JPH08169836A - Agent for sodium bicarbonate dialysis and its production - Google Patents

Abstract

PURPOSE: To obtain an agent for sodium bicarbonate dialysis, containing an electrolyte, an organic acid and glucose, having a laminar structure containing each component in each layer successively laminated from the 1st layer on a core, keeping excellent stability over a long period, effective for preventing the deposition of precipitate and having easy handleability. CONSTITUTION: This dialyzing agent consists of a core composed of sodium chloride, a 1st layer containing a calcium salt and/or a magnesium salt and free from organic acid and bicarbonate, a 2nd layer containing an organic acid and free from calcium salt, magnesium salt and bicarbonate and a 3rd layer containing a bicarbonate and free from calcium salt, magnesium salt and organic acid. These layers are successively laminated on the core. The lamination is carried out by using a glucose solution as a binder and the agent is formed preferably in a spherical laminated form and filled together with a desiccant in a moistureproof air-tight container in carbon dioxide gas stream. The reaction between the constituent components can be prevented because the organic acid and the bicarbonate are laminated in the dialyzing agent in separated state.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a layered preparation for preparing a dialysate containing hydrogen carbonate ions, that is, a sodium bicarbonate dialysate.

[0002]

2. Description of the Related Art Conventionally, when performing hemodialysis, a sodium bicarbonate dialysate having the following composition has been used. ^{Na + 120~150 mEq / l K +} 0.5~3.0 mEq / l Ca ++ 1.5~4.5 mEq / l Mg ++ 0~2.0 mEq / l Cl - 90~135 mEq ^{_{/ l HCO 3 - 20~ 35 mEq}} / l CH 3 CO 2 - 5~ 10 mEq / l glucose 0 to 2.5 g / l, however, dialysate having such a composition is from about 350 to one single dialysis Since a large amount of liter was used and the formulation was unstable, it had to be prepared immediately before use and required complicated work.

Therefore, in order to reduce the above-mentioned work, a concentrated stock solution (about 11 liters) in which sodium hydrogen carbonate as a necessary component is excluded has been put on the market in a packaging unit for one person. However, since sodium hydrogen carbonate in the composition reacts with calcium salts and magnesium salts to cause precipitation of carbonate salts, the dialysate currently used cannot be made into one solution as a stock solution, and is divided into two solutions. Have been commercialized. Therefore, it cannot be said that it has been sufficiently improved in transportation, storage place, handling, etc., and various proposals have been made since then. In view of these points, attempts have been made to powder the dialysis agent. For example, JP-A-3-7433
No. 1 discloses a mixture of components necessary for a dialysate, which is a granulated product composed of a group containing a calcium component and no sodium bicarbonate and a granulated product composed of a group containing sodium bicarbonate and not containing a calcium component. There is. This is so that a dialysate can be prepared by simply dissolving a predetermined amount of dialysis agent in water. However, acetic acid used as a pH adjusting agent contains calcium salt, magnesium salt and bicarbonate. Since it dissolves at the same time as the salt, it has the drawbacks that insoluble precipitates occur and carbon dioxide gas is generated, which tends to raise the pH. Also,
There are problems that the reaction proceeds even during long-term storage, aggregation occurs, and the content decreases. On the other hand, Japanese Unexamined Patent Publication No. 2-311418 discloses a powdery dialysis preparation comprising a powdery composition comprising a dialysis solid electrolyte and a liquid acid, a sodium hydrogencarbonate and glucose powdery composition, and two compositions. Has been done. In addition, Japanese Patent Laid-Open No. 4-257
No. 522, a granule of two agents consisting of a group consisting of one or more components selected from components other than baking soda among electrolyte components for dialysis and a group containing sodium bicarbonate as a main component, JP-A-5-70357. Discloses a dialysis agent in which three components of a dialysis electrolyte, glucose and sodium bicarbonate are prepared as separate granular compositions.
However, since all of them are manufactured by dividing them into two or three parts, no problems in handling have been solved.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The subject of the present invention is baking soda dialysis, which is excellent in stability for long-term storage, can prevent precipitation due to sequential dissolution of each component during use, and can be easily prepared. It is to provide an agent.

[0005]

[Means for Solving the Problems] The present inventors provide a stable multi-layered preparation including a pH adjusting agent while considering the stability and hygroscopicity of each electrolyte and glucose required for a dialysis agent. I researched earnestly. As a result, sodium chloride was used for the nucleus, a group containing calcium salt and / or magnesium salt and containing no organic acid and bicarbonate, a group containing organic acid and containing no calcium salt, magnesium salt and bicarbonate, and heavy salt. When laminating a group containing a carbonate but not a calcium salt, a magnesium salt and an organic acid, by sequentially laminating the group selected from components other than the calcium salt, the magnesium salt, the organic acid and the bicarbonate, The inventors have found that the problems can be solved and completed the present invention.

