature of 130° C. to coat the coating portion forming aqueous solution. The entire amount was sprayed onto anhydrous sodium acetate to perform surface coating. Thereafter, the air temperature was set to 130° C., and drying was performed for 20 minutes to obtain a granulated product.

Example 6
707.0 g of calcium chloride dihydrate was dissolved in 254.5 g of purified water to prepare an aqueous solution for forming a covering portion. 356.0 g of magnesium chloride hexahydrate was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and operation was started at a rotation speed of 480 rpm and an air temperature of 50°C. It was dried for 3 minutes at 80°C, 3 minutes at 110°C, and 3 minutes at 130°C. Thereafter, 1089.3 g of anhydrous sodium acetate was added, and the operation was restarted at a rotation speed of 750 rpm and an air temperature of 80° C., and the entire amount of the aqueous coating solution was sprayed onto the mixture of anhydrous sodium acetate and magnesium chloride hexahydrate. After surface coating was performed, the air temperature was set to 130°C and drying was performed for 20 minutes to obtain a granulated product. In this production condition, magnesium chloride hexahydrate is sufficiently dried and then mixed with anhydrous sodium acetate, so before spraying the aqueous solution for forming the coating, magnesium chloride and sodium acetate, which are the raw materials for the core particles, are mixed with sodium acetate. are considered to exist in a mixture without reacting with each other. Therefore, the obtained granules are (A) a granule in which a coating containing calcium chloride is formed on the surface of a core particle containing sodium acetate, and (B) a granule in which a coating containing calcium chloride is formed on the surface of a core particle containing magnesium chloride. It is assumed that it is a mixture with granules in which a coating containing calcium is formed.

Example 7
707.0 g of calcium chloride dihydrate and 249.2 g of magnesium chloride hexahydrate were dissolved in 498.4 g of purified water to prepare an aqueous solution for forming a coating portion. 1089.3 g of anhydrous sodium acetate and 106.8 g of magnesium chloride hexahydrate were placed in a plastic bag and mixed for 1 minute to obtain a mixture. The mixture was placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), and operation was started at a rotation speed of 750 rpm and an air temperature of 80° C., and the entire amount of the aqueous solution for coating portion formation was added to the mixture. After surface coating was performed by spraying, the air temperature was set to 130°C and drying was performed for 20 minutes to obtain a granulated product. Under these manufacturing conditions, magnesium chloride hexahydrate is mixed with anhydrous sodium acetate without drying, so before spraying the aqueous coating solution, some of the magnesium chloride and acetic acid, which will be the raw material for the core particles, are mixed with anhydrous sodium acetate without drying. It is thought that a reaction product is generated due to the interaction of some of the sodium, and the resultant mixture is sodium acetate, magnesium chloride, and the reaction product. Therefore, the obtained granules are (A) granules in which a coating containing calcium chloride and magnesium chloride is formed on the surface of core particles containing sodium acetate, and (B1) granules in which a coating part containing calcium chloride and magnesium chloride is formed on the surface of core particles containing sodium acetate. A granulated product in which a coating containing calcium chloride and magnesium chloride is formed on the surface, and (B2) a granulated product in which a coating containing calcium chloride and magnesium chloride is formed on the surface of the core particle containing the reaction product. It is assumed that it is a mixture of

Comparative example 1
35.4 g of calcium chloride dihydrate, 17.8 g of magnesium chloride hexahydrate, and 54.6 g of anhydrous sodium acetate were placed in a tumbling fluid granulation coating device (manufacturer: Powrex Co., Ltd., model number: MP-01), The operation was started and thoroughly mixed to obtain a mixture.

