JPH0338527A - Preparation for blood dialysis and its production - Google Patents

Abstract

PURPOSE:To obtain the subject preparation consisting of a powdery composition consisting of a solid inorganic salt for dialysis, saccharide, glucose, sodium acetate and acetic acid and powdery composition consisting of sodium hydrogen carbonate and sodium acetate and having excellent storage stability and good handling properties. CONSTITUTION:(A) The preparation consisting of the first powdery composition containing a solid inorganic salt for dialysis, glucose, sodium acetate and acetic acid at a ratio of Na<+> of 85-135mm mol, K<+> of 0-4mm mol, Ca<+> of 0.5-2.2mm mol, Mg<++> of 0.2-1.0mm mol, Cl<-> of 90-14-mm mol, CH3COO<-> of 4-10mm mol; glucose of 4-12mm mol when dissolve in a definite amount of water and (B) the second powdery composition containing sodium hydrogen carbonate and sodium acetate at a ratio of Na<+> of 15-40mm mol, HCO of 15-40mm mol and CH3COO<-> of 0.5-3mm mol when dissolved in a definite amount of water.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a hemodialysis preparation and a method for producing the same. More specifically, the present invention relates to a uniform powdered hemodialysis preparation with excellent storage stability and a method for producing the same.

(Prior art) When performing hemodialysis, a patient's blood is purified in an artificial kidney, and a dialysate is circulated inside this artificial kidney and comes into contact with the blood through a permeable J7 membrane. The blood is purified by transferring waste products in the blood to the dialysate side. This dialysate is inseparable from improving the performance of artificial kidneys.

Acetic acid dialysate, which has traditionally been the mainstream, has become a burden to patients as the amount of acetic acid taken into the body has increased due to the improved performance of artificial kidneys, which causes discomfort for patients such as headaches and a drop in blood pressure. People are now switching to bicarbonate dialysis, which has less oxidation.

Bicarbonate dialysate cannot be made into a single stock solution like acetic acid dialysate because sodium bicarbonate reacts with calcium and magnesium to form a precipitate. For this reason, bicarbonate dialysate contains sodium bicarbonate (base solution) and calcium, magnesium, sodium, etc. (prescription solution).
It is formulated in two parts.

The dosage form of the basic solution is powder or liquid, and the dosage form of the prescription solution is liquid.
00-1,000g powder or 10-12U liquid,
There are also prescription liquids ranging from 9 to 1211. however,
In facilities with a large number of patients, the dialysis fluid requires a large amount of labor to carry in the storage tank. For example, in a facility where 20 people can undergo dialysis at the same time, the base solution and prescription solution must be delivered for 2140 people (approximately 380 to 480 kg). Additionally, there is a problem in that manpower and space are required for the delivery and storage of these stock solutions.

In view of this, attempts have been made to reduce the weight of dialysate preparations by pulverizing them. For example,
No. 27,246 discloses a method for uniformly dispersing liquid acid by mixing ultrafine powders of sodium chloride acidified with acetic acid to obtain flooded hydrolyzate compound powder for heavy carbon dialysis. .

In addition, JP-A No. 62-30,540 discloses that in a dialysis preparation containing sodium acetate as the main ingredient, MgCl2 6H20 and CaCl2, which are trace components in dialysis ITL, are
A technique has been disclosed in which the variation in trace components is reduced by blending 2.2H20 with sodium acetate and water and pulverizing it.

Furthermore, JP-A No. 64-25.725 discloses a formulation of ionic components of 0.5 to 3III for preparing dialysate.
A method of forming granules with a particle size of II is disclosed.

(Issue 8 to be solved by the invention) However, in these powdered dialysis preparations based on sodium bicarbonate, calcium chloride and magnesium chloride are deliquescent, and sodium chloride has a tendency to coexist with calcium chloride and magnesium chloride. Due to its strong hygroscopicity, it may deliquesce or solidify during production, transportation, and storage, resulting in variations in composition and poor long-term storage stability. be. Furthermore, since acetic acid is used as the liquid acid, its vapor pressure is high, and therefore, even if it is adsorbed to inorganic salts, it tends to volatilize easily, resulting in a lack of stability and workability. Furthermore, in recent years, in clinical practice, a method of adding glucose to dialysate to suppress fluctuations in blood sugar levels has been adopted, but there have been no preparations for dialysis that can maintain long-term storage stability.

