Title of the invention: Standard liquid filler and its use
Technical field
[0001]
　The present invention is a filler in which a container is filled with a dialysate and a standard solution used to confirm that the bicarbonate-containing preparation used for preparing the dialysate is used at an appropriate concentration during hemodialysis. Also, it relates to the use of this standard liquid filler.
Background technology
[0002]
　Hemodialysis therapy (or artificial dialysis therapy, hereinafter abbreviated as "hemodialysis") is a treatment method adopted for patients with chronic renal failure and the like, and artificially replaces renal function. In hemodialysis, blood is drawn from the body to the outside of the body, permeated through a dialyzer, and then pulled back into the body. In the dialyzer, by indirectly contacting the blood with the dialysate through the dialysis membrane, waste products in the blood are removed and the electrolyte and water content in the blood are maintained. In hemodialysis, for example, 100 to 300 liters of dialysate is used at one time.
[0003]
　The dialysate is usually prepared just before use. In a general method for preparing a dialysate, agent A containing an electrolyte component and agent B containing a hydrogen carbonate (bicarbonate) are mixed immediately before use, and then dialysate water is replenished. This adjusts the concentration of each component. This is because when a part of the electrolyte component contained in the agent A coexists with the hydrogen carbonate which is the main component of the agent B, these react with each other with the passage of time to generate an insoluble carbonate. Is. The generation of insoluble carbonate causes precipitation in the dialysate and changes the component concentration and pH of the dialysate. In addition, 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.
[0004]
　Conventionally, as one method for avoiding the generation of insoluble carbonate and the decomposition of hydrogen carbonate ion, for example, as disclosed in Patent Document 1 or 2, the agent A and the agent B are separated by a partition wall. A method of accommodating each in a multi-chamber container is known. In this method, the dialysate can be prepared immediately before use by breaking the partition wall at the site of use and mixing the agent A and the agent B.
Prior art literature
Patent documents
[0005]
Patent Document 1: Japanese Patent Application Laid-Open No. 11-197240
Patent Document 2: Japanese Patent Application Laid-Open No. 2005-028108
Outline of the invention
Problems to be solved by the invention
[0006]
　As described above, preparing the dialysate immediately before use means, in other words, preparing a required amount of dialysate at the site of use at any time. Therefore, the concentration of the dialysate tends to vary as compared with the case where the dialysate is prepared while quality control is performed on a large scale in a factory or the like provided with dedicated equipment.
[0007]
　Here, in the method using a multi-chamber container as disclosed in Patent Document 1 or 2, the agent A and the agent B can be prepared in advance at the factory, filled in the multi-chamber container, and shipped. It is possible to suppress variations in the concentration of the liquid. However, in this method, the amount of dialysate to be prepared is limited to the amount of Agents A and B that can be accommodated in the multi-chamber container. Therefore, for example, when a dialysate larger than the capacity of the multi-chamber container is required. Cannot be fully addressed.
[0008]
　The present invention has been made to solve such a problem, and when preparing a dialysate at any time at the site of use, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared. The purpose is to provide a method that enables.
Means to solve problems
[0009]
　The standard solution filler according to the present disclosure is a filler in which a standard solution of a bicarbonate-containing preparation used when preparing a dialysate for hemodialysis is filled in a closed container in order to solve the above-mentioned problems. The closed container is made of a material having a gas barrier property, and the initial pH after filling in the standard solution is lower than the pH of the bicarbonate-containing preparation to be prepared.
[0010]
　According to the above configuration, when the bicarbonate-containing preparation used for preparing the dialysate is filled in a closed container, the initial pH is lowered in anticipation of an increase in the pH of the filled standard solution. As a result, the pH of the standard solution can be maintained within a suitable range even during storage, and it is possible to avoid the formation of insoluble salts as the pH of the standard solution rises. Therefore, since the standard solution can be stably stored for a long period of time, the concentration of the dialysate prepared at the site of use can be appropriately adjusted. As a result, even when the dialysate is prepared at the site of use at any time, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared.
[0011]
　In the standard solution filler having the above constitution, the bicarbonate-containing preparation is a dialysate, and the standard solution is preset with at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water. It is prepared by mixing at the same mixing ratio, and the initial pH after filling in the standard solution may be lower than the pH of the dialysate to be prepared within 0.4. ..
[0012]
　According to the above configuration, when the bicarbonate-containing preparation is a dialysate, the initial pH of the filled dialysate standard solution is lowered within 0.4. Therefore, the pH of the dialysate standard solution can be maintained within a suitable range even during storage, and it is possible to avoid the formation of insoluble salts as the pH of the dialysate standard solution rises. .. Therefore, the dialysate standard solution can be stably stored for a long period of time, and the concentration of the dialysate prepared at the site of use can be appropriately adjusted.
[0013]
　Further, in the standard solution filler having the above constitution, the standard solution contains an acid component which is a weak acid and a plurality of types of monovalent or divalent metal ions including sodium ion, potassium ion, calcium ion, and magnesium ion. A composition in which the content of the metal ion is equivalent to the standard and the content of the acid component is higher than the standard when the composition of the bicarbonate-containing preparation to be prepared is used as a reference. It may have a configuration having.
[0014]
　According to the above configuration, the pH is set low by adjusting the content ratio of the weak acid and the metal salt of the weak acid. At this time, since the content ratio of the weak acid and the metal salt of the weak acid is adjusted without substantially changing the content of the metal ion, the pH is set low while maintaining the substantial composition as a standard solution. be able to. Moreover, if a metal salt of a weak acid is contained as a source of metal ions, the weak acid can behave as an acid of the pH buffer system, and the metal salt of the weak acid can behave as a conjugate base of the pH buffer system. Therefore, depending on the composition of the standard solution, not only the initial pH is lowered in anticipation of an increase in pH, but also the pH of the filled standard solution can be made difficult to increase due to the pH buffering action.
[0015]
　Further, in the standard liquid filler having the above structure, the acid component may be citric acid or acetic acid, and the metal ion serving as a conjugate base may be a sodium ion.
[0016]
　Alternatively, in the standard liquid filler having the above configuration, the closed container is filled with the filling gas that fills the voids in the closed container together with the standard liquid, and the filled gas is air or nitrogen gas. It may be a mixed gas composed of carbon dioxide and having a carbon dioxide content in the range of 3 to 20% by volume.
[0017]
　According to the above configuration, at least a standard solution prepared by mixing sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water and a smaller volume of the filling are enclosed inside the filler. It is filled with gas, and this filled gas is a mixed gas containing carbon dioxide in the range of 3 to 20% by volume. This makes it possible to substantially lower the initial pH of the standard solution after filling. Therefore, even if the pH of the filled standard solution rises, it can be maintained within a suitable range, and it is possible to avoid the formation of insoluble salts as the pH of the standard solution rises. In addition, a significant decrease in pH that occurs when the enclosed gas is only carbon dioxide can be effectively suppressed.
[0018]
　Therefore, with the standard solution filler having the above structure, the standard solution can be stably stored for a long period of time. Therefore, when preparing the dialysate at any time in the field of use, the concentration of the prepared bicarbonate-containing preparation is appropriate by comparing the standard solution in the standard solution-filled body with the prepared bicarbonate-containing preparation. Can be adjusted to. As a result, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared, even when the dialysate is prepared at any time at the site of use.
[0019]
　Further, in the standard liquid filling body having the above configuration, when the capacity of the closed container is 100% by volume, the filling rate of the standard liquid is in the range of 70 to 99% by volume, and the filling rate of the enclosed gas. May be in the range of 1 to 30% by volume.
[0020]
　Further, in the standard solution filler having the above structure, the standard solution may have a structure in which the initial pH is lowered by bubbling carbon dioxide.
[0021]
　Further, in the standard solution filler having the above structure, the standard solution may have a structure in which the initial pH is lowered by adding an acid.
[0022]
　The other standard solution filler according to the present disclosure is a filler in which a standard solution of a bicarbonate-containing preparation used when preparing a dialysate for hemodialysis is filled in a closed container in order to solve the above-mentioned problems. The closed container is made of a material having a gas barrier property, and the standard solution is placed in the closed container until it does not overflow up to the capacity limit of the closed container or exceeds the capacity limit of the closed container. It is a filled configuration.
[0023]
　According to the above configuration, the inside of the closed container is substantially filled with only the standard solution of the bicarbonate-containing preparation. As a result, it is possible to avoid the generation of insoluble carbonate and the decomposition of hydrogen carbonate into carbon dioxide in this standard solution, and it is possible to maintain the pH within a predetermined range even after long-term storage. Therefore, the standard solution can be stably stored for a long period of time. As a result, when the dialysate is prepared at any time in the field of use, the concentration of the prepared bicarbonate-containing preparation is appropriate by comparing the standard solution in the standard solution-filled body with the prepared bicarbonate-containing preparation. Can be adjusted to. As a result, even when the dialysate is prepared at the site of use at any time, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared.
[0024]
　In the standard solution filler having the above constitution, the bicarbonate-containing preparation is a dialysate, and the standard solution is preset with at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water. The composition may be prepared by mixing at the same mixing ratio.
[0025]
　According to the above configuration, the inside of the closed container is substantially filled with at least a dialysate standard solution prepared by mixing sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water. It will be in a state of As a result, it is possible to avoid the generation of insoluble carbonate and the decomposition of hydrogen carbonate into carbon dioxide in the dialysate standard solution, and it is possible to maintain the pH within a predetermined range even after long-term storage. Therefore, the dialysate standard solution can be stably stored for a long period of time.
[0026]
　In the standard liquid filler having the above configuration, when the total volume of the closed container is 100% by volume, the standard liquid is filled in the closed container so that the filling rate is within the range of 80 to 100% by volume. It may be the configuration that has been set.
[0027]
　Further, in the standard solution filler having any of the above configurations, the standard solution of the bicarbonate-containing preparation contains an acidic aqueous solution A containing sodium ions, potassium ions, calcium ions and magnesium ions, and carbonic acid. A standard solution of the dialysate prepared by mixing a hydrogen salt-containing agent B and water at a preset mixing ratio, or a standard solution of the agent B may be used.
[0028]
　Further, in the standard liquid filler having any of the above configurations, the closed container may have at least a configuration in which the main body is made of glass.