Comparative example 2
7.19 kg of magnesium chloride hexahydrate and 22.04 kg of anhydrous sodium acetate were mixed for about 20 minutes in a Nauta mixer (manufacturer: Hosokawa Micron Co., Ltd., model number: NX-2J) to obtain a mixture. 6.68 kg of the obtained mixture was placed in a vertical granulator (manufacturer: Powrec Co., Ltd., model number: FM-VG25), and while stirring, 1.68 kg of potassium chloride and 3.27 kg of calcium chloride dihydrate were sequentially added. After granulation, drying was performed at 130° C. for 12 minutes using a fluidized bed dryer (manufacturer: Nagato Electric Works Co., Ltd., model number: 10F) to obtain granules.

2. Performance evaluation of granules for hemodialysis agents
2-1. Test method
(1) Moisture content Weigh 10g of the sample (granules or mixture) and use a halogen moisture meter (model: MX-50) to calculate the mass loss value (%) when drying at 150°C for 15 minutes. It was measured as

(2) Mix 119.3 g of hygroscopic potassium iodide and 100 mL of purified water to prepare a saturated aqueous potassium iodide solution, pour the saturated aqueous potassium iodide solution into the bottom of a desiccator, cover the desiccator, and seal it at 25°C. I waited for more than 8 hours under this environment. Note that when the vapor pressure of the saturated potassium iodide aqueous solution and the atmosphere are in equilibrium, the humidity of the atmosphere is 69% RH. Next, accurately weigh 1.0 g of the sample (granules or mixture) into a pre-weighed aluminum container, and place the aluminum container containing the sample (the aluminum container is uncovered) into a desiccator. The desiccator was sealed with a lid, and 16 hours after the start of sealing, the sample was taken out from the desiccator together with the aluminum container and weighed. The weight of the aluminum container was subtracted from the weighed value to calculate the amount of the product, and the hygroscopicity (increase rate) was calculated according to the following calculation formula.

y(50)：中位径（D50）
x₁：重量累積が50％未満になる最後の篩（重量累積50％未満を満たす目 開きが最小の篩）までの重量累積量（％）
x₂：重量累積が50％以上になる最初の篩（重量累積50％以上を満たす目 開きが最大の篩）までの重量累積量（％）
y₁：重量累積が50％未満になる最後の篩の目開き（μｍ）
y₂：重量累積が50％以上になる最初の篩の目開き（μｍ） (3) Average particle diameter (D50)
The particle size distribution of the sample (granulated product) was measured according to "General Test Methods 3.04 Particle Size Measurement Method 2. Method 2 Sieving Method" described in the 18th edition of the Japanese Pharmacopoeia. Specifically, the particle size distribution was determined using sieves with openings of 1700 μm, 1000 μm, 850 μm, 710 μm, 500 μm, 355 μm, 250 μm, and 180 μm using a robot sifter (manufacturer: Seishin Enterprise Co., Ltd., model number: RPS-105). The measurement was carried out under the following conditions: a sonic strength of 20, a sonic frequency of 51 Hz, a classification time of 5 minutes, a sweep time of 0.3 minutes, and a pulse interval of 1 second. From the obtained particle size distribution results, the average particle diameter (median diameter (D50)) was calculated according to the following formula.

y(50): Median diameter (D50)
x ₁ : Cumulative weight amount (%) up to the last sieve where the cumulative weight is less than 50% (the sieve with the smallest opening that satisfies the cumulative weight of less than 50%)
x ₂ : Cumulative weight (%) up to the first sieve with a cumulative weight of 50% or more (the sieve with the largest opening that satisfies the cumulative weight of 50% or more)
y ₁ : The opening of the last sieve where the weight accumulation is less than 50% (μm)
y ₂ : The first sieve opening where the weight accumulation is 50% or more (μm)

(4) Powder X-ray Diffraction Measurement was performed in the range of 2θ = 5 to 90° using an X-ray diffraction device “SmartLab” (manufacturer: Rigaku Co., Ltd.) (measurement conditions were: target: Cu, tube voltage: 40 kV, tube Current: 30mA, scan range: 5-90°, scan speed: 10.000°/min, scan step: 0.02°, scan mode: continuous).