Therefore, an object of the present invention is to provide a novel powdered dialysis preparation and a method for producing the same. Another object of the present invention is to provide a powdered dialysis preparation that has excellent transportation and storage properties, maintains uniformity in powder production, and has good stability, and a method for producing the same.

(Means for solving the problem) These various points include solid inorganic salt for dialysis, grape V! is achieved by a hemodialysis preparation comprising two compositions: a powdered first composition consisting of sodium acetate and acetic acid, and a powdered second composition consisting of sodium bicarbonate and sodium acetate. .

The present invention provides a first composition of solid inorganic salts for dialysis, glucose, sodium acetate and ``acetic acid'' containing 85-135 mmol of Na'' when dissolved in a fixed amount of water.
0-4 mmol Ca” 0
．． 5-2.2 mmol Mg" 0.2-i
, o mmol Cl-''-90-140 mmol CH3COO-4-10 mmol glucose 4-12 mmol, and as a second composition sodium bicarbonate and sodium acetate Na+ 15-40 mmol HCO315
-40 mmol CH3COO - 0.5-3 mmol hemodialysis formulation.

The present invention is also a hemodialysis preparation further comprising sodium chloride in the second composition. The present invention further includes:
When dissolved in a fixed amount of water, the first composition contains dialysis solid inorganic salts, dextrose, sodium acetate and acetic acid ranging from 6 to 135 mmol Na+
0-4 mmol Ca" 0.5-2.2 mmol++ Mg O, 2-1.0 mmol Cl-
4-140 mmol CH3COO4-1O
4 to 12 mmol glucose, and sodium bicarbonate as a second composition;
Sodium acetate and sodium chloride are Na+
15-135 mmol Cl-''-1-120 mmol HCO315-40 mmol CH3COO''-0.5-3 mmol for hemodialysis.

Various methods of these methods include mixing the components of the solid inorganic salt for dialysis, sodium acetate and glucose, pulverizing them and granulating them, then distributing acetic acid to the granules obtained in this way. A powdery first composition comprising a solid inorganic salt for dialysis, glucose, sodium acetate, and acetic acid, and a powdery first composition comprising sodium bicarbonate and sodium acetate, which is characterized by producing acetic acid into granules produced by This can also be achieved by a method for producing a hemodialysis preparation comprising two compositions.

These methods involve spraying an aqueous solution of each component of a solid inorganic salt for dialysis other than sodium chloride, with or without sodium acetate, into a fluidized bed of a mixed powder of sodium chloride and glucose, with or without sodium acetate. Acetic acid is distributed to the granules obtained in this way to produce acetic acid. This is also achieved by a method for producing a liquid dialysis preparation consisting of two compositions, including a second composition.

The present invention also provides a method for producing a hemodialysis preparation, wherein the second composition is obtained by mixing powder of sodium acetate or a mixture of sodium acetate and sodium chloride with sodium hydrogen carbonate, and then granulating the mixture. It is.

(Function) The hemodialysis preparation according to the present invention comprises a powdered first composition comprising a solid inorganic salt for dialysis, glucose, sodium acetate and acetic acid, and a second composition comprising sodium bicarbonate and sodium acetate. It consists of two compositions.

The solid inorganic salt for dialysis used in the first composition includes:
Easily soluble in water is preferred, such as sodium chloride,
Potassium chloride, calcium chloride, magnesium chloride, sodium acetate, etc.

Thus, the solid inorganic salts for dialysis, glucose, sodium acetate and acetic acid as the first composition, when dissolved in a certain amount of water, have Na+ 85-135 mmol K"
0-4 mmol Ca” 0.
5-2.2 mmol Mg” 0.2-1.0
mmol Cl-"-90-140 mmol CH3COO-4-10 mmol glucose 4-12 mmol, especially Na"95-125 mmol K"
1.5-3 mmol++ Ca 0.75-1.8 mmol Mg"
0. ．． 3-0.8 mmol Cl-
Preferably 100-130 mmol CH3COO 5-9 mmol glucose 6-10 mmol.

