WO2004066977A1

WO2004066977A1 - Solid agent for dialysis and process for producing the same

Info

Publication number: WO2004066977A1
Application number: PCT/JP2004/000892
Authority: WO
Inventors: Yoshiaki Kawashima; Hirofumi Takeuchi; Ryoji Oura; Masaru Mori; Masao Nakashima; Shinichi Kadono
Original assignee: Manac Inc.
Priority date: 2003-01-31
Filing date: 2004-01-30
Publication date: 2004-08-12

Abstract

A solid agent for dialysis comprising an electrolyte, glucose and a pH adjusting agent required for the preparation of a bicarbonate dialyzing fluid, which solid agent for dialysis ensures stable presence of glucose in the stage of not only production but also storage, being free from the danger of decomposition and coloring and excels in storage stability, content uniformity and abrasion resistance, realizing extremely high workability on medical spots. In particular, a solid agent for dialysis comprising an electrolyte composition (the electrolyte composition composed of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate), a pH adjusting agent and glucose characterized in that base particles are covered by a coating layer comprising a salt having, in thin-film X-ray diffraction, specified peaks at 2θ = 21.3 to 21.5° and 2θ = 27.6 to 27.8° (CuKα: λ = 1.54058 Å, and incident angle θ = 1°).

Description

Specification

Technical Field

The present invention relates to a dialysis solid preparation for preparing bicarbonate dialysis solution used in dialysis therapy for patients with renal failure. More specifically, the surface of particles (mother particles) serving as mother nuclei during granulation is specified. The present invention relates to a solid agent for dialysis, which is covered with a fused coating layer containing a salt, has excellent stability, uniform content, and excellent attrition resistance, and a method for producing the same. Background art

Dialysis therapy has been established as a treatment method for patients with renal failure, and is performed as a regular permanent treatment for the purpose of removing waste products and regulating electrolytes. The dialysate used for dialysis therapy is made to have a composition similar to the normal serum electrolyte concentration, and in recent years, bicarbonate dialysate with less burden on the living body has been used. Bicarbonate dialysis solution is generally a formulation containing sodium chloride and magnesium chloride and containing no sodium bicarbonate because sodium bicarbonate reacts with calcium chloride and magnesium chloride to precipitate carbonate. And a formulation containing sodium bicarbonate and containing no sodium chloride or magnesium chloride (agent B), which are dissolved, diluted and mixed immediately before use to prepare a bicarbonate dialysate.

Currently, the main types of preparations used in hemodialysis are "Liquid-liquid type" of A concentrate + B concentrate, "Liquid powder type" of A concentrate + B powder (sodium bicarbonate), and A There are three types: powder + B powder. Among the “liquid-liquid type” and “liquid-powder type”, concentrate concentrates are usually bulky and heavy because polyethylene containers are filled with around 1 kg of concentrated liquid. There are various issues regarding loading, storage space, handling methods, and disposal of used containers.

In order to solve these problems, in recent years, “powder-powder type” solidifying agents obtained by pulverizing agent A have been developed and used. This solid preparation is once dissolved in a stock solution of the same concentration as the “liquid-liquid type” concentrated stock solution using a dedicated dissolution apparatus at a medical site such as a hospital, and then further dissolved and diluted to a dialysate concentration. Be prepared. As a method for formulating such a solid preparation, a spray drying method, a wet granulation method, a dry granulation method and the like have been well known. Each method has its advantages and disadvantages and cannot be said to be satisfactory in terms of manufacturing method and quality. Formulations by the spray-dry method are bulky, vary in moisture and particle size, and it is difficult to give a constant pH due to the volatilization of acid components. Japanese Patent Application Laid-Open No. 2002-102703 discloses a method for producing a two-part solid baking soda dialysis preparation using a tumbling stirred fluidized bed granulator. There is a disadvantage that the coating layer is easily peeled off due to the collision of the granules. Furthermore, since the electrolyte component ゃ glucose, which contains sodium chloride in part, must be dissolved in a considerable amount of water and then spray-dried, the unit energy consumption is significantly deteriorated. The wet granulation method and the dry granulation method have the disadvantage that complicated steps such as pulverization and mixing are inevitable in order to maintain uniformity, and are liable to be contaminated by foreign substances from the equipment used or from outside.

Therefore, attention has been paid to such a point, and a compact solid preparation having a good bulk specific gravity, an angle of repose, and a dissolution rate has been proposed by a manufacturing method which does not require complicated steps such as pulverization. For example, each electrolyte compound is mixed and heated (73 ° C) in the presence of sodium acetate and water, and then glucose is added, mixed with acetic acid, and a plurality of sodium chloride particles pass through the coating layer. A method for producing a granular or fine granular agent A for perfusion of an artificial kidney for dialysis of bicarbonate composed of combined granules is disclosed (see Japanese Patent No. 2769592). The granulation is performed at 60 ° C, a core layer containing at least one member selected from the group consisting of sodium chloride and potassium chloride as a main component, a double salt formed by a reaction between sodium acetate and calcium chloride, and the like. There is disclosed a solid dialysis agent having a double-layered structure with an electrolyte composition and a double salt layer containing a pH adjusting agent (see Japanese Patent No. 2987488).