[0029]
　The present invention also includes a dialysate preparation kit containing a standard solution filler having any of the above configurations.
[0030]
　Furthermore, the present invention also includes a method for producing a standard liquid filler having the above-mentioned constitution. Specifically, the method for producing a standard solution filler according to the present disclosure is a standard solution by filling a closed container with a standard solution of a bicarbonate-containing preparation used when preparing a dialysate for hemodialysis. In a method for producing a filler, the closed container is made of a material having a gas barrier property, and the initial pH after filling in the standard solution is adjusted to be lower than the pH of the dialysate to be prepared. Any configuration may be used.
[0031]
　In the method for producing a standard solution filler having the above constitution, the bicarbonate-containing preparation is a dialysate, and the standard solution is at least sodium ion, potassium ion, calcium ion, magnesium ion, hydrogen carbonate and water. It 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. May be good.
[0032]
　In the method for producing a standard solution filler, the standard solution contains an acid component which is a weak acid and a plurality of types of monovalent or divalent metal ions including sodium ion, potassium ion, calcium ion, and magnesium ion. When the composition of the bicarbonate-containing preparation to be prepared is used as a reference, the content of the metal ion is made equal to the standard, and the content of the acid component is made higher than the standard. As described above, the initial pH may be adjusted by adjusting the composition of the standard solution.
[0033]
　In the method for producing a standard liquid filler, the sealed container is filled with the standard solution so that the volume of the filled gas filling the voids in the closed container is smaller than that of the standard solution. The initial pH is adjusted, and the enclosed gas may be composed of air or nitrogen gas and carbon dioxide, and may be a mixed gas having a carbon dioxide content in the range of 3 to 20% by volume.
[0034]
　Further, in the method for producing a standard solution filler having the above configuration, the initial pH may be adjusted by bubbling the standard solution with carbon dioxide.
[0035]
　Further, in the method for producing a standard solution filler having the above structure, the initial pH may be adjusted by adding dilute hydrochloric acid to the standard solution.
[0036]
　Further, in another method for producing a standard solution filler according to the present disclosure, a dialysate standard is obtained by filling a closed container with a standard solution of a bicarbonate-containing preparation used when preparing a dialysate for hemodialysis. In a method for producing a liquid filler, the closed container is made of a material having a gas barrier property, and the standard liquid overflows up to the capacity limit of the closed container or exceeds the capacity limit of the closed container. The closed container is filled until it is not in a state.
[0037]
　In the method for producing a standard solution filler having the above constitution, the bicarbonate-containing preparation is a dialysate, and the standard solution is at least sodium ion, potassium ion, calcium ion, magnesium ion, hydrogen carbonate and water. The configuration may be prepared by mixing at a preset mixing ratio.
[0038]
　In the method for producing a standard solution filler having any of the above configurations, the standard solution of the bicarbonate-containing preparation is the standard solution of the dialysate, and is acidic containing sodium ions, potassium ions, calcium ions and magnesium ions. A standard solution of the dialysate is prepared by mixing the agent A which is an aqueous solution of the above solution, the agent B containing a hydrogen carbonate, and water at a preset mixing ratio, or the bicarbonate-containing standard solution is prepared. The standard solution of the preparation may be a standard solution of the agent B.
Effect of the invention
[0039]
　According to the above configuration, it is possible to provide a method capable of suppressing variations in the concentration of dialysate without being limited by the amount of dialysate when preparing the dialysate at any time at the site of use. , Has the effect.
A brief description of the drawing
[0040]
FIG. 1 is a graph showing the results of typical examples of the standard solution filler according to the present disclosure and comparative examples thereof, showing the results of changes in pH over time when the standard solution filler is stored at room temperature. Is.
FIG. 2 is a graph showing the results of a comparative example of the standard solution filler shown in FIG. 1 and the results of changes in pH over time when the standard solution filler was stored at room temperature.
FIG. 3 is a result of a typical example of the standard solution filler according to the present disclosure and a comparative example thereof, and changes in pH over time when the standard solution filler is stored under an acceleration condition of 40 ° C. It is a graph which shows the result of.
FIG. 4 is a graph showing the result of a comparative example of the standard liquid filler shown in FIG. 3 and the result of a change in pH over time when the standard liquid filler is stored under an acceleration condition of 40 ° C. Is.
FIG. 5 shows the results of typical examples of other standard solution fillers according to the present disclosure and comparative examples thereof, and the results of changes in pH over time when the standard solution fillers were stored at room temperature. It is a graph which shows.
FIG. 6 is a graph showing the results of a comparative example of the standard solution filler shown in FIG. 5 and the results of changes in pH over time when the standard solution filler was stored at room temperature.
FIG. 7 is a result of a comparative example with respect to an example of another standard liquid filler according to the present disclosure, and shows the result of a change in pH over time when the standard liquid filler is stored under an acceleration condition of 40 ° C. It is a graph which shows.
FIG. 8 shows the results of examples of other standard solution fillers according to the present disclosure, showing the results of changes in pH over time when the standard solution fillers were stored at room temperature or under accelerated conditions of 40 ° C. It is a graph which shows.
FIG. 9 shows the results of typical examples of other standard solution fillers according to the present disclosure and comparative examples thereof, and the results of changes in pH over time when the standard solution fillers were stored at room temperature. It is a graph which shows.
FIG. 10 is a graph showing the results of typical examples of other standard solution fillers according to the present disclosure, showing the results of changes in pH over time when the standard solution fillers were stored at room temperature.
Mode for carrying out the invention
[0041]
　The standard solution filler and the method for producing the same according to the present disclosure are fillers in which a standard solution of a bicarbonate-containing preparation used for preparing a dialysate for hemodialysis is filled in a closed container, and the closed container is a closed container. It is composed of a material having a gas barrier property. In the present disclosure, when the dialysate is prepared at the site of use at any time, a plurality of configurations can be adopted in order to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared.
[0042]
　As a typical configuration, 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 closed container or is sealed. It can be mentioned that the closed container is filled to the extent that the capacity limit of the container is not exceeded and the container does not overflow.
[0043]
　More specifically, the former configuration includes (1) a standard solution and an encapsulating gas that fills the voids in the closed container, and the encapsulating gas is composed of air or nitrogen gas and carbon dioxide. The composition is a mixed gas in which the carbon dioxide content is in the range of 3 to 20% by volume. (2) The standard solution contains a plurality of weak acid acid components and sodium ion, potassium ion, calcium ion, and magnesium ion. When the composition of the bicarbonate-containing preparation to be prepared is used as a reference for containing monovalent or divalent metal ions of the seed, the content of the metal ions is equivalent to the standard and the content of the acid component is contained. A structure having a composition in which the amount is larger than the standard, (3) a structure in which the initial pH of the standard solution is lowered by bubbling carbon dioxide, and (4) a structure in which an acid is added to the standard solution. As a result, the configuration in which the initial pH is lowered can be mentioned.
[0044]
　Here, the bicarbonate-containing preparation in the present disclosure may be one containing a bicarbonate (bicarbonate) and used for preparing a dialysate. A typical example is the dialysate itself. Alternatively, if the dialysate is prepared by mixing agent A, which is an acidic aqueous solution containing sodium ions, etc., agent B containing bicarbonate, and water, bicarbonate in the present disclosure. Agent B is also included as the contained preparation.
[0045]
　Hereinafter, typical embodiments according to the present disclosure will be specifically described, but in each of the following embodiments, a case where a dialysate is used as the bicarbonate-containing preparation will be described. Of course, the present disclosure is not limited to this, and it goes without saying that the bicarbonate-containing preparation may be agent B or another preparation for dialysis.
[0046]
　(Embodiment 1)
　The dialysate standard solution filler according to the present embodiment is a filler in which a dialysate standard solution used when preparing a dialysate for hemodialysis is filled in a closed 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, and is typically prepared. Is a preset 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. Examples thereof include those prepared by mixing in. The closed container is made of a material having a gas barrier property. The closed container is filled with a sealing gas that fills the voids in the closed container together with the dialysate standard solution, and the filled gas is composed of air or nitrogen gas and carbon dioxide, and has a carbon dioxide content. Is a mixed gas in the range of 3 to 20% by volume.
[0047]
　Hereinafter, a typical example of the present embodiment will be specifically described. In the following description, not only this embodiment but also other embodiments are included, and for convenience of explanation, the dialysate standard solution filler is appropriately abbreviated as "standard solution filler", and the dialysate standard solution is appropriately referred to as "standard solution filler". It shall be abbreviated as "standard solution".
[0048]
　[Dialysate standard solution] In the
　standard solution filler according to the present embodiment, the standard solution filled in the closed container has an appropriate composition (or an appropriate electrolyte concentration and pH) according to the type of dialysate to be compared. ) Is prepared. In the following description, the configuration of the standard solution will be described by taking a general dialysate as an example.
[0049]
　In the present embodiment, as a general dialysate (that is, a standard solution filled in a closed container), a predetermined amount of an agent A containing an electrolyte component and an acid component and an agent B containing a bicarbonate component are used. An example is a two-agent mixed type prepared by mixing with water for dialysis and diluting. The method for preparing the dialysate is not limited to such a two-agent mixed type, and as described above, a preset mixture of sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water. It may be prepared by mixing in a ratio.
[0050]
　The electrolyte component contained in the agent A is not particularly limited and is appropriately selected according to the type of dialysate, but in general, for example, monovalent or 2 such as sodium ion, potassium ion, magnesium ion, calcium ion and the like. Valuable metal ions; chloride ions; organic anions such as citrate ions, lactic acid ions, gluconate ions, succinate ions, malate ions; and the like can be mentioned. Normally, the dialysate contains at least sodium ions, potassium ions, calcium ions, and magnesium ions among these electrolyte components. Therefore, the standard solution according to the present embodiment also contains these electrolyte components. Is preferable.
[0051]
　The sodium ion contained in the standard solution is generally supplied from a sodium salt. The specific sodium salt is not particularly limited, and examples thereof include sodium chloride, sodium acetate, sodium citrate, sodium lactate, sodium gluconate, sodium succinate, sodium malate and the like. Only one type of these sodium salts may be used, or two or more types may be used in combination as appropriate. In particular, sodium chloride is the most important salt essential in the living body, and therefore, as a sodium salt. It is preferable that at least sodium chloride is used.