In addition, as will be described later, when used in combination with a sodium chloride-containing composition as the second composition, the solid inorganic salt for dialysis, glucose, sodium acetate, and acetic acid as the first composition may be used in fixed amounts. When dissolved in water, 6 to 135 mmol of Na+
0-4 mmol Ca" 0.5-2.2 mmol++ Mg 0.2-1.0 mmol Cl-
4-140 mmol CH3COO4-1
Preferably 0 mmol glucose 4-12 mmol, especially Na"30-100 mmol K"
1.5-3 mmol++ Ca O, 75~! , 8 mmol Mg”
0.3-0.8 mmol Cl--100-130
Preferably, it is mmol CH3COO 5-9 mmol glucose 6-10 mmol.

The average particle size of the first composition is 10 to 200 mesh, preferably 14 to 100 mesh on a standard sieve.

Preferably, the first composition is produced by either a dry method or a fluidized bed method.

In the dry method, the solid inorganic salt for dialysis and sodium acetate are stirred and mixed in a mixer such as a vertical granulator, then ground in a grinder such as a pin mill, and then mixed in a mixer such as a vertical granulator. mix,
After granulation with a small dry granulator such as a roller compactor, acetic acid is added to the granules thus obtained and mixed with a mixer such as a vertical granulator or Nauta mixer.

In the fluidized bed method, solid inorganic salts for diafiltration other than sodium chloride are dissolved in water in an amount of 0.8 to 30 times, preferably 1.5 to 15 times, and the resulting aqueous solution is added to a mixed powder of sodium chloride and glucose. is fluidized in a fluidized bed granulator,
The granules are granulated while being sprayed into the fluidized bed, and acetic acid is added to the granules thus obtained and mixed in a mixer such as a vertical granulator or Nauta mixer. In this case, sodium acetate may be blended into an aqueous solution, a mixed powder of sodium chloride and glucose, or both.

The second composition is a powder consisting of sodium hydrogen carbonate and sodium acetate, and when dissolved in a certain amount of water, sodium hydrogen carbonate and sodium acetate become
15-40 mmol, Hco3″″15-40 mmol and CH3000-0,5-339 mol, preferably Na 18-32 mmol, HCO3-18-3
5 mmol and CH3COO-0.8-2.5 mmol. In addition, when adding sodium chloride,
The second composition, when dissolved in a certain amount of water, contains sodium bicarbonate, sodium acetate, and thorium chloride.
a+15 to 135 mmol, C11 to 120 mmol,
HCO3-15-40 mmol and CH3COO-0
, 5-3 mmol, preferably Na+40-120 mmol, C135-115 mmol, HCO3-20-3
5 mmol and 0.8-2.5 mmol. Further, the average viscosity is 10 to 100 mesh, preferably 14 to 100 mesh, using a standard sieve.

The second composition is prepared by mixing powder of a mixture of sodium acetate or sulfur-lium acetate and sodium chloride with powder of sodium bicarbonate in a mixer such as a vertical granulator, and then mixing the mixture thus obtained. This is done by granulating the powder in a dry granulator such as a roller compactor.

The first and second compositions obtained in this way are stored in separate containers, and dissolved in water at the time of use.
The aqueous solution is supplied to an artificial kidney and used as a hemodialysis fluid.

The container packaging material preferably has a low moisture permeability; for example, it is desirable to use a moisture-proof packaging material with a moisture permeability (20° C.) of 2.0 g/ba·24 hr or less.

Such packaging materials include, for example, polyethylene terephthalate/polyethylene/aluminum foil/polytylene, each having a thickness of 12 μm, 115 μm, 7 μm, and 30 μm.
There is a laminated film obtained by forming a VL layer with a thickness of m (moisture permeability 0.1 g/+f・24 hr).

