JPH09124491A - Bicarbonate ion-containing aseptic blend liquid agent or its pharmaceutical preparation and production of the preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bicarbonate ion-containing aseptic blend liquid agent containing calcium ion and/or magnesium ion together with bicarbonate ion, where the simultaneous blend of them has been impossible. SOLUTION: This aseptic blend liquid agent comprises a solution containing at least a metal ion (e.g. calcium ion and/or magnesium ion) capable of producing an insoluble compound by reacting with bicarbonate ion, bicarbonate ion and carboxylic ion (e.g. citric acid ion or malic acid ion) and having 50-300mmHg CO2 partial pressure.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an aseptic mixed solution or preparation containing bicarbonate ion and a method for producing the same, and more specifically, it does not allow simultaneous mixing because it forms a precipitate due to coexistence. And / or magnesium ion and bicarbonate ion (hydrogencarbonate ion: HCO ^3- ) "at least coexistent, and relates to an aseptic mixed solution or preparation containing bicarbonate ion and a method for producing the same. Further, the present invention particularly relates to a bicarbonate ion relating to “a sterile infusion solution for use in medical applications, a dialysate solution, etc.” in which calcium ions and / or magnesium ions, which are important as human body fluid components, are co-blended with bicarbonate ions. TECHNICAL FIELD The present invention relates to an aseptic compounded liquid preparation or preparation and a method for producing the same.

[0002]

2. Description of the Related Art Aseptic infusion solutions used for medical purposes, dialysate solutions such as filter-type artificial kidney replenisher solutions and peritoneal dialysate solutions are based on the human blood electrolyte composition. Prescription (Na, K, Ca, Mg, C
1, bicarbonate ion, etc.) is required.

[0003] However, calcium ions, magnesium ions and the like cannot co-form at the same time because they coexist with bicarbonate ions to form insoluble compounds (metal carbonates such as calcium carbonate and magnesium carbonate) and precipitate. Met. Therefore, calcium ions and / or
Alternatively, when a liquid preparation containing magnesium ion and bicarbonate ion is administered, it is generally practiced to mix the two before use.

[0004]

When calcium ions and / or magnesium ions and bicarbonate ions are mixed and used at the time of use, special techniques such as weakening the pH or mixing aseptically are necessary. In addition, there is a problem that the operation is complicated, and when used for a long period of time after mixing, insoluble compounds such as calcium carbonate are also formed, and there is a disadvantage that precipitation occurs.

On the other hand, bicarbonate ion used in combination with calcium ion and / or magnesium ion is the most preferred compounding component as an alkalizing agent to be administered to the human body.
In a solution containing sodium bicarbonate that generates bicarbonate ions, the pH of the solution becomes slightly alkaline.
Weakly alkaline solutions have strong vasostimulant properties and damage blood vessels.
Therefore, in a liquid formulation containing sodium bicarbonate, it is necessary to adjust it to neutral.

As a means for adjusting the solution to neutral, it is common to use a strong acid and / or an organic acid. However, the bicarbonate ion is decomposed by reacting with the acid, and the bicarbonate ion of the solution is increased. There is a disadvantage that the content is reduced, and therefore, there is a problem that the pH adjustment cannot be performed using the above-mentioned strong acid or organic acid in the liquid preparation containing bicarbonate ions. In addition, the bicarbonate ion-containing solution also has a problem that the bicarbonate ion is decomposed during storage or under the influence of heat during sterilization, and the content of the bicarbonate ion is reduced.

The present invention has been made in view of the above-mentioned problems and drawbacks, and the purpose thereof is as follows: Firstly, since coexistence causes precipitation, simultaneous blending is impossible. The present invention is to provide a “bicarbonate ion-containing aseptic compounded liquid preparation or preparation containing calcium ion and / or magnesium ion together with bicarbonate ion and a method for producing the same”. The present invention is to provide a bicarbonate ion-containing aseptic compounded liquid preparation or preparation that suppresses the decomposition of ions and suppresses the decrease of bicarbonate ion content and the increase of liquid agent pH with time. Aseptic infusion solution for medical use, which is particularly important as a human body fluid component, in which calcium ions and / or magnesium ions are simultaneously mixed with bicarbonate ions,
It is to provide "dialysis solution" etc. ・ Fourthly, it passes not only "precipitation-free aseptic mixed solution containing bicarbonate ion" but also injection level which does not allow the inclusion of fine particles. To provide an infusion solution.

