JPH10259133A - Particulate agent for dialysis and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a solid dialysis solvent having good storage stability and solubility, not causing precipitation and aggregation in dissolution and composed of one pack type not causing mistake of liquid composition ratio. SOLUTION: In this particulate agent for dialysis, the innermost layer is composed of a material containing sodium hydrocarbonate and not containing an acid, a calcium salt and a magnesium salt and the outermost layer is composed of a material containing sodium acetate and acetic acid and not containing sodium hydrocarbonate. This method for producing the particulate agent for dialysis comprises spraying acetic acid into a particulate material composed of these materials.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug for a dialysate used for hemodialysis performed as a treatment for a patient with renal failure, and in particular, a granular dialysate in which each particle contains all of the dialysate components used. The present invention relates to an agent and a production method thereof.

[0002]

2. Description of the Related Art In recent years, the composition of hemodialysis, which is a sodium bicarbonate dialysis solution using sodium bicarbonate as an alkalizing agent, has almost the following composition. Na ⁺ 120 to 150 mEq / l K ⁺ 0.5 to 3.0 mEq / l Ca ⁺⁺ 1.5 to 4.5 mEq / l Mg ^{++ 0 to} 2.0 mEq / l Cl ⁻ 90 to 135 mEq / l _{^{HCO 3 - 20~ 35 mEq / l}} CH 3 CO 2 - 5~ 10 mEq / l glucose 0 to 2.5 g / l

[0003] However, this dialysate must be neutral or slightly alkaline in view of medical needs, and therefore, the balance between an alkalizing agent such as sodium bicarbonate or sodium acetate and a weak acid such as acetic acid causes the formation of hydrogen ions. Concentration (P
H) is adjusted, but in the case of using sodium bicarbonate as an alkalizing agent, the concentration of HCO ₃ ⁻ during storage is unstable, the PH at the time of dissolution does not reach a predetermined value, And sodium bicarbonate and carbonate are likely to precipitate, so only sodium bicarbonate is separated from other components (agent A) and supplied as a single concentrated solution or powder (agent B) It is dissolved and mixed with other components just before use. Further, when an acid for adjusting pH is coexisted, the acid is volatilized as carbon dioxide gas and becomes more unstable. Therefore, the acid is usually used when diluting or dissolving the agent A and the agent B.
It is added to water in advance or added last. That is, the acid is stored separately from the A agent and the B agent. It has also been proposed to add in advance to the agent A containing no sodium bicarbonate, but acetic acid, which is commonly used as a weak acid, is volatile and has a problem in storage stability.

In recent years, there has been a movement to supply dialysate components as solid drugs rather than solutions, due to the irrationalities of transporting significant amounts of water and other reasons.

[0005]

Even in such a case, the above-mentioned storage stability and the formation of a precipitate upon dissolution become problems. The problem of sedimentation during dissolution is relatively small when dissolving in the dialysate suddenly, but still completely dissolved immediately after dissolution, but after a long time, aggregates float on the liquid surface Sometimes. Also, if a solid drug is suddenly dissolved in a low-concentration dialysate, a large storage facility is required.
It is also considered to dissolve the solution once as a concentrated solution, and then continuously dilute it with water to supply the solution to a folding apparatus. However, in this case, a precipitate or an aggregate is easily generated at the time of dissolution, and the problem becomes large. Further, only acetic acid and hydrochloric acid which do not need to change the composition of the dialysate to those described above at the present time are approved as the acid of the pH adjuster after dissolution, and both are volatile liquids (instead of hydrochloric acid). When hydrogen chloride is used, it is a gas.) Not only does it itself have a problem of preservation due to its reduced volume due to volatilization, but when its vapor comes in contact with sodium bicarbonate, it becomes carbon dioxide gas. Which causes the problem of reduction of bicarbonate ions due to its volatilization. Although the idea of using citric acid, tartaric acid, or other solid organic acids instead of acetic acid or hydrochloric acid is disclosed,
The composition of the dialysate is different from the generally accepted one, and it is not yet clarified whether there is any medical problem.

The present inventors have proposed sodium diacetate (sodium diacetate) obtained from acetic acid and sodium acetate.
aceto). The Merck index; M
ERCK & CO. , Inc. The publication states that this substance is stable at temperatures below 150 ° C. and produces acetic acid when dissolved in water. This is used in Japan as powdered vinegar as a raw material for sushi. Japanese Patent Application Laid-Open No. Hei 3-31419 describes a technique of spraying acetic acid onto a granulated dialysis agent containing sodium acetate. It is unclear whether the conditions are such that acetate can be produced, but good stability of the acetic acid concentration during storage is advocated, so it may be used depending on the conditions.

