WO2017038099A1 - Article rempli de solution étalon et son utilisation - Google Patents

Article rempli de solution étalon et son utilisation Download PDF

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Publication number
WO2017038099A1
WO2017038099A1 PCT/JP2016/003999 JP2016003999W WO2017038099A1 WO 2017038099 A1 WO2017038099 A1 WO 2017038099A1 JP 2016003999 W JP2016003999 W JP 2016003999W WO 2017038099 A1 WO2017038099 A1 WO 2017038099A1
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Prior art keywords
standard solution
dialysate
standard
bicarbonate
filling
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PCT/JP2016/003999
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English (en)
Japanese (ja)
Inventor
佐野　嘉彦
増田　利明
衛 島田
俊成 高橋
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ニプロ株式会社
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Priority to JP2017537554A priority Critical patent/JP6879208B2/ja
Publication of WO2017038099A1 publication Critical patent/WO2017038099A1/fr

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    • 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

Definitions

  • the present invention relates to a filling body in which a container is filled with a standard solution used for confirming that a dialysate and a bicarbonate-containing preparation used for preparing a dialysate are used at an appropriate concentration in hemodialysis,
  • the present invention relates to the use of the standard solution filling.
  • Hemodialysis therapy (or artificial dialysis therapy, hereinafter abbreviated as “hemodialysis”) is a treatment method that is adopted for patients with chronic renal failure and that artificially replaces renal function.
  • hemodialysis blood is drawn out of the body, passed through a dialyzer, and pulled back into the body.
  • a dialyzer blood and dialysate are contacted indirectly through a dialysis membrane, whereby waste in the blood is removed and the electrolyte and water content in the blood are maintained.
  • 100 to 300 liters of dialysate is used.
  • Dialysis fluid is usually prepared immediately before use.
  • agent A containing an electrolyte component and agent B containing a bicarbonate (bicarbonate) are mixed immediately before use and replenished with dialysis water.
  • the concentration of each component is adjusted. This is because, when part of the electrolyte component contained in the agent A coexists with the hydrogen carbonate that is the main component of the agent B, they react with each other over time to produce an insoluble carbonate. It is. If insoluble carbonate is generated, precipitation will occur in the dialysate, and the concentration and pH of the components of the dialysate will be changed.
  • the bicarbonate contained in the dialysate is decomposed into carbon dioxide over time. This decomposition reaction also changes the component concentration and pH of the dialysate.
  • Agent A and Agent B were separated by a partition wall.
  • a method of accommodating each in a multi-chamber container is known.
  • the dialysate can be prepared immediately before use by breaking the partition wall at the site of use and mixing the A agent and the B agent.
  • preparing the dialysate immediately before use in other words, preparing the necessary amount of dialysate at the site of use as needed. For this reason, the concentration of dialysate tends to vary as compared to preparing dialysate with quality control on a large scale in a factory or the like where dedicated equipment is provided.
  • agent A and agent B can be prepared in advance at the factory and filled into the multi-chamber container before shipping. It is possible to suppress variations in liquid concentration.
  • the amount of dialysate prepared is limited to the amount of agent A and agent B that can be accommodated in the multi-chamber container. For example, when the dialysate exceeds the capacity of the multi-chamber container. Can't cope with it enough.
  • the present invention has been made to solve such problems, and suppresses variations in the concentration of the dialysate without being limited by the amount of preparation when the dialysate is prepared as needed at the site of use.
  • the purpose is to provide a method capable of
  • the standard solution filling body is a filling body in which a standard solution of a bicarbonate-containing preparation used for preparing a dialysate for hemodialysis is filled in a sealed container.
  • the closed container is made of a material having gas barrier properties, and the initial pH after filling in the standard solution is lower than the pH of the bicarbonate-containing preparation to be prepared.
  • the initial pH is lowered in anticipation of the increase in pH of the filled standard solution.
  • the pH of the standard solution can be maintained within a suitable range even during storage, and the generation of insoluble salts with an increase in the pH of the standard solution can be avoided. Therefore, the standard solution can be stably stored over a long period of time, and the concentration of the dialysate prepared at the site of use can be adjusted appropriately. Thereby, even when dialysate is prepared at any time at the site of use, variations in dialysate concentration can be suppressed without being limited by the amount of preparation.
  • the bicarbonate-containing preparation is a dialysis solution
  • the standard solution is preset with at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate and water.
  • the initial pH after filling in the standard solution may be less than 0.4 than the pH of the dialysate to be prepared. .
  • the bicarbonate-containing preparation is a dialysate
  • the initial pH of the filled dialysate standard solution is lowered within 0.4. Therefore, it is possible to maintain the pH of the dialysate standard solution within a suitable range even during storage, and it is also possible to avoid the formation of an insoluble salt as the pH of the dialysate standard solution increases. . Therefore, it is possible to stably store the dialysis standard solution over a long period of time, so that the concentration of the dialysis solution prepared at the site of use can be adjusted appropriately.
  • the standard solution includes an acid component that is a weak acid, and a plurality of types of monovalent or divalent metal ions including sodium ions, potassium ions, calcium ions, and magnesium ions.
  • an acid component that is a weak acid
  • a plurality of types of monovalent or divalent metal ions including sodium ions, potassium ions, calcium ions, and magnesium ions.
  • the pH is set low by adjusting the content ratio of the weak acid and the metal salt of the weak acid.
  • the pH is set low while maintaining a substantial composition as a standard solution. be able to.
  • a metal salt of a weak acid is included as a metal ion supply source, the weak acid can behave as a pH buffered acid, and the weak acid metal salt can behave as a pH buffered conjugate base.
  • the pH of the filled standard solution can be made difficult to increase due to the pH buffering action.
  • the acid component may be citric acid or acetic acid
  • the metal ion serving as a conjugate base may be a sodium ion
  • the sealed container is filled with a sealed gas that fills a gap in the sealed container together with the standard liquid, and the sealed gas includes air or nitrogen gas.
  • the composition may be a mixed gas composed of carbon dioxide and having a carbon dioxide content of 3 to 20% by volume.
  • a standard solution prepared by mixing sodium ions, potassium ions, calcium ions, magnesium ions, hydrogen carbonate and water, and a smaller volume are enclosed inside the packing body.
  • Gas is filled, and this sealed gas is a mixed gas containing carbon dioxide in the range of 3 to 20% by volume.
  • the initial pH of the standard solution after filling can be substantially reduced. Therefore, even if the pH of the filled standard solution increases, it can be maintained within a suitable range, and it is also possible to avoid the formation of insoluble salts with the increase in pH of the standard solution.
  • a significant decrease in pH that occurs when the enclosed gas is only carbon dioxide can be effectively suppressed.
  • the standard solution filling body having the above-described configuration makes it possible to stably store the standard solution for a long period of time. Therefore, when preparing dialysate as needed at the site of use, the concentration of the prepared bicarbonate-containing preparation should be adjusted appropriately by comparing the standard solution in the standard solution filling body with the prepared bicarbonate-containing preparation. Can be adjusted. As a result, even when the dialysate is prepared at any time at the site of use, it is possible to suppress variations in the dialysate concentration without being limited by the amount of preparation.
  • the filling rate of the standard liquid is in the range of 70 to 99% by volume
  • the filling rate of the sealed gas is May be in the range of 1 to 30% by volume.
  • the standard solution may have a configuration in which the initial pH is lowered by bubbling carbon dioxide.
  • the standard solution may have a configuration in which the initial pH is lowered by adding an acid.
  • Another standard solution filling body is a filling body in which a standard solution of a bicarbonate-containing preparation used for preparing a dialysate for hemodialysis is filled in a sealed container in order to solve the above-described problems.
  • the sealed container is made of a material having a gas barrier property, and the standard solution is stored in the sealed container until the capacity limit of the sealed container or until it does not overflow beyond the capacity limit of the sealed container.
  • the configuration is filled.
  • the closed container is substantially filled with only the standard solution of the bicarbonate-containing preparation.
  • generation of insoluble carbonate and decomposition of hydrogen carbonate into carbon dioxide can be avoided in this standard solution, and pH can be maintained within a predetermined range even when stored for a long period of time. Therefore, it is possible to stably store the standard solution for a long period of time.
