JP2986256B2 - Granules for hemodialysis - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to granules for hemodialysis.

[0002]

2. Description of the Related Art In hemodialysis therapy, a patient's blood is circulated extracorporeally and purified in an artificial kidney. A dialysate is refluxed inside the artificial kidney, and the dialysate is passed through a dialysis membrane. The blood is purified by contacting the blood and transferring waste products in the blood to the dialysate side. Conventionally, acetate has been used as a buffer contained in hemodialysis fluid.However, as dialysis membranes have been improved and permeability has been improved, and high-efficiency dialysis has been carried out, dialysate has been introduced into blood. It has been pointed out that the amount of acetic acid to be transferred increases, which causes a bad influence on the cardiovascular system. For this reason, in recent years, a bicarbonate dialysate using sodium bicarbonate (sodium bicarbonate) as a buffer, which has a small burden on a living body, has become mainstream. Sodium bicarbonate reacts with calcium and magnesium to form carbonate and precipitate.
Currently used bicarbonate dialysis solutions are in the form of a two-liquid type or a one-liquid one-powder type containing a concentrated stock solution containing sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc., and an aqueous solution or powder of sodium hydrogen carbonate. It is commercially available. This concentrated stock solution is usually 10-1
Commercially available in 1 liter polyethylene containers,
The weight of the set is 12 to 24 kg, and there is a problem that a man and a place are required for transporting and storing the undiluted solution.

[0003] In response to such problems, attempts have been made to reduce the weight of the preparation for dialysis fluid by powdering. For example, Japanese Patent Publication No. 57-34248 discloses a method for producing an electrolyte powder for dialysis by a spray drying method. Japanese Patent Publication No. 58-27246 discloses a method for obtaining an electrolyte powder for bicarbonate dialysis in which pH is adjusted by spray addition of glacial acetic acid to sodium chloride which is a component of the electrolyte powder. Further, Japanese Patent Application Laid-Open No. Sho 62-30540 discloses that in a dialysis preparation containing sodium acetate as a main component, calcium chloride and magnesium chloride are mixed and finely powdered with sodium acetate and water, whereby the composition of the electrolyte mixture is partially impaired. Techniques for reducing uniformity have been disclosed.

[0004]

However, in the spray drying method, there are variations in the moisture and particle size of the product. Particularly, it is difficult to give a constant pH to the bicarbonate dialysate because the acid component volatilizes during drying. . Further, the method of spray-adding glacial acetic acid has a problem that the working environment is deteriorated due to the generation of odor, and furthermore, the spray is uneven and it is difficult to suppress the variation in the composition of the electrolyte mixture between product lots.
The method of pulverizing calcium chloride and magnesium chloride together with sodium acetate and water reduces the possibility of partial heterogeneity in the composition of the electrolyte mixture, but deliquesces or congeals during manufacture, transfer and storage. For this reason, not only the composition becomes partially non-uniform, but also the long-term storage stability is low.

[0005]

According to the present invention, there is provided a granulation for hemodialysis containing (a) an electrolyte for hemodialysis, (b) glucose and (c) sodium bicarbonate, according to the present invention. (A), (B) and (C) are separate granular compositions. (Ii) (A) is an aqueous solution of at least one of the components of (A), and the remaining components are fine powder. And preparing it into a granular composition by using a granule for hemodialysis. In a preferred embodiment, (A) a granular composition comprising an electrolyte for hemodialysis, particularly an electrolyte powder for hemodialysis other than calcium chloride and magnesium chloride, after dissolving calcium chloride and magnesium chloride in water, adding acetic acid and adding acid. A granulated composition prepared by adding, kneading, granulating, drying and sizing, a granulated composition consisting of (b) glucose and a granulated composition consisting of (c) sodium hydrogencarbonate. Granules for hemodialysis consisting of two compositions are used.