That is, the present invention is a dialysis agent containing an electrolyte, an organic acid and glucose, wherein the organic acid is selected from acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid and malic acid. 1 or 2 or more selected from the group consisting of, the laminated preparation has a multilayer structure of a core, a first layer, a second layer and a third layer, the core is sodium chloride, in the dialysis agent, One layer is calcium salt or /
And a layer containing a magnesium salt and containing no organic acid and bicarbonate, the second layer being a laminate of two or more layers and containing an organic acid and containing no calcium salt, magnesium salt or bicarbonate salt. The third layer is a sodium bicarbonate dialysis agent characterized by being a layer containing bicarbonate and not containing calcium salt, magnesium salt and organic acid. This laminated preparation is filled in a moisture-proof airtight container in a carbon dioxide gas stream,
Stored with desiccant.

The preferred blending range of the components contained in the sodium bicarbonate dialysis agent of the present invention is shown below in terms of the composition range after preparation of the dialysate, and the pH thereof is 7.0 to 8.0, more preferably. It is 7.2 to 7.6. ^{Na + 120~150 mEq / l K +} 0~ 4 mEq / l Ca ++ 1~ 6 mEq / l Mg ++ 0~ 2 mEq / l Cl - 90~135 mEq / l CH 3 CO 2 - 2~ 15 _{mEq / l HCO 3 - 10~ 40} mEq / l glucose 0 to 10 g / l

In the production of the sodium bicarbonate dialysis agent of the present invention, when the compounds are selected and the mixing ratio is set, for example, the concentration of each component is set based on the above, and the back calculation is performed by the combination of the compounds capable of supplying each component. Good.

The electrolyte used in the present invention must be pharmacologically acceptable. For example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, calcium gluconate and the like can be mentioned. The laminated preparation constituting the present invention, together with the electrolyte as described above, other components contained in blood,
For example, glucose can be included.

The layered preparation comprises a group containing calcium salt and / or magnesium salt and no organic acid and bicarbonate (first layer), a group containing organic acid and no calcium salt, magnesium salt and bicarbonate salt. The (second layer) and the group containing bicarbonate and calcium salt, magnesium salt and organic acid (third layer) are important. That is, a group containing a calcium salt and / or a magnesium salt and not containing an organic acid and a bicarbonate salt, and a group containing a bicarbonate salt and containing no calcium salt, a magnesium salt and an organic acid are treated with a calcium salt, a magnesium salt, an organic acid and a bicarbonate salt. By stacking so as not to contact via a group selected from components other than carbonate, it is possible to prevent the calcium salt and the magnesium salt from reacting with the bicarbonate salt. In addition, except for calcium salts, magnesium salts, organic acids and bicarbonates, the groups containing organic acids and not containing calcium salts, magnesium salts and bicarbonates and those containing bicarbonates and containing calcium salts, magnesium salts and organic acids are excluded. It is possible to prevent the reaction between the bicarbonate and the organic acid by laminating the components so that they do not come in contact with each other via the group selected from the above components. That is, when the dialysate is prepared, it is sequentially dissolved from the outer layer of the laminated preparation in distilled water, and the pH is adjusted from neutral to slightly alkaline, so that the generation of carbon dioxide gas and the last of calcium salt and magnesium salt are generated. Because it dissolves in
It is possible to prevent precipitation of calcium carbonate and magnesium carbonate. If desired, the stacking order may be changed, and the first layer, the second layer, and the third layer may be further composed of two or more layers.

The laminating operation of the present invention will be described below. The manufacturing method of the present invention comprises steps of sequentially stacking on the core, and is carried out by a commonly used granulating and coating apparatus. For example, the group to be used is a group containing calcium salt and / or magnesium salt and not containing organic acid and bicarbonate,
Organic acid-containing calcium salt, magnesium salt and bicarbonate-free group, bicarbonate salt-containing calcium salt, magnesium salt and organic acid-free group and components other than calcium salt, magnesium salt, organic acid and bicarbonate salt The ingredients of each group are appropriately pulverized with a pulverizer such as a sample mill (manufactured by Fuji Paudal Co.). Next, the sodium chloride crystal particles of the nucleus are placed in a centrifugal fluidized coating granulator, rotated, and the fine powder is sequentially added while spraying an appropriate amount of glucose solution as a binder to obtain a spherical laminated preparation. .

The dosage form of the sodium bicarbonate dialysis agent of the present invention is preferably a spherical multi-layered preparation which is sequentially laminated on the surface of the core from the first layer.