  • the concentration of the prepared bicarbonate-containing preparation is appropriately determined by comparing the standard solution in the standard solution filling body with the prepared bicarbonate-containing preparation. Can be adjusted. As a result, even when the dialysate is prepared at any time at the site of use, it is possible to suppress variations in the dialysate concentration without being limited by the amount of preparation.
  • the bicarbonate-containing preparation is a dialysis solution
  • the standard solution is preset with at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate and water.
  • the composition may be one prepared by mixing at a mixing ratio.
  • the inside of the sealed container is substantially filled only with a dialysate standard solution prepared by mixing at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water. It becomes a state. Thereby, generation of insoluble carbonate and decomposition of hydrogen carbonate into carbon dioxide can be avoided in the dialysate standard solution, and the pH can be maintained within a predetermined range even when stored for a long period of time. Therefore, the dialysate standard solution can be stably stored for a long period of time.
  • the standard solution filling body having the above configuration, when the total volume of the sealed container is 100% by volume, the standard solution is filled in the sealed container so that the filling rate is in the range of 80 to 100% by volume. It may be configured.
  • the standard solution of the bicarbonate-containing preparation includes an agent A that is an acidic aqueous solution containing sodium ions, potassium ions, calcium ions, and magnesium ions, and carbonic acid.
  • the composition may be a standard solution of the dialysate prepared by mixing a B salt containing hydrogen salt and water at a preset mixing ratio or a standard solution of the B agent.
  • the sealed container may have a structure in which at least the main body is made of glass.
  • the present invention also includes a dialysate preparation kit including the standard solution filling body having any one of the above-described configurations.
  • the present invention includes a method for producing a standard liquid filling body having the above-described configuration.
  • the method for producing a standard solution filling body according to the present disclosure includes filling a standard solution of a bicarbonate-containing preparation used in preparing a dialysate for hemodialysis into a sealed container, thereby providing a standard solution.
  • the bicarbonate-containing preparation is a dialysis solution
  • the standard solution is at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water
  • the mixture is prepared by mixing at a preset mixing ratio, and the initial pH after filling in the standard solution is adjusted to be lower than the pH of the dialysate to be prepared within 0.4. Also good.
  • the standard solution includes an acid component that is a weak acid and a plurality of types of monovalent or divalent metal ions including sodium ions, potassium ions, calcium ions, and magnesium ions.
  • the metal ion content is equivalent to the standard, and the acid component content is higher than the standard.
  • the initial pH may be adjusted by adjusting the composition of the standard solution.
  • the sealed gas filling the voids in the sealed container is filled into the sealed container together with the standard solution so as to have a volume smaller than that of the standard solution.
  • the initial pH is adjusted, and the sealed gas may be composed of air or nitrogen gas and carbon dioxide, and a mixed gas having a carbon dioxide content of 3 to 20% by volume.
  • the initial pH may be adjusted by bubbling the standard solution with carbon dioxide.
  • the initial pH may be adjusted by adding dilute hydrochloric acid to the standard solution.
  • the method for producing another standard solution filling body includes filling a standard solution of a bicarbonate-containing preparation used in preparing a dialysate for hemodialysis into a sealed container, thereby providing a dialysate standard.
  • the bicarbonate-containing preparation is a dialysis solution
  • the standard solution is at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water
  • the structure prepared by mixing by the preset mixing ratio may be sufficient.
  • the standard solution of the bicarbonate-containing preparation is a standard solution of the dialysis solution, and contains acidic ions containing sodium ions, potassium ions, calcium ions, and magnesium ions.
  • a standard solution of the dialysate is prepared by mixing A agent, which is an aqueous solution of B, B agent containing bicarbonate, and water at a preset mixing ratio, or containing bicarbonate What is necessary is just the structure whose said standard solution of a formulation is a standard solution of the said B agent.
  • the above-described configuration can provide a technique capable of suppressing variations in dialysate concentration without being limited by the amount of preparation. , Has the effect.
  • FIG. 4 is a graph showing results of a comparative example with respect to the example of the standard liquid filling body shown in FIG.
  • FIG. 3 is a graph which shows the result of the change of the time-dependent pH of the typical example of other standard liquid filling bodies concerning this indication, and the result of a comparative example with respect to this, when standard liquid filling body is stored at room temperature.
  • FIG. 6 is a graph showing a result of a comparative example with respect to the example of the standard liquid filling body shown in FIG. 5 and a result of a change in pH with time when the standard liquid filling body is stored at room temperature.
  • a standard solution filling body and a manufacturing method thereof according to the present disclosure are a filling body in which a standard solution of a bicarbonate-containing preparation used for preparing a dialysate for hemodialysis is filled in a sealed container, It is made of a material having gas barrier properties.
  • a plurality of configurations can be employed in order to suppress variations in the concentration of the dialysate without being limited by the amount of preparation.
  • the initial pH after filling in the standard solution is lower than the pH of the bicarbonate-containing preparation to be prepared, or the standard solution reaches the capacity limit of the sealed container or is sealed.
  • capacitance limit of a container can be mentioned.
  • a sealed gas that fills a void in the sealed container together with a standard solution is filled, and the sealed gas is composed of air or nitrogen gas and carbon dioxide,
  • the standard solution includes a plurality of acid components that are weak acids and sodium ions, potassium ions, calcium ions, and magnesium ions; Containing a monovalent or divalent metal ion of a species, the content of the metal ion being equivalent to the standard when the composition of the bicarbonate-containing preparation to be prepared is used as a standard, and the inclusion of an acid component A composition having a composition in which the amount is greater than the reference; (3) a composition in which the standard solution has a reduced initial pH by bubbling carbon dioxide; and (4) a standard solution in which an acid is added.
  • the initial pH by being can be cited a structure such as those which are low.
  • the bicarbonate-containing preparation in the present disclosure may be any one containing bicarbonate (bicarbonate) and used for preparing a dialysate.
  • a typical example is the dialysate itself.
  • the dialysate is prepared by mixing A agent, which is an acidic aqueous solution containing sodium ions, etc., B agent containing bicarbonate, and water, the bicarbonate in the present disclosure B preparation is also contained as a containing formulation.
  • bicarbonate-containing preparation may be B agent or other dialysis preparation.
  • the dialysate standard solution filling body is a filling body in which a dialysate standard solution used when preparing a dialysate for hemodialysis is filled in an airtight container.
  • the dialysate standard solution to be filled is prepared by mixing at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water at a preset mixing ratio, Is a pre-set mixing ratio of agent A which is an acidic aqueous solution containing sodium ion, potassium ion, calcium ion and magnesium ion, agent B containing bicarbonate (bicarbonate) and water. And those prepared by mixing in the above.
  • the sealed container is made of a material having gas barrier properties.
  • the sealed container is filled with a sealed gas that fills the void in the sealed container together with the dialysate standard solution, and the sealed gas is composed of air or nitrogen gas and carbon dioxide, and the carbon dioxide content rate Is a mixed gas in the range of 3 to 20% by volume.
  • dialysate standard solution filling body is appropriately abbreviated as “standard solution filling body” for convenience of explanation, including not only this embodiment but also other embodiments, and the dialysate standard solution is appropriately used. It shall be abbreviated as “standard solution”.
  • the standard solution filled in the sealed container is prepared to have an appropriate composition (or appropriate electrolyte concentration and pH) according to the type of dialysate to be compared. Is done.
  • the configuration of the standard solution will be described using a general dialysate as an example.
  • a predetermined amount of agent A containing an electrolyte component and an acid component and agent B containing bicarbonate is used as a general dialysate.
  • a two-component mixed type prepared by mixing and diluting with water for dialysis.
  • the dialysate preparation method is not limited to such a two-component mixing type, and as described above, sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water are mixed in advance. Any material prepared by mixing at a ratio may be used.
  • the electrolyte component contained in the agent A is not particularly limited, and is appropriately selected according to the type of dialysate.
  • monovalent or 2 ions such as sodium ion, potassium ion, magnesium ion, calcium ion, etc.
  • the dialysate contains at least sodium ions, potassium ions, calcium ions, and magnesium ions among these electrolyte components, the standard solution according to the present embodiment also contains these electrolyte components. Is preferred.
  • the sodium ion contained in the standard solution is generally supplied from a sodium salt.