However, this manufacturing method has major problems. That is, in Japanese Patent No. 27695992, sodium chloride, potassium chloride, magnesium chloride, calcium chloride and pure water are mixed, stirred, heated, and sodium acetate is added, and heating and mixing are continued. According to Japanese Patent No. 298774888, sodium chloride, chloride chloride, magnesium chloride, sodium acetate and pure water are mixed, stirred, heated, and calcium chloride is added, and heating and mixing are continued. In any case, the inherent stickiness of the contents And the viscosity increases remarkably, making it difficult to stir. It is difficult to manufacture with a normal stirrer, and equipment with extremely large stirring capacity is required. Is required.

Further, in each of Patent No. 27695992, Patent No. 27984888 and Japanese Patent Application Laid-Open No. 2002-102337, 60 ° C. As described above, it is necessary to heat for a long time, there is a strong possibility that glucose is decomposed and colored during granulation, and the dialysis preparation obtained by the above method may have poor content uniformity. Furthermore, the coating layer of the preparation manufactured by such a manufacturing method is a layer in which fine particles are adhered and laminated via a binder, and are easily affected by external factors, so that glucose is decomposed and colored. It has the drawback that it can proceed more easily over time, and has a major problem of lack of storage stability.

Furthermore, due to the structural characteristics of the coating layer, the coating layer is easily peeled off during transportation, so that fine powder is produced. This is combined with the generation of static electricity, causing various problems. For example, in the manufacturing process, static electricity is generated at the same time as dust is generated at the time of product filling, and fine powder adheres to the sealing part of the packaging bag and the strength of the seal decreases, and in the worst case, the bag may be broken. . On the other hand, when handling dialysis, there is a problem in that dust containing acetic acid is scattered during the preparation of the dialysate, which deteriorates the working environment, and that the solidifying agent tends to remain in the bag due to static electricity. In addition, foreign matter adheres to the outside of the packaging material due to the generation of static electricity, which also causes foreign matter to enter during melting, and there is a strong need for improvement.

An object of the present invention is to provide a solid solution for dialysis comprising an electrolyte, pudose, and a pH adjuster necessary for preparing a bicarbonate dialysis solution, in which glucose is stably present both in the production stage and during storage. Offers storage stability, uniform content, excellent abrasion resistance, and excellent solubility, no danger of decomposition and coloration, extremely low dusting, and prevention of static electricity. To do. Summary of the invention

The present inventors have conducted intensive studies to achieve the above object, and as a result, In a system where calcium chloride and sodium acetate are present, in the presence of a small amount of water, if the stirring temperature and the shearing force are set within the specified range and stirred and mixed for a specified time or longer, complicated granulation operations and special equipment must be used. Instead, a fused coating layer was formed on the base particles, and the above-mentioned problem was achieved.

That is, the present invention (1) relates to a thin film X-ray diffraction method for an electrolyte composition comprising sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, a pH adjusting agent, and a solid dialysis agent comprising glucose. With specific peaks at 20 = 21.3-21.5 ° and 20 = 27.6-27.8 ° (CuKo:;; L = l. 54058 A, incident angle Θ ^ 1 ° :) A solid preparation for dialysis, wherein the base particles are covered with a coating layer containing a salt.

Further, the present invention (2) is the solidifying agent according to the above-mentioned invention (1), which is in the form of granules and Z or fine granules.

Further, the present invention (3) is the solid preparation for dialysis according to the above-mentioned invention (1) or (2), wherein the salt is a reaction product of glucose, calcium chloride and sodium acetate.

The present invention (4) is the solid agent for dialysis according to any one of the inventions (1) to (3), wherein the coating layer is in a fused state.

Further, the present invention (5) is a solid agent for bicarbonate dialysis comprising the solid agent for dialysis according to any one of the inventions (1) to (4) and a solid agent containing sodium bicarbonate.

Further, the present invention (6) has a moisture permeability (40 ° C., 90% RH) of 2.0 g / m ² -24 hr or less, and is housed in a moisture-proof packaging material having a laminated structure having a back electrode effect. The solid agent for dialysis according to any one of the inventions (1) to (5).