That is, an object of the present invention is to provide a granular dialysis agent excellent in storage stability and solubility and a method for producing the same, and the agent is not separated into the A agent and the B agent. The agent is a single-agent dialysis agent that covers all the components of the dialysate by itself.

[0008]

According to a first aspect of the present invention, an innermost layer is made of a material containing sodium bicarbonate and not containing an acid, a calcium salt and a magnesium salt, and the outermost layer is made of a material containing no acid, calcium salt and magnesium salt. A granular dialysis agent comprising sodium acetate and acetic acid and containing no sodium bicarbonate, wherein the amount of sodium acetate present in the outermost layer is based on the amount of acetic acid. The third aspect of the present invention is a granular dialysis agent having an equimolar or higher, wherein sodium bicarbonate, a calcium salt, a magnesium salt, and acetic acid are used as a layer inside the outermost layer and contacting the innermost layer and the outermost layer. A fourth aspect of the present invention is the granular dialysis agent described above, wherein the outermost layer comprises a material containing sodium bicarbonate and containing no acid, calcium salt and magnesium salt. A method for producing dialysis agent particulate, characterized by spraying the acetate granulated material made of a material that does not contain sodium bicarbonate comprises sodium acetate.

The granular dialysis agent of the present invention comprises at least 2
Layer, preferably composed of grains having a structure of three or more layers. Sodium bicarbonate is present substantially only in the innermost layer, where there are virtually no calcium and magnesium salts, sodium acetate and acetic acid in the outermost layer, and acetic acid substantially only in the outermost layer. It is an essential requirement that it be present. The amount of sodium acetate present in the outermost layer is at least equimolar to the required amount of acetic acid. Acetic acid is present in the form of sodium diacetate in combination with sodium acetate. Sodium chloride, potassium chloride, the remaining sodium acetate,
Components other than sodium bicarbonate, calcium chloride, and magnesium chloride, such as glucose added if necessary, can be appropriately added to each layer. It is a preferred embodiment that a layer not containing calcium chloride and magnesium chloride is formed in the layer next to the innermost layer to separate those salts from the sodium bicarbonate layer. Further, it is preferable not to allow components other than sodium acetate to coexist in the outermost layer because the efficiency of converting acetic acid into sodium diacetate is high.

[0010] The ratio of each component in the whole grain is determined from the target composition of the dialysate. Other components can be added as long as the object of the present invention is not impaired. The granular dialysis agent of the present invention is a so-called one-part dialysis agent containing all necessary components without combining the A agent and the B agent. Each solid raw material is preferably ground to a size of 250 μm or less. The particle size of the dialysis solvent obtained therefrom is 0.1 to 10 mm, preferably 0.2 to 5 mm
It is. The range is preferable from the viewpoint of solubility in water and fluidity.

Next, a method for producing the granular dialysis solvent of the present invention will be described. The sodium bicarbonate constituting the innermost layer, which is the core of the granular dialysis agent, may be finely pulverized in advance and formed into granules, or a large lump may be crushed to a predetermined size to form a granulation process. May be omitted. From the viewpoint of solubility, granulation after pulverization is preferable. When other components are allowed to coexist, it is preferable that the components are preliminarily pulverized, densely mixed, and then granulated. Other coexisting components include sodium chloride, potassium chloride, sodium acetate, glucose and the like. The coexistence of acids, calcium salts, and magnesium salts must be avoided. The core is usually granulated by adding a small amount of water by an extrusion-type granulator. When glucose is contained, it is also possible to mix each layer, but when forming the outer layer, use a glucose solution instead of water for wetting the surface of the grains, and use the viscosity to prepare a ready-made product. It is preferable to suppress the permeation of water into the inside of the particles and to make glucose function as a binder between the component particles and between the layers.

In order to form the next outer layer on the thus obtained innermost layer only, the surface of a ready-made particle is wetted with a small amount of water, mixed with a fine powder of the component of the layer, and dried. Done. It is also possible to spray water while mixing the ready-made particles and the fine powder for the outer layer. At that time, it is necessary to select conditions so that new particles are not formed only from the fine powder component. When a layer having a required thickness cannot be formed in one step, the same step can be repeated. This step is performed for the number of outer layers having different components.