(5) Amount of Components in Granules 71.8 g of the granules obtained in Example 5 were dissolved in water to make a total volume of 500 mL to obtain a concentrated solution of the granules. The content of the obtained concentrate was measured by liquid ion chromatography based on the ratio of the peak area of each standard substance to the peak areas of magnesium ions, calcium ions, and sodium ions in the granules. The theoretical content of each component in 71.8 g of granules was set as 100, and the ratio (%) of each content was calculated.

(6) Content uniformity of agent A for hemodialysis 197.4 g of the granules obtained in Example 5, 2178.0 g of sodium chloride, 52.2 g of potassium chloride, a mixture of acetic acid and sodium acetate (acetic acid: sodium acetate) After mixing 105.1 g (mole ratio: 1:1.1) and 437.5 g of glucose in a plastic bag, the mixture was placed in a V-type mixer (manufacturer: Irie Shokai Co., Ltd., model number: VK-5) for 15 minutes. The mixture was mixed to obtain a solid agent A for hemodialysis. 297.0 g of the obtained agent A for hemodialysis was dissolved in water to make a total volume of 1000 mL to obtain a concentrated solution of agent A for hemodialysis. This operation for producing a concentrated solution of agent A for hemodialysis was performed three times to prepare three concentrated solutions of agent A for hemodialysis (n1 to n3). For each concentrated solution, the content was determined by liquid ion chromatography measurement based on the ratio of the peak area of each standard substance and the peak area of sodium ion, potassium ion, calcium ion, magnesium ion, acetate ion, and glucose in agent A for hemodialysis. Measurements were taken. The theoretical content of each component in 297.0 g of agent A for hemodialysis was set as 100, and the ratio (%) of each content was calculated.

2-2. Test Results Table 2 shows the measurement results of the water content and hygroscopicity of the granules or mixtures, and Table 3 shows the measurement results of the particle size distribution and average particle diameter (D50) of the granules. Further, Table 4 shows the measurement results of the component amounts of the granules, and Table 5 shows the measurement results of the content uniformity of agent A for hemodialysis.

Granules (Examples 1, 4, and 5) in which a coating containing magnesium chloride and calcium chloride was formed on the surface of core particles containing sodium acetate had a hygroscopicity of about 17% or less after 16 hours. It was low. In addition, in the case of granules (Examples 2 and 3) in which a coating containing magnesium chloride, calcium chloride, and sodium acetate was formed on the surface of core particles containing sodium acetate, the granules were treated for 16 hours as in Example 1. The subsequent hygroscopicity was as low as about 17% or less. In addition, (A) a granulated product in which a coating part containing calcium chloride is formed on the surface of a core particle containing sodium acetate, and (B) a granule in which a coating part containing calcium chloride is formed on the surface of a core particle containing magnesium chloride. Even the mixture (Example 6) that was assumed to contain granulated material had low hygroscopicity. Furthermore, (A) a granulated material in which a coating part containing calcium chloride and magnesium chloride is formed on the surface of a core particle containing sodium acetate, and (B1) a granulated material in which a coating part containing calcium chloride and magnesium chloride is formed on the surface of a core particle containing magnesium chloride; and (B2) a granulated product in which a coating containing calcium chloride and magnesium chloride is formed on the surface of a core particle containing a reaction product of sodium acetate and magnesium chloride. A mixture analogous to that (Example 7) also had low hygroscopicity.

That is, a granulated product in which a coating containing magnesium chloride and/or calcium chloride is formed on the surface of core particles containing sodium acetate can suppress moisture absorption during storage and has excellent storage stability. was confirmed. Furthermore, considering the above-mentioned properties of the granules, by blending the granules with the dialysis agent A, the caking of the dialysis agent A due to storage can be suppressed, and the glucose ( It is believed that the negative impact on the stability of 5HMF) is reduced.

