JP5370716B2 - Method for preventing deformation of container filled with sodium bicarbonate-containing aqueous preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a deformation prevention method of a container filled up with a sodium hydrogencarbonate-containing aqueous formulation as a "B formulation" comprising a dialysate formulation for dialysis of artificial kidney. <P>SOLUTION: According to the deformation prevention method of the container filled up with the sodium hydrogencarbonate-containing aqueous formulation, a head space is provided in a plastic container and is filled up with the sodium hydrogencarbonate-containing aqueous formulation, a fixed amount of the air, 20 to 40% in particular, in the head space is discharged and the container is sealed up. Also, the sodium hydrogencarbonate content of the sodium hydrogencarbonate-containing aqueous formulation to fill up the container ranges from 5 to 9 w/v%. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a method for preventing deformation of a container filled with a sodium bicarbonate-containing aqueous preparation. More specifically, the present invention relates to a method for preventing deformation of a container observed in a plastic container filled with a high concentration sodium bicarbonate-containing aqueous preparation, and a package filled with the sodium bicarbonate-containing aqueous preparation.

  Conventionally, artificial kidney dialysis treatment has been performed in patients with chronic renal failure. That is, there is hemodialysis (HD) as a blood purification therapy in an artificial kidney dialysis treatment that is received by a patient with chronic renal failure, and a perfusate obtained by adding and diluting an aqueous solution containing blood, electrolyte, and sugar to be delivered from a human body to a dialysis artificial kidney. The solute is moved from the blood side to the dialysis side by a diffusion phenomenon with the concentration difference between blood and perfusate as a driving force across the semipermeable membrane, and the dialysis drainage is discharged from the discharge port and into the blood. It removes uremic substances such as urea and creatinine, and returns only clean blood from the outlet to the body.

  Conventionally, as a preparation for artificial kidney dialysis for preparing this perfusion solution for hemodialysis, so-called “agent A” containing various electrolyte components, pH adjusting agents and / or glucose, and high-concentration bicarbonate as an alkalizing agent. A so-called “agent B” consisting of an aqueous sodium bicarbonate solution containing ions is set, and in actual use, “agent B” is diluted with water to prepare a predetermined bicarbonate ion concentration, “Agent A” is added to the diluted solution, and 150 to 300 L is used as a perfusate.

  As the “A agent” and “B agent” constituting the preparation for dialysis, the reason why the individual components are individually packed as a preparation for artificial kidney dialysis is that the electrolyte component such as calcium ion or magnesium ion is provided. This is because it reacts with the bicarbonate ion of the alkalizing agent to produce a metal carbonate salt which is an insoluble compound, and is prepared as a dialysate for artificial kidney after use, after dilution and mixing.

  By the way, the sodium hydrogen carbonate contained in the “B agent” as the alkali agent is specifically a high concentration (about 7 to 9 w / v%) of carbonic acid obtained by dissolving 670 to 940 g of sodium hydrogen carbonate in 11.5 L. It is an aqueous solution of sodium hydride, and is a highly concentrated preparation that is not normally considered. Conventionally, a glass container has been used as a container filled with this high-concentration sodium bicarbonate aqueous solution because it requires sterilization. The reason for this is that when sterilizing a package of an aqueous solution containing sodium bicarbonate, carbon dioxide gas melted in the solution is released from the aqueous solution as the temperature rises due to heating and accumulates in the head space of the packaging container. Since the internal pressure of the packaging container is increased, when a plastic container is used as the packaging container, the plastic container is deformed by the increased internal pressure of the packaging body.

This deformation of the plastic container is observed not only in the sterilization process but also in the storage process after the preparation is prepared.
However, glass containers have the disadvantages of being easily damaged and heavy. Furthermore, when a glass container is used as a container, the glass is corroded by sodium bicarbonate, flakes are formed in the solution, and the effectiveness of sodium bicarbonate is reduced. Has the disadvantage of deteriorating.
Therefore, currently, a method of filling a plastic container with a high-concentration sodium hydrogen carbonate aqueous solution has been adopted, and various measures for preventing the plastic container from being deformed (for example, Patent Document 1) have been effective. The current situation is that there is no specific measure.
Japanese Patent Publication No. 3-3209

  Accordingly, an object of the present invention is to provide a method for preventing deformation of a sodium hydrogen carbonate-containing aqueous preparation as a “B agent” constituting an artificial kidney dialysate preparation, in a container filled with such a sodium hydrogen carbonate-containing aqueous preparation. The present invention also provides a package filled with the sodium bicarbonate-containing aqueous preparation.