It is preferable that the outermost layer contains sodium acetate in an amount of at least equimolar to acetic acid added in the next step.
The absorption of acetic acid in the sodium acetate layer ensures that acetic acid does not penetrate into the other layers, thereby suppressing the volatilization of acetic acid and preventing the volatilization of carbon dioxide gas due to contact between sodium bicarbonate and acetic acid. Because you can. For that purpose, the outermost layer consists only of sodium acetate or sodium acetate and a small amount of glucose as a binder, and the resulting dried granules having sodium acetate in the outermost layer are sprayed with acetic acid, if necessary. Dry at low temperature. The drying temperature is at most 150 ° C, preferably at most 100 ° C. When glucose is contained, the temperature is further preferably 60 ° C. or lower. Drying under reduced pressure is also possible. In the drying step, if components other than sodium acetate are present in the outermost layer, free acetic acid may be present on the surface, and if the acetic acid spray is not uniform, the amount of acetic acid may partially decrease. And it may be left in a free state in an amount equivalent to or more than the above, and is carried out when there is a possibility. Since it is not preferable that the innermost layer is exposed to acetic acid vapor for a long time, it is not preferable that the innermost layer is left for a long time until drying after spraying with acetic acid.
Should be stopped by no more than 24 hours.

[0014] The amount of acetic acid contained in the granules depends on the target pH of the solution in which it is dissolved in water and the other components contained in the finished dialysis agent. Usually PH7.1-
7.4, preferably 7.2 to 7.3, is selected. It is preferable that stirring at the time of spraying acetic acid is as slow as possible to avoid that the surface of the particles becomes partially high due to friction between the particles and the generated sodium diacetate is decomposed to release acetic acid. When acetic acid is included without binding to sodium acetate, it is volatilized by storage for a long time, and the solution pH changes or diffuses into a layer containing sodium bicarbonate to generate carbon dioxide gas. Since the bicarbonate ion concentration is lowered and the pH is also changed, the free acetic acid is removed by drying under reduced pressure if necessary, and the amount of acetic acid used is determined in advance so that the aqueous solution has a predetermined pH in the subsequent state Is also preferred.

As an example of the configuration of the granular dialysis agent, the inner layer has a two-layer structure in which sodium bicarbonate is bound and the outer layer is bound with sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, and the like using glucose, and the outer layer is formed in the outer layer. Acetic acid in the form of sodium diacetate, the innermost layer is sodium bicarbonate and sodium chloride, the second layer is potassium chloride, calcium chloride, magnesium chloride, and the outermost layer is sodium acetate and acetic acid (acetic acid is sodium diacetate). Only) and a three-layer structure with glucose as the binder, the innermost layer is sodium bicarbonate and sodium chloride, the second layer is sodium chloride, and the third layer is sodium chloride, potassium chloride, calcium chloride, magnesium chloride. , The outermost layer is sodium acetate and acetic acid (acetic acid is sodium diacetate And see there), those four-layer structure using glucose in a binder, can be exemplified. In the above example, sodium acetate, sodium chloride, and potassium chloride may be appropriately dispersed and present in each layer. Most preferred in terms of the least amount of free acetic acid is that the outermost layer consists of sodium diacetate alone or a mixture thereof with sodium acetate. When a solid acid other than acetic acid or a metal salt having poor solubility in water of bicarbonate or carbonate is used in common, it is preferable to avoid containing it in the innermost layer, preferably the innermost layer and the next layer. Good.

In order to form sodium diacetate in the outermost layer, sodium diacetate can be produced in advance from acetic acid and sodium acetate, crushed, and coated with ready-made particles. There are problems that sodium diacetate is decomposed due to the high temperature partially generated in the broken part of the powder grains, and that water cannot be sprayed during coating. The reason that sodium diacetate is not formed inside the outermost layer is that if the sodium acetate layer is coated first, then the outer layer is coated and then acetic acid is absorbed, acetic acid is absorbed in the outer layer and free acetic acid is added. It will be present and free acetic acid will volatilize during storage, which is not preferred. When a sodium acetate layer is formed on the inner side and acetic acid is sprayed to form sodium diacetate, and then the outer layer is coated, the spray of water decomposes the sodium diacetate.

Next, the present invention will be described with reference to examples, but the present invention is not limited thereto. In the examples, the bicarbonate ion concentration was measured by ion chromatography, and the pH was measured by a pH meter. Further, the solubility was determined by visually charging the sample and putting it into stirred water, and determining the dissolution time and the presence or absence of aggregates in the aqueous solution.