The granules for hemodialysis of the present invention are, as described above, composed of three types of granular compositions (a) to (c). The granular composition (a) comprising an electrolyte for hemodialysis is obtained by dissolving at least one of the components (a) in water and adding an aqueous solution of acetic acid to a fine electrolyte powder for hemodialysis containing the remaining components. And kneaded, granulated, dried and sized. In addition, glacial acetic acid, dilute acetic acid, and the like can also be used to make acetic acid acidic.

[0007] Electrolytes for hemodialysis include Na ⁺ , K ⁺ , and Ca.
²⁺ , Mg ²⁺ , Cl ⁻ , CH ₃ COO ^−, etc., and are generally in units of mEq / l, Na ⁺ is 132-140, K ⁺
Is 2.0-2.5, Ca ²⁺ is 2.5-3.5, and Mg ²⁺ is 1.
0-1.5, Cl ^- is 105-110, CH ₃ COO ^- is 6
-8. In the component (a), the component to be dissolved in water is preferably deliquescent, and is usually magnesium chloride or calcium chloride. Examples of the electrolyte powder other than magnesium chloride and calcium chloride include sodium chloride, potassium chloride, and sodium acetate. These amounts are usually in the following ranges: sodium chloride; 80-90% by weight, potassium chloride; 1-3% by weight, sodium acetate; 6-9% by weight, calcium chloride; %, Magnesium chloride; 1-2% by weight.

In this case, the hemodialysis electrolyte containing the remaining components (a), glucose and sodium bicarbonate are preferably in the form of fine powder in order to improve dispersibility and uniformity. Accordingly, the lower limit of the particle size is not particularly limited, but the term "fine powder" means that most of the particle size is 150 µm or less, preferably 50 µm or less, and more preferably 50 µm to 10 µm. The majority is preferably at least 90%, usually at least 70%, even more preferably at least 50%. The granular compositions (b) and (c) generally do not contain any other solid components.

[0009] The granular compositions of the present invention are each finally
The particles are sized to 250 μm (60 mesh) -1000 μm (16 mesh), and stored and transported as a preparation. In use, the mixed granular composition may be dissolved in water, or each may be dissolved in water and mixed. The use ratio (weight ratio) of the granular compositions (a), (b) and (c) in the granules of the present invention is 35-15: 6-2.
5: 9-5, preferably 30-20: 6-3: 8-6,
More preferably, 25: 3.5: 8.8 or 26: 5.
3: 7.4.

[0010]

Next, the present invention will be described in more detail with reference to Examples, but it should not be construed that the invention is limited thereto. Example 1 (1) Production of granular composition (a) comprising electrolyte for hemodialysis 84.88 kg of sodium chloride, 2.08 k of potassium chloride
g and 6.86 kg of sodium acetate were crushed using a pulverizer (Atomizer manufactured by Fuji Paudal Co., Ltd.) and passed through a screen to obtain a fine powder of 50 μm or less, and then each component was mixed. To this mixed powder, 3.08 kg of calcium chloride and 1.42 kg of magnesium chloride were dissolved in 3.5 l of purified water, a suitable amount of glacial acetic acid was added thereto, and the mixture was acidified with acetic acid.
Granulation was performed using a basket type granulator having a diameter of 7 mm. The obtained granules were subjected to a glacial acetic acid content of 1.6 using a fluid bed dryer.
It dried so that it might be -1.8 weight%. 100 dried products
The granules were sized using shifters of 0 μm (16 mesh) and 250 μm (60 mesh) to obtain a granular composition (a). (2) Production of Granular Composition Made of Glucose (b) 100 kg of glucose was pulverized using a pulverizer (Atomizer manufactured by Fuji Paudal Co., Ltd.) and passed through a screen to form a fine powder of 50 μm or less. After adding 8.0 l of purified water to the mixture and kneading the mixture, the mixture was granulated using a basket-type granulator having a diameter of 0.7 mm. The obtained granules were dried using a fluid bed dryer so that the water content was 0.5% or less. Dry the product to 1000 μm (16 mesh) and 2
The granules were sized using a 50 μm (60 mesh) shifter to obtain a granular composition (b). (3) Production of granular composition (c) composed of sodium bicarbonate 100 kg of sodium bicarbonate was pulverized using a pulverizer (Atomizer manufactured by Fuji Paudal Co., Ltd.) and passed through a screen to obtain a fine powder of 50 μm or less. After adding 10.0 l of purified water to the mixture and kneading the mixture, the mixture was granulated using a basket type granulator having a diameter of 0.7 mm. The obtained granules were dried using a fluid bed dryer so that the water content was 0.5% or less. The dried product was sized using a shifter of 1000 μm (16 mesh) and 250 μm (60 mesh) to obtain a granular composition (c).