  • Specific sodium salts are not particularly limited, and examples include sodium chloride, sodium acetate, sodium citrate, sodium lactate, sodium gluconate, sodium succinate, and sodium malate. Only one kind of these sodium salts may be used, or two or more kinds may be used in appropriate combination. However, since sodium chloride is the most important salt essential in vivo, Preferably, at least sodium chloride is used.
  • the potassium ions contained in the standard solution are generally supplied from potassium salts.
  • Specific potassium salts are not particularly limited, and examples include potassium chloride, potassium acetate, potassium lactate, potassium citrate, potassium gluconate, potassium succinate, and potassium malate. Only one kind of these potassium salts may be used, or two or more kinds may be used in appropriate combination. However, since potassium chloride is positioned as a particularly important salt in the living body like sodium chloride, It is preferable that at least potassium chloride is used as the potassium salt.
  • the magnesium ions contained in the standard solution are generally supplied from magnesium salts.
  • Specific magnesium salts are not particularly limited, and examples include magnesium chloride, magnesium acetate, magnesium lactate, magnesium citrate, magnesium gluconate, magnesium succinate, and magnesium malate.
  • One of these magnesium salts may be used, or two or more may be used in appropriate combination.
  • These magnesium salts may be used in the form of hydrates.
  • Typical magnesium salts include magnesium chloride.
  • Calcium salts in the standard solution are generally supplied from calcium salts.
  • Specific calcium salts are not particularly limited, and examples include calcium chloride, calcium acetate, calcium lactate, calcium gluconate, calcium succinate, and calcium malate. Only one kind of these calcium salts may be used, or two or more kinds may be used in appropriate combination. These calcium salts may be used in the form of hydrates.
  • a typical calcium salt includes calcium chloride.
  • the chloride ion contained in the standard solution is generally supplied from a chloride salt.
  • Specific chloride salts are not particularly limited, and examples thereof include the above-described monovalent or divalent metal ion chloride salts, that is, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and the like.
  • These chloride salts of metal ions are preferably used because they can be a source of not only chloride ions but also sodium ions, potassium ions, magnesium ions, and calcium ions.
  • only 1 type of these chloride salts may be used, and 2 or more types may be used in combination as appropriate.
  • hydrochloric acid when hydrochloric acid is used as the acid component contained in the standard solution, this hydrochloric acid can also be a source of chloride ions.
  • the organic acid ion contained in the standard solution is not particularly limited, and generally a salt of each organic acid is used as the supply source, similarly to the chloride ion. Furthermore, when each organic acid is used as the acid component contained in the standard solution, these organic acids can also be a source of each organic acid ion.
  • the specific content of the electrolyte component contained in the standard solution is not particularly limited, and can be appropriately set according to various conditions.
  • content of sodium chloride is normally set to the maximum compared with content of each other electrolyte component. This is because the sodium chloride content is set according to the electrolyte concentration in the blood.
  • the specific content (concentration) of sodium chloride in the prepared dialysate (filled standard solution) is, for example, within the range of 75 mEq / L to 150 mEq / L, preferably based on the sodium ion content. Can be in the range of 80 mEq / L to 145 mEq / L.
  • the agent A may contain a sodium supply source such as sodium chloride so that the sodium ion content is within the above range in the standard solution.
  • a sodium supply source such as sodium chloride
  • electrolyte components other than sodium ions it is only necessary that the source of each ion is contained in the agent A so as to be in a desired range in the standard solution.
  • organic acids or inorganic acids that are common in the field of dialysate can be suitably used.
  • specific examples include acetic acid, citric acid, lactic acid, hydrochloric acid and the like.
  • These acid components may be anhydrides or hydrates.
  • Representative acid components include acetic acid or citric acid.
  • a salt of an acid component having a buffering action may be added for the purpose of stabilizing the pH.
  • Typical salts include sodium acetate and sodium citrate.
  • the specific content of the acid component contained in the standard solution is not particularly limited, and can be set as appropriate according to various conditions.
  • the acid component when the acid component is acetic acid, it can be within the range of 2 mEq / L to 6 mEq / L, preferably within the range of 3 mEq / L to 5 mEq / L, based on the acetate ion.
  • the acid component when the acid component is citric acid, it can be in the range of 1.5 mEq / L to 5 mEq / L, preferably in the range of 2 mEq / L to 3 mEq / L, based on citrate ions. .
  • the pH of the standard solution can be adjusted within a suitable range.
  • the acid component is acetic acid (in the case of a standard solution containing acetic acid)
  • the pH is adjusted within the range of 6.5 to 8.0, preferably within the range of 7.1 to 7.4. be able to.
  • the acid component is citric acid (in the case of a standard solution containing citric acid)
  • the pH is within the range of 7.0 to 8.5, preferably within the range of 7.5 to 8.0.
  • the agent A only needs to contain an acid component so as to be within the appropriate range as described above in the standard solution.
  • the agent A may contain components other than the electrolyte component and the acid component described above.
  • the prepared dialysate can contain various components that are acceptable as components of the dialysate in addition to the electrolyte component and the acid component.
  • Specific examples of other components include glucose (glucose) and pH adjusters.
  • Glucose can be added to the dialysate for the purpose of maintaining the blood sugar level of the hemodialysis subject.
  • the specific content (concentration) of glucose is not particularly limited, and can be appropriately set according to various conditions.
  • the typical glucose content is, for example, in the range of 0 to 2.5 g / L, preferably in the range of 1.0 to 2.0 g / L in the prepared dialysate (filled standard solution). Can be mentioned. Therefore, the agent A only needs to contain glucose so as to be within the appropriate range as described above in the standard solution.
  • the pH adjuster can be added separately from the acid component contained in the agent A for the purpose of adjusting the pH of the standard solution.
  • the standard solution may contain a pH adjuster separately from the acid component for the purpose of assisting the pH adjustment function of the standard solution by the acid component.
  • the pH adjuster include organic acids such as citric acid, oxalic acid, tartaric acid, maleic acid, ascorbic acid, oxaloacetic acid, gluconic acid, isocitric acid, malic acid, and pyruvic acid.
  • organic acids such as citric acid, oxalic acid, tartaric acid, maleic acid, ascorbic acid, oxaloacetic acid, gluconic acid, isocitric acid, malic acid, and pyruvic acid.
  • these organic acids may be used, or two or more types may be used in appropriate combination.
  • these organic acids may be used as salts such as sodium salt, potassium salt, magnesium salt and the like.
  • the specific content (concentration) of the pH adjuster is not particularly limited.
  • the pH adjuster can adjust the pH of the prepared dialysis solution (filled standard solution) within a suitable range and does not affect the functions of the electrolyte component and acid component described above (or these). It is only necessary to add an amount that does not interfere with the function of the components. Therefore, the pH adjuster may be contained in the agent A so that the pH of the standard solution can be adjusted and the amount does not affect the functions of the electrolyte component and the acid component.
  • bicarbonate (bicarbonate) contained in the B agent examples include sodium bicarbonate (sodium bicarbonate).
  • a bicarbonate other than sodium bicarbonate may be used, but the bicarbonate contained in the agent B is preferably only sodium bicarbonate.
  • the specific content of the bicarbonate is not particularly limited, and can be appropriately set according to various conditions. Generally, in the prepared dialysis solution (filled standard solution), it can be in the range of 15 mEq / L to 45 mEq / L, preferably in the range of 25 mEq / L to 40 mEq / L.
  • the B agent may be composed of at least a bicarbonate such as sodium hydrogen carbonate, but may contain other components.
  • examples of other components include sodium chloride.
  • the content of other components is not particularly limited, and can be appropriately set according to various conditions. Therefore, in B agent, other components should just be added to such an extent that the function of bicarbonate is not affected.
  • agent A is formulated as an acidic liquid (aqueous solution) containing at least the electrolyte component and the acid component described above.
  • agent B may be formulated as a solid (for example, a powder) or as a liquid (aqueous solution). It may be formulated. Even when the agent B is liquid, the concentration of bicarbonate is not particularly limited. When the bicarbonate contained in the agent B is sodium hydrogen carbonate, for example, it can be in the range of 40 to 80 g / L, preferably in the range of 60 to 80 g / L.
  • the standard solution filled in the sealed container is preferably prepared by mixing the above-mentioned agent A and agent B and diluting with dialysis water.