Examples of the organic acid include acetic acid, lactic acid,
Examples thereof include citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid and malic acid, with citric acid being particularly preferred. The amount of acid used is such that the pH of the dialysate is 7.0.
It is preferable to add it so as to be in the range of to 8.0. A more preferable range is pH 7.2 to 7.6. These organic acids may be used alone or in combination of two or more.

The binder used in the method for producing a laminated preparation of the present invention is safe because glucose is used as a component, and since the binding strength is strong, a laminated preparation having high strength and hardly powdered can be obtained. You can Glucose is used by appropriately dissolving it in a solvent, and a preferable concentration is 0.5 to 5
5 W / W% is suitable. The solvent is not particularly limited as long as it is used for formulation and dissolves glucose, but water or a mixed solvent of water and ethanol is preferable.

The material used for the storage container for the sodium bicarbonate dialysis agent of the present invention is not particularly limited as long as it is substantially moisture-proof and gas-impermeable, and examples thereof include polyethylene, polypropylene and polyvinyl chloride. Alternatively, a laminate film in which a metal foil such as aluminum, nylon, cellophane, etc. are appropriately laminated in two layers or multiple layers can be given.

It is convenient to seal the airtight container in the above-mentioned packaging form together with a desiccant in a carbon dioxide gas stream because the stability can be further improved. As the desiccant, silica gel, calcium chloride, calcium carbonate or the like is used.

[0017]

The sodium dialysis agent thus obtained is laminated so that the organic acid and the bicarbonate are not in contact with each other, so that the reaction between the components can be prevented. Further, when preparing a dialysis solution, the pH of the solution is adjusted from neutral to slightly alkaline by sequentially dissolving from bicarbonate without any particular pH adjustment.
Finally, the calcium and magnesium salts dissolve, so that no carbonate precipitate forms.

[0018]

The present invention will be described in more detail based on the following examples and test examples, but the present invention is not limited to these examples. [Example 1] 17.9 g of magnesium chloride and calcium chloride
Stir 38.7 g and potassium chloride 26.1 g with a universal stirrer (SD-02 type, manufactured by Shinagawa Kogyo) and pulverize with a sample mill (Fuji Paudal, pulverizer KIIW-1) to obtain a fine powder for the first layer. It was Similarly, citric acid 35g, sodium chloride 105
g was mixed and pulverized to obtain a fine powder of the second layer (inner layer). Glucose (91.0 g), sodium acetate (85.9 g) and sodium chloride (100.9 g) were treated in the same manner as above to obtain a fine powder for the second layer (intermediate layer). Sodium chloride 15 as the second layer (outer layer)
7.5 g was crushed to obtain a fine powder. Further, 441 g of sodium hydrogen carbonate was crushed as a third layer to obtain a fine powder. Next, 700 g of sodium chloride having a particle diameter of 350 to 500 μm is put into a centrifugal fluidized granulation coating device (CF-360S type manufactured by Freund Sangyo Co., Ltd.) and rotated (rotation speed 200 rpm), while spraying the glucose solution, the first layer, A fine powder was added in the order of the second layer (inner layer), the second layer (intermediate layer), the second layer (outer layer) and the third layer to obtain a spherical laminated preparation. The obtained laminated preparation was dried by a conventional method to obtain the intended dialysis agent.

Example 2 Magnesium chloride (17.9 g), calcium chloride (38.7 g) and potassium chloride (26.1 g) were stirred with a universal stirrer and ground with a sample mill to obtain a fine powder for the first layer. Similarly, citric acid 35g, sodium chloride 105
g was mixed and pulverized to obtain a fine powder of the second layer (inner layer). Glucose 91.0 g and sodium chloride 100.9 g were treated in the same manner as above to obtain a fine powder of the second layer (intermediate layer). As the second layer (outer layer), 85.9 g of sodium acetate and 157.5 g of sodium chloride were pulverized to obtain a fine powder. Further, 441 g of sodium hydrogen carbonate was crushed as a third layer to obtain a fine powder. Next, 700 g of sodium chloride having a particle diameter of 350 to 500 μm is centrifugally fluidized and granulated by a coating device (manufactured by Freund Sangyo Co., Ltd., CF-360S).
Molds) and rotate (rotation speed 200 rpm), spraying the glucose solution, the first layer, the second layer (inner layer), the second layer (intermediate layer), the second layer (outer layer) and the third layer in this order. Fine powder was added to obtain a spherical laminated preparation. The obtained laminated preparation was dried by a conventional method to obtain the intended dialysis agent.

