JP3647898B2 - Sodium bicarbonate dialysis agent and method for producing the same - Google Patents

Description

【００２４】
以上の結果から、シリカゲルと共に収納することにより着色が抑制され、炭酸ガスで置換することにより炭酸水素イオン含量が安定に維持されることが明らかとなった。また溶解に際し、いずれも数分以内に、速やかに溶解した。
【００２５】
【発明の効果】
本発明の重曹透析用剤は、前記のように多層に積層されているので、長期間の安定性に優れている。また、一剤中に必要な成分をすべて含んでいることから取扱いが容易である。[0001]
[Industrial application fields]
The present invention relates to a layered preparation for preparing a dialysate containing bicarbonate ions, that is, a sodium bicarbonate dialysate.
[0002]
[Prior art]
Conventionally, when hemodialysis is performed, a sodium bicarbonate dialysis solution having the following composition is 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 0-2.5 g / l
However, the dialysate having such a composition is used in a large amount of about 350 liters per dialysis per person, and because it is unstable in terms of formulation, it must be prepared immediately before use, and complicated work is required. It was necessary.
[0003]
In order to alleviate the above work, a concentrated stock solution (about 11 liters) in which the sodium bicarbonate contained in the necessary components is separated from the packaging unit for one person is now on the market. However, since sodium bicarbonate in the composition reacts with calcium salt and magnesium salt to cause precipitation of carbonate, currently used dialysate cannot be made into one solution, and it is divided into two solutions. Have been commercialized. Therefore, it cannot be said that it has been sufficiently improved in transportation, storage location, handling, etc., and various proposals have been made thereafter.
In view of these points, attempts have been made to powder dialysis agents. For example, Japanese Patent Laid-Open No. 3-74331 discloses a component required for a dialysis solution, a granulated product composed of a group containing a calcium component and not containing sodium bicarbonate, and a granulated product consisting of a group containing sodium bicarbonate and not containing a calcium component; Is disclosed. In this method, a dialysate can be prepared by simply dissolving a predetermined amount of a dialysis agent in water. However, acetic acid used as a pH adjuster is a calcium salt, magnesium salt and bicarbonate. Since it dissolves at the same time as the salt, there are disadvantages that insoluble precipitation occurs and carbon dioxide gas is generated, resulting in a high pH. In addition, the reaction proceeds during long-term storage, causing problems such as aggregation and a decrease in content. On the other hand, JP-A-2-31418 discloses a powdered composition comprising a solid electrolyte for dialysis and a liquid acid, a powdered composition of sodium bicarbonate and glucose, and a powdery composition for dialysis comprising two compositions. Has been. JP-A-4-257522 discloses a two-part granulated product comprising a group consisting of one or more selected from components other than baking soda among dialysis electrolyte components, and a group consisting mainly of sodium bicarbonate. Japanese Laid-Open Patent Publication No. 5-70357 discloses a dialysis agent in which three components of a dialysis electrolyte, glucose and baking soda are used as separate granular compositions. However, since these are manufactured separately in two or three parts, the problem of handling has not been solved at all.
[0004]
[Problems to be solved by the invention]
An object of the present invention is to provide a sodium bicarbonate dialysis agent that is excellent in stability with respect to long-term storage and that can be easily prepared by preventing the precipitation of precipitates by dissolving each component sequentially during use.
[0005]
[Means for Solving the Problems]
The present inventors diligently studied to provide a stable laminated preparation including a pH adjuster while considering the stability and hygroscopicity of each electrolyte and glucose required for the dialysis agent. As a result, using sodium chloride as the nucleus, the group containing calcium salt and / or magnesium salt and not containing organic acid and bicarbonate, the group containing organic acid and not containing calcium salt, magnesium salt and bicarbonate, and When laminating a group containing carbonate and not containing calcium salt, magnesium salt and organic acid, by laminating sequentially through a group selected from components other than calcium salt, magnesium salt, organic acid and bicarbonate The present invention has been completed by finding out that the problem can be solved.
[0006]
That is, the present invention is a dialysis agent comprising 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, which is one or more selected, the layered preparation has a multilayer structure of a core, a first layer, a second layer, and a third layer, and the core is sodium chloride, the first layer is The layer contains calcium salt and / or magnesium salt and does not contain organic acid and bicarbonate, the second layer is laminated in two or more layers, and contains organic acid and contains calcium salt, magnesium salt and bicarbonate. It is a layer that does not contain, and the third layer is a sodium bicarbonate dialysis agent characterized in that it contains bicarbonate and does not contain calcium salt, magnesium salt and organic acid. This laminated preparation is filled in an airtight container that is moisture-proof in a carbon dioxide gas stream, and stored together with a desiccant.
[0007]
A preferable blending range of the components contained in the sodium bicarbonate dialysis agent of the present invention is shown as follows in terms of the composition range after preparation of the dialysate, and the pH is 7.0 to 8.0, more preferably 7.2. ~ 7.6.
Na ⁺ 120-150 mEq / l
K ⁺ 0 to 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 0-10 g / l
[0008]
In the production of the sodium bicarbonate dialysis agent of the present invention, when selecting a compound and setting the blending ratio, for example, the concentration of each component may be set based on the above, and the back calculation may be performed according to the combination of compounds capable of supplying each component.
[0009]
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 can contain other components contained in blood, such as glucose, together with the electrolyte as described above.
[0010]
The laminated preparation includes a group containing a calcium salt and / or a magnesium salt and not containing an organic acid and a bicarbonate (first layer), a group containing an organic acid and not containing a calcium salt, a magnesium salt and a bicarbonate (second). Layer) and the group containing bicarbonate (calcium salt, magnesium salt and organic acid) (third layer) is important. That is, a group containing calcium salt and / or magnesium salt and not containing organic acid and bicarbonate and a group containing bicarbonate and not containing calcium salt, magnesium salt and organic acid are classified into calcium salt, magnesium salt, organic acid and bicarbonate. By laminating so as not to contact through a group selected from components other than carbonate, it is possible to prevent calcium salt and magnesium salt from reacting with bicarbonate. In addition, a group containing organic acid and not containing calcium salt, magnesium salt and bicarbonate and a group containing bicarbonate containing calcium salt, magnesium salt and organic acid other than calcium salt, magnesium salt, organic acid and bicarbonate By laminating so as not to contact through a group selected from the above components, the reaction between the bicarbonate and the organic acid can be prevented. That is, during the preparation of dialysate, it is dissolved in distilled water sequentially from the outer layer of the layered preparation, and the pH is adjusted from neutral to slightly alkaline, so that carbon dioxide is generated, and calcium salt and magnesium salt are the last. Therefore, precipitation of calcium carbonate and magnesium carbonate can be prevented. Further, the stacking order may be changed as desired, and the first layer, the second layer, and the third layer may be composed of two or more layers.