  • the standard solution may be prepared in the same manner as the dialysis solution actually prepared and then filled in the sealed container.
  • the acid component is citric acid
  • the pH of a general dialysate is usually set in the range of 7.4 to 8.0. Therefore, the pH of the standard solution may be adjusted within this range.
  • the specific method for preparing the standard solution including the adjustment of pH is not particularly limited, and may be the same as the general method for preparing a dialysis solution.
  • the specific type of the closed container filled with the standard solution described above is not particularly limited.
  • a known container can be suitably used as long as it has a sealing property and a gas barrier property that can stably hold the filled standard solution and the sealed gas described later.
  • a glass container whose container body is made of glass can be cited.
  • Specific examples of the glass container include a vial, an ampoule, and a cartridge. It is necessary to prepare a large amount of dialysate, but the standard solution used as a standard for preparing dialysate may be a small volume. Therefore, a small volume glass container used for injections such as vials or ampoules is preferably used. be able to. Depending on the use conditions of the standard solution, a syringe can be used as a glass container.
  • a stopper member is used to hermetically seal the opening.
  • the specific stopper member is not particularly limited, and a known stopper member that does not substantially affect the standard solution and can suitably hermetically seal the opening of a vial or the like is preferably used. Can be used.
  • a known rubber stopper, silicone stopper, cork stopper, or the like can be suitably used as the stopper member.
  • a cap made of aluminum or an alloy thereof can be used in combination.
  • a known resin container (resin container) can be suitably used in addition to the glass container.
  • the container body may be formed of a hard resin material, or may be formed of a soft resin material having flexibility or flexibility.
  • a known stopper member for hermetically sealing the opening may be used in the same manner as the vial.
  • the capacity of the sealed container is not particularly limited.
  • the standard solution needs to have such an amount that the concentration of the electrolyte component, acid component, and bicarbonate (and other components) contained in the dialysate can be confirmed. Therefore, the capacity of the sealed container only needs to have a capacity that is equal to or larger than the amount of the standard solution necessary for confirming the concentration of each component.
  • the sealed gas is filled in addition to the standard liquid, and the volume of the sealed gas is less than the volume of the standard liquid (the volume smaller than the standard liquid). . Therefore, the capacity of the sealed container only needs to have a capacity in consideration of the filling amount of the sealed gas in addition to the required amount of the standard solution.
  • at least sodium ions, potassium ions, calcium ions, magnesium ions, hydrogen carbonate and water are mixed at a preset mixing ratio (as described above, a preferred example)
  • a standard solution is prepared by mixing the agent A and the agent B and diluting with dialysis water, and this standard solution is prepared (manufactured) by filling the hermetically sealed container and sealing hermetically.
  • the sealed container is filled with a sealed gas having a volume smaller than the volume of the standard solution.
  • the sealed gas filled in the sealed container may be air or a mixed gas of nitrogen and carbon dioxide (carbon dioxide), but the upper limit of the carbon dioxide content in the mixed gas is 20% by volume or less. It has become. Thereby, since volatilization of bicarbonate from the standard solution can be effectively suppressed, an increase in pH with time can also be suppressed. Moreover, since the content of carbon dioxide in the sealed gas is not excessive, it is possible to effectively suppress a significant drop in pH resulting from the dissolution of carbon dioxide.
  • carbon dioxide nitrogen and carbon dioxide
  • the pH of the standard solution is preferably the lower limit (for example, if the acid component is a citric acid component in the standard solution filling body, 7. There is a risk of falling below 4).
  • the lower limit of the carbon dioxide content in the mixed gas may be 3% by volume or more.
  • the pH of the standard solution may exceed a preferable upper limit (for example, 8.0 if the acid component is a citric acid component) in the standard solution filling body. If the pH of the standard solution exceeds a predetermined range, the concentration of each component of the standard solution is deviated from the predetermined range, as in the case of a decrease in pH. As a result, the standard solution cannot be used.
  • a preferable upper limit for example, 8.0 if the acid component is a citric acid component
  • the filling rate (filled volume) of the sealed gas in the sealed container is smaller than the filling rate of the standard solution. It is preferable. Specifically, when the capacity of the closed container is 100% by volume, the filling rate of the standard solution may be 50% by volume or more, preferably in the range of 70 to 99% by volume, and 80 to 95% by volume. The range can be mentioned more preferably. Therefore, the filling rate of the enclosed gas may be less than 50% by volume, preferably in the range of 1 to 30% by volume, and more preferably in the range of 5 to 20% by volume. When the filling rate of the filled gas is higher than the filling rate of the standard solution, carbon dioxide in the filled gas may be excessively dissolved in the standard solution, and the pH of the standard solution may fall below a preferable lower limit value in the standard solution filled body.
  • the method of filling the standard solution and the enclosed gas in the sealed container is not particularly limited, and a known method in the field of dialysate or drug packaging can be suitably used.
  • a known method in the field of dialysate or drug packaging can be suitably used.
  • the method for preparing the mixed gas that is the sealed gas there is no particular limitation on the method for preparing the mixed gas that is the sealed gas, and a known method can be suitably used.
  • the method of filling the sealed container with the standard solution and the sealed gas and sealing and sealing and a known method can be suitably used.
  • the standard solution filling body according to the present embodiment can be used when confirming each component contained in the dialysate when preparing the dialysate at the dialysis site. Specifically, for example, agent A and agent B are mixed at the dialysis site and diluted with dialysis water to prepare a dialysate, and the dialysate is sampled to measure the concentration of the electrolyte component. Further, the standard solution filling body is opened, the standard solution is sampled, and the concentration of the electrolyte component is measured.
  • the dialysate is prepared with a suitable concentration of the electrolyte component.
  • the concentration of the electrolyte component of the dialysate is adjusted as appropriate, and the concentration comparison is repeated between the dialysate and the standard solution.
  • the method for measuring the concentration of the electrolyte component used at this time is not particularly limited, and a commercially available measuring device or a known measuring method may be used.
  • the pH of the prepared dialysis solution can be compared with the pH of the standard solution.
  • the pH measurement method used at this time is not particularly limited, and a commercially available pH measurement device, a pH measurement method, or the like may be used.
  • the standard solution filling body according to the present embodiment can be stored at room temperature for a predetermined storage period. As shown in the examples described later, the standard solution filling material according to the present embodiment can be stored at room temperature for at least two weeks. Further, as shown in the examples described later, since the pH can be maintained within a predetermined range even when stored at 40 ° C. under accelerated conditions for 2 weeks, the standard liquid filling material according to the present embodiment is about 1 month. It is also possible to save. Furthermore, it is possible to store for about one year by appropriately setting the storage conditions.
  • the room temperature here may be within the range of the normal temperature (20 ⁇ 15 ° C., 5 to 35 ° C.) defined by JIS.
  • the standard solution filling body according to the present embodiment can be suitably used for the preparation of the dialysate, but the method of using the standard solution filling body is not limited to the preparation of the dialysate, for example, It can be used as one of the components of the dialysate preparation kit. Therefore, the present embodiment also includes a dialysate preparation kit including a standard solution filling body or an evaluation kit for evaluating the quality of the dialysate.
  • the dialysate preparation kit or the evaluation kit only needs to include at least the standard solution filling described above, and the other elements constituting these kits are not particularly limited.
  • the above-mentioned agent A and agent B may be made into a kit together with the standard solution filler.
  • an instrument for sampling the dialysate an instrument (or measuring instrument) used for measuring the concentration of the electrolyte component, an instrument used for measuring pH (along with a standard solution filling body)
  • a measuring device or the like may be made into a kit.
  • the present embodiment also includes a manufacturing method (manufacturing method) of the standard liquid filling body described above.
  • a dialysate standard solution is prepared by filling a dialysate standard solution used in preparing a dialysate for hemodialysis into a sealed container.
  • a method for producing a filler wherein a standard solution is prepared by mixing at least a sodium ion, a potassium ion, a calcium ion, a magnesium ion, a bicarbonate and water at a preset mixing ratio, and sealed.
  • the container is made of a material having a gas barrier property, and the sealed gas filling the gap in the sealed container is filled into the sealed container together with the standard solution so that the volume is smaller than that of the standard solution.
