JP2007037601A - Solid agent a for dialysis which has improved solubility - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid agent A for dialysis which contains various electrolytic components, pH adjusters and/or glucose used for hemodialysis treatment of renal failure patients which has high cleanliness, high dissolution rate and good workability preventing generation of powder (dust). <P>SOLUTION: The solid agent A for dialysis is used for preparing a bicarbonate dialysis fluid. When particle size distribution of granulated materials contained in the agent A is measured by screening method, a fraction retainable on a 850 μm mesh screen is ≤5% and a fraction retainable on a 355 μm mesh screen but passing through 600 μm mesh screen is ≥50%. With such a particle size distribution, dissolution rate of the agent A is improved and generation of powder is prevented. In addition, by using electrolytic components having silicon content of ≤5 ppb, the cleanliness of perfusion fluid for dialysis is improved. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a dialysis preparation used for hemodialysis therapy, and more particularly, a weight of an electrolyte component, a pH adjuster and / or glucose which has improved solubility, improved workability and improved cleanliness. The present invention relates to a solid dialysis agent A for preparing a carbonic acid dialysis solution.

  Dialysis fluids used in recent hemodialysis treatments have been replaced by bicarbonate dialysis fluids that are less burdensome for patients from conventional acetic acid dialysis fluids. However, in bicarbonate dialysate, bicarbonate ions react with calcium and magnesium ions, which are electrolyte components, to produce insoluble compounds (metal carbonates such as calcium carbonate and magnesium carbonate). It is difficult to make it.

Therefore, in general, a concentrated solution “A agent” containing each electrolyte component of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, glucose and a pH adjuster added as necessary, and powdered A two-agent configuration of “agent B” made of sodium hydrogen carbonate is employed.
However, the "A agent" that is this concentrated liquid is normally filled with 5 to 15 L of concentrated liquid in a polyethylene container. From its size and weight, transportation cost, securing of storage space in the hospital, and use The later disposal method is a big problem.

  Therefore, in order to solve these problems, powdering (solidification) of the agent A itself has been proposed (Patent Document 1, Patent Document 2, Patent Document 3, etc.) and has already been commercialized. . The manufacturing method of this A agent for solid dialysis currently marketed is mixing each raw material component (powder), adding a binder liquid in some cases, granulating, drying and sizing, etc., and commercializing it. Is generally done. In many cases, a granulating apparatus for granulating each component and a drying apparatus for drying the granulated product are manufactured using different apparatuses.

  In the production of the solid dialysis agent A by this production method, when the granulated product is transferred to the drying apparatus after granulation, the granulated product is in a wet state, and thus becomes a large lump. There is a drawback that it becomes necessary, and fine powder increases due to crushing. Furthermore, when this large lump is dried, it is necessary to increase the amount of dry air in order to prevent agglomeration of the granulated material, and there is a disadvantage that the amount of fine powder increases due to drying with this large amount of air. there were.

  In such a solid dialysis agent with a lot of fine powder, dust (powder) is likely to be generated when the preparation is put into a dissolution apparatus, and the acetic acid odor used as a pH adjuster at that time is quite strong. This is also a cause of worsening the working environment in the medical field.

  Furthermore, in the conventional A agent for solid dialysis, the solubility of the granulated product itself is poor, and when preparing the perfusate, the dissolution time close to 20 minutes is required until the prescribed concentration of the dialysis perfusate is reached. It took a long time, and the workability in the medical field was extremely bad.

  In addition, dirt on the electrolyte component particles that are the core of the solid dialysis agent or dirt that may be caused by contamination in the solidification manufacturing process may adhere to the dissolution apparatus. For example, such a problem is particularly likely to occur in a method in which a solid electrolyte for dialysis described in Patent Document 2 is stirred and mixed, pulverized, and then granulated.

Moreover, in order to prepare a dialysis perfusate, when the solid dialysis agent A is dissolved and mixed with a sodium bicarbonate aqueous solution which is a so-called dialysis agent B, the cleanliness of the solution is not improved so much. There was also a problem.
Japanese Patent Publication No.57-88116 Japanese Patent Laid-Open No. 2-311418 Japanese Patent Laid-Open No. 6-237991

  Therefore, in view of the above-mentioned present situation, the present invention improves the cleanliness in the solid dialysis agent A consisting of various electrolyte components, pH adjusters and / or glucose in dialysis preparations used in hemodialysis therapy for patients with renal failure. It is another object of the present invention to provide a solid dialysis agent A with good workability, in which the dissolution rate is increased and generation of dust (dust) is suppressed.

