JP3384841B2 - Baking soda dialysis agent - Google Patents

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art In recent years, the demand for the following sodium bicarbonate dialysate has been increasing. ^{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 the one single hemodialysis Since a large amount (about 350 liters) is used and the formulation is unstable, it has to be prepared just before use, and in the old days, it requires complicated work such as accurate weighing, dissolution, and pH adjustment of various electrolytes. there were.

To reduce the above work, therefore, 1
A concentrated stock solution (about 11 liters) from which sodium hydrogen carbonate as a necessary component has been removed has been put on the market in a packaging unit for one person. However, it cannot be said that it has been sufficiently improved in transportation, storage location, handling during preparation of dialysate, and various proposals have been made since then. For example, Japanese Patent Laid-Open No. 3-7
No. 4331 discloses components necessary for preparation of sodium bicarbonate dialysate,
It was divided into a group containing calcium component and no sodium hydrogen carbonate and a group containing sodium hydrogen carbonate and no calcium component. The former was mixed with acetic acid as a pH adjuster, and both groups were granulated and mixed. A dialysis agent is disclosed. This invention is a sodium bicarbonate dialysate can be prepared by simply dissolving a predetermined amount of dialysis agent in a calculated amount of water, but since a liquid acid is used as a pH adjusting agent, Even if the amount is small, the reaction between the acid and sodium hydrogencarbonate may proceed over time, resulting in a decrease in the hydrogencarbonate ion content.Furthermore, agglomeration of the granulated product may occur during long-term storage, which makes handling inconvenient. There is a problem that it may come.

[0004]

An object of the present invention is a solid preparation containing an electrolyte and a pH adjusting agent necessary for preparing a sodium bicarbonate dialysate, which is excellent in stability and dissolves rapidly in water when used. To provide a dialysis agent.

[0005]

DISCLOSURE OF THE INVENTION The inventors of the present invention include a pH adjusting agent while considering the stability of each electrolyte necessary for a dialysis agent and the stability and hygroscopicity of glucose added as necessary. We have conducted intensive studies on the possibility of stable and stable solid preparations. As a result, a solid organic acid which is pharmacologically acceptable is used as a pH adjuster, and the necessary components are a group containing an organic acid and no bicarbonate (group A), an organic acid and a bicarbonate. The above problems can be solved by dividing into a group not containing both (group B) and a group containing bicarbonate and not containing an organic acid (group C), and forming a formulation in which each group is laminated with a layer consisting of group B in the middle. I found that I could solve it. The present invention has been completed based on the findings.

That is, the present invention provides at least Na ⁺ ,
What is claimed is ^{: 1. A} multi-layered preparation comprising an electrolyte necessary for the preparation of a dialysate containing Ca ⁺⁺ , Cl ⁻ and HCO ₃ ⁻ and a pharmacologically acceptable solid organic acid, which contains the organic acid. The present invention provides a dialysis agent in which a layer containing no carbonate and a layer containing bicarbonate and not containing the organic acid are laminated with an intermediate layer interposed therebetween.

Examples of the solid organic acid include citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid, malic acid and the like, with citric acid being preferred. These organic acids may be used alone or in combination of two or more.

The electrolyte used in the present invention must be pharmacologically acceptable. For example, as giving the ingredients of the baking soda dialysate described in the section of the prior art,
Examples thereof include sodium hydrogen carbonate, potassium hydrogen carbonate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, calcium gluconate and the like. The granules constituting the present invention can contain other components contained in blood, such as glucose, in addition to the electrolyte as described above.

The preferred blending range of the components contained in the 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 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 COO - 2 ~ 15 mEq ^{_{/ l HCO 3 - 10 ~ 40}} mEq / l solid organic acid 1 ~ 5 mEq / l dextrose 0 ~ 10 g / l