[0052]
　Potassium ions contained in the standard solution are generally supplied from potassium salts. The specific potassium salt is not particularly limited, and examples thereof include potassium chloride, potassium acetate, potassium lactate, potassium citrate, potassium gluconate, potassium succinate, and potassium malate. Only one type of these potassium salts may be used, or two or more types may be used in combination as appropriate. In particular, 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.
[0053]
　Magnesium ions contained in the standard solution are generally supplied from magnesium salts. The specific magnesium salt is not particularly limited, and examples thereof include magnesium chloride, magnesium acetate, magnesium lactate, magnesium citrate, magnesium gluconate, magnesium succinate, magnesium malate and the like. Only one type of these magnesium salts may be used, or two or more types may be used in combination as appropriate. Moreover, these magnesium salts may be used in the form of a hydrate. As a typical magnesium salt, magnesium chloride can be mentioned.
[0054]
　Calcium ions contained in the standard solution are generally supplied from calcium salts. The specific calcium salt is not particularly limited, and examples thereof include calcium chloride, calcium acetate, calcium lactate, calcium gluconate, calcium succinate, calcium malate and the like. Only one type of these calcium salts may be used, or two or more types may be used in combination as appropriate. Moreover, these calcium salts may be used in the form of a hydrate. Calcium chloride can be mentioned as a typical calcium salt.
[0055]
　Chloride ions contained in the standard solution are generally supplied from chloride salts. The specific chloride salt is not particularly limited, and examples thereof include the above-mentioned chloride salts of monovalent or divalent metal ions, that is, sodium chloride, potassium chloride, magnesium chloride, calcium chloride and the like. Chloride salts of these metal ions are preferably used because they can serve as a source of not only chloride ions but also sodium ions, potassium ions, magnesium ions, and calcium ions. In addition, only one kind of these chloride salts may be used, or two or more kinds may be used in appropriate combination. Furthermore, 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.
[0056]
　The organic acid ion contained in the standard solution is not particularly limited, and as with the chloride ion, the salt of each organic acid is generally used as the supply source. Further, when each organic acid is used as an acid component contained in the standard solution, these organic acids can also be a source of each organic acid ion.
[0057]
　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. Of the above-mentioned electrolyte components, the content of sodium chloride is usually set to the maximum as compared with the content of each of the other electrolyte components. This is because the content of sodium chloride is set according to the concentration of electrolyte in blood. The specific content (concentration) of sodium chloride in the prepared dialysate (filled standard solution) is, for example, preferably in the range of 75 mEq / L to 150 mEq / L based on the sodium ion content. Can be mentioned in the range of 80 mEq / L to 145 mEq / L.
[0058]
　Therefore, the agent A may contain a sodium supply source such as sodium chloride so that the sodium ion content in the standard solution is within the above range. Similarly, for the electrolyte components other than sodium ions, the source of each ion may be contained in the agent A so as to be in a desired range in the standard solution.
[0059]
　As the acid component contained in the agent A, an organic acid or an inorganic acid that is common in the field of dialysate can be preferably used. Specifically, for example, acetic acid, citric acid, lactic acid, hydrochloric acid and the like can be mentioned. These acid components may be anhydrides or hydrates. Typical acid components include acetic acid and citric acid. Further, 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.
[0060]
　The specific content of the acid component contained in the standard solution is not particularly limited, and can be appropriately set according to various conditions. For example, when the acid component is acetic acid, it can be mentioned in the range of 2 mEq / L to 6 mEq / L, preferably in the range of 3 mEq / L to 5 mEq / L, based on the acetate ion, but is particularly limited. Not done. When the acid component is citric acid, it can be mentioned 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 the citric acid ion. ..
[0061]
　If the acid component is contained within an appropriate range, the pH of the standard solution can be adjusted within an appropriate range. For example, when the acid component is acetic acid (in the case of a standard solution containing acetic acid), the pH is adjusted in the range of 6.5 to 8.0, preferably in the range of 7.1 to 7.4. be able to. When the acid component is citric acid (in the case of a standard solution containing citric acid), the pH is in the range of 7.0 to 8.5, preferably in the range of 7.5 to 8.0. Can be adjusted. Therefore, the acid component may be contained in the agent A so as to be within an appropriate range as described above in the standard solution.
[0062]
　The agent A may contain components other than the above-mentioned electrolyte component and acid component. In other words, the dialysate to be prepared (the standard solution to be filled) can contain various components that are acceptable as components of the dialysate, in addition to the electrolyte component and the acid component. Specific other components include, for example, glucose (dextrose), a pH adjuster and the like.
[0063]
　Glucose can be added to the dialysate for the purpose of maintaining the blood glucose level of the hemodialysis subject. The specific content (concentration) of glucose is not particularly limited and can be appropriately set according to various conditions. A typical glucose content is, for example, in the range of 0 to 2.5 g / L, preferably 1.0 to 2.0 g / L in the prepared dialysate (filled standard solution). Can be mentioned. Therefore, the agent A may contain glucose so as to be within an appropriate range as described above in the standard solution.
[0064]
　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. In other words, the standard solution may contain a pH adjuster separately from the acid component for the purpose of assisting the pH adjusting function of the standard solution by the acid component. Specific examples of the pH adjuster include organic acids such as citric acid, oxalic acid, tartaric acid, maleic acid, ascorbic acid, oxaloacetate, gluconic acid, isocitric acid, malic acid, and pyruvic acid. Only one kind of these organic acids may be used, or two or more kinds may be used in combination as appropriate. Further, these organic acids may be used as salts such as sodium salt, potassium salt and magnesium salt.
[0065]
　The specific content (concentration) of the pH adjuster is not particularly limited. The pH adjuster can adjust the pH of the dialysate to be prepared (the standard solution to be filled) within a suitable range, and does not affect the functions of the above-mentioned electrolyte component and acid component (or these). An amount (to the extent that it does not interfere with the function of the component) may be added. Therefore, it is sufficient that the pH adjuster is 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.
[0066]
　Examples of the bicarbonate (bicarbonate) contained in the agent B include sodium hydrogen carbonate (sodium bicarbonate). Bicarbonates other than sodium hydrogen carbonate may be used, but it is preferable that the bicarbonate contained in the agent B is only sodium hydrogen carbonate. The specific content of the bicarbonate is not particularly limited and can be appropriately set according to various conditions. In general, the dialysate to be prepared (the standard solution to be filled) may be in the range of 15 mEq / L to 45 mEq / L, preferably in the range of 25 mEq / L to 40 mEq / L.
[0067]
　Agent B 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 and the like. The content of other components is not particularly limited, and can be appropriately set according to various conditions. Therefore, in the agent B, other components may be added to such an extent that the function of the bicarbonate is not affected.
[0068]
　The above-mentioned agent A is prepared as an acidic liquid (aqueous solution) containing at least the above-mentioned electrolyte component and acid component, while the above-mentioned agent B may be prepared as a solid (for example, powder) or as a liquid (aqueous solution). It may be formulated. Even when the agent B is a liquid, the concentration of bicarbonate is not particularly limited. When the bicarbonate contained in the agent B is sodium hydrogen carbonate, for example, it may be in the range of 40 to 80 g / L, preferably in the range of 60 to 80 g / L.
[0069]
　In the standard solution filler according to the present embodiment, the standard solution to be filled in the closed container is preferably prepared by mixing the above-mentioned agents A and B and diluting them with dialysis water. In other words, the standard solution may be prepared in the same manner as the dialysate actually prepared and then filled in a closed container. For example, when the acid component is citric acid as in Examples described later, 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 method for preparing a general dialysate.
[0070]
　[Sealed Container] In the
　standard liquid filler according to the present embodiment, the specific type of the closed container filled with the standard liquid described above is not particularly limited. As the closed container, a known container can be preferably used as long as it has a tightness and a gas barrier property that can stably hold the filled standard solution and the filled gas described later.
[0071]
　As a typical closed container, at least a glass container whose main body is made of glass can be mentioned. Specific examples of the glass container include vials, ampoules, and cartridges. It is necessary to prepare a large amount of dialysate, but since the standard solution used as a reference for preparing the dialysate may be a small volume, a small volume glass container used for an injection such as a vial or an ampoule is preferably used. be able to. Depending on the conditions of use of the standard solution, the syringe can also be used as a glass container.
[0072]
　If the closed container is a vial or the like, a stopper member is used to hermetically seal the opening. The specific plug member is not particularly limited, and a known plug member that does not substantially affect the standard solution and can suitably seal and seal the opening of the vial or the like is preferable. Can be used. When the closed container is a vial, a known rubber stopper, silicone stopper, cork stopper or the like can be preferably used as the stopper member. Further, in order to improve the reliability of the hermetically sealed seal, a cap made of aluminum or an alloy thereof can be used in combination.
[0073]
　Further, as the closed container, a known resin container (resin container) can be preferably used in addition to the glass container. In such a resin container, the container body may be made of a hard resin material, or may be made of a soft resin material having flexibility or flexibility. When the closed container is a resin container and has an opening like the above-mentioned vial, a known stopper member for hermetically sealing the opening may be used like the vial.
[0074]
　The capacity of the closed container is not particularly limited. When preparing the dialysate, the standard solution is required to have an amount capable of confirming the concentrations of the electrolyte component, the acid component, and the bicarbonate (and other components) contained in the dialysate. Therefore, the capacity of the closed container may be larger than the amount of the standard solution required for confirming the concentration of each component. In the standard liquid filler according to the present embodiment, as will be described later, the filled gas is also filled in addition to the standard liquid, but the volume of the filled gas is less than the volume of the standard liquid (volume smaller than the standard liquid). .. Therefore, the capacity of the closed container may have a capacity in consideration of the filling amount of the enclosed gas in addition to the required amount of the standard solution.
[0075]
　[Filling of dialysate standard solution] In the standard solution filler according to the
　present embodiment, at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water are mixed at a preset mixing ratio. (As described above, as a preferable example, agent A and agent B are mixed and diluted with dialysis water) to prepare a standard solution, and the standard solution is filled in a closed container and sealed tightly. (Manufactured). At this time, in addition to the standard solution, the closed container is filled with a filled gas having a volume smaller than the volume of the standard solution.