Example 2 (1) Production of granular composition (a) comprising electrolyte for hemodialysis 85.89 kg of sodium chloride, 2.01 k of potassium chloride
g and 6.63 kg of sodium acetate were crushed and pulverized in the same manner as described in Example 1 to form a fine powder of 50 μm or less, and then each component was mixed. 2.48 kg of calcium chloride and 1.37 of magnesium chloride are added to this mixed powder.
kg was dissolved in 3.5 l of purified water, and a solution made acidic by adding an appropriate amount of glacial acetic acid was added and kneaded.
Granulation was performed using a basket-type granulator having a diameter. The obtained granulated product was subjected to glacial acetic acid content of 1.6 to 1.8 using a fluidized bed drier.
It was dried to a weight percent. 1000 μm dry matter
(16 mesh) and 250 μm (60 mesh) using a shifter to obtain a granular composition (a). (2) Production of Granular Composition (b) Made of Glucose 100 kg of glucose was crushed and pulverized in the same manner as described in Example 1 to a fine powder of 50 μm or less, and purified water 8.0.
After adding 1 and kneading, granulation was performed using a basket type granulator having a diameter of 0.7 mm. The obtained granules were dried using a fluid bed dryer so that the water content was 0.5% or less. Dry the product to 1000 μm (16 mesh) and 25
Using a 0 μm (60 mesh) shifter, size
A granular composition (b) was obtained. (3) Production of Granular Composition (C) Consisting of Sodium Bicarbonate 100 kg of sodium bicarbonate was taken and pulverized in the same manner as described in Example 1 to obtain a powder having a particle size of 50 μm or less. After addition and kneading, the mixture was granulated using a basket type granulator having a diameter of 0.7 mm. The obtained granules were dried using a fluid bed dryer so that the water content was 0.5% or less. The dried product was sized using a shifter of 1000 μm (16 mesh) and 250 μm (60 mesh) to obtain a granular composition (c).

Comparative Example 1 (1) Production of Granular Composition Comprising Hemodialysis Electrolyte and Glucose 74.48 kg of sodium chloride and 1.83 k of potassium chloride
g, sodium acetate 6.03 kg and glucose 12.2
5 kg was taken, each was pulverized in the same manner as described in Examples, and passed through a 50 μm shifter to form a fine powder of 50 μm or less, and then each component was mixed. 2.70 kg of calcium chloride and 1.25 kg of magnesium chloride are added to this mixed powder.
Was dissolved in 3.5 l of purified water, and a solution made acidic by adding an appropriate amount of glacial acetic acid was added and kneaded, followed by granulation using a basket type granulator having a diameter of 0.7 mm. The obtained granules were dried using a fluid bed dryer so that the glacial acetic acid content was 1.4 to 1.6% by weight. The dried product is 1000 μm (16
And a 250 μm (60 mesh) shifter to obtain a granular composition. (2) Production of granular composition comprising sodium hydrogencarbonate
(3) The same operation as in the preparation of the granular composition (c) composed of sodium hydrogen carbonate was performed to obtain a granular composition composed of sodium bicarbonate.