Further, the present invention (7) provides an electrolyte composition comprising sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and sodium acetate, a pH adjuster, and a solid preparation for dialysis produced from bead bran. In the method, for the powder and Z or granules containing one or more raw material components of the solid agent, 0.1 to 2 weight based on the weight of the powder and / or granules. /. Water in the form of purified water or an aqueous solution containing at least one raw material component of the solid agent (wherein the mixture contains at least glucose, calcium chloride and sodium acetate) at 50 ° C or lower. Agitating and granulating the mixture under a shearing force of 0.003 kW / kg or more per kg of the mixture for 1 minute or more. The manufacturing method is characterized in that:

In this specification, “shearing force” refers to a value calculated by the following equation:

Shearing force [kW / kg] == {(current value at load [A] -current value at no load [A]) / rated current value [A]} X motor capacity [kW] / content weight [ kg]

Current value under load: Current value of stirring motor of stirring type mixing granulator during stirring granulation [A]

Current value under no load: current value of the stirring motor of the device during idle operation (same number of revolutions as during stirring granulation) [A]

Rated current value: Rated current value of the stirring motor of the device [A]

Motor capacity: Motor capacity of the stirring motor of the device [kW]

Content weight: Weight of the mixture in the device during stirring granulation [kg]

Further, the present invention (8) is the production method according to the above-mentioned invention (7), wherein the aqueous solution has a viscosity of 0.001 to 2 Pa's.

Furthermore, the present invention (9) is the production method according to the above invention (7) or (8), wherein the aqueous solution is an aqueous solution containing glucose and magnesium chloride.

Further, the present invention (10) provides the dialysis solid preparation according to any one of the inventions (7) to (9), wherein the dialysis solid preparation is any one of the inventions (1) to (6). There are two manufacturing methods. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an image diagram showing a cross-sectional state of a solidifying agent according to the present invention of a type in which particles cannot be recognized on the surface or inside at a glance. In the figure, 1 indicates a coating layer and 2 indicates a mother particle.

FIG. 2 is an image diagram showing a cross-sectional state of a solid agent according to the present invention of a type in which particles can be confirmed on the surface and inside. In the figures, A indicates particles, and B indicates a fusion layer.

FIG. 3 is an image diagram showing a state of a cross section of a conventional solid agent in which countless particles appear to be deposited. In the figure, 1 'indicates a sedimentary layer, 2' indicates a base particle, and C indicates a particle. FIG. 4 is an image diagram showing the significance of “fused” in the present invention.

FIG. 5 is an image diagram showing the significance of “stacking” in the conventional technology. In the figures, D indicates a binder.

FIG. 6 is a digital micrograph of the solid preparation for dialysis obtained in Example 1 (digital photograph).

FIG. 7 is an electron micrograph of the solid preparation for dialysis obtained in Example 1 (digital photograph).

FIG. 8 shows an elemental analysis result (energy dispersive X-ray analyzer (EDX)) of the base particles of the solid preparation for dialysis obtained in Example 1.

FIG. 9 shows the results of elemental analysis (energy dispersive X-ray analyzer (EDX)) of the coating layer of the solid agent for dialysis obtained in Example 1.

FIG. 10 shows the result of thin-film X-ray diffraction of the solid preparation for dialysis obtained in Example 1.

FIG. 11 shows the result of thin-film X-ray diffraction of the solid preparation for dialysis obtained in Example 2.

FIG. 12 is an electron micrograph of the dialysis solid obtained in Comparative Example 1 (digital photograph).

FIG. 13 shows the result of thin-film X-ray diffraction of the solid preparation for dialysis obtained in Comparative Example 1.

FIG. 14 shows the result of thin-film X-ray diffraction of the solid preparation for dialysis obtained in Comparative Example 2. BEST MODE FOR CARRYING OUT THE INVENTION

First, the solid agent for dialysis according to the present invention will be described. The solid composition for dialysis according to the present invention is essentially the same in composition as conventional ones, and includes various electrolytes (sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate), pH adjusters. And grape bran. Here, the pH adjuster is not particularly limited as long as it is pharmacologically acceptable. Examples thereof include liquid acids such as acetic acid and hydrochloric acid, lactic acid, citric acid, malic acid, and diacid. Examples thereof include solid acids such as sodium acetate, and these may be used alone or in combination of two or more. Preferably, acetic acid and sodium diacetate.

A feature of the solid agent for dialysis according to the present invention is that the base particles are covered with a coating layer containing a specific salt. First, the coating layer according to the present invention will be described. In the thin film X-ray diffraction, the coating layer has a thickness of 20 = 21.3 to 21.5 ° and 20 = 27.6 to 27.8 ° (CuK a; λ = 1.5). 4 0 5 8 Α, Includes a salt having a specific peak at an incident angle 0 = Γ :). Here, as a result of specifying the essential components of the salt by the elimination method, it was found that the salt was a reaction product of glucose, calcium chloride, and sodium acetate.

Normally, calcium chloride as a raw material, when coexisting with glucose, promotes the decomposition of glucose and significantly degrades the storage stability of the agent. However, the solid agent for dialysis according to the present invention uses most of calcium chloride in the stirring granulation process. Is presumed to be specifically reacted with glucose and sodium acetate and contained in the coating layer as the salt, so that the storage stability is extremely good. In addition, it has been confirmed that the solid agent for dialysis containing the salt has a predetermined electrolyte ion concentration and a predetermined glucose concentration when dissolved in predetermined water.

The coating layer according to the present invention may contain components other than the salt. For example, sodium chloride, potassium chloride, magnesium chloride, sodium acetate, glucose and / or ρ ΗIt may contain a regulator.