[0076]
　The enclosed gas filled in the closed 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. As a result, the volatilization of the hydrogen carbonate from the standard solution can be effectively suppressed, so that the increase in pH with time can also be suppressed. Moreover, since the content of carbon dioxide in the enclosed gas is not excessive, it is possible to effectively suppress a significant decrease in pH due to the dissolution of carbon dioxide.
[0077]
　When the carbon dioxide content exceeds 20% by volume, carbon dioxide is excessively dissolved in the standard solution, and the pH of the standard solution is a preferable lower limit value in the body filled with the standard solution (for example, if the acid component is a citric acid component, 7. It may be less than 4). If the pH of the standard solution is lower than the predetermined range, the concentration of each component of the standard solution deviates from the predetermined range, and as a result, the standard solution cannot be used. Further, the lower limit of the carbon dioxide content in the mixed gas may be 3% by volume or more. When the carbon dioxide content is less than 3% by volume, the pH of the standard solution in the standard solution-filled body may exceed a preferable upper limit value (for example, 8.0 if the acid component is a citric acid component). If the pH of the standard solution exceeds a predetermined range, the concentration of each component of the standard solution deviates from the predetermined range, as in the case of a decrease in pH, and as a result, the standard solution cannot be used.
[0078]
　In the standard solution-filled body, the filled gas may be filled so as to fill the voids in the closed container, but the filling rate (filled volume) of the filled gas in the closed container is smaller than the filling rate of the standard solution. 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 filled 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 enclosed gas is higher than the filling rate of the standard solution, carbon dioxide in the enclosed gas may be excessively dissolved in the standard solution, and the pH of the standard solution in the filled body of the standard solution may be lower than the preferable lower limit value.
[0079]
　The method of filling the airtight container with the standard solution and the enclosed gas is not particularly limited, and a method known in the field of dialysate or drug packaging can be preferably used. The method for preparing the mixed gas as the filled gas is not particularly limited, and a known method can be preferably used. Further, the method of filling the closed container with the standard solution and the filled gas and sealing the closed container is not particularly limited, and a known method can be preferably used.
[0080]
　[Use of Standard Solution Filler]
　The standard solution filler according to the present embodiment can be used when preparing the dialysate at the dialysis site and confirming each component contained in the dialysate. Specifically, for example, an agent A and an agent B are mixed at a dialysis site and diluted with dialysis water to prepare a dialysate, and the dialysate is sampled to measure the concentration of an electrolyte component. In addition, the standard solution filler is opened and the standard solution is sampled to measure the concentration of the electrolyte component. Compare the concentration of the electrolyte component of the dialysate with the concentration of the electrolyte component of the standard solution, and compare these concentrations with each other, or compare the concentration of the electrolyte component of the dialysate with the concentration of the electrolyte component of the standard solution. To determine if it is within the permissible range.
[0081]
　If the concentrations of the dialysate are substantially the same as each other or the concentration of the electrolyte component of the dialysate is within the permissible range, the dialysate is prepared at a suitable concentration of the electrolyte component. On the other hand, if the concentrations are different from each other and are out of the permissible range, the concentration of the electrolyte component of the dialysate is appropriately adjusted, 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, a known measuring method, or the like may be used. Further, since the pH of the standard solution is also maintained within a predetermined range in the body filled with the standard solution, the pH of the prepared dialysate can be compared with the pH of the standard solution. The pH measuring method used at this time is not particularly limited, and a commercially available pH measuring device, a pH measuring method, or the like may be used.
[0082]
　The standard liquid filler according to the present embodiment can be stored at room temperature for a predetermined storage period. As shown in Examples described later, the standard solution filler according to this embodiment can be stored at room temperature for at least 2 weeks. Further, as shown in Examples described later, the pH can be maintained within a predetermined range even when stored for 2 weeks under the acceleration condition of 40 ° C. Therefore, the standard solution filler according to this embodiment is about 1 month. It is also possible to save. Further, by appropriately setting the storage conditions, it is possible to store the product for about one year. The room temperature referred to here may be within the range of the room temperature (20 ± 15 ° C., 5 to 35 ° C.) specified by JIS.
[0083]
　As described above, the standard solution filler according to the present embodiment can be suitably used for the preparation of dialysate, but the method of using the standard solution filler is not limited to the preparation of 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 containing a standard solution filler or an evaluation kit for evaluating the quality of the dialysate. The dialysate preparation kit or evaluation kit may include at least the above-mentioned standard solution filler, and the other elements constituting these kits are not particularly limited.
[0084]
　For example, in the case of a dialysate preparation kit, the above-mentioned agents A and B may be made into a kit together with the standard solution filler. Alternatively, if it is a dialysate evaluation kit, along with a standard solution filler, an instrument for sampling the dialysate, an instrument (or measuring instrument) used for measuring the concentration of electrolyte components, and an instrument used for measuring pH (an instrument used for measuring pH). Alternatively, a measuring device) or the like may be made into a kit.
[0085]
　Further, the present embodiment also includes the method (production method) for producing the standard liquid filler described above. For example, as a method for producing a standard solution filler according to the present embodiment, a dialysate standard solution is filled in a closed container with a dialysate standard solution used when preparing a dialysate for hemodialysis. A method for producing a filler, in which a standard solution is prepared by mixing at least sodium ion, potassium ion, calcium ion, magnesium ion, 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 that fills the voids in the closed container is filled in the closed container together with the standard solution so as to have a volume smaller than that of the standard solution. It can be mentioned that the gas is composed of nitrogen gas and carbon dioxide and has a carbon dioxide content in the range of 3 to 20% by volume.
[0086]
　In the method for producing such a standard solution filler, the standard solution contains agent A, which is an acidic aqueous solution containing sodium ions, potassium ions, calcium ions and magnesium ions, and a bicarbonate, as described above. It can be prepared by mixing the agent B and water at a preset mixing ratio.
[0087]
　As described above, in the present embodiment, the dialysate is exemplified as the bicarbonate-containing preparation to be filled in the closed container, but the present disclosure is not limited to this, and the bicarbonate-containing preparation is a bicarbonate (carbonic acid). Anything that contains (hydrogen salt) and is used for the preparation of dialysate may be used. Therefore, also in the present embodiment, the agent B may be filled in a closed container as a bicarbonate-containing preparation, or another bicarbonate-containing preparation may be filled in the closed container.
[0088]
　(Embodiment 2) In the
　dialysate standard solution filler according to the present embodiment, the dialysate standard solution used when preparing the dialysate for hemodialysis is contained in a closed container in the same manner as in the first embodiment. It is a filler filled in. The dialysate standard solution to be filled is prepared by mixing at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate (bicarbonate) and water at a preset mixing ratio. Yes, typically, 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 are prepared in advance. Examples thereof include those prepared by mixing at a set mixing ratio. The closed container is made of a material having a gas barrier property. The standard solution is filled in the closed container up to the capacity limit of the closed container or until it does not overflow beyond the capacity limit of the closed container.
[0089]
　Hereinafter, a typical example of the present embodiment will be specifically described. Since the standard solution used in the standard solution filler according to the present embodiment is the same as that described in the first embodiment, the specific description of the standard solution will be omitted in the present embodiment.
[0090]
　Further, the specific configuration of the closed container used for the standard liquid filler according to the present embodiment is not particularly limited, and the closed container described in the first embodiment can be preferably used. That is, as the closed container, a known container can be preferably used as long as it has a tightness and a gas barrier property that can stably hold the filled standard solution. Therefore, in the present embodiment, the specific description of the closed container will be omitted. In the standard liquid filler according to the present embodiment, as described later, the standard liquid is filled so that the inside of the closed container is almost filled with the standard liquid. Therefore, the volume of the closed container may have a volume obtained by adding a predictable reserve amount to the required amount of the standard solution.
[0091]
　[Filling of dialysate standard solution] In the standard solution filler according to the
　present embodiment, at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water are mixed at a preset mixing ratio. (As described above, as a preferable example, agent A and agent B are mixed and diluted with dialysis water) to prepare a standard solution, and the standard solution is filled in a closed container and sealed tightly. (Manufactured). At this time, the standard solution is filled in the closed container up to the capacity limit of the closed container or until the capacity limit of the closed container is not exceeded and the standard solution does not overflow. As a result, since the inside of the closed container is substantially filled with only the dialysate standard solution, it is possible to prevent a substantial gap from being generated inside the closed container. If the generation of voids can be substantially avoided, the hydrogen carbonate in the standard solution can be substantially prevented from being decomposed into carbon dioxide and released into the voids. It can be suppressed.
[0092]
　In the standard liquid filler, when the total volume of the closed container is 100% by volume, the standard liquid is filled in the closed container so that the filling rate is ideally within the range of 100% by volume. preferable. However, when it is difficult (or) to fill the standard solution in the closed container so that the filling rate is 100% by volume due to the shape of the closed container, the closed sealing method, the filling method according to the closed container, etc. There is a case where it is not necessary to fill the container so as to be 100% by volume). Therefore, in the present embodiment, the standard solution may be filled in the closed 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. Is preferable, and it is more preferable to fill the standard solution so as to be 95% by volume or more.
[0093]
　For example, in Examples and Comparative Examples described later, a glass vial is used as a closed container. 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 portion having a narrower inner diameter than the container body is formed on the upper part of the container. An opening that is hermetically sealed by a plug member is provided at the upper end of the portion. When a vial is used as a closed container, 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 does not have to be filled until the standard solution is filled.
[0094]
　As described above, the inner diameter of the shoulder portion is smaller than that of the container body, and the height of the shoulder portion is significantly smaller than the height of the container body. Therefore, it can be said that the capacity inside the shoulder portion is sufficiently smaller than the capacity inside the container body, so that the capacity inside the shoulder portion can be regarded as an error range when viewed from the total capacity of the closed container. Further, in a state where the container body is filled with the standard solution, even if the inside of the shoulder portion is a gap portion, the standard solution is in a state of facing a very small volume gap portion in a very small area. Therefore, it can be considered that almost no carbon dioxide (generated by decomposition of bicarbonate) is released from the standard solution to the voids.