[0008]

[Means for Solving the Problems] The present invention focuses on the CO ₂ partial pressure in an aseptic compounded liquid preparation (or formulation) containing bicarbonate ion, and the CO ₂ partial pressure is specified (50 to 300 mmHg By doing so, the above object is achieved. That is, the aseptic mixed solution containing bicarbonate ion according to the present invention is a metal ion that reacts with bicarbonate ion to produce an insoluble compound,
An aseptic liquid mixture containing at least bicarbonate ion and carboxylate ion, and having a CO ₂ partial pressure of “50 to 3”.
It is set to 00 mmHg "(Claim 1).

The aseptic combination preparation containing bicarbonate according to the present invention is a preparation comprising a gas impermeable container (particularly a glass container such as a vial or ampoule) filled with the above liquid agent. , The carbon dioxide concentration of the head space of the container is 5
-35 v / v% (Claim 2), comprising a gas-permeable plastic container packaged with a gas-impermeable secondary packaging material, and comprising the container filled with the liquid agent, The carbon dioxide concentration in the space between the packaging material and the container is 5 to 35 v / v% (claim 3).

Further, the method for producing a sterile mixed solution or preparation containing bicarbonate according to the present invention comprises: at least a metal ion, a bicarbonate ion and a carboxylate ion which react with bicarbonate ion to form an insoluble compound The pH of the aqueous solution is adjusted to “pH: 7.4 or less” by using carbon dioxide as a means for adjusting the pH of the aqueous solution, and then sterilized by heating (Claim 5). Fill a permeable container, enclose 5 to 35 v / v% carbon dioxide in the head space of the container, and sterilize by heating.
(Claim 6), ・ A gas-permeable plastic container is filled, the container is packaged with a gas-impermeable secondary packaging material, and "5-3" is placed in the space of the packaging material.
Carbon dioxide gas of 5 v / v% "is enclosed, and then heat sterilization is performed (Claim 7).

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. As described above, the bicarbonate ion-containing aseptic compounding solution or formulation according to the present invention has at least (1) weight as an essential compounding ingredient of the solution. It contains metal ions that react with carbonate ions to form insoluble compounds, (2) bicarbonate ions, and (3) carboxylate ions.

In the present invention, specific examples of the metal ion (1) include calcium ion and / or magnesium ion. Further, as the bicarbonate ion of (2), sodium hydrogen carbonate, a hydrogen carbonate such as sodium carbonate, or a carbonate which produces this ion can be blended.

Further, as the carboxylate ion of the above (3), acetic acid, malic acid, succinic acid, oxaloacetic acid, isocitric acid, maleic acid, fumaric acid, phthalic acid, malonic acid, α-ketoglutar which produces this ion. Acids, organic carboxylic acids such as oxalosuccinic acid can be added, but it is particularly preferable to use dicarboxylic acids or tricarboxylic acids such as citric acid and malic acid.

Further, in the present invention, when the above organic carboxylic acid is blended in the state of containing bicarbonate ion, the pH of the liquid agent shifts to the acidic side, so that the decomposition of bicarbonate ion occurs and the content thereof increases. Will be reduced. Therefore, the organic carboxylic acids to be blended are neutral salts (Na salt, K salt, Ca) in order to suppress the decomposition of bicarbonate ion.
(Salt, Mg salt, Li salt, ammonium salt, amino acid salt, etc.)
Is preferably used as.

In the aseptic mixed solution containing bicarbonate ion according to the present invention, it is necessary to adjust (lower) the pH of the solution, but with acids such as strong acids and organic acids generally used for this purpose, As described above, since sodium hydrogencarbonate is decomposed to reduce the bicarbonate ion content, it is not possible to use such acids as strong acids and organic acids for pH adjustment of the liquid preparation according to the present invention. Therefore,
The present invention is characterized in that carbon dioxide gas is particularly used as the pH adjuster.