Still further, the coating layer according to the present invention is in a fused state. First, "fused" means ^ as when a melt is solidified, and may be referred to as "agglomerated". It should be noted that the appearance is a fused state, and does not mean that the material is actually heated to a melting point or more to be melted. It can also be described as being amorphous (this does not mean that it is composed of amorphous but means that the appearance appears to be amorphous). Not all of them need to be fused together, and they may be in a state of containing particles on the surface or inside. Here, the difference between the conventional coating layer of the solid agent for dialysis and the “fused coating layer” according to the present invention will be described with reference to an image diagram. First, as shown in FIG. 3, the conventional coating layer has a structure in which innumerable particles C are deposited on the base particles 2 ′. And, as shown in Fig. 5, it can be understood that the particles C and the particles C have a force of binding via the binder D, that is, a structure simply riding on the particles. On the other hand, the “fused coating layer” according to the present invention, as shown in FIG. Have. However, it is sufficient if the external appearance is such that most of the particles are integrated, and even if particles に that are not in a fused state exist on the surface or inside of the coating layer 1 as shown in FIGS. Invention "Fused coating layer".

Next, the base particles according to the present invention will be described. The base particles according to the present invention are not particularly limited, and are composed of a raw material component of a solid agent. For example, base particles composed of sodium salt and mother particles composed of other components (for example, potassium chloride, sodium acetate, and glucose) can be exemplified. In the examples, for example, the base particles of most of the particles are made of sodium chloride, and the base particles of the remaining particles are made of other raw material components. .

As described above, as long as the salt is contained in the coating layer, for example, even if sodium chloride is contained in the coating layer, glucose is contained in the mother particles, and solid The raw material components and reaction products of the agent may be contained in either the base particles or the coating layer, or may be contained in both. However, magnesium chloride is preferably contained in the coating layer.

The solid agent for dialysis according to the present invention is typically a granular and / or fine granulated product. The average particle size is preferably about 220 to 800 m, and the thickness of the coating layer is preferably 10 to 70 μπι. Here, the granulated product may be a single particle in which a coating layer is formed on the surface of a base particle, or a product in which a plurality of coated base particles are bonded via a coating layer. Good. The shape of a single particle of the granulated material is mainly a slightly rounded cube. On the other hand, what is bound via the coating layer is a shape in which several coated cubic particles are bound.

Next, a method for producing the solid agent for dialysis according to the present invention will be described. The method for producing a solid preparation for diffusion according to the present invention comprises the steps of: providing a powder and / or granules containing at least one raw material component of the solid preparation; 22% by weight of water in the form of purified water or an aqueous solution containing at least one raw material component of the solid agent (wherein the mixture contains at least pudose sugar, calcium chloride and sodium acetate), A step of stirring and granulating the mixture at a shearing force of not less than 0.003 kW / kg per 1 kg of the mixture at 50 ° C or less for 1 minute or more. Details will be described below.

First, the “powder and Z or granule” according to the present invention will be described. The “powder and / or granule” according to the present invention comprises at least one raw material component (sodium chloride, potassium chloride, sodium acetate, calcium chloride, magnesium chloride, glucose, and a pH adjuster) of the solid agent. One or more selected from raw material groups). In addition, The powders and / or granules are basically in dry form, optionally impregnated with a liquid pH adjuster.

Here, `` When sodium chloride, potassium chloride, sodium acetate, or glucose is used as the powder and / or granules J, the particle size of each particle is not particularly limited, but the difference between the particle sizes is as small as possible. From the viewpoint of maintaining uniformity, the average particle diameter is preferably about 200 to 600 μπι, and the difference between the average particle diameters of the respective particles is The combination is preferably such that the average particle size of the particles is within 30%, and the particle size of calcium chloride is preferably not more than 300 m in order to promote the reaction between glucose and sodium acetate.

Next, the “aqueous solution” of the “aqueous solution containing one or more raw material components of purified water or the solid agent” according to the present invention will be described. Hereinafter, this aqueous solution is referred to as “the aqueous solution” unless otherwise specified. The solute of the aqueous solution is not particularly limited, and is one selected from the group consisting of sodium chloride salt, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, a pH adjuster, and glucose, which are raw material components of the solid agent. That is all. It is not necessary that all of the components are dissolved, and some of them may be in a solid state.