  In order to solve such a problem, the present inventor has made various studies, and when a sodium bicarbonate-containing aqueous preparation is filled in a plastic container with a headspace, it is released from the aqueous solution after filling into the headspace. The plastic container can be prevented from being deformed by devising to keep the volume of the head space that is expanded by the generated carbon dioxide and the concentration of carbon dioxide in the head space in equilibrium with the concentration of carbon dioxide dissolved in the aqueous solution. The inventors have found that this is possible and have completed the present invention.

  Thus, as a basic aspect of the present invention for solving the above-described problems, a head space is provided in a plastic container and a sodium bicarbonate-containing aqueous preparation is filled, and a certain amount of air in the head space is filled. A method for preventing deformation of a container filled with a sodium hydrogencarbonate-containing aqueous preparation characterized by being evacuated and sealed.

  In more detail, this invention is said deformation | transformation prevention method about the container filled with the high concentration sodium hydrogencarbonate containing aqueous formulation whose content of sodium hydrogencarbonate is 5-9 w / v%.

  More specifically, as the deformation preventing method, a head space is provided in a plastic container and filled with a sodium bicarbonate-containing aqueous preparation, and the air in the head space is exhausted by 20 to 40%. This is a method for preventing deformation of a container filled with a sodium bicarbonate-containing aqueous preparation.

  According to another aspect of the present invention, a head space is characterized in that a plastic container is provided with a head space, which is filled with an aqueous preparation containing sodium hydrogen carbonate, and a certain amount of air in the head space is exhausted and sealed. This is a method of bringing the carbon dioxide concentration in the aqueous solution and the carbon dioxide concentration in the sodium hydrogencarbonate-containing aqueous preparation into an equilibrium state, and further, a package body filled with the sodium hydrogencarbonate-containing aqueous preparation thus filled.

  In more detail, the air in the head space is exhausted by 20 to 40%, and the carbon dioxide concentration in the head space and the carbon dioxide concentration in the sodium hydrogen carbonate-containing aqueous preparation are balanced. And also. It is the package body filled with the filled sodium hydrogencarbonate containing aqueous preparation.

By the method of the present invention, it is possible to prevent deformation of a plastic container filled with a high-concentration sodium hydrogen carbonate aqueous solution by a simple method.
In particular, the present invention provides a method for preventing deformation of a container filled with a sodium hydrogencarbonate-containing aqueous preparation, simply by forcing the air in the headspace (space) after filling the plastic container with the sodium bicarbonate-containing aqueous preparation. It can be performed by simple means such as exhausting and sealing, and improvement in productivity can be ensured.

Since the deformation | transformation of the container filled with the sodium hydrogencarbonate containing aqueous formulation can be prevented with the simple method of this invention, it will have the following advantages specifically.
(1) “A agent” and “B agent” constituting the dialysis preparation are enclosed in a cardboard box as a set and provided as an artificial kidney dialysis preparation, but deformation of the “B agent” container is prevented. For this reason, the bundled state with the “agent A” in the cardboard box is maintained, and as a result, the cardboard is not deformed and load collapse does not occur.
(2) Since the deformation of the cardboard box is also prevented, it is possible to avoid the difficulty in stacking products, and in particular, it is possible to avoid the problem that the pallet stacking strength used when transporting products is reduced, and the workability is reduced. Has the advantage of further improvement.
(3) “Agent A” and “Agent B” enclosed in a set in a cardboard box can be taken out smoothly. Conventionally, a considerable amount of force is required for taking out the “agent B” from the cardboard box due to the expansion of the container, but since there is no deformation, there is an advantage that it can be taken out very smoothly.
(4) Furthermore, liquid leakage from the cap due to container expansion can be avoided, and generation of defective products can be prevented.
(5) Moreover, it has the advantage that it avoids the point that the sitting of a container worsens and a deformation | transformation of an external shape can be prevented as a product.

  As described above, the present invention is basically characterized in that a plastic container is provided with a head space, which is filled with a sodium hydrogen carbonate-containing aqueous preparation, and a certain amount of air in the head space is exhausted and sealed. This is a method for preventing deformation of a container filled with a sodium bicarbonate-containing aqueous preparation.