Comparative Example 2 (1) Production of granular composition comprising hemodialysis electrolyte and glucose 71.44 kg of sodium chloride, 1.67 k of potassium chloride
g, 5.51 kg of sodium acetate and glucose 16.8
After taking 3 kg, each was pulverized in the same manner as described in the Examples to obtain a fine powder of 50 μm or less, and then each component was mixed.
To this mixed powder, 2.06 kg of calcium chloride and 1.14 kg of magnesium chloride were dissolved in 3.5 l of purified water, and a solution made acidic by adding an appropriate amount of glacial acetic acid was kneaded, and then kneaded. Was granulated using a basket type granulator. The obtained granules were dried using a fluid bed dryer so that the glacial acetic acid content was 1.3 to 1.5% by weight. The dried product is 1000 μm (16 mesh) and 250 μm
The granules were sized using a (60 mesh) shifter to obtain a granular composition. (2) Production of Granular Composition Consisting of Sodium Bicarbonate The same operation as in the production of (3) Granular Composition Consisting of Sodium Bicarbonate in Example 2 was carried out, and a granular composition consisting of sodium bicarbonate was used. I got

Test Example 1 In the granular composition obtained in Example 1, 71.60 g of an electrolyte granular composition (a) and a glucose granular composition
(B) Take 10.00 g, dissolve in purified water to make 10.0 liters, and add each electrolyte and glucose content and p
H was measured, and the uniformity of each component and pH was examined. Table 1 shows the results.

[Table 1]

Test Example 2 In the granulated composition obtained in Example 2, 74.14 g of an electrolyte granulated composition (a) and a glucose granulated composition
(B) 15.0 g of each solution was dissolved in purified water to make 10.0 liters, and the contents of each electrolyte and glucose and the pH were measured to examine the uniformity of each component and pH. Table 2 shows the results.

[Table 2]

Test Example 3 In the granular composition obtained in Example 1, 2506 g of the electrolyte granular composition (a) was taken and sealed in an aluminum bag. In addition, 350 g of the glucose granule composition (b) was taken and sealed in an aluminum bag. Further, 882 g of the sodium hydrogencarbonate granular composition (c) was taken and sealed in a polyethylene bag. Place each bag at room temperature or under humidified conditions (40
At 75 ° C., 75% RH) for a certain period of time.
g and (b) 10.00 g, and dissolved in purified water.
The content of each component and the pH were measured with respect to the 0 l liquid,
The stability during long-term storage was studied. However,
Regarding the content, in order to compare the rate of change over time, the value immediately after production was set to 100, and the value at each subsequent measurement was converted into a ratio to the value immediately after production to standardize the comparison scale.
Table 3 shows the results.

[Table 3] Similarly, for (c), the content and pH after storage for a certain period of time were measured.
00 and expressed as a ratio to it.
The values when a 5% aqueous solution was used were shown. Table 4 shows the results.

[Table 4]

Test Example 4 From the granular composition obtained in Example 2, 2595 g of the electrolyte granular composition (a) was taken and sealed in an aluminum bag. In addition, 525 g of the glucose granule composition (b) was taken and sealed in an aluminum bag. Further, 735 g of the sodium hydrogencarbonate granular composition (c) was taken and sealed in a polyethylene bag. Place each bag at room temperature or under humidified conditions (40
At 75 ° C., 75% RH) for a certain period of time.
g and (b) 15.00 g, and dissolved in purified water.
The content of each component and the pH were measured with respect to the 0 l liquid,
The stability during long-term storage was studied. However,
Regarding the content, in order to compare the rate of change over time, the value immediately after production was set to 100, and the value at each subsequent measurement was converted into a ratio to the value immediately after production to standardize the comparison scale.
Table 5 shows the results.

[Table 5] Similarly, for (c), the content and pH after storage for a certain period of time were measured.
00 and expressed as a ratio to it.
The values when a 5% aqueous solution was used were shown. Table 6 shows the results.