A preferred embodiment is an aqueous solution containing butdu sugar and magnesium chloride. In this case, a stronger coating layer can be formed. Here, the glucose concentration in this aqueous solution is preferably 10 to 70% by weight, more preferably 20 to 60% by weight, and the concentration of magnesium chloride (hexahydrate) is preferably There are 10-70 weight ⁰ /. More preferably, it is 25 to 60% by weight. Thus, in a state where both coexist {the pH of the aqueous solution becomes acidic (for example, about 4.5)}, the pudose is stably maintained and both the concentration is much higher than the solubility of a single substance. Can be dissolved, and the viscosity of the aqueous solution can be appropriately reduced, and adjusted to a viscosity suitable for granulation. For this reason, an extremely small amount of aqueous solution can be uniformly applied in a short time as compared with other granulation methods. In addition, this aqueous solution may contain components other than these, for example, an embodiment further including an electrolyte such as calcium chloride. This aqueous solution can be prepared simply by dissolving grape bran in an aqueous solution of magnesium chloride. The aqueous solution preferably has a viscosity of 0.01 to 2 Pa's, more preferably 0.01 to 1.5 Pa's, and still more preferably 0.01 to 15 Pa's. 1 Pa 's. The viscosity here indicates a value measured by a B-type viscometer.

A mixture consisting of “powder and powder or granules” and “purified water or an aqueous solution containing at least one raw material component of the solidifying agent” contains at least glucose, calcium chloride and sodium acetate. Here, these components may be contained only in the powder and Z or granules, may be contained only in the aqueous solution, or may be contained in both.

Preferable examples of the combination of "powder and / or granule" and "aqueous solution" include "powder and / or granule" .1 Includes sodium chloride, potassium chloride, sodium acetate, pudose sugar, and optionally calcium chloride. "Aqueous solution" contains glucose and magnesium chloride, and optionally contains calcium chloride.All raw materials of the solid preparation are defined as "powder and / or granules" + "aqueous solution". It is not necessary to use it, and part of the raw material may be added in the subsequent steps. For example, with respect to pH adjusters, they can be added in advance in “powder and Z or granules”, added during granulation, added before drying, or added during drying. May also be added after drying.

Next, various conditions in the manufacturing method will be described. First, the amount of water in the “purified water or the aqueous solution containing at least one raw material component of the solid agent” to be added to the system is from 0.1 to the total amount of the “powder and / or granules” present in the system. It is preferably 2.0% by weight, more preferably 0.2 to 1.4% by weight. Here, the amount of water added to the system does not include water of crystallization in the raw materials.

'' The time from the addition of purified water or the aqueous solution to the completion of granulation is as follows: the time required for the reaction of the salt, the uniformity of the content of the formed granules, and the smoothness (even though the water content is about 2% by weight) Considering that the fluidity is good, the moisture resistance is high, and free water that causes adhesion and coagulation hardly forms on the surface of the coating layer), it is preferable that the time is 1 minute or more. It is preferably at least 3 minutes, more preferably at least 10 minutes. Also, from the viewpoint of preventing fracture, the time is preferably 30 minutes or less.

Next, the shearing force applied during stirring will be described. First, the definition of the shearing force according to the present invention will be described. When a stirring-type mixing granulator is used, the stirring granulation according to the present invention At the time of granulation, a shear force is applied to the mixture between the stirring blade and the inner wall of the device due to the rotation of the stirring blade. The magnitude of this shearing force was calculated by the above equation using the load of the stirring motor of the apparatus (motor current value), and the value was defined as the shearing force applied per kg of the mixture. Next, the required shearing force is not less than 0.003 kWZkg, preferably not less than 0.01 kW / kg, and more preferably not less than 0.05 kW / kg. Also, the upper limit is preferably 0.1 kW / kg or less from the viewpoint of increasing the internal temperature and preventing crushing.

In addition, the temperature at which stirring granulation is performed is sufficient at a temperature around room temperature, and granulation can be performed at a temperature that is extremely effective in preventing decomposition of pudose. That is, it is essential that the temperature at which the granulation of the present invention is carried out is not more than 50 ° C. from the viewpoint of salt formation. The lower limit is not particularly limited, but is preferably at least o ° c. In addition, more preferably

It is 10 to 50 ° C, most preferably 20 to 40 ° C.

This is a method of adding purified water / the aqueous solution to the powder and / or the granules, but is not particularly limited, and may be a batch addition or a divided addition, or a spraying method. The temperature of the purified water or the aqueous solution (before addition) is preferably 15 to 50 ° C. In addition, as a stirring-type mixing granulation apparatus used in the stirring-granulation step, a high-speed stirring-type granulation apparatus is suitable. The operating conditions are sufficiently achieved within the range of general conditions for granulation.

The steps after the granulation step, the equipment to be used, and the operating conditions are not particularly limited, but the obtained granules are dried, and if necessary, before or after drying, a pH adjuster is added and mixed, and the granules are granulated. A granulated and Z- or fine-grained solid for dialysis is obtained.

