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WO2004066977A1 - Agent solide utilise pour la dialyse et procede de production de ce dernier - Google Patents

Agent solide utilise pour la dialyse et procede de production de ce dernier Download PDF

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Publication number
WO2004066977A1
WO2004066977A1 PCT/JP2004/000892 JP2004000892W WO2004066977A1 WO 2004066977 A1 WO2004066977 A1 WO 2004066977A1 JP 2004000892 W JP2004000892 W JP 2004000892W WO 2004066977 A1 WO2004066977 A1 WO 2004066977A1
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WO
WIPO (PCT)
Prior art keywords
dialysis
solid
chloride
glucose
agent
Prior art date
Application number
PCT/JP2004/000892
Other languages
English (en)
Japanese (ja)
Inventor
Yoshiaki Kawashima
Hirofumi Takeuchi
Ryoji Oura
Masaru Mori
Masao Nakashima
Shinichi Kadono
Original Assignee
Manac Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/JP2003/007356 external-priority patent/WO2004067014A1/fr
Application filed by Manac Inc. filed Critical Manac Inc.
Priority to JP2005504763A priority Critical patent/JP4603977B2/ja
Publication of WO2004066977A1 publication Critical patent/WO2004066977A1/fr
Priority to HK06109554A priority patent/HK1089089A1/xx

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1654—Dialysates therefor
    • A61M1/1656—Apparatus for preparing dialysates
    • A61M1/1666—Apparatus for preparing dialysates by dissolving solids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • 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.
  • 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.
  • “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.
  • 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 ⁇ 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.
  • 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.
  • 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).
  • Patent No. 27695992 Patent No. 27984888 and Japanese Patent Application Laid-Open No. 2002-102337, 60 ° C.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • a 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. /.
  • the manufacturing method is characterized in that:
  • shearing force refers to a value calculated by the following equation:
  • 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.
  • the present invention 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.
  • the present invention 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).
  • the dialysis solid preparation is any one of the inventions (1) to (6).
  • 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.
  • 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.
  • A indicates particles
  • 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.
  • 1 ' indicates a sedimentary layer
  • 2' indicates a base particle
  • 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.
  • 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.
  • EDX energy dispersive X-ray analyzer
  • 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.
  • EDX energy dispersive X-ray analyzer
  • 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.
  • the solid agent 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.
  • 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.
  • the coating layer according to the present invention will be described.
  • the salt was a reaction product of glucose, calcium chloride, and sodium acetate.
  • 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.
  • sodium chloride, potassium chloride, magnesium chloride, sodium acetate, glucose and / or ⁇ ⁇ It may contain a regulator.
  • the coating layer according to the present invention is in a fused state.
  • 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.
  • the conventional coating layer of the solid agent for dialysis has a structure in which innumerable particles C are deposited on the base particles 2 ′.
  • 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.
  • 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 ⁇ 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".
  • the base particles according to the present invention are not particularly limited, and are composed of a raw material component of a solid agent.
  • base particles composed of sodium salt and mother particles composed of other components for example, potassium chloride, sodium acetate, and glucose
  • the base particles of most of the particles are made of sodium chloride
  • the base particles of the remaining particles are made of other raw material components. .
  • 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.
  • 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 ⁇ .
  • 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.
  • what is bound via the coating layer is a shape in which several coated cubic particles are bound.
  • 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.
  • the “powder and Z 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).
  • the powders and / or granules are basically in dry form, optionally impregnated with a liquid pH adjuster.
  • the particle size of each particle is not particularly limited, but the difference between the particle sizes is as small as possible.
  • the average particle diameter is preferably about 200 to 600 ⁇ , 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.
  • 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.
  • 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.
  • a stronger coating layer can be formed.
  • 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.
  • the pudose is stably maintained and both the concentration is much higher than the solubility of a single substance.
  • 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.
  • 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.
  • 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.
  • 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.
  • the shearing force applied during stirring will be described.
  • the stirring granulation according to the present invention 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.
  • 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.
  • the upper limit is preferably 0.1 kW / kg or less from the viewpoint of increasing the internal temperature and preventing crushing.
  • 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
  • the temperature of the purified water or the aqueous solution (before addition) is preferably 15 to 50 ° C.
  • 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.
  • the bicarbonate dialysate can be adjusted to, for example, the following concentrations:
  • 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.
  • 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.
  • 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 ⁇ 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • EDX elemental analysis
  • 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.
  • Example 2 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
  • Example 2 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 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 ⁇ 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
  • 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.
  • 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.
  • 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.
  • electrolytes such as sodium chloride and chlorine-containing rim
  • 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.
  • 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.
  • 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.

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Abstract

Un agent solide utilisé pour la dialyse comprend un électrolyte, du glucose et un correcteur d'acidité nécessaires pour préparer un fluide de dialyse au bicarbonate, ledit agent solide pour la dialyse assurant la présence stable de glucose non seulement pendant l'étape de production amis également pendant l'étape de stockage, ne pouvant se décomposer ni se colorer et présentant une excellente stabilité de stockage, une uniformité du contenu et une résistance à l'abrasion, ce qui implique ainsi une maniabilité extrêmement élevée sur des lieux d'intervention médicale ponctuelle. De manière plus particulière, un agent solide pour la dialyse comprend une composition d'électrolyte (la composition d'électrolyte étant constituée de chlorure de sodium, de chlorure de potassium, de chlorure de calcium, de chlorure de magnésium et d'acétate de sodium), un correcteur d'acidité et du glucose et se caractérise en ce que les particules de base sont recouvertes par une couche de revêtement comprenant un sel présentant, par diffraction des rayons X en film mince, des valeurs maximales spécifiées à 2υ = 21,3 21,5° et 2υ = 27,6 27,8° (CuKα : μ = 1,54058 Å et un angle d'incidence υ = 1°).
PCT/JP2004/000892 2003-01-31 2004-01-30 Agent solide utilise pour la dialyse et procede de production de ce dernier WO2004066977A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2005504763A JP4603977B2 (ja) 2003-01-31 2004-01-30 透析用固形剤及びその製造方法
HK06109554A HK1089089A1 (en) 2003-01-31 2006-08-28 Solid agent for dialysis and process for producingthe same