Examples of the plastic container filled with the sodium hydrogencarbonate-containing aqueous preparation according to the present invention include plastic containers conventionally used for filling the “B agent” constituting the preparation for dialysis. For example, polyethylene (PE) , Polypropylene (PP), ethylene vinyl acetate copolymer (EVA), polyvinyl chloride (PVC), cyclic polyolefin (COC), and those blended or laminated at an appropriate ratio. it can.
The plastic container is preferably gas barrier.

The aqueous sodium bicarbonate-containing preparation filled in the plastic container according to the present invention is a preparation as a so-called “agent B” in the dialysate preparation for artificial kidney.
As described above, the dialysate preparation for artificial kidney is a hydrogen carbonate containing a so-called “agent A” containing various electrolyte components, a pH adjuster and / or glucose, and a high concentration bicarbonate ion as an alkalizing agent. It is comprised from what is called a "B agent" which consists of sodium aqueous solution, and this invention provides the container deformation | transformation prevention means about this "B agent".

  Generally in dialysis preparations for artificial kidneys, the amount of each component in the prepared perfusate is preferably the following concentration as a dialysis solution when diluted and mixed to an appropriate concentration.

Sodium ion 120-150 mEq / L,
Potassium ion 0-5 mEq / L,
Calcium ion 0-5 mEq / L,
Magnesium ion 0-2 mEq / L,
Chloride ion 55-135 mEq / L,
Bicarbonate ion 20-45 mEq / L,
Citrate ion 0.02-5 mEq / L,
Glucose 0-3.0 g / L

  Therefore, as a more specific prescription example, the following prescription examples can be given, for example.

  The above example is a specific example. For example, 26 volumes of water are added to 1 volume of the “B agent” and diluted, and 1 volume of “A agent” is added to 34 volumes of the diluted solution. Usually, 150 to 300 L is to be used as the perfusate.

  In addition, the above-mentioned specific prescription is a prescription preferably used to the last, and as the prepared perfusate, the compounding amount of each component is the above-described dialysate when diluted to an appropriate concentration and mixed. Any concentration is acceptable.

In the present invention, the plastic container is prevented from being deformed with respect to the “B agent” constituting the above-mentioned dialysis preparation, and this B agent specifically has a sodium bicarbonate concentration as the preparation. About 5 to 9 w / v%, preferably 7 to 8 w / v% (about 1,000 mEq / L), it is a high concentration aqueous preparation which is not usually considered.
In such a high concentration sodium hydrogen carbonate aqueous solution, the carbon dioxide partial pressure, that is, the carbon dioxide concentration in the space (head space) in contact with the solution increases in proportion to the concentration.

  That is, when a sodium bicarbonate aqueous solution is filled in a sealed container with a space, the sodium hydrogen carbonate aqueous solution is mixed with bicarbonate ions and carbonic acid (dissolved state) in a weakly acidic to neutral (pH 4 to 8) solution. The carbon dioxide gas is in an equilibrium state, the carbon dioxide gas is released out of the liquid, and the container is expanded and deformed by the released carbon dioxide gas.

  Specifically, sodium hydrogen carbonate in the chemical solution is dissociated to generate carbon dioxide, and a part thereof moves to the space. That is, the following equilibrium relationship is established in a closed system.

  That is, when the released carbon dioxide partial pressure, that is, the concentration of carbon dioxide in the space reaches the above equilibrium state between the carbon dioxide in the chemical solution, the carbon dioxide is not released, and no more containers No deformation occurs.

According to the study by the present inventor, it has been found that the carbon dioxide gas concentration (carbon dioxide partial pressure) is about 40% in the case of the high concentration sodium hydrogen carbonate aqueous solution as described above.
Therefore, if the amount corresponding to this carbon dioxide partial pressure is exhausted from the head space of the plastic container, the expansion of the container is recognized by the carbon dioxide released into the head space, but the expansion has reached the equilibrium state. The amount of exhausted gas is limited by the partial pressure, and no further expansion (deformation) of the container occurs.