[0011]
The laminating operation of the present invention will be described below. The production method of the present invention comprises a step of sequentially laminating the core, and is carried out by a commonly used granulating and coating apparatus.
For example, the group to be used includes a calcium salt and / or a magnesium salt and does not include an organic acid and a bicarbonate, an organic acid includes a calcium salt, a group that does not include a magnesium salt and a bicarbonate, a bicarbonate that includes a calcium salt In addition, a group not containing magnesium salt and organic acid and a group selected from components other than calcium salt, magnesium salt, organic acid and bicarbonate, and each component of each group is appropriately sample mill (manufactured by Fuji Paudal) etc. Micronize with a pulverizer. Next, the core sodium chloride crystal particles are put into a centrifugal flow type 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. .
[0012]
As the dosage form of the sodium bicarbonate dialysis agent of the present invention, a spherical laminated preparation is preferably laminated on the surface of the core sequentially from the first layer.
[0013]
Examples of the organic acid include acetic acid, lactic acid, citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid, malic acid and the like, and citric acid is particularly preferable. The amount of acid used is preferably added so that the pH of the dialysate is in the range of 7.0 to 8.0. A more preferable range is pH 7.2 to 7.6. These organic acids can be used alone or in combination of two or more.
[0014]
The binder used in the method for producing a layered preparation of the present invention is safe because glucose in the component is used, and since the binding force is strong, it is possible to obtain a layered preparation that is high in strength and hardly powdered. Glucose is appropriately dissolved in a solvent and used, but a preferable concentration is 0.5 to 55 W / W%. The solvent is not particularly limited as long as it is used for formulation and dissolves glucose, but is preferably water or a mixed solvent of water and ethanol.
[0015]
The material used in 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, but for example, polyethylene, polypropylene, polyvinyl chloride, or aluminum A laminate film in which such metal foil, nylon, cellophane, etc. are appropriately laminated in two or multiple layers can be mentioned.
[0016]
It is advantageous to seal the airtight container in the packaging form as described above 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 and the like are used.
[0017]
[Action]
Since the baking soda dialysis agent thus obtained is laminated so that the organic acid and the bicarbonate are not in contact with each other, reaction between components can be prevented. Also, when preparing the dialysate, it is dissolved from bicarbonate in order without adjusting pH, the pH of the solution is adjusted from neutral to slightly alkaline, and finally calcium salt and magnesium salt are dissolved. Therefore, no carbonate precipitate is formed.
[0018]
【Example】
EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example and a test example, this invention is not limited to these Examples.
[Example 1]
Magnesium chloride 17.9g, calcium chloride 38.7g and potassium chloride 26.1g were stirred with a universal stirrer (Shinagawa Kogyo, SD-02 type), and pulverized with a sample mill (Fuji Paudal, pulverizer KIIW-1). One layer of fine powder was obtained. 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 100.9 g were subjected to the same operation as above to obtain a fine powder of the second layer (intermediate layer). As the second layer (outer layer), 157.5 g of sodium chloride was pulverized to obtain a fine powder. Further, 441 g of sodium bicarbonate was pulverized 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 placed in a centrifugal fluidized granulating coating apparatus (Freund Sangyo Co., Ltd., CF-360S type), rotated (rotation speed 200 rpm), and sprayed with the glucose solution, the first layer, Fine powders were 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.
[0019]
[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 pulverized with a sample mill 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). The same operation as described above was performed on 91.0 g of glucose and 100.9 g of sodium chloride 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 bicarbonate was pulverized 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 placed in a centrifugal fluidized granulating coating apparatus (Freund Sangyo Co., Ltd., CF-360S type), rotated (rotation speed 200 rpm), and sprayed with the glucose solution, the first layer, Fine powders were 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 layered preparation was dried by a conventional method to obtain the intended dialysis agent.
[0020]
Example 3
Put 700g of sodium chloride with a particle size of 350-500μm in a tumbling fluidized granulation dryer (multiplex, MP-01 type, manufactured by Paulex) and refine 17.9g of magnesium chloride, 38.7g of calcium chloride and 26.1g of potassium chloride. The liquid of the first layer dissolved in 193 g of water was coated. Next, a second layer (inner layer) solution in which 35 g of citric acid and 105 g of sodium chloride were dissolved in 326.7 g of purified water was coated, and 148.75 g of glucose, 85.9 g of sodium acetate, and 100.9 g of sodium chloride were sequentially added to semen water. The liquid of the second layer (intermediate layer) dissolved in 4139.1 g and the liquid of the second layer (outer layer) prepared by dissolving 157.5 g of sodium chloride in 472.5 g of water were coated. Third, 700 g of the above-mentioned granulated product was put into a centrifugal fluidized granulating coating device (Freund Sangyo Co., Ltd., CF-360S type), rotated (rotation speed: 200 rpm), and ground with a sample mill while spraying a glucose solution. 214 g of fine powder of sodium hydrogen carbonate in the layer was added to obtain a spherical laminated preparation. The obtained laminated preparation was dried by a conventional method to obtain the intended dialysis agent.
[0021]
Example 4
Magnesium chloride 17.9g, calcium chloride 38.7g and potassium chloride 26.1g were stirred with a universal stirrer (Shinagawa Kogyo, SD-02 type), and pulverized with a sample mill (Fuji Paudal, pulverizer KIIW-1). One layer of fine powder was obtained. 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 of the second layer (outer layer). Further, 441 g of sodium bicarbonate was pulverized 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 placed in a centrifugal fluidized granulating coating apparatus (Freund Sangyo Co., Ltd., CF-360S type), rotated (rotation speed 200 rpm), and sprayed with the glucose solution, the first layer, Fine powder was added in the order of the second layer (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.
[0022]
[Test Example 1] Stability Test The dialysis agent obtained in Example 1 was 1) no desiccant and carbon dioxide replacement, 2) silica gel was stored as the desiccant, 3) the container was replaced with carbon dioxide, and 4) dried. Silica gel is stored as an agent, and the container is placed in a glass bottle under four conditions of carbon dioxide replacement, sealed and stored at 40 ° C., then color difference (ΔE), presence / absence of aggregation, concentration of bicarbonate ion after dissolution And the pH was measured.
The color difference was measured using a color difference meter (manufactured by Nippon Denshoku Industries Co., Ltd., Σ80 type) using a standard white plate as a control. For bicarbonate ion and pH, dissolve 10.76 g of sample in purified water to 1000 ml, and use ion chromatography (Yokogawa Electric, IC-500S type) and pH meter (Horiba, F-16 type), respectively. It was measured.
The results are shown in Table 1.
[0023]
[Table 1]