That is, in the present invention, carbon dioxide is dissolved in the liquid agent to suppress the precipitation of Ca ⁺⁺ , Mg ^++, etc., but carbon dioxide is dissolved in the liquid agent as a means for dissolving the carbon dioxide. A method of bubbling, a method of enclosing carbon dioxide gas in the head space portion of a gas impermeable container filled with a liquid agent, or a liquid agent is filled in a gas permeable plastic container, and the container is gas impermeable.
A method of wrapping with the next packaging material and enclosing carbon dioxide in the space between this container and the packaging material, a method of sterilizing a gas permeable plastic container filled with a liquid agent in a carbon dioxide gas atmosphere of a desired concentration, Can be used alone or in combination.

In the present invention, in order to suppress the formation of precipitates and stabilize the liquid agent, it is essential to keep the carbon dioxide content (CO ₂ partial pressure) in the liquid agent in a stable state.
For example, it is necessary to dissolve carbon dioxide gas in the liquid agent and adjust its pH as follows by the above-mentioned "method of bubbling carbon dioxide gas into the liquid agent", which is also a feature of the present invention. That is, in the liquid agent according to the present invention,
The stable pH range is 7.4 to 6.5 (50 to 300 mmHg), the more stable range is 7.2 to 6.7 (70 to 250 mmHg), and the optimum range is 7.0 to 6.8 (120 to 200 mmHg). The numerical values in () is a CO ₂ partial pressure in the liquid (CO ₂ partial pressure which corresponds to the pH of each) in the pH range.

In addition, the preparation according to the present invention, after adjusting the pH of the liquid agent within the above range, fills the gas impermeable container with the liquid agent after the pH adjustment,
Carbon dioxide gas is sealed in the head space of the container, or, the liquid agent after the pH adjustment is filled in a gas-permeable plastic container, and the container is packaged with a gas-impermeable secondary packaging material. It is characterized in that carbon dioxide gas is sealed in the space portion of the material. In this case, the carbon dioxide concentration in the head space or the secondary packaging material space portion is within the following range. It is a feature of the present invention.

That is, in the preparation according to the present invention, the stable carbon dioxide concentration range is 5 to 35 V / V%, the more stable range is 7 to 25 V / V%, and the optimum range is 12 to 20 V / V%. Is. In this case, it is preferable that the CO ₂ partial pressure in the liquid agent and the carbon dioxide concentration in the head space of the gas-impermeable container or in the space of the secondary packaging material are in an equilibrium state.

Further, according to the present invention, a stable liquid agent can be obtained even if the head space or the secondary packaging material space is simply replaced with carbon dioxide gas without adjusting the pH of the liquid agent. It is included in the invention. In this case, the CO ₂ partial pressure in the liquid agent is 50 to 300 mmHg (preferably 70 to 250 mmH
g, optimally 120 to 200 mmHg), the concentration of the substituted carbon dioxide gas can be appropriately selected.

In this case, when the carbon dioxide gas having the same volume as that of the liquid agent (aqueous solution) is filled, the concentration of the substituted carbon dioxide gas is preferably selected within the following range.・ Stable carbon dioxide gas concentration range: 6-40V / V% → CO ₂ partial pressure in liquid agent: 50-300mmHg, pH: 7.
4 to 6.5.・ More stable carbon dioxide gas concentration range: 9-33V / V% → As a result, CO ₂ partial pressure in the liquid agent: 70-250mmHg, pH: 7.
2 to 6.7. - optimum carbon dioxide concentration range: 15~26V / V% → Thus CO ₂ partial pressure in the liquid: 120~200mmHg, pH:
It will be 7.0-6.8.

In the present invention, the CO ₂ partial pressure in the liquid agent is set to 50 to 3
The reason why the pressure is set to 00 mmHg is that when it is less than 50 mmHg, the effect of preventing precipitation associated with the formation of insoluble compounds of metal ions and the effect of suppressing decomposition of bicarbonate ion contained as an active ingredient, which is intended in the present invention, are less likely to occur. , 300 mm
If more than Hg, Injection of high liquid of such CO ₂ partial pressure, CO ₂ partial pressure in the blood is higher than the CO ₂ partial pressure in the cells, the intracellular pH by CO ₂ diffuses into the cell Is decreased, which causes a problem of inducing intracellular acidosis.