[0095]
　In other words, in the vial, it can be said that the capacity limit is reached at least when the container body is filled, and the internal space of the shoulder portion is a space outside the capacity limit of the vial. Therefore, if the closed container is a vial, if the container body is filled and the standard solution reaches a part of the shoulder, the vial (closed container) capacity limit (internal space of the container body) will not be exceeded. It means that the standard solution has been filled to the state. Further, the standard solution can be filled until the internal space of the shoulder is filled. In this case, the standard solution is filled up to the capacity limit of the vial (closed container) (substantially the total capacity of the closed container).
[0096]
　Further, as the closed container, as described above, a glass ampoule can also be used. A general ampoule has a cylindrical container body similar to a vial, and a head (neck) located above the container body, which is significantly smaller in inner diameter than the container body and whose tip is melt-sealed. .. Since the head (neck) is folded during use, the inside of the cylindrical container body constitutes substantially the entire capacity of the closed container.
[0097]
　In other words, even in the ampoule, it can be said that the capacity limit is reached when the container body is filled, and the internal space of the head (neck) is a space outside the capacity limit of the ampoule. Therefore, if the closed container is an ampoule, and if the container body is filled and the standard solution reaches a part of the head (neck), the standard solution will not overflow beyond the capacity limit of the ampoule (closed 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 (closed container).
[0098]
　The closed container is composed of a "main body portion" of the container and a "small capacity portion" such as a shoulder or head (a portion having a smaller internal volume than the main body portion), such as the vial or ampoule described above. If this is the case, when the volume of only the main body is 100% by volume (the maximum capacity of the closed container exceeds 100% by volume), the filling rate of the standard solution in the main body is 100% by volume. It is preferable that it exceeds. In this case, the standard solution exceeds the volume limit of the main body portion and extends to a small volume portion such as the shoulder or the head. Therefore, the volume of the void portion remaining inside the small volume portion can be sufficiently reduced.
[0099]
　In the present embodiment, the method of filling the airtight container with the standard solution is not particularly limited, and a method known in the field of dialysate or drug packaging can be preferably used. Further, the method of filling the airtight container with the standard solution and hermetically sealing the container is not particularly limited, and a known method can be preferably used.
[0100]
　Since the use of the standard liquid filler according to the present embodiment is the same as that of the first embodiment, a specific description of its use will be omitted. Here, the present embodiment also includes the above-mentioned manufacturing method (manufacturing method) of the standard liquid filler, as in the first embodiment. For example, as a method for producing a standard solution filler according to the present embodiment, a dialysate standard solution is filled in a closed container with a dialysate standard solution used when preparing a dialysate for hemodialysis. A method for producing a filler, in which a standard solution is prepared by mixing at least sodium ion, potassium ion, calcium ion, magnesium ion, bicarbonate and water at a preset mixing ratio, and sealed. The container is made of a material having a gas barrier property, and the standard solution is filled in the closed container up to the capacity limit of the closed container or until the container does not overflow beyond the capacity limit of the closed container. be able to.
[0101]
　Further, as described above, in the second embodiment as well, the dialysate is exemplified as the bicarbonate-containing preparation to be filled in the closed container as in the first embodiment, but the present disclosure is not limited to this, and the present disclosure is heavy. The carbonic acid-containing preparation may be any as long as it contains bicarbonate (bicarbonate) and is used for the preparation of dialysate. Therefore, also in the second embodiment, the agent B may be filled in a closed container as a bicarbonate-containing preparation, or another bicarbonate-containing preparation may be filled in the closed container.
[0102]
　(Embodiment 3)
　The dialysate standard solution filler according to the present embodiment seals the dialysate standard solution used when preparing the dialysate for hemodialysis, as in the above-described first or second embodiment. It is a filler filled in a 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, and is typically prepared. Is a preset 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. Examples thereof include those prepared by mixing in. The closed container is made of a material having a gas barrier property. The initial pH of the dialysate standard solution after filling is 0.4 or less lower than the pH (reference pH) of the dialysate to be prepared.
[0103]
　Hereinafter, a typical example of the present embodiment will be specifically described. Since the standard solution, the closed container, the filling method, the use of the filler, etc. used in the standard solution filler according to the present embodiment are the same as or common to those described in the above-described first or second embodiment. , These specific explanations will be omitted in this embodiment.
[0104]
　The "initial pH" in the present embodiment means the pH in the period from immediately after the standard solution is filled in the closed container to the first day. The method of 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 a weak acid and monovalent or divalent metal ions to the standard solution. When the same weak acid metal salt as the source is contained, 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 include a method of adjusting the content of a metal salt of a weak acid, a method of bubbling a standard solution with carbon dioxide, and (3) a method of adding a small amount of acid so that the content exceeds this standard.
[0105]
　First, the method (1) will be described. As described in the first embodiment, a two-agent mixed type of agent A and agent B is used as a typical dialysate, and agent A contains an electrolyte component and an acid component. As described above, acetic acid, citric acid, lactic acid, and hydrochloric acid can be used as the acid component, and a plurality of types of monovalent or divalent including sodium ion, potassium ion, calcium ion, and magnesium ion can be used as the electrolyte component. Contains metal ions. Further, as a source of these metal ions, acetates, citrates, lactates, chlorides and the like of these metal ions can be used.
[0106]
　Therefore, based on the composition of the dialysate to be prepared, the composition of the standard solution is adjusted so that the content of the metal ion is equivalent to this standard and the content of the acid component is larger than this standard. Specifically, for example, if a metal salt of a weak acid which is an acid component is used as a source of metal ions, the metal salt of the weak acid becomes a factor for raising the pH of the standard solution. Therefore, by increasing the content of the weak acid, 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 maintained at the same level as the standard. adjust.
[0107]
　More specifically, in the method (1), when the composition of the dialysate to be prepared is used as the reference composition, the content of metal ions in the composition of the standard solution is compared with the content of the reference composition. It is in a range that can be regarded as substantially equivalent, and 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.
[0108]
　For example, in Example 7 or 8 described later, 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 sodium chloride is increased in order to increase the content of anhydrous citric acid, decrease the content of sodium citrate, and make the content of sodium ions substantially equal to the standard. Therefore, the initial pH of the standard solution can be lowered within 0.4.
[0109]
　Here, when viewed as a component in the standard solution, a weak acid can behave as a pH-buffering acid, and any one of the metal ions can behave as a pH-buffering conjugate base. In Example 7, anhydrous citric acid can behave as a weak acid in the pH buffer system and sodium citrate hydrate can behave as a conjugate base in the pH buffer system. Therefore, it is possible not only to lower the initial pH in anticipation of an increase in pH, but also to make it difficult for the pH of the dialysate standard solution to increase due to the pH buffering action.
[0110]
　The specific type of the weak acid is not particularly limited, and acetic acid, lactic acid, or the like described in the first embodiment can be used in addition to the citric acid exemplified in the examples. The type of metal ion is not particularly limited, and a potassium salt or the like can be used in addition to the sodium salt exemplified in the examples. In particular, sodium ion or potassium ion can be a strong base, and it is easy to construct a pH buffer system by combining with a weak acid. Further, as described above, sodium chloride is the most important salt essential in the living body, and it is preferable that at least sodium chloride is used as a source of sodium ions. Therefore, sodium ion is more preferably used as the metal ion. Further, depending on the degree of pH adjustment, as illustrated in Example 8, a metal salt of a weak acid such as sodium citrate may not be contained.
[0111]
　Next, the method (2) will be described. By bubbling carbon dioxide with respect to the prepared standard solution, the initial pH of the standard solution can be adjusted low. The bubbling conditions (bubbling method, bubbling time, etc.) at this time are not particularly limited, and a known method can be preferably used. The standard solution after bubbling does not need to be dissolved until carbon dioxide is saturated, and the initial pH of the standard solution may be lower than the reference pH within 0.4 by bubbling. .. In the examples described later, Example 9 corresponds to the method (2).
[0112]
　Next, the method (3) will be described. The initial pH of the standard solution can be adjusted to be low by adding an acid to the prepared standard solution. Here, the type 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 by decomposition or alteration. Specifically, for example, strong acids such as hydrochloric acid, nitric acid, and sulfuric acid; acid components (acetic acid, citric acid, lactic acid, hydrochloric acid, etc.) that can be contained in the agent A; organic acids described as the pH adjuster in the first embodiment. (Citric acid, oxalic acid, tartaric acid, maleic acid, ascorbic acid, oxaloacetic acid, gluconic acid, isocitrate, malic acid, pyruvate, etc.); and the like. Only one type of these acids may be used, but two or more types may be used in appropriate combinations.
[0113]
　Here, in 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, and among them, the electrolyte component contained in the standard solution. Hydrochloric acid is preferably used. Further, the concentration of the acid is not particularly limited as long as it is thin enough to adjust the initial pH to be lower than the reference pH within 0.4. In particular, when hydrochloric acid is used, dilute hydrochloric acid is preferably used from the viewpoint that the pH can be easily adjusted by dropping. In the examples described later, Example 10 corresponds to the method (3).
[0114]
　In any of the methods (1) to (3) (or in any other method), the degree to which the initial pH of the standard solution is lowered 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 will be lower than the reference pH, and there is a risk that it cannot be properly used as the standard solution. For example, if 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. In this case, if the initial pH of the standard solution is adjusted to less than 7.85 and 7.45 or more, preferably about 7.5 (for example, within the range of 7.45 to 7.65), as in Examples 7 to 10. In addition, the maximum pH value at the time of storage can be maintained at around 7.85 (for example, within the range of 7.7 to 8.0). However, if the initial pH of the standard solution is lowered by more than 0.4 as in Comparative Example 14, the maximum pH value at the time of storage also remains low.
[0115]
　Here, as described in the second embodiment, in the standard solution filler, when the voids are present, the bicarbonate in the standard solution is decomposed into carbon dioxide and released into the voids over time in pH. Will lead to a sharp rise. Therefore, in the present embodiment, for example, in any of the methods (1) to (3), if the volume of the void portion is too large, there is a possibility that the increase in pH during storage cannot be effectively suppressed. Therefore, in the present embodiment, in any of the methods (1) to (3) (or other methods), the filling rate of the standard solution is preferably 70% or more, and is 75% or more. Is more preferable.
