JP2022148893A - Combination container including liquid, container set and manufacturing method for container including liquid - Google Patents

Abstract

To provide a combination container restricting oxygen-induced deterioration of a container including liquid.SOLUTION: A combination container 10 L including liquid has a first container 30 that stores liquid L of a volume γ(mL) and is pervious to oxygen at least partially, and a second container 40 that stores the first container and has an oxygen barrier property. A sum of a value obtained by subtracting the volume γ(mL) from a maximum capacity (mL) of the first container and a value obtained by subtracting the volume occupied by the first container (mL) from a maximum capacity (mL) of the second container is equal to or greater than (2.56×10-4×(β×T/α)) times of the volume γ(mL). T is an ambient temperature (K). β is a saturation solubility (mg/L) of oxygen to the liquid in the air atmosphere under air pressure at the temperature T(K). α is oxygen concentration (%) in the second container.SELECTED DRAWING: Figure 1

Description

TECHNICAL FIELD The present invention relates to a liquid-filled combination container, a container set, and a method for manufacturing a liquid-filled container.

A container for containing liquid is known (for example, Patent Document 1). Depending on the type of liquid, oxygen will decompose the liquid in the container. In order to deal with this problem, it is conceivable to use a container having oxygen barrier properties.

JP 2011-212366 A

However, oxygen may dissolve in the liquid during its manufacture. A container having an oxygen barrier property cannot deal with deterioration of the liquid caused by dissolved oxygen in the liquid. In other words, the conventional technology cannot sufficiently suppress oxygen deterioration of the liquid contained in the container. An object of the present disclosure is to suppress degradation caused by liquid oxygen.

A first liquid-filled combination container according to the present disclosure comprises:
a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container containing the first container and having an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The sum is at least (2.56×10 ⁻⁴ ×(β×T/α)) times the volume γ (mL), where T is the temperature of the environment (K) and β is the temperature T ( K) is the saturation solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure, and α is the oxygen concentration (%) in the second container.

A second liquid-filled combination container according to the present disclosure comprises:
a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container containing the first container and having an oxygen barrier property,
The first container and the second container collectively contain a volume of gas greater than (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL), where T is the volume of the environment. is the temperature (K) and β is the saturated solubility (mg/L) of oxygen in said liquid in an air atmosphere under atmospheric pressure at temperature T(K).

In the first and second liquid-filled combination containers according to the present disclosure, said oxygen concentration α may be less than 1%.

In the first and second liquid-filled combination containers according to the present disclosure, the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the maximum volume (mL) of the second container The total value of the value obtained by subtracting the volume (mL) occupied by the first container from the value obtained by multiplying the volume γ (mL) by (2.56 × 10 ^-4 × (β × T / α)), It may be equal to or greater than the sum of (21.0/α) times the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container.

In the first and second liquid-filled combination containers according to the present disclosure, the first container and the second container total the volume γ (mL) times (2.56 × 10 ^-4 × β × T) and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container multiplied by 21.0.

In the first and second liquid-filled combination containers according to the present disclosure, said volume γ (mL) may be greater than half of said maximum volume (mL) of said first container.

In the first and second liquid-filled combination containers according to the present disclosure, the volume γ may be 0.5 mL or more.

In the first and second liquid-filled combination containers according to the present disclosure, the volume γ may be 97.5% or more of the maximum volume (mL) of the first container.

In the first and second liquid-filled combination containers according to the present disclosure, the volume γ may be 20 mL or less.

In the first and second liquid-filled combination containers according to the present disclosure, the first container may be capable of containing a gas maintained at a negative pressure.

In the first and second liquid-filled combination containers according to the present disclosure, a negative pressure may be present within said second container.

In the first and second liquid-filled combination containers according to the present disclosure, a negative pressure may be present within said first container.

In the first and second liquid-filled combination containers according to the present disclosure,
The first container has a container body having an opening and a stopper closing the opening,
The oxygen may be permeable through the plug.

In the first and second liquid-filled combination containers according to the present disclosure, the container body may have oxygen barrier properties.

In the first and second liquid-filled combination containers according to the present disclosure,
The first container has a container body having an opening and a stopper closing the opening,
The oxygen permeability coefficient of the material forming the stopper may be higher than the oxygen permeability coefficient of the material forming the container body.

In the first and second liquid-filled combination containers according to the present disclosure,
The first container has a container body having an opening and a stopper closing the opening,
The plug may be at least partially composed of silicone.

In the first and second liquid-filled combination containers according to the present disclosure, the container body may be made of glass.

In the first and second liquid-filled combination containers according to the present disclosure,
The first container includes a syringe having a cylinder and a piston having a gasket disposed in the cylinder and defining a space containing the liquid,
The oxygen may be permeable through the gasket.

In the first and second liquid-filled combination containers according to the present disclosure, the cylinder may have oxygen barrier properties.

In the first and second liquid-filled combination containers according to the present disclosure,
The first container includes a syringe having a cylinder and a piston having a gasket disposed in the cylinder and defining a space containing the liquid,
The oxygen permeability coefficient of the material forming the gasket may be higher than the oxygen permeability coefficient of the material forming the cylinder.

In the first and second liquid-filled combination containers according to the present disclosure,
The first container includes a syringe having a cylinder and a piston having a gasket disposed in the cylinder and defining a space containing the liquid,
The gasket may be at least partially composed of silicone.

In the first and second liquid-filled combination containers according to the present disclosure, the cylinder may be constructed of glass.

A first container set according to the present disclosure comprises:
a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container that can accommodate the first container and has an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The sum is greater than 0.663 times the volume γ (mL).

A second container set according to the present disclosure comprises:
a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container that can accommodate the first container and has an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The sum is greater than 0.921 times the volume γ (mL).

A third container set according to the present disclosure comprises:
a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container that can accommodate the first container and has an oxygen barrier property,
In a state where the first container is housed and the second container is closed, the first container and the second container collectively contain a volume of gas larger than 0.663 times the volume γ (mL). can be accommodated.

A fourth container set according to the present disclosure comprises:
a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container that can accommodate the first container and has an oxygen barrier property,
In a state in which the first container is housed and the second container is closed, the first container and the second container collectively contain a volume of gas greater than 0.921 times the volume γ (mL). can be accommodated.

In the first to fourth container sets according to the present disclosure, the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container, and the maximum volume (mL) of the second container from the first The sum of the value obtained by subtracting the volume (mL) occupied by the container is the value obtained by multiplying the volume γ (mL) by 0.663 and the volume γ (mL) from the maximum volume (mL) of the first container It may be greater than the sum of the subtracted value multiplied by 21.0.

In the first to fourth container sets according to the present disclosure, the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container, and the maximum volume (mL) of the second container from the first The sum of the values obtained by subtracting the volume (mL) occupied by the container is the value obtained by multiplying the volume γ (mL) by 0.921 and the volume γ (mL) from the maximum volume (mL) of the first container It may be greater than the sum of the subtracted value multiplied by 21.0.

In the first to fourth container sets according to the present disclosure, in a state in which the first container is accommodated and the second container is closed, the first container and the second container have a total volume γ ( mL) multiplied by 0.663 and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container multiplied by 21.0. may be accommodated.

In the first to fourth container sets according to the present disclosure, in a state in which the first container is accommodated and the second container is closed, the first container and the second container have a total volume γ ( mL) multiplied by 0.921 and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container multiplied by 21.0. may be accommodated.

In the first to fourth container sets according to the present disclosure, the volume γ (mL) may be larger than half the maximum volume (mL) of the first container.

In the first to fourth container sets according to the present disclosure, the volume γ may be 0.5 mL or more.

In the first to fourth container sets according to the present disclosure, the volume γ may be 20 mL or less.

In the first to fourth container sets according to the present disclosure, the first container may be capable of containing gas while maintaining a negative pressure.

In the first to fourth container sets according to the present disclosure, the oxygen concentration within the first container may be 1.5% or less.

A first liquid-filled container manufacturing method according to the present disclosure includes:
closing a second container containing the first container and filled with an inert gas;
storing the first container within the second container;
the first container contains a volume γ (mL) of liquid and is at least partially permeable to oxygen;
The second container has an oxygen barrier property,
In a state in which the first container is accommodated and the second container is closed, the first container and the second container total the volume γ (mL) of (2.56 × 10 ^-4 × β ×T) times larger volume of gas, where T is the temperature of the environment (K) and β is the saturated solubility of oxygen in said liquid in an air atmosphere under atmospheric pressure at temperature T (K) (mg/L).

A second liquid-filled container manufacturing method according to the present disclosure includes:
closing a second container containing the first container and filled with an inert gas;
storing the first container within the second container;
the first container contains a volume γ (mL) of liquid and is at least partially permeable to oxygen;
The second container has an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The sum is at least (2.56×10 ⁻⁴ ×(β×T/α)) times the volume γ (mL), where T is the temperature of the environment (K) and β is the temperature T ( K) is the saturation solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure, and α is the oxygen concentration (%) in the second container.

In the method of manufacturing the first and second liquid-filled containers according to the present disclosure, the oxygen concentration in the first container before closing the second container may be 1.5% or less.

In the method of manufacturing the first and second liquid-filled containers according to the present disclosure, in a state in which the first container is housed and the second container is closed, the first container and the second container are in total: The value obtained by multiplying the volume γ (mL) by (2.56 × 10 ^-4 × β × T) and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container is 21.0 A larger volume of gas may be accommodated than the sum of the multiplied values.

In the method for manufacturing the first and second liquid-filled containers according to the present disclosure, the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the maximum volume (mL) of the second container The sum of the value obtained by ^subtracting the volume (mL) occupied by the first container from the It may be equal to or greater than the sum of (21.0/α) times the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container.

In the method of manufacturing the first and second liquid-filled containers according to the present disclosure, the volume γ (mL) may be larger than half the maximum volume of the first container.

In the method of manufacturing the first and second liquid-filled containers according to the present disclosure, the volume γ may be 0.5 mL or more.

In the method of manufacturing the first and second liquid-filled containers according to the present disclosure, the volume γ may be 20 mL or less.

In the method of manufacturing the first and second liquid-filled containers according to the present disclosure, the first container may be capable of containing gas while maintaining a negative pressure.

According to the present invention, deterioration due to liquid oxygen can be suppressed.