  In order to solve such a problem, the present inventors have conducted extensive research, and as a solid dialysis agent A, the particle size distribution of a granulated product composed of various electrolyte components, pH adjusters and / or glucose is sharp. Therefore, by setting the fraction of 355 μm on / 600 μm pass as an average particle diameter to 50% or more, and particularly making the granulated product of 850 μm or more to a certain specific weight% or less, The solubility is remarkably improved, the dissolution rate is increased, the occurrence of precipitation due to agglomeration and the undissolved residue are eliminated, and the fraction of the 63 μm pass is reduced to 10 ppm or less, so that unpleasant powdering ( It was confirmed that dust) can be reduced.

  Furthermore, the present inventors conducted various studies on various electrolyte components used in dialysis preparations, and focused on the content of silicon contained in these raw materials. That is, as an electrolyte component in the solid dialysis agent A, attention was focused on the content of silicon inherently contained in a trace amount in sodium chloride accounting for 80% or more. As a result, it was confirmed that the difference in the degree of silicon content greatly affects the cleanliness in the agent A for solid dialysis, and the present invention has been completed.

Therefore, the present invention includes, as one basic aspect thereof,
(1) As a granulated product constituting the solid dialysis agent A, the fraction of 355 μm on / 600 μm pass is 50% or more when the particle size distribution is measured by the sieving method, thereby improving the dissolution rate. , A agent for solid dialysis characterized by suppression of powdering;
It is.

More specifically,
(2) A agent for solid dialysis according to (1) above, wherein the fraction of 850 μm on is 5% or less;
(3) The solid dialysis agent A according to the above (1) or (2), wherein the fraction of the 355 μm pass is 20% or less;
(4) The solid dialysis agent A according to the above (1), (2) or (3), wherein the fraction of 63 μm pass is 10 ppm or less;
And more specifically,
(5) The dissolution agent A for solid dialysis as described in (1) to (4) above, wherein the dissolution time to reach the prescribed concentration of the electrolyte component is within 10 minutes as the dissolution rate;
It is.

Furthermore, the present invention as another aspect,
(6) A solid dialysis agent A comprising an electrolyte component, a pH adjuster and / or glucose for preparing a bicarbonate dialysis solution, comprising a mixed granulated product of each raw material component (powder), and containing silicon A solid dialysis agent A characterized in that the cleanliness of the dialysis perfusate is improved by using each electrolyte component in an amount of 5 ppb or less;
It is.

More specifically, the present invention provides:
(7) As a cleanliness, when the solid dialysis agent A is dissolved in water, filtered, and the color of the filter is measured with a color difference meter, the color difference (ΔE) is 3.5 or less. A agent for solid dialysis according to (6) above;
(8) A agent for solid dialysis according to (6) or (7) above, wherein each electrolyte component having a silicon content of 3 ppb or less is used;
(9) The A agent for solid dialysis according to (6) or (7) above, wherein each electrolyte component having a silicon content of 2 ppb or less is used;
It is.

The solid dialysis agent A of the present invention provided as described above has improved solubility and can avoid generation of precipitates due to aggregation or generation of undissolved residue at the time of dissolution. Is extremely fast, and the cleanliness thereof is remarkably improved, and the operability in the medical field is further improved.
Furthermore, in the granulated product of the agent A for solid dialysis of the present invention, since the particle size distribution is very sharp, there are few large aggregates and fine powders, and the mixing property is also good. In mass production, the productivity is high and the cost can be greatly reduced.

  Therefore, when the agent A for solid dialysis of the present invention is charged into the dissolution apparatus, dust (powder) is not generated, and there is almost no acetic acid odor used as a pH adjuster, It has the advantage that the working environment at the medical site can be maintained well.

  The agent A for solid dialysis provided by the present invention is an agent comprising various electrolyte components and a pH adjuster, which is obtained by adding glucose as necessary, and comprises an agent B comprising sodium bicarbonate. After being diluted and mixed to an appropriate concentration, it is used as a perfusate for hemodialysis.

  In the solid dialysis agent A provided by the present invention, the essential electrolyte components are sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, but sodium citrate should be added instead of sodium acetate. You can also. Further, other electrolyte components can be used without particular limitation as required. Moreover, as a pH adjuster, what is generally used, such as an acetic acid, lactic acid, hydrochloric acid, a citric acid, malic acid, may be sufficient, but an acetic acid and a citric acid are especially preferable. At that time, it is more preferable to use sodium acetate as an electrolyte component in the case of acetic acid and sodium citrate in the case of citric acid.