Here, a preferred embodiment of the method for producing the aseptic compounded preparation containing bicarbonate according to the present invention will be described.
First, a calcium salt (for example, CaCl), sodium citrate and sodium hydrogen carbonate are dissolved in water, and carbon dioxide gas is bubbled through this aqueous solution to adjust the pH to neutral (6.8 to 7.0). The solution is then filtered and then filled into a gas impermeable container, or into a gas permeable plastic container, which is then packaged with a gas impermeable secondary packaging material, and
In the head space of the gas impermeable container or in the space between the gas permeable plastic container and the secondary packaging material.
Enclose 12 to 20V / V% carbon dioxide gas. Then, high-pressure steam sterilization is carried out to produce a sterile mixed solution containing bicarbonate ions.

Further, in the above-described preferred embodiment of the present invention, calcium salt excluding sodium hydrogen carbonate and citric acid are dissolved in water, and this aqueous solution is treated with an alkali (for example, N 2
pH is adjusted beforehand with (aOH), sodium hydrogencarbonate is added to this, and then carbon dioxide gas is bubbled to adjust the pH to neutral.
It is preferably adjusted to (6.8 to 7.0).

Further, in the production method according to the present invention, a liquid agent which is not subjected to pH adjustment by bubbling carbon dioxide gas is filled in a gas impermeable container, or the liquid agent is filled in a gas permeable plastic container and further gas impermeable. A method of wrapping with a permeable secondary packaging material and replacing the head space portion of the gas impermeable container or the space portion of the packaging material with a desired amount of carbon dioxide gas is also a preferred embodiment of the present invention. is there.

As the above-mentioned "gas impermeable container", it is preferable to use a glass vial bottle or ampoule, but other than this, a gas impermeable plastic container can also be used. It is included in the invention.

[0027]

EXAMPLES Next, the present invention will be described in detail by giving Examples of the aseptic combination preparation containing bicarbonate ion of the present invention together with Comparative Examples.

Table 1 collectively shows the formulations 1 to 6 of the respective compounding components in Examples 1 to 6 below. (However, the present invention is not limited to only "prescriptions 1 to 6" shown in Table 1 below.)

[0029]

[Table 1]

(Example 1-1: Ringer's preparation) First, all the reagents of "formulation 1" shown in Table 1 above were dissolved in water and the volume was adjusted to 10 liters (pH measured value: 8.1), and 200 ml after filtration. Filled into a glass vial. Next, after replacing the head space (HS) part (HS volume: 75 ml) of this bottle with carbon dioxide gas having the concentration shown in Table 2 below, [pre-sterilization "replacement gas (CO ₂ : V / V%) ”column], and subjected to high-pressure steam sterilization at 115 ° C. for 15 minutes to obtain a Ringer's preparation. [Substitution gas (CO ₂ : V / V%): 10] in Table 2 below is a comparative example.

With regard to this Ringer's preparation, the "fine particle number (piece / ml)" after storage at 40 ° C for 3 months was measured, and the "presence or absence of precipitation" was visually inspected. The results are shown in Table 2. Further, "pH", "CO ₂ partial pressure", "CO ₂ concentration of HS" and "bicarbonate ion content" were measured after sterilization and after storage at 40 ° C for 3 months, and are also shown in Table 2.

[0032]

[Table 2]

Glass vial head space (HS)
In the comparative example in which 10 V / V% concentration of carbon dioxide gas was replaced in the part,
As is apparent from Table 2, the pH, CO ₂ partial pressure, and CO ₂ concentration of HS after storage at 40 ° C. for 3 months were “7.6”, “33 mmHg”, and “3.6 V / V” that were outside the ranges specified in the present invention. % ”. As a result of visual inspection, precipitation was recognized. On the other hand, “pH: 7.4 or less” and “CO ₂ partial pressure” specified in the present invention:
In the formulation of Example 1-1 in the range of 50 to 300 mmHg "CO ₂ concentration of HS: 5 to 35 V / V%", as is clear from Table 2 above, after storage at 40 ° C for 3 months, No precipitation was observed, and the bicarbonate ion concentration was maintained, and a good Ringer's preparation was obtained.