(Example) Next, the present invention will be described in further detail by giving examples. In addition, "1 part" and "2%" in the following examples are based on weight unless otherwise specified.

Example 1 Sodium chloride 2188.7 parts, potassium chloride 52.2 parts
part, calcium chloride [CaCl2 ・2H20] 77
．． 2 parts, magnesium chloride [MgCl2 ・6H201
35.6 parts of sodium acetate, 175.3 parts of sodium acetate, and 525 parts of glucose were supplied to a vertical granulator (stirring mixer VG-25P manufactured by Fudo Sangyo Co., Ltd.) and mixed by stirring.
Next, a pin mill (pulverizer manufactured by Fudo Sangyo Co., Ltd., KOLL)
PLEX 16Z) and further stirred and mixed using a vertical granulator. The resulting mixture was processed using a roller compactor (a dry granulator manufactured by Turbo Kogyo Co., Ltd., W
P-160X60 type).

4,145 parts of acetic acid was added to this granulated material, and the mixture was stirred and mixed using a vertical granulator. The flow rate distribution of the first composition thus obtained was as follows.

Mesh~12 12~32 32~48 48~80 80~150 150~ % 0, 20 47.11 16.35 7, 29 5, 38 23, 17 Example 2 Potassium chloride 52.2 parts, calcium chloride [Ca C1
2.2H20177, 2 parts, sodium acetate 175.3
and 35.6 parts of magnesium chloride [MgCl2.6H20] were dissolved in 1500 parts of water (approximately 3 times the amount of the electrolyte) to obtain an aqueous solution.

On the other hand, 2188.7 parts of sodium chloride and 5 parts of glucose
After stirring and mixing 25 parts using a vertical granulator, a fluidized bed granulator (5TREA- manufactured by Fudo Sangyo Co., Ltd.) was used.
15), and the aqueous solution was sprayed into this fluidized bed to increase its volume. The granules thus obtained were supplied to a vertical granulator, and 41.5 parts of acetic acid was further added and mixed with stirring. The flow rate distribution of the first composition thus obtained was as follows.

Mesh % ~12 0.82 12-32 8.78 32-48 15.57 48-80 44.14 80-150 25.74 150-4.76 Example 3 750 parts of sodium bicarbonate and sodium acetate [
A mixed powder consisting of 40.0 parts of CH3C00Nal was supplied to a vertical granulator and mixed with stirring. The resulting mixture was fed to a roller compactor and granulated.

The particle size distribution of the second composition thus obtained was as follows.

Mesh % ~12 6.23 12-32 30.11 32-48 15.87 48-80 10.69 80, ~150 4.80 150-32.30 Example 4 The first and second compositions were each mixed with a separate polyethylene terephthalate (12μ
m), polyethylene (15 μm), aluminum foil (7
μm) and polyethylene (30 μm), and stored in a bag made of laminated film obtained by laminating polyethylene (30 μm) without a desiccant.
When the storage stability at ℃ was investigated, the results shown in Table 1 were obtained.

Table 1 Time item O Months 1 month later 2 months later First composition color difference (ΔE) 0.00 0.05・
0.11 Acetate ion residual rate (%) 100.0 99.9 99.7
Presence of aggregation No aggregation No aggregation Second composition color difference (ΔE) 0.00 0.03
0.05 Presence or absence of aggregation No aggregation No aggregation The color difference (ΔE) is a value (no unit) measured using a color difference system (CD-200 manufactured by Minolta Camera Co., Ltd.), and the residual acetate ion The ratio was determined by taking a portion of the wiping material and using a solution dissolved in water using high-performance liquid chromatography (BIP-I system manufactured by Kuchimoto Bunko Co., Ltd.).