[0116]
　Even in the method of (4) filling a closed container with an enclosed gas composed of air or nitrogen gas and carbon dioxide together with the standard solution as in the first embodiment, the initial pH of the standard solution can be adjusted. It can be lower than the reference pH within 0.4 (see, for example, the results of the first day in Examples 1 to 4, FIGS. 1 and 2 described later). Therefore, it can be said that the configuration disclosed in the first embodiment is one of the configurations disclosed in the third embodiment.
[0117]
　Further, as described above, also in the third embodiment, the dialysate is exemplified as the bicarbonate-containing preparation to be filled in the closed container as in the first or second embodiment, but the present disclosure is not limited to this. , The bicarbonate-containing preparation may be any as long as it contains bicarbonate (bicarbonate) and is used for the preparation of dialysate. Therefore, also in the third embodiment, the agent B may be filled in a closed container as a bicarbonate-containing preparation, or another bicarbonate-containing preparation may be filled in the closed container.
Example
[0118]
　The present invention will be described in more detail based on Examples, Comparative Examples and Reference Examples, but the present invention is not limited thereto. One of ordinary skill in the art can make various modifications, modifications, and modifications without departing from the scope of the present invention.
[0119]
　(Preparation of dialysate standard solution) As
　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 citrate 3.9 g / L and sodium citrate hydrate 1.4 g / L are used, and sodium chloride 2.35 g / L and sodium hydrogen carbonate 5.92 g / L are contained as the agent B. I used what I did. A 1 L standard solution was prepared by mixing 27.2 mL of Agent A and 49.7 mL of Agent B with dialysis water and diluting them.
[0120]
　(Example 1)
　A glass vial having a capacity of 10 mL is filled with the above-mentioned standard solution so as to have a volume of 80% by volume, and a mixed gas of 12% by volume of carbon dioxide and 88% by volume of air is used as a filling gas. It was filled to 20% by volume and sealed with a rubber stopper with an aluminum cap. As a result, the standard liquid filler of Example 1 was prepared (manufactured).
[0121]
　This standard solution filler was stored at room temperature (within the range of room temperature (25 ° C. ± 15 ° C.)) for up to 2 weeks. Using a commercially available pH meter (manufactured by HORIBA, Ltd., trade name LAQUAtwin B712), measure the pH of the standard solution before filling, and measure the pH of the standard solution 1 day after storage, 1 week after storage, and 2 weeks after storage. Were measured respectively. The results are shown in graphs of the black rhombus symbols of FIGS. 1 and 2. The pH of the dialysate standard solution before filling was 7.8.
[0122]
　(Example 2)
　A standard liquid filler of Example 2 is prepared (manufactured) in the same manner as in Example 1 except that an enclosed gas of 19% by volume of carbon dioxide and 81% by volume of air is used as the encapsulating gas. At the same time, the pH of the standard solution before filling, 1 day after storage, 1 week after storage, and 2 weeks after storage was measured. The result is shown in the graph of the black circle symbol in FIG. The pH of the standard solution before filling was 7.8.
[0123]
　(Comparative Example 1)
　A standard liquid filler of Comparative Example 1 was prepared (manufactured) in the same manner as in Example 1 except that only air (100% by volume of air) was used as the filled gas, and before filling, The pH of the standard solution 1 day after storage, 1 week after storage, and 2 weeks after storage was measured. The result is shown in the graph of the white rectangular symbol in FIG. The pH of the standard solution before filling was 7.8.
[0124]
　(Comparative Example 2)
　A standard liquid filler of Comparative Example 2 was prepared (manufactured) in the same manner as in Example 1 except that nitrogen (100% by volume of nitrogen) was used as the encapsulating gas, and was stored before filling. The pH of the standard solution after 1 day, 1 week after storage, and 2 weeks after 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.
[0125]
　(Comparative Example 3)
　A standard liquid filler of Comparative Example 3 was prepared (manufactured) and filled in the same manner as in Example 1 except that only carbon dioxide (100% by volume of carbon dioxide) was used as the filled gas. The pH of the standard solution before, 1 day after storage, 1 week after storage, and 2 weeks after storage was measured. The result is shown in the graph of the white circle symbol in FIG. The pH of the standard solution before filling was 7.9.
[0126]
　(Comparison of Examples 1 and 2 and Comparative Examples 1 to 3)
　As is clear from the results of Examples 1 and 2, a mixed gas containing carbon dioxide in the range of 3 to 20% by volume was used as the encapsulating gas. If the standard solution filler was prepared, the pH of the standard solution could be maintained in the range of 7.4 to 8.0 without excessively decreasing even after storage for 2 weeks.
[0127]
　On the other hand, as is clear from the results of Comparative Examples 1 and 2, when the standard solution filler was prepared using only air or nitrogen as the enclosed gas, the pH of the standard solution exceeded 8.0. Further, as is clear from the results of Comparative Example 3, when the enclosed gas is only carbon dioxide, the pH drops to less than 7.0 (pH 6.8) on the first day of storage, and after 1 week and 2 weeks, In each case, the pH was about 7.0, which was lower than 7.4.
[0128]
　In particular, as is clear from FIG. 2, if the enclosed gas is only carbon dioxide (Comparative Example 3), the pH drops significantly in the initial stage after filling, but according to the present invention (Examples 1 and 2). , It is possible to effectively suppress a large change in the initial pH.
[0129]
　(Example 3)
　A standard liquid filler of Example 3 is prepared (manufactured) in the same manner as in Example 1 except that the storage temperature is set to an acceleration condition of 40 ° C. instead of room temperature (therefore, as the enclosed gas, , 12% by volume of carbon dioxide and 88% by volume of air), and the pH of the standard solution before filling, 1 day after storage, 1 week after storage, and 2 weeks after storage was measured. The result is shown in the graph of the black rhombus symbol in FIG. The pH of the standard solution before filling was 7.8.
[0130]
　(Example 4)
　A standard liquid filler of Example 4 is prepared (manufactured) in the same manner as in Example 2 except that the storage temperature is set to an acceleration condition of 40 ° C. instead of room temperature (therefore, as the enclosed gas, , A mixed gas of 19% by volume of carbon dioxide and 81% by volume of air was used), and the pH of the standard solution before filling, 1 day after storage, 1 week after storage, and 2 weeks after storage was measured. The result is shown in the graph of the black circle symbol in FIG. The pH of the standard solution before filling was 7.8.
[0131]
　(Comparative Example 4)
　A standard liquid filler of Comparative Example 4 is prepared (manufactured) in the same manner as in Comparative Example 1 except that the storage temperature is set to an acceleration condition of 40 ° C. instead of room temperature (therefore, as the enclosed gas, The pH of the standard solution before filling, 1 day after storage, 1 week after storage, and 2 weeks after storage was measured together with (using only air). The result is shown in the graph of the white rectangular symbol in FIG. The pH of the standard solution before filling was 7.8.
[0132]
　(Comparative Example 5)
　A standard liquid filler of Comparative Example 5 is prepared (manufactured) in the same manner as in Comparative Example 2 except that the storage temperature is set to an acceleration condition of 40 ° C. instead of room temperature (therefore, as the enclosed gas, The pH of the standard solution before filling, 1 week after storage, and 2 weeks after storage was measured together with (using only nitrogen). 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.
[0133]
　(Comparative Example 6)
　A standard liquid filler of Comparative Example 6 is produced (manufactured) in the same manner as in Comparative Example 3 except that the storage temperature is set to an acceleration condition of 40 ° C. The pH of the standard solution before filling, 1 week after storage, and 2 weeks after storage was measured together with (using only carbon dioxide). The result is shown in the graph of the white circle symbol in FIG. The pH of the standard solution before filling was 7.9.
[0134]
　(Comparison of Examples 3 and 4 and Comparative Examples 4 to 6) Since all of
　Examples 3 and 4 and Comparative Examples 4 to 6 are stored at 40 ° C., the pH rise of the standard solution is accelerated compared to storage at room temperature. It is a condition to do. Even under such acceleration conditions, as is clear from the results of Examples 3 and 4, a standard liquid filler is filled with a mixed gas containing carbon dioxide in the range of 3 to 20% by volume as the encapsulating gas. The pH of the standard solution could be maintained in the range of 7.4 to 8.0 without being excessively lowered even after storage for 2 weeks.
[0135]
　On the other hand, as is clear from the results of Comparative Examples 4 and 5, when the standard solution filler was prepared using only air or nitrogen as the enclosed gas, the pH of the standard solution exceeded 8.0. Further, as is clear from the result of Comparative Example 6, when the enclosed gas was only carbon dioxide, the pH decreased with time, and the pH was lower than 7.4 after 2 weeks.
[0136]
　(Example 5)
　A glass vial having a capacity of 10 mL was filled with the above-mentioned standard solution so as to have a volume of about 100%, and sealed with a rubber stopper with an aluminum cap. As a result, the standard liquid filler of Example 5 was prepared (manufactured).
[0137]
　This standard solution filler was stored at room temperature (within the range of room temperature (25 ° C. ± 15 ° C.)) for up to 4 weeks. Using a commercially available pH meter (manufactured by HORIBA, Ltd., trade name LAQUAtwin B712), the pH of the standard solution before filling is measured, and 1 day after storage, 1 week after storage, 2 weeks after storage, and 4 weeks after storage. The pH of the dialysate standard solution was measured. The results are shown in the graphs of the black diamond symbols of FIGS. 5 and 6. The pH of the standard solution before filling was 7.8.
[0138]
　(Comparative Example 7) Comparative Example 7 in the same
　manner as in Example 5 except that the glass vial was filled with a standard solution so as to be 80% by volume and air was filled so as to be 20% by volume. In addition to preparing (manufacturing) the standard solution filler, the pH of the standard solution before filling, 1 day after storage, 1 week after storage, 2 weeks after storage, and 4 weeks after storage was measured. The result is shown in the graph of the white rectangular symbol of FIG. The pH of the standard solution before filling was 7.8.
[0139]
　(Comparative Example 8)
　A standard liquid filler of Comparative Example 8 was prepared (manufactured) in the same manner as in Comparative Example 7 except that nitrogen was filled in place of air so as to be 20% by volume, and before filling, The pH of the standard solution was measured 1 day after storage, 1 week after storage, and 2 weeks after storage. 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.