(Example 1-2: Ringer's preparation) First, all the reagents of "Formulation 1" shown in Table 1 above were dissolved in water, and the volume was adjusted to 10 liters (pH measured value: 8.1). 500 ml
Filled into a glass vial. Next, after the head space portion (HS capacity: 125 ml) of this bottle was replaced with carbon dioxide gas having the concentration shown in Table 3 below, [pre-sterilization “replacement gas (CO ₂ : V / V%) in Table 3 below] See, for example, high-pressure steam sterilization at 115 ° C. for 15 minutes to obtain a Ringer's preparation.

With respect to this Ringer's preparation, the "fine particle number (piece / ml)" after storage at 40 ° C for 6 months was measured, and the "presence or absence of precipitation" was visually inspected. Table 3 shows the results. Furthermore, after sterilization and storage at 40 ° C for 6 months, "pH", "CO ₂ partial pressure", "HS (head space)"
CO ₂ concentration ”and“ bicarbonate ion content ”of
Also shown in Table 3.

[0036]

[Table 3]

As is apparent from Table 3 above, in the Ringer's preparation of the present Example 1-2 within the ranges of "pH", "CO ₂ partial pressure" and "HS CO ₂ concentration" defined by the present invention, 40 No precipitation was observed even after storage at 6 ° C. for 6 months, and the bicarbonate ion concentration was maintained, and a good Ringer's preparation was obtained.

(Example 2: Infusion preparation) First, all the reagents of "formulation 2" shown in Table 1 above were dissolved in water, the volume was adjusted to 10 liters (pH measured value: 8.1), and carbon dioxide gas was bubbled. Then, the pH was adjusted to the value shown in Table 4 below, and the solution was filtered and then filled in a 200 ml glass vial. Then, high pressure steam sterilization was performed at 115 ° C for 15 minutes to obtain an infusion solution.

With respect to this infusion solution, the "fine particle number (piece / ml)" after storage at 40 ° C for 2 months was measured, and the "presence or absence of precipitation" was visually inspected. The results are shown in Table 4. Further, after sterilization and after storage at 40 ° C. for 2 months, “pH”, “CO ₂ partial pressure”, “CO ₂ concentration of HS” and “bicarbonate ion content” were measured, respectively, and also shown in Table 4.

[0040]

[Table 4]

As is apparent from Table 4 above, the infusion preparation of Example 2 in the range of "pH", "CO ₂ partial pressure" and "HS ₂ CO ₂ concentration" defined in the present invention was 40 ° C. No precipitation was observed even after storage for 2 months, and the bicarbonate ion concentration was retained, and a good infusion preparation was obtained.

(Example 3: Filter type replenisher for artificial kidney) First, all the reagents of "formulation 3" shown in Table 1 above were dissolved in water and the volume was adjusted to 10 liters (pH measured value: 8.1). ,
Carbon dioxide was bubbled to adjust the pH to 7.1, and after filtration, 500 ml was filled in a polyethylene plastic container. Next, the above-mentioned container is put into a secondary packaging bag (PE / glass vapor deposition P
ET / NY), and filled the space between the secondary packaging bag and the container with 10 V / V% carbon dioxide gas (space volume: 100 m
l). Then, high-pressure steam sterilization was performed at 110 ° C. for 30 minutes to obtain a filter-type artificial kidney replenisher solution formulation.

The replenisher solution preparation after sterilization was measured for "fine particle number (piece / ml)" and visually examined for "presence or absence of precipitation". Table 5 shows the results. Further, "pH", "CO ₂ partial pressure", "CO ₂ concentration in space" and "bicarbonate ion content" after sterilization were measured, respectively, and the results are also shown in Table 5.