These points are described below based on the test results examined by the present inventors instead of the examples.
Examination Example 1 : Examination of container expansion when the headspace of a plastic container is evacuated and sealed after filling with a high concentration sodium bicarbonate aqueous preparation
(1) The “B” agent of dialysis preparation 1 described in Table 1 above was used as an aqueous preparation containing high-concentration sodium hydrogen carbonate, which was used for confirming the exhaust effect of the headspace . That is, it is an aqueous preparation containing 672 g of sodium bicarbonate in 11.5 L.
When this aqueous preparation (11.5 L) is filled into a plastic container (made of PE), air is blown into the head space (about 1.0 L), the state is replaced with carbon dioxide-free condition, and sealed (plugged). The headspace air volume was exhausted by half (0.5 L) and plugged (exhaust product), and the plugged without exhausting as it was (normal product).
Each preparation (exhaust product and normal product) was allowed to stand at normal room temperature, and after 2 days, the expansion of the body width of the container, the internal pressure of the container, and the carbon dioxide concentration were measured.
In addition, the head space (the amount of air in the container) when filling the plastic container with 11.5 L of the aqueous preparation is about 1.0 L, and the concentration of carbon dioxide released to the head space is at least less than 50% and balanced. Assuming that it reaches the state, the exhaust amount from the head space was reduced to half (0.5 L), and the exhaust method was to evacuate by holding both sides of the container body by hand and denting it.
The results are summarized in Table 2 below.

(2) Examination of changes over time in trunk width, container internal pressure and carbon dioxide concentration Using the same “B agent” as in 1 above, after filling the plastic container, the normal product which does not exhaust the headspace, and the headspace An exhaust product was prepared by removing 500 mL of air accurately and plugging it. Exhaust from the head space was exactly 500 mL using an injection cylinder.
Changes in the body width, the container internal pressure, and the carbon dioxide concentration of the container from immediately after filling to 2 days later were measured over time.
The results are summarized in Table 3 below.

(3) Examination of carbon dioxide gas concentration in the headspace with respect to the concentration of the sodium hydrogencarbonate-containing solution The relationship between the sodium hydrogencarbonate concentration in the sodium hydrogencarbonate-containing solution and the carbon dioxide gas concentration in the headspace during filling was examined.
Two kinds of sodium hydrogen carbonate-containing solutions having different sodium hydrogen carbonate concentrations (two kinds of sodium hydrogen carbonate concentrations of 29 g / 500 mL and 41 g / 500 mL) are filled in a plastic container, respectively, under different temperature conditions (5, 25, The carbon dioxide concentration in the head space was measured after storage for 3 days (at the time of vapor-liquid equilibrium).
In the examination, after filling each sodium hydrogen carbonate-containing solution into a 500 mL plastic container, welding the cap, all the air in the container was drained with a syringe, 100 mL of air was correctly injected again, and stored under each condition. .
The 41 g / 500 mL sodium hydrogen carbonate-containing solution as the sodium hydrogen carbonate concentration is a concentration close to the saturation concentration, and both the 29 g / 500 mL 500 mL sodium hydrogen carbonate-containing solution are similar to the actual “B agent” concentration. .
The results are shown in Table 4 below.

From the above examination results, the following points were found.
(1) The carbon dioxide gas concentration in the headspace immediately after filling with the high concentration sodium bicarbonate-containing aqueous preparation is slight, but then the carbon dioxide concentration in the headspace gradually increases and reaches an almost equilibrium state in about half a day. .
(2) The carbon dioxide gas concentration in the headspace when reaching an equilibrium state varies depending on the storage temperature conditions, but when considering the normal distribution conditions, it is less than about 40%, and the headspace is caused by the released carbon dioxide gas. Increases to 1.5 times the capacity.
(3) By exhausting about half of the air in the head space, expansion (deformation) of the container can be prevented.

From the above studies, when filling the “B agent”, which is a high concentration sodium bicarbonate-containing aqueous preparation, into a plastic container, if the headspace air is exhausted at least about half and sealed, It has been found that the expansion (deformation) of the plastic container can be avoided at the stage where the gas concentration and the carbon dioxide concentration in the aqueous sodium hydrogen carbonate-containing preparation reach an equilibrium state.
Therefore, based on the above results, we examined the appropriate displacement from the headspace.

Examination example 2 : Examination about the appropriate exhaust amount from the head space (1) Preliminary examination A plastic container was filled with 11.5 L of water and plugged. The head space at that time was 1 L. The body width and the internal pressure of the container were measured when the air in the container was extracted from the head space using a syringe (negative pressure) and injected (positive pressure).
The results are shown in the following table.

  The deformation of the plastic container when filled with a high-concentration carbon dioxide-containing aqueous preparation is due to the increase in internal pressure due to the carbon dioxide released from the solution into the head space (space). For example, when the air in the container is extracted from the head space using a syringe, the internal pressure changes from normal pressure to negative pressure, so that the release of carbon dioxide gas from the solution until the equilibrium state is reached. Yes, even if the internal pressure rises, it is offset by the negative pressure, and in the equilibrium state, the head space can be brought to a substantially normal pressure state, thereby preventing the plastic container from being deformed. .