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

As a dosage form of the dialysis agent of the present invention, a laminated type spherical granule comprising a core substance (core), an inner layer, an intermediate layer and an outer layer is preferable. The preferred compound groups for forming each of these layers are as follows. Core substance (core) Sodium chloride inner layer Solid organic acid (citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid, malic acid),
Acid salt (calcium chloride, magnesium chloride) Sodium chloride, potassium chloride, glucose intermediate layer Sodium chloride, potassium chloride, sodium acetate, potassium acetate, calcium gluconate, glucose outer layer bicarbonate (sodium hydrogen carbonate, potassium carbonate), sodium chloride , Potassium chloride, sodium acetate, potassium acetate, calcium gluconate, glucose In the above, the compound contained in the outer layer is particularly important.
That is, if the outer layer contains bicarbonate alone or as a mixture with other salts, the basic bicarbonate-containing layer, the intermediate layer, and the organic acid-containing layer are sequentially dissolved in distilled water during the preparation of dialysate. Since it is adjusted to be neutral to slightly alkaline, the generation of carbon dioxide gas can be prevented, which is convenient.

The layered preparation of the present invention can be produced by a known method. For example, the compounds to be used are divided into three groups, a group containing solid organic acids, calcium and magnesium, a group containing sodium acetate and glucose, and a group containing bicarbonate, and the mixture of each group is mixed with a sample mill (Fuji Paudal Company). Pulverized by a crusher such as Then the particle size is 355-500
Spherical laminated granules are obtained by putting sodium chloride (μm) into a centrifugal fluidized coating granulator and sequentially adding the fine powder while spraying a glucose solution.

The dialysis agent of the present invention is more stable if it is stored in the substantially absence of oxygen gas. For packaging, a container having a high oxygen gas barrier property may be filled in a nitrogen stream or carbon dioxide gas and sealed.

[0014]

A solid organic acid is used in place of the liquid acetic acid or lactic acid conventionally used as a pH adjusting agent, and a sodium bicarbonate dialysate is prepared by forming a multi-layered preparation so that the pH adjusting agent and bicarbonate do not come into contact with each other. A stable formulation is obtained that contains all the ingredients necessary for its preparation. Moreover, since it is a granule, it is easy to handle and quickly dissolves in water.

[0015]

EXAMPLES "%" in the following examples is by weight. Example 1 Citric acid 80 g, calcium chloride dihydrate 88.4 g
And 40.8 g of magnesium chloride hexahydrate were stirred with a universal stirrer (SD-02 type, manufactured by Shinagawa Kogyo Co., Ltd.) and crushed with a sample mill (Fuji Paudal, crusher KIIW-1 type). One fine powder was obtained. 59.6 g of potassium chloride, 196.4 g of sodium acetate and 200 g of glucose were mixed and pulverized in the same manner as above to obtain a second fine powder. Furthermore, 1008 g of sodium hydrogen carbonate was crushed with a sample mill and the third
A fine powder was obtained. Next, 2430.8 g of sodium chloride having a particle diameter of 355 to 500 μm was placed in a centrifugal fluidized coating granulation apparatus (CF-360S type manufactured by Freund Sangyo Co., Ltd.), rotated (rotation speed 500 rpm) and a 50% glucose solution (solvent). Was sprayed with a 1: 1 mixture of ethanol and water), and the first fine powder, the second fine powder and the third fine powder were added in this order to obtain spherical granules. The liquid volume of the spray was 400 ml in total. The obtained granules were dried under reduced pressure at 40 ° C. for 5 hours and then classified to obtain granules of 12 to 24 mesh, which was used as a target dialysis agent. Particle size distribution 12-18 mesh 82.3% 18-24 mesh 17.7% Specific volume 0.828 g / ml

Example 2 In the same manner as in Example 1, the first fine powder was prepared from 80 g of citric acid, 88.4 g of calcium chloride dihydrate and 40.8 g of magnesium chloride hexahydrate, and 63 g of sodium chloride.
0.8 g, potassium chloride 59.6 g, sodium acetate 1
A second fine powder was obtained from 96.4 g and 200 g of glucose, and a third fine powder was obtained from 1008 g of sodium hydrogencarbonate, which were sequentially laminated on 1800 g of sodium chloride having a particle diameter of 355 to 500 μm (rotation speed by a granulating device: 2
50 rpm). The amount of the 50% glucose solution sprayed was 400 ml in total. The following operations were carried out in the same manner as in Example 1 to obtain granules of 12 to 24 mesh, which was used as the target dialysis agent. Particle size distribution 12-18 mesh 99.6% 18-24 mesh 0.4% Specific volume 0.802 g / ml