[0044]

[Table 5]

As is clear from Table 5 above, precipitation was observed in the formulation of Example 3 within the ranges of "pH", "CO ₂ partial pressure", and "CO ₂ concentration in space" defined in the present invention. However, the bicarbonate ion concentration was maintained, and a good replenisher solution preparation for filtration type artificial kidney was obtained.

(Example 4: Infusion formulation) First, the reagent of "formulation 4" shown in Table 1 except sodium hydrogen carbonate was dissolved in water (pH measured value: 3.0), and pH was adjusted to 7 with 1N sodium hydroxide. After adjusting to, the amount shown in Table 1 (25.20 g)
Sodium hydrogencarbonate of was dissolved, the volume was adjusted to 10 liters (pH measured value: 8.1), and carbon dioxide was bubbled to p.
The H was adjusted to 7.1.

Next, 500 ml of this was filled in a gas-permeable plastic container, and this container was packaged in a secondary packaging bag (PE / glass vapor deposition PET / NY). Then, the space between the secondary packaging bag and the container (volume of space: 100 ml) was replaced with carbon dioxide gas having the concentration shown in Table 6 below [pre-sterilization "replacement gas (CO ₂ % in Table 6 below) ) ”Column], and then autoclaved at 110 ° C. for 20 minutes to obtain an infusion preparation.

Regarding the infusion preparation after this sterilization,
(Pieces / ml) "and visually inspected for" presence or absence of precipitation. "The results are shown in Table 6. Also," pH "," CO ₂ partial pressure ", and" CO ₂ concentration in space "after sterilization. The “bicarbonate ion content” was measured and is also shown in Table 6.

[0049]

[Table 6]

As is apparent from Table 6 above, in the infusion solution preparation of Example 4 which is within the ranges of "pH", "CO ₂ partial pressure", and "CO ₂ concentration in the space" defined in the present invention, precipitation does not occur. It was not observed, and the bicarbonate ion concentration was retained, and a good preparation was obtained.

In this preparation, in order to examine whether or not each component agrees with the theoretical value, a sample after sterilization of "replacement gas concentration (CO ₂ %): 0" in the above Table 6 is taken as an example. The concentration of each electrolyte ion in the sample was measured. The measured values are shown in Table 7 below in comparison with the theoretical values. From Table 7 below, it was confirmed that a formulation having the theoretical value of each component was obtained.

[0052]

[Table 7]

(Comparative Example) As a comparative example to Example 4, as in Example 4, "formulation 4" in Table 1 above is used, except that all reagents of "formulation 4" are dissolved in water and then hydroxylated. A comparative test was conducted by a method in which neither pH adjustment with sodium nor pH adjustment with carbon dioxide was performed.

That is, in this comparative example, all the reagents of "Formulation 4" in Table 1 above were dissolved in water and the volume was adjusted to 10 liters.
(Measured value pH: 7.1), 500m in a polyethylene container
l. Next, this container is wrapped with a secondary packaging bag (PE / glass-deposited PET / NY), and then the space of the packaging bag is filled with 15 V / V% carbon dioxide gas (space volume: 100 m
l), autoclaved at 110 ° C. for 20 minutes.

No precipitation was observed in the thus-obtained preparation, but as shown in Table 8 below, the bicarbonate ion content was 24.9 mEq / l, which was moderate to that of sodium hydroxide. A decrease of bicarbonate ion content of 4.9 mEq / l was recognized as compared with the measured value of 29.8 mEq / l when the summing process (pH adjusting process) was adopted.

[0056]

[Table 8]

(Example 5: Preparation for peritoneal dialysis) First, the reagents of "formulation 5" shown in Table 1 except sodium hydrogen carbonate were dissolved in water (pH measured value: 3.0), and 1N sodium hydroxide was used. After adjusting the pH to 7 with the amount shown in Table 1 (29.
4 g) of sodium hydrogen carbonate was dissolved, the volume was adjusted to 10 liters (pH measured value: 8.1), and after filtration, 500 ml of polyethylene plastic bag was filled.