For example, the amount of each component in such an agent (the prescription amount of the preparation) is generally as follows.
Na ⁺ 130-145 mEq / L
K ⁺ 0-4 mEq / L
Ca ⁺⁺ 0-4 mEq / L
Mg ⁺⁺ 0-2 mEq / L
Cl ^- 55-135 mEq / L
HCO ₃ ^- 20~45 mEq / L
Acetate ion 0-20 mEq / L
(Or citrate ion 0-10 mEq / L)

That is, as a solid (powder) dialysis agent A contained when dissolved in a certain amount of water, Na ⁺ : 90 to 140 mmol, K ⁺ : 0 to 4 mmol, Ca ⁺⁺ : 0.5 to 2 .2 ^mmol, Mg ++: 0.2 to 1.0 ^mmol, Cl -: 90 to 140 _mmol, CH ³ COO -: 6 to 15 mmoles, glucose: is preferably 4 to 12 mmol.
Further, it is preferable to use a combination of 0 to 2.0 g / L as glucose and Na ⁺ : 15 to 40 mmol and HCO ₃ ⁻ : 15 to 40 mmol as sodium bicarbonate.

The first feature of the present invention is that the granulated product constituting the solid dialysis agent A composed of various electrolyte components, pH adjusting agents and / or glucose, has a particle size distribution by a sieving method so as to have a sharp particle size distribution. The following composition when measuring the distribution:
a) 850 μm ON fraction: 5% or less,
b) 355 μm on / 600 μm pass fraction: 50% or more,
Therefore, it is an A agent for solid dialysis that improves the dissolution rate and suppresses dusting (generation of dust).

Furthermore, another feature of the present invention is that, among the components constituting the solid dialysis agent A, the silicon content of the electrolyte component is adjusted. By adjusting the content of silicon contained in trace amounts, the cleanliness is remarkably improved.
These features of the present invention will be described with reference to test examples instead of examples, and the present invention will be described in more detail.

  The agent A for solid dialysis targeted by the present invention is an agent comprising various electrolyte components and a pH adjuster, and is provided as a granulated product by adding glucose as necessary. However, regarding the granulated product in this case, according to the study by the present inventors, the particle size distribution is sharpened, and in particular, a granulated product of 850 μm or more is a fraction of a specific amount by weight%, 63 μm pass. By making the content of 10 ppm or less, the solubility of the agent A for solid dialysis is remarkably improved, the generation of precipitation due to aggregation, the dissolution of undissolved residue, and the unpleasant dusting (generation of dust) etc. when thrown into the dissolution apparatus, etc. It was found that can be reduced.

  More specifically, in the solid dialysis agent A of the present invention, in order to make the particle size distribution sharp, the fraction of 355 μm on / 600 μm pass, which is the average particle size, is 50% or more, and 850 μm. By setting the ON fraction to 5% or less, the solubility is remarkably improved.

The actual situation will be described with reference to Test Example 1 below.
Test Example 1: Solubility Test As the product of the present invention, the granulated fraction of 355 μm on / 600 μm pass was about 66%, and the granulated fraction of 850 μm on was granulated to 0.7% or less. An agent A for solid dialysis having a very sharp distribution was prepared.
A conventional product A for solid dialysis was used as an object. In this conventional product, the granule fraction with a particle size of 355 μm on / 600 μm pass was about 48%, and the granule fraction with 850 μm on was 8%.
The particle size distribution of these preparations is summarized in Table 1 below.

[Method]
Dissolution test No. 2 of the general test method of the Japanese Pharmacopoeia: A dissolution test was conducted according to the paddle method.
238 g of each sample was put into a 1000 mL vessel, 810 mL of purified water was poured in, stirred at 140 rpm, and the sodium concentration was measured over time. Measurements were taken 1 minute after stirring and then 3, 5, 7, 9, 11, 13, 15, 17 and 19 minutes every 2 minutes. As the target of completion of dissolution, the time until the sodium concentration (mEq / L) reached 115 mEq / L, which is the prescribed concentration, was evaluated.