On the other hand, in the case of a simple mixture of sodium acetate, magnesium chloride and calcium chloride (Comparative Example 1) and a granulated material containing a simple mixture of sodium acetate, magnesium chloride and calcium chloride (Comparative Example 2), after 16 hours The hygroscopicity exceeds 22% (the hygroscopicity increases by about 1.4 times or more compared to Examples 1 to 3, and about 1.3 times or more compared to Examples 4 to 7). It also had poor storage stability. If dialysis agent A is prepared using the mixture and granules, there is a risk of caking of dialysis agent A, and the stability of glucose (5HMF) contained in dialysis agent A may also be adversely affected. There is also concern that it may have a negative impact.

Further, FIG. 1 shows an X-ray diffraction pattern of the granulated product of Example 1. From FIG. 1, although sodium chloride was not used as a raw material in the granulated product of Example 1, a peak of sodium chloride was confirmed. This is considered to be due to the fact that sodium acetate contained in the core particles reacted with magnesium chloride and calcium chloride contained in the coating, and a small amount of sodium chloride was produced as a by-product.

Moreover, as shown in Table 4, it was confirmed that the granulated material obtained in Example 5 had the component composition as set. Furthermore, as shown in Table 5, in the dialysis agent A containing the granules obtained in Example 5, the concentration of the components of each concentrated solution of the hemodialysis agent A prepared three times was constant, It was confirmed that the content uniformity was also excellent.

Claims (14)

A granulated product used in a hemodialysis agent,
A granulated product having a core particle and a coating formed on the surface of the core particle,
the core particles contain sodium acetate and are substantially free of sodium chloride;
A granulated material in which the coating portion contains magnesium chloride and/or calcium chloride. The granulated material according to claim 1, wherein the coating portion contains an acetate. A mixture of granules used in hemodialysis agents, comprising:
(A) the granulated material according to claim 1;
(B) A granulated mixture comprising: (B) a granulated material in which a coating containing magnesium chloride and/or calcium chloride is formed on the surface of a core particle containing magnesium chloride; A mixture of a first component group consisting of the granules according to claim 1 or 2 or a mixture of the granules according to claim 3 , and a second component group containing potassium chloride, acetic acid and acetate. Solid A agent for hemodialysis. The solid agent A for hemodialysis according to claim 4 , wherein the second component group contains sodium chloride and/or glucose. The solid according to claim 4 , wherein a coating containing magnesium chloride and/or calcium chloride is not formed on the surface of at least one of potassium chloride, acetic acid, and acetate included in the second component group. Agent A for hemodialysis. The solid agent A for hemodialysis according to claim 5 , wherein the sodium chloride included in the second component group has no coating portion containing magnesium chloride and/or calcium chloride formed on its surface. According to claim 4 , the acetic acid and acetate included in the second component group are at least one selected from the group consisting of a mixture of acetic acid and acetate, an alkali metal diacetate, and a higher acetate compound. The solid hemodialysis agent A described above. The solid agent A for hemodialysis according to claim 4 , wherein the acetate included in the second component group is sodium acetate and/or potassium acetate. A solid hemodialysis agent comprising the solid hemodialysis agent A according to claim 4 and a hemodialysis agent B containing sodium bicarbonate. A method for producing a solid hemodialysis agent A, comprising:
A first step of obtaining granules by spraying an aqueous solution for forming a coating containing magnesium chloride and/or calcium chloride onto core particles containing sodium acetate and substantially free of sodium chloride and drying the mixture. , and a second step of obtaining a preparation containing the granules obtained in the first step, potassium chloride, acetic acid, and acetate;
A method for producing a solid agent A for hemodialysis, comprising: The method for producing a solid agent A for hemodialysis according to claim 11 , wherein in the second step, the preparation further contains sodium chloride. The method for producing a solid agent A for hemodialysis according to claim 11 or 12 , wherein in the second step, the preparation further contains glucose. The method for producing a solid agent A for hemodialysis according to claim 11 or 12 , wherein the aqueous solution for forming the coating portion contains an acetate.