By dissolving the solid agent for dialysis according to the present invention and sodium bicarbonate in predetermined water, the bicarbonate dialysate can be adjusted to, for example, the following concentrations:

Na ⁺ 125-150 mE q / 1

K ⁺ 1.0 to 3.0 mE q / 1

C a ²⁺ 1.5-3.5 mEq / 1

Mg ²⁺ 0.5 to 1.5 mEq / 1

C I— 90.0 to 135 mE q / 1

CH ₃ C〇 ₂ 1 5.0 to: 10.0 mEq / 1 HCO ₃ "20.0-30.0 mEq / 1

Glucose 0.5-2.5 g / 1

As the packaging material for the solid preparation for dialysis obtained in this manner, a material having good moisture-proof performance and having a back electrode effect is preferable. In the past, there was an example where a film was made by kneading an antistatic agent into a resin and then processed into a packaging material having an antistatic function.However, foreign materials mixed into the product due to the bleeding phenomenon from the resin were used. Inconvenience was seen. In contrast, in the present invention, since the antistatic agent is contained in the adhesive used for bonding the film, it does not penetrate the film, and the bleeding phenomenon does not occur. The antistatic agent is contained in the adhesive on the back side of the film surface in contact with the solid agent for dialysis, and is a laminated film having an antistatic function up to the back surface. That is, moisture permeability (40.C, 90% RH) 2. Og / m 2 - 24h r following film, for example, using a silica-deposited film, antistatic个生adhesive, for example Bonn dip (Konishi Co., Ltd.) It is preferable to fill and package a dialysis solid in a packaging material having a back electrode effect, which is processed using a laminated film adhered and used. Examples of the configuration of a laminated film having such a laminated structure include:

PETZS i O _x / Bondip / PE,

PVA / S i O _x / bondip //,

ONY / S i〇 _x / Bondip ZPE,

PET / S i O _x / bondip / CPP,

OPP / S i O _x / Bondip ZCPP,

These can be processed into packaging materials and used. The laminating film can be easily produced by a known method. As an example of the production method, measure the required amount of the antistatic adhesive, dilute it with a solvent if necessary, mix the liquid evenly, and use a coater such as a gravure coater or reverse coater. Then, it is applied to the above-mentioned film, dried with hot air, and completely cured. The obtained laminated film can be processed into a packaging material by heat sealing. Example Hereinafter, the present invention will be described more specifically with reference to Examples.

[Example 1]

Sodium chloride 5000. Og, potassium chloride 121.6 g, calcium chloride 178.5 g, sodium acetate 667.4 g, glucose 760.2 g, high-speed stirring granulator (High speed mixer FS—GS—manufactured by Fukae Patech Co., Ltd.)

25 J) and mixed and stirred. While mixing agitation at a rotation number 6 Orpm (shear 0. 04 kW / kg), at an internal temperature of 25 ^D C, previously prepared glucose had been 54. purification 6 g and Shioi匕magnesium 82. 8 g The temperature of the solution dissolved in 36.4 g of water is

An aqueous solution (viscosity: 0.035 Pa's) at 30 ° C was added. Immediately after the addition, the contents, which were in the form of wet particles, became smooth granules after mixing and stirring for 15 minutes. The granules were taken out and dried until the water content became 0.5% by weight or less. 98.3 g of acetic acid was added to the obtained granules, mixed and stirred for 5 minutes, and then the granules were taken out and sized to obtain a granular and fine granular preparation.

[Example 2]

5000. Og of sodium chloride, 122.7 g of potassium chloride, 181.5 g of calcium chloride, 202.3 g of sodium acetate, and 766.6 g of glucose were added to a high-speed agitation type granulator and mixed and stirred. While mixing and stirring at a rotation speed of 7 Orpm (shear force: 0.06 kW / kg), at a temperature of 25 ° C, 55.2 g of glucose and 83.7 g of magnesium chloride prepared in advance were purified water. An aqueous solution (viscosity: 0.043 Pa's) having a temperature of 30 ° C. dissolved in 2 g was added. Immediately after the addition, the contents in the form of wet particles became smooth granules after mixing and stirring for 10 minutes. The granules were taken out and dried until the water content became 0.5% by weight or less. Further, 98.7 g of acetic acid prepared in advance and adsorbed on 202.0 g of sodium acetate was added to the granulated product, and the mixture was stirred and mixed, and then sized to obtain a granular and fine granular preparation.

[Comparative Example 1]

Add 1063.5 g of sodium chloride, 26.lg of potassium chloride, 17.8 g of magnesium chloride, 86.lg of sodium acetate, 175.0 g of glucose, and 20.0 g of purified water to an Eder (manufactured by Moriyama), and mix and stir. Heated. The viscosity began to increase from around 55 ° C, and became a paste at an internal temperature of 60 ° C. 38.6 g calcium chloride When the mixture was added and stirring was continued at 60 ° C., the contents became bulky and the viscosity further increased. Acetic acid 21. Og was added and stirring was continued to circulate the contents, but the-part became clumpy and some were finely powdery. The contents were taken out, sized, and dried to obtain a preparation.

[Comparative Example 2]

An aqueous solution was prepared by dissolving 26.1 g of potassium chloride, 17.8 g of magnesium chloride, 38.6 g of calcium chloride and 86.1 g of sodium acetate in 400 g of purified water. Sodium chloride 1063. 6 g and Pudou sugars 175. Og were charged into a tumbling fluidized bed granulator, the air supply temperature 80 ° C, the rotor rotational speed 15 Orpm, under the conditions of supply air volume 0. 7 m ³ / min The aqueous solution was sprayed and dried at the same time to obtain a granulated product. After sizing, 21. Og of acetic acid was added to the obtained granules and mixed to obtain a preparation.