Applications Claiming Priority (4)

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JP2003-023261 2003-01-31
JP2003023261 2003-01-31
JPPCT/JP03/07356 2003-06-10
PCT/JP2003/007356 WO2004067014A1 (fr) 2003-01-31 2003-06-10 Preparation solide destinee a la dialyse et procede de fabrication correspondant

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007131563A (ja) * 2005-11-09 2007-05-31 Manac Inc 透析用固形剤およびその製造方法
JP2016153391A (ja) * 2015-02-16 2016-08-25 日本合成化学工業株式会社 無水酢酸ナトリウム結晶
US9931453B2 (en) 2012-10-10 2018-04-03 Tomita Pharmaceutical Co., Ltd. Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof
US10525078B2 (en) 2013-10-02 2020-01-07 Tomita Pharmaceutical Co., Ltd. Solid dialysis A agent containing alkali metal diacetate, and two-part type low-acetate dialysis agent using same
CN113975292A (zh) * 2021-12-28 2022-01-28 广州康盛生物科技股份有限公司 一种不易结块的血液透析干粉a组分的制备方法
WO2025052855A1 (fr) * 2023-09-07 2025-03-13 富田製薬株式会社 Agent a pour hémodialyse et agent d'hémodialyse

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JPH02311418A (ja) * 1989-05-26 1990-12-27 Terumo Corp 血液透析用製剤およびその製造方法
EP0602921A1 (fr) * 1992-12-14 1994-06-22 Tomita Pharmaceutical Corporation Limited Composant de dialysat pour la dialyse au bicarbonate et méthode de fabrication
JPH06335527A (ja) * 1993-04-02 1994-12-06 Morishita Roussel Kk 重曹透析用剤
JPH0892071A (ja) * 1994-09-27 1996-04-09 Morishita Roussel Kk 重炭酸透析用剤
JPH0892070A (ja) * 1994-09-27 1996-04-09 Morishita Roussel Kk 血液透析用剤
JPH11343230A (ja) * 1998-05-27 1999-12-14 Nissho Corp 固形重曹透析用剤
JP2001149468A (ja) * 1999-11-25 2001-06-05 Nissho Corp 固形重曹透析用剤およびその製造方法
JP2002102337A (ja) * 2000-09-27 2002-04-09 Nipro Corp 固形透析用製剤およびその製造方法

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02311418A (ja) * 1989-05-26 1990-12-27 Terumo Corp 血液透析用製剤およびその製造方法
EP0602921A1 (fr) * 1992-12-14 1994-06-22 Tomita Pharmaceutical Corporation Limited Composant de dialysat pour la dialyse au bicarbonate et méthode de fabrication
JPH06335527A (ja) * 1993-04-02 1994-12-06 Morishita Roussel Kk 重曹透析用剤
JPH0892071A (ja) * 1994-09-27 1996-04-09 Morishita Roussel Kk 重炭酸透析用剤
JPH0892070A (ja) * 1994-09-27 1996-04-09 Morishita Roussel Kk 血液透析用剤
JPH11343230A (ja) * 1998-05-27 1999-12-14 Nissho Corp 固形重曹透析用剤
JP2001149468A (ja) * 1999-11-25 2001-06-05 Nissho Corp 固形重曹透析用剤およびその製造方法
JP2002102337A (ja) * 2000-09-27 2002-04-09 Nipro Corp 固形透析用製剤およびその製造方法

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007131563A (ja) * 2005-11-09 2007-05-31 Manac Inc 透析用固形剤およびその製造方法
US9931453B2 (en) 2012-10-10 2018-04-03 Tomita Pharmaceutical Co., Ltd. Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof
US10251988B2 (en) 2012-10-10 2019-04-09 Tomita Pharmaceutical Co., Ltd. Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof
US10525078B2 (en) 2013-10-02 2020-01-07 Tomita Pharmaceutical Co., Ltd. Solid dialysis A agent containing alkali metal diacetate, and two-part type low-acetate dialysis agent using same
JP2016153391A (ja) * 2015-02-16 2016-08-25 日本合成化学工業株式会社 無水酢酸ナトリウム結晶
CN113975292A (zh) * 2021-12-28 2022-01-28 广州康盛生物科技股份有限公司 一种不易结块的血液透析干粉a组分的制备方法
CN113975292B (zh) * 2021-12-28 2022-03-25 广州康盛生物科技股份有限公司 一种不易结块的血液透析干粉a组分的制备方法
WO2025052855A1 (fr) * 2023-09-07 2025-03-13 富田製薬株式会社 Agent a pour hémodialyse et agent d'hémodialyse
JP7653748B1 (ja) 2023-09-07 2025-03-31 富田製薬株式会社 血液透析用ａ剤及び血液透析用剤

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