Example 5 Sodium chloride 1038.6 parts, potassium chloride 52.2 parts
part, calcium chloride [CaCl2 ・2H20] 77
．． 2 parts, magnesium chloride [MgCl2 ◆6H20F
35.6 parts, sodium acetate [C1 (3C00Nal
175.3 parts and 525 parts of glucose were mixed in a vertical granulator (stirring mixer VG-25 manufactured by Fudo Sangyo Co., Ltd.).
P) and stirred and mixed, then pulverized with a pin mill (FUDO SANGYO CO., LTD., KOLLPLEX 162), and further stirred and mixed with a vertical granulator. The resulting mixture was granulated using a roller compactor (dry granulator manufactured by Yuichipo Kogyo Co., Ltd., model WP-160X60). 5 parts of 41.degree. acetic acid was added to this granulated material, and the mixture was stirred and mixed using a vertical granulator. The tI'/degree distribution of the first composition thus obtained was as follows.

Mesh % ~12 3.25 12-32 24.38 32-48 26.71 48-80 9.21 80-150 5.51 150-30.94 Example 6 Potassium chloride 52.2 parts, calcium chloride [CaC12
・2H20F 77.2 parts and sodium acetate [CH
8 parts of 3COONa @3H201290° and 1500 parts of water
% to obtain an aqueous solution.

On the other hand, 1038.6 parts of sodium chloride and 5 parts of glucose
After stirring and mixing 25 parts using a vertical granulator, a fluidized bed granulator (5TREA- manufactured by Fudo Sangyo Co., Ltd.) was used.
15), and the aqueous solution was sprayed into this fluidized bed to increase its volume. The granules thus obtained were supplied to a vertical granulator, and 41.5 parts of acetic acid was further added and mixed with stirring. The flow rate distribution of the first composition thus obtained was as follows.

Mesh % ~12 2.37 12-32 9.36 32-48 16.81 48-80 43.44 80-150 23.98 150-4.04 Example 7 99 sodium bicarbonate 50 parts, sodium acetate [ CH3C
00Nal 40.4 parts and sodium chloride 1150 parts
．． A mixed powder consisting of 0 parts was supplied to a vertical granulator and mixed by stirring. The resulting mixture was fed to a roller compactor and granulated. The particle size distribution of the second composition thus obtained was as follows.

Mesh % ~12 7.12 12-32 32.48 32-48 20.77 48-80 7.51 80-150 4.53 150-27. 59 Comparative Example 1 A first composition obtained using the same formulation as in Example 2 except that sodium acetate was not added, and a first composition obtained using the method in Example 3 with the amount of sodium acetate being 215.3 parts. A second composition obtained with the same formulation except for this was stored separately in the same hue as Example 4, and the storage stability at 40°C was examined, and the results shown in Table 2 were obtained. It was done.

As a result, it was found that this sample was superior to Comparative Example 1 in terms of coloration, aggregation, and residual rate of acetate ions.

Table 2 Time item O Monthly After 1 month After 2 months First composition color difference (ΔE) 0.00 0.69
2.07 Acetate ion residual rate (%) 100.0 g7.6
76.5 Presence or absence of aggregation Aggregation Aggregation Second composition color difference (ΔE) 0.00 0.0?
0.19 Presence or absence of aggregation Aggregation Aggregation The color difference (ΔE) is a value measured using a color difference system (CD-200 manufactured by Minolta Camera Co., Ltd.) (no unit)
, and the residual rate of acetate ion is calculated by taking a part of the cost,
For the liquid dissolved in water, perform immediate liquid chromatography (
Quantification was performed using a BIP-1 system (manufactured by JASCO Corporation).

(Effects of the Invention) As described above, the hemodialysis preparation according to the present invention comprises a powdered first composition consisting of a solid inorganic salt for dialysis, glucose, sodium acetate, and acetic acid, and sodium bicarbonate and sodium acetate. Because it is composed of two compositions: a powdered second composition consisting of Since acetic acid is impregnated into the solid inorganic salt particles containing the narcotic acid salt, the product has the advantages of extremely long-term storage stability and excellent usability during use. .

In addition, since the hemodialysis preparation according to the present invention is manufactured by a dry method or a fluidized bed method, it uses calcium chloride and magnesium chloride, which are conventionally difficult to grind uniformly due to their high deliquescent properties. , the powder production can be made uniform, and the problem that it was difficult to uniformly distribute each component due to the difference in specific gravity of each component can be solved by the above method.