(2) Examination of proper displacement The internal pressure of a plastic container filled with “B agent” of dialysate 1 in Table 1, that is, a high-concentration sodium bicarbonate aqueous solution containing 940 g of sodium bicarbonate in 11.5 L. The amount of exhaust from the container head space in the case of setting to normal pressure (± several mmHg) was estimated.
[Estimation conditions]
Container headspace: 1000 mL
Carbon dioxide concentration during filling (room temperature): 5%
Carbon dioxide gas concentration in the head space in vapor-liquid equilibrium (normal temperature): about 40%

  The results are summarized in Table 6 below.

From the above specific results, it has been found that an appropriate displacement of 300 to 400 mL (30 to 40% exhaust) is appropriate for a head space of 1000 mL.
In addition, in the case of “agent B” of dialysate 2 in Table 1, that is, a high-concentration sodium bicarbonate aqueous preparation containing 940 g of sodium bicarbonate in 11.5 L, the amount of carbon dioxide at the time of gas-liquid equilibrium is considered. Then, it can be said that a larger amount of exhaust from the head space is better.

  From the above examination, a head space is provided in a plastic container and filled with a sodium hydrogencarbonate-containing aqueous preparation, and the air in the head space is exhausted and sealed. In particular, the air in the head space is exhausted by 20 to 40%. By doing so, it was found that prevention of deformation of the container filled with the aqueous sodium bicarbonate-containing preparation can be achieved.

  In addition, the sodium hydrogencarbonate-containing aqueous preparation filled in the plastic container in the present invention contains a high concentration of sodium hydrogencarbonate, and the degree of carbon dioxide release is greatly affected by temperature and is high temperature. The more carbon dioxide is released, the more easily the container is deformed. Therefore, the exhaust of air in the head space in the above is performed by discharging 20 to 40% of the air in the head space at normal temperature (20 ° C. ± 15 ° C.), preferably around 25 ° C. under normal working conditions. Prevention of deformation of a container filled with a sodium-containing aqueous preparation can be achieved.

  Considering that point, in the present invention, when a head space is provided in a plastic container and filled with an aqueous preparation containing sodium hydrogen carbonate, if about half of the air in the head space is exhausted and sealed, It can be said that the deformation | transformation of the container filled with the sodium hydrogencarbonate containing aqueous formulation can be prevented.

About the "B agent" of the actual dialysis preparation (AK-Solita DL) by the method of the present invention, when filling the plastic container, 35% of the headspace air is exhausted and sealed, and sterilized. Although the storage stability was examined, no deformation of the container was observed even after storage for 1 month at room temperature.
Therefore, this invention also provides the package filled with such a high concentration sodium hydrogencarbonate containing aqueous formulation as another aspect.

As described above, the method of the present invention can prevent deformation observed in a plastic container filled with a high concentration sodium hydrogencarbonate-containing aqueous preparation.
Therefore, since the deformation of the “B agent” container of the actual dialysis preparation is prevented, there is no liquid leakage from the container, and the binding state with the “A agent” in the cardboard box is maintained. There is no deformation and no cargo collapse occurs.
Further, the preparation can be taken out from the cardboard box very smoothly, and its medical contribution is great.

Claims (3)

Provided headspace within a plastic container having a gas barrier property, the content of sodium hydrogen filled with sodium hydrogen carbonate containing aqueous preparation is 5~9w / v%, the air in the headspace 20 to 40 A method for preventing deformation of a container filled with a sodium hydrogencarbonate-containing aqueous preparation, characterized in that it is evacuated and sealed. A head space is provided in a plastic container having gas barrier properties, and a sodium hydrogen carbonate-containing aqueous preparation having a sodium hydrogen carbonate content of 5 to 9 w / v% is filled, and the air in the head space is 20 to 40%. A method of bringing the carbon dioxide gas concentration in the head space and the carbon dioxide gas concentration in the sodium hydrogen carbonate-containing aqueous preparation into an equilibrium state, characterized by exhausting and sealing. A head space is provided in a plastic container having gas barrier properties, and a sodium hydrogen carbonate-containing aqueous preparation having a sodium hydrogen carbonate content of 5 to 9 w / v% is filled, and the air in the head space is 20 to 40%. A package filled with a sodium hydrogencarbonate-containing aqueous preparation characterized by being evacuated and sealed.