[0140]
　(Comparative Example 9)
　A standard liquid filler of Comparative Example 9 was prepared (manufactured) in the same manner as in Comparative Example 7 except that carbon dioxide was filled in place of air so as to be 20% by volume, and before filling. The pH of the standard solution was measured 1 day after storage, 1 week after storage, and 2 weeks after storage, respectively. The result is shown in the graph of the white circle symbol in FIG. The pH of the standard solution before filling was 7.9.
[0141]
　(Example 6)
　A standard liquid filler of Example 6 was prepared (manufactured) in the same manner as in Example 5 except that the storage temperature was set to an acceleration condition of 40 ° C. instead of room temperature, and storage before filling and storage 1 After a week and after 2 weeks of storage, the pH of the standard solution was measured. The result is shown in the graph of the black rhombus symbol in FIG. The pH of the standard solution before filling was 7.7.
[0142]
　(Comparative Example 10) The
　glass vial is filled with a standard solution so as to be 70% by volume, air is filled with 30% by volume, and the storage temperature is set to an acceleration condition of 40 ° C. instead of normal temperature. The standard solution filler of Comparative Example 10 was prepared (manufactured) in the same manner as in Example 6 and the pH of the standard solution before filling, 1 week after storage, 2 weeks after storage, and 4 weeks after storage. Were measured respectively. The result is shown in the graph of the white rectangular symbol of FIG. The pH of the standard solution before filling was 7.7.
[0143]
　(Comparative Example 11)
　A standard solution filler of Comparative Example 10 is prepared (manufactured) in the same manner as in Comparative Example 8 except that the storage temperature is set to an acceleration condition of 40 ° C. instead of room temperature (thus, nitrogen is produced together with the standard solution. The pH of the standard solution was measured before filling, 1 week after storage, and 2 weeks after storage. The result is shown in the graph of the white circle symbol in FIG. The pH of the standard solution before filling was 7.8.
[0144]
　(Comparative Example 12)
　A standard solution filler of Comparative Example 12 is prepared (manufactured) in the same manner as in Comparative Example 9 except that the storage temperature is set to an acceleration condition of 40 ° C. instead of room temperature (thus, carbon dioxide is produced together with the standard solution). The pH of the standard solution before filling, 1 week after storage, and 2 weeks after storage was measured together with (filled with carbon dioxide). 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.
[0145]
　(Comparison between Examples 5 and 6 and Comparative Examples 7 to 12)
　As is clear from the results of Example 5, a standard solution filled with a standard solution at the capacity limit (or until the capacity limit is not exceeded and does not overflow) of the closed container. In the packed material, since the inside of the closed container is substantially only the standard solution, the pH of the dialysate standard solution does not change excessively even after storage for 4 weeks, and the pH is 7.4 to 8.0. Was able to be maintained within the range of.
[0146]
　On the other hand, as is clear from the results of Comparative Examples 7 and 8, when air or nitrogen was filled together with the standard solution, the pH of the standard solution increased to around 8.0 or exceeded 8.0. Furthermore, as is clear from the results of Comparative Example 9, when carbon dioxide was filled together with the standard solution, the pH dropped significantly to less than 7.0 (pH 6.8) on the first day of storage, and after 1 week and 2 After a week, the pH was about 7.0, which was lower than 7.4.
[0147]
　In both Example 6 and Comparative Examples 10 to 6, since the standard solution filler is stored at 40 ° C., it is a condition that the pH increase of the dialysate standard solution is accelerated more than the storage at room temperature. Under such acceleration conditions, if air is filled with the standard solution as in Comparative Example 10 or nitrogen is filled with the standard solution as in Comparative Example 11, the pH will exceed 8.0. When carbon dioxide was filled 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 in the range of 7.4 to 8.0 even when stored for 2 weeks under accelerated conditions. Was made.
[0148]
　(Comparative Example 13) As
　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. The one contained in 3.9 g / L of citrate and 1.4 g / L of sodium citrate hydrate is used, and 23.5 g / L of sodium chloride and 59.2 g / L of sodium hydrogen carbonate are contained as the agent B. I used the one. A 1 L standard solution was prepared by mixing 27.2 mL of Agent A and 49.7 mL of Agent B with dialysis water and diluting them.
[0149]
　The initial pH of the adjusted standard solution was measured using a commercially available pH meter (manufactured by HORIBA, Ltd., trade name LAQUAtwin B712) and found to be 7.85. This pH = 7.85 is a reference value (reference pH) for pH adjustment in Examples 7 to 10 and Comparative Example 14 below.
[0150]
　A glass vial having a capacity of 10 mL was filled with the standard solution to a volume of 80% by volume, and sealed with a rubber stopper with an aluminum cap. As a result, the standard liquid filler of Comparative Example 13 was prepared (manufactured).
[0151]
　This standard solution filler was allowed to stand at room temperature (within the range of room temperature (25 ° C. ± 15 ° C.)) for 2 weeks and stored. Using the pH meter, the pH of the standard solution was measured multiple times during the storage period. The result is shown in the graph of the white triangle symbol in FIG. The maximum pH value of the standard solution during the storage period was 8.13 (1 week after storage).
[0152]
　(Example 7)
　The content of sodium chloride in Agent A was 183.6 g / L, the content of anhydrous citric acid was 4.06 g / L, and the content of sodium citrate hydrate was 0.35 g / L. A standard solution was prepared in the same manner as in Comparative Example 13 except that. The initial pH of this standard solution was measured and found to be 7.55. As described above, if the reference pH is 7.85, in this example, the initial pH of the standard solution is adjusted so as to be lowered by about 0.3 from the reference value.
[0153]
　Then, in the same manner as in Comparative Example 13, the standard solution filler of Example 7 was prepared (manufactured) using the standard solution. This standard solution filler was allowed to stand at room temperature for 12 weeks in the same manner as in Comparative Example 13 and stored. Using the pH meter, the pH of the standard solution was measured after 1 week of storage, 2 weeks after storage, 4 weeks after storage, 8 weeks after storage, and 12 weeks after storage, respectively. The result is shown by a solid line graph of the black circle symbol in FIG. The pH (initial pH) of the standard solution before filling was 7.55 as described above, and the maximum pH value of the standard solution during the storage period was 7.85 (2 weeks after storage).
[0154]
　(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). A standard solution was prepared in the same manner as in Comparative Example 13 except for / L). The initial pH of this standard solution was measured and found to be 7.58. As described above, if the reference pH is 7.85, in this example, the initial pH of the standard solution is adjusted so as to be lowered by about 0.27 from the reference value.
[0155]
　Then, in the same manner as in Comparative Example 13, the standard liquid filler of Example 8 was prepared (manufactured) using the standard liquid. The pH of the standard solution was measured multiple times during the storage period of the standard solution filler. The result is shown in the graph of the black rhombus symbol in FIG. The maximum pH value of the standard solution during the storage period was 7.98 (2 weeks after storage).
[0156]
　(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). A standard solution was prepared in the same manner as in Comparative Example 13 except for / L). The initial pH of this standard solution was measured and found to be 7.30. As described above, if 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.
[0157]
　Then, in the same manner as in Comparative Example 13, the standard solution filler of Comparative Example 14 was prepared (manufactured) using the standard solution. The pH of the standard solution was measured multiple times during the storage period of the standard solution filler. The result is shown in the graph of the white circle symbol in FIG. The maximum pH value of the standard solution during the storage period was 7.74 (2 weeks after storage).
[0158]
　(Example 9)
　A standard liquid filler of Example 9 was prepared (manufactured) in the same manner as in Example 7 except that the storage temperature was set to an acceleration condition of 40 ° C. instead of room temperature, and storage before filling 1 The pH of the standard solution was measured after 1 week, 2 weeks after storage, 4 weeks after storage, 8 weeks after storage, and 12 weeks after storage, respectively. The result is shown by a dotted line graph of the black rhombus symbol in FIG. The pH (initial pH) of the standard solution before filling was 7.55, and the maximum pH value of the standard solution during the storage period was 7.95 (1 week after storage).
[0159]
　(Example 10)
　A standard solution having the same composition as that of Comparative Example 13 was prepared, and the standard solution was bubbled with carbon dioxide before being filled in a glass vial having a capacity of 10 mL. The initial pH of the standard solution after bubbling was 7.61. As described above, assuming that 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.
[0160]
　Then, in the same manner as in Comparative Example 13, the standard solution filler of Example 10 was prepared (manufactured) using the standard solution after bubbling. The pH of the standard solution was measured multiple times during the storage period of the standard solution filler. The result is shown by a 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 (2 weeks after storage).
[0161]
　(Example 11)
　A standard solution having the same composition as that of Comparative Example 13 was prepared, and dilute hydrochloric acid was added dropwise to the standard solution before filling it in a glass vial having a capacity of 10 mL to adjust the initial pH to 7.61. .. As described above, assuming that 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 dilute hydrochloric acid.
[0162]
　Then, in the same manner as in Comparative Example 13, the standard solution filler of Example 11 was prepared (manufactured) using the standard solution after dropping dilute hydrochloric acid. The pH of the standard solution was measured multiple times during the storage period of the standard solution filler. The result is shown by a dotted line graph of the black triangle symbol in FIG. The maximum pH value of the standard solution during the storage period was 7.94 (1 week after storage).
[0163]
　(Comparison between Examples 7 to 11 and Comparative Examples 13 and 14)
　As is clear from the results of Comparative Example 13, if the initial pH is the reference pH, the maximum value of pH at the time of storage exceeds 8.0. .. On the other hand, as is clear from the results of Examples 7 and 8, if the content ratio of citric acid and sodium ion is adjusted so that the initial pH is lowered within 0.4, the pH at the time of storage is adjusted. The maximum value of can be around the reference pH.
[0164]
　Further, as is clear from the results of Examples 7 and 9, the pH of the dialysate standard solution may be stored at room temperature (Example 7) for 12 weeks or under accelerated conditions (Example 9) for 12 weeks. Was able to maintain around the reference pH without excessive change.