Next, the secondary packaging bag (PE / glass vapor deposition PE
T / NY) and after filling the space of this packaging bag with 25V / V% carbon dioxide gas (space volume: 100ml), at 20 ℃ at 20 ℃
A peritoneal dialysis preparation was obtained by sterilizing with heating steam for minutes. With respect to the preparation after sterilization, its pH, CO ₂ partial pressure, carbon dioxide concentration in the space, bicarbonate ion content, and the number of fine particles (pieces / ml) were measured, and "presence or absence of precipitation" was visually inspected. . Table 9 shows the results.

[0059]

[Table 9]

From Table 9, in the preparation of Example 5, no precipitation was observed and a good preparation for peritoneal dialysis was obtained. In addition,
As in this Example 5, the reagents except for sodium hydrogen carbonate in “formulation 5” were dissolved in water, and the pH was adjusted with sodium hydroxide in advance.
It was confirmed that the content of bicarbonate ion did not decrease unlike the comparative example.

(Example 6: Infusion formulation) First, all the reagents of "formulation 6" shown in Table 1 above were dissolved in water, the volume was adjusted to 10 liters (pH measured value: 8.0), and carbon dioxide gas was bubbled. After adjusting the pH to 6.7, it was filled in a 500 ml glass vial. This was subjected to heat steam sterilization at 117 ° C for 10 minutes to obtain an infusion preparation.

Regarding the infusion preparation after the heating steam sterilization,
The pH, the CO ₂ partial pressure, the carbon dioxide gas concentration of HS, the bicarbonate ion content, the number of fine particles (pieces / ml) were measured, and the “presence or absence of precipitation” was visually inspected. The results are shown in Table 10.

[0063]

[Table 10]

From Table 10 above, in the formulation of this Example 6,
No precipitation was observed and a good infusion preparation was obtained. In addition,
Unlike Example 5, unlike Example 5, by dissolving all the reagents of "formulation 6" in water and then adjusting the pH by bubbling carbon dioxide gas, a preparation with no decrease in bicarbonate ion content can be obtained. It was confirmed that it could be obtained.

In each measurement in Tables 2 to 10 above,
The following equipment was used.・ PH measurement → glass electrode type hydrogen ion concentration meter "Toa Denpa Co., Ltd .: HM-60S type" ・ Carbon dioxide partial pressure measurement → ACID BASE ANALYSER "radio meter"
Tera: ABL-30 type ・ Carbonate ion content measurement → Non-suppressor method ion chromatograph "Toso: CM-8020 type" ・ HS carbon dioxide concentration measurement → Gas chromatograph "Shimadzu : GC-9A "・ Particle counting → Light shielding type automatic particle counting system" RION "
Company: KL-01 type ”

[0066]

As described in detail above, the present invention provides a metal ion which reacts with bicarbonate ion to form an insoluble compound,
A bicarbonate-containing aseptic compounded liquid preparation (formulation) containing at least bicarbonate and carboxylate ions, characterized in that the CO ₂ partial pressure in the liquid preparation is 50 to 300 mmHg, and The liquid agent is filled in a gas impermeable container, or the liquid agent is filled in a gas permeable plastic container, and the container is further packaged with a gas impermeable secondary packaging material, and the head space of the gas impermeable container is filled. 5 to 35 v / in the space of the secondary packaging material
It is characterized by encapsulating v% carbon dioxide gas, which prevents the precipitation of metal ions such as calcium ions and magnesium ions due to the formation of insoluble compounds, and further decomposes the bicarbonate ions contained as an active ingredient. The remarkable effect of suppression occurs.

According to the present invention, since coprecipitation is generated by coexistence, simultaneous blending was impossible. "A sterile compound solution containing bicarbonate ion containing calcium ion and / or magnesium ion together with bicarbonate ion ( Formulation), and also suppresses decomposition of bicarbonate ion due to the heat during heat sterilization, suppresses decrease of bicarbonate ion content and increase of solution pH with time. A mixed solution (formulation) can be provided.