[Comparative Example 3]

1066.6 g of sodium chloride, 26.lg of potassium chloride, 17.8 g of magnesium chloride, 38.6 g of calcium chloride, 86.lg of sodium acetate, and 175.0 g of glucose are powder-framed to about 75 m, mixed, and compressed. Granulation was performed using a rotary granulator. After sizing, acetic acid was added to the obtained granules and mixed to obtain a preparation.

[Test Example 1]

FIG. 6 shows a micrograph (manufactured by Keyence Corporation) of the preparation obtained in Example 1. From this figure, it can be seen that the present preparation obtained in Example 1 is present as a single particle, or as an aggregate in which a plurality of base particles are bonded via a coating layer. Fig. 7 shows the structure of the coating layer of the same preparation using a digitally operated electron microscope (manufactured by Hitachi, Ltd.). From this figure, it can be confirmed that the coating layer of the same preparation has an appearance as if fused. 8 and 9 show the results of elemental analysis (EDX) of the mother particles and the coating layer, respectively. From FIG. 8, it was confirmed that sodium chloride was present as mother particles. In addition, elemental analysis of the other mother particles confirmed that potassium chloride, sodium acetate and grape bran were present as mother particles.

From Fig. 9, it was confirmed that magnesium chloride, potassium chloride, glucose and the like were present in the coating layer.

[Test Example 2] The results of thin-film X-ray diffraction of each preparation obtained in Examples 1 and 2 are shown in FIGS. 10 and 11.

The measurement was performed using a thin-film X-ray diffractometer (CUKQ ::; L = 1.54058 A, incident angle 0 = 1 °) using a thin-film X-ray diffraction method to clarify the coating layer structure of the drug product. I went.

A sample preparation method will be described. Approximately 0.5 g of each sample was taken from each preparation and compression molded into a disk of uniform thickness using a tableting machine. The tableting pressure was such that the base particles of the drug product did not break, and the sample size was about 2 Omm in diameter and about 2 mm in thickness.

From FIGS. 10 and 11, it can be seen that peaks are detected at around 20 = 21.4 ° and 27.7 °, which indicate the reaction products of glucose, calcium chloride and sodium acetate.

[Test Example 3]

Among the preparations obtained in Comparative Example 1, one particle was taken out, and its cross section was observed with a digitally operated electron microscope. From this figure, it can be seen that, unlike that of Example 1, in the preparation, fine particles were deposited. FIGS. 13 to 14 show thin-film X-ray diffraction results of the preparations obtained in Comparative Examples 1 and 2 measured in the same manner as in Test Example 2. It can be seen that no peak was detected at around 20 = 21.4 ° and 27.7 °, indicating the reaction product of glucose, calcium chloride, and sodium acetate.

[Test Example 4]

Six samples were randomly sampled from the preparation obtained in Example 1, and 8.5 Og of sample was dissolved in water to make exactly 20 Oml for each sample, and this was diluted 50-fold to obtain Na ⁺ , K ⁺ , The concentration of each of the electrolytes Mg ²⁺ , Ca ²⁺ , C 1— and CH ₃ CO— was measured by an ion chromatograph manufactured by Tosoh Corporation. For glucose, 8.50 g of the sample was dissolved in water to make exactly 100 ml, and the glucose was measured by liquid chromatography manufactured by Tosoh Corporation. Table 1 shows the measurement results. table 1

Unit: g / L for glucose, mEq / L for other components

[Test Example 5]

The concentration of each component of the preparation obtained in Example 2 was carried out in the same manner as in Example 1, and the results are shown in Table 2.

Table 2

(Note) Unit: g / L for glucose, mEq / L for other components

[Test Example δ]

Each of the preparations of Example 1, Example 2, Comparative Example 1, and Comparative Example 2 was filled in an aluminum packaging material, heat-sealed, and then subjected to a stability test at 40 ° C (RH = 75%). The experiment was performed. In order to measure the glucose decomposition rate, the absorbance was measured based on the ultraviolet-visible absorbance measurement method of the purity test for glucose injection described in the Japanese Pharmacopoeia, 14th Edition. The results are shown in Table 3.