Example 3 In the same manner as in Example 1, 80 g of citric acid, 88.4 g of calcium chloride dihydrate, 40.8 g of magnesium chloride hexahydrate and 59.6 g of potassium chloride were used to produce a first fine powder. 630.8 g of sodium chloride and 19% of sodium acetate
A second fine powder was obtained from 6.4 g and glucose 200 g, and a third fine powder was obtained from sodium hydrogencarbonate 1008 g, and sodium chloride 1 having a particle diameter of 355 to 500 μm was obtained.
Sequentially stacked on 800 g (rotation speed by granulator: 40
0 rpm). The amount of the 50% glucose solution sprayed was 400 ml in total. The following operations were performed in the same manner as in Example 1 to obtain granules of 12 to 24 mesh, which were filled in a polyethylene-aluminum foil-polyethylene three-layer laminated sheet container in a nitrogen stream and sealed. Particle size distribution 12-18 mesh 92.2% 18-24 mesh 7.8% Specific volume 0.817 g / ml

[Test Example 1] The dialysis agents of Examples 1, 2 and 3 were placed in glass bottles, respectively, and the bottles were tightly sealed and stored at 40 ° C. for 3 months (only the dialysis agents produced in Example 3 were glass bottles). The interior space was replaced with nitrogen gas), and the color difference (ΔE) from the control, the presence or absence of aggregation, the hydrogen carbonate ion concentration after dissolution in water, and the pH were measured every one month. At the time of the dissolution, all the samples were dissolved within a few minutes. The color difference was determined by storing the dialysis agent of the corresponding Example at 5 ° C. as a control,
It was measured using a color difference meter (Nippon Denshoku Industries Co., Ltd., Σ80 type). The hydrogen carbonate ion concentration and the pH were measured according to Sample 10.
Dissolve 76 g in distilled water to make 1000 ml, and perform ion chromatography (Yokogawa Electric Co., IC-
500S type and pH meter (H-16, F-16)
Type). The results are shown in Table 1.

[0019]

[Table 1]

From Table 1, it can be seen that the dialysis agent of the present invention hardly changes in appearance (color) and sodium hydrogen carbonate content even after long-term storage, dissolves rapidly in water, and does not generate aggregates.

Test Example 2 100 parts of the dialysis agent of Example 1 was tested.
Put 800g in a 0ml polyethylene container and collect samples from the upper, middle and lower parts of the container.
0.76 g was dissolved in distilled water to 1000 ml, and sodium ion concentration, calcium ion concentration and hydrogen carbonate ion concentration were measured. The results are shown in Table 2.

[0022]

[Table 2]

From Table 2, it can be seen that the dialysis agent of the present invention has no content segregation.

[0024]

The dialysis agent of the present invention is a granule that can be stored for a long period of time, is easy to handle, and a sodium bicarbonate dialysate can be rapidly prepared by dissolving a predetermined amount or calculated amount thereof in water.

─────────────────────────────────────────────────── --Continued from the front page (56) References JP-A-6-237991 (JP, A) JP-A-4-257522 (JP, A) JP-B-63-52009 (JP, B1) (58) Field (Int.Cl. ⁷ , DB name) A61M 1/14-1/28 A61K 9/08

Claims (4)

(57) [Claims] 1. At least Na ⁺ , Ca ⁺⁺ , Cl ⁻ and H.
CO ₃ ^- A multilayer preparation containing the electrolyte and pharmacologically organic acids acceptable solid necessary for the preparation of a dialysis solution containing a layer without bicarbonate containing the organic acid A dialysis agent comprising a layer containing a bicarbonate and not containing the organic acid, with an intermediate layer interposed therebetween. 2. The dialysis agent according to claim 1, wherein the solid organic acid is one or more selected from the group consisting of citric acid, tartaric acid, maleic acid, oxaloacetic acid, isocitric acid and malic acid. . 3. A laminated preparation having a multilayer structure of a core substance (core), an inner layer, an intermediate layer and an outer layer, wherein the core substance is sodium chloride, the inner layer contains a solid organic acid, and the outer layer contains The dialysis agent according to claim 1 or 2, which is a spherical granule containing a carbonate. 4. The dialysis agent according to claim 1, which is stored in a state in which oxygen gas is substantially absent.