JPH1119178A - Manufacture of medical container containing medical solution with carbonic acid component - Google Patents

Abstract

PROBLEM TO BE SOLVED: To nearly constantly keep a PH value in any stage before/after production or after long-term preservation and also to constantly keep a carbonic acid gas density by containing a carbonic acid component in one chamber and containing a mother solution consisting of electrolyte except the carbonic acid component by means of liquid-tight in the other chamber, executing a steam sterilization processing in a divided state and mixing them after the processing. SOLUTION: In the producing method of a medical container containing a medical solution with the carbonic acid component, a transparent and flexible resin sheet which is inflation-molded is cut by prescribed size at first. Then, separating sheal parts 3 and 3 for dividing containing chambers 4 and 5 are formed in the intermediate part of the cut sheet as a heat seal and the seal parts are formed as the ripping and opening possible seal part. Then, the carbonic acid component 6 generated by the suspension liquid of a bicarbonate or carbonic acid salt is contained by liquid-tight in one chamber 5 and the mother liquid 7 generated by electrolyte except the carbonic acid component is contained in the other chamber by liquid-tight. After that, the carbonic acid component 6 and the mother solution 7 are steam sterilization-processed in a separated state and they are mixed after the sterilizing processing.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a medical container containing an infusion solution, a dialysate, an organ preservation solution and the like, and more particularly to a medical solution containing a carbonic acid component lacking stability. The present invention relates to a method for manufacturing a contained medical container.

[0002]

2. Description of the Related Art Generally, when a sodium bicarbonate solution is contained in a resin container or the like, it is decomposed during heating or storage to generate carbon dioxide gas, and the carbon dioxide gas passes through the container wall and disappears. Due to such decomposition, [OH ⁻ ] increases in the solution due to ionization equilibrium, and the PH value of the solution increases. For this reason, in order to preserve the medical container for a long time, the medical container is hermetically sealed in a gas-barrier package, and carbon dioxide is introduced into the package or a carbon dioxide-generating type oxygen absorber is disposed. A technique has been proposed in which the carbon dioxide gas inside the resin container is prevented from flowing out of the resin container by setting the outside of the medical container to a carbon dioxide gas atmosphere (Japanese Patent No. 2527532, Japanese Unexamined Patent Application Publication No. Sho 6-1).
05905).

[0003]

However, the conventional method for producing a medical container containing a carbonic acid component has the following problems. Regarding the package containing carbon dioxide gas or the package containing an oxygen scavenger, the initial PH value of the solution in the medical container is set at 8 to prevent the loss of carbonate ions during steam sterilization. It is as high as .32 or 8.60. After 10 days, the PH value in the medical container shows 8.0 or less. This is considered to be because the solution in the medical container was present in the package and took in carbon dioxide gas that had permeated the container wall. However, in such a medical container, it is clearly different from the initial composition, and it is unclear how much carbon dioxide dissolved in the solution in the medical container. Further, in a solution in which carbon dioxide gas is excessively taken in, a solution may react with calcium ions or magnesium ions in the solution to form a precipitate. Therefore, the present invention is applicable to any phase before, after, or after long-term storage.
An object of the present invention is to provide a method for manufacturing a medical container containing a medical solution containing a carbonic acid component, in which the H value is maintained substantially constant and the carbon dioxide gas concentration is also maintained constant.

[0004]

SUMMARY OF THE INVENTION According to the present invention, a carbonic acid component comprising a salt or a salt solution of bicarbonate or carbonic acid is contained in one chamber in a liquid-tight manner, and a mother liquor comprising an electrolyte other than the carbonic acid component is contained in another chamber. Production of a medical container containing a carbonated medical solution containing the carbonic acid component and the mother liquor after the liquid carbonate is stored in a liquid-tight manner and then subjected to steam sterilization with the carbonic acid component and the mother liquor separated. The object has been achieved by providing a method.

The medical container is usually a resin container having a flexible wall. The flexible wall may be any as long as the volume in the container is easily changed by bending. Further, it is desirable that the container wall has transparency to the extent that the contents can be confirmed.
This is because it is necessary to confirm the state of the medicine in the container. The above containers are blown films, tubes, sheets and those molded from films, extrusion molding,
Injection molding or blow molding. Polyolefin resin, vinyl chloride,
It is a general-purpose resin such as a vinylidene chloride resin, a polyester resin, a polyvinyl alcohol resin, a polyacrylonitrile resin, a polyacrylic resin, and a polyamide resin. Further, the resin container may be formed in a single layer or a multilayer. The innermost layer in contact with the drug in the resin container is desirably a resin layer that does not affect the drug and does not generate elutes. As such a resin, a polyolefin-based resin is desirable, and examples thereof include low-, middle-, and high-density lower-grade olefin resins such as polyethylene and polypropylene. It is desirable that a gas barrier layer is formed on the resin container wall. In particular, a layer that does not easily transmit oxygen or the like is desirable. Examples of such a gas barrier layer include a metal layer made of aluminum or the like which hardly transmits gas at all or an inorganic vapor-deposited layer made of silicon oxide, magnesium oxide, titanium oxide, etc., and polyvinylidene chloride, polyester, nylon, ethylene, and the like. -A resin layer having a high gas barrier property, such as a vinyl alcohol copolymer and a fluororesin. The oxygen permeation amount of the gas barrier layer is 40 cc · 20 μ / m ² · day · atm (temperature: 20 ° C.) or less, particularly, 30 cc · 20 μ / m ² · d
ay · atm or less, and preferably 5 cc · 20 μ / m
²・ day ・ atm or less, 1cc ・ 20μ / m ²・
It is desirably not more than day · atm. Further, it is desired that the wall of the resin container has such transparency that the medicine inside can be confirmed. For this reason, it is desirable that at least a part of the wall made of a metal layer such as the aluminum layer having an excellent function of not allowing gas to permeate at all be formed so that the metal layer can be peeled off. In the resin container having such a layer, the deterioration of the internal medicine by heat during the high-pressure steam sterilization can be sufficiently prevented.