Table 3

[Test Example 7]

23 Og of each of the preparations of Example 1, Example 2 and Comparative Example 1 was weighed in two samples at a time, and each was filled in an aluminum packaging material of 13 OmmX 85 thighs, heat-sealed, and then sealed at 40 ° C ( Under the condition of (RH = 75%), a load of 3 Okg was applied evenly, and the consolidated state was observed over time. Table 4 shows the results of the consolidation test. The sample was opened after applying a load for a predetermined period of time, lightly sieved with a 16-mesh sieve, and the amount of the unsieved residue was measured. The sieving residue is represented by 〇 when the content is within 10% by weight, the △ when the content is 10 to 50% by weight, and X when the remaining amount is more than 10%. Table 4

[Test Example 8]

400 ml of water (20 ° C.) was placed in a 1000 ml beaker, and 12 Og of each of the preparations of Example 2 and Comparative Examples 1 to 3 was charged with stirring, and the time required for complete dissolution was measured. Table 5 shows the measurement results. Table 5

[Test Example 9]

2 Og was collected from each of the preparations obtained in Example 1, Example 2, Comparative Example 1 and Comparative Example 2, and 2 O ml of clonal form was added, and the mixture was gently shaken and the supernatant was collected. . Similarly, 2 Og was collected from each preparation, shaken for 5 minutes, added with 2 Oml of black-mouthed form, mixed gently, and the supernatant was collected. The turbidity test of each sample was performed in accordance with the case of using the kaolin standard solution of JIS K 0101 “Industrial water test method”. The difference in the amount of fine powder generated by shaking was evaluated as the difference in turbidity before and after shaking. The results are shown in Table 6, and the results show that the preparation obtained by the present invention had a smaller amount of fine powder than the comparative example, and was less susceptible to physical forces such as shaking. Was done. Table 6

The composition of each component in the preparation covered with the coating agent in such a fused state is a preparation having a composition very close to the theoretical value as shown in Tables 1 and 2, and the solid preparation for dialysis of the present invention is It can be seen that the content uniformity of each component is sufficient. In addition, the results of the stability test are excellent as shown in Table 3, and as shown in Table 4, the results of the caking test are good and the product can be stored for a long period of time. In addition, as shown in Table 5, the dissolution rate is high, and as shown in Table 6, the formulation is easy to handle due to extremely low dusting. The invention's effect

The solid agent according to the present invention is a granulated product in which the coating layer in a state of being strongly fused is coated with the mother particles, and other examples include electrolytes such as sodium chloride and chlorine-containing rim, and aqueous solutions of glucose. Compared to a film manufactured by spray granulation method or the like as shown in Fig. 3 or a film as shown in Fig. 3, the surface is denser, so it is less susceptible to external factors and has excellent long-term storage stability. It is said that the workability of the dissolution operation at the medical site is much better than before because it has good fluidity, good abrasion resistance and good consolidation resistance, hardly generates dust, and has a high dissolution rate. It works.

Further, according to the method for producing a solid preparation according to the present invention, it is not necessary to heat for a long time as compared with the conventional method, so that danger of glucose being decomposed and colored during granulation can be avoided, and A solid preparation having excellent content uniformity can be obtained without requiring complicated operations such as grinding and sieving. Specifically, according to the production method of the present invention, the mixture that has been in the form of wet particles becomes a smooth, apparently dry granule, Z or fine granule in a short time at around room temperature, and is easily formed. The granulation is completed. Therefore, handling such as transfer, drying, and mixing, which is the next step, becomes extremely easy.

Claims

The scope of the claims

1. In the electrolyte composition consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, the pH adjuster and the solid preparation for dialysis consisting of glucose, 20 = 21. 21.5 ° and 20 = 27.6 to 27.8 ° (CuKa; e = 1.54058 A, incident angle 0 = 1 °) A solidifying agent for permeation characterized in that it is covered.

2. The solid preparation for dialysis according to claim 1, which is in the form of granules and / or fine granules.

3. The solid agent for dialysis according to claim 1, wherein the salt is a reaction product of glucose, calcium chloride, and sodium acetate.

4. The method according to any one of claims 1 to 3, wherein the coating layer is in a fused state.

, Solid for dialysis.

5. A solid agent for bicarbonate dialysis, comprising the solid agent for dialysis according to any one of claims 1 to 4 and a solid agent containing sodium bicarbonate.

6. moisture permeability (40, 90% RH) 2. 0 g / m 2 - 24h r or less, are housed in the moisture-proof packaging material of a laminated structure having a back electrode effect, claim 1, wherein, second Item 6. The solid preparation for dialysis according to any one of Items 5.

7. In a method for producing a solid composition for dialysis produced from sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, a pH adjuster and glucose as raw materials, Powders and / or granules containing one or more kinds of raw material components are mixed with 0.1 to 2% by weight of water based on the weight of the powders and / or granules, and purified water or raw material components of the solid agent. (Herein, the mixture contains at least glucose, calcium chloride and sodium acetate) at a temperature of 50 ° C or less for 1 minute or more, and 0.003 per kg of the mixture. a process for agitating and granulating the mixture under a shearing force of kW / kg or more.

8. The method according to claim 7, wherein the aqueous solution has a viscosity of 0.001 to 2 Pa's.

9. The production method according to claim 7, wherein the aqueous solution is an aqueous solution containing grape bran and magnesium chloride.

10. The solid preparation for dialysis is the solid preparation for dialysis according to any one of claims 1 to 6, wherein the solid preparation for dialysis is any one of claims 7 to 9, Manufacturing method.