[0165]
　Further, as is clear from the results of Examples 10 and 11, even if the standard solution is bubbled with carbon dioxide or dilute hydrochloric acid is added dropwise, if the initial pH is lowered within 0.4, it will be stored. The maximum value of pH can be around the reference pH. However, as is clear from the results of Comparative Example 14, if the initial pH is lowered beyond 0.4, the maximum pH value at the time of storage will be significantly lower than the reference pH.
[0166]
　As described above, the dialysate standard solution filler according to the present disclosure is filled with the dialysate standard solution in a volume smaller than that of the standard solution by filling the voids in the closed container with the filling gas. It is composed of air or nitrogen gas and carbon dioxide, and is a mixed gas having a carbon dioxide content in the range of 3 to 20% by volume.
[0167]
　As a result, even if the pH of the filled dialysate standard solution rises, it can be maintained within a suitable range, and insoluble salts are prevented from being generated as the pH of the dialysate standard solution rises. be able to. In addition, a significant decrease in pH that occurs when the enclosed gas is only carbon dioxide can be effectively suppressed. Therefore, the dialysate standard solution can be stably stored for a long period of time, and the concentration of the dialysate prepared at the site of use can be appropriately adjusted. As a result, even when the dialysate is prepared at the site of use at any time, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared.
[0168]
　Further, in the other dialysate standard solution fillers according to the present disclosure, the standard solution is filled in the closed container until the capacity limit of the closed container or the capacity limit of the closed container is not exceeded and the standard solution does not overflow. .. As a result, the inside of the closed container is substantially filled with the dialysate standard solution, so that the generation of insoluble carbonate in the dialysate standard solution and the decomposition of the hydrogen carbonate into carbon dioxide are avoided. At the same time, the pH can be maintained within a predetermined range even after long-term storage. Therefore, the dialysate standard solution can be stably stored for a long period of time, and the concentration of the dialysate prepared at the site of use can be appropriately adjusted. As a result, even when the dialysate is prepared at the site of use at any time, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared.
[0169]
　Further, in the other dialysate standard solution filler according to the present disclosure, the initial pH of the dialysate standard solution after filling in a closed container is within 0.4 than the pH (reference pH) of the dialysate to be prepared. It is set low so that it becomes. 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 possible to avoid the formation of insoluble salts as the pH of the dialysate standard solution rises. it can. Therefore, the dialysate standard solution can be stably stored for a long period of time, and the concentration of the dialysate prepared at the site of use can be appropriately adjusted. As a result, even when the dialysate is prepared at the site of use at any time, it is possible to suppress variations in the concentration of the dialysate without being limited by the amount to be prepared.
[0170]
　Here, in any of the above-mentioned Examples and Comparative Examples, a standard solution of dialysate is filled in a closed container as a bicarbonate-containing preparation to prepare (manufacture) a standard solution filler, and the pH stability of the standard solution is stable. Is evaluated. However, the present disclosure is not limited to this, and as described in the above-described first to third embodiments, the bicarbonate-containing preparation contains a bicarbonate (bicarbonate) and is used for preparing a dialysate. Anything that can be done is sufficient. Therefore, whether it is a standard liquid filler in which Agent B is filled in a closed container as a bicarbonate-containing preparation, or a standard liquid filler in which another bicarbonate-containing preparation is filled in a closed container, the above-mentioned Examples and the like Needless to say, the same result as the above can be obtained.
[0171]
　The present invention is not limited to the description of the above-described embodiment, and various modifications can be made within the scope of the claims, and the present invention is disclosed in different embodiments and a plurality of modifications. Embodiments obtained by appropriately combining the above technical means are also included in the technical scope of the present invention.
Industrial applicability
[0172]
　The present invention can be widely and suitably used in the field of preparing a dialysate used for hemodialysis.
The scope of the claims
[Claim 1]
　A filler in which a standard solution of a bicarbonate-containing preparation used for preparing a dialysate for hemodialysis is filled in a closed container, and the
　closed container is made of a material having a gas barrier property, and the
　standard solution is used. A
standard liquid packing material , wherein the initial pH after filling is lower than the pH of the bicarbonate-containing preparation to be prepared .
[Claim 2]
　The bicarbonate-containing preparation is a dialysate, and the
　standard solution is prepared by mixing at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate and water at a preset mixing ratio. The
　standard solution filler according to
claim 1 , wherein the initial pH of the standard solution after filling is lower than the pH of the dialysate to be prepared within 0.4. ..
[Claim 3]
　The standard solution contains
　an acid component that is a weak acid and a plurality of types of monovalent or divalent metal ions including sodium ion, potassium ion, calcium ion, and magnesium ion, and the
　bicarbonate-containing preparation to be prepared. The composition according to
claim 1 or that the content of the metal ion is equal to the standard and the content of the acid component is larger than the standard. 2. The standard liquid filler according to 2.
[Claim 4]

The standard liquid filler according to claim 3, 　wherein the acid component is citric acid or acetic acid, and the metal salt of the weak acid is sodium citrate or sodium acetate .
[Claim 5]
　The closed container is filled with a filling gas that fills the voids in the closed container together with the standard solution, and the
　filled gas is composed of air or nitrogen gas and carbon dioxide, and has a carbon dioxide content.
The standard liquid filler according to claim 1 or 2, wherein the mixed gas is in the range of 3 to 20% by volume .
[Claim 6]
　When the capacity of the closed container is 100% by volume, the filling rate of the standard solution is in the range of 70 to 99% by volume, and the filling rate of the enclosed gas is in the range of 1 to 30% by volume. and wherein,
standard solution filling body according to claim 5.
[Claim 7]

The standard solution filler according to claim 1 or 2, 　wherein the standard solution is one in which carbon dioxide is bubbled .
[Claim 8]

The standard solution filler according to claim 1 or 2, 　wherein the standard solution is one to which an acid is added .
[Claim 9]
　A filler in which a standard solution of a bicarbonate-containing preparation used for preparing a dialysate for hemodialysis is filled in a
　closed container. The closed container is made of a material having a gas barrier property, and the
　standard solution is A
standard liquid filler , which is filled in the closed container up to the capacity limit of the closed container or to a state where the closed container does not overflow beyond the capacity limit .
[Claim 10]
　The bicarbonate-containing preparation is a dialysate, and the
　standard solution is prepared by mixing at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate and water at a preset mixing ratio.
The standard liquid filler according to claim 9 , characterized in that it is a product.
[Claim 11]
　The total volume of the closed container is 100 vol%, the as standard solutions filling rate is in the range of 80 to 100% by volume, characterized in that it is filled in the closed container,
wherein Item 9. The standard liquid filler according to Item 9.
[Claim 12]
　In the standard solution of the bicarbonate-containing preparation,
　agent A, which is an acidic aqueous solution containing sodium ion, potassium ion, calcium ion, and magnesium ion, agent B containing hydrogen carbonate, and water are preset. The standard solution filling according to any one of claims 1 to 11
　, characterized in that it is a standard solution of the dialysate prepared by mixing at the mixing ratio, or the standard solution of the agent B.
body.
[Claim 13]

The standard liquid filler according to any one of claims 1 to 12, 　wherein the closed container is made of glass at least .
[Claim 14]
　A
dialysate preparation kit comprising the standard solution filler according to any one of claims 1 to 13 .
[Claim 15]
　A method for producing a standard solution filler by filling a closed container with a standard solution of a bicarbonate-containing preparation used when preparing a dialysate for hemodialysis. The
　closed container has a gas barrier property. A method for producing
　a
standard solution-filled body, which comprises a material to be prepared, and the initial pH after filling in the standard solution is adjusted to be lower than the pH of the dialysate to be prepared.
[Claim 16]
　The bicarbonate-containing preparation is a dialysate, which is
　prepared by mixing at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate and water at a preset mixing ratio. The
　standard solution filler according to
claim 15 , wherein 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 . Production method.
[Claim 17]
　The standard solution contains an acid component which is a weak acid and a plurality of types of monovalent or divalent metal ions including sodium ion, potassium ion, calcium ion, and magnesium ion, and the
　weight to be prepared. When the composition of the carbonic acid-containing preparation is used as a reference, the composition of the standard solution is adjusted so that the content of the metal ion is equal to the standard and the content of the acid component is higher than the standard. The
method for producing a standard solution filler according to claim 15 or 16, wherein the initial pH of the standard solution is adjusted accordingly .
[Claim 18]
　The initial pH is adjusted by filling the closed container together with the standard solution so that the volume of the filled gas filling the voids in the closed container is smaller than that of the standard solution
　.
The preparation of the standard liquid filler according to claim 15 or 16 , which is a mixed gas composed of air or nitrogen gas and carbon dioxide and having a carbon dioxide content in the range of 3 to 20% by volume. Method.
[Claim 19]
　The
method for producing a standard solution filler according to claim 15 or 16, wherein the initial pH of the standard solution is adjusted by bubbling the standard solution with carbon dioxide .
[Claim 20]
　The
method for producing a standard solution filler according to claim 15 or 16, wherein the initial pH of the standard solution is adjusted by adding an acid to the standard solution.
[Claim 21]
　A method for producing a standard solution filler by filling a closed container with a standard solution of a bicarbonate-containing preparation used when preparing a dialysate for hemodialysis. The
　closed container has a gas barrier property. The
　standard liquid is composed of the material to be contained, and the standard liquid is filled in the closed container until the capacity limit of the closed container or the capacity limit of the closed container is not exceeded and the
standard liquid does not overflow. Method of manufacturing a filler.
[Claim 22]
　The bicarbonate-containing preparation is a dialysate, which is
　prepared by mixing at least sodium ions, potassium ions, calcium ions, magnesium ions, bicarbonate and water at a preset mixing ratio. The
method for producing a standard liquid filler according to claim 21, wherein the standard liquid filler is produced.
[Claim 23]
　The standard solution of the bicarbonate-containing preparation is the standard solution of the dialysate, and is
　an acidic aqueous solution containing sodium ion, potassium ion, calcium ion and magnesium ion. Agent A and agent B containing a hydrogen carbonate. And water are mixed at a preset mixing ratio to prepare a standard solution of the dialysate, or the standard solution of the
　bicarbonate-containing preparation is the standard solution of the agent B. The
method for producing a standard liquid filler according to any one of claims 15 to 22, which is characterized .