[Table 6]

Test Example 5 The granular composition obtained in Example 1 was packaged in the same manner as in Test Example 3, and was room temperature or heated and humidified conditions (40 ° C., 75% RH).
After storing for a certain period of time, the electrolyte granular composition (a) 25.
06 g and 3.50 g of the glucose granule composition (b) were dissolved in purified water to make 100 ml, and the transmittance was measured. Similarly, the granular composition obtained in Example 2 was packaged in the same manner as in Test Example 4, stored under a certain period of time under each condition, and (25) 95 g and (25) 5.25 g of (b) were taken. The transmittance was measured for a solution dissolved in purified water to make 100 ml. Also, with regard to the granular composition obtained in Comparative Example 1, 28.56 g of the granular composition comprising the electrolyte and glucose was packed in a 2856 g aluminum bag package and stored for a certain period under each condition. The sample was dissolved in purified water to make 100 ml, and the transmittance was measured. Similarly, with regard to the granular composition obtained in Comparative Example 2, one granular composition comprising an electrolyte and glucose
After storing in a 120 g aluminum bag and storing it for a certain period under each condition, 31.20 g was taken and dissolved in purified water to make 100 ml, and the transmittance was measured. Table 7 shows the above measurement results. However, in order to compare the rate of change with time, the value immediately after production was set to 100, and the value at each subsequent measurement point was converted into a ratio to the value immediately after production to standardize the comparison scale.

[Table 7] At a transmittance of 97% or less, coloring is visually observed.

As is apparent from the above results, the granules for hemodialysis obtained according to the present invention have very small coefficients of variation of 1 or less in Test Examples 1 and 2, and there is no change in the composition of each component. It turns out. Also, there is almost no variation in pH. Further, as shown in Test Examples 3 to 5, the stability in long-term storage was excellent.

Since the preparation for hemodialysis according to the present invention is a granular composition, it is not only lighter than a conventional dialysate using a concentrated undiluted solution, but also adheres unlike a powder.
Since the cohesion is negligible, it has excellent fluidity and filling properties. Further, since the surface area is smaller than that of powder, it is hardly affected by changes due to moisture absorption or the like. Furthermore, because calcium chloride and magnesium chloride, which had previously been difficult to uniformly mix because of their high deliquescent, were made into aqueous solutions, they were made into granules,
There is no variation in the composition of each component. Furthermore, since acetic acid is diluted with water and added, there is very little variation in pH in the drying step. In addition, since the present granules are granules obtained by granulating fine powder, they are excellent in solubility. By sealing and packaging this granule, it can withstand long-term storage and can be made into a simple preparation such as transport.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Toshifumi Shimizu 4-1 Hiranoya Shinmachi, Daito-shi, Osaka Fuso Pharmaceutical Co., Ltd. Daito Plant (56) References JP-A-3-74331 (JP, A) JP 56-131515 (JP, A) JP-A-3-38527 (JP, A) Nakano, Yoshinobu, "Development of Pharmaceuticals", Volume 11, Preparation unit operation and machine, Hirokawa Shoten, published November 10, 1989 (Int.Cl. ⁶ , DB name) A61K 33/00 A61K 31/70

Claims (3)

(57) [Claims] 1. A granule for hemodialysis containing (a) an electrolyte for hemodialysis, (b) glucose and (c) sodium bicarbonate, wherein (i) (a), (b) and (c) are separated from each other. (Ii) the granular composition of the electrolyte for hemodialysis of (a),
An aqueous solution of at least one of calcium chloride and magnesium chloride contained as the component (a) is made acidic by adding acetic acid to the aqueous solution, and then the remaining components are used in the form of fine powder to prepare a granule. A granule for hemodialysis, characterized in that: 2. The granule for hemodialysis according to claim 1, wherein the granule composition of glucose in (b) is obtained by adding water to finely powdered glucose to prepare a granule. 3. The hemodialysis composition according to claim 1, wherein the granular composition of sodium bicarbonate (c) is obtained by adding water to finely divided sodium bicarbonate to prepare a granular composition. Granules.