The present inventors have previously disclosed an invention (Japanese Patent Application No. 1-134.339 and No. 1-134,340) relating to a uniform powder preparation with excellent storage stability and a method for producing the same for the same purpose.
However, these inventions had the following problems.

(1) It is expensive because a moisture absorbent is put inside the moisture-proof packaging as a packaging material.

(2) When used in smaller portions than the packaging material, the storage stability after opening is poor.

Based on the above, the inventors of the present invention have conducted extensive studies, and as a result,
By blending only the necessary amount of sodium acetate into the first composition to adsorb acetic acid, and blending the remaining amount into the second composition, it has better storage stability than the above application. This led to the invention of a composition.

Even more surprisingly, it has been discovered that sodium chloride can be incorporated into either the first or second composition without compromising stability. Being able to mix the sodium chloride freely means that the amounts of sodium chloride in the first composition and the second composition can be made as close to the same as possible, and these preparations can be dissolved and supplied. This eliminates the need for different devices for different uses, and simplifies the process.

teenager Reason Man

Claims (7)

[Claims] (1) From two compositions: a powdered first composition consisting of a solid inorganic salt for dialysis, glucose, sodium acetate and acetic acid, and a powdered second composition consisting of sodium bicarbonate and sodium acetate. A hemodialysis preparation. (2) When dissolved in a certain amount of water, the first composition of solid inorganic salts for dialysis, glucose, sodium acetate, and acetic acid contains Na^+85-135 mmol K^+0-4 mmol Ca^+^+0. 5-2.2 mmol Mg^+^+0.2-1.0 mmol Cl^-90-140 mmol CH_3COO^-4-10 mmol glucose 4-12 mmol, and also sodium bicarbonate as a second composition. The hemodialysis preparation according to claim 1, wherein the sodium acetate is Na^+15-40 mmol HCO_3^-15-40 mmol CH_3COO^-0.5-3 mmol. (3) The hemodialysis preparation according to claim 1, wherein the second composition further contains sodium chloride. (4) When dissolved in a certain amount of water, the fixed inorganic salts for dialysis, glucose, sodium acetate, and acetic acid as the first composition have a concentration of Na^+6 to 135 mmol K^+0 to 4 mmol Ca^+^+0. 5-2.2 mmol Mg^+^+0.2-1.0 mmol Cl^-4-140 mmol CH_3COO^-4-10 mmol glucose 4-12 mmol, and also sodium bicarbonate as a second composition. ,
Sodium acetate and sodium chloride are Na^+15~
The hemodialysis preparation according to claim 4, wherein the concentration is 135 mmol Cl^-1 to 120 mmol HCO_3^-15 to 40 mmol CH_3COO^-0.5 to 3 mmol. (5) Each component of the solid inorganic salt for dialysis, sodium acetate and glucose are mixed, pulverized and granulated, and then acetic acid is blended and mixed with the granulated product thus obtained. A first composition in powder form consisting of a solid inorganic salt for dialysis, glucose, sodium acetate and acetic acid, and a second composition in powder form consisting of sodium bicarbonate and sodium acetate. A method for producing a hemodialysis preparation comprising two compositions. (6) An aqueous solution containing or not containing sodium acetate of each component of a solid inorganic salt for dialysis other than sodium chloride is sprayed into a fluidized bed of a mixed powder of sodium chloride and glucose, which does not contain or contains sodium acetate. A powder consisting of a solid inorganic salt for dialysis, glucose, sodium acetate, and acetic acid, characterized in that the first composition is produced by granulating and mixing acetic acid with the granules thus obtained. A method for producing a hemodialysis preparation comprising two compositions: a first composition in the form of a powder, and a second composition in the form of a powder comprising sodium bicarbonate and sodium acetate. (7) For hemodialysis according to claim 5 or 6, the second composition is obtained by mixing powder of sodium acetate or a mixture of sodium acetate and sodium chloride with sodium bicarbonate and then granulating the mixture. Method of manufacturing the formulation.