Example 1 Sodium bicarbonate was pulverized with a ball mill to an average particle diameter of 50 μm, about 3% by weight of water was spray-mixed, and an average particle diameter of about 450 μm was obtained using a biaxial granulator.
m particles were obtained. 24.82k of dried particles
sodium chloride 3 ground to an average particle size of about 50 μm
6.95 kg was put into a coating granulator, and granulated while spraying an aqueous glucose solution, and after drying, the obtained particles, 1.968 kg of calcium chloride and 0.5 mg of magnesium chloride were dried.
622 kg (all calculated as anhydrous), potassium chloride 1.7
A mixture of 63 kg and 36.95 kg of sodium chloride particles each having an average particle diameter of 50 μm was placed in the coating granulator, and granulated while spraying an aqueous glucose solution in the same manner as described above. After drying, 7.754 kg of sodium acetate having an average particle diameter of 50 μm was added, and the same procedure was repeated except that water was sprayed instead of glucose to obtain an average particle diameter of about 800 μm.
Particles were obtained. The total amount of glucose added was 11.82.
kg. After drying, 1.577 kg of acetic acid was sprayed while stirring at a low speed with a stirrer further cooled to 20 ° C., and the mixture was allowed to stand in a sealed state for 1 hour to obtain a dialysis agent.
Immediately after the production or 1 month, 3 months, 6 months, and 12 months after sealed storage in a polypropylene bottle, 10.6 g of the multiparticulates was added with water to form a 1 liter solution. Solubility, pH, bicarbonate ion concentration Was measured. Tables 1 to 3 show the measurement results. Almost no odor of acetic acid, which was present immediately after production, was observed in the stored sample.

Example 2 The procedure of Example 1 was repeated except that magnesium chloride in the third layer was mixed with sodium chloride in the second layer. Almost no odor of acetic acid, which was present immediately after production, was observed in the stored sample. Comparative Example 1 The procedure was the same as in Example 1 except that calcium chloride used in the third layer was moved to the innermost layer and mixed with sodium bicarbonate. Almost no odor of acetic acid, which was present immediately after production, was observed in the stored sample. [Comparative Example 2] 36.95 kg of sodium bicarbonate and 73.889 mg of sodium chloride pulverized to an average particle size of 50 µm.
kg, 1.765 kg of potassium chloride, 0.564 kg of magnesium chloride, 1.968 kg of calcium chloride, 7.761 kg of sodium acetate, 0.118 kg of glucose are added and mixed well. It was granulated to a diameter of about 1 mm. After drying, 1.66 kg of acetic acid was sprayed while stirring at a low speed with a stirring device further cooled to 20 ° C., and the mixture was allowed to stand for 1 hour in a sealed state to obtain a dialysis agent.
This sample was evaluated in the same manner as in Example 1. A considerable amount of acetic acid odor was observed in the stored sample.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Effect] In the granular dialysis agent of the present invention, acetic acid is bonded to the outermost layer of sodium acetate, so that acetic acid does not volatilize even if stored for a long time as long as it is kept in a dry state. Then, a predetermined PH can be achieved. Also, since dissolution proceeds from the surface of the grains, an acidic aqueous solution is formed first, and magnesium and calcium salts dissolve in the acidic solution to form a uniform dilute solution, and then sodium bicarbonate begins to dissolve. No precipitation occurs. Acetic acid and sodium bicarbonate do not react during storage to evaporate carbon dioxide gas. In addition, since it is a one-drug type, the composition of the dialysate does not differ from a predetermined value due to a wrong use ratio as in the two-drug type of the A agent and the B agent.

Claims (4)

[Claims] The innermost layer is made of a material containing sodium bicarbonate and free of acids, calcium salts and magnesium salts, and the outermost layer is made of a material containing sodium acetate and acetic acid and not containing sodium bicarbonate. Characterized granular dialysis agent. 2. The granular dialysis agent according to claim 1, wherein the amount of sodium acetate present in the outermost layer is at least equimolar to the amount of acetic acid. 3. A layer which is inside the outermost layer and which is in contact with the innermost layer on the outer side thereof, wherein sodium bicarbonate, calcium salt,
The granular dialysis agent according to claim 1, wherein a layer containing no magnesium salt or acetic acid is provided. 4. An innermost layer comprising a material containing sodium bicarbonate and free of acids, calcium salts and magnesium salts,
A method for producing a granular dialysis agent, wherein acetic acid is sprayed on a granular agent whose outermost layer comprises a material containing sodium acetate and not containing sodium bicarbonate.