  • a configuration in which the gas mixture is composed of nitrogen gas and carbon dioxide and the carbon dioxide content is in the range of 3 to 20% by volume can be mentioned.
  • the standard solution contains an agent A which is an acidic aqueous solution containing sodium ions, potassium ions, calcium ions and magnesium ions, and a bicarbonate. It can be prepared by mixing the B agent to be mixed with water at a preset mixing ratio.
  • agent A is an acidic aqueous solution containing sodium ions, potassium ions, calcium ions and magnesium ions, and a bicarbonate. It can be prepared by mixing the B agent to be mixed with water at a preset mixing ratio.
  • the dialysate is exemplified as the bicarbonate-containing preparation to be filled in the closed container.
  • the bicarbonate-containing preparation includes bicarbonate (carbonic acid). Hydrogen salt) may be used as long as it is used for the preparation of dialysate. Therefore, also in the present embodiment, the B agent may be filled in the closed container as a bicarbonate-containing preparation, or another bicarbonate-containing preparation may be filled in the sealed container.
  • the dialysate standard solution filling body is a filling body in which a dialysate standard solution used for preparing a dialysate for hemodialysis is filled in an airtight container. is there.
  • the dialysate standard solution to be filled is prepared by mixing at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate (bicarbonate) and water at a preset mixing ratio.
  • agent A which is an acidic aqueous solution containing sodium ion, potassium ion, calcium ion and magnesium ion
  • agent B containing bicarbonate (bicarbonate) containing bicarbonate (bicarbonate)
  • the sealed container is made of a material having gas barrier properties.
  • the standard solution is filled in the airtight container until the capacity limit of the airtight container or until the capacity limit of the airtight container is not exceeded.
  • the specific configuration of the sealed container used for the standard solution filling body according to the present embodiment is not particularly limited, and the sealed container described in the first embodiment can be suitably used. That is, as the sealed container, a known container can be suitably used as long as it has a sealing property and a gas barrier property that can stably hold the filled standard solution. Therefore, in this embodiment, a specific description of the sealed container is also omitted.
  • the standard solution filling body according to the present embodiment as will be described later, the standard solution is filled so that the inside of the sealed container is almost filled with the standard solution. Therefore, the capacity of the sealed container only needs to have a capacity obtained by adding a predicted amount to the required amount of the standard solution.
  • at least sodium ions, potassium ions, calcium ions, magnesium ions, hydrogen carbonate and water are mixed at a preset mixing ratio (as described above, a preferred example)
  • a standard solution is prepared by mixing the agent A and the agent B and diluting with dialysis water, and this standard solution is prepared (manufactured) by filling the hermetically sealed container and sealing hermetically. At this time, the standard solution is filled in the hermetic container until the capacity limit of the hermetic container or until the capacity limit of the hermetic container is exceeded.
  • the sealed solution when the total volume of the sealed container is 100% by volume, the sealed solution may be filled with the standard solution so that the filling rate is ideally within the range of 100% by volume. preferable.
  • the standard solution when it is difficult to fill the standard solution in the closed container so that the filling rate of the standard solution is 100% by volume by the shape of the closed container, the sealing method, the filling method according to the closed container, etc. (or There is a case where it is not necessary to fill to 100% by volume). Therefore, in the present embodiment, the standard solution may be filled in the sealed container so that the lower limit of the filling rate of the standard solution is 80% by volume or more, and the standard solution is filled so as to be 90% by volume or more. It is preferable to fill the standard solution so as to be 95% by volume or more.
  • glass vials are used as the sealed containers.
  • the container body of a general vial has a cylindrical shape having substantially the same inner diameter from the bottom to the top of the container, but a shoulder with a narrower inner diameter than the container body is formed at the top of the container, An opening that is hermetically sealed by a plug member is provided at the upper end of the part.
  • the standard solution is preferably filled with the standard solution including the internal space from the shoulder to the opening in addition to the internal space of the cylindrical container body. The internal space may not be filled until the standard solution is filled.
  • the inner diameter of the shoulder is smaller than the container body, and the height of the shoulder is significantly smaller than the height of the container body. Accordingly, it can be said that the capacity in the shoulder is sufficiently smaller than the capacity in the container main body, so that the capacity in the shoulder can be regarded as an error range when viewed from the total capacity of the sealed container.
  • the standard solution faces a very small space with a very small area. Therefore, it can be considered that almost no release of carbon dioxide (generated by decomposition of bicarbonate) from the standard solution into the voids.
  • the state where at least the container body is filled has reached the capacity limit, and it can be said that the internal space of the shoulder portion is a space outside the capacity limit of the vial. Therefore, if the sealed container is a vial, it will not overflow beyond the capacity limit (internal space of the container body) of the vial (sealed container) if the container body is filled and the standard solution reaches a part of the shoulder.
  • the standard solution is filled to the state. Furthermore, the standard solution can be filled until the interior space of the shoulder is filled. In this case, the standard solution is filled up to the capacity limit of the vial (sealed container) (substantially full capacity of the sealed container).
  • a glass ampoule As the closed container, a glass ampoule can be used as described above.
  • a general ampoule has a cylindrical container main body similar to a vial, and a head (neck part) positioned at the top of the container main body and having a significantly smaller inner diameter than that of the container main body and a melt-sealed tip. . Since the head (neck) is folded during use, the inside of the cylindrical container body constitutes substantially the entire capacity of the sealed container.
  • the state where the container body is filled has reached the capacity limit, and it can be said that the internal space of the head (neck) is a space outside the capacity limit of the ampoule. Therefore, if the sealed container is an ampoule, if the standard solution fills the container body and the standard solution reaches a part of the head (neck), the standard solution will not exceed the capacity limit of the ampoule (sealed container). Will be filled. Furthermore, it is possible to fill the standard solution to the limit as long as it does not interfere with melting and sealing the tip of the head. In this case, the standard solution is filled up to the capacity limit of the ampoule (sealed container).
  • the sealed container is composed of the “main body part” of the container and the “small volume part” such as the shoulder or the head (the part having a smaller internal volume than the main body part), such as the aforementioned vial or ampoule.
  • the filling rate of the standard solution in the main body part is 100% by volume. It is preferable that it exceeds.
  • the standard solution exceeds the volume limit of the main body portion and reaches a small volume portion such as the shoulder portion or the head portion. Therefore, the volume of the void portion remaining inside the small capacity portion can be sufficiently reduced.
  • the method of filling the standard solution in the sealed container is not particularly limited, and a known method in the field of dialysate or drug packaging can be suitably used.
  • the method of filling the airtight container with the standard solution and hermetically sealing is not particularly limited, and a known method can be suitably used.
  • the use of the standard liquid filling material according to the present embodiment is the same as that of the first embodiment, and a specific description thereof will be omitted.
  • the present embodiment includes the above-described method for manufacturing the standard liquid filling body (manufacturing method).
  • a dialysate standard solution is prepared by filling a dialysate standard solution used in preparing a dialysate for hemodialysis into a sealed container.
  • a method for producing a filler wherein a standard solution is prepared by mixing at least a sodium ion, a potassium ion, a calcium ion, a magnesium ion, a bicarbonate and water at a preset mixing ratio, and sealed.
  • the container is composed of a material having a gas barrier property, and the standard solution is filled in the sealed container until the capacity limit of the sealed container or until it does not overflow beyond the capacity limit of the sealed container. be able to.
  • the dialysate is exemplified as the bicarbonate-containing preparation to be filled in the closed container.
  • the carbonate-containing preparation may contain any bicarbonate (bicarbonate) and can be used for preparing a dialysate. Therefore, also in this Embodiment 2, B agent may be filled into a closed container as a bicarbonate-containing preparation, or another bicarbonate-containing preparation may be filled into a closed container.
  • the dialysis fluid standard solution filling body is a filling in which a dialysis fluid standard solution used when preparing a dialysis fluid for hemodialysis is filled in an airtight container, as in the first or second embodiment. Is the body.
  • the dialysate standard solution to be filled is prepared by mixing at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water at a preset mixing ratio, Is a pre-set mixing ratio of agent A which is an acidic aqueous solution containing sodium ion, potassium ion, calcium ion and magnesium ion, agent B containing bicarbonate (bicarbonate) and water. And those prepared by mixing in the above. Further, the sealed container is made of a material having gas barrier properties. The initial pH after filling in the dialysate standard solution is lower than 0.4 in the dialysate to be prepared (reference pH).