Example 3 700 g of sodium chloride having a particle diameter of 350 to 500 μm was put into a tumbling fluidized granulation drying device (Multiplex, MP-01 type, manufactured by Paulex Co.), and 17.9 g of magnesium chloride and calcium chloride. The first layer liquid dissolved in 38.7 g and 26.1 g of potassium chloride and 193 g of purified water was coated. Next, citric acid 35g, sodium chloride 105
The second layer (inner layer) of 326.7g of purified water is coated, and 148.75g of glucose, 85.9g of sodium acetate and 100.9g of sodium chloride are sequentially purified water 4139.1g.
Liquid of the second layer (intermediate layer) dissolved in, sodium chloride 157.
A second layer (outer layer) solution in which 5 g was dissolved in 472.5 g of water was coated. Centrifugal fluidized granulation coating device (CF-360S type, manufactured by Freund Sangyo) for 700 g of the above-mentioned laminated granules
Then, 214 g of a fine powder of sodium hydrogencarbonate of the third layer crushed by a sample mill was added while spraying the glucose solution, and a spherical laminated preparation was obtained. The obtained laminated preparation was dried by a conventional method to obtain the intended dialysis agent.

Example 4 Magnesium chloride (17.9 g), calcium chloride (38.7 g) and potassium chloride (26.1 g) were stirred with a universal stirrer (Shinagawa Kogyo, SD-02 type), and a sample mill (Fuji Paudal, crusher KIIW) was used. It was crushed in -1) to obtain a fine powder of the first layer. Similarly, 35 g of citric acid and 105 g of sodium chloride were mixed and pulverized to obtain a fine powder of the second layer (inner layer). Glucose (91.0 g), sodium acetate (85.9 g) and sodium chloride (258.4 g) were treated in the same manner as above to obtain a fine powder for the second layer (outer layer). Further, 441 g of sodium hydrogen carbonate was crushed as a third layer to obtain a fine powder. Then the particle size 3
Put 700 g of 50-500 μm sodium chloride into a centrifugal fluidized granulation coating device (CF-360S type, manufactured by Freund Sangyo Co., Ltd.) and rotate (rotation speed 200 rpm) to spray the glucose solution with the first layer and the second layer ( Fine powder was added in the order of the inner layer), the second layer (outer layer), and the third layer to obtain a spherical laminated preparation. The obtained laminated preparation was dried by a conventional method to obtain the intended dialysis agent.

[Test Example 1] Stability Test The dialysis agent obtained in Example 1 was used for 1) no desiccant and carbon dioxide substitution, 2) silica gel was stored as a desiccant, 3)
The containers were filled with carbon dioxide gas, 4) Silica gel was stored as a desiccant, and the containers were placed in glass bottles under the four conditions of carbon dioxide gas replacement, sealed and stored at 40 ° C.
E), presence / absence of aggregation, hydrogen carbonate ion concentration after dissolution and p
H was measured. The color difference was measured with a color difference meter (Nippon Denshoku Industries Co., Ltd., Σ80 type) using a standard white plate as a reference. For the hydrogen carbonate ion and pH, 10.76 g of the sample was dissolved in purified water to 1000 ml, and ion chromatography (Yokogawa Denki IC-500S type) and pH meter (Horiba Seisakusho F-16 type) were used, respectively. It was measured. The results are shown in Table 1.

[0023]

[Table 1]

From the above results, it has been clarified that the coloration is suppressed by storing it together with silica gel, and the hydrogen carbonate ion content is stably maintained by replacing with carbon dioxide gas. In addition, upon dissolution, within a few minutes,
It quickly dissolved.

[0025]

EFFECT OF THE INVENTION Since the sodium bicarbonate dialysis agent of the present invention is laminated in multiple layers as described above, it is excellent in long-term stability. In addition, it is easy to handle because all the necessary components are contained in one agent.

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Claims (5)

[Claims] 1. A dialysis agent containing an electrolyte, an organic acid and glucose, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid and malic acid. In the dialysis agent having a multilayer structure in which a core, a first layer, a second layer and a third layer are laminated in this order, and the core is sodium chloride, One layer is a layer containing calcium salt and / or magnesium salt and no organic acid and bicarbonate salt, the second layer is a layer containing organic acid and no calcium salt, magnesium salt and bicarbonate salt, A sodium bicarbonate dialysis agent, wherein the three layers are layers containing bicarbonate and not containing calcium salt, magnesium salt and organic acid. 2. The sodium bicarbonate dialysis agent according to claim 1, wherein the second layer is divided into two layers, an inner layer and an outer layer, and the inner layer contains at least an organic acid. 3. The second layer is divided into three layers of an inner layer, an intermediate layer and an outer layer, and the inner layer or the intermediate layer contains at least an organic acid, and the outer layer contains at least sodium chloride. The sodium bicarbonate dialysis agent according to claim 1. 4. The sodium bicarbonate dialysis according to claim 1, wherein the laminated preparation is stored together with a desiccant in a moisture-proof container, and the inside of the container is replaced with carbon dioxide gas. Agent. 5. A method for producing a sodium bicarbonate dialysis agent, which comprises laminating a glucose solution as a binder.