[0024]
From the above results, it was revealed that coloring was suppressed by storing together with silica gel, and that the hydrogen carbonate ion content was stably maintained by substitution with carbon dioxide gas. Moreover, in the case of dissolution, all dissolved quickly within several minutes.
[0025]
【The invention's effect】
Since the baking soda dialysis agent of the present invention is laminated in multiple layers as described above, it is excellent in long-term stability. Moreover, since all necessary components are contained in one agent, handling is easy.

Claims (5)

  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 in which the layered preparation has a multilayer structure in which the core, the first layer, the second layer, and the third layer are stacked in this order, and the core is sodium chloride, the first layer is a calcium salt. Or / and a magnesium salt containing organic acid and bicarbonate, the second layer is an organic acid containing calcium salt, magnesium salt and bicarbonate, and the third layer is bicarbonate. A sodium bicarbonate dialysis agent characterized by being a layer containing a salt and not containing a calcium salt, a magnesium salt and an organic acid.   2. The baking soda 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.   The said 2nd layer is divided | segmented into three layers, an inner layer, an intermediate | middle layer, and an outer layer, is laminated | stacked at least, an organic acid is contained in an inner layer or an intermediate | middle layer, and at least sodium chloride is contained in the outer layer. The baking soda dialysis agent described.   4. The baking soda dialysis agent according to claim 1, 2 or 3, wherein the layered preparation is stored together with a desiccant in a moisture-proof container, and the inside of the container is replaced with carbon dioxide gas. It laminates using a glucose solution as a binder, The manufacturing method of the baking soda dialysis agent in any one of Claims 1-4 characterized by the above-mentioned .