  • “Initial pH” in the present embodiment means pH in a period from immediately after filling the standard solution into the sealed container to the first day.
  • the method for setting the initial pH of the standard solution to be lower than the reference pH within 0.4 is not particularly limited, but typically (1) supply of weak acid and monovalent or divalent metal ion to the standard solution
  • the content of the metal ion is equivalent to this standard and the content of the acid component is based on the content of the dialysate to be prepared.
  • Examples of the method include adjusting the content of the metal salt of the weak acid so as to exceed the standard, (2) a method of bubbling the standard solution with carbon dioxide, and (3) a method of adding a small amount of acid.
  • agent A contains an electrolyte component and an acid component.
  • acetic acid, citric acid, lactic acid, and hydrochloric acid can be used as the acid component
  • the electrolyte component includes a plurality of types of monovalent or divalent ions including sodium ion, potassium ion, calcium ion, and magnesium ion.
  • metal ions include a plurality of types of monovalent or divalent ions including sodium ion, potassium ion, calcium ion, and magnesium ion.
  • metal ions include a plurality of types of monovalent or divalent ions including sodium ion, potassium ion, calcium ion, and magnesium ion.
  • metal ions include a plurality of types of monovalent or divalent ions including sodium ion, potassium ion, calcium ion, and magnesium ion.
  • metal ions include a supply source of these metal ions.
  • the composition of the standard solution is adjusted so that the content of metal ions is equivalent to this standard and the content of the acid component is larger than this standard.
  • the metal salt of the weak acid becomes a factor that raises the pH of the standard solution. Therefore, by increasing the content of the weak acid and decreasing the metal salt of the weak acid, and further increasing the amount of other sources of metal ions, the content of the metal ions is kept equal to the standard. adjust.
  • the content of metal ions in the composition of the standard solution is compared with the content of the reference composition.
  • the content of the acid component in the composition of the standard solution is adjusted to be larger than the content of the reference composition.
  • anhydrous citric acid is used as the acid component of the agent A, and sodium citrate (hydrate) and sodium chloride are used as the source of sodium ions. Therefore, the content of anhydrous citric acid is increased, the content of sodium citrate is decreased, and the content of sodium chloride is increased in order to make the content of sodium ions substantially equivalent to the standard. Thus, the initial pH of the standard solution can be lowered within 0.4.
  • a weak acid when viewed as a component in the standard solution, a weak acid can behave as a pH buffered acid, and any one of the metal ions can behave as a pH buffered conjugate base.
  • anhydrous citric acid can behave as a weak acid in a pH buffer system and sodium citrate hydrate can behave as a conjugate base in a pH buffer system. Therefore, not only can the initial pH be lowered in anticipation of an increase in pH, but also the pH of the dialysate standard solution can be made difficult to increase due to the pH buffering action.
  • the specific kind of weak acid is not specifically limited, In addition to the citric acid illustrated in an Example, the acetic acid or lactic acid etc. which were demonstrated in the said Embodiment 1 can also be used.
  • the kind of metal ion is not specifically limited, In addition to the sodium salt illustrated in an Example, potassium salt etc. can be used.
  • sodium ions or potassium ions can be strong bases, and it is easy to construct a pH buffer system by combining with weak acids.
  • sodium chloride is the most important salt essential in vivo, and at least sodium chloride is preferably used as a supply source of sodium ions. Therefore, sodium ion is more preferably used as the metal ion.
  • a metal salt of a weak acid such as sodium citrate may not be included.
  • Example 9 corresponds to the method (2).
  • the initial pH of the standard solution can be adjusted low by adding an acid to the prepared standard solution.
  • the kind of acid to be added is not particularly limited, and any acid may be used as long as it does not affect the components contained in the standard solution, such as decomposition or alteration.
  • strong acids such as hydrochloric acid, nitric acid, sulfuric acid, etc .
  • acid components that can be contained in the agent A acetic acid, citric acid, lactic acid, hydrochloric acid, etc.
  • organic acids described as pH adjusters in the first embodiment Citric acid, oxalic acid, tartaric acid, maleic acid, ascorbic acid, oxaloacetic acid, gluconic acid, isocitric acid, malic acid, pyruvic acid, etc.
  • Only one type of these acids may be used, but two or more types may be used in appropriate combination.
  • the method (3) since it is better to lower the initial pH satisfactorily with a small amount as much as possible, strong acids such as hydrochloric acid, nitric acid, and sulfuric acid are preferably used.
  • the electrolyte component is included in the standard solution.
  • Hydrochloric acid is preferably used.
  • the acid concentration is not particularly limited as long as the initial pH can be adjusted to be lower than the reference pH within 0.4.
  • dilute hydrochloric acid is preferably used from the viewpoint of easy pH adjustment by dropping.
  • Example 10 corresponds to the method (3).
  • the degree of lowering the initial pH of the standard solution is 0.4 or less than the reference pH as described above. preferable. If the initial pH is lowered beyond 0.4, even if the pH of the filled standard solution rises during storage, it may become lower than the reference pH and cannot be appropriately used as the standard solution.
  • the standard solution is citric acid
  • 7.85 can be set as the reference pH of the dialysate as in Comparative Example 13 described later.
  • the initial pH of the standard solution is adjusted to less than 7.85 and not less than 7.45, preferably about 7.5 (for example, in the range of 7.45 to 7.65), as in Examples 7 to 10.
  • the maximum pH during storage can be maintained at around 7.85 (for example, within the range of 7.7 to 8.0). However, as in Comparative Example 14, if the initial pH of the standard solution is lowered beyond 0.4, the maximum pH during storage will remain low.
  • the filling rate of the standard solution is preferably 70% or more, and 75% or more. Is more preferable.
  • the initial pH of the standard solution is adjusted.
  • the pH can be lowered within 0.4 from the reference pH (for example, see Examples 1 to 4 described later, the results of the first day in FIGS. 1 and 2, etc.). Therefore, it can be said that the configuration disclosed in the first embodiment is one mode of the configuration disclosed in the third embodiment.
  • the dialysate is exemplified as the bicarbonate-containing preparation to be filled in the sealed container.
  • the bicarbonate-containing preparation may contain any bicarbonate (bicarbonate) and can be used for preparing a dialysate. Therefore, also in this Embodiment 3, B agent may be filled into a closed container as a bicarbonate-containing preparation, or another bicarbonate-containing preparation may be filled into a sealed container.
  • agent A sodium chloride 183 g / L, potassium chloride 5.5 g / L, calcium chloride dihydrate 8.1 g / L, magnesium chloride hexahydrate 3.8 g / L, anhydrous citric acid 3.9 g / L , And sodium citrate hydrate containing 1.4 g / L, and B agent containing sodium chloride 2.35 g / L and sodium bicarbonate 5.92 g / L was used.
  • a 1 L standard solution was prepared by mixing and diluting 27.2 mL of agent A and 49.7 mL of agent B in dialysis water.
  • Example 1 A 10 mL capacity glass vial is filled with the above-mentioned standard solution at 80% by volume, and a mixed gas of 12% by volume of carbon dioxide and 88% by volume of air is used as the enclosed gas, which is 20% by volume. Then, it was hermetically sealed with a rubber stopper with an aluminum cap. This produced (manufactured) the standard solution filling body of Example 1.
  • the standard solution filling was stored at room temperature (room temperature (25 ° C. ⁇ 15 ° C.)) for a maximum of 2 weeks.
  • room temperature room temperature (25 ° C. ⁇ 15 ° C.)
  • the pH of the standard solution before filling was measured, and the pH of the standard solution after 1 day of storage, 1 week after storage, and 2 weeks after storage. was measured respectively.
  • the result is shown by the graph of the black rhombus symbol of FIG. 1 and FIG.
  • the dialysate standard solution before filling had a pH of 7.8.
  • Example 2 A standard liquid filling material of Example 2 was produced (manufactured) in the same manner as in Example 1 except that 19% by volume of carbon dioxide and 81% by volume of air were used as the enclosed gas, and before filling, The pH of the standard solution after one day of storage, one week after storage and two weeks after storage was measured. The result is shown by a black circle symbol graph in FIG. The pH of the standard solution before filling was 7.8.