[result]
The results are shown in FIG. As can be seen from the results shown in the figure, the solid dialysis agent A according to the present invention has a rapid onset of dissolution and reaches the prescribed concentration of sodium in about 7 minutes, whereas the conventional product is The solid dialysis agent A required 17 minutes or more.
In view of the above, the solid dialysis agent A of the present invention has a granulated fraction of 355 μm on / 600 μm pass of 50% or more in order to make the particle size distribution extremely sharp, and then granulate of 850 μm on. It was found that the solubility was improved by suppressing the product fraction to 5% or less.

Furthermore, the agent A for solid dialysis of the present invention has one feature in that the particle size distribution is made extremely sharp so that the mixing of the granulated product of fine powder is reduced.
In particular, the granulated fraction of 355 μm pass is 20% or less, and among them, the granulated fraction of 63 μm pass is 10 ppm or less. . As a result, the dissolution rate is increased, and when the solid dialysis agent A is charged into the dissolution apparatus, dust (dusting) is not generated, and there is almost no acetic acid odor used as a pH adjuster. Is.

The details were evaluated by measuring the amount of scattering in solid dialysis agent A.
Test Example 2: Measurement of scattering amount [Method]
As an apparatus for measuring the amount of scattering, an apparatus based on the schematic diagram schematically shown in FIG. 2 was prepared. That is, as a measuring device, a cylinder for collecting scattered matters is provided at the bottom of an acrylic cylinder having a diameter of 10 cm and a length of 1.5 m, and a filter paper for collection is provided at the tip of the cylinder for collection. It was.
One sample of the agent A for solid dialysis was placed as a sample on the sample stage at the upper part of the cylinder, and the granulated product was allowed to fall naturally within the acrylic cylinder by opening the charging cock. When the granulated material was dropped, the scattered material scattered in the cylinder was collected on a filter paper collected by a suction fan, and the weight was measured as the amount of scattering.
The test was performed for 15 samples (15 times) for one sample.

[Test sample]
The following samples were used as test samples.
(1) As a product of the present invention;
Invention product A: The granule fraction of 355 μm on / 600 μm pass is about 65%, the granule fraction of 850 μm on is less than 5%, and the granule fraction of 63 μm pass is hardly recognized.
Invention product B: The granule fraction of 355 μm on / 600 μm pass is about 60%, the granule fraction of 850 μm on is less than 5%, and the granule fraction of 63 μm pass is hardly recognized.
(2) As a conventional product;
Conventional product A: The granule fraction of 355 μm on / 600 μm pass is about 45%, the granule fraction of 850 μm on is 8% or more, and the granule fraction of 63 μm pass is 0.3%.
Conventional product B: The granule fraction of 355 μm on / 600 μm pass is about 48%, the granule fraction of 850 μm on is 8% or more, and the granule fraction of 63 μm pass is 1.0%.
(3) Other companies 'products A to D (The details of the particle size of these other companies' products are unknown)

[result]
The results are shown in Table 2 below. The number “invention product A” in the table indicates the degree of relative scattering when the scattering amount of invention product A is 1.

  As can be seen from the results shown in the table, it is understood that the amount of scattering of the agent A for solid dialysis of the present invention is extremely small. This decrease in the amount of scattering is 50% or more of the granulated product fraction of 355 μm on / 600 μm pass as the granulated product, granulated the granulated product fraction of 850 μm on to 5% or less, and further 63 μm pass. It is found that this is caused by the fact that the granule fraction is hardly recognized and the particle size distribution is very sharp.

On the other hand, in the present invention, the cleanness is remarkably improved by adjusting the silicon content of the electrolyte component constituting the solid dialysis agent A. The silicon content is 5 ppb (10 ⁻⁹ ) or less, preferably 3 ppb or less, more preferably 2 ppb or less.

  The silicon content can be adjusted by selecting carefully selected raw materials and further removing foreign substances to obtain an electrolyte component having a target silicon content. For example, in sodium chloride accounting for 80% of the electrolyte component, specifically, clean seawater is filtered through a filtration tank and purified by passing through an ion exchange membrane, and the silicon content is low. After passing through the crystallization step, foreign matter can be removed and manufactured. Even in other electrolyte components, it is preferable to carefully select and use an electrolyte component having a low silicon content.

As a result of the study by the present inventors, in the solid dialysis agent A provided by the present invention, the cleanness is extremely good by setting the silicon content to 5 ppb, that is, 5 × 10 ⁻⁹ or less. Turned out to be.
About examination of the silicon content, the result compared with the silicon content in the A agent for solid dialysis conventionally marketed was confirmed by the following tests.