According to the present invention, Ringer's preparation capable of suppressing the progress of metabolic acidosis and suppressing the rate of decrease in blood pressure, as compared with Ringer's lactate and Ringer's acetate preparations marketed as Ringer's preparations. Can be provided. Furthermore, aseptic infusion for use in medical applications, in which "calcium ion and / or magnesium ion are co-blended with bicarbonate ion, which is particularly important as a human body fluid component,
It is possible to provide a "dialysis solution", and further it is possible to provide an infusion solution that passes the level of an injection that does not allow inclusion of fine particles.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 33/14 B65D 81/20 A61M 1/14 523 81/24 B65D 81/20 A61J 1/00 330A 81/24 390S // (A61K 33/00 33:14 31:19)

Claims (9)

[Claims] 1. At least containing metal ions, bicarbonate ions and carboxylate ions which react with bicarbonate ions to produce insoluble compounds, and have a CO ₂ partial pressure of 50 to 300 mmHg.
A sterile compound solution containing bicarbonate ion, which is composed of a solution of 2. It contains at least a metal ion, a bicarbonate ion and a carboxylate ion which react with bicarbonate ions to form an insoluble compound, and has a CO ₂ partial pressure of 50 to 300 mmHg.
Which is a formulation consisting of a gas impermeable container filled with a solution of which the carbon dioxide concentration of the head space of the container is 5 to 3
A sterile combination preparation containing bicarbonate, which is 5 v / v%. 3. A gas-permeable plastic container packaged with a gas-impermeable secondary packaging material, containing at least metal ions, bicarbonate ions, and carboxylate ions that react with bicarbonate ions to form insoluble compounds. And CO ₂
A pharmaceutical preparation comprising the container filled with a solution having a partial pressure of 50 to 300 mmHg, wherein the carbon dioxide concentration in the space between the packaging material and the container is 5 to 35 v / v%. Aseptic combination preparation containing bicarbonate ion. 4. The metal ion is a calcium ion and / or a magnesium ion, and the carboxylate ion is a citrate ion or a malate ion, according to claim 1, 2 or 3. Aseptic compounded solution or formulation containing bicarbonate ion. 5. An aqueous solution containing at least a metal ion, a bicarbonate ion, and a carboxylate ion, which react with bicarbonate ions to form an insoluble compound, is prepared, and the pH of the aqueous solution is adjusted.
Is adjusted to 7.4 or less by using carbon dioxide gas, and then heat sterilized, and a method for producing a sterile compound solution containing bicarbonate ion. 6. An aqueous solution containing at least a metal ion, a bicarbonate ion, and a carboxylate ion, which react with bicarbonate ions to form an insoluble compound, is prepared, and carbon dioxide gas is bubbled into the aqueous solution to adjust the pH of the aqueous solution. After being adjusted to 7.4 or less, it is filled in a gas impermeable container, 5 to 35 v / v% carbon dioxide gas is enclosed in the head space of the container, and sterilized by heating, which is characterized by sterilization containing bicarbonate ion. Method for manufacturing compounded preparation. 7. An aqueous solution containing at least a metal ion, a bicarbonate ion, and a carboxylate ion, which react with bicarbonate ions to form an insoluble compound, is prepared, and carbon dioxide gas is bubbled into the aqueous solution to adjust the pH of the aqueous solution. After adjusting to 7.4 or less, it is filled in a gas-permeable plastic container, the container is packaged with a gas-impermeable secondary packaging material, and the space between the container and the packaging material is filled with 5 to 35 v / v% carbonic acid. A method for producing a sterile mixed preparation containing bicarbonate ions, which comprises enclosing gas and sterilizing by heating. 8. An aqueous solution containing an ion other than bicarbonate as a means for preparing an aqueous solution containing at least a metal ion, a bicarbonate ion and a carboxylate ion which react with the bicarbonate ion to form an insoluble compound. 8. A method for producing a bicarbonate ion-containing sterile liquid preparation or formulation according to claim 5, 6, or 7, wherein the aqueous solution is adjusted in pH with an alkali and then bicarbonate ion is added. 9. The metal ion is a calcium ion and / or a magnesium ion, and the carboxylate ion is a citrate ion or a malate ion, according to claim 5, 6, 7 or 8. A method for producing a sterile mixed solution or preparation containing a bicarbonate ion described in the above.