  • Comparative Example 1 A standard liquid filling material of Comparative Example 1 was produced (manufactured) in the same manner as in Example 1 except that only air (100% by volume of air) was used as the sealing gas, and was stored before filling and after 1 day of storage. The pH of the standard solution after one week and two weeks after storage was measured. The result is shown by the graph of the white rectangular symbol in FIG. The pH of the standard solution before filling was 7.8.
  • Comparative Example 2 A standard liquid filling material of Comparative Example 2 was produced (manufactured) in the same manner as in Example 1 except that nitrogen (nitrogen 100% by volume) was used as the sealing gas, and before filling, 1 day after storage, and Storage 1 After a week, the pH of the standard solution after 2 weeks of storage was measured. The result is shown in the graph of the white triangle symbol in FIG. The pH of the standard solution before filling was 7.9.
  • Comparative Example 3 A standard liquid filling material of Comparative Example 3 was produced (manufactured) in the same manner as in Example 1 except that only carbon dioxide (100% by volume of carbon dioxide) was used as the sealing gas, and before filling and one day after storage. The pH of the standard solution after 1 week of storage and 2 weeks after storage was measured. The result is shown by the white circle symbol graph of FIG. The pH of the standard solution before filling was 7.9.
  • Example 3 The standard liquid filling material of Example 3 is produced (manufactured) in the same manner as in Example 1 except that the storage temperature is set to 40 ° C. instead of room temperature.
  • the pH of the standard solution was measured before filling, after 1 day of storage, after 1 week of storage, and after 2 weeks of storage. The result is shown by the graph of the black diamond symbol in FIG.
  • the pH of the standard solution before filling was 7.8.
  • Example 4 The standard liquid filling material of Example 4 is produced (manufactured) in the same manner as in Example 2 except that the storage temperature is set to 40 ° C. instead of room temperature (therefore, the enclosed gas is 19 volumes of carbon dioxide.
  • the pH of the standard solution was measured before filling, after 1 day of storage, after 1 week of storage, and after 2 weeks of storage, respectively. The result is shown by a black circle symbol graph in FIG.
  • the pH of the standard solution before filling was 7.8.
  • Comparative Example 4 The standard liquid filling material of Comparative Example 4 is produced (manufactured) in the same manner as in Comparative Example 1 except that the storage temperature is set to 40 ° C. instead of room temperature (therefore, only air is used as the sealing gas). ), The pH of the standard solution before filling, after 1 day of storage, after 1 week of storage, and after 2 weeks of storage was measured. The result is shown by the graph of the white rectangular symbol in FIG. The pH of the standard solution before filling was 7.8.
  • Comparative Example 5 The standard liquid filling material of Comparative Example 5 is produced (manufactured) in the same manner as in Comparative Example 2 except that the storage temperature is 40 ° C. instead of room temperature (therefore, only nitrogen is used as the sealing gas).
  • the pH of the standard solution before filling, after 1 week of storage, and after 2 weeks of storage was measured. The result is shown in the graph of the white triangle symbol of FIG. The pH of the standard solution before filling was 7.9.
  • Comparative Example 6 The standard liquid filling material of Comparative Example 6 is produced (manufactured) in the same manner as in Comparative Example 3 except that the storage temperature is set to 40 ° C. instead of room temperature (therefore, only carbon dioxide is used as the sealing gas).
  • the pH of the standard solution was measured before filling, after 1 week of storage, and after 2 weeks of storage. The result is shown by a white circle symbol graph in FIG. The pH of the standard solution before filling was 7.9.
  • Example 5 A 10 mL capacity glass vial was filled with the above-mentioned standard solution so as to be almost 100% by volume, and hermetically sealed with a rubber stopper with an aluminum cap. This produced (manufactured) the standard solution filling body of Example 5.
  • the standard solution filling was stored at room temperature (room temperature (25 ° C. ⁇ 15 ° C.)) for a maximum of 4 weeks.
  • room temperature room temperature (25 ° C. ⁇ 15 ° C.)
  • LAQUAtwin® B712 commercially available pH meter
  • the pH of each dialysate standard solution was measured. The result is shown by the graph of the black rhombus symbol of FIG. 5 and FIG.
  • the pH of the standard solution before filling was 7.8.
  • Comparative Example 7 Standard solution filling material of Comparative Example 7 in the same manner as in Example 5 except that the glass vial was filled with the standard solution to 80% by volume and air was filled to 20% by volume. was prepared (manufactured), and the pH of the standard solution was measured before filling, 1 day after storage, 1 week after storage, 2 weeks after storage, and 4 weeks after storage. The result is shown by the graph of the white rectangular symbol in FIG. The pH of the standard solution before filling was 7.8.
  • Comparative Example 8 A standard solution filling material of Comparative Example 8 was produced (manufactured) in the same manner as in Comparative Example 7 except that nitrogen was filled instead of air so as to be 20% by volume, and was stored before filling and after 1 day of storage. The pH of the standard solution after one week and two weeks after storage was measured. The result is shown in the graph of the white triangle symbol of FIG. The pH of the standard solution before filling was 7.9.
  • Comparative Example 9 A standard liquid filling material of Comparative Example 9 was produced (manufactured) in the same manner as in Comparative Example 7 except that carbon dioxide was charged in an amount of 20% by volume instead of air, and before filling, one day after storage, After 1 week of storage, the pH of the standard solution after 2 weeks of storage was measured. The result is shown by a white circle symbol graph in FIG. The pH of the standard solution before filling was 7.9.
  • Example 6 The standard solution filling material of Example 6 was produced (manufactured) in the same manner as in Example 5 except that the storage temperature was set to 40 ° C. instead of room temperature, and before filling, one week after storage, and storage 2 The pH of the standard solution after a week was measured. The result is shown in the graph of the black diamond symbol in FIG. The pH of the standard solution before filling was 7.7.
  • Comparative Example 10 The glass vial is filled with 70% by volume of the standard solution and 30% by volume of air, and the storage temperature is 40 ° C. instead of room temperature.
  • the standard solution filling material of Comparative Example 10 was produced (manufactured), and the pH of the standard solution before filling, after 1 week of storage, after 2 weeks of storage, and after 4 weeks of storage was measured. The result is shown by the graph of the white rectangular symbol in FIG. The pH of the standard solution before filling was 7.7.
  • Comparative Example 11 A standard solution filling body of Comparative Example 10 is produced (manufactured) in the same manner as in Comparative Example 8 except that the storage temperature is set to 40 ° C. instead of room temperature, and nitrogen is filled together with the standard solution.
  • the pH of the standard solution was measured before filling, after 1 week of storage, and after 2 weeks of storage. The result is shown by a white circle symbol graph in FIG.
  • the pH of the standard solution before filling was 7.8.
  • Comparative Example 12 A standard solution filling material of Comparative Example 12 is produced (manufactured) in the same manner as in Comparative Example 9 except that the storage temperature is set to 40 ° C. instead of room temperature (accordingly, carbon dioxide is filled together with the standard solution).
  • the pH of the standard solution was measured before filling, after 1 week of storage, and after 2 weeks of storage. The result is shown in the graph of the white triangle symbol of FIG. The pH of the standard solution before filling was 7.9.
  • Example 6 and Comparative Examples 10 to 6 since the standard solution filling material was stored at 40 ° C., the conditions for accelerating the pH increase of the dialysate standard solution were higher than those stored at room temperature. Under such acceleration conditions, when air is filled with the standard solution as in Comparative Example 10, or when nitrogen is filled with the standard solution as in Comparative Example 11, the pH exceeds 8.0, When carbon dioxide was charged together with the standard solution as in Comparative Example 12, the pH was lower than 7.4. On the other hand, in Example 6, the pH of the dialysate standard solution does not change excessively and is maintained within the range of pH 7.4 to 8.0 even when stored for 2 weeks under accelerated conditions. I was able to.
  • agent A sodium chloride 183.0 g / L, potassium chloride 5.50 g / L, calcium chloride dihydrate 8.10 g / L, magnesium chloride hexahydrate 3.80 g / L, anhydrous citrate 3.9 g / L and sodium citrate hydrate 1.4 g / L were used, and as B agent, sodium chloride 23.5 g / L and sodium bicarbonate 59.2 g / L were used.