Test 3: Examination of silicon content The silicon content of the solid dialysis agent A of the present invention (each 3 packs / 3 lots) and the conventional solid dialysis agent A 3 products (each 3 packs) were measured. did.
[Method]
The silicon content was measured with reference to hygiene test method, environmental test method, water quality silicic acid measurement method and the like. That is, one sachet of solid A preparation for dialysis is dissolved in 9 L of purified water (ion-exchanged water), and the impurities obtained by filtration through a membrane filter are extracted with a 4% hydrochloric acid aqueous solution, and the absorbance at 810 nm is measured. Thus, the silicon content was determined.
[result]
The results are shown in Table 3 below.

  As can be seen from the results shown in the above table, the silicon content in the solid dialysis agent A of the present invention was extremely low as compared with the conventional solid dialysis agent A.

As the cleanliness of these solid dialysis agents A, color differences when the solid dialysis agents A used in Test 1 are dissolved in purified water, filtered, and the degree of coloration of the filter is measured with a color difference meter. I examined it.
The results are described below.

Test 4: Measurement of color difference For each of the solid dialysis agent A (lot A) of the present invention and the conventional solid dialysis agent A (three products of conventional products X, Y, and Z) used in the above test 3, one package each. It was dissolved in purified water, filtered through a filter, and the color of the filter was measured with a color difference meter. About color difference ((DELTA) E), it means that there is so little coloring that a value is small.
The results are summarized in Table 4 below.

As can be seen from the above results, in Test 3, the agent A for solid dialysis having a lower silicon content (the product A of the present invention) is a conventional product having a higher silicon content (lots X, Y, Z). It is understood that the color difference (ΔE) is small in comparison with little coloration and high cleanliness.
That is, it is understood that the cleanliness can be improved by reducing the silicon content in the solid dialysis agent A.

  As described above, the present invention is a dialysis preparation used for hemodialysis therapy, and particularly a solid dialysis agent A composed of various electrolyte components, pH adjusters and / or glucose, and its cleanliness is remarkably high. In addition to being improved, the solubility is improved, and at the time of dissolution, generation of precipitates due to aggregation or generation of undissolved residue can be avoided, while the dissolution rate is extremely fast.

  Furthermore, in the granulated product of the agent A for solid dialysis of the present invention, the particle size distribution is very sharp, there are few large aggregates and fine powders, and the mixing property is also good. In the mass production, the productivity is high and the cost can be greatly reduced. On the other hand, when the solid dialysis agent of the present invention is introduced into the dissolution apparatus, dust (dusting) is not generated. In addition, it has almost no acetic acid odor used as a pH adjuster, and therefore has the advantage of maintaining a good working environment in the medical field, and its medical contribution is great. It is.

It is a graph which shows the result of the test example 1 replaced with the Example of this invention. It is a typical schematic diagram of a test device of example 2 of a test instead of the example of the present invention.

Claims (9)

  As the granulated material constituting the solid dialysis agent A, the fraction of 355 μm on / 600 μm pass is 50% or more when the particle size distribution is measured by the sieving method, so that the dissolution rate is improved and the An A agent for solid dialysis characterized by   The agent A for solid dialysis according to claim 1, wherein the fraction of 850 µm on is 5% or less.   The solid dialysis agent A according to claim 1 or 2, wherein the fraction of the 355 µm pass is 20% or less.   The solid dialysis agent A according to claim 1, 2 or 3, wherein the fraction of the 63 µm pass is 10 ppm or less.   The dissolution agent A for solid dialysis according to any one of claims 1 to 4, wherein the dissolution time to reach the prescribed concentration of the electrolyte component is 10 minutes or less as a dissolution rate.   A solid dialysis agent A consisting of an electrolyte component, a pH adjuster and / or glucose for preparing a bicarbonate dialysis solution, comprising a mixed granulated product of each raw material component (powder) and having a silicon content of 5 ppb An agent A for solid dialysis, wherein the cleanliness of the dialysis perfusate is improved by using the following electrolyte components.   As the cleanliness, when the solid dialysis agent A is dissolved in water, filtered, and the color of the filter is measured with a color difference meter, the color difference (ΔE) is 3.5 or less. Item 6. A solid dialysis agent A according to Item 6.   The agent A for solid dialysis according to claim 6 or 7, wherein each electrolyte component having a silicon content of 3 ppb or less is used. The agent A for solid dialysis according to claim 6 or 7, wherein each electrolyte component having a silicon content of 2 ppb or less is used.

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