The carbonic acid component and the mother liquor are separately filled in a liquid-tight manner and subjected to steam sterilization. To separately store the carbonate component and the mother liquor in a liquid-tight manner may use a resin container having a plurality of chambers for individually storing the carbonate component and the mother liquor. When such a container is divided into a plurality of chambers, it is desirable to form a communicating means for communicating the chambers with each other by an operation through the container wall at a portion separating the chambers from each other. Such communication means may be one in which the end of a closed tube is broken through the container wall to make the tube a communication tube, one in which an isolated portion is stopped with a clip or the like, or an operation in which the isolated portion is operated from outside. Other known means for enabling aseptic communication, such as a peel seal portion that can be peeled off. Alternatively, the carbonic acid component and the mother liquor may be housed in separate containers and connected to form a plurality of containers, each of which may be a chamber. The connection between the containers is such that the ends of the containers formed by the peel seal portion are connected to each other so as to be able to communicate by operation through the container at the time of use, and a communication means having a communication needle known per se between the containers. And those that can be communicated. still,
When the container is composed of a plurality of containers, at least one of the containers may be a glass container, but it is preferable that the containers are composed of resin containers. In particular, it is desirable that the plurality of chambers are containers formed or connected by a peel seal portion capable of continuous passage through the container and the package.

That is, the peel seal portion is also referred to as a weak seal portion, and is an isolation seal portion that presses against a chamber or a container from the outside and peels off when the inside is pressurized to a certain level. The peel strength of the peel seal portion is such that the indoor pressure is 0.
01 to 1.0 kgf / cm ² , particularly 0.05 to 0.5
It is desirable to have a peeling strength at a pressure of Kgf / cm ² . If the strength is lower than the above range, the safety for maintaining an isolated state at the time of production, transportation, storage and the like is lacking. If the strength exceeds the above range, there is a possibility that the communication operation between the rooms cannot be easily performed at the time of use. In the case of forming a peel seal between the inner layers of the resin container or forming a completely fixed seal, a technique known per se can be used. In order to form these seals surely different from each other, the inner layer of the resin container must be formed. Is desirably a blend of different resins. In particular, it is desirable that the different resins be made of resin blends having different hot-melting onset temperatures or Picad softening points and little compatibility. By having such a blended material layer, it is possible to easily set the sealing temperature conditions for complete hermetic seal bonding with the same inner layer, but also to easily set the sealing temperature conditions for peel seal bonding. Further, the relationship between the seal strength required for peel seal adhesion, that is, the easy peelability due to external force during use, and the seal strength that does not cause peeling during storage can be strictly set. That is,
The resin having different compatibility is melt-mixed in the inner layer and formed into a sheet to form a surface which is microscopically separated into portions having different thermal adhesiveness. Then, by determining the thermal fusibility of the microscopic portion between the surfaces of the sheet at an arbitrary temperature, the strength of the sealing strength is accurately provided, and the above-mentioned effect is easily achieved.

[0008] The mother liquor is a component used for infusion, dialysate and organ preservation solution.
Magnesium, calcium, chlor, phosphorus, etc., other inorganic electrolytes present in the human body, acetic acid, lactic acid, citric acid, etc., and other organic electrolytes present in the human body, and, in addition to electrolytes, saccharides, amino acids, proteins, Energy such as fat and, if necessary, physiologically active substances and vitamins are also included. The mother liquor may be filled in the resin container aseptically, but is subjected to steam sterilization after being housed in a liquid-tight manner in the storage chamber of the resin container. This is because such a sterilization process ensures that the mother liquor is sterilized and can be safely administered to a patient. The carbonic acid component refers to one or both of bicarbonate and carbonic acid, and may be only bicarbonate or only carbonic acid. Further, the carbonic acid component may be present as a solid salt of bicarbonate or carbonate,
Such an alkali salt solution may be present. The salt contained in the carbonic acid component is an alkali metal salt, an alkaline earth metal salt, or the like, and particularly preferably a sodium salt or a potassium salt. Further, it is desirable that the carbonate component contains an alkali hydroxide salt. For example, sodium hydroxide or potassium hydroxide. As described above, if an excessive amount of the alkali salt is mixed in the carbonic acid component, the decomposition of carbon dioxide gas can be suppressed as much as possible.

The above-mentioned carbonic acid component is desirably housed in the above-mentioned chamber in a state where the bicarbonate is not decomposed into carbon dioxide gas at a maximum of 20% during high-pressure steam sterilization or long-term storage for 2-3 years. . As a method of not releasing carbon dioxide gas from the carbonic acid component, it is desirable to form the resin container wall with a gas barrier layer or to seal at least the chamber containing the carbonic acid component of the resin container with a gas barrier package. Steam sterilization in a resin container is performed at a temperature of 100.
It is desirable to carry out sterilization at a temperature in the range of from 140C to 140C, especially from 105C to 115C. At a sterilization temperature below the above range, it takes time and sterilization may be insufficient. On the other hand, if the sterilization temperature exceeds the above range, the plastic container and the packaging material are undesirably subjected to thermal deformation, thermal deterioration and the like.

In the method for manufacturing a medical container constructed as described above, the carbonic acid component is present in an alkaline state during steam sterilization, so that the generation of carbon dioxide gas is suppressed as much as possible even during heating. In particular, thermal decomposition can be suppressed even with a carbonate component in a solution state that is more easily decomposed than a solid state. Therefore, steam sterilization of the carbonic acid component is also possible, and safe administration to a patient can be achieved. In addition, since the carbonic acid component can be maintained in an alkaline state even after sterilization and cooling, generation of carbon dioxide gas can be suppressed as much as possible during long-term storage.

[0011] manufacturing method of a medical container according to claim 2, wherein according to the present invention is the manufacturing method according to claim 1, wherein the mother liquor [OH ^-] negative electrolyte content except the mother liquor [H ^+] 1.5 mEq / L to 14 mEq / L from the weight of the positive electrolyte excluding
(However, if the carbonic acid component contains an excess of positive electrolyte mass (salt) than the amount of bicarbonate in the carbonic acid component, the excess amount of the positive electrolyte must be added after adding the negative electrolyte). Features. Since the mother liquor is an electrolyte solution, the solution usually contains {OH ⁻ , X ⁻ , Y ⁻ , Z ⁻ ,...} And {H ⁺ , A ⁺ ,
Various positive and negative ions with B ⁺ , C ⁺ ··· are dissociated. If the PH value is around 7, ΔX ⁻ , Y ⁻ , Z can be obtained even when hydrogen ions and hydroxyl ions are excluded.
^- · ·} and {A ^+, B ^+, positive and negative electrolyte ions of the C ⁺ ...} are equal. However, when the negative electrolyte is present in excess of the positive electrolyte, the excess negative electrolyte ion amount ΔX ⁻ , Y ⁻ ,
Z ⁻ ··· −−A ⁺ , B ⁺ , C ⁺ ··}, and the PH value decreases while maintaining the equilibrium between the amount of negative electrolyte ions and the hydrogen ions [H ⁺ ] in the solution. Here, weak acid in excess negative electrolyte,
For example, when lactic acid or acetic acid is present, the PH value of the mother liquor is substantially determined by the ionization constant K of lactic acid or acetic acid and the excess negative electrolytic mass C. That is, chlorine other than lactic acid or acetic acid is almost ionized,
The pH value is determined by lactic acid or acetic acid, which is difficult to ionize.
The H value approximately follows the equation of PH ≒ -1 / 2 · logK · C.
Therefore, if the ionization constant of lactic acid is K = 1.38 × 10 ⁻⁴ and the excess negative electrolytic mass C is 1.5 mEq / L, the solution has a PH value of 3.34. Also, if acetic acid having an extremely low ionization constant is contained in the mother liquor and 1.5 mEq / L is an excess negative electrolytic mass, the dissociation constant K of acetic acid is 1.85 × 10 ^-5 and the PH value of the mother liquor is 3 .80. In the case where there is no weak acid and only strong acid, for example, in the case of only hydrochloric acid, 90%
% Is dissociated, the excess negative electrolytic mass C is directly reflected, and the PH value is about 2.74.

Except for [OH ⁻ ] and [H ⁺ ], the mother liquor in which the negative electrolytic mass is in excess of the positive electrolytic mass consists of, for example, sodium bicarbonate equivalent to 25.5 mmol / L. The carbonic acid component is converted to a negative electrolyte excess of 1.5 mEq.
/ L of the mother liquor, the carbonic acid component is weaker than lactic acid.
The sodium ion in 1 has an ionizing relationship with the negative electrolyte of acetic acid or lactic acid by 1.5 mEq / L. Here, when the pH value of the mixed solution is maintained at around 7 due to the buffering action of the other electrolytes, both the hydroxyl ions and the hydrogen ions are in a nano unit amount, so that 1.5 mmol [HCO ₃ in 25.5 mEq / L]. ^- ] Combines with [H ⁺ ] to generate carbon dioxide gas.
Some of the generated carbon dioxide gas is dissolved or ionized in the mixed solution, and the other is released as carbon dioxide gas out of the solution due to solubility and the like. On the other hand, the total amount of bicarbonate ions and carbonate ions is maintained at 24.0 mEq / L in the solution.

The method for producing a medical container according to the present invention is characterized in that the mother liquor has such an excess negative electrolyte so that the PH value of a solution obtained by mixing the mother liquor and a carbonate component is substantially constant, and the same as that of plasma in the body. And a medical container such as an infusion solution containing predetermined bicarbonate ions and carbon dioxide gas. That is, it is generally expected that the carbonic acid component will be eliminated as a carbon dioxide gas at a minimum of about 5 ± 3% and a maximum of about 20 ± 3% during steam sterilization or storage. The carbonic acid component is added to a medical solution such as an infusion solution or a dialysate.
It is desirable that the bicarbonate ion is finally contained so as to have a bicarbonate ion concentration of 0 to 35 mEq / L, particularly 20 to 28 mEq / L. Therefore, in storage for three years or more, at the lower limit of 10 mEq / L, a loss of at least 2% of the error value is expected, and at the upper limit of 35 mEq / L, the error value of the maximum is 2%.
3% disappearance is expected. Therefore, 0.2 (10 × 0.
02) to 8.1 (35 × 0.23) mEq / L, loss during the storage period is expected.

By the way, when the mother liquor according to the present invention is mixed with a carbonic acid component, at any stage of mixing, initially or during storage, part of the carbonic acid component always reacts during mixing due to the action of the excess negative electrolyte in the mother liquor. Occurs, the PH value of the medical solution can be maintained in a substantially predetermined range, and the bicarbonate ion concentration can be kept constant. For example, in the electrolyte component close to the simulated plasma, the excess negative electrolytic mass in the mother liquor is 4 mEq /
L excess, sodium bicarbonate initially 27 mm
ol / L. When the mother liquor and the carbonic acid component are mixed without being subjected to high-pressure steam sterilization, bicarbonate ions equivalent to 4 mEq / L are changed as carbon dioxide gas from the mixed solution, and the carbon dioxide gas is partially contained in the medical solution. It is dissolved or ionized, and a part is released out of the solution. That is, the excess negative electrolyte is 27 mmol / bicarbonate ion.
The cation salt is deprived of 4 mmol / L bicarbonate ion in L and has an ionization relationship. The bicarbonate ion concentration in the mixed solution is approximately 23 mEq / L (strictly speaking, when the pH value is around 7, [HCO ₃ ⁻ ] ≒ [HCO ₃ ⁻ ] + [CO ₃ ²⁻ ] +
^{[OH -] = 23mEq / L} ) to become. Assuming that the PH value at this time substantially follows the Henderson-Hasselbarch equation of the following chemical formula 1, the PH value depends on the concentration of carbon dioxide in the medical solution, and 4 mmol (4%) of carbon dioxide generated in the mixed solution. /0.03 [mmHg]), about 40% is released out of the solution from experiments and the like, so that the PH value of the medical solution is about 7.10.

[0015]

Embedded image

Further, when the carbonic acid component is steam-sterilized in a room together with the container, the carbonic acid component is decomposed and disappeared by heating, and the bicarbonate is reduced to an amount equivalent to 25 mmol / L, and 2 mmol / L.
Even if a considerable amount of hydroxide or the like is formed, bicarbonate equivalent to 2 mEq / L is converted into carbon dioxide gas from the mixed medical solution. That is, 2 mEq / L of the excess negative electrolyte has an ionization relationship with the hydroxide salt, and the remaining 2 mEq / L has an ionization relationship with the cation salt deprived of the bicarbonate ion. Assuming that about 30% of the generated carbon dioxide gas is released out of the solution from an experiment or the like, the PH value of the medical solution is about 7.31, and the bicarbonate ion concentration is approximately 23 mEq / L as described above.

[0017] The above mother liquor ^- contained in excess in such a [H ^+] range from positive electrolyte mass 1.5mEq / L~14mEq / L, except for the negative electrolyte mass mother liquor except [OH] . In a medical solution such as an infusion solution, it is desirable that the dissolved carbon dioxide gas has a carbon dioxide partial pressure of at least around 40 mmHg. For this reason, it is desirable that carbon dioxide gas of 1.2 (40 × 0.03) mEq / L or more is generated and dissolved in the infusion solution during mixing. Since the amount of decomposition and disappearance of the carbonate component during storage may range from 0.2 to 8.1 mmol / L, the lower limit of the excess negative electrolytic mass in the mother liquor is 1.4 mEq / L including the decomposition amount. The lower limit should be set to 1.5 mEq / L, which is higher than the lower limit. On the other hand, the partial pressure of carbon dioxide gas decomposed by the excess negative electrolytic mass in the mother liquor is limited to 200 mmHg. For this reason, as an infusion solution, a maximum of 6.0 in the solution.
Any dissolution of carbon dioxide gas below (200 × 0.03) mEq / L may be used. Therefore, the upper limit of the excess negative electrolytic mass in the mother liquor is 14.1 mEq / L including the amount of decomposition during storage, and the upper limit is 14.0 mE, which is lower than the upper limit.
It should be set to q / L. The mother liquor having such an excess negative electrolyte has a PH value of 3.80 or less, particularly a PH value of 3.80.
It is desirable that the PH value be 20 or less, and more preferably the PH value be 2.90 or less. The lower limit of the PH value of the mother liquor does not need to be limited because the carbonate component can contain an alkali salt exceeding the amount of bicarbonate. That is, the range of the excess negative electrolytic mass in the mother liquor is obtained by adding an excess of the negative electrolyte in the excess of the positive electrolytic mass when a positive electrolytic mass (salt) is present in the carbonate component in excess of the bicarbonate ion amount. Range. For example,
In the above example, 27m of sodium bicarbonate
mol / L equivalent to 27 mmol of sodium hydroxide
/ L equivalent amount, the mother liquor contains 27 mEq /
The excess amount of the negative electrolyte corresponding to L is further added to the above range of the excess negative electrolyte mass of 1.5 to 14.0 mEq / L. Therefore, in the method of manufacturing a medical container in which the mother liquor having such a composition is filled separately from the carbonic acid component, it is necessary to use the mother liquor so that the PH value is almost in a predetermined range even at the beginning of use or after use for a long period of time. In addition, the amount of bicarbonate ions can be kept constant. In addition, saccharides may be added to the mother liquor, but the pH value of the mother liquor is 3.8.
Because of the following, there is no possibility that saccharides or the like will be discolored or deteriorated during high-pressure steam sterilization of the mother liquor.

According to a third aspect of the present invention, there is provided the medical container according to the second aspect, wherein the carbonate component is contained as an alkaline suspension or solution, and the negative electrolytic mass in the mother liquor is the same as that in the mother liquor. 2. From the positive electrolytic mass excluding [H ⁺ ]
In the range of 1 mEq / L to 14 mEq / L (however, when the carbonic acid component contains a positive electrolytic mass (salt) in excess of the bicarbonate amount, the range after adding an excessive amount of the negative electrolyte to the positive electrolyte is added. ) Is included in excess. When the carbonic acid component is an alkaline suspension or solution,
Decomposition is faster than solid salts, and particularly when heat or the like is applied, about 20% of the whole decomposes during a storage period such as a severe test. For this reason, the range of the amount of decomposition and disappearance of the carbonic acid component is 1.7 to 8.1 mEq / L, and when the preferable dissolved amount of the carbon dioxide gas when the mother liquor is mixed with the carbonic acid component at the time of use is added, The negative electrolytic mass is desirably not less than 3.1 mEq / L.

According to a fourth aspect of the present invention, there is provided a method of manufacturing a medical container, comprising the steps of:
The medical solution after mixing the carbonic acid component and the mother liquor has a carbon dioxide gas concentration of 10 to 200 mHg. When the mother liquor and the carbonic acid component are mixed, the excess negative electrolyte in the mother liquor causes an ionization relationship with a part of the salt in the carbonic acid component as described above, so that a part of the carbonic acid component becomes carbon dioxide gas. It is desirable that the concentration of the carbon dioxide gas in the mixed solution after mixing is in the range of 10 to 200 mHg, particularly 20 to 80 mHg. The carbon dioxide gas concentration in the mixed solution is a value calculated based on the PH value of the solution of the above-mentioned Henderson-Hasselbarch equation and the amount of bicarbonate ions present theoretically near PH7. If the medical solution as a mixed solution is below the above range, a transient respiratory alkali losis may be caused in plasma or the like, and the equilibrium balance of carbon dioxide concentration in the body may be lost. Above the above range, transient respiratory acidosis occurs, exceeding the metabolism from the lungs, and a sufficient balance cannot be achieved.

According to a fifth aspect of the present invention, there is provided a method for manufacturing a medical container, comprising the steps of:
The storage chamber for the carbonic acid component is covered with a gas barrier package before or after the steam sterilization. If the accommodation room for the carbonic acid component is covered before the steam sterilization, the carbon dioxide gas is confined in the package during the heating during the steam sterilization, and the decomposition of the carbonic acid component can be suppressed as much as possible. Also, after steam sterilization, the decomposition of carbonic acid components during storage and immediately before use can be suppressed as much as possible. The package according to the present invention is a package in which the entire container or only a part of the container for containing the carbonated component is hermetically sealed. As a specific gas barrier packaging, the packaging wall has little or no gas permeation, such as a metal layer such as aluminum, polyvinylidene chloride, polyester, nylon, ethylene-vinyl alcohol copolymer, and a fluororesin. As a resin layer with high gas barrier properties, or aluminum, silicon, magnesium, titanium,
It has an earth metal such as silver, gold or the like, or a vapor-deposited layer of a metal or an oxide thereof. The oxygen permeation amount of the gas barrier layer in the package is 40 cc · 20 μ / m ² · day
・ Atm (temperature: 20 ° C.) or less, especially 30 cc ・ 20
μ / m ² · day · atm or less, preferably 5 cc
・ 20μ / m ²・ day ・ atm or less, 1cc ・
It is desirable to be 20 μ / m ² · day · atm or less. The amount of carbon dioxide gas permeated by the gas barrier layer in the package is 200 cc · 20 μ / m ² · day · atm (temperature: 25 ° C.) or less, particularly 100 cc · 20 μ / m ² ·.
day · atm or less, preferably 10 cc · 20μ
/ M ² · day · atm or less, and 1 cc · 20μ /
Desirably, it is equal to or less than m ² · day · atm.

According to a sixth aspect of the present invention, in the method for manufacturing a medical container, a carbon dioxide-generating type oxygen absorber is disposed in the gas barrier package. I do. If a carbon dioxide-generating type oxygen scavenger is disposed in the package, decomposition of the carbonic acid component during steam sterilization or storage can be suppressed as much as possible in combination with the gas barrier property of the package. Examples of the oxygen scavenger include organic compounds mainly composed of ascorbic acid and catechol-based compounds, and powdery compounds composed of metals such as iron and metal halides. Specifically, it is commercially available from the trade name “Ageless” (Mitsubishi Gas Chemical Co., Ltd.) or other manufacturers. The oxygen absorber absorbs oxygen to generate carbon dioxide gas.

[0022]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A preferred embodiment of the method for producing a medical container containing a carbonated medical solution according to the present invention will be described below in detail with reference to the accompanying drawings. FIG. 1 is a front view of the medical container of the first embodiment in the method for producing a medical container containing a carbonated medical solution according to the present invention. FIG.
FIG. 3 is a front view of a medical container according to the first embodiment, in which a packaging material is provided in a storage compartment for a carbonated component. FIG. 3 is a sectional view of the packaging material provided in the accommodation room of the medical container of the first embodiment.

The method of manufacturing the medical container 2 containing the carbonated medical solution according to the present embodiment is as follows. As shown in FIGS. 1 and 2, a bicarbonate or carbonate salt suspension is placed in one chamber 5. After the carbonic acid component 6 is housed in a liquid-tight manner, the mother liquor 7 made of an electrolyte other than the carbonic acid component 6 is housed in another chamber 4 in a liquid-tight manner, and then the carbonic acid component 6 and the mother liquor 7 are separated and steam sterilized. After the sterilization treatment, the carbonate component 6 and the mother liquor 7 are mixed. In the method for manufacturing the medical container 2 according to the present embodiment, the pH of the mother liquor 7 is set to 3.8 or less, and the [O]
The negative electrolytic mass excluding H ⁻ ] is in the range of 1.5 mEq / L to 10 mEq / L from the positive electrolytic mass excluding [H ⁺ ] in the mother liquor 7 (provided that the excess amount of bicarbonate in the carbonic acid component 6 is larger than the amount of bicarbonate). If the electrolyte mass (salt) is present, it is included in excess (in the range after adding the excess amount of the negative electrolyte to the negative electrolyte). Further, the method for manufacturing the medical container 2 according to the present embodiment includes the above-described carbonic acid component 6.
Of the mixed solution 1 after the mixing of the
Present at ~ 200 mHg. Further, the accommodation room 5 for the carbonic acid component 6 is covered with a gas barrier package 11 before the steam sterilization, and a carbon dioxide-generating type oxygen absorber 16 is arranged in the gas barrier package 11.

The method for manufacturing the medical container 2 containing the carbonated medical solution according to the first embodiment will be described in more detail. First, a transparent and flexible flexible resin sheet formed by inflation molding is formed into a predetermined size. Cut into pieces. The resin sheet is a blend of linear low-density polyethylene and polypropylene with a thickness of 250 μm and an inner layer of 50 μm,
The outer layer has a two-layer structure of low-density polyethylene having a thickness of 200 μm. Linear low density polyethylene has a melting point of 126 ° C
The melting point of polypropylene is 160 ° C. The inner layer is made of linear low-density polyethylene and polypropylene.
Blend at a ratio of 5:35. Next, isolation seal portions 3 for separating the storage chamber 4 and the storage chamber 5 are formed in the middle of the cut sheet. The isolation seal part 3 has a temperature of 140
It is formed by heat sealing at 10 ° C. for 10 seconds. The isolation seal portion is formed as a peelable sealable seal portion.
Is peeled and opened when pressed at 0.2 kgf / cm ² or more. The cut end 2A of the resin sheet is filled with the carbonic acid component 6 and the cut end 2A is heat-sealed and sealed in a liquid-tight manner. The cut end 2A is completely fixed and sealed by heat sealing at 170 ° C. for 6 seconds. Carbonic acid component 6 is composed of a suspension (3 ml) of alkaline sodium bicarbonate, and Table 1 shows the contents of Samples 1 to 5 (corresponding concentrations in the case of 1 L solution).

[0025]

[Table 1]

The other end 2B of the cut sheet is connected to the end 2A.
Sealing is performed in the same manner as described above. The outlet 1
Install 01. The discharge port 101 is formed of a cylindrical member made of resin. Next, 1 L of the mother liquor 7 is filled from the outlet 101, and the outlet 101 is closed liquid-tight with a rubber stopper. A drip needle is pierced through the rubber stopper. In the mother liquor 7, electrolytes and saccharides close to the maintenance solution of the infusion solution are dissolved, and
Shows the contents of Samples 1 to 5.

[0027]

[Table 2]

As shown in FIG. 2, the housing chamber 5 of the medical container 2 is covered with two gas-barrier front and back sheets 12 and 13, and the peripheral edges of the front and back sheets 12 and 13 are air-tightly sealed. Seal by welding. As shown in FIG.
The innermost layer 21 is a linear low-density polyethylene having a thickness of 100 μm, the first intermediate layer 22 is a stretched nylon having a thickness of 15 μm, the second intermediate layer 23 is an aluminum layer having a thickness of 9 μm, and the outer layer 24 has a thickness of 12 μm. Of a polyethylene terephthalate layer. On the other hand, in the back sheet 13, the innermost layer 31 is a linear low-density polyethylene having a thickness of 100 μm, the first intermediate layer 32 is a polyvinylidene chloride layer having a thickness of 15 μm, the second intermediate layer 33 and the third intermediate layer 34. Is a stretched nylon layer, the fourth intermediate layer 35 is a 9 μm-thick aluminum layer, and the outer layer 36 is a 12 μm-thick polyethylene terephthalate layer. Then, a release surface C is formed between the second intermediate layer 33 and the third intermediate layer 34,
The backing sheet 13 is separated from the peeled surface C by the peeled wall D and the peeled wall E.
And divided into The non-transparent fourth intermediate layer 35 (aluminum layer) is present on the peeling wall E, and the gas barrier first intermediate layer 32 (vinylidene chloride layer) is present on the wall D to be peeled. Since the peeled wall D has the first intermediate layer 32, its oxygen gas permeability is 1 cc / m ² · day ·
Atm or less, it has transparency to the extent that the contents can be confirmed. Therefore, the innermost layer 21 of both sheets 12, 13
Reference numeral 31 denotes a heat-sealing seal layer, which is formed on both sheets 12, 13 at a temperature of 130 ° C. and a heat sealing time of 20 seconds.
Are heat sealed together at the periphery.

A part of the heat-sealing seal portion 14 at the periphery is formed between the isolation seal portions 3 with the medical container 2 interposed therebetween. Such a heat-sealed seal portion 14 is formed at a temperature that does not affect the peeling function such as the peel strength of the isolation seal portion 3. In addition, a suspension hole 15 is formed in the upper portion of the heat-sealing seal portion 14, and a hook such as a stand is locked in the suspension hole 15 during use. Thereby, the package 1 is formed. Before completely sealing the peripheral edges of the front and back sheets 12 and 13, an oxygen absorber 16 is disposed in the oxygen-absorbing package 11, and the oxygen absorber 16 is a carbon dioxide-generating type containing bicarbonate. It is an oxygen scavenger. Next, a sample was prepared by dividing the sample into one that was left as it was for one day and one that was then subjected to an autoclave sterilization treatment (110 ° C.). Next, in order to evaluate each sample, after separating the seal portion 3 of the medical container, the PH value of each sample, measurement of bicarbonate ion (quantitative measurement according to the Japanese Pharmacopoeia method), and carbon dioxide gas based on the PH value The partial pressure was measured. The results are shown in Tables 3 and 4.

[0030]

[Table 3]

[0031]

[Table 4]

From the results in Tables 3 and 4, the carbonate component 6 and the mother liquor 7
It can be seen that if the components are separately stored and subjected to the steam sterilization treatment, the PH value and the bicarbonate ion amount of the mixed solution after sterilization can be constantly obtained for each sample. Regarding the carbon dioxide partial pressure, since the PH value of Samples 4 and 5 is low and does not maintain around 7, it is doubtful that Formula 1 is obeyed. The amount of change before and after sterilization did not differ much, and the carbon dioxide partial pressure was 20% after sterilization.
Since it falls below 0 mmHg, it can be expected to be used as a medical solution. In Samples 2 and 5, the PH value and the bicarbonate ion concentration in the closed container after mixing were tracked. The results are shown in Tables 5 and 6. As a result, it was found that the change in the PH value was that the release of carbon dioxide gas was small in the closed system. In sample 2, the carbon dioxide concentration in the mixed solution was found to be 92 mmH at the initial mixing value according to the formula 1.
g and 58 mmHg after standing for 1 day. This is a sufficient amount of absorption that the body allows, and sufficient stability is seen.

[0033]

[Table 5]

[0034]

[Table 6]

In this embodiment, sodium carbonate is used in an amount equivalent to 28 mmol / L for the carbonic acid component 6, and the mother liquor 7 contains an excess negative electrolyte (including lactic acid) of 4.5 mE.
q / L, a composition in which hydrochloric acid (28 mEq / L) was additionally added as a regulator of an excess amount of an alkali salt in the carbonic acid component 6. As a result, the PH value of the mother liquor 7 was 1.60, and the pH value and the amount of bicarbonate ions of the mixed solution after sterilization were 23.5 mEq / L for bicarbonate and 7.70 for bicarbonate. It was 11.

Next, the carbonic acid component 6 in the medical container 2 is changed to an alkaline sodium bicarbonate solution (3 ml).
The amount of sodium bicarbonate is as shown in Samples 6 and 7 in Table 7 (corresponding concentration when a 1 L solution was used). 1 L of the mother liquor 7 in the medical container 2 is stored, and the components of the mother liquor 7 are shown in Table 8
As shown in Samples 6 and 7. The medical container 2
Was subjected to high-pressure steam sterilization, and after the sterilization, the bicarbonate amount and the PH value were measured at a storage temperature of 60 ° C. for 1 month, 2 months, 4 months, and 6 months. In addition, while measuring the amount of bicarbonate ions and the PH value thereof when the mother liquor and the heavy carbon component were mixed, the carbonic acid component 6 was diluted not to the mother liquor but to a 1-liter solution, and
Was measured. The results are shown in Table 9.

[0037]

[Table 7]

[0038]

[Table 8]

[0039]

[Table 9]

As a result, the carbonic acid component 6 in the chamber 5 was reduced to nearly 80% by the severe test, but the carbonic acid component 6 and the mother liquor 7
No change was observed in the amount of bicarbonate ions when
Also, the PH value and the amount of carbon dioxide gas are maintained at necessary and sufficient amounts. In the above embodiment, the composition of the infusion solution was used, but the composition may be used for an organ preservation solution or the like. In the above embodiment, the mother liquor of the infusion solution is stored in one storage chamber 4, but the storage chamber 4 may be further divided into two or more chambers containing an amino acid and a sugar. In the above example, the container body was molded from the inflation resin sheet, but as long as it has flexibility and transparency,
It may be a blow molded product, an injection molded product, a vacuum molded product, or the like. In the above embodiment, the main compounding agent and the auxiliary compounding agent are separated by dividing the chamber into containers, but may be formed by connecting another container, and the aseptic communication means is a detachable isolation seal. It doesn't have to be a department.

[0041]

As described above, according to the method for producing a medical container containing a medical solution containing a carbonic acid component according to the present invention, the carbonic acid component comprising a salt or a salt solution of bicarbonate or carbonic acid in one chamber. After the mother liquor containing an electrolyte other than bicarbonate is housed in another chamber in a liquid-tight manner, the carbonic acid component and the mother liquor are subjected to steam sterilization in a separated state. And mother liquor, so before and after production,
Or, at any stage after long-term storage,
The PH value of the medical solution is kept almost constant, and the concentration of carbon dioxide is also kept constant.

[Brief description of the drawings]

FIG. 1 is a front view of a medical container of a first embodiment in a method for producing a medical container containing a carbonated medical solution according to the present invention.

FIG. 2 is a front view of the medical container according to the first embodiment, in which a packaging material is provided in a carbonic acid component accommodating chamber.

FIG. 3 is a sectional view of a packaging material provided in a storage chamber of the medical container of the first embodiment.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Chemical solution 2 Medical container 3 Isolation seal part 4 Mother liquid storage room 5 Carbonic acid component storage room 6 Carbonic acid component 7 Mother liquid

Claims (6)

[Claims] (1) A carbonic acid component comprising a salt or a salt solution of bicarbonate or carbonic acid is accommodated in one chamber in a liquid-tight manner, and a mother liquor comprising an electrolyte other than the carbonic acid ingredient is accommodated in another chamber in a liquid-tight manner. A method for producing a medical container containing a medical solution containing a carbonic acid component, which is subjected to steam sterilization in a state where the carbonic acid component and the mother liquor are separated, and after the sterilization treatment, the carbonic acid component and the mother liquor are mixed. 2. The pH of the mother liquor is set to 3.8 or less, and the negative electrolytic mass excluding [OH ⁻ ] in the mother liquor is 1.5 mEq / L from the positive electrolytic mass excluding [H ⁺ ] in the mother liquor. ~ 14
In the range of mEq / L (however, in the case where the amount of the positive electrolyte (salt) in excess of the amount of bicarbonate is present in the above-mentioned carbonic acid component, the range is obtained after adding the excess amount of the negative electrolyte to the excess amount of the positive electrolyte). The method for producing a medical container according to claim 1, wherein: 3. The method according to claim 1, wherein the carbonic acid component is contained as an alkaline suspension or solution, and the negative electrolytic mass in the mother liquor is [H] in the mother liquor.
⁺ ] From 3.1 mEq / L to 14 mE
In the range of q / L (however, when there is an excess of the positive electrolyte mass (salt) in the carbonic acid component in excess of the bicarbonate amount, the range after adding the negative electrolyte in an excess amount of the positive electrolyte) 3. The method for manufacturing a medical container according to claim 2, wherein the method includes: 4. The method for producing a medical container according to claim 2, wherein a carbon dioxide gas concentration of the medical solution after mixing the carbonic acid component and the mother liquor is in a range of 10 to 200 mHg. 5. The method for producing a medical container according to claim 4, wherein the accommodation room for the carbonic acid component is covered with a gas barrier package before or after the steam sterilization. 6. The method for producing a medical container according to claim 5, wherein a carbon dioxide-generating type oxygen scavenger is disposed in the gas barrier package.