  • a 1 L standard solution was prepared by mixing and diluting 27.2 mL of agent A and 49.7 mL of agent B in dialysis water.
  • the standard solution filling was stored at room temperature (room temperature (25 ° C. ⁇ 15 ° C.)) for 2 weeks. Using the pH meter, the pH of the standard solution was measured several times during the storage period. The result is shown in the graph of the white triangle symbol of FIG. The maximum pH value of the standard solution during the storage period was 8.13 (after one week of storage).
  • Example 7 Except for the content of sodium chloride in agent A being 183.6 g / L, the content of anhydrous citric acid being 4.06 g / L, and the content of sodium citrate hydrate being 0.35 g / L, A standard solution was prepared in the same manner as in Comparative Example 13. The initial pH of this standard solution was measured and found to be 7.55. As described above, when the reference pH is 7.85, in this embodiment, the initial pH of the standard solution is adjusted so as to decrease by about 0.3 from the reference value.
  • Example 8 The content of sodium chloride in agent A was 183.8 g / L, the content of anhydrous citric acid was 4.70 g / L, and sodium citrate hydrate was not contained (content 0 g / L).
  • a standard solution was prepared. The initial pH of this standard solution was measured and found to be 7.58. As described above, when the reference pH is set to 7.85, in this example, the initial pH of the standard solution is adjusted so as to decrease by about 0.27 from the reference value.
  • Comparative Example 14 The content of sodium chloride in agent A was 183.8 g / L, the content of anhydrous citric acid was 7.80 g / L, and sodium citrate hydrate was not contained (content 0 g / L).
  • a standard solution was prepared. The initial pH of this standard solution was measured and found to be 7.30. As described above, when the reference pH is 7.85, in this comparative example, the initial pH of the standard solution is adjusted so as to be lowered by about 0.55 from the reference value.
  • Example 9 A standard liquid filling material of Example 9 was produced (manufactured) in the same manner as in Example 7 except that the storage temperature was set to 40 ° C. instead of room temperature, and before filling, 1 week after storage, and Storage 2 After 4 weeks, 4 weeks after storage, 8 weeks after storage, and 12 weeks after storage, the pH of the standard solution was measured. The result is shown by the dotted line graph of the black diamond symbol in FIG. The pH of the standard solution before filling (initial pH) was 7.55, and the maximum pH value of the standard solution during the storage period was 7.95 (after one week of storage).
  • Example 10 A standard solution having the same composition as in Comparative Example 13 was prepared, and the standard solution was bubbled with carbon dioxide before filling into a 10 mL glass vial.
  • the initial pH of the standard solution after bubbling was 7.61.
  • the reference pH is 7.85, in this example, the initial pH of the standard solution is lowered by about 0.24 from the reference value by bubbling.
  • Example 10 a standard solution filling body of Example 10 was produced (manufactured) using the standard solution after bubbling.
  • the pH of the standard solution was measured several times. The result is shown by the solid line graph of the black circle symbol in FIG.
  • the maximum pH value of the standard solution during the storage period was 7.94 (after 2 weeks of storage).
  • Example 11 A standard solution having the same composition as in Comparative Example 13 was prepared, and diluted hydrochloric acid was added dropwise to the standard solution before filling into a 10 mL glass vial to adjust the initial pH to 7.61. As described above, when the reference pH is 7.85, in this example, the initial pH of the standard solution is lowered by about 0.24 from the reference value with dilute hydrochloric acid.
  • Example 11 a standard solution filling body of Example 11 was produced (manufactured) using the standard solution after dropwise addition of diluted hydrochloric acid.
  • the pH of the standard solution was measured several times. The result is shown by the dotted line graph of the black triangle symbol of FIG. Further, the maximum pH value of the standard solution during the storage period was 7.94 (after one week of storage).
  • the pH of the dialysate standard solution can be stored for 12 weeks at room temperature (Example 7) or for 12 weeks under accelerated conditions (Example 9). Was able to maintain around the reference pH without excessive change.
  • the dialysate standard solution filling body is filled with the dialysate standard solution together with the filled gas filling the void in the sealed container in a smaller volume than the standard solution.
  • It is composed of air or nitrogen gas and carbon dioxide, and is a mixed gas having a carbon dioxide content of 3 to 20% by volume.
  • the standard solution is filled in the sealed container until the capacity limit of the sealed container or until it does not overflow beyond the capacity limit of the sealed container. .
  • the inside of the sealed container is substantially filled with only the dialysate standard solution, generation of insoluble carbonate and decomposition of bicarbonate into carbon dioxide are avoided in the dialysate standard solution.
  • the pH can be maintained within a predetermined range even when stored for a long time. Therefore, it is possible to stably store the dialysate standard solution over a long period of time, so that the concentration of the dialysate prepared at the site of use can be adjusted appropriately. Thereby, even when dialysate is prepared at any time at the site of use, variations in dialysate concentration can be suppressed without being limited by the amount of preparation.
  • the initial pH of the dialysate standard solution after filling the sealed container is within 0.4 from the pH (reference pH) of the dialysate to be prepared. It is set so low. Therefore, the initial pH is lowered in anticipation of an increase in the pH of the filled dialysate standard solution. As a result, the pH of the dialysate standard solution can be maintained within a suitable range even during storage, and it is also possible to avoid the formation of insoluble salts as the pH of the dialysate standard solution increases. it can.
  • the standard solution of dialysis solution as a bicarbonate-containing preparation was filled in a sealed container to prepare (manufacture) a standard solution filling body, and the stability of the pH of the standard solution Is evaluating.
  • the bicarbonate-containing preparation contains bicarbonate (bicarbonate) and is used for preparing a dialysate. Anything can be used.
  • the present invention can be widely and suitably used in the field of preparing a dialysis solution used for hemodialysis.

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Abstract

L'invention concerne un procédé permettant de supprimer les variations de concentration d'un dialysat sans limiter la quantité préparée lors de la préparation du dialysat selon les besoins du site d'utilisation. L'article rempli de solution étalon selon la présente invention est un article rempli constitué d'un récipient étanche rempli d'une solution étalon d'une préparation contenant du carbonate. Le récipient étanche est conçu à partir d'un matériau possédant une propriété de barrière contre les gaz. Le récipient étanche est rempli jusqu'à ce que le pH initial de la solution étalon après remplissage devienne plus faible que le pH de la préparation contenant du bicarbonate qui doit être préparée, ou jusqu'à la limite de capacité du récipient étanche ou jusqu'à un niveau ne dépassant pas la limite de capacité du récipient étanche et ne provoquant pas de fuite.
PCT/JP2016/003999 2015-09-04 2016-09-01 Article rempli de solution étalon et son utilisation WO2017038099A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018036099A (ja) * 2016-08-30 2018-03-08 ニプロ株式会社 透析液分析用標準試薬キット
WO2018043492A1 (fr) * 2016-08-30 2018-03-08 ニプロ株式会社 Kit de réactif étalon pour l'analyse du liquide de dialyse, solution aqueuse pour réactif étalon, liquide de dialyse, et régénération du liquide pour rein artificiel

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009044919A1 (fr) * 2007-10-05 2009-04-09 National University Corporation Chiba University Solution médicamenteuse stable renfermant l'ion bicarbonate
JP2015003871A (ja) * 2013-06-19 2015-01-08 扶桑薬品工業株式会社 酸化ストレス抑制型透析用剤およびその調製方法

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JP2002308782A (ja) * 2001-02-06 2002-10-23 Otsuka Pharmaceut Factory Inc 重炭酸溶液の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009044919A1 (fr) * 2007-10-05 2009-04-09 National University Corporation Chiba University Solution médicamenteuse stable renfermant l'ion bicarbonate
JP2015003871A (ja) * 2013-06-19 2015-01-08 扶桑薬品工業株式会社 酸化ストレス抑制型透析用剤およびその調製方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018036099A (ja) * 2016-08-30 2018-03-08 ニプロ株式会社 透析液分析用標準試薬キット
WO2018043492A1 (fr) * 2016-08-30 2018-03-08 ニプロ株式会社 Kit de réactif étalon pour l'analyse du liquide de dialyse, solution aqueuse pour réactif étalon, liquide de dialyse, et régénération du liquide pour rein artificiel

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