FIG. 1 is a diagram for explaining an embodiment according to the present disclosure, and is a perspective view showing an example of a liquid-filled combination container. 2 is a longitudinal cross-sectional view showing a liquid-filled first container that can be included in the liquid-filled combination container of FIG. 1; FIG. FIG. 3 is a view showing an example of a method of manufacturing the liquid-filled combination container of FIG. 1 and the liquid-filled first container of FIG. FIG. 4 is a diagram showing an example of a method of manufacturing the liquid-filled combination container of FIG. 1 and the liquid-filled first container of FIG. FIG. 5 is a diagram showing an example of a method of manufacturing the liquid-filled combination container of FIG. 1 and the liquid-filled first container of FIG. 6 is a perspective view showing how to use the liquid-filled first container of FIG. 2. FIG. FIG. 7 is a longitudinal sectional view showing a modified example of the second container. FIG. 8 is a longitudinal sectional view showing a modified example of the first container. FIG. 9 is a longitudinal sectional view showing another modification of the first container.

An embodiment of the present invention will be described below with reference to the drawings. In the drawings attached to this specification, for the convenience of illustration and ease of understanding, the scale and the ratio of vertical and horizontal dimensions are changed and exaggerated from those of the real thing.

1 to 9 are diagrams for explaining an embodiment of the present disclosure. The container set 20 has a liquid-filled first container 30L and a second container 40 . The liquid-filled first container 30</b>L has the first container 30 and the liquid L contained in the first container 30 . The first container 30 includes a portion that is at least partially permeable to oxygen. The second container 40 has oxygen barrier properties. The second container 40 can accommodate the liquid-filled first container 30L. The liquid-filled combination container 10L has a liquid-filled first container 30L and a liquid-filled second container 40 , and the liquid-filled first container 30L is housed in the second container 40 . According to this liquid-filled combination container 10L, by adjusting the oxygen concentration in the second container 40, not only the oxygen concentration in the first container 30 but also the dissolved amount of oxygen in the liquid L can be adjusted.

Each component of the liquid-filled combination container 10L will be described in further detail with reference to the illustrated specific example. First, the liquid-filled first container 30L will be described.

As described above, the liquid-filled first container 30L has the first container 30 and the liquid L contained within the first container 30 . At least a portion of the first container 30 may be permeable to oxygen. Meanwhile, the first container 30 can seal the liquid L. That is, the first container 30 is impermeable to the liquid L while being permeable to oxygen.

The liquid L contained in the first container 30 is not particularly limited. A liquid may be a solution comprising a solvent and a solute dissolved in the solvent. The solvent is not particularly limited, and may be water or alcohol. The liquid is not limited to a liquid in the strict sense, and may be a suspension in which solid particles are dispersed. The liquid L as food may be tea, coffee, black tea, soup, juice, soup stock, or a concentrated liquid obtained by concentrating one or more of these. A liquid as a medicine may be an internal medicine, an external medicine, or an injection. The liquid L may be blood or body fluid other than food and medicine.

The interior of the first container 30 may be sterile. That is, the liquid L may be a liquid that should be kept sterile. Foods and medicines are exemplified as the liquid L to be kept sterile. The liquid L as food or medicine is highly sensitive and is preferably stored in an aseptic state from the viewpoint of suppressing deterioration. The liquid L used as food or medicine is likely to deteriorate due to post-sterilization treatment performed after manufacturing. Post-sterilization (also called final sterilization) such as high pressure steam method, dry heat method, radiation method, ethylene oxide gas method, hydrogen peroxide gas plasma method, etc. cannot be applied to highly sensitive liquids. Such highly sensitive liquid L can be manufactured using a manufacturing line arranged in an aseptic environment. That is, it can be manufactured by aseptic techniques. In order to adjust the oxygen content of the liquid L produced by the aseptic method, the entire space in which the production line for the liquid L is arranged should be replaced with an inert gas. However, creating an inert gas atmosphere in the entire space where the production line for the liquid L is arranged entails a huge investment in equipment and may raise safety concerns for workers. Based on the above background, generally, the adjustment of the oxygen content of the liquid L has been entrusted to replacing the atmosphere in the formulation container containing the liquid L with an inert gas.

In contrast, according to the ideas of the present inventors, which will be described below, the oxygen concentration (%) in the first container 30 and the The oxygen dissolution amount (mg/L) of the liquid L in one container 30 can be sufficiently reduced. It can be said that the effects resulting from such ingenuity of the inventors of the present invention are remarkable beyond the range predicted from the technical level.

In addition, the inside of the product (liquid L) labeled as “sterilized” or “sterile”, the inside of the container containing the product, and the product such as pharmaceuticals ( The liquid L) and the interior of the container containing the product fall under "sterile conditions" as used herein. The product (liquid L) that satisfies the sterility assurance level (SAL) of 10 ^-6 specified in JIS T0806:2014 and the inside of the container containing the product also fall under the "sterile condition" used here. . Products that do not grow bacteria when stored at room temperature (e.g. 20°C) or higher for 4 weeks, the inside of the container containing the product, or the inside of the container containing the product, or stored in a refrigerated state (e.g. 8°C or lower) for 8 weeks or longer without bacterial growth The product and the interior of the container containing the product are also "sterile" as used herein. Furthermore, a drug that does not grow bacteria after being stored at a temperature of 28° C. or more and 32° C. or less for two weeks and the inside of a container containing the drug also correspond to the “aseptic condition” used here.

Next, the first container 30 containing the liquid L will be described. The first container 30 can seal the liquid L as described above. That is, the first container 30 can hold the liquid L without leakage.

The first container 30 includes a portion that is at least partially permeable to oxygen. The entire first container 30 may be permeable to oxygen. Only a portion of the first container 30 may be permeable to oxygen. Also, all gases may be permeable through the first container 30 . Only some gases including oxygen, for example only oxygen, may be permeable through the first container 30 .

The material constituting the portion having oxygen permeability should be 1×10 ⁻¹² (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or more, more preferably 5×10 ⁻¹² (cm ³ ( STP)·cm/(cm ² ·sec·Pa)) or more, more preferably 1×10 ⁻¹¹ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or more. ing. When the portion having oxygen permeability has a plurality of layers, the material constituting at least one layer preferably has such a permeability coefficient, and the materials constituting all layers may have the above permeability coefficient. more preferred. As a result, oxygen permeation through the first container 30 is promoted, and the oxygen concentration in the first container 30 can be quickly adjusted.

In order to suppress the leakage of water vapor or the like and to suppress the influence on the liquid in the first container 30 due to the high gas permeation rate after the second container 40 is opened, a portion having oxygen permeability An upper limit may be set for the oxygen permeability coefficient of the material that constitutes the . Specifically, the oxygen permeability coefficient is 1×10 ⁻¹ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less, preferably 1×10 ⁻² (cm ³ (STP)·cm/ (cm ² ·sec·Pa)) or less, more preferably 1×10 ⁻³ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less. When the portion having oxygen permeability has a plurality of layers, the material constituting at least one layer preferably has such a permeability coefficient, and the materials constituting all layers may have the above permeability coefficient. more preferred.

When the object to be measured is a resin film or resin sheet, the oxygen permeability coefficient is a value measured according to JIS K7126-1. When the measurement object is rubber, the oxygen permeability coefficient is a value measured according to JIS K6275-1. The oxygen permeability coefficient can be measured using an OXTRAN (February 21) permeation meter manufactured by MOCON, USA under an environment of temperature 25° C. and humidity 60 RH%.

The area of the oxygen-permeable portion is preferably 1 mm ² or more, more preferably 10 mm ² or more, and even more preferably 30 mm ² or more. Similarly, the thickness of the oxygen-permeable portion is preferably 3 mm or less, more preferably 1 mm or less, and even more preferably 0.5 mm or less. It is several millimeters or less. As a result, the gas permeation of the first container 30 is promoted, and the oxygen concentration in the first container 30 can be quickly adjusted.

The amount of oxygen that permeates the entire first container 30 is preferably 1×10 ⁻³ (mL/(day×atm)) or more, more preferably 1×10 ⁻² (mL/(day×atm)) or more, More preferably, it is 1×10 ⁻¹ (mL/(day×atm)) or more. As a result, oxygen permeation through the first container 30 is promoted, and the oxygen concentration in the first container 30 can be quickly adjusted. The amount of oxygen that permeates the entire first container 30 is preferably 100 (mL/(day×atm)) or less, more preferably 50 (mL/(day×atm)) or less, and even more preferably 10 (mL/( day x atm)) or less. As a result, leakage of water vapor or the like can be suppressed. Moreover, the influence on the liquid in the first container 30 due to the high gas permeation rate after the second container 40 is opened can be suppressed. The amount of oxygen that permeates the entire first container 30 can be measured, for example, as follows. First, the oxygen concentration in the first container 30 is set to approximately 0%, and the first container 30 is left in the atmosphere. A change in oxygen concentration in the first container 30 is measured over time. The amount of oxygen permeating the entire first container 30 can be specified by calculating how much oxygen has entered the first container 30 per day from the change in oxygen concentration over time.

For example, the oxygen concentration (%) in the first container 30 is reduced by 5% or more by storing the first container 30 containing a liquid having an oxygen dissolution amount of 8 mg/L in the second container 40 for four weeks. To obtain, the configuration of the oxygen permeable portion of the first container may be determined.

The illustrated first container 30 has a container body 32 with an opening 33 and a stopper 34 held in the opening 33 of the container body 32 . The plug 34 regulates leakage of the liquid L from the opening 33 . In such an example, even if the plug 34 is made of a material having oxygen permeability and the oxygen permeability coefficient (cm ³ (STP)·cm/(cm ² ·sec·Pa)) described above, good. The oxygen permeability coefficient of the material forming the plug 34 may be greater than the oxygen permeability coefficient of the material forming the container body 32 . A portion of plug 34 may also be oxygen permeable. A portion of plug 34 may be constructed of a material that is permeable to oxygen throughout its entire thickness. For example, plug 34 may be oxygen permeable through its entire thickness in a central portion spaced from the peripheral edge and oxygen barrier in a peripheral portion surrounding the central portion.

In the illustrated example, the area of the opening 33, that is, the opening area of the container body 32 is preferably 1 mm ² or more, more preferably 10 mm ² or more, and even more preferably 30 mm ² or more. Similarly, the thickness of the plug 34 is preferably 3 mm or less, more preferably 1 mm or less, and even more preferably 0.5 mm or less. It is several millimeters or less. As a result, oxygen permeation through the first container 30 is promoted, and the oxygen concentration in the first container 30 can be quickly adjusted. Moreover, from the viewpoint of ensuring flexibility and tightness, the thickness of the stopper, for example, the thickness of the rubber stopper may be 20 mm or less. In addition, from the viewpoint of allowing the needle or straw of the syringe to pierce, the thickness of the stopper, for example, the thickness of the rubber stopper may be 1 mm or less.

From the viewpoint of suppressing the leakage of water vapor and the like, and from the viewpoint of suppressing the influence on the liquid in the first container 30 due to the high gas permeation rate after the second container 40 is opened, the area of the opening 33 is An upper limit may be set. Specifically, the area of the opening 33 may be 5000 mm ² or less. From the viewpoint of securing strength, the thickness of the plug, for example, the thickness of the rubber plug may be 0.01 mm or more.

The oxygen-permeable plug 34 is not particularly limited, and various configurations can be adopted. In the illustrated example, the plug 34 is inserted into the opening 33 of the container body 32 to block the opening 33 . Other than the stopper shown in the figure, a cap of a sake bottle, more specifically, a stopper having a stopper main body portion inserted into the opening 33 and a flange portion enlarged in diameter from the stopper main body portion may be used. . Also, a plug having an outer spiral or an inner spiral and attached to the container body by meshing of the spirals may be used.

Plug 34 may be formed from silicone. Silicone is a substance having a siloxane bond as a main chain. The plug 34 may be made of silicone rubber. Silicone rubber refers to a rubber-like material made of silicone. Silicone rubber is a synthetic resin containing silicone as a main component, and is a rubber-like substance. Silicone rubber is a rubber-like substance having a siloxane bond as a main chain. The silicone rubber may be a thermosetting compound containing siloxane bonds. Examples of silicone rubber include methylsilicone rubber, vinyl-methylsilicone rubber, phenyl-methylsilicone rubber, dimethylsilicone rubber, and fluorosilicone rubber. The oxygen permeability coefficient of silicone and the oxygen permeability coefficient of silicone rubber are 1×10 ⁻¹² (mL/(m ² ×day×atm)) or more, and further 1×10 ⁻¹¹ (mL/(m ² ×day×atm)). ) or more. The oxygen permeability coefficient of silicone and the oxygen permeability coefficient of silicone rubber are 1×10 ⁻⁹ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less. Silicone and silicone rubber have a hydrogen permeability coefficient about 10 times higher, an oxygen permeability coefficient about 20 times higher, and a nitrogen permeability coefficient about 30 times higher than that of natural rubber. Silicone and silicone rubber have a hydrogen permeability coefficient that is 70 times or more, an oxygen permeability coefficient that is 40 times or more, and a nitrogen permeability coefficient that is 650 times or more as compared to butyl rubber.

Plug 34 may be constructed at least in part from silicone. That is, the plug 34 may be wholly or partially made of silicone or silicone rubber. For example, a portion of plug 34 may be constructed of silicone or silicone rubber over its entire thickness. The portion may be the central portion of plug 34 or some or all of the peripheral portion surrounding the central portion.

As shown in FIG. 2, the illustrated container body 32 has a bottom portion 32a, a trunk wall portion 32b, a neck portion 32c and a head portion 32d in this order. A storage space for the liquid L is mainly formed by the bottom portion 32a and the trunk wall portion 32b. The head 32 d forms the tip of the container body 32 . The head portion 32d is thicker than other portions. The neck portion 32c is positioned between the trunk wall portion 32b and the head portion 32d. The neck portion 32c has a reduced width, particularly a reduced diameter, with respect to the trunk wall portion 32b and the head portion 32d. The container body 32 may be transparent so that the contained liquid L can be observed from the outside. Here, the term “transparency” refers to transmission at each wavelength when measured using a spectrophotometer (“UV-3100PC” manufactured by Shimadzu Corporation, compliant with JIS K 0115) within a measurement wavelength range of 380 nm to 780 nm. It means that the visible light transmittance specified as the average value of the transmittance is 50% or more, preferably 80% or more.

In the illustrated example, the container body 32 is made of a material having an oxygen permeability coefficient lower than that of the material forming the plug 34 . The container body 32 may have oxygen barrier properties. That is, the first container 30 may be permeable to oxygen only partially. Having an oxygen barrier property means being composed of a material having an oxygen permeability coefficient of 1×10 ⁻¹³ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less. The structure having oxygen barrier properties may preferably be made of a material having an oxygen permeability coefficient of 1×10 ⁻¹⁷ (cm ³ (STP)·cm/(cm ² ·sec·Pa)) or less.

Examples of the container body 32 having oxygen barrier properties include a can made of metal, a container body having a metal layer formed by vapor deposition or transfer, and a glass bottle. Oxygen barrier properties can also be imparted to the container body 32 produced using a resin sheet or resin plate. In this example, the resin sheet or resin plate may include an oxygen barrier layer such as ethylene-vinyl alcohol copolymer (EVOH) or polyvinyl alcohol (PVA). Further, the container body 32 may have a layered body including a metal deposition film. The container body 32 using a laminate and the container body 32 using glass or resin can be imparted with oxygen barrier properties and transparency. If the first container 30 and the container main body 32 are transparent, it is preferable in that the liquid L contained therein can be confirmed from the outside of the first container 30 .

The volume of the first container 30 may be, for example, 1 mL or more and 1100 mL or less, 3 mL or more and 700 mL or less, or 5 mL or more and 200 mL or less.

In the illustrated example, the container body 32 is a clear or colored glass bottle. The container body 32 is made of borosilicate glass, for example. This first container 30 is a vial. The volume of the first container 30, which is a vial bottle, may be 1 mL or more, or 3 mL or more. The volume of the first container 30, which is a vial bottle, may be 500 mL or less, or may be 200 mL or less.

If the first container 30 is a vial bottle, the oxygen permeability coefficient of the material forming the stopper 34 may be greater than the oxygen permeability coefficient of the glass forming the container body 32 .

The illustrated primary container 30 further includes a fastener 36 . The fixture 36 restricts the stopper 34 from coming off the container body 32 . The fixture 36 is attached to the head portion 32 d of the container body 32 . A fixture 36 surrounds the periphery of plug 34, as shown in FIGS. As a result, the fixture 36 restricts the stopper 34 from being removed from the container body 32 while partially exposing the stopper 34 . The fixture 36 may be a sheet of metal secured to the head 32d. The fixture 36 may be a cap that screws onto the head 32d.

The illustrated first container 30 can maintain a negative internal pressure in the atmosphere. That is, the first container 30 can contain the gas while maintaining the gas at a negative pressure in the atmosphere. Also, the first container 30 may be able to contain the gas while maintaining the gas at a positive pressure in the atmosphere. In these examples, the first container 30 may have sufficient rigidity to maintain its shape. However, the first container 30 may deform to some extent under the atmosphere when the internal pressure is maintained at negative pressure or positive pressure. As the first container 30 capable of maintaining the internal pressure at negative pressure or positive pressure, the specific examples illustrated above and cans made of metal are exemplified.

Next, the second container 40 will be explained.

The second container 40 can be hermetically sealed by, for example, welding such as heat sealing or ultrasonic bonding, or bonding using a bonding material such as an adhesive material or an adhesive material. The second container 40 has oxygen barrier properties. Examples of the oxygen barrier second container 40 include a can made of metal, a container having a metal layer formed by vapor deposition or transfer, and a glass bottle. Also, the second container 40 may include a laminate having oxygen barrier properties. The laminate may include a resin layer having an oxygen barrier property such as ethylene-vinyl alcohol copolymer (EVOH) or polyvinyl alcohol (PVA), or a metal deposition film. At least a portion of the second container 40 may be transparent. The second container 40 using a laminate and the second container 40 using glass or resin can be imparted with oxygen barrier properties and transparency. By imparting transparency to the second container 40, it is preferable in that the liquid-filled first container 30L accommodated inside can be checked from the outside of the second container 40. FIG.

The second container 40 has a volume that can accommodate the first container 30 . The volume of the second container 40 may be, for example, 500 mL or more, 1 L or more, 5 L or more, 10 L or more, or 20 L or more. The volume of the second container 40 may be, for example, 50 L or less, 40 L or less, or 30 L or less. From the viewpoint of adjusting the oxygen concentration in the first container 30 and the amount of oxygen dissolved in the liquid L, the second container 40 contains a predetermined volume of gas determined in consideration of the volume γ (mL) of the liquid L and the like. obtain. The predetermined volume will be detailed later.

In the illustrated example, the second container 40 is made of a resin film having oxygen barrier properties. The second container 40 is formed as a so-called pouch. The second container 40 is formed as a so-called gusset bag. Specifically, the second container 40 has a first main film 41a, a second main film 41b, a first gusset film 41c and a second gusset film 41d. The first main film 41a and the second main film 41b are arranged facing each other. The first gusset film 41c is creased and arranged between the first main film 41a and the second main film 41b. The first gusset film 41c connects one side edge of the first main film 41a and one side edge of the second main film 41b. The second gusset film 41d is creased and arranged between the first main film 41a and the second main film 41b. The second gusset film 41d connects the other side edge of the first main film 41a and the other side edge of the second main film 41b. The first and second main films 41a, 41b and the first and second gusset films 41c, 41d are also joined together at their upper and lower edges. The films 41a to 41d are airtightly joined by, for example, welding such as heat sealing or ultrasonic joining, or joining using a joining material such as an adhesive or an adhesive. However, instead of joining separate films, one film may be folded to form two or more adjacently arranged films 41a-41d. As shown in FIG. 1, the gusset bag can form a rectangular bottom surface on the second container 40 . By arranging the first container 30 on the bottom surface, the first container 30 can be stored stably within the second container 40 . However, the second container 40 may be a pouch having a bottom film together with the first main film 41a and the second main film 41b instead of the gusset bag. Such a pouch can also form the bottom surface, and the first container 30 can be stably stored in the second container 40 . In these examples, the film forming the second container 40 may be transparent.

As another example, the second container 40 may have a container body 42 and a lid 44, as shown in FIG. The container body 42 has a housing portion 42a and a flange portion 42b. The accommodation portion 42a forms a rectangular parallelepiped accommodation space. The first container 30 is housed in this housing space. The accommodating portion 42a has a rectangular parallelepiped outer shape with one open surface. The flange portion 42b is provided on the periphery of the opening of the housing portion 42a. The lid 44 is flat. A peripheral portion of the lid 44 can be airtightly joined to the flange portion 42 b of the container body 42 . The container main body 42 and the lid 44 may be made of a resin plate having gas barrier properties. Lid 44 and container body 42 may be transparent. The thickness of the gas barrier resin plate may be 0.05 mm or more and 2 mm or less, or may be 0.1 mm or more and 1.5 mm or less. The second container 40 can maintain a negative internal pressure in the atmosphere. That is, the second container 40 can accommodate the gas while maintaining the gas at a negative pressure in the atmosphere. This second container 40 may be able to contain the gas while maintaining the gas at a positive pressure in the atmosphere. The second container 40 has sufficient rigidity to maintain its shape. However, the second container 40 may be somewhat deformed in the atmosphere when the internal pressure is maintained at negative pressure or positive pressure.

The container set 20 is configured by the liquid-filled first container 30L and the second container 40 described above. Using a container set 20 having a liquid-filled first container 30L and a liquid-filled second container 40, a liquid-filled combination container 10L is obtained. Combined container 10 is obtained using first container 30 and container set 20 .

Next, a method for manufacturing the liquid-filled combination container 10L will be described. By manufacturing the liquid-filled combination container 10L, the liquid-filled first container 30L with the adjusted oxygen concentration is obtained.

First, the liquid-filled first container 30L and the second container 40 before closing are prepared. The liquid-filled first container 30L is manufactured by filling the liquid L into the first container 30 . For example, a liquid L such as food or medicine is manufactured using a manufacturing line installed in an aseptic environment maintained at positive pressure. The internal pressure of the liquid-filled first container 30L thus obtained is a positive pressure as in the manufacturing environment.

As shown in FIG. 3, the second container 40 before closing still has an opening 40a for accommodating the liquid-filled first container 30L. In the second container 40 shown in FIG. 1, for example, the upper edges of the films 41a-41d are not joined together to form the opening 40a. In the second container 40 shown in FIG. 7, a container body 42 without a lid 44 is prepared. Then, as shown in FIG. 3, the liquid-filled first container 30L is accommodated in the second container 40 through the opening 40a.

After that, the second container 40 is filled with an inert gas such as nitrogen. In the example shown in FIG. 4 the inert gas is supplied from the supply pipe 55 . The supply pipe 55 enters the second container 40 through the opening 40a. A discharge port 56 of the supply pipe 55 is located inside the second container 40 . By supplying the inert gas from the supply pipe 55, the inside of the second container 40 is replaced with the inert gas. That is, the liquid-filled first container 30L is placed in an inert gas atmosphere. The inert gas is a stable gas with low reactivity. Examples of inert gases other than nitrogen include rare gases such as helium, neon, and argon.

Either filling of the inert gas into the second container 40 or arrangement of the liquid-filled first container 30L in the second container 40 may be performed first, or may be performed in parallel. good.

Next, as shown in FIG. 5, the second container 40 is closed while containing the first liquid-filled container 30L and filled with the inert gas. In the second container 40 shown in FIG. 1, the second container 40 is closed by joining the upper edges of the films 41a-41d together to block the opening 40a. In the second container 40 shown in FIG. 7, the second container 40 is closed by joining the peripheral portion of the lid 44 to the flange portion 42b of the container body 42. As shown in FIG. The bonding may be performed using a bonding material such as an adhesive or an adhesive, or may be welding by heat sealing, ultrasonic bonding, or the like.

Instead of supplying the inert gas from the supply pipe 55, the second container 40 containing the liquid-filled first container 30L may be closed under an inert gas atmosphere. Also by this method, the liquid-filled first container 30L is sealed inside the second container 40 together with the inert gas.

Also, the steps up to closing the second container 40 may be performed in an aseptic environment. That is, the aseptically manufactured liquid-filled first container 30L and the sterilized or aseptically manufactured second container 40 are brought into a sterile environment, such as a sterile chamber. If this chamber is separated from the atmosphere and has an inert gas atmosphere, the supply of the inert gas through the supply pipe 55 can be omitted. Then, the second container 40 containing the liquid-filled first container 30L is closed under an aseptic environment. Therefore, the inside of the second container 40 containing the liquid-filled first container 30L is also kept sterile. That is, the liquid-filled first container 30L can be stored in the second container 40 in an aseptic state.

After that, the liquid-filled first container 30L is stored in the second container 40 . As described above, the second container 40 has oxygen barrier properties. Therefore, permeation of oxygen through the second container 40 is effectively suppressed. On the other hand, the first container 30 is at least partially permeable to oxygen. In addition, the second container 40 is filled with inert gas, and the oxygen concentration in the second container 40 is very low. In this liquid-filled combination container 10L, oxygen in the first container 30 permeates the first container 30 and moves into the second container 40 . As the oxygen moves from the first container 30 to the second container 40, the oxygen concentration in the second container 40 increases and the oxygen concentration in the first container 30 decreases. The oxygen concentration in the first container 30 may match the oxygen concentration in the second container 40 at a final equilibrium state in which the permeation of oxygen through the first container 30 is in equilibrium.

In addition, when the oxygen concentration within the first container 30 decreases, the oxygen partial pressure within the first container 30 decreases. When the oxygen partial pressure within the first container 30 decreases, the saturation solubility (mg/L) of oxygen in the liquid L within the first container 30 also decreases. Then, the oxygen dissolution amount (mg/L) of the liquid L decreases.

By the way, in order to sufficiently reduce the oxygen concentration (%) of the liquid L and the dissolved oxygen amount (mg/L) dissolved in the liquid L, a large amount of inert gas is supplied to the second container 40 together with the first container 30L containing the liquid. It is preferred to fill and close the second container 40 . Similarly, it is preferable to fill the first container 30 with a large amount of inert gas together with the liquid L and close the first container 30 . That is, the maximum effective volume EV _2MAX (mL) of the second container 40 obtained by subtracting the volume occupied by the first container 30 from the maximum volume V _2MAX (mL) of the second container 40 is preferably large. Also, assuming that the inside of the first container 30 is replaced with an inert gas, the maximum effective volume of the first container 30 obtained by subtracting the volume γ (mL) from the maximum volume V _1MAX (mL) of the first container 30 EV _1MAX (mL) is preferably large. The maximum effective volume EV _2MAX (mL) of the second container 40 is the maximum volume of gas that can be accommodated in the second container 40 when the second container 40 contains only the first container 30L containing liquid and gas. . The maximum effective volume EV _1MAX (mL) of the first container 30 is the maximum volume of gas that can be contained in the first container 30 when the first container 30 contains only the liquid L and gas.

Specifically, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ ( mL) (2.56×10 ⁻⁴ ×(β×T/α)) times or more. Here, T is the temperature (K) of the environment in which the liquid-filled combination container 10L is placed. T can also be said to be the temperature (K) inside the accommodation space of the liquid-filled combination container 10</b>L, that is, the second container 40 . β is the saturated solubility (mg/L) of oxygen in liquid L in an air atmosphere at temperature T (K) and atmospheric pressure. α is the oxygen concentration (%) in the second container 40 . α may be the oxygen concentration (%) in the second container 40 in the equilibrium state.

Note that the maximum volume V _1MAX (mL) and the maximum volume V _2MAX (mL) mean maximum volumes when the volumes of the target containers 30 and 40 change due to deformation or the like. Therefore, when the target containers 30 and 40 have a constant volume, the constant volume corresponds to the maximum volume V _1MAX (mL) and the maximum volume V _2MAX (mL).

The maximum amount of oxygen that can be dissolved in a liquid L of volume γ (mL) placed in an air atmosphere of temperature T (K) is expressed as follows. The amount of oxygen expressed as follows is, as an example, the maximum amount of oxygen that can be dissolved in liquid L with volume γ (mL) that is produced in an air atmosphere at temperature T (K) and stored in first container 30. can be.
Oxygen molecular weight: β × γ / 1000 (mg)
Oxygen molar amount: β × γ/1000/32 (mmol)
Then, the maximum amount of oxygen dissolved in the liquid L is all degassed from the liquid L, the oxygen solubility becomes 0 (mg/L), and the oxygen concentration in the first container 30 and the second container 40 becomes α (%). Suppose it becomes In this assumption, oxygen gas is not contained in the first container 30 and the second container 40 immediately after the second container 40 containing the first container 30 is closed. At this time, the volume Vx (mL) of oxygen in the first container 30 and the second container 40 is specified as follows using the equation of state.
Vx=nRT/P
= (β x γ/1000/32) x 0.082 x T/(α/100)
= 2.56 × 10 ^-4 × (β × T/α) × γ (mL)
In this equation of state, the gas constant was set to 0.082 (L×atm/K/mol). If the oxygen concentration in the first container 30 and the second container 40 is α (%), the partial pressure of oxygen is "α/100" (atm).

That is, (2.56 × 10 ^-4 × (β × T/α)) times the volume γ (mL) of the liquid L contained in the first container 30 is It is the volume of oxygen in the liquid combination container 10L in the degassed state. Therefore, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 2.56×10 ⁻⁴ × (β×T/α)” times or more, the maximum amount of oxygen that can be dissolved in the liquid L can exist in the first container 30 and the second container 40 as degassed gas. . As a result, the dissolved oxygen amount (mg/L) in the liquid L can be sufficiently reduced, and the dissolved oxygen amount in the liquid L can be sufficiently reduced.

In practice, oxygen dissolves in the liquid L at an equilibrium state with a solubility corresponding to the oxygen concentration (%) or partial pressure of oxygen in the first container 30 . For example, if the liquid L is produced in an air atmosphere where the partial pressure of oxygen is 21.0 (%), the amount of dissolved oxygen in the liquid L in the equilibrium state is "β×α/21.0" (mg/ L). Therefore, the volume of oxygen degassed from the liquid L and present as gas is less than the volume γ (mL) of the liquid L times 2.56×10 ⁻⁴ ×(β×T/α).

Based on the above considerations, the volume of the first container 30 and the volume of the second container 40 can be calculated from the target oxygen concentration in the liquid-filled combination container 10L and the target oxygen dissolution amount (mg/L) of the liquid L. may decide. Further, from the target oxygen concentration in the liquid-filled combination container 10L and the target oxygen dissolution amount (mg/L) in the liquid L, the total volume of the gas contained in the first container 30 and the second container 40 is calculated. may decide.

For example, the volume of the containers 30 and 40 and the volume of the gas accommodated in the containers 30 and 40 may be determined so that the oxygen concentration in the first container 30 and the second container 40 can be reduced to less than 1%. In this example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL ) times (2.56×10 ⁻⁴ ×β×T). More specifically, when the liquid L is an aqueous solution, and the temperature T is about room temperature of 293 K, the oxygen saturation solubility β of water as a solvent is 8.84 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 0.663 times the volume γ (mL) of the liquid L. You can make it bigger. In addition, the total volume of the first container 30 and the second container 40 is larger than (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30. of gas can be accommodated. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature of 293 K, the total amount of the liquid L contained in the first container 30 and the second container 40 is A volume of gas greater than 0.663 times the volume γ (mL) may be accommodated.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K in a refrigerated state, the oxygen saturation solubility β of the solvent water is 13.04 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 0.921 times the volume γ (mL) of the liquid L. You can make it bigger. In addition, the first container 30 and the second container 40 may contain gas with a total volume larger than 0.921 times the volume γ (mL) of the liquid L contained in the first container 30 .

Also, the volume of the containers 30 and 40 and the volume of the gas accommodated in the containers 30 and 40 may be determined so that the oxygen concentration in the first container 30 and the second container 40 can be reduced to 0.5% or less. In this example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL ) may be (5.12×10 ⁻⁴ ×β×T) times or more. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature 293 K, the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 are mL) may be 1.32 times or more the volume γ (mL) of the liquid L. In addition, the total volume of the first container 30 and the second container 40 is at least (5.12×10 ⁻⁴ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30 of gas can be accommodated. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature of 293 K, the total amount of the liquid L contained in the first container 30 and the second container 40 is A gas with a volume 1.32 times or more the volume γ (mL) may be accommodated.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K in a refrigerated state, the oxygen saturation solubility β of the solvent water is 13.04 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 1.84 times the volume γ (mL) of the liquid L. You can make it bigger. In addition, the first container 30 and the second container 40 may contain gas with a total volume larger than 1.84 times the volume γ (mL) of the liquid L contained in the first container 30 .

Furthermore, the volume of the containers 30 and 40 and the volume of the gas accommodated in the containers 30 and 40 may be determined so that the oxygen concentration in the first container 30 and the second container 40 can be reduced to 0.2% or less. In this example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL ) may be (1.28×10 ⁻³ ×β×T) times or more. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature 293 K, the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 are mL) may be 3.32 times or more the volume γ (mL) of the liquid L. In addition, the total volume of the first container 30 and the second container 40 is at least (1.28×10 ⁻³ ×β×T) times the volume γ (mL) of the liquid L contained in the first container 30 of gas can be accommodated. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature of 293 K, the total amount of the liquid L contained in the first container 30 and the second container 40 is A gas with a volume 3.32 times or more of the volume γ (mL) may be accommodated.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K in a refrigerated state, the oxygen saturation solubility β of the solvent water is 13.04 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 4.61 times the volume γ (mL) of the liquid L. You can make it bigger. In addition, the first container 30 and the second container 40 may contain gas with a total volume larger than 4.61 times the volume γ (mL) of the liquid L contained in the first container 30 .

It is also conceivable that oxygen is present in the space not occupied by the liquid L of the first container 30, the so-called headspace HS, during the manufacture of the liquid-filled first container 30L. For example, when the liquid L is contained in the first container 30 and the first container 30 is closed in an air atmosphere, air exists in the head space HS of the first container 30 . That is, the oxygen concentration in the liquid-filled first container 30L is approximately 21.0%. That is, in the initial state, the liquid-filled first container 30L contains oxygen dissolved in the liquid L and gaseous oxygen in the headspace HS. At this time, the amount of oxygen in the headspace HS is specified as follows.
Oxygen mol amount: 0.210 × EV _1MAX / 0.082 / T (mmol)
Here, EV _1MAX is the maximum effective volume EV _1MAX (mL) of the first container 30 obtained by subtracting the volume γ (mL) from the maximum volume V _1MAX (mL) of the first container 30, and the maximum headspace HS. Volume (mL). The volume of gaseous oxygen in the headspace HS expands to (EV _1MAX ×21.0/α) (mL) in an equilibrium state where the oxygen concentration is α (%).

(2.56 × 10 ^-4 × (β × T / α)) times the volume γ (mL) of the liquid L described above is It is the volume of gas in the liquid-filled combination container 10L. Therefore, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL of the liquid L of (2.56×10 ⁻⁴ × (β×T/α)) and the maximum effective volume EV _1MAX (mL) of the first container 30 multiplied by (21.0/α).According to this design, , the maximum amount of oxygen that can be dissolved in liquid L can be present in the first and second containers 30 and 40 as degassed gas, along with the oxygen present in the headspace HS. The dissolved amount can be sufficiently reduced, and the dissolved oxygen amount in the liquid L can be sufficiently reduced.

From the viewpoint of suppressing deterioration of the liquid L due to oxygen, it is preferable that the oxygen concentration in the first container 30 immediately after manufacturing the liquid-filled first container 30L is low. The oxygen concentration in the first container 30 may preferably be 1.5% or less. Such an oxygen concentration in the first container 30 can be achieved by supplying an inert gas into the first container 30 containing the liquid L.

When the oxygen in the air present in the head space HS is taken into consideration when manufacturing the first liquid-filled container 30L, the target oxygen concentration in the liquid-filled combination container 10L and the target oxygen dissolution amount of the liquid L ( mg/L), the volume of the first container 30 and the volume of the second container 40 may be determined. Further, from the target oxygen concentration in the liquid-filled combination container 10L and the target oxygen dissolution amount (mg/L) in the liquid L, the total volume of the gas contained in the first container 30 and the second container 40 is calculated. may decide.

For example, the volume of the containers 30 and 40 and the volume of the gas accommodated in the containers 30 and 40 may be determined so that the oxygen concentration in the first container 30 and the second container 40 can be reduced to less than 1%. In this example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL ) multiplied by (2.56×10 ⁻⁴ ×β×T) and the maximum effective volume EV _1MAX (mL) of the first container 30 multiplied by 21.0. . More specifically, when the liquid L is an aqueous solution, the oxygen saturation solubility β of water is 8.84 (mg/L) when the temperature T is 293 K, which is about room temperature. In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL) of the liquid L multiplied by 0.663. and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 21.0. Further, the total value of the first container 30 and the second container 40 is a value obtained by multiplying the volume γ (mL) of the liquid L contained in the first container 30 by 2.56×10 ⁻⁴ ×β×T), A gas with a volume larger than the sum of the maximum effective volume EV 1MAX (mL) of the first container 30 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) by 21.0 may be accommodated. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature of 293 K, the total amount of the liquid L contained in the first container 30 and the second container 40 is A gas having a volume larger than the sum of the value obtained by multiplying the volume γ (mL) by 0.663 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 21.0 may be accommodated.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K in a refrigerated state, the oxygen saturation solubility β of the solvent water is 13.04 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 0.921 times the volume γ (mL) of the liquid L. and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 21.0. In addition, the total of the first container 30 and the second container 40 is the value obtained by multiplying the volume γ (mL) of the liquid L contained in the first container 30 by 0.921, and the maximum effective volume EV of the first container 30 A gas with a volume larger than the sum of the value obtained by multiplying _1MAX (mL) by 21.0 may be accommodated.

Also, the volume of the containers 30 and 40 and the volume of the gas accommodated in the containers 30 and 40 may be determined so that the oxygen concentration in the first container 30 and the second container 40 can be reduced to 0.5% or less. In this example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL ) multiplied by (5.12×10 ⁻⁴ ×β×T) and the maximum effective volume EV _1MAX (mL) of the first container 30 multiplied by 41.9. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature 293 K, the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 are mL) is equal to or greater than the sum of the value obtained by multiplying the volume γ (mL) of the liquid L by 1.32 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 41.9 good. In addition, the total value of the first container 30 and the second container 40 is a value obtained by multiplying the volume γ (mL) of the liquid L contained in the first container 30 by 5.12×10 ⁻⁴ ×β×T), A gas with a volume equal to or greater than the sum of the maximum effective volume EV 1MAX (mL) of the first container 30 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) by 41.9 may be accommodated. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature of 293 K, the total amount of the liquid L contained in the first container 30 and the second container 40 is A gas having a volume equal to or greater than the sum of the value obtained by multiplying the volume γ (mL) by 1.32 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 41.9 may be accommodated.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K in a refrigerated state, the oxygen saturation solubility β of the solvent water is 13.04 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 1.84 times the volume γ (mL) of the liquid L. and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 41.9. In addition, the first container 30 and the second container 40 have a total value obtained by multiplying the volume γ (mL) of the liquid L contained in the first container 30 by 1.84 and the maximum effective volume EV of the first container 30 A gas with a volume larger than the sum of _1MAX (mL) multiplied by 41.9 may be accommodated.

Furthermore, the volume of the containers 30 and 40 and the volume of the gas accommodated in the containers 30 and 40 may be determined so that the oxygen concentration in the first container 30 and the second container 40 can be reduced to 0.2% or less. In this example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is the volume γ (mL ) multiplied by (1.28×10 ⁻³ ×β×T) and the maximum effective volume EV _1MAX (mL) of the first container 30 multiplied by 105. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature 293 K, the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 are mL) may be equal to or greater than the sum of the value obtained by multiplying the volume γ (mL) of the liquid L by 3.32 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 105. Further, the total value of the first container 30 and the second container 40 is a value obtained by multiplying the volume γ (mL) of the liquid L contained in the first container 30 by 1.28×10 ⁻³ ×β×T), A gas with a volume equal to or greater than the sum of the maximum effective volume EV 1MAX (mL) of the first container 30 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) by 105 may be accommodated. More specifically, assuming that the liquid L is an aqueous solution and the temperature T is about room temperature of 293 K, the total amount of the liquid L contained in the first container 30 and the second container 40 is A gas with a volume equal to or greater than the sum of the value obtained by multiplying the volume γ (mL) by 3.32 and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 105 may be accommodated.

Considering refrigerated storage as another example, if the liquid L is an aqueous solution and the temperature T is 276 K in a refrigerated state, the oxygen saturation solubility β of the solvent water is 13.04 (mg/L). In this specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX (mL) of the second container 40 is 4.61 times the volume γ (mL) of the liquid L. and the value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 105. In addition, the total of the first container 30 and the second container 40 is the value obtained by multiplying the volume γ (mL) of the liquid L contained in the first container 30 by 4.61, and the maximum effective volume EV of the first container 30 A gas with a volume larger than the sum of _1MAX (mL) multiplied by 105 may be accommodated.

As described above, by storing the liquid-filled first container 30L in the second container 40, the oxygen concentration of the gas accommodated together with the liquid in the first container 30 can be reduced. Additionally, the amount of dissolved oxygen dissolved in the liquid L in the first container 30 can also be reduced. On the other hand, highly sensitive liquids L, such as foods and medicines, can be decomposed by oxygen. By storing the liquid L in the first container 30 stored in the second container 40, division of the liquid L by oxygen can be suppressed. That is, the present embodiment, in which the oxygen concentration in the first container 30 can be adjusted after the liquid L is enclosed, is suitable for the highly sensitive liquid L such as food and medicine.

It should be noted that the amount of dissolved oxygen in the liquid contained in the container can be reduced by producing the liquid in an atmosphere replaced with an inert gas and storing the liquid in a container having an oxygen barrier property. Conceivable. However, installing the entire liquid manufacturing line in an atmosphere replaced with an inert gas requires large-scale renovation of manufacturing equipment and a huge capital investment. Further, in the field of expensive chemicals, etc., in order to ensure stability against temperature, oxygen, moisture, light, etc., the chemicals are freeze-dried and stored in the form of powder. However, powdering a liquid chemical for storage and reconstituting a powdered chemical to a liquid before use have significant disadvantages in terms of labor, time, and cost.

On the other hand, according to the present embodiment, the existing equipment or the like can be used to manufacture the liquid-filled first container in the conventional manner. Therefore, equipment repair and equipment investment can be avoided. In particular, when applied to liquids such as chemicals, it is also useful in that it is possible to omit the need to apply for approval of changes in manufacturing equipment and manufacturing processes to public institutions. Further, it is possible to omit the labor of drying and freezing the liquid L and returning the powder to the liquid. Furthermore, the first container 30 is not subject to any special restrictions. Therefore, materials that are widely used as containers for food, medicine, etc. due to their low elution amount, such as glass and resins such as polyethylene and polypropylene, can be used as the material for the first container.

Additionally, in the embodiment described above, the first container 30 has a container body 32 and a closure 34 . This first container 30 may be a vial. However, conventionally, vials containing liquids, particularly vials containing liquids in an aseptic state, are manufactured using butyl rubber or fluororubber having low oxygen permeability and further oxygen barrier properties. On the other hand, oxygen can permeate the plug 34 in the specific example described above. That is, the oxygen permeability coefficient (cm ³ (STP)·cm/(cm ² ·sec·Pa)) of the material forming the plug 34 is set large. Specifically, the plug 34 is made of silicone or silicone rubber. Furthermore, the oxygen permeability coefficient of the silicone or silicone rubber forming the plug 34 is higher than the oxygen permeability coefficient of the material forming the container body 32 . According to such embodiments, oxygen passes through plug 34 and out of first container 30 . Therefore, oxygen permeability can be easily imparted to existing containers such as vials that have been conventionally used.

In this embodiment, the time to equilibrium depends on the oxygen permeability of plug 34 . Therefore, by adjusting the lower limit of the area of the opening 33 of the container body 32 and the upper limit of the thickness of the plug 34 as described above, the first container 30 can be removed after the first container 30 is accommodated in the second container 40 . The time required for oxygen permeation through the membrane to equilibrate can be shortened. Thereby, decomposition of the liquid L by oxygen can be suppressed.

Further, the maximum effective volume EV _1MAX of the first container 30 obtained by subtracting the volume γ of the liquid L from the maximum volume V _1MAX of the first container 30 may be 20 mL or less, or may be 5 mL or less. The volume of the gas accommodated together with the liquid L in the first container 30 may be 20 mL or less, or may be 5 mL or less. According to such a liquid-filled combination container 10L, it is possible to shorten the time from closing the second container 40 containing the first container 30 until the permeation of oxygen through the first container 30 is balanced. Thereby, decomposition of the liquid L by oxygen can be suppressed.

Similarly, the volume of the liquid L contained in the first container 30 may be 20 mL or less, or may be 5 mL or less. According to such a liquid-filled combination container 10L, it is possible to shorten the time from closing the second container 40 containing the first container 30 until the permeation of oxygen through the first container 30 is balanced. Thereby, decomposition of the liquid L by oxygen can be suppressed. In addition, by setting the upper limit of the amount of liquid in the first container 30 in this way, it is possible to prevent the second container 40 from becoming large and the handleability of the combined container 10 from deteriorating. In addition, it is suitable for use in which a high-concentration undiluted solution of tea or soup stock is stored as a liquid in the first container, or for use in which an expensive and highly pharmacologically active chemical is stored as a liquid in the first container.

Furthermore, the maximum effective volume EV _1MAX of the first container 30 obtained by subtracting the volume γ of the liquid L from the maximum volume V _1MAX of the first container 30, and the volume occupied by the first container 30 from the maximum volume V _2MAX of the second container 40 An upper limit and a lower limit may be set for the ratio (%) of the subtracted second container 40 to the maximum effective volume EV _2MAX . This ratio may be 50% or less, or may be 20% or less. By setting such an upper limit, the oxygen concentration in the first container 30 can be reduced. In addition, a space for accommodating the first container 30 can be secured within the second container 40 , and the first container 30 can be easily accommodated within the second container 40 . Furthermore, the time from closing of the second container 40 containing the first container 30 to equilibrium of oxygen permeation through the first container 30 can be shortened. Thereby, decomposition of the liquid L by oxygen can be suppressed. Also, this ratio may be 5% or more, or 1% or more. By setting the lower limit in this manner, the second container 40 does not become too large with respect to the first container 30, and deterioration in handleability of the combination container 10 can be suppressed.

Whether or not oxygen permeation through the first container 30 is in an equilibrium state is determined based on the oxygen concentration in the first container 30 . For this determination, the difference between the oxygen concentration value (%) in the first container 30 at a certain time and the oxygen concentration value (%) in the first container 30 24 hours before the certain time is If the oxygen concentration value (%) in the first container 30 at a certain time is ±5% or less, it is determined that an equilibrium state has been reached.

As described above, the liquid-filled first container 30L and the liquid-filled combination container 10L with adjusted oxygen concentration and dissolved oxygen amount can be obtained. In an equilibrium state in which the permeation of oxygen through the first container 30 is balanced, as an example, the oxygen concentration in the first container 30 and the oxygen concentration in the second container 40 may be less than 1%. It may be difficult to reduce the oxygen concentration (%) in the head space HS in the first container 30 only by replacing with an inert gas in the conventional technology because the first container 30 contains the liquid L. There were many. As a result, it has been difficult to reduce the amount of dissolved oxygen dissolved in the liquid L in large amounts. On the other hand, according to a specific example of the above-described embodiment, the second container 40 contains the container 30LF containing the liquid preparation and the gas, and there is no need to contain the liquid L as it is. The oxygen concentration in container 40 can be sufficiently reduced. Therefore, by adjusting the volume of the second container 40, the oxygen concentration in the first container 30 in the equilibrium state can be less than 1%, preferably 0.5% or less, more preferably 0.2% or less. . Such effects are suitable when the liquid L is a highly sensitive chemical or food.

On the other hand, without using the second container 40, a large maximum effective volume EV _1MAX of the first container 30 obtained by subtracting the volume γ of the liquid L from the maximum volume V _1MAX of the first container 30 is secured. Filling 30 with an inert gas can also be considered. However, in this case, the extra space in the first container becomes large compared to the volume γ (mL) of the liquid, making it difficult to discharge the liquid from the first container. Also, the liquid is sold in the first container, and oxygen deterioration may be accelerated. In addition, when applied to liquids such as foods, it impairs the desire to buy and lowers the product attractiveness. When applied to a liquid such as a chemical, it becomes difficult to check the state of the liquid in the first container, and it becomes difficult to take out an appropriate amount of the liquid from the first container.

If it takes a long time for the oxygen concentration and the amount of dissolved oxygen to decrease, deterioration of the liquid L due to oxygen will progress. The period or time from closing of the second container 40 to equilibration of oxygen permeation through the first container 30 is also preferably no more than four weeks. If the equilibrium state is reached within four weeks, for example, if the oxygen concentration in the second container 40 becomes less than 1%, deterioration of the liquid L as a chemical can be effectively suppressed. In addition, with regard to the more sensitive liquid L, the period to equilibrium is preferably within 20 days, more preferably within 1 week, and even more preferably within 3 days. On the other hand, it takes a certain period of time to reach an equilibrium state in which the amount of dissolved oxygen in the liquid L is reduced to some extent. In order to achieve effective oxygen dissolution adjustment, the period or time from closing of the second container 40 to equilibrium of oxygen permeation through the first container 30 may be one hour or more.

As a measuring device used to specify the oxygen concentration (%) and the oxygen dissolution amount (mg/L), an oxygen measuring device Fibox3 manufactured by PreSens in Germany is exemplified. According to the oxygen content measuring device Fibox3, for example, the combination container containing the liquid preparation shown in FIG. 1 and the liquid preparation container containing the liquid preparation shown in FIG. can be measured by Alternatively, oxygen concentration (%) and oxygen dissolution amount (mg/L) may be measured using an oxygen content measuring device Microx4 manufactured by PreSens of Germany. The oxygen meter Microx4 is a needle-type device. The oxygen content measuring device Microx4 can measure the oxygen concentration and dissolved oxygen amount in the container by piercing the container with a needle.

Storage of the first container 30 within the second container 40 may be performed until oxygen permeation through the first container 30 equilibrates. Storage of the first container 30 within the second container 40 may be performed until the oxygen concentration within the second container 40 rises to a predetermined value. Storage of the first container 30 within the second container 40 may be performed until the oxygen concentration within the first container 30 is reduced to a predetermined value. Storage of the first container 30 in the second container 40 may be performed until the amount of dissolved oxygen in the liquid L in the first container 30 decreases to a predetermined value. Storage of the first container 30 within the second container 40 may be performed until the liquid L of the combination container 10 is used. Also, while the first container 30 is stored in the second container 40, the liquid-filled combination container 10L may be circulated.

Next, a method for using the liquid-filled combination container 10L will be described.

When using the liquid L stored in the combination container 10, first, the second container 40 is opened. Next, the liquid-filled first container 30L is taken out from the opened second container 40 . After that, the liquid L can be taken out from the liquid-filled first container 30L and used. For the illustrated first container 30 , the first container 30 can be opened by removing the fastener 36 from the container body 32 and removing the stopper 34 from the container body 32 . Thereby, the liquid L in the first container 30 can be used.

Alternatively, the liquid L may be a chemical injected into a syringe 60 as shown in FIG. That is, the liquid L may be an injection. The syringe 60 has a cylinder 62 and a piston 66 . The cylinder 62 has a cylinder body 63 and a needle 64 projecting from the cylinder body 63 . A tubular needle 64 allows access to the space for containing the liquid L in the cylinder body 63 . The piston 66 has a piston body 67 and a gasket 68 retained on the piston body 67 . Gasket 68 may be made of rubber or the like. The gasket 68 is inserted into the cylinder body 63 to partition the housing space for the liquid L within the cylinder body 63 .

By the way, it is preferable that the pressure in the liquid-filled first container 30L is adjusted. As an example, it is preferable that the pressure in the first liquid-filled container 30L is maintained low, particularly negative pressure. According to this example, it is possible to effectively suppress unintended leakage of the liquid during storage of the first liquid-filled container 30L, splashing of the liquid L when the first container 30 is opened, and the like. Container leakage and splashing problems are exacerbated with toxic liquids, such as highly active drugs. In the example shown in FIG. 6, the liquid L automatically enters the syringe 60 when the pressure inside the first liquid container 30L is positive. In this case, it becomes difficult to inject a desired amount of the liquid L into the syringe 60 with high accuracy.

On the other hand, highly sensitive liquids, such as foods and drugs, which are degraded by post-sterilization processes carried out after manufacture using, for example, gas, heat, gamma rays, etc., are manufactured and packaged in an aseptic environment. . That is, liquids to which terminal sterilization cannot be applied are produced by aseptic procedures. This aseptic environment is usually maintained at a predetermined positive pressure in order to suppress invasion of bacteria. Therefore, the pressure inside the container becomes a predetermined positive pressure corresponding to the sterile environment, and it is difficult to adjust the internal pressure of the container after the container is closed.

According to the specific example described above, such a problem can be dealt with. As described above, the liquid-filled first container 30L is stored within the second container 40 . During this storage, oxygen in the first container 30 permeates the first container 30 and moves into the second container 40 due to a decrease in oxygen concentration in the second container 40 due to inert gas replacement. Thereby, the pressure in the first container 30 can be lowered. That is, the pressure of the first container 30 containing the liquid L can be adjusted after the first container 30 is closed and the liquid L is enclosed.

From the viewpoint of adjusting the internal pressure of the first container 30, the second container 40 that can contain the gas while maintaining the negative pressure may be used. For example, using the second container 40 shown in FIG. 7, the second container 40 containing the first container 30 may be closed under an inert gas atmosphere maintained at a negative pressure. The pressure in the closed second container 40 will be below atmospheric pressure. In this case, oxygen permeation from the first container 30 to the second container 40 is promoted. In particular, by securing a large volume of the second container 40 or greatly reducing the initial pressure of the second container 40, the pressure in the first container 30 can be adjusted significantly. As a result, the pressure inside the first container 30 , which was initially positive, can be adjusted to a negative pressure by storing the first container 30 inside the second container 40 . As a result, the pressure-regulated liquid-filled first container 30L can be manufactured without depending on the method of manufacturing the liquid L, the method of sealing the liquid L in the first container 30 of the liquid, or the like.

A desired amount of the liquid L can be taken out from the first container 30 by adjusting the pressure inside the first container 30L containing the liquid. From the viewpoint of enabling the desired amount of the liquid L to be extracted from the first container 30 with high accuracy, the volume of the liquid L contained in the first container 30 may be 0.5 mL or more, more preferably 1 mL or more. good too.

Also, closing the second container 40 with negative pressure promotes oxygen permeation of the first container 30 . Therefore, the time from closing the second container 40 containing the liquid-filled first container 30L until the permeation of oxygen through the first container 30 reaches equilibrium can be shortened.

The negative pressure means a pressure of less than 1 atm which is atmospheric pressure. Positive pressure means pressure above 1 atm, which is atmospheric pressure. It should be noted that whether or not the inside of any of the containers has a negative pressure can be determined using the pressure gauge if the container is provided with a pressure gauge. If the container is not equipped with a pressure gauge, it can be determined using a syringe. Specifically, when the target container is pierced with the needle of the syringe, whether the liquid or gas contained in the syringe flows into the container while only the atmospheric pressure is applied to the piston of the syringe. You can judge whether or not When the liquid or gas contained in the syringe flows into the container, it is determined that the pressure inside the container was negative. Similarly, whether or not the pressure inside any container is positive can be determined using a pressure gauge, but it can also be determined using a syringe. Specifically, when the target container is pierced with the needle of the syringe, whether the liquid or gas contained in the container flows into the syringe while only the atmospheric pressure is applied to the piston of the syringe. You can judge whether or not If the liquid or gas contained in the container flows into the syringe, it is determined that the pressure inside the container was positive.

In the embodiment described above, the container set 20 includes the first container 30 that contains the liquid L and is at least partially permeable to gas, and the first container 30 that can contain the first container 30 and has gas barrier properties. and a second container 40 . Combination container 10 is obtained by housing first container 30 in second container 40 . That is, the liquid-filled combination container 10L includes a first container 30 that contains the liquid L and is at least partially permeable to gas, and a second container 40 that contains the first container 30 and has an oxygen barrier property. have. Further, the method for manufacturing the first liquid-filled container 30L includes the steps of closing the second container 40 containing the first liquid-filled container 30L and filled with an inert gas; and storing. In the storing step, the oxygen in the first container 30 permeates the first container 30, thereby reducing the oxygen concentration in the first container 30. FIG. The amount of dissolved oxygen dissolved in the liquid L can be reduced by reducing the oxygen concentration in the first container 30 .

According to such an embodiment, oxygen within the first container 30 may pass through the first container 30 and into the second container 40 . By replacing the atmosphere in the second container 40 with an inert gas, the oxygen concentration (%) in the first container 30 can be lowered. As the oxygen concentration (%) in the first container 30 decreases, the oxygen dissolution amount (mg/L) in the liquid L also decreases. Therefore, the amount of oxygen dissolved in the liquid L can be reduced, and decomposition of the liquid L by oxygen can be suppressed.

In this combination container 10, the second container 40 is responsible for reducing the amount of oxygen and providing oxygen barrier properties. On the other hand, the liquid-filled first container 30L may be responsible for the sterility of the liquid L contained therein. In this way, the storage environment required for the liquid L is efficiently realized by the combination of the first container 30 and the second container 40 . According to the combination container 10 and the container set 20, the storage environment required for the liquid L can be easily realized with a high degree of freedom at low cost.

In this embodiment, the maximum effective volume EV _1MAX (mL) of the first container 30, which is obtained by subtracting the volume γ (mL) from the maximum volume V _1MAX (mL) of the first container 30, and the maximum volume of the second container 40 The sum of the maximum effective volume EV _2MAX of the second container 40 obtained by subtracting the volume (mL) occupied by the first container 30 from V _2MAX (mL) is (2.56×10 ⁻ It may be ⁴ ×(β×T/α)) times or more. Here, T is the temperature (K) of the environment in which the liquid-filled combination container 10L is placed. β is the saturated solubility (mg/L) of oxygen in liquid L in an air atmosphere at temperature T (K) and atmospheric pressure. α is the oxygen concentration (%) in the second container 40 when the permeation of oxygen through the first container 30 is in equilibrium. By using the first container 30 and the second container 40 having such a volume, the first container 30 and the second container 40 can contain a sufficient volume of gas. As a result, the oxygen concentration in the second container 40 can be reduced to α (%) or less in an equilibrium state in which the permeation of oxygen through the first container 30 is in equilibrium.

As a specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX of the second container 40 is greater than 0.663 times the volume γ (mL) of the liquid L. good too. According to this example, the oxygen concentration in the second container 40 can be reduced to less than 1% in an air atmosphere with a temperature of 293K and atmospheric pressure.

Further, in this embodiment, when the first container 30 is accommodated and the second container 40 is closed, the total volume of the first container 30 and the second container 40 is γ (mL) of the liquid L. It may contain a volume of gas greater than (2.56×10 ⁻⁴ ×β×T) times. According to this example, the oxygen concentration in the second container 40 can be reduced to less than 1%. As a specific example, when the first container 30 is accommodated and the second container 40 is closed, the total volume of the first container 30 and the second container 40 is 0.663 of the volume γ (mL) of the liquid L. More than double the volume of gas may be accommodated. According to this example, the oxygen concentration in the second container 40 can be reduced to less than 1% in an air atmosphere with a temperature of 293K and atmospheric pressure.

According to the above embodiment, the amount of dissolved oxygen dissolved in the liquid L can be reduced, and decomposition of the liquid L by oxygen can be suppressed. For example, in applications where a drug is stored as a liquid in the first container, the disappearance of the pharmacological component in three years can be 5% or less, more preferably 3% or less, and even more preferably 1% or less.

Note that if the volume for accommodating a large amount of gas is secured only by the first container without using the second container, the extra space in the first container becomes larger than the liquid volume γ (mL). , the liquid is not easily removed from the first container. Also, the liquid is agitated in the first container, which may accelerate deterioration due to oxygen. Furthermore, when applied to liquids such as food, it impairs the willingness to purchase and lowers the product attractiveness. When applied to a liquid such as a chemical, it becomes difficult to check the state of the liquid in the first container, and it becomes difficult to take out an appropriate amount of the liquid from the first container. In contrast, according to the embodiment described above, the liquid-filled combination container 10L has a second container 40 in addition to the liquid-filled first container 30L. Therefore, extra space in the first container 30 that does not contain the liquid L can be reduced. Moreover, since the second container 40 does not directly contain the liquid L, the internal atmosphere of the second container 40 can be easily replaced with an inert gas.

As a specific example of the embodiment described above, the volume γ (mL) of the liquid L may be larger than half the maximum volume (mL) of the first container 30 . By reducing the space in the first container 30 in which the liquid L is not contained, the so-called head space HS, when the first container 30 containing the liquid L is closed, the flow of liquid into the first container 30 is reduced. The residual amount of oxygen gas can be reduced. Thereby, decomposition of the liquid L by oxygen can be suppressed. In addition, the first container 30 finally taken out from the second container 40 can be made smaller, and the handleability of the first container 30 can be improved. Furthermore, taking out the liquid L from the first container 30 can be facilitated.

More preferably, the volume γ (mL) of the liquid L contained in the first container 30 may be 97.5% or more of the maximum volume V _{1MAX (} (mL) of the first container 30. According to this example, , the number of moles of oxygen dissolved in the liquid L in the first container 30 is greater than the number of moles of oxygen in the headspace HS of the first container 30. As described above, the amount of dissolved oxygen dissolved in the liquid L is reduced. is difficult to be sufficiently lowered by inert gas replacement.Therefore, the volume γ (mL) of the liquid L is 97.5% or more of the maximum volume V _{1MAX (} (mL) of the first container 30). This embodiment is particularly useful for the first container 30L.

As a specific example of the embodiment described above, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX of the second container 40 is the volume γ (mL) of (2.56 ×10 ⁻⁴ ×(β×T/α)) and the maximum effective volume EV _1MAX (mL) of the first container 30 multiplied by (21.0/α). By using the first container 30 and the second container 40 having such a volume, the first container 30 and the second container 40 can contain a sufficient volume of gas. By storing the liquid-filled first container 30L in which air is accommodated in the head space HS in the second container 40, in an equilibrium state in which oxygen permeation through the first container 30 is balanced, Oxygen concentration can be reduced to α (%) or less.

As a more specific example, the sum of the maximum effective volume EV _1MAX (mL) of the first container 30 and the maximum effective volume EV _2MAX of the second container 40 is a value obtained by multiplying the volume γ (mL) of the liquid L by 0.663. and a value obtained by multiplying the maximum effective volume EV _1MAX (mL) of the first container 30 by 21.0. According to this example, by storing the liquid-filled first container 30L in which air is contained in the headspace HS in the second container 40, the temperature inside the second container 40 is 293K and the air atmosphere is under atmospheric pressure. oxygen concentration can be reduced to less than 1%.

As a specific example of the above-described embodiment, when the first container 30 is accommodated and the second container 40 is closed, the total volume of the first container 30 and the second container 40 is γ (mL) multiplied by (2.56×10 ⁻⁴ ×β×T) and the maximum effective volume EV _1MAX (mL) of the first container 30 multiplied by 21.0 It may contain gas. According to this example, the oxygen concentration in the second container 40 can be reduced to less than 1% by storing the liquid-filled first container 30L in which air is contained in the head space HS in the second container 40 . As a more specific example, when the first container 30 is accommodated and the second container 40 is closed, the total volume γ (mL) of the liquid L in the first container 30 and the second container 40 is 0. A gas having a volume larger than the sum of the value multiplied by 0.663 and the value multiplied by 21.0 of the maximum effective volume EV _1MAX (mL) of the first container 30 may be accommodated. According to this example, by storing the liquid-filled first container 30L in which air is contained in the head space HS in the second container 40, the second container 40 can be stored in an air atmosphere having a temperature of 293 K and an atmospheric pressure. Oxygen concentration in can be reduced to less than 1%.

In one specific example of the embodiment described above, the volume γ of the liquid L may be 0.5 mL or more, more preferably 1 mL or more. By setting the lower limit for the amount of liquid in the first container 30 in this way, a certain amount of liquid can be taken out from the first container 30, and errors in the amount taken out can be reduced.

In one specific example of one embodiment described above, the first container 30 has a container body 32 having an opening 33 and a plug 34 closing the opening 33 . The oxygen permeability coefficient of the material forming the plug 34 may be 1×10 ⁻¹² (mL/(m ² ×day×atm)) or more. The plug 34 may be made of silicone rubber. The oxygen permeability coefficient (mL/(m ² ×day×atm)) of the material forming the plug 34 is greater than the oxygen permeability coefficient (mL/(m ² ×day×atm)) of the material forming the container body 32. good too. According to such embodiments, oxygen passes through plug 34 and out of first container 30 . Therefore, oxygen permeability can be imparted to a region exposed from the liquid L in the first container 30 such as the so-called headspace HS. As a result, the permeation of oxygen through the first container 30 proceeds smoothly, and the time from when the first container 30 is accommodated in the second container 40 until the permeation of oxygen through the first container 30 is balanced is can be shortened.

In one specific example of one embodiment described above, the container body 32 may have an oxygen barrier property. Oxygen that permeates the first container 30 enters a region in the first container 30 , such as the headspace HS, which is spaced apart from the liquid L. As shown in FIG. Therefore, dissolution of oxygen that has permeated through the first container 30 into the liquid L can be suppressed.

Although one embodiment has been described with reference to specific examples, the above specific examples do not limit one embodiment. The embodiment described above can be implemented in various other specific examples, and various omissions, replacements, changes, additions, etc. can be made without departing from the scope of the invention.

An example of modification will be described below with reference to the drawings. In the following description and the drawings used in the following description, the same reference numerals as those used for the corresponding portions in the above-described specific example are used for portions that can be configured in the same manner as in the above-described specific example, and redundant description is omitted. omitted.

Although the specific configuration of the first container 30 has been described in the above-described specific example, the present invention is not limited to this example, and various containers may be used. For example, as shown in FIG. 8, the plug 34 of the first container 30 may be in the form of a film or sheet that covers the opening 33 . The stopper 34 shown in FIG. 8 is joined to the tip surface of the container body 32 by using a joining material or by welding, for example. The plug 34 may have oxygen permeability or oxygen barrier properties.

FIG. 9 shows another modification of the first container 30 . The first container 30 shown in FIG. 9 is a syringe 60 . Similar to the syringe previously described with reference to FIG. 6, the syringe 60 shown in FIG. 9 has a cylinder 62 and a piston 66. As shown in FIG. The cylinder 62 has a cylinder body 63 made of glass or resin and a needle 64 made of metal. The cylinder 62 is the container body 32 of the first container 30 and forms a storage space for the liquid L. As shown in FIG. The piston 66 has a glass or resin piston body 67 and a gasket 68 arranged in the opening 33 of the cylinder 62 . A gasket 68 is the plug 34 of the first container 30 and closes the opening 33 . A storage space for the liquid L is defined between the cylinder 62 and the gasket 68 . The illustrated syringe 60 also has a cap 69 . Cap 69 is removably attached to needle 64 . Cap 69 regulates leakage of liquid L from needle 64 and seals liquid L to syringe 60 . In the example shown in FIG. 9, by using the syringe 60 as the first container 30, the syringe 60 taken out from the second container 40 can be used for the patient or the like as it is.

In the example shown in FIG. 9, gasket 68 may be made oxygen permeable. A plug made of silicone rubber may be used as the oxygen-permeable gasket 68 . The cylinder 62 may be provided with oxygen barrier properties. The oxygen permeability coefficient of the gasket 68 may be set similarly to the oxygen permeability coefficient of the plug 34 described above. The oxygen permeability coefficient of the cylinder 62 may be set similarly to the oxygen permeability coefficient of the container body 32 described above.

In the example shown in FIG. 9 , permeation of oxygen through the gasket 68 causes oxygen to be discharged from the inside of the first container 30 defined by the cylinder body 63 and the gasket 68 . As a result, the oxygen concentration in the syringe 60 decreases, and the dissolved oxygen amount dissolved in the liquid L decreases. As a result, decomposition of the liquid L by oxygen can be effectively suppressed.

In the embodiment described above, the first container 30 had a container body 32 and a stopper 34, the stopper 34 being gas permeable. However, at least a portion of the container body 32 may be permeable to gas and the plug 34 may have gas barrier properties. Further, the specific configuration of the second container 40 described above is merely an example, and various modifications are possible.

10L: combination container containing liquid, 10: combination container, 20: container set, 30L: first container containing liquid, 30: first container, 32: container body, 33: opening, 34: stopper, 36: fixture, 40: Second container, 40a: Opening, 41a: First main film, 41b: Second main film, 41c: First gusset film, 41d: Second gusset film, 42: Container main body, 42a: Storage part, 42b: Flange part, 44: Lid, 55: Supply pipe, 56: Discharge port, 60: Syringe, 62: Cylinder, 63: Cylinder body, 64: Needle, 66: Piston, 67: Piston body, 68: Gasket, 69: Cap , L: liquid

Claims (21)

a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container containing the first container and having an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The sum is at least (2.56×10 ⁻⁴ ×(β×T/α)) times the volume γ (mL), where T is the temperature of the environment (K) and β is the temperature T ( K) is the saturation solubility (mg/L) of oxygen in the liquid in an air atmosphere under atmospheric pressure, and α is the oxygen concentration (%) in the second container. 2. The liquid-filled combination container according to claim 1, wherein said oxygen concentration [alpha] is less than 1%. A value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and a value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container is the value obtained by multiplying the volume γ (mL) by (2.56 × 10 ^-4 × (β × T/α)), and the maximum volume (mL) of the first container to the volume γ 3. The liquid-filled combination container according to claim 1 or 2, which is equal to or greater than the sum of the value obtained by subtracting (mL) and multiplying it by (21.0/α). a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container containing the first container and having an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The sum is at least (2.56×10 ⁻⁴ ×β×T) times the volume γ (mL), where T is the temperature of the environment (K) and β is the large volume at temperature T (K). A combination container containing a liquid, which is the saturation solubility (mg/L) of oxygen in said liquid in an air atmosphere under atmospheric pressure. A value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and a value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container is the value obtained by multiplying the volume γ (mL) by (2.56 × 10 ^-4 × β × T), and the volume γ (mL) from the maximum volume (mL) of the first container 4. The liquid-filled combination container according to claim 3, which is equal to or greater than the sum of the subtracted value multiplied by 21.0. A liquid-filled combination container according to any one of claims 1 to 5, wherein said volume γ (mL) is greater than half of said maximum volume (mL) of said first container. The liquid-filled combination container according to any one of claims 1 to 6, wherein the volume γ is 0.5 mL or more. The liquid-filled combination container according to any one of claims 1 to 7, wherein the volume γ is 20 mL or less. 9. The liquid-filled combination container according to any one of claims 1 to 8, wherein the first container can contain a gas while maintaining a negative pressure. a first container containing a liquid having a volume γ (mL) and at least partially permeable to oxygen;
a second container that can accommodate the first container and has an oxygen barrier property,
The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container A container set, the sum of which is greater than 0.663 times said volume γ (mL). The value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container and the value obtained by subtracting the volume (mL) occupied by the first container from the maximum volume (mL) of the second container The total is the sum of the value obtained by multiplying the volume γ (mL) by 0.663 and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container multiplied by 21.0 11. A container set according to claim 10, greater than a value. The container set according to claim 10 or 11, wherein the volume γ (mL) is greater than half the maximum volume (mL) of the first container. The container set according to any one of claims 10 to 12, wherein the volume γ is 0.5 mL or more. The container set according to any one of claims 10 to 13, wherein said volume γ is 20 mL or less. The container set according to any one of claims 10 to 14, wherein the first container can contain a gas while maintaining a negative pressure. closing a second container containing the first container and filled with an inert gas;
storing the first container within the second container;
the first container contains a volume γ (mL) of liquid and is at least partially permeable to oxygen;
The second container has an oxygen barrier property,
In a state in which the first container is accommodated and the second container is closed, the first container and the second container total the volume γ (mL) of (2.56 × 10 ^-4 × β ×T) times larger volume of gas, where T is the temperature of the environment (K) and β is the saturated solubility of oxygen in said liquid in an air atmosphere under atmospheric pressure at temperature T (K) (mg/L), a method for manufacturing a liquid-filled container. In a state in which the first container is housed and the second container is closed, the total volume γ (mL) of the first container and the second container is (2.56 × 10 ^-4 × β ×T) and the value obtained by subtracting the volume γ (mL) from the maximum volume (mL) of the first container multiplied by 21.0. 17. The method of manufacturing a liquid-filled container according to claim 16. 18. The method of manufacturing a liquid-filled container according to claim 16 or 17, wherein said volume γ (mL) is larger than half of the maximum volume of said first container. The method for manufacturing a liquid-filled container according to any one of claims 16 to 18, wherein the volume γ is 0.5 mL or more. The method for manufacturing a liquid-filled container according to any one of claims 16 to 19, wherein the volume γ is 20 mL or less. The method for manufacturing a liquid-filled container according to any one of claims 16 to 20, wherein the first container can contain gas